Anaplastic thyroid cancer

Authors:
R Michael Tuttle, MD
Eric J Sherman, MD
Section Editors:
David S Cooper, MD
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jun 04, 2021.
INTRODUCTIONAnaplastic thyroid cancers are undifferentiated tumors of the
thyroid follicular epithelium. In marked contrast to differentiated thyroid cancers,
anaplastic cancers are extremely aggressive, with a disease-specific mortality
approaching 100 percent. Given the very rapid course of disease progression and the
poor treatment outcomes, end-of-life issues and plans for comfort care measures are an
integral part of initial disease management planning [1]. Early recognition of the disease
is essential to allow prompt initiation of therapy.
The major clinical issues related to anaplastic thyroid cancer will be reviewed here. The
molecular pathogenesis of this disorder is discussed separately. (See "Oncogenes and
tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer".)
EPIDEMIOLOGYThe age-adjusted annual incidence of anaplastic cancer is
approximately one to two per million persons [2,3] and accounts for 0.9 to 9.8 percent of
all thyroid cancers globally [4,5]. Patients with anaplastic cancer are older than those
with differentiated cancer; the mean age at diagnosis is 65 years, and fewer than 10
percent are younger than 50 years. Sixty to 70 percent of tumors occur in women [6,7].
CLINICAL FEATURES
Antecedent thyroid disease — Approximately 20 percent of patients with anaplastic
thyroid cancer have a history of differentiated thyroid cancer, and 20 to 30 percent have
a coexisting differentiated cancer [8-12]; the percentage may be even higher with
extensive sectioning of the thyroid gland [13]. The majority of synchronous thyroid
tumors are papillary cancers, but coexisting follicular cancers have also been reported.
Nearly 10 percent of patients with Hürthle cell cancers have foci of anaplastic cancer
within the Hürthle cell cancer [14]. In addition, transformation from differentiated to
anaplastic cancer has been described in a patient who was followed with serial biopsies
[15].
These findings lend support to the hypothesis that anaplastic cancer develops from
more differentiated tumors as a result of one or more dedifferentiating events [16]. Since
activating mutations in BRAF and RAS are seen in both well-differentiated thyroid
malignancies and anaplastic thyroid cancer, these are presumed to be early events in
the progression pathway [17]. Late events that are seen more commonly in the
anaplastic tumor rather than the precursor well-differentiated tumor include mutations in
p53 tumor suppressor protein [18-21], 16p [22], catenin (cadherin-associated protein),
beta 1, and PIK3CA [23].

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Up to one-half of patients have a history of multinodular goiter, and some have a history
of partial thyroidectomy for goiter.

Disease presentation — Nearly all patients with anaplastic cancer present with a

thyroid mass. However, regional or distant spread is apparent at the time of initial
diagnosis in 90 percent of cases [11-13,24]. Sites of regional involvement can include
the perithyroidal fat and muscle, lymph nodes, larynx, trachea, esophagus, tonsil, and
great vessels of the neck and mediastinum. Distant metastases are found at initial
disease presentation in 15 to 50 percent of patients [8-10,12].
●The lungs are the most common site of distant metastases, being involved in up
to 90 percent of patients with distant disease [9,10]. These metastases are usually
intrapulmonary mass lesions, but pleural involvement can occur.
●Approximately 5 to 15 percent of patients have bone metastases.
●Five percent have brain metastases, and a few have metastases to the skin,
liver, kidneys, pancreas, heart, and adrenal glands [9-11,25-29].
●Rare patients have no detectable thyroid tumor at the time of diagnosis,
presenting with metastatic disease [13].
Clinical manifestations
●Symptoms – The primary symptom of anaplastic cancer is a rapidly enlarging
neck mass, occurring in approximately 85 percent of patients. The enlarging
thyroid tumor may cause neck pain and tenderness, and compression (or
invasion) of the upper aerodigestive tract, resulting in dyspnea (approximately 35
percent of patients), dysphagia (30 percent), hoarseness (25 percent), and cough
(and sometimes hemoptysis, 25 percent). Less common symptoms are chest
pain, bone pain, headache, confusion, or abdominal pain from metastases [25,30].
Constitutional symptoms can occur, including anorexia, weight loss, fatigue, and
fever of unknown origin [30-33]. Rarely, rapid growth of the tumor within the
thyroid causes thyroiditis, with symptoms of hyperthyroidism and more severe
neck pain and tenderness [25,34,35].
●Physical examination – On physical examination, most patients have bilateral
but asymmetric thyroid enlargement. The goiter is typically hard and nodular and
may be tender. A dominant nodule is often present. Some nodules may be softer
and fluctuant, indicating focal tumor necrosis [13]. A few patients have a solitary
nodule or a diffuse non-nodular goiter. The goiter is often fixed to the surrounding
structures and does not move with swallowing. By the time of presentation, the
primary tumor is usually greater than 5 cm in diameter, but exact measurements
are often difficult because the borders of the tumor are indistinct.
Approximately 50 percent of patients have enlarged cervical lymph nodes. Other
findings of local extension of the disease include stridor, tracheal deviation, vocal
cord paralysis due to compression or invasion of the trachea, and venous
dilatation and superior vena cava syndrome due to retrosternal tumor growth.
The skin overlying the tumor may be erythematous or even ulcerated, and there
may be metastases in the skin of the chest and abdomen [13,36]. Focal
neurologic symptoms or signs suggesting brain metastases may also be present.
●Laboratory – Most patients have normal serum thyroid hormone and thyroid-
stimulating hormone (TSH) concentrations, except for those few patients with
tumor-related thyroiditis and hyperthyroidism from presumed rapid tumor growth
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 and concomitant tissue destruction [25,34,35]. Serum thyroglobulin concentrations
may be high, most often due to secretion from a coexisting differentiated cancer,
rather than the anaplastic cancer. Rare patients have leukocytosis due to tumor
secretion of lymphokines [37,38].
●Ultrasound – The findings on thyroid ultrasound are not specific for anaplastic
thyroid cancer. Ultrasonography cannot distinguish benign from malignant
intrathyroidal tumors (both tend to be hypoechoic). However, detection of
extrathyroidal invasion can provide support for the diagnosis of cancer.
Ultrasonography of the neck also can accurately identify involvement of local and
regional nodes. (See "Overview of the clinical utility of ultrasonography in thyroid
disease", section on 'Criteria for identifying cancer'.)
DIAGNOSISWe agree with the American Thyroid Association (ATA) guidelines that
note while fine-needle aspiration (FNA) cytology can yield important diagnostic
information, a core biopsy may be necessary to firmly establish the diagnosis and to
obtain adequate material for molecular testing and immunostaining [39]. Evaluation of
the biopsy material should include routine light microscopy and analysis with
immunohistochemistry (table 1). (See 'Molecular testing' below and "Diagnostic
approach to and treatment of thyroid nodules" and "Thyroid biopsy".)
The diagnosis of anaplastic cancer is usually established by cytologic examination of
cells obtained by FNA biopsy [40,41] and/or of tissue obtained by large-needle or
surgical biopsy [42]. Sometimes the diagnosis is made only after surgery is done for
what was thought to be a poorly differentiated or occasionally a well-differentiated
tumor. Differentiation of anaplastic and poorly differentiated thyroid cancer may be
difficult in some patients. (See 'Differential diagnosis' below.)
On cytopathology, morphologic patterns of anaplastic thyroid cancer include spindle
cell, pleomorphic giant cell, and/or squamoid [9]. Many anaplastic thyroid cancers have
a mixed morphology of two or all three patterns. One common mixed morphologic type
is biphasic spindle and giant cell tumor (picture 1). Numerous mitotic figures and
atypical mitoses are present (picture 2). There is typically extensive necrosis. Unlike
differentiated thyroid cancer, anaplastic thyroid cancer cells are much less likely to stain
positive for thyroid transcription factor 1 (TTF1) or PAX-8 and do not stain positive for
thyroglobulin in the anaplastic component of the tumor (may see thyroglobulin staining
in the associated more well-differentiated component of the tumor) (table 1). (See "Atlas
of thyroid cytopathology", section on 'Anaplastic'.)
DIFFERENTIAL DIAGNOSISOther malignancies that may look histologically
similar to anaplastic thyroid cancer but have significantly different treatment and
prognosis include:
●Poorly differentiated thyroid cancer (see "Oncogenes and tumor suppressor
genes in thyroid nodules and nonmedullary thyroid cancer", section on 'Anaplastic
and poorly differentiated thyroid cancer')
●Medullary thyroid cancer (see "Medullary thyroid cancer: Clinical manifestations,
diagnosis, and staging", section on 'Diagnosis')
●Lymphoma (see "Atlas of thyroid cytopathology", section on 'Lymphoma')
●Melanoma (see "Pathologic characteristics of melanoma", section on
'Histopathologic diagnosis')

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 ●Sarcoma (see "Clinical presentation, histopathology, diagnostic evaluation, and
staging of soft tissue sarcoma", section on 'Histopathology')
Differentiation of anaplastic and poorly differentiated thyroid cancer may be difficult in
some patients with anaplastic thyroid cancer who have coexisting poorly differentiated
(or well-differentiated) thyroid cancer. Careful attention to morphology and
immunohistochemical studies (table 1) is required to distinguish anaplastic thyroid
cancer from poorly differentiated thyroid cancer and other malignancies.
The differential diagnosis in a patient presenting with a neck mass is extensive and
varies with the age of the patient at presentation. Although the majority of these masses
represent benign thyroid nodules and cysts or differentiated thyroid cancer, a rapidly
growing neck mass is concerning for anaplastic thyroid cancer or primary lymphoma of
the thyroid (see "Diagnostic approach to and treatment of thyroid nodules"). Neck
masses that are not of thyroidal origin may be congenital (ie, vascular anomaly),
inflammatory (lymph node enlargement), or other neoplastic (primary or metastatic
disease) disorders. The differential diagnosis of a neck mass is reviewed separately.
(See "Differential diagnosis of a neck mass".)
EVALUATIONFor patients diagnosed with anaplastic thyroid cancer on the basis of
the findings on cytopathology, further evaluation should include laboratory evaluation,
imaging studies, and testing for BRAF V600E mutation [39].
History and physical exam — All patients with anaplastic thyroid cancer should
undergo evaluation of the airway and vocal cords. Some patients may require
emergency intervention to secure the airway or avert impending neurovascular
compromise.
Laboratory evaluation — We typically measure:
●Thyroid function tests (TSH, free thyroxine [T4]), if not previously measured
●Complete blood count
●Electrolytes, blood urea nitrogen (BUN), creatinine, glucose, and liver function
tests
●Serum calcium and phosphorus (to assess for hypercalcemia of malignancy or
hypocalcemia due to compromise of the parathyroid glands secondary to invading
anaplastic thyroid cancer)
●Serum thyroglobulin
We measure serum thyroglobulin as part of the initial evaluation to assess for the
possibility of metastatic well-differentiated thyroid cancer (20 to 30 percent of patients
with anaplastic thyroid cancer have coexisting differentiated thyroid cancer) and to
assist in determining if the metastatic lesions are from the well-differentiated component
of the tumor (rather than anaplastic metastatic sites). In patients with metastatic
differentiated thyroid cancer, the thyroglobulin level is markedly elevated, whereas it
should be normal in patients with anaplastic thyroid cancer. Elevated serum
thyroglobulin can also be seen in nodular thyroid disease and goiter.
(See "Differentiated thyroid cancer: Role of serum thyroglobulin".)
Imaging — Appropriate imaging is critical for defining the extent of disease, planning
therapy, and monitoring the response to treatment. We typically obtain the following:
●Ultrasound of the neck (if not already performed)
●Positron emission tomography (PET)/computed tomography (CT) using 18F-
fluorodeoxyglucose (18FDG; neck to pelvis)
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 ●Brain magnetic resonance imaging (MRI) or CT
●Skeletal radiographs if bony metastases are present (radiographs typically show
lytic lesions)

If PET/CT scanning is not readily available, cross-sectional imaging of the brain, neck,
chest, abdomen, and pelvis with CT or MRI provides adequate initial staging
information.

PET/CT scan is being used with increasing frequency to evaluate and monitor patients
with anaplastic thyroid cancer [43]. Compared with differentiated thyroid cancer,
anaplastic cancer is very hypermetabolic with intense uptake of 18FDG in the primary
thyroid tumor, cervical and mediastinal lymph nodes, and in distant metastases [44-47].
CT of the neck and mediastinum can accurately delineate the extent of the thyroid
tumor and identify tumor invasion of the great vessels and upper aerodigestive tract
[48]. Typical findings include masses that are isodense or slightly hyperdense relative to
skeletal muscle, dense calcifications, and areas of necrosis (image 1). MRI is similarly
useful for defining the local extent of disease and for identifying distant metastases
[49,50].
Molecular testing — We perform a rapid test for BRAF V600E mutations as quickly as
possible (using immunohistochemical staining on FNA or core biopsy samples with an
antibody specific for the BRAF V600E-mutated protein) so as not to delay treatment
[51]. In addition, next-generation molecular sequencing (if available) should be
performed to evaluate for the presence of other targetable mutations that might be able
to be treated in the context of a clinical trial (preferred), through standard of care, or
through a compassionate use program. Promising targets that are seen in anaplastic
thyroid cancer and should be included in the evaluation include, at the
minimum, BRAF, TSC1, TSC2, ALK fusion genes, NTRK fusion genes, and RET fusion
genes. (See 'Our approach to treatment' below.)
Other — Rarely, fine-needle biopsy of distant metastatic sites is required to differentiate
anaplastic from differentiated thyroid cancer. In patients with surgically resectable
disease, biopsy of distant metastases can be performed after completion of primary
surgery [39].

Patients with anaplastic thyroid cancer who present with a rapidly growing neck mass
and voice hoarseness require evaluation by an otolaryngologist/head and neck surgeon
to assess for vocal cord function, airway invasion, and resectability.

STAGINGThe Union for International Cancer Control (UICC) and the American Joint
Committee on Cancer (AJCC) have adopted the eighth (2017) TNM (tumor, node,
metastasis) classification system (table 2) [52]. In the updated staging system, the T
category follows the same definitions as those used for differentiated thyroid cancers,
rather than classifying all anaplastic thyroid cancer as T4 disease. (See "Differentiated
thyroid cancer: Clinicopathologic staging", section on 'TNM system'.)
All anaplastic cancers are considered stage IV cancers [53]. Intrathyroidal anaplastic
cancers are designated IVA, whereas anaplastic cancers with gross extrathyroidal
extension or cervical lymph node metastases are IVB and with distant metastases IVC.

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OUR APPROACH TO TREATMENTSelection of initial therapy is guided by
stage of disease and results of molecular testing (if available) (algorithm 1).
(See 'Molecular testing' above.)
The following approach, which is largely consistent with the American Thyroid
Association (ATA) and the National Comprehensive Cancer Network (NCCN) guidelines
for management of patients with anaplastic thyroid cancer [39,54], is based upon case
series and clinical experience. Because this is a rare tumor and many of the patients
may be elderly and/or have significant symptoms related to the disease that may affect
their performance status, accruing patients to large clinical studies is very difficult but
should be a priority.
BRAF V600E mutation identified
Stage IVA — For patients who present with resectable tumors, we suggest complete
resection followed by combined chemotherapy and radiation (algorithm 1).
●Extent of surgery – For most patients with an intrathyroidal anaplastic cancer,
we suggest total thyroidectomy (if it can be done with complete gross resection of
tumor and minimal morbidity) rather than lobectomy. The rationale for this is that
differentiated thyroid cancer and anaplastic thyroid cancer often coexist, and total
thyroidectomy offers a greater chance of complete resection, which facilitates
subsequent treatment with radioiodine of the accompanying differentiated thyroid
cancer. For the rare patients with intrathyroidal anaplastic thyroid cancer, without
a coexistent well-differentiated thyroid cancer component, thyroid lobectomy with
wide margins of adjacent soft tissue on the side of the tumor is an appropriately
aggressive alternative surgical approach.
In a systematic review of surgery in anaplastic thyroid cancer (stage IVA 10
percent, IVB 48 percent, and IVC 36 percent), median survival was 6.6 months in
patients undergoing primary surgery and 2.1 months for nonsurgical patients [55].
●Chemoradiation – At Memorial Sloan Kettering Cancer Center (MSKCC) and
other centers, intensity-modulated radiation therapy (IMRT) is given [56,57]. A
randomized phase II study through the Radiation Therapy Oncology Group
(RTOG 0912) for anaplastic thyroid cancer is also using IMRT with a total dose of
66 Gy in 33 daily fractions [58].
At MSKCC, a total dose of 70 Gy to gross tumor is used, 60 to 66 Gy to the
postoperative bed, and 50 to 54 Gy to potential microscopic residual disease
regions with standard daily fractionation. The dose of radiation can change if
clinically indicated. Doxorubicin 20 mg/m2 weekly or paclitaxel 50 mg/m2 weekly is
used throughout the radiation course but there are other reasonable regimens
described in the literature [59-62].
There are very little data about the optimal chemotherapy to be used with radiation
therapy for anaplastic thyroid cancer. The majority of the data includes either
anthracyclines [56,63], taxanes [61,64,65], or even the combination of both
[57,66].
As examples:
•In one study, 37 patients were treated with weekly doxorubicin (10 mg/m2)
with hyperfractionated radiation therapy (given three days per week) for a
median total dose of 5760 cGy [56]. Median survival was six months with 28
percent alive at one year. The median locoregional, progression-free survival
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 was 10.1 months. Older patients (≥70 years) had worse outcomes than
younger patients, with 60 percent dying in the first three months.
•Another study evaluated a more intensive regimen combining surgery (if
possible) with cisplatin (120 mg/m2) and doxorubicin (60 mg/m2), both before
and after hyperfractionated radiation therapy [59]. For 30 patients, median
survival was 10 months and three-year survival was 27 percent.
Although these reports support a possible survival advantage for combined
modality therapy combining radiation and chemotherapy, selection bias is a major
confounding factor in determining the effect of treatment on outcome. Patients
who undergo resection followed by adjuvant therapy often have less extensive
disease. The optimal timing of the individual components and the selection of
chemotherapy regimen are uncertain.
Randomized controlled trials are not available to definitively prove benefit for
combined modality therapy. Thus, there are no standard regimens. However, the
use of weekly doxorubicin (10 mg/m2) concurrently with radiation therapy is both
reasonable and commonly applied [56], while more aggressive regimens have
combined docetaxel and doxorubicin [62] or cisplatin and doxorubicin [59] with
radiation. Given the overall poor prognosis of current treatment modalities,
consideration should always be given to referring a patient with anaplastic cancer
for participation in a clinical trial.
Stage IVB — If a BRAF V600E mutation is present, we initiate
neoadjuvant dabrafenib (150 mg twice daily) plus trametinib (2 mg daily) to improve the
chance of complete tumor resection (algorithm 1) [67,68]. If initial surgery is going to be
attempted without neoadjuvant dabrafenib plus trametinib in a patient whose scans
suggest resectable disease, it should be performed by an experienced thyroid cancer
surgeon with the understanding that surgery should be stopped early if the chance for
morbidity is high.
●Resectable – If the response to dabrafenib plus trametinib is favorable and
disease is considered resectable, complete resection should be attempted, as
long as gross tumor resection can be achieved with minimal morbidity. For
patients with locally advanced disease, the extent of surgery depends upon the
degree of soft tissue involvement. Options include total thyroidectomy, lobectomy
with wide margins of adjacent soft tissue, or en bloc resection.
In patients with resectable disease, surgery is followed with chemoradiation as
described for stage IVA (see 'Stage IVA' above). Some patients have prolonged
survival (>2 years) with surgery combined with postoperative adjuvant
chemoradiation [6,11,69,70].
●Unresectable – If disease remains unresectable, dabrafenib plus trametinib can
be continued if associated with disease stability or improvement. If the response is
not favorable, alternative management options include chemoradiation, clinical
trials, or best supportive care.
In nonrandomized small studies, improvements in outcomes
with dabrafenib plus trametinib have been reported in a few cases [67,71-73]. In a
nine-cohort study enrolling patients with rare cancers with the BRAF V600E
mutation (23 patients with anaplastic thyroid cancer), the complete and partial
response rates were 4 and 57 percent, respectively, with a response duration of at

7
 least six months in 64 percent of responding patients [71,72]. Adverse effects
included fatigue, fever, and nausea, occurring in 38, 37, and 35 percent,
respectively [71].
In another small study in patients with BRAF-mutated anaplastic thyroid cancer
who were treated with the BRAF inhibitor, vemurafenib, there was a 29 percent
response rate [74].
Stage IVC — There is no curative therapy for metastatic anaplastic thyroid cancer, and
the disease is uniformly fatal. In one case series, the median survival in patients with
anaplastic thyroid cancer with distant metastases at the time of initial diagnosis was 4.2
months, compared with 6 months in those without metastases [75].
Active therapy preferred — For patients who present with metastatic disease who
desire active therapy (rather than palliative care), enrollment in clinical trials of BRAF-
targeted therapy (based on molecular testing) is strongly encouraged (algorithm 1).
(See 'Molecular testing' above.)
If clinical trials are not available, we suggest dabrafenib plus trametinib. Surgical
resection for residual tumor can be considered if the disease is responsive [59,69]. If
resectable, surgery should then be followed by re-initiation of dabrafenib plus trametinib
if the distant metastases are stable or improved during prior therapy [71,73]. If not
resectable, we continue dabrafenib plus trametinib if we are seeing an otherwise
favorable response to therapy. If the response to dabrafenib plus trametinib is not
favorable, options include chemoradiation, clinical trials, or best supportive care. If a
patient's performance status is adequate, participation in a clinical study is strongly
recommended. If a clinical study is not available, and a patient seems to be a good
candidate to receive systemic therapy after progression on dabrafenib and trametinib,
we would follow a similar approach as noted below when there is no targetable
mutation. (See 'Another targetable mutation absent or unknown' below.)
End-of-life care — Given the very rapid course of disease progression and the poor
treatment outcomes, end-of-life issues and plans for comfort care measures are an
integral part of initial disease management planning [39]. Palliative and end-of-life care
issues are reviewed in detail separately. (See "Approach to symptom assessment in
palliative care" and "Assessment and management of dyspnea in palliative
care" and "Overview of managing common non-pain symptoms in palliative care".)
BRAF V600E mutation absent or unknown
Stage IVA or resectable IVB disease — For patients with tumor localized to the
thyroid or if locoregional disease is resectable, complete resection should be attempted,
as long as gross tumor resection can be achieved with minimal morbidity (algorithm 1).
After complete resection, some patients have prolonged survival (>2 years), often in
conjunction with postoperative adjuvant chemoradiation [6,11,55,69,70]. (See 'Stage
IVA' above.)
Stage IVB (unresectable) or IVC disease — For patients with unresectable
locoregional or metastatic disease, options include systemic therapy, chemoradiation, or
supportive care depending on the clinical setting.
Another targetable mutation present — If another targetable mutation is present,
enrollment in a clinical trial of mutation-directed therapy is preferred. Specific inhibitors
of oncogenic ALK, NTRK, or RET fusion mutations can be considered for unresectable
stage IVB or IVC disease, preferably within the context of a clinical trial.

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Significant activity in metastatic disease has been shown in anaplastic thyroid cancer
with NTRK fusion genes [76] and RET fusion genes [77] (although all studies have been
small and, in some cases, equivalent to case reports). Other potential targets
include TSC1/TSC2 mutations [78] and ALK fusion genes [79].

Mutation-specific kinase inhibitor regimens include:

●Larotrectinib or entrectinib (NTRK gene fusion) – Larotrectinib and entrectinib,

highly selective inhibitors of TRK kinases, have been US Food and Drug
Administration (FDA) approved for treatment of any solid tumor bearing
an NTRK1-3 fusion mutation, including anaplastic thyroid cancer [80,81].
●Selpercatinib or pralsetinib (RET fusion) – Selpercatinib and pralsetinib are oral
kinase inhibitors that selectively target RET kinase. They have been approved by
the FDA for the treatment of advanced or metastatic RET fusion-positive thyroid
cancer, RET-mutant medullary thyroid cancer, and other types of cancers which
have an alteration (mutation or fusion) in the RET gene [77,82]. In the clinical
study, activity was seen in anaplastic thyroid cancer with a RET fusion gene [77].
●Other – A prolonged response was reported in a phase II study
with everolimus in a patient with anaplastic thyroid cancer containing
a TSC2 mutation [78]. (See "Oncogenes and tumor suppressor genes in thyroid
nodules and nonmedullary thyroid cancer", section on 'Anaplastic and poorly
differentiated thyroid cancer'.)
Considering that high expression of programmed cell death protein 1
(PD-1)/programmed cell death ligand 1 (PD-L1) in anaplastic thyroid cancer [83],
immunotherapy may be a promising approach. There have been several
promising small studies of immunotherapy alone or in combination with other
agents [84-87], but these still need to be better evaluated. Many studies are in
progress, evaluating if there is activity with immunotherapy in metastatic
anaplastic thyroid cancer. However, there are concerns about the safety of using
immunotherapy with radiation therapy in anaplastic thyroid cancer [66].
Another targetable mutation absent or unknown — If a targetable mutation is absent
or testing is unavailable, options include chemoradiation followed by observation or
clinical trials.

In patients who would otherwise be eligible for systemic therapy but do not have a
clinical trial available, there are other reasonable options, but they are all based on fairly
small, single studies and the lack of extensive data needs to be considered in
discussion with the patient.

●Cytotoxic chemotherapy – There are some data to support the use of cytotoxic
chemotherapy. As an example, in a randomized trial comparing
combination cisplatin and doxorubicin versus doxorubicin alone, the complete
response rate was higher in the combination group (3 of 18 patients [17 percent]
compared with none of 21 patients in the doxorubicin group) [88]. Paclitaxel as a
single agent has been reported to have a response rate of 53 percent [89]. We
have not seen such responses to either of these approaches; however, both of
these regimens are reasonable to consider.
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 ●Immunotherapy – The Anaplastic Thyroid
Carcinoma Lenvatinib Pembrolizumab (ATLEP) study evaluated the combination
of lenvatinib and pembrolizumab in both anaplastic and poorly differentiated
thyroid cancer [90]. In the group with anaplastic thyroid cancer, four of six patients
had a partial response. A single institution study of ipilimumab and nivolumab in
anaplastic thyroid cancer reported partial responses in 3 of 10 patients [86].
In patients with advanced disease who do not desire or who are not eligible for systemic
therapy, palliation of symptoms is a high priority [39]. Treatment should be directed
toward securing the airway and ensuring access for nutritional support. Locoregional
resection may be necessary for palliation of airway or esophageal obstruction. However,
death is usually attributable to upper airway obstruction and suffocation (often despite
tracheostomy) in 50 to 60 percent of patients and to a combination of complications of
local and distant disease in the remainder [11,91]. For patients with bone metastases,
palliative radiotherapy may be beneficial in improving pain. (See 'End-of-life
care' above.)
MONITORINGPatients who respond to initial management (M0 disease) require
surveillance for recurrence. There is no known role for adjuvant therapy.
●Imaging – We typically obtain chest computed tomography (CT) at four weeks
and a single positron emission tomography (PET)/CT scan at three months after
the completion of chemoradiation therapy [45]. Thereafter, we monitor with CT
scans (with contrast) of the neck, chest, and abdomen (including adrenal glands)
every one to three months for the first 24 months and then less frequently (every
four to six months) thereafter. Brain imaging during the first three months after
treatment is recommended with a low threshold of repeating if concerning
symptoms develop. Other imaging studies should be based upon clinical
symptoms that develop during follow-up. The benefit of continued imaging after
four years is questionable, although annual imaging of the neck and chest are
reasonable.
Radioactive iodine has no role in the primary treatment of anaplastic thyroid
cancer. However, radioactive iodine scanning/ablation/therapy should be
considered in survivors, one to two years after initial therapy, if a significant
component of the original tumor was well differentiated or if the serum
thyroglobulin level remains inappropriately elevated during follow-up.
(See "Differentiated thyroid cancer: Radioiodine treatment".)
●Thyroid hormone replacement – Patients who have total thyroidectomy require
thyroid hormone therapy to replace normal thyroid hormone production. T4
(approximately 1.6 mcg/kg of body weight) should be started immediately after
surgery. The adequacy of therapy should be evaluated clinically and by
measurement of serum TSH in one month. The goal of T4 therapy should be to
restore and maintain euthyroidism; suppression of serum TSH concentrations to
less than normal is not indicated, unless for treatment of coexisting differentiated
thyroid cancer. (See "Differentiated thyroid cancer: Surgical treatment", section on
'Postoperative thyroid hormone therapy'.)
PROGNOSISAnaplastic thyroid cancers are extremely aggressive, with a disease-
specific mortality approaching 100 percent. The median survival from diagnosis ranges
from three to seven months, and the one- and five-year survival rates are 20 to 35
10
percent and 5 to 14 percent, respectively [11,12,24,69,92-94], although many feel that
these estimates are overly optimistic. In a review of published case series (1771
patients treated between 1949 and 2007), the median survival was five months, and the
one-year survival was 20 percent [4]. Several important prognostic characteristics have
been identified. Patients with disease either confined to the thyroid or with only local and
regional metastases survive longer than those with distant metastases [6,8,10,95].
Tumor size also appears to be important. In one study, as an example, the two-year
survival was 25 versus 3 to 15 percent in patients with tumors less than 6 cm versus
larger than 6 cm in maximum dimension [8,11].
Other variables that may predict a worse prognosis include older age at diagnosis, male
sex, and dyspnea as a presenting symptom [6,8-11,92,95,96]. Patients who were
previously treated for differentiated cancer and subsequently developed anaplastic
cancer have outcomes similar to those without an antecedent cancer [9,10].

Relatively favorable prognostic factors include unilateral tumor, diameter of less than 5
cm, and the absence of extrathyroidal invasion or cervical lymph node involvement.

The use of targeted therapy will likely change the overall median survival rates.
(See 'BRAF V600E mutation identified' above and 'Another targetable mutation
present' above.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
●Anaplastic thyroid cancer is almost always rapidly fatal, the few exceptions being
patients whose tumors are small and who are treated very aggressively.
(See 'Introduction' above.)
●Approximately 20 percent of patients have a history of differentiated thyroid
cancer, and 20 to 30 percent have a coexisting differentiated cancer.
(See 'Antecedent thyroid disease' above.)
●The primary symptom of anaplastic cancer is a rapidly enlarging neck mass,
occurring in approximately 85 percent of patients. (See 'Clinical
manifestations' above.)
●The diagnosis of anaplastic cancer is usually established by cytologic
examination of cells obtained by fine-needle aspiration (FNA) biopsy and/or of
tissue obtained by large-needle or surgical biopsy. Evaluation of the biopsy
material should include routine light microscopy and analysis with
immunohistochemistry (table 1). On cytopathology, morphologic patterns of
anaplastic thyroid cancer include spindle cell, pleomorphic giant cell, and/or
squamoid (picture 1). Many anaplastic thyroid cancers have a mixed morphology
of two or all three patterns. (See 'Diagnosis' above.)
●Other malignancies that may look histologically similar to anaplastic thyroid
cancer but have significantly different treatment and prognosis include poorly
differentiated thyroid cancer, medullary thyroid cancer, lymphoma, melanoma, and
sarcoma. Careful attention to morphology and immunohistochemical studies (table

11
1) are required to distinguish anaplastic thyroid cancer from poorly differentiated
thyroid cancer and other malignancies. (See 'Differential diagnosis' above.)
●For patients diagnosed with anaplastic thyroid cancer on the basis of the findings
on cytopathology, evaluation should include laboratory (thyroid-stimulating
hormone [TSH], free thyroxine [T4], thyroglobulin, complete blood count,
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, liver function tests,
calcium, and phosphorus), imaging studies, and testing for BRAF V600E mutation.
Initial imaging to determine extent of disease should include ultrasound of the
neck (if not already performed), positron emission tomography (PET)/computed
tomography (CT) using 18 F-fluorodeoxyglucose (18FDG; neck to pelvis), and
brain magnetic resonance imaging (MRI) or CT. If PET/CT scanning is not readily
available, cross-sectional imaging of the brain, neck, chest, abdomen, and pelvis
with CT or MRI provides adequate initial staging information.
(See 'Evaluation' above.)
●All tumors should be evaluated for the presence of a BRAF mutation as quickly
as possible after the diagnosis (using immunohistochemical staining on FNA or
core biopsy samples with an antibody specific for the BRAF V600E-mutated
protein) (algorithm 1). If available, next-generation molecular sequencing of the
cancer should be performed to evaluate for the presence of other targetable
mutations that might be able to be treated. Promising and approved targets that
are seen in anaplastic thyroid cancer and should be included in the evaluation
include BRAF, TSC1, TSC2, ALK fusion genes, RET fusion genes,
and NTRK fusion genes. (See 'Molecular testing' above.)
●For patients with a small intrathyroidal anaplastic cancer (stage IVA) associated
with a differentiated thyroid cancer, we suggest total thyroidectomy (if it can be
done with complete gross resection of tumor and minimal morbidity) rather than
lobectomy (Grade 2C). Total thyroidectomy will facilitate subsequent treatment of
the differentiated thyroid cancer. However, for the rare patients with intrathyroidal
anaplastic thyroid cancer, without a coexistent well-differentiated thyroid cancer
component, thyroid lobectomy with wide margins of adjacent soft tissue on the
side of the tumor is an appropriately aggressive alternative surgical approach.
(See 'Stage IVA' above.)
●For patients with locally advanced (stage IVB) resectable disease without
a BRAF V600E mutation, we also suggest surgery (Grade 2C). The extent of
surgery depends upon the degree of soft tissue involvement. Options include total
thyroidectomy, lobectomy with wide margins of adjacent soft tissue, or en bloc
resection. (See 'Stage IVA or resectable IVB disease' above.)
●For those patients whose tumors are resected completely, we suggest
postoperative combined modality therapy with radiation and chemotherapy rather
than single-agent therapy (algorithm 1) (Grade 2C). Chemotherapy options
include doxorubicin, docetaxel, or cisplatin and doxorubicin. (See 'Stage
IVA' above and 'Stage IVB' above and 'Stage IVA or resectable IVB
disease' above.)
●For patients with stage IVB or IVC disease with a BRAF V600E mutation, we
suggest dabrafenib plus trametinib (Grade 2C), followed by evaluation for
resectability (algorithm 1). If the response to dabrafenib plus trametinib is

12
favorable and disease is resectable, resection is followed by chemoradiation for
stage IVB disease and re-initiation of dabrafenib plus trametinib for stage IVC
disease. If disease remains unresectable, dabrafenib plus trametinib can be
continued if associated with disease stability or improvement. If the response is
not favorable, alternative management options include chemoradiation, clinical
trials, or best supportive care. (See 'Stage IVB' above and 'Stage IVC' above.)
●For patients with unresectable stage IVB or IVC disease without a BRAF V600E
mutation, options include targeted therapy (if another targetable mutation is
present), chemoradiation, clinical trials, or supportive care, depending on the
clinical setting. (See 'Stage IVB (unresectable) or IVC disease' above.)
●In patients with advanced disease without a targetable mutation, palliation of
symptoms is a high priority. Treatment should be directed toward securing the
airway and ensuring access for nutritional support. If the patient has a good
performance status, enrollment in clinical trials of targeted therapy is strongly
encouraged. (See 'Another targetable mutation absent or unknown' above.)
●Palliative/comfort care should be an integral part of initial treatment planning.
(See 'End-of-life care' above.)

13
Differentiated thyroid cancer refractory to
standard treatment: Systemic therapy
Authors:
Steven I Sherman, MD
Andrew G Gianoukakis, MD, FACE
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: May 20, 2021.
INTRODUCTIONTreatment of most patients with differentiated thyroid cancer
(DTC; both papillary and follicular histologies) includes surgery, thyroid hormone
therapy, and selective use of radioactive iodine. When metastatic disease occurs,
radioactive iodine can be curative in a minority of patients, and thyroid-stimulating
hormone (TSH)-suppressive thyroid hormone therapy can help to slow the pace of
the disease. In addition, external radiotherapy may be useful in some patients.
(See "Differentiated thyroid cancer: Overview of management" and "Differentiated
thyroid cancer: Radioiodine treatment" and "Differentiated thyroid cancer: External
beam radiotherapy".)

However, for those patients with metastatic DTC that progresses despite systemic
treatment such as radioiodine and TSH-suppressive thyroid hormone therapy, or
focal treatments such as surgery and external beam radiotherapy (EBRT),
treatment options have historically been limited. New approaches based upon
application of targeted chemotherapies are emerging as effective alternatives for
progressive disease.

Systemic therapy for advanced DTC will be reviewed here. Therapies for medullary
and anaplastic thyroid cancers are discussed separately. (See "Medullary thyroid
cancer: Systemic therapy and immunotherapy" and "Anaplastic thyroid cancer".)
PATIENT SELECTION FOR SYSTEMIC THERAPYIt is important to consider
use of systemic treatments in patients at significant risk for morbidity or mortality
due to progressive metastatic disease in whom benefit of therapy is likely to
reasonably outweigh the risks and cost. The rate of disease progression is variable
in patients with metastatic differentiated thyroid cancer (DTC), and therefore the
pace of disease progression is an important factor in the decision to treat with

14
systemic therapy. In addition, patients treated with systemic agents should have a
baseline performance status sufficiently functional to tolerate these
interventions, such as being ambulatory at least 50 percent of the day (Eastern
Cooperative Oncology Group [ECOG] performance status 2 or better). The most
commonly used systemic therapies, kinase inhibitors, are associated with adverse
effects that may significantly impact quality of life. (See 'Side effects shared by oral
kinase inhibitors inhibiting VEGFR' below.)
●Prior to considering systemic therapy, patients should be evaluated with
comprehensive computed tomography (CT) and/or magnetic resonance
imaging (MRI) to establish the baseline extent of disease. Prior to therapy or
in any patient with suspicious central nervous system symptoms, imaging of
the brain should be performed to rule out intracranial metastases that might
require other forms of intervention first, such as surgery or radiation.
●Patients with asymptomatic metastatic tumors generally less than 1 to 2 cm
in diameter and growing in diameter less than 20 percent per year can
usually be monitored for disease progression (active surveillance). Known
sites of metastatic disease should be imaged by CT or MRI every six months,
and potential new sites of disease should be imaged every 12 to 24 months.
We continue treatment with TSH suppression (with TSH levels as low as the
patient can tolerate, though not necessarily undetectable [1]).
●Patients with unresponsive metastatic tumors of at least 1 to 2 cm in
diameter and growing by at least 20 percent per year, or patients with
symptoms related to multiple metastatic foci that cannot be alleviated with
localized treatment such as surgery or external beam radiotherapy (EBRT) are
candidates for systemic therapy. Emphasis should be placed on overall
tumor burden or individual lesion location, growth trajectory, and potential
for morbidity if disease is allowed to progress further.
INITIAL SYSTEMIC THERAPYThe following treatment strategy is based upon
clinical experience and data from placebo-controlled randomized trials (algorithm
1). Our approach is largely consistent with the American Thyroid Association (ATA)
and National Comprehensive Cancer Network (NCCN) guidelines, with
modifications based upon subsequent research findings [2-4].
General principles
●We prefer to administer systemic treatment in the context of a clinical trial.
(Active clinical trials can be identified at: ClinicalTrials.gov.) Increasingly, the
selection of a specific systemic agent is dictated by the presence of specific
gene mutations or signaling pathway abnormalities that are the targets of
approved or investigational therapies.

15
 ●For patients who are unable to participate in clinical trials, first-line
treatment options include oral kinase inhibitors that target either
angiogenesis or oncogenic signaling pathways. The choice of initial kinase
inhibitor depends on the result of somatic mutation testing, if available.
(See 'Mutation not identified' below and 'Mutation identified' below.)
●For patients whose disease burden, rate of tumor growth, or symptoms
necessitate consideration of systemic therapy options, somatic mutation
testing can be performed to identify oncogenic kinase abnormalities that
might suggest specific treatment options that cannot be administered in the
absence of mutational data (eg, gene rearrangements in NTRK, ALK, or RET, or
point mutations in BRAF). Given the high cost of such testing and lack of
coverage by some insurance providers, this option may not be realistic for
some patients, even if the lack of testing limits therapeutic options. Options
for reduced cost mutation testing may be available through pharmaceutical
companies marketing such targeted drugs.
In most tumors, kinases function as key signaling intermediates that stimulate
tumor proliferation, angiogenesis, invasion, metastasis, and avoidance of
apoptosis, affecting both the cancer cells as well as the other components of the
tumor microenvironment, such as the vascular endothelium. Antiangiogenic
multikinase inhibitors (aaMKIs) can improve progression-free survival. However,
kinase inhibitors are disease-modifying agents, usually tumoristatic rather than
tumoricidal, and only one published study has demonstrated that one of these
new agents improved overall survival in a specific prespecified subgroup of
patients with thyroid cancer [5].
Conventional cytotoxic agents are rarely used for the treatment of patients with
progressive symptomatic differentiated thyroid cancer (DTC) that is unresponsive
or not amenable to surgery, radioiodine therapy, or external radiotherapy;
complete remission is rare, and long-term responses are uncommon [6,7].
(See 'Therapies infrequently used' below.)
In the studies described below, the definitions of tumor response are based upon
the now-standard Response Evaluation Criteria in Solid Tumors (RECIST) (table 1)
[8].
Mutation not identified
Multitargeted kinase inhibitor — In the absence of a specific targetable
mutation (eg, NTRK, ALK, RET,  or BRAF), or if mutation profiling results are not
available, we suggest lenvatinib as first choice among oral aaMKIs (algorithm
1). Sorafenib is an alternative option.
As head-to-head comparisons among the various aaMKIs have not been
performed and the various trials often have recruited patients with differing

16
eligibility criteria, the selection of which agent to use for initial treatment should
prioritize both better study design (such as randomized trials) and a somewhat
subjective ranking of drug efficacy and adverse events. Randomized trial evidence
supports benefit with lenvatinib [9,10], sorafenib [11], and vandetanib [12], but
nonrandomized trials have also indicated efficacy
with pazopanib [13], sunitinib [14-16], and other aaMKIs. We prefer lenvatinib as
first-line therapy because of the high rate of efficacy and evidence of improved
survival in older patients, although it has not been directly compared with other
aaMKIs in randomized trials.
Many of the aaMKIs partially inhibit multiple tyrosine kinases (ie, they are
multitargeted) at nanomolar concentrations in vitro and often affect multiple
signaling pathways. The primary target for all of these effective tyrosine kinase
inhibitors is angiogenic signaling in the tumor microenvironment, particularly the
vascular endothelial growth factor receptor (VEGFR) family. Although it may take
several months before maximum radiographic response is achieved, targeting
angiogenesis (and specifically VEGFR signaling pathways) has produced valuable
clinical responses and prolonged progression-free survival in randomized trials for
metastatic DTC. In phase III trials, median progression-free survival times of 11 to
18 months are reported, with partial responses in up to 63 percent of patients
(though complete responses are rare) [10,11].
●Lenvatinib – Lenvatinib is an inhibitor of VEGFR, and to a lesser degree, RET
and fibroblast growth factor receptor kinases 1 to 4. In 2015, lenvatinib was
approved by the US Food and Drug Administration (FDA) for the treatment of
locally recurrent or metastatic, progressive DTC that no longer responds to
radioactive iodine treatment [9,17]. The approved starting dose (used in the
pivotal phase III trial) is 24 mg orally once daily.
In an international, randomized, double-blind phase III trial, 392 patients with
progressive, radioiodine refractory thyroid cancer were randomly assigned in
a 2:1 ratio to lenvatinib or placebo [10]. Tumor assessments for initial
eligibility as well as serially while on therapy were performed centrally. The
median progression-free survival (18.3 versus 3.6 months; hazard ratio [HR]
for progression or death 0.21, 99% CI 0.14-0.31) and the response rate (64.8
versus 1.5 percent) were significantly better in the lenvatinib group. A similar
response was seen in patients previously treated with another aaMKI,
indicating benefit despite previous therapy. Compared with no complete
responses in the placebo group, four patients (1.5 percent) in the lenvatinib
group experienced durable complete responses. The median overall survival
was not reached in either group. A preplanned subgroup analysis
demonstrated that patients above the age of 65 years at the time of therapy

17
initiation with lenvatinib had a significantly longer overall survival than those
randomized to placebo (HR 0.53, 95% CI 0.31-0.91) [5].
In a randomized trial comparing the efficacy of two different starting doses
of lenvatinib, the objective response rate at 24 weeks in patients who started
24 mg daily was 57 percent compared with 40 percent for those who started
18 mg daily (odds ratio 0.50, 95% CI 0.26-0.96), thus not meeting criteria for
noninferiority of the two doses [18]. Despite differences in the starting doses,
the rates of grade 3 or higher treatment-emergent adverse events were
similar across the two arms.
●Sorafenib – Sorafenib is an inhibitor of VEGFR 1, 2, and 3, platelet-derived
growth factor receptor (PDGFR), common RET/PTC subtypes, c-kit, and less
potently, BRAF [19]. In 2013, sorafenib was approved by the FDA for the
treatment of locally recurrent or metastatic, progressive DTC that no longer
responds to radioiodine treatment [20]. A typical starting dose of 400 mg
orally twice daily is being used in selected patients with radiographically
progressive metastatic papillary thyroid cancer for whom clinical trials are
not available or appropriate; the efficacy of a lower starting dose has not
been reported [2,21].
In several small phase II trials, sorafenib had beneficial effects on tumor
progression in patients with DTC [22-26]. In a subsequent phase III trial, 417
patients with radioiodine-refractory DTC with locally advanced or metastatic
disease that had radiographically progressed within 14 months of entry were
randomized to either sorafenib or placebo [11]. Refractory disease was
defined as at least one focus of tumor lacking radioiodine uptake, disease
that had progressed within one year after radioiodine therapy, or cumulative
treatment with at least 600 mCi of iodine 131 (131-I). Median progression-
free survival was improved from 5.8 months on placebo to 10.8 with
sorafenib (HR 0.59, 95% CI 0.45-0.76). Similar efficacy was seen across a wide
variety of predefined subgroups. In a subsequent analysis, it was reported
that the presence of a BRAF or RAS mutation was not predictive of response to
treatment [27]. Although tumor responses were uncommon, six-month
disease control rate was 54 percent. Toxicities led to dose modification in 78
percent of patients and permanent discontinuation of therapy in 19 percent.
(See 'Side effects shared by oral kinase inhibitors inhibiting VEGFR' below.)
●Vandetanib – Vandetanib is an oral inhibitor that targets VEGFR, RET/PTC,
and the epidermal growth factor receptor (EGFR). Vandetanib is available in
the United States through a Risk Evaluation and Mitigation Strategy (REMS)
program for the treatment of unresectable locally advanced or metastatic
medullary thyroid cancer (see "Medullary thyroid cancer: Systemic therapy

18
 and immunotherapy", section on 'Vandetanib'). Use outside of the indications
defined in the REMS program is discouraged; however, given the strength of
the data from a well-designed randomized trial [12], vandetanib may be a
treatment option to consider for a patient with radioiodine-refractory,
progressive papillary thyroid cancer for whom clinical trials, lenvatinib,
and sorafenib are inappropriate. Given the low objective response rate,
however, the drug is not likely to yield significant benefit for patients
requiring major tumor shrinkage to palliate symptoms.
In the randomized trial, 145 patients with locally advanced or metastatic DTC
unresponsive to radioactive iodine were randomly assigned
to vandetanib (300 mg once daily) or placebo [12]. After a median follow-up
of approximately 19 months, fewer patients treated with vandetanib had
disease progression (52 versus 61 patients in the placebo group [72 versus 84
percent]). Median progression-free survival was 11.1 and 5.9 months in the
vandetanib and placebo groups, respectively (HR 0.63, 95% CI 0.54-0.74).
There was no difference in objective partial response (8 percent of 72 and 5
percent of 73 patients, respectively) or overall survival (19 and 21 deaths,
respectively). In subgroup analysis, efficacy may have been highest in
patients with papillary thyroid cancer, and little difference in progression-free
survival was suggested in patients with either follicular or poorly
differentiated carcinomas. The most common adverse events resulting in
discontinuation of vandetanib were prolongation of the QT interval and
diarrhea. A larger, randomized, placebo-controlled phase III trial in patients
with progressive, radioiodine-refractory DTC is underway.
Contraindications to aaMKI — Relative contraindications to antiangiogenic
multikinase inhibitors (aaMKIs) may include major surgery within 28 days, active
bleeding, untreated hemorrhagic brain metastases, encasement by tumor of
major arteries such as the carotid, or arterial thromboembolic event within the last
6 to 12 months. We also try to minimize use of potent antiangiogenic agents in
patients with prior external beam radiotherapy (EBRT) to the neck due to reports
of tracheoesophageal fistulas [28].
For patients with contraindications to aaMKIs, a BRAF inhibitor
(eg, vemurafenib, dabrafenib) with or without an MEK inhibitor is an alternative.
(See 'Mutation-specific kinase inhibitor' below.)
Mutation identified
Mutation-specific kinase inhibitor — If a targetable driver mutation is present
(eg, NTRK, ALK, RET, BRAF), we suggest a mutation-specific kinase inhibitor (eg, an
FDA-approved selective TRK or RET inhibitor, or off-label use of a BRAF inhibitor)
(algorithm 1). Off-label use of a BRAF inhibitor is typically reserved for patients

19
with BRAF V600-mutant papillary thyroid cancer for whom aaMKI therapy might be
contraindicated.
BRAF, RET, or TRK inhibitors frequently produce objective responses in DTC,
though prolongation of progression-free survival has not yet been demonstrated
in randomized trials. Of note, kinases that inhibit signaling along the mitogen-
activated protein kinase (MAPK) pathway (eg, the BRAF
inhibitors vemurafenib, dabrafenib) may allow re-expression of genes responsible
for iodine metabolism in radioiodine-refractory DTC, thus permitting restoration of
radioiodine uptake (also called "redifferentiation"). (See 'Assess for restoration of
radioiodine uptake' below.)
●TRK inhibition – Rearrangements of one of the neurotrophic tropomyosin
receptor kinase (NTRK) genes leading to constitutive activation of signaling
and tumor proliferation has been reported in a small percentage of patients
with DTC [29]. Larotrectinib and entrectinib, highly selective inhibitors of TRK
kinases, have been FDA approved for treatment of any solid tumor bearing
an NTRK1-3 fusion mutation, including DTC. Of 15 patients with progressive
radioiodine-refractory metastatic DTC bearing an NTRK  rearrangement
treated with larotrectinib across three clinical trials, 87 percent were reported
to experience a partial response [30-33]. In an analysis of three phase I or II
trials, one of five patients had a response with entrectinib [34]. (See "Systemic
treatment of metastatic soft tissue sarcoma", section on 'NTRK fusion genes'.)
Restoration of radioiodine uptake has been reported with larotrectinib [35].
(See 'Assess for restoration of radioiodine uptake' below.)
●RET inhibition – Rearrangements leading to RET/PTC oncogenes are the
third most common driver mutations in papillary thyroid cancer, although
they may be less commonly associated with advanced, radioiodine-refractory
disease. Similar fusion abnormalities exist as well in non-small cell lung
cancer along with other malignancies, leading to interest in development of
selective RET kinase inhibitors.
Selpercatinib and pralsetinib, oral kinase inhibitors that selectively target RET
kinase, are approved by the FDA for the treatment of advanced or
metastatic RET fusion-positive thyroid cancer, RET-mutant medullary thyroid
cancer, and other types of cancers that have an alteration (mutation or
fusion) in the RET gene [36,37]. Of note, high response rates were seen with
both selpercatinib and pralsetinib to treat medullary thyroid carcinoma with
point mutations, but effectiveness may be less than reported for
rearrangements in the RET gene. (See "Medullary thyroid cancer: Systemic
therapy and immunotherapy".)

20
 •Selpercatinib – In the open-label LIBRETTO-001 trial of selpercatinib in 19
patients with previously treated, radioiodine-refractory, RET fusion-
positive, non-medullary thyroid cancer, objective response (complete or
partial) was reported in 79 percent [38]. The most common grade 3 or 4
adverse events included hypertension (21 percent), increased alanine
aminotransferase (11 percent), increased aspartate aminotransferase (9
percent), hyponatremia (8 percent), and diarrhea (6 percent).
•Pralsetinib – In the open-label ARROW trial, in which nine patients
with RET-fusion thyroid carcinoma were treated with pralsetinib, the
overall response rate was 89 percent, all partial responses [37,39-41]. The
most common grade 3 or 4 adverse events included hypertension (21
percent), fatigue (6 percent), diarrhea (5 percent), fever (2.2 percent), and
dyspnea (2.2 percent).
●BRAF inhibition – Vemurafenib and dabrafenib, inhibitors of BRAF kinase,
have been studied in patients with BRAF-mutated DTC. Although not
approved for the treatment of papillary thyroid cancer, these drugs can be
considered for those patients with radiographically progressive, radioiodine-
refractory BRAF V600-mutant papillary thyroid cancer for whom
antiangiogenic therapy might be contraindicated.
•Vemurafenib – In a phase II trial in which 51 patients with progressive
radioiodine-refractory BRAF V600-mutant papillary thyroid cancer were
treated with vemurafenib, the partial response rate was 38.5 percent, and
median progression-free survival was 18.2 months in the anti-VEGFR-naïve
group [42]. Less benefit was seen in the group previously treated with
anti-VEGFR kinase inhibitors (27.3 percent and 8.9 months), but the study
was not designed to compare formally the outcomes between the two
arms. Common adverse events included rash, fatigue, weight loss, taste
alteration, and alopecia; squamous cell carcinomas were identified in 22
percent of patients and noncutaneous squamous cell carcinomas in
another 6 percent.
•Dabrafenib – In a multicenter, randomized phase II trial comparing
dabrafenib (150 mg twice daily) alone or in combination with the MEK
inhibitor trametinib (2 mg daily) in 53 patients with BRAF-mutant
metastatic papillary thyroid cancer, objective response rates were similar,
50 and 54 percent, respectively [43]. Median progression-free survival and
durations of response also did not differ between the two groups, and
treatment-related adverse events were similar as well. Thus, the
combination did not appear to have an advantage over single therapy
with dabrafenib. Notably, the combination of dabrafenib and trametinib

21
 has been approved for BRAF-mutated anaplastic thyroid carcinoma, and
we have observed durable complete responses in patients with BRAF-
mutated poorly differentiated thyroid carcinoma treated with both drugs
as well [3]. (See "Anaplastic thyroid cancer", section on 'BRAF V600E
mutation identified'.)
Mutations of BRAF are associated with the greatest degree of MAPK activation
and functional dedifferentiation. Restoration of radioiodine uptake has been
demonstrated in small studies using either of the BRAF
inhibitors, dabrafenib or vemurafenib [44]. (See 'Assess for restoration of
radioiodine uptake' below.)
●PI3K inhibition – Both papillary and follicular carcinomas often develop
mutations or upregulation of signaling through phosphoinositide 3-kinase
(PI3K) as the disease progresses, leading to the suggestion that targeting this
pathway may be of value. A phase II study of everolimus included 25 patients
with progressive metastatic DTC who were treated with everolimus 10 mg
daily [45]. Although the partial response rate was only 4 percent, median
progression-free survival was 43 weeks. A second trial has also preliminarily
reported efficacy from monotherapy with everolimus, as has a third with the
combination of everolimus and sorafenib; in these trials, particular efficacy
was suggested in patients with metastatic Hürthle cell carcinoma [46,47].
Further investigation of the role of targeting this signaling pathway is
expected. In patients whose tumors bear PI3K pathway mutations, we may
add everolimus to lenvatinib using starting doses approved for renal cell
carcinoma (5 mg and 18 mg daily, respectively).
EVALUATING RESPONSE TO TREATMENT
General
●While on therapy, we perform computed tomography (CT) or magnetic
resonance imaging (MRI) of known or suspected sites of disease every two to
four months to determine how the disease is responding to therapy (ie,
tumor burden).
●Patients should also be assessed for potential treatment-related and
disease-related complications. It is highly recommended that clinicians using
these agents follow a comprehensive and standardized approach to
assessment of adverse events during therapy, including careful
documentation of the extent of baseline symptoms present prior to initiation
of kinase inhibitors [48]. Subsequent management should include
consideration of limited drug interruptions and dose modifications, carefully
observing for balance of continued anti-tumor efficacy and reduced toxicity

22
 [49]. (See 'Side effects shared by oral kinase inhibitors inhibiting
VEGFR' below.)
Assess for restoration of radioiodine uptake — In patients treated with
mitogen-activated protein kinase (MAPK) pathway inhibitors such
as vemurafenib, dabrafenib, and trametinib, we may perform diagnostic
radioiodine imaging after one to three months of therapy to determine if sufficient
restoration of radioiodine uptake (redifferentiation) has occurred to permit
subsequent radioiodine therapy.
●In patients who have previously had significant radioiodine dosing, or with
extensive pulmonary metastases, diagnostic radioiodine imaging with
concurrent dosimetry may allow calculation of radioiodine activity for
administration in order to minimize risk of subsequent pulmonary toxicity.
●In patients with a negative diagnostic radioiodine scan despite
redifferentiation therapy, an empiric activity of 100 to 150 mCi may yet be
considered.
Rearrangements of RET and NTRK1 tyrosine kinases, activating mutations of BRAF,
and activating mutations of RAS are sequential components leading to activation of
MAPK. Activation of MAPK promotes cell division and inhibits the sodium-iodide
symporter (which usually facilitates iodine uptake) and thyroid peroxidase
(facilitates organification). Mutations of BRAF are associated with the greatest
degree of MAPK activation and functional dedifferentiation, followed
by RET and NTRK fusions, and least by RAS mutations [50]. Thyroid cancers with
these mutations are more likely to be refractory to radioiodine. (See "Oncogenes
and tumor suppressor genes in thyroid nodules and nonmedullary thyroid
cancer".)
Inhibition of kinases signaling along the MAPK pathway may allow re-expression of
genes responsible for iodine metabolism in radioiodine-refractory differentiated
thyroid cancer (DTC), thus restoring sufficient radioiodine uptake to permit
subsequent radioiodine therapy [51-54]. Restoration of radioiodine uptake has
been demonstrated in small studies using either of the BRAF
inhibitors, dabrafenib or vemurafenib, as well as inhibitors of MEK [44,55]. As
examples:
●In a study involving 10 patients with radioiodine-refractory BRAF V600E
mutated papillary thyroid cancer, six patients (60 percent) demonstrated new
radioiodine uptake after nearly four weeks of therapy with dabrafenib (150
mg orally twice daily) [44]. Following radioiodine treatment with 150 mCi
iodine 131 (131-I) in those six patients, two experienced partial response and
four remained stable on imaging three months after
therapy. Vemurafenib similarly restored radioiodine uptake and sensitivity,

23
 with selected tumor biopsies confirming increased thyroid-specific gene
expression following effective MAPK pathway inhibition [55].
●In an interim analysis of results from another study in which 21 patients
were treated with a combination of trametinib and dabrafenib, partial
response at six months was 38.1 percent with stable disease in 52.4 percent
[56]. There were encouraging increases in radioiodine uptake and decreases
in thyroglobulin levels (in the 15 of 21 patients who were antithyroglobulin
antibody negative).
Selumetinib is an investigational drug that selectively inhibits MEK 1 and MEK 2
(downstream effectors of MAPK pathway signaling) [57]. In a study of 20 patients
with radioiodine-refractory papillary thyroid cancer, 12 patients (60 percent) had
new and/or increased radioiodine uptake after treatment with selumetinib (75 mg
orally twice daily for four weeks) [54]. In eight patients (40 percent), the absorbed
radiation dose in the lesion was sufficient enough to continue selumetinib and
receive a therapeutic dose of radioiodine. During six months of follow-up, there
were partial responses in five patients and stable disease in three. Selumetinib was
most effective in patients with NRAS-mutant thyroid cancers. Although there is an
ongoing trial to evaluate the role of selumetinib in augmenting radioiodine
responsiveness in metastatic DTC that retains some iodine uptake on diagnostic
imaging, another randomized trial to determine if selumetinib improves the
complete response rate with initial adjuvant radioiodine therapy in patients at high
risk for recurrent disease after thyroidectomy was halted after a preplanned
interim analysis due to futility [58].
REFRACTORY DISEASE OR KINASE INTOLERANCEPatients with
refractory disease or with intolerance to one kinase inhibitor may benefit from
treatment with another. Although cross-resistance has not been reported,
likelihood of response is likely somewhat lower, however, with each successive
regimen.
●For patients who cannot tolerate or who fail first-line therapy with an
antiangiogenic multikinase inhibitor (aaMKI), we discuss investigational
agents, further attempts with other aaMKIs (eg, cabozantinib), or (if
appropriate) a BRAF inhibitor (eg, vemurafenib or dabrafenib) or TRK or RET
inhibitor (eg, larotrectinib or selpercatinib, respectively).
In a phase II trial, patients with radioiodine-refractory differentiated thyroid
cancer (DTC) that had progressed on one or two previous regimens of aaMKI
therapy were treated with cabozantinib, starting at 60 mg daily [59]. Of the 25
patients, 10 (40 percent) had a partial response, 13 (52 percent) had stable
disease, and 2 (8 percent) had nonevaluable disease. The median
progression-free survival and overall survival were 12.7 months and 34.7
24
 months, respectively. Toxicities were similar to those experienced with other
tumor types, including fatigue, weight loss, diarrhea, palmar-plantar
erythrodysesthesia, and hypertension.
In an interim analysis of results from a randomized phase III trial
comparing cabozantinib (starting dose 60 mg daily) with placebo in patients
with metastatic, radioiodine-refractory DTC which progressed after treatment
with lenvatinib or sorafenib, patients in the cabozantinib group showed
improved progression-free survival (HR 0.22, 95% CI 0.13-0.36), although
there was no significant difference in the co-primary endpoint of objective
response [60].
●For patients who cannot tolerate first-line therapy with a mutation-specific
kinase inhibitor, we suggest an aaMKI such as lenvatinib as the next-line
option.
●Doxorubicin or a taxane are alternatives for patients who are unable to
tolerate or who fail several attempts at kinase inhibitor therapy.
(See 'Therapies infrequently used' below.)
SIDE EFFECTS SHARED BY ORAL KINASE INHIBITORS INHIBITING
VEGFRSide effects of vascular endothelial growth factor receptor (VEGFR)-
targeted antiangiogenic multikinase inhibitors (aaMKIs) may include hypertension,
renal toxicity, proteinuria, arthralgia/myalgia, headache, bleeding,
myelosuppression, arterial thromboembolism, cardiotoxicity including prolonged
QT intervals and risk for arrhythmia, thyroid dysfunction, cutaneous toxicity
including hand-foot skin reaction, delayed wound healing, hepatotoxicity, nausea,
vomiting, diarrhea, muscle wasting, fistula formation, osteonecrosis of the jaw,
and reversible posterior leukoencephalopathy syndrome. TSH may become
elevated during treatment, requiring an increase in the dose of thyroid hormone
replacement or suppression therapy. Monitoring for and management of these
side effects are discussed in detail elsewhere. (See "Toxicity of molecularly
targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of
molecularly targeted antiangiogenic agents: Cardiovascular
effects" and "Cutaneous adverse events of molecularly targeted therapy and other
biologic agents used for cancer therapy".)
THERAPIES INFREQUENTLY USED
●Immunotherapy – The use of agents that accentuate the capacity of a
patient's own immune system to attack a malignant tumor has rapidly
expanded in the past few years with the introduction of "checkpoint
inhibitors." Drugs that block key cell-surface components on tumor cells or T
lymphocytes, regulating the interaction between these two cell types, permit
the immune system to recognize tumor-specific epitopes or neoantigens
25
presented on the surface and thus allow immune targeting of these
abnormal cells. In differentiated thyroid cancer (DTC), one trial evaluated the
programmed cell death receptor 1 (PD-1) inhibitor pembrolizumab, 10 mg/kg
given intravenously every two weeks for 24 months or until progression or
intolerable toxicity [61]. Of 22 patients with progressive metastatic disease
and programmed cell death ligand 1 (PD-L1) expression in at least 1 percent
of tumor or stroma cells, only two (9.1 percent) experienced a partial
response and 54.5 percent had stable disease as their best overall response.
The median progression-free survival rate was seven months. Adverse events
were typical of those seen in other tumor types, including diarrhea, fatigue,
and colitis.
In a preliminary report from a phase II study,
adding pembrolizumab to lenvatinib as first-line therapy led to similar rates
of partial response and stable disease as lenvatinib alone [62].
Low efficacy was reported from a phase II trial of the CTLA-4
inhibitor, ipilimumab, in combination with the PD-1 inhibitor, nivolumab, in
32 patients, with overall response rate of 9 percent and median progression-
free survival 4.9 months [63]. Further clinical trials of checkpoint inhibitors in
combination with targeted agents are underway.
●Cytotoxic agents – Although conventional cytotoxic agents are occasionally
used for the treatment of patients with progressive symptomatic thyroid
cancer that is unresponsive or not amenable to surgery, radioiodine therapy,
or external radiotherapy, complete remission is rare, and long-term
responses are uncommon. In addition, the availability of kinase inhibitors
that induce durable responses or stability has changed the standard
approach to treating patients with progressive metastatic disease, further
limiting the role of cytotoxic agents [6,7]. (See 'Initial systemic
therapy' above.)
Doxorubicin is the only cytotoxic agent approved by the US Food and Drug
Administration (FDA) for metastatic thyroid cancer. Other single
chemotherapeutic agents, including (but not limited
to) paclitaxel, bleomycin, cisplatin, carboplatin, methotrexate, melphalan, mit
oxantrone, etoposide, and aclarubicin, have not been shown to improve
response rates. Similarly, combination therapy with doxorubicin and cisplatin
has not been shown to improve the overall response compared with
doxorubicin alone, and combination therapy may increase toxicity [64,65].
Thus, we typically reserve conventional cytotoxic agents (eg, doxorubicin) for
patients with metastatic refractory DTC who are unable to participate in
clinical trials or who either cannot tolerate or fail antiangiogenic multikinase

26
 inhibitors (aaMKIs). Cisplatin or other agents may be considered in patients
for whom doxorubicin is inappropriate (eg, those with pre-existing impaired
cardiac function or myelosuppression). Data regarding combination
regimens are even sparser than for single drugs. Such regimens may be
appropriate in select patients.
•Doxorubicin – In the initial studies with doxorubicin, 19 patients with
metastatic papillary or follicular carcinoma were enrolled [7,66]. Partial
responses (defined as >50 percent reduction in tumor area on serial
radiographs) to doxorubicin were seen in seven patients (37 percent), and
stable disease was reported in another six. Pulmonary metastases
appeared to be more likely to respond than bone metastases. By 1974,
doxorubicin was considered the "drug of choice" for treating progressive,
metastatic thyroid cancer [67]. Other studies of doxorubicin monotherapy
have utilized varying definitions of response, but with similar results (30 to
40 percent partial response) [64].
In a subsequent report of patients with documented progressive disease
prior to chemotherapy, partial response (using World Health Organization
[WHO] criteria) after six months of doxorubicin treatment was seen in only
5 percent of patients, and stable disease between 1 and 22 months of
duration was described in another 42 percent [68]. Response was
significantly higher in those patients treated with 60 mg/m2 every three
weeks, compared with 15 mg/m2 weekly. Overall, best responses occurred
in patients with pulmonary metastases and high performance status.
The recommended dose of doxorubicin for monotherapy is 60 to 75
mg/m2 every three weeks, administered as a continuous intravenous
infusion for 48 to 72 hours to minimize the risk of cardiac toxicity.
Cumulative doses of up to 600 mg/m2 can be administered in responsive
patients. Common adverse events can include granulocytopenia with
accompanying infections, nausea, vomiting, and alopecia.
•Taxanes – The use of taxanes in DTC is primarily based upon suggestion
of efficacy in anaplastic carcinoma [69], rather than specific clinical trials.
One report described three patients with metastatic DTC, all of whom had
progressed despite radioiodine therapy [70]. Biweekly treatment
with docetaxel led to disease stabilization in all three, lasting 14 to 18
months, but no objective responses were described.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
27
●For patients with metastatic differentiated thyroid cancer (DTC) that
progresses despite systemic treatment such as radioiodine and thyroid-
stimulating hormone (TSH)-suppressive thyroid hormone therapy, or focal
treatments such as surgery and external beam radiotherapy (EBRT),
treatment options have historically been limited. New approaches based
upon application of targeted chemotherapies are emerging as effective
alternatives for progressive disease. (See 'Introduction' above.)
●Prior to considering systemic therapy, patients should be evaluated with
comprehensive computed tomography (CT) and/or magnetic resonance
imaging (MRI) to establish the baseline extent of disease. Prior to therapy or
in any patient with suspicious symptoms, imaging of the brain should be
performed to rule out intracranial metastases that might require other forms
of intervention first, such as surgery or radiation. (See 'General
principles' above.)
●Patients with asymptomatic metastatic tumors generally less than 1 to 2 cm
in diameter and growing in diameter less than 20 percent per year can
usually be monitored for disease progression (active surveillance). Known
sites of metastatic disease should be imaged by CT or MRI every six months,
and potential new sites of disease should be imaged every 12 to 24 months.
(See 'Patient selection for systemic therapy' above.)
●Patients with metastatic, unresponsive tumors at least 1 to 2 cm in diameter
and growing by at least 20 percent per year, or patients with symptoms
related to multiple metastatic foci that cannot be alleviated with surgery or
EBRT are candidates for systemic therapy (algorithm 1). (See 'Patient
selection for systemic therapy' above.)
●We prefer to administer systemic treatment in the context of a clinical trial.
(Active clinical trials can be identified at: ClinicalTrials.gov.) Increasingly, these
options are dictated by the presence of specific gene mutations or signaling
pathway abnormalities that are the targets of approved or investigational
therapies. (See 'Initial systemic therapy' above.)
●For patients whose disease burden, rate of tumor growth, or symptoms
necessitate consideration of systemic therapy options, somatic mutation
testing can be performed to identify oncogenic kinase abnormalities that
might suggest specific treatment options that cannot be administered in the
absence of mutational data (eg, gene rearrangements in NTRK, ALK, or RET, or
point mutations in BRAF). Given the high cost of such testing and lack of
coverage by many insurance providers, this option may not be realistic for
many patients even if the lack of testing limits therapeutic options.
(See 'Initial systemic therapy' above.)

28
●For patients, who are unable to participate in clinical trials, the choice of
initial kinase inhibitor depends on the result of somatic mutation testing, if
available.
•In the absence of a mutation, or if results are not available, we
suggest lenvatinib rather than another antiangiogenic multikinase
inhibitor (aaMKI) (Grade 2B). Among the other aaMKIs, sorafenib is our
next preferred option. (See 'Mutation not identified' above.)
•If tumor mutation results are available, we suggest a mutation-specific
kinase inhibitor (eg, a RET, TRK, or BRAF inhibitor) if one of those
mutations has been documented (Grade 2C). Although not approved for
the treatment of papillary thyroid cancer, BRAF inhibitors can be
considered for those patients with radiographically progressive,
radioiodine-refractory BRAF V600-mutant papillary thyroid cancer for
whom antiangiogenic therapy might be contraindicated. (See 'Mutation
identified' above.)
●For patients who cannot tolerate or in whom initial therapy with an aaMKI
fails, we discuss investigational agents, further attempts with other aaMKIs,
or, if not done previously, somatic mutation testing to suggest mutation-
specific treatment options, eg, a BRAF inhibitor
(eg, vemurafenib or dabrafenib), a RET inhibitor (selpercatinib), or TRK
inhibitor (eg, larotrectinib or entrectinib). (See 'Refractory disease or kinase
intolerance' above.)
●For patients who cannot tolerate or in whom initial therapy with a mutation-
specific kinase inhibitor fails, an aaMKI such as lenvatinib is an alternative.
(See 'Mutation identified' above and 'Refractory disease or kinase
intolerance' above.)
●Patients being treated with a BRAF or other mitogen-activated protein
kinase (MAPK)-pathway inhibitor may undergo diagnostic radioiodine
imaging to determine if sufficient restoration of radioiodine uptake has
occurred to permit subsequent radioiodine therapy. (See 'Assess for
restoration of radioiodine uptake' above.)
●Doxorubicin is an alternative for patients who are unable to tolerate or who
fail several attempts at kinase inhibitor therapy. (See 'Refractory disease or
kinase intolerance' above and 'Therapies infrequently used' above.)

29
Differentiated thyroid cancer: Clinicopathologic
staging
Author:
R Michael Tuttle, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Nov 09, 2021.
INTRODUCTIONClinicopathologic staging of patients with cancer is valuable
for many reasons, including the following [1]:
●To estimate risk of recurrence and disease-specific mortality for an
individual patient
●To tailor decisions regarding postoperative adjunctive therapy (such as the
need for radioiodine [RAI] ablation and degree of thyroid-stimulating
hormone [TSH] suppression) to the patient's risk for disease recurrence and
mortality
●To make decisions regarding the frequency, modality, and intensity of
follow-up based upon an individual patient's risk of recurrence and mortality
●To enable accurate communication regarding a patient among health care
professionals
●To allow evaluation of differing therapeutic strategies applied to comparable
groups of patients in clinical studies
●To provide "a method of conveying clinical experience to others without
ambiguity" [2]
The clinicopathologic staging of differentiated thyroid cancer will be discussed
here. The management of differentiated thyroid cancer is reviewed separately.
(See "Differentiated thyroid cancer: Overview of management".)
STAGING FOR DIFFERENTIATED THYROID CANCER
●Initial postoperative staging – In our practice, we use the tumor, node,
metastasis (TNM) (table 1) or Metastases, Age, Completeness of Resection,
Invasion, Size (MACIS) staging systems to estimate disease-specific mortality
and then an additional clinicopathologic staging system, such as the
American Thyroid Association (ATA) system, to estimate the risk of recurrence
(table 2) [3-5].

30
 ●Restaging during follow-up – These initial risk assessments are then
actively modified based upon data obtained during follow-up that reflect the
individualized patient's response to therapy [4,6]. This dynamic risk
assessment approach allows for more accurate risk assessments than either
a static estimate of risk based on the TNM staging system or the ATA risk of
recurrence classification system [4].
The ATA recommends the TNM staging system (table 1) for all patients with
differentiated thyroid cancer and any of the postoperative clinicopathologic
staging systems to achieve more accurate risk factor stratification [5]. It should be
recognized, however, that no staging system reliably predicts outcome in
individual patients; as a result, clinicians should use individual clinicopathologic
characteristics to determine the specific treatment for a given patient.
It is important to note that the initial stage assigned to a patient is based upon
information available in the first few weeks to months after diagnosis. The eighth
edition of the American Joint Committee on Cancer (AJCC)/TNM staging system
specifically allows all data collected within the first four months after surgery to be
used as part of the initial AJCC staging for each patient [7]. In practical terms, this
initial stage assignment does not change over time. In contrast, the estimates of
the risk of recurrence and death usually do change over time depending upon how
well the patient responds to initial therapy (surgery with or without radioiodine
[RAI] ablation). As an example, patients who have had an excellent response to
initial therapies would be considered to be at much lower risk for recurrence and
death from disease than may have been predicted based on initial staging.
Conversely, patients with an incomplete response to therapy may be at a higher
risk of clinically significant disease recurrence or death than would have been
predicted based on initial staging factors. Thus, we restratify patients on each
follow-up visit using a reclassification system that emphasizes the response to
therapy for each individual patient. (See 'Dynamic risk stratification' below.)
Staging systems for predicting disease-specific mortality — Given their relative
ease of use and widespread acceptance, we prefer the TNM or MACIS staging
systems to estimate disease-specific mortality. (See 'TNM system' below
and 'MACIS system' below.)
In differentiated thyroid cancer, there are several staging systems for estimating
disease-specific mortality (table 3). Each of the staging systems tend to use a core
set of data that usually includes age at diagnosis, size of the primary tumor, extent
of local extrathyroidal extension, and the presence/absence of distant metastases.
The estimated mortality rates reflect both the predictive accuracy of the staging
system and the variations in therapy at different institutions. There are sufficient

31
differences among the staging systems such that practitioners using different
schema cannot be assured that they are classifying patients in a similar fashion.
Application of several different staging systems to 1225 patients with
differentiated thyroid cancer treated with total thyroidectomy and radioiodine
(131-I) therapy revealed that the TNM system was best for separating groups of
patients with distinctly different survival curves [8]. Even so, none of the static
initial staging systems were able to explain more than a small proportion of the
variance in mortality in the patient population, while the dynamic risk staging
systems that incorporate response to therapy variables into an active ongoing risk
stratification system account for a much higher proportion of variance.
(See 'Dynamic risk stratification' below.)

The more commonly used staging systems for predicting disease-specific mortality
are reviewed below.

TNM system — The Union for International Cancer Control (UICC) and the AJCC
have adopted the eighth (2017) tumor, node, metastasis (TNM) classification
system, which took effect globally on January 1, 2018 (table 1) [2]. The TNM system
is optimized to predict survival in patients with thyroid cancer, based primarily on
pathologic findings accumulated preoperatively, intraoperatively, and during the
first four months after thyroid surgery [9].
The updated 2017 TNM staging system is notable for the following changes [9,10]:
●The age at diagnosis cutoff for prognostic staging was raised from 45 to 55
years of age. Mortality from thyroid cancer increases progressively with
advancing age starting at approximately age 35 years. While previous
editions of the TNM staging system used 45 years of age as a discrete point
to differentiate patients at higher risk for dying from thyroid cancer from
lower risk patients, the 2017 TNM staging system increased the age cutoff to
55 years.
●Regional lymph node metastases and microscopic extrathyroidal extension
were removed from the definition of T3 disease.
●T3a is a new category for tumors >4 cm confined to the thyroid gland.
●T3b is a new category for tumors of any size demonstrating gross
extrathyroidal extension into strap muscles.
●Level VII lymph nodes, previously classified as lateral neck lymph nodes
(N1b) were reclassified as central neck lymph nodes (N1a) to be more
anatomically consistent and to facilitate uniform coding for tumor registrars,
clinicians, and researchers.
●The presence of distant metastases in older patients is classified as IVB,
rather than IVC disease.
32
Compared with the seventh edition, the changes implemented in the eighth
edition downstage many patients into lower stages, more accurately reflecting
their lower risk of thyroid cancer mortality [11-13]. The updated system classifies
fewer patients as having stage III or IV disease but conveys a poorer prognosis for
those who do. The expected 10-year, disease-specific survival for patients <55
years old with stage I or II disease is 98 to 100 and 85 to 95 percent, respectively.
For patients ≥55 years of age, the expected 10-year, disease-specific survival for
stages I, II, III, and IV disease is 98 to 100, 85 to 95, 60 to 70, and <50 percent,
respectively [9].
While the AJCC eighth edition performs well when analyzed across large cohorts of
patients, it is important to note that as many as 6 percent of AJCC stage I patients
less than 55 years old at diagnosis will have high-risk features (eg, gross
extrathyroidal extension or incomplete tumor resection). These patients have a
poorer prognosis than predicted for the entire cohort of stage I patients but can
easily be identified by being classified as ATA high risk (see 'ATA risk
stratification' below), even though they are classified as having AJCC eighth edition
stage I disease [1].
MACIS system — The Metastases, Age, Completeness of Resection, Invasion, Size
(MACIS) system was introduced to eliminate the need for histologic grading of the
tumor [14,15]. The MACIS score is calculated as follows:
●3.1 (for patients less than 40 years old at diagnosis) or 0.08 x age (if 40 or
more years old) plus
●0.3 x tumor size (in cm) plus
●1 if tumor incompletely resected plus
●1 if tumor locally invasive plus
●3 if distant metastases present

Using this system in patients with papillary cancer, the 20-year, disease-specific
mortality for patients with a MACIS score less than 6 was 1 percent; with a MACIS
score between 6.0 and 6.99, 11 percent; with a MACIS score between 7.0 and 7.99,
44 percent; and with a MACIS score of 8.0 or more, 76 percent.

National Thyroid Cancer Treatment Cooperative Study — The National Thyroid

Cancer Treatment Cooperative Study (NTCTCS) created a staging approach that
was applied prospectively to a registry of patients drawn from 14 cooperating
institutions [16]. Clinicopathologic staging was based upon patient age at
diagnosis, tumor histology, tumor size, intrathyroidal multifocality, extraglandular
invasion, metastases, and tumor differentiation. Between 1987 and 1995, 1607
patients were registered; 43 percent were classified as having stage I disease, 24
percent stage II, 24 percent stage III, and 9 percent stage IV. Patients with
33
follicular cancer were more likely to have stage III or IV disease than those with
papillary cancer. Of 1562 patients for whom censored follow-up was available
(median follow-up 40 months), 78 died from thyroid cancer or complications of
treatment. Five-year, product-limit, disease-specific survival was 99.8 percent for
stage I, 100 percent for stage II, 91.9 percent for stage III, and 48.9 percent for
stage IV. The frequency of remaining disease free also significantly declined with
increasing stage (94.3 percent for stage I, 93.1 percent for stage II, 77.8 percent for
stage III, and 24.6 percent for stage IV) (table 4).
Staging systems used to predict initial risk of recurrence — In our practice, we
use one of the popular staging systems to provide initial estimates of disease-
specific mortality (usually TNM or MACIS) and then an additional clinicopathologic
staging system, such as the ATA system (table 2), to provide initial estimates of risk
of recurrence [3-5]. During follow-up, these initial risk estimates are continually
refined as new data are used to assess response to therapy. (See 'Dynamic risk
stratification' below.)
All of the popular staging systems reliably predict disease-specific mortality;
however, they usually are not designed to adequately predict recurrence for
individual patients. As an example, in a study comparing recurrence-free survival
in patients with successfully treated differentiated thyroid carcinoma
(undetectable stimulated thyroglobulin [Tg] and negative whole-body iodine scan),
there was no difference in recurrence-free survival in patients initially classified as
high or low risk based upon TNM stage at diagnosis [17]. Because of this limitation
in current staging systems, the ATA proposed a novel clinicopathologic staging
system designed to risk stratify patients as having either a low (papillary thyroid
cancer confined to the thyroid), intermediate (regional metastases, worrisome
histologies, extrathyroidal extension, or vascular invasion), or high (gross
extrathyroidal extension or distant metastases) risk of recurrence (table 2) [5].
ATA risk stratification — The 2009 American Thyroid Association (ATA) guidelines
for the management of thyroid cancer proposed a system to estimate the risk of
recurrence in differentiated thyroid cancer based upon selected clinicopathologic
features (table 2) [18]. Several retrospective studies have demonstrated that the
2009 ATA clinicopathology staging system accurately predicted the risk of disease
recurrence and can be used to guide initial follow-up recommendations [19-22]. As
an example, in a retrospective review of 588 patients with differentiated thyroid
cancer followed at Memorial-Sloan Kettering Cancer Center (MSKCC) in New York,
the ATA risk of recurrence staging system effectively predicted the risk of either
recurrence or persistent structural disease, which occurred in 3, 21, and 68 percent
of patients in the low-, intermediate-, and high-risk groups [4].

34
In the 2015 ATA guidelines, the ATA low-risk group was extended to include
patients with small-volume lymph node metastases (≤5 micrometastases smaller
than 0.2 cm), intrathyroidal encapsulated follicular variants of papillary thyroid
cancer, intrathyroidal follicular thyroid cancer with no more than minimal vascular
invasion, and intrathyroidal papillary microcarcinomas even if
V600E BRAF mutation is present (table 2) [5]. Furthermore, the ATA high-risk
category was extended to include patients with large-volume cervical metastases
(≥3 cm) and follicular thyroid cancer with extensive vascular invasion. While still
formally endorsing the three-tiered risk stratification systems, the ATA recognizes
that risk of recurrence follows a continuum across the three discrete risk
categories (low, intermediate, and high).
Dynamic risk stratification — While initial staging systems can be used to guide
initial therapeutic and diagnostic follow-up strategy decisions, it is important to
recognize that initial risk estimates may need to change as new data are
accumulated during follow-up monitoring [23]. We typically restratify patients on
each follow-up visit using a reclassification system that emphasizes the response
to therapy for each individual patient. As originally conceived, these clinical
outcomes described the best response to initial therapy during the first two years
of follow-up [4,23] but are now being used to describe the clinical status at any
point during follow-up. At each follow-up visit, patients are classified as having one
of the following clinical outcomes [4,5,21]:
●Excellent response – No clinical, biochemical, or structural evidence of
disease.
●Biochemical incomplete response – Abnormal Tg or rising Tg antibody
values in the absence of localizable disease.
●Structural incomplete response – Persistent or newly identified locoregional
or distant metastases.
●Indeterminate response – Nonspecific biochemical or structural findings
that cannot be confidently classified as either benign or malignant. This
includes patients with stable or declining anti-Tg antibody levels without
definitive structural evidence of disease.
The precise definition of excellent response and biochemical incomplete response
is dependent on the extent of initial therapy (table 5) [24]. In patients treated with:
●Total thyroidectomy and RAI remnant ablation, we define an excellent
response as a stimulated Tg value <1 ng/mL (or highly sensitive,
nonstimulated Tg <0.2 ng/mL) with negative cross-sectional imaging (most
commonly a normal postoperative neck ultrasound).
●Total thyroidectomy without RAI ablation, we define an excellent response
as a stimulated Tg value <2 ng/mL (or highly sensitive, nonstimulated Tg <0.2

35
 ng/mL) with negative cross-sectional imaging (most commonly a normal
postoperative neck ultrasound).
●Less than total thyroidectomy (eg, lobectomy or lobectomy with
isthmusectomy), nonstimulated Tg values less than 30 ng/mL are considered
excellent (approximately 50 percent of the Tg expected from an intact normal
thyroid).
Serum Tg values above the range considered "excellent" without structural
evidence of disease are classified as biochemical incomplete response.
Reclassification at each follow-up visit allows the clinician to tailor ongoing
management recommendations to the current clinical status (rather than the
initial risk stratification estimates). (See "Differentiated thyroid cancer: Overview of
management", section on 'Monitoring response to therapy'.)
Two studies have demonstrated the importance of adjusting risk estimates during
follow-up based on the response to initial therapy [4,6]. Restratification during the
first two years of follow-up in a cohort of 588 patients reduced the likelihood of
finding persistent structural disease or disease recurrence to 2 percent in the low-
risk, 2 percent in the intermediate-risk, and 14 percent in the high-risk patients
that achieved an excellent response to therapy (stimulated Tg less than 1 ng/mL
and no evidence of structural disease on cross-sectional imaging). Conversely, an
incomplete response to therapy (suppressed Tg >1 ng/mL, stimulated Tg >10
ng/mL, or structural evidence of persistent/recurrent disease within the first two
years of follow-up) increased the subsequent risk of recurrence to 13 percent in
low-risk, 41 percent in intermediate-risk, and 79 percent in high-risk patients [4].
Similar findings were reported in a study of 548 patients followed in Italy; the risk
of recurrence decreased to 2 percent in low-risk and 5 percent in high-risk patients
who demonstrated an excellent response to therapy [6]. In both of these dynamic
risk stratification systems, the proportion of variance explained by these dynamic
staging systems (84 and 62 percent, respectively) is significantly better than any of
the static staging systems that rely only on initial clinicopathologic data to predict
final outcomes.
Following these two initial validation studies [4,6], multiple studies have
demonstrated the clinical utility of dynamic risk stratification [24].
OTHER PROGNOSTIC FACTORSIn addition to the clinical and
histopathologic factors included in most thyroid cancer staging systems (age at
diagnosis, size of the primary tumor, extent of local extrathyroidal extension, and
the presence/absence of distance metastases), several other factors have been
described that also appear to have prognostic significance. However, it is unclear
how much these various factors improve one's ability to accurately risk stratify an

36
individual patient beyond that achieved with the previously described staging
systems.
Multifocality — Although not included in the tumor, node, metastasis (TNM) or
Metastases, Age, Completeness of Resection, Invasion, Size (MACIS) staging
systems, many, but not all, analyses suggest that multifocality is a predictor of
recurrence. For example, in a study of 2095 patients with papillary cancer, both
multifocality (odds ratio [OR] 1.45, 95% CI 1.01-2.10) and the number of tumors
(OR 1.75, 95% CI 1.04-2.97) were significantly associated with disease recurrence
[25].
Lymphocytic infiltration — Although not usually considered in staging systems,
the presence of lymphocytic thyroiditis in the thyroid glands of patients with
differentiated thyroid cancer appears to affect prognosis. In a retrospective study
of 631 patients with this type of thyroid cancer who were followed for an average
of 11 years, the recurrence rate (6 versus 24 percent; p<0.001) and the mortality
rate (1 versus 8 percent; p<0.001) were lower in the 128 patients with thyroiditis
[26].
PET-positive tumors — Also not presently considered in any staging system,
thyroid cancers initially detected by fluorodeoxyglucose positron emission
tomography (PET) are more likely to be more aggressive variants of thyroid cancer
[27].
Histologic subtypes — While the Age, Grade, Extent, Size (AGES) and Memorial
Sloan-Kettering Cancer Center (MSKCC) staging systems incorporate "tumor
grade" into their staging systems (table 3), the other staging systems treat all
papillary thyroid cancers the same regardless of the specific histologic subtype.
Several studies have demonstrated a poorer prognosis for specific subtypes of
papillary thyroid cancers, including tall cell variants [28] and poorly differentiated
tumors [29].
Molecular characteristics — Some studies suggest that specific molecular
profiles may be used to predict risk of extrathyroidal extension, lymph node
metastases, and even distant metastases. While these observations need further
validation, it is likely that the specific molecular profile of the primary tumor may
have significant prognostic value that could be incorporated into staging systems
in the future. (See "Oncogenes and tumor suppressor genes in thyroid nodules
and nonmedullary thyroid cancer".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS

37
●In differentiated thyroid cancer, several classification and staging systems
are available (table 3), all of which reliably predict disease-specific mortality.
However, they usually are not designed to adequately predict recurrence for
individual patients. In addition, the estimates of the risk of recurrence and
death usually do change over time depending upon how well the patient
responds to initial therapy. (See 'Staging for differentiated thyroid
cancer' above.)
●In our practice, we use tumor, node, metastasis (TNM) (table 1) or
Metastases, Age, Completeness of Resection, Invasion, Size (MACIS) staging
systems to estimate disease-specific mortality and then an additional
clinicopathologic staging system, such as the American Thyroid Association
(ATA) three-tiered risk stratification system, to estimate the risk of recurrence
(table 2). The risk of recurrence, however, follows a continuum across the
three discrete risk categories (low, intermediate, and high). (See 'Staging
systems for predicting disease-specific mortality' above and 'Staging systems
used to predict initial risk of recurrence' above.)
●Initial risk assessments are actively modified based on data obtained during
follow-up that reflect the individualized patient's response to therapy. This
dynamic risk assessment approach allows for more accurate risk
assessments than either a static estimate of risk based on the TNM staging
system or the ATA risk of recurrence classification system. (See 'Dynamic risk
stratification' above.)
It should be recognized, however, that no staging system predicts outcome
in individual patients with 100 percent accuracy; as a result, clinicians should
use individual clinicopathologic characteristics to determine the specific
treatment for a given patient.
●In addition to the clinical and histopathologic factors included in most
thyroid cancer staging systems (age at diagnosis, size of the primary tumor,
extent of local extrathyroidal extension, and the presence/absence of
distance metastases), several other factors have been described that also
appear to have prognostic significance, including multifocality, histologic
subtypes, and molecular characteristics. (See 'Other prognostic
factors' above.)

38
Differentiated thyroid cancer: External beam
radiotherapy
Author:
James D Brierley, MB, BS, FRCP, FRCR, FRCPC
Section Editors:
Douglas S Ross, MD
David M Brizel, MD
Deputy Editors:
Jean E Mulder, MD
Sonali Shah, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Mar 05, 2020.
INTRODUCTIONSurgical resection is the primary treatment for patients with
differentiated (ie, papillary and follicular) thyroid cancer, followed by radioiodine,
and then thyroxine therapy. Most patients with well-differentiated thyroid cancer
have resectable tumors, and the results from surgery, radioiodine, and thyroxine
therapy are excellent.

External beam radiotherapy (EBRT) is used infrequently in the management of

differentiated thyroid cancer. It is predominantly indicated for palliation of locally
advanced unresectable or recurrent/metastatic disease in patients whose tumors
do not concentrate radioiodine. The role of EBRT in other settings is less certain.

The use of EBRT in the treatment of differentiated thyroid cancer will be reviewed
here. Other aspects of the management of differentiated thyroid cancer are
discussed separately, as is the role of EBRT in other thyroid malignancies, such as
anaplastic and medullary thyroid cancer.

●(See "Differentiated thyroid cancer: Overview of management".)

●(See "Differentiated thyroid cancer: Surgical treatment".)
●(See "Anaplastic thyroid cancer", section on 'Our approach to treatment'.)
●(See "Medullary thyroid cancer: Surgical treatment and prognosis", section
on 'Management of persistent/recurrent disease'.)
INDICATIONS FOR EBRTFor patients with differentiated thyroid cancer, the
main indication for external beam radiotherapy (EBRT) is for palliation in patients
with unresectable locally advanced disease or symptomatic metastatic disease that
is refractory to radioiodine. We also suggest EBRT to the thyroid bed and known
39
sites of disease for the treatment of patients who have inoperable macroscopic or
microscopic residual disease after thyroidectomy, with absent or inadequate
radioiodine avidity. In addition, for older patients (age 55 years or older) who have
gross extrathyroid extension (T4 disease) (table 1) at the time of surgery and
selected younger patients with T4b or extensive T4a disease and poor histologic
features (ie, insular or poorly differentiated histology) whose disease is resected,
but in whom there is a high likelihood of residual microscopic disease that is
known or strongly suspected to be non-radioiodine avid, we suggest EBRT.

For patients undergoing complete resection, lymph node involvement by itself is

not an indication for EBRT, because regional control is usually achieved with
surgery and radioiodine. However, EBRT could also be considered for older
patients with unresectable lymph node involvement (eg, nodal involvement that
intimately involves the carotid artery).

In patients with local or regional recurrence, when feasible, repeat surgery and, if
the tumor is iodine avid, additional radioiodine, is the preferred approach.
However, patients with multiple recurrences in the thyroid bed or cervical nodes,
especially if the interval between recurrences is short, may achieve control with
EBRT. The risk of multiple operations versus the risks of EBRT should be reviewed
for each such patient. EBRT also represents a reasonable approach to the rare
patient with locally recurrent disease with loss of radioiodine avidity, such as may
occur with multiple local recurrences in the thyroid bed or cervical nodes.

There are no randomized trials that address specific indications for EBRT in
patients with differentiated thyroid cancer, and practice is variable [1-3]. In
general, indications for EBRT in patients with differentiated thyroid cancer are
based upon clinical experience and retrospective studies, which are described
below.
Localized disease
Macroscopic — For patients with macroscopic unresectable disease in the neck
that does not concentrate radioiodine, we suggest EBRT. Some thyroid cancer
experts also administer EBRT to patients with unresectable disease in the neck
despite radioiodine uptake, if the degree of iodine uptake compared with the size
of the residual disease suggests that the radioiodine alone will be insufficient to
control disease.
Many retrospective studies have shown a benefit of EBRT in patients with
macroscopic residual disease [3-12]. Radioiodine therapy alone is unlikely to
eradicate residual tumor unless the absorbed dose of radiation is high, ie, at least

40
100 Gy [13]. In one study, as an example, a single dose of radioiodine producing an
absorbed dose over 80 Gy resulted in destruction of tumor in cervical lymph nodes
in only 74 percent of patients with small-volume disease (less than 2 grams) [14].
Further radiation in the form of EBRT can improve local control.

The efficacy of EBRT in controlling macroscopic residual disease is illustrated by

the following observations:

●In a study from Hong Kong of 842 patients, 124 of whom had gross residual
disease, the 69 patients who had EBRT had better local regional control at 10
years compared with those who did not have EBRT (56 versus 24 percent) [6].
●In a series of 88 patients with well-differentiated thyroid cancer that had
been incompletely resected, the five-year survival was 77 percent with EBRT
compared with 38 percent after surgery alone [8].
●In another study, the five-year locoregional control was 69.2 percent for 19
patients with macroscopic residual or inoperable disease, and the five-year
cause-specific survival was 58.3 percent [15].

Even better results have been seen in more contemporary series, many of which
utilized advanced radiation therapy approaches such as intensity-modulated
radiotherapy (IMRT):

●As an example, Memorial Sloan-Kettering Cancer Center reported on 66

patients with gross residual/unresectable non-anaplastic, non-medullary
thyroid cancer who received EBRT (77 percent with IMRT) over a 22-year
period [11]. The median overall survival was 42 months, and the three-year
locoregional progression-free survival rate was 77.3 percent.
●The MD Anderson group reported on 131 patients with high-risk or
recurrent disease [10]. For the 15 patients with gross residual or unresectable
disease treated with IMRT (43.5 percent) or conventional EBRT, four had a
complete response. The locoregional control rate was 22 percent.
Microscopic residual and completely resected high-risk disease — We suggest
EBRT for the following subsets of patients with microscopic residual and
completely resected high risk disease:
●Patients over 55 with a microscopically positive resection and non-
radioiodine-avid disease who are not candidates for reoperation.
●Older patients age 55 years or older who have T4 disease (ie, gross
widespread/multifocal extrathyroid extension, tracheal perichondrium, or
esophageal muscularis involvement) (table 1) at the time of surgery.

41
 ●Selected younger patients with poor histologic features (ie, insular or poorly
differentiated histology) and resected T4b or extensive T4a disease, as these
patients have a high likelihood of residual microscopic disease that is known
or strongly suspected to be non-radioiodine avid.

The role of EBRT in patients with suspected microscopic persistent disease or a

completely resected but high-risk tumor is poorly defined. EBRT may be beneficial
for patients with complete resection who are at high risk of recurrence after
radioiodine, but defining which patients are at risk and determining the population
for whom EBRT should be offered remains controversial.

Modern-day studies of EBRT in patients receiving standard management suggest

benefit in some patient groups. However, the role of EBRT in this setting has not
been successfully studied in randomized trials. As an example, in one trial, patients
with locally invasive completely resected differentiated thyroid cancer with
extrathyroid extension or microscopically positive resection margins, treated with
radioiodine and thyroid hormone suppression, were randomly assigned to receive
additional EBRT or not [4]. There was inadequate recruitment, and the trial became
a prospective cohort study. Of the 47 patients participating in the study, 26
received EBRT. After a mean follow-up of 930 days, recurrences occurred in 0
versus 3 percent, and the difference was not statistically significant. One limitation
of this study was the inclusion of patients at low risk of recurrence who were
unlikely to benefit from the EBRT. Another was that the follow-up in this study is
much too short to properly assess the effectiveness of EBRT, given that
differentiated thyroid cancer has a decades-long natural history.
Retrospective studies suggest a benefit of EBRT in high-risk groups, particularly
older patients with evidence of extrathyroidal extension at the time of surgery
[1,5,9,10,15-18]. Most of the literature combines patients with completely resected
high-risk disease, those with microscopically positive margins, and patients with
locally recurrent tumors. As examples:
●In a pooled quantitative analysis of eight studies (2388 patients) evaluating
the role of EBRT in differentiated thyroid cancer, the mean recurrence rate in
patients receiving EBRT regardless of stage or residual disease status was 8
percent, and in those who did not receive EBRT, it was 25 percent [19]. There
appeared to be an improvement in local regional control following EBRT in
patients over age 45 at high risk for locoregional recurrence.
●In a subgroup analysis of 70 patients from a single institution who were over
60 years of age, had extrathyroidal extension (T4 disease), and no gross
residual disease after surgery, 47 received radiotherapy and 23 did not [5].
The 10-year cause-specific survival (81 versus 65 percent) and locoregional
42
 relapse-free rate (86 versus 66 percent) were significantly higher in patients
who received radiotherapy than in those who did not.
●In another study of 169 patients with extrathyroidal extension who were
free of disease after thyroidectomy, radioiodine, and thyroxine therapy, there
were significantly fewer local and regional recurrences in patients who had
received EBRT (7 versus 21 patients) [17].
●In a retrospective study of 88 patients with T4a disease treated with
radioiodine with or without EBRT, locoregional control was worse with
radioiodine alone compared with radioiodine and EBRT (five-year disease-free
survival 43 versus 57 percent) [20]. In patients with only recurrent laryngeal
nerve invasion, radioiodine alone appeared to give good disease control.
However, radioiodine alone was insufficient if there was widespread
multifocal, extrathyroidal extension, tracheal perichondrium, or esophageal
muscularis involvement. These patients appeared to benefit from EBRT.
While the results of these studies are generally favorable, the absence of a
randomized control group makes it difficult to conclude that there is a definite
benefit from EBRT. This approach may be offered to patients with resected disease
and with high-risk features on postoperative pathology (eg, widespread/multifocal
extrathyroidal extension, tracheal perichondrium, or esophageal muscularis
involvement). The decision to pursue EBRT must not be made lightly, as EBRT can
have lasting late toxicity, including feeding tube dependence and xerostomia. In
one retrospective report, 5 percent of patients were dependent on feeding tubes
because of significant late toxicity following EBRT [9]; feeding tube dependence
was not reported in other studies [7,17]. The risk of potential late toxicity must be
weighed against the risk of unresectable recurrent disease. (See 'Adverse
effects' below.)
Palliative — For patients with locally advanced unresectable disease, when
radioiodine fails to control local growth and spread of disease, we suggest EBRT
for palliation. EBRT can be given alone or in combination with chemotherapy. The
role of chemotherapy for such patients is reviewed separately. (See "Differentiated
thyroid cancer refractory to standard treatment: Systemic therapy", section on
'Patient selection for systemic therapy'.)
Distant disease — EBRT may be useful for patients with differentiated thyroid
cancer who have progressive or symptomatic metastatic disease (soft tissue, bone,
or central nervous system [CNS]) that is refractory to radioiodine and not
amenable to surgery [21]. The role of chemotherapy for such patients is reviewed
separately. (See "Differentiated thyroid cancer refractory to standard treatment:
Systemic therapy", section on 'Patient selection for systemic therapy'.)

43
For patients with symptomatic and/or progressive unresectable lung metastases
not amenable to radioiodine, we suggest EBRT. This may be stereotactic body
radiotherapy (SBRT), if appropriate. For patients with asymptomatic indolent soft
tissue metastases, monitoring without therapy may be acceptable. Stereotactic
radiotherapy approaches, as opposed to EBRT, are preferred for unresectable CNS
oligometastases. (See "Radiation therapy techniques in cancer treatment", section
on 'Stereotactic radiation therapy techniques' and "Stereotactic cranial
radiosurgery".)
We suggest EBRT (or SBRT for vertebral metastases) for patients with unresectable
bone metastases or multiple bone metastases that are refractory to radioiodine
therapy. All patients with painful bone metastases should be referred for
EBRT/SBRT to aid pain control. EBRT is also used to control asymptomatic bone
metastases if they are in weightbearing sites. Although many patients now receive
a single dose of EBRT for palliation of a painful bone metastasis, we prefer multiple
fractions because of the frequent association of a soft tissue mass and the fact that
survival in these patients is often prolonged. For patients with multiple bone
metastases or a very limited life expectance (less than three months), single-
fraction EBRT is appropriate (image 1). (See "Radiation therapy for the
management of painful bone metastases", section on 'Single-dose versus
fractionated treatment' and "Radiation therapy for the management of painful
bone metastases", section on 'Stereotactic radiation therapy'.)
Radioiodine is often less effective in patients with bone metastases. As an
example, in one report of 214 patients with distant metastases, the metastases
took up radioiodine in 60 percent of those with bone involvement, but only 3
percent of these patients achieved complete remission after radioiodine therapy
[22]. Given these disappointing results of radioiodine therapy in patients with bone
metastases, an aggressive surgical approach has been recommended [23].
However, not all bone metastases are amenable to surgical resection. Therefore,
EBRT or SBRT (for vertebral metastasis) is usually administered to patients with
solitary or oligometastatic, iodine-refractory, unresectable bone metastases.
Patients with bone metastases should also be considered for treatment with an
osteoclast inhibitor to reduce the rate of skeletal-related events (including
fracture). This subject is addressed elsewhere. (See "Osteoclast inhibitors for
patients with bone metastases from breast, prostate, and other solid tumors".)
Guidelines from expert groups — Guidelines from several groups are variable in
their recommendations regarding the role of EBRT in differentiated thyroid cancer:
●The 2015 guidelines from the American Thyroid Association (ATA)
recommend EBRT (in combination with surgery and radioiodine) for patients
with aerodigestive invasive disease [24]. They recommend against routine

44
 adjuvant EBRT in patients who have had initial complete surgical resection.
However, the use of EBRT in this latter setting is controversial. Selective use
of EBRT may be considered in patients with initial complete surgical resection
who have locally advanced disease and in patients >60 years with
extrathyroidal extension. It is unknown whether EBRT reduces the risk of
recurrence in patients with aggressive histologic subtypes who have
adequate initial surgery and/or radioiodine.
EBRT may also be considered in patients undergoing multiple and frequent
neck reoperations for palliation of locoregional recurrent disease.
●The National Comprehensive Cancer Network (NCCN) recommends
consideration of EBRT for patients with gross or recurrent locoregional or
distant metastatic disease that is not amenable to radioiodine (ie, radioiodine
imaging shows inadequate uptake) [21].
●A 2015 statement from the American Head and Neck Society recommends
EBRT for patients with gross residual or unresectable locoregional disease,
except for patients <45 years with limited gross disease that is radioiodine
avid [25]. Adjuvant EBRT may be considered in selected patients >45 years old
with high likelihood of microscopic residual disease and low likelihood of
responding to radioiodine. This statement preceded the release of the
American Joint Committee on Cancer (AJCC) eighth edition (table 1) that uses
55 years as the cutoff age for poor prognosis, and 55 years may be a more
appropriate age cut-off.
●In updated 2014 guidelines from the British Thyroid Association, the
indications for primary management with EBRT are rare and fall into the
palliative setting where a specific symptom is to be addressed with no intent
to cure [26]. Adjuvant EBRT is recommended for patients with a high risk of
recurrence/progression who have gross evidence of local tumor invasion at
surgery with significant macroscopic residual disease, or residual or
recurrent tumor that fails to concentrate radioiodine (ie, locoregional disease
where further surgery or radioiodine is ineffective or impractical).
●Guidelines from the European Society of Medical Oncology (ESMO) state that
EBRT may be indicated when complete surgical excision is not
possible or when there is no significant radioiodine uptake in the tumor [27].
RADIATION PROTOCOLFor patients with well-differentiated thyroid cancer,
we usually treat the thyroid bed alone (from the hyoid to just below the
suprasternal notch), rather than treating the whole nodal chain, as this reduces
the risk of toxicity. The clinical target volume is defined to cover thyroid bed,
jugular, and posterior cervical lymph nodes within the limits defined above,
including level III, IV, VI, and partially level V nodal regions (figure 1), and this
45
volume is adjusted according to the surgical and pathology findings. Although
some groups give more extensive nodal irradiation, we typically only treat the
whole cervical and upper mediastinal lymph node chain in differentiated thyroid
cancer that persists after neck dissection and radioiodine therapy or has extensive
nodal extracapsular extension.

Typically, we prescribe 66 Gy in 33 fractions to the site of gross residual disease or

area of high concern for microscopic residual disease, ie, the tracheoesophageal
groove, concurrently with 56 Gy in 33 fractions to the rest of the clinical target
volume.

External beam radiotherapy (EBRT) should ideally be delivered using advanced

techniques such as intensity-modulated radiotherapy (IMRT). IMRT should be the
standard for care for treating cancers of the head and neck, including the thyroid
[1,9,10,28]. IMRT allows for more precise delivery of EBRT, sparing more normal
tissue and potentially reducing acute and late toxicity (image 2). These advantages
are due to the fact that IMRT utilizes variable, computer-controlled intensities
within each radiation therapy beam. This allows the volume of tissue receiving full-
dose radiation to more closely conform to the shape of the region that is intended
to be treated than can be achieved using uniform doses that are delivered with
conventionally planned two-dimensional EBRT or three-dimensional conformal
radiation therapy (3D-CRT) techniques. The advantages of IMRT are particularly
evident when the target volumes have complex shapes, concave regions, or are
adjacent to many critical normal structures. (See "Radiation therapy techniques in
cancer treatment", section on 'Intensity-modulated radiation therapy'.)
The benefits of IMRT were shown in a series from MD Anderson in which IMRT was
associated with less frequent late morbidity (eg, esophageal stricture, chronic
dysphagia, laryngeal edema) than conventionally planned two-dimensional EBRT
[10].
ADVERSE EFFECTSExternal beam radiotherapy (EBRT) is associated with acute
and long-term adverse effects. Minimizing the dose and volume of tissue exposed
reduces adverse effects but must not compromise disease control [1,11,29].

Acute toxicity occurs during radiotherapy and may include the following:

●Moderate skin erythema

●Dry desquamation and, rarely, moist desquamation
●Mucositis of the esophagus, trachea, and larynx, which may require a soft
diet, analgesics, and possibly enteral feeding, may develop towards the end

46
 of radiation therapy; this will subside within two to four weeks after the end
of treatment
●Dysphagia
Well-planned radiotherapy treatment regimens rarely have serious long-term
complications. The most common manifestations of late toxicity are skin
telangiectasias and skin pigmentation. The development of esophageal stenosis is
rare, and tracheal stenosis is extremely rare. Dry mouth, esophageal stricture
requiring dilation, and chronic dysphagia requiring a feeding tube have been
reported [10]. A survey of 34 patients treated for advanced thyroid cancer showed
that compared with thyroidectomy or thyroidectomy with postoperative
radioiodine, there were significant decreases in chewing, swallowing, and appetite
and significant increases in pain in patients who received EBRT [30].

Long-term toxicity to normal tissues depends in part upon the size of each
treatment fraction as well as the total radiation dose. Late effects can be
minimized by delivering the lowest effective dose to the smallest area. Decreasing
the size of each radiation fraction should permit higher total doses without
increasing late morbidity.

While EBRT does not preclude future surgical intervention if required, surgery may
be more challenging, and many surgeons are uncomfortable operating on a
previously irradiated site.

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
●Surgical resection is the primary treatment of patients with differentiated
thyroid cancer, followed by radioiodine, and then thyroxine therapy. External
beam radiotherapy (EBRT) is used infrequently in the management of
differentiated thyroid cancer. (See 'Introduction' above and "Differentiated
thyroid cancer: Overview of management".)
●EBRT is indicated for palliation in patients with differentiated thyroid cancer
who have unresectable locally advanced or symptomatic metastatic disease
that is refractory to radioiodine. (See 'Indications for EBRT' above
and 'Palliative' above and 'Distant disease' above.)
●For patients who have inoperable macroscopic residual disease after
thyroidectomy, with absent or inadequate radioiodine avidity, we suggest

47
EBRT to the thyroid bed and known sites of disease (Grade 2C).
(See 'Macroscopic' above.)
Some thyroid cancer experts also administer EBRT to patients with
unresectable disease in the neck despite radioiodine uptake, if the degree of
iodine uptake compared with the size of the residual disease suggests that
the radioiodine alone will be insufficient to control disease.
●For patients age 55 years or older with microscopically positive resection
margins and non-radioiodine-avid disease who are not candidates for
reoperation, we suggest EBRT (Grade 2C). (See 'Microscopic residual and
completely resected high-risk disease' above.)
●For older patients (age 55 years or older) who have T4 disease (table 1) at
the time of surgery, we suggest EBRT (Grade 2C). Similarly, for younger
patients with poor histologic features and either resected T4b or extensive
T4a disease (table 1), we suggest EBRT (Grade 2C), as these patients have a
high likelihood of having residual non-radioiodine avid disease. Poor
histologic features include insular or poorly differentiated histology.
(See 'Microscopic residual and completely resected high-risk disease' above.)
●For patients with local or regional recurrence, when feasible, repeat surgery
and, if the tumor is iodine avid, additional radioiodine is the preferred
approach. However, patients with multiple recurrences in the thyroid bed or
cervical nodes, especially if the interval between recurrences is short, may
achieve control with EBRT. The risk of multiple operations versus the risks of
EBRT should be reviewed for each such patient. (See 'Indications for
EBRT' above.)
When it is indicated, EBRT to the neck should ideally be delivered using
advanced techniques such as intensity-modulated radiation therapy (IMRT).
(See 'Radiation protocol' above.)
●For patients with symptomatic and/or progressive unresectable lung
metastases not amenable to radioiodine, EBRT is used for palliation. For
patients with asymptomatic indolent soft tissue metastases, monitoring
without therapy may be acceptable. Stereotactic radiosurgery is preferred
over EBRT for unresectable central nervous system (CNS) metastases.
(See 'Distant disease' above.)
●Patients with unresectable, painful bone metastases or multiple bone
metastases that are refractory to radioiodine therapy should be referred for
EBRT or SBRT to aid pain control. EBRT is also used to control asymptomatic
bone metastases if they are in weightbearing sites. Patients with bone
metastases should also be considered for osteoclast inhibitor therapy to

48
reduce the frequency of skeletal-related events, including fracture.
(See 'Distant disease' above.)
●EBRT is associated with acute (skin erythema, mucositis, dysphagia) and
long-term (skin pigmentation, dry mouth, esophageal stricture) adverse
effects. Minimizing the dose and volume of tissue exposed reduces adverse
effects but must not compromise disease control. (See 'Adverse
effects' above.)

49
Differentiated thyroid cancer: Overview of
management
Author:
R Michael Tuttle, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jul 15, 2021.
INTRODUCTIONSurgery is the primary mode of therapy for patients with
differentiated thyroid cancer, followed by radioiodine therapy (when indicated)
and thyroid hormone suppression therapy. After initial surgery, patients with
thyroid cancer are typically managed by endocrinologists specializing in the
treatment of thyroid cancer.

This topic will provide a broad overview of the therapeutic options for patients with
differentiated thyroid cancer. The specific therapies for differentiated thyroid
cancer are reviewed in detail separately.

●(See "Differentiated thyroid cancer: Surgical treatment".)

●(See "Differentiated thyroid cancer: Radioiodine treatment".)
●(See "Differentiated thyroid cancer refractory to standard treatment:
Systemic therapy".)
●(See "Differentiated thyroid cancer: External beam radiotherapy".)
●(See "Overview of thyroid disease and pregnancy", section on 'Thyroid
cancer'.)
CLASSIFICATIONThyroid follicular epithelial-derived cancers are divided into
three categories:
●Papillary cancer – 85 percent
●Follicular cancer – 12 percent
●Anaplastic (undifferentiated) cancer – <3 percent
Papillary and follicular cancers are considered differentiated cancers, and patients
with these tumors are often treated similarly, despite numerous biologic
differences. Most anaplastic (undifferentiated) cancers appear to arise from
differentiated cancers. The treatment of anaplastic thyroid cancer is reviewed
separately. (See "Anaplastic thyroid cancer".)
50
Other malignant diseases of the thyroid include medullary thyroid cancer (MTC)
(which can be familial, either as part of the multiple endocrine neoplasia type 2
[MEN2] syndrome or isolated familial MTC) and primary thyroid lymphoma.
Cancers that metastasize to the thyroid include breast, colon, renal cancer, and
melanoma. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and
staging".)
GUIDELINESThe American Thyroid Association (ATA) published evidence-based
guidelines in 2015 for the staging and management of differentiated thyroid
cancer [1]. In addition, guidelines have been published by the National
Comprehensive Cancer Network (NCCN) [2] and a European consensus group [3].
Our approach below is largely consistent with the ATA and NCCN guidelines [1,2].
SURGICAL MANAGEMENTSurgery is the primary mode of therapy for
patients with differentiated thyroid cancer. Preoperative ultrasound is important
for planning the surgical procedure. In the absence of prospective trials,
conclusions regarding the optimal surgical approach are based upon retrospective
analyses and expert consensus opinions [1,3-7].

After initial surgery, patients with thyroid cancer are typically managed by
endocrinologists specializing in the treatment of thyroid cancer.

Preoperative imaging — All patients should have a preoperative ultrasound

evaluation of the central and lateral neck lymph nodes in order to plan the surgical
procedure. Additional imaging beyond routine preoperative neck ultrasound
should be obtained in patients presenting with locally advanced disease. The role
of preoperative imaging in determining the surgical approach is reviewed
separately. (See "Differentiated thyroid cancer: Surgical treatment", section on
'Importance of preoperative imaging'.)
Choice of surgical procedure — Surgery is the primary mode of therapy for
patients with differentiated thyroid cancer. Surgery should be performed by an
experienced thyroid surgeon to minimize the risk of hypoparathyroidism and
recurrent laryngeal nerve (RLN) injury. In one study, complications were lower
when surgery was performed by surgeons performing at least 25 thyroidectomies
per year [8].
The operative approach depends upon the extent of the disease (eg, primary
tumor size and the presence of extrathyroidal extension or lymph node
metastases), the patient's age, and the presence of comorbid conditions. The
choice of procedure is discussed briefly below and in more detail elsewhere.
(See "Differentiated thyroid cancer: Surgical treatment", section on 'Choice of
procedure'.)

51
●Tumor <1 cm without extrathyroidal extension and no lymph nodes –
When surgery is planned for unilateral intrathyroidal differentiated thyroid
cancer <1 cm, a thyroid lobectomy is preferred unless there are clear
indications to remove the contralateral lobe (eg, clinically evident thyroid
cancer in the contralateral lobe, previous history of head and neck radiation,
strong family history of thyroid cancer, or imaging abnormalities that will
make follow-up difficult).
●Tumor 1 to 4 cm without extrathyroidal extension and no lymph nodes –
For intrathyroidal tumors between 1 and 4 cm, the initial surgical procedure
can either be a total thyroidectomy or thyroid lobectomy. Total
thyroidectomy would be chosen either based on patient preference, the
presence of ultrasonographic abnormalities in the contralateral lobe
(nodules, thyroiditis in the contralateral lobe, or nonspecific
lymphadenopathy that will make follow-up difficult), or on a decision by the
treatment team that radioiodine therapy may be beneficial either as adjuvant
therapy or to facilitate follow-up.
●Tumor ≥4 cm, extrathyroidal extension, or metastases – Total
thyroidectomy is recommended if the primary tumor is 4 cm in diameter or
greater, there is extrathyroidal extension of tumor, or there are metastases
to lymph nodes or distant sites.
●Any tumor size and history of childhood head and neck radiation – Total
thyroidectomy should also be performed in all patients with thyroid cancer
who have a history of exposure to ionizing radiation of the head and neck,
given the high rate of tumor recurrence with lesser operations in these
patients [9]. (See "Radiation-induced thyroid disease".)
●Multifocal papillary microcarcinoma (fewer than five foci) – Unilateral
lobectomy and isthmusectomy is an appropriate procedure for patients
whose pathology reports subsequently show multifocal papillary
microcarcinomas with fewer than five foci.
●Multifocal papillary microcarcinoma (more than five foci) – When
multifocal papillary cancer is appreciated preoperatively, particularly when a
large number of microcarcinoma are suspected (eg, greater than five foci,
especially if the foci are in the 8 to 9 mm size range), we are more likely to
perform a total thyroidectomy.
For patients whose initial procedure was a lobectomy and in whom pathology
shows multifocal papillary microcarcinomas with more than five foci,
especially if the foci are in the 8 to 9 mm range, we typically refer patients for
completion thyroidectomy.

52
The approach to lymph node dissection is reviewed separately. (See "Differentiated
thyroid cancer: Surgical treatment", section on 'Approach to lymph node
dissection' and "Neck dissection for differentiated thyroid cancer".)
Postoperative complications — The management of potential metabolic (eg,
hypoparathyroidism) and anatomic (eg, laryngeal nerve damage) postsurgical
complications is reviewed separately. (See "Differentiated thyroid cancer: Surgical
treatment", section on 'Complications'.)
Postoperative thyroid hormone — After thyroid surgery, all patients (except
selected low-risk patients undergoing lobectomy) require postoperative thyroid
hormone therapy (T4 [levothyroxine]) to replace normal hormone production
and/or to suppress regrowth of tumor.
●Lobectomy – For low-risk patients whose initial surgery was a lobectomy,
we do not begin thyroid hormone (T4) immediately postoperatively (unless
the patient has Hashimoto's thyroiditis and the preoperative thyroid-
stimulating hormone [TSH] was high normal) [10]. Instead, we measure
serum TSH six weeks after surgery and determine the need for T4 based
upon the TSH and evaluation of postoperative disease status.
●Total thyroidectomy – For patients whose initial surgery was total
thyroidectomy, the initial dose and type of thyroid hormone (T4 or T3
[liothyronine]) depend upon the likelihood of needing radioiodine
scanning/ablation and the method of preparation for radioiodine scanning.
These decisions are based upon the estimated risk of persistent/recurrent
disease. In the immediate postoperative period, complete clinicopathologic
findings may be unavailable to fully estimate these risks, and the clinician
may need to modify dosing four to six weeks postoperatively. (See 'Initial risk
stratification' below.)
T4 (usually 1.6 to 2 mcg/kg per day) can be started immediately
postoperatively in the following patients:
•American Thyroid Association (ATA) low- and intermediate-risk patients
(table 1) who are unlikely to need radioiodine scanning or ablation.
(See "Differentiated thyroid cancer: Radioiodine treatment", section on
'Indications'.)
•Selected ATA intermediate- and high-risk patients (table 1) in whom
radioiodine scanning and ablation will be done using recombinant human
TSH (rhTSH [thyrotropin alfa]). (See "Differentiated thyroid cancer:
Radioiodine treatment", section on 'Choice of method for increasing TSH'.)
The higher doses are used in selected intermediate- and high-risk patients,
modified by age and other comorbid conditions. TSH is measured four to six
weeks postoperatively, and the dose is adjusted as needed to achieve goal

53
 TSH. The initial TSH goal is based upon the risk of recurrence as determined
by clinicopathologic findings and postoperative thyroglobulin (Tg).
(See 'Thyroid hormone suppression' below.)
The long-term TSH goals depend upon structural and biochemical response
to initial therapy, which is determined by ongoing assessment and risk
stratification. (See 'Dynamic risk stratification' below.)
•For patients in whom radioiodine scanning and ablation will be done
using thyroid hormone withdrawal (typically ATA high-risk patients), short-
term thyroid hormone replacement can be initiated postoperatively with
T3, 25 mcg two to three times daily. After two to three weeks, T3 is
discontinued and imaging is performed once the patient's serum TSH
concentration is above 25 to 30 mU/L.
Another alternative is simply to withhold any thyroid hormone therapy
until the patient's serum TSH concentration is above 30 mU/L. These
options are reviewed in detail separately. (See "Differentiated thyroid
cancer: Radioiodine treatment", section on 'Choice of method for
increasing TSH'.)
INITIAL RISK STRATIFICATIONAfter surgery, the presence or absence of
persistent disease and risk for recurrent disease should be assessed in order to
determine the need for additional treatment, in particular radioiodine therapy.
Postoperative evaluation — We typically obtain a serum TSH and a
nonstimulated serum thyroglobulin (Tg) approximately four to six weeks after
thyroidectomy or lobectomy in order to better define the postoperative disease
status.
While we agree with the American Thyroid Association (ATA) guidelines that the
optimal cutoff value for either a stimulated or nonstimulated postoperative Tg four
to six weeks after surgery is not clearly established [1], we expect nonstimulated
Tg values of:
●<5 ng/mL after a total thyroidectomy
●<30 ng/mL after thyroid lobectomy

Serum Tg values above these cutoffs should prompt reevaluation of the

completeness of the initial surgery (usually with neck ultrasonography) and
consideration of the possibility of persistent metastatic disease.

Diagnostic (pre-radioiodine treatment) whole-body scans for localization of

persistent disease before remnant ablation, adjuvant radioiodine therapy, or
radioiodine treatment of metastatic thyroid cancer are performed less often. They
can be performed when the extent of residual disease cannot be determined from
surgery and neck ultrasonography and when the presence of residual disease may
54
alter the decision to treat with radioiodine or the administered activity [1].
However, because almost all patients have thyroid remnants, our approach is to
omit the pre-radioiodine treatment diagnostic scan, administer empiric
therapeutic doses of iodine-131 (131-I) therapy (based upon surgical and
ultrasonography findings), and obtain only a post-radioiodine treatment scan for
localization of uptake. (See 'Radioiodine therapy' below and "Differentiated thyroid
cancer: Radioiodine treatment", section on 'Pretreatment scanning'.)
Risk classification — The clinicopathologic features of each case are important for
providing prognostic information. Since the tumor, node, metastases (TNM)
staging system is designed to stratify risk based upon disease-specific mortality
and may not accurately predict the risk of recurrence/persistent disease in thyroid
cancer, we use TNM staging (table 2) to estimate mortality and the ATA risk
stratification system to estimate the risk of recurrence (table 1).
Staging is reviewed briefly below and in more detail separately.
(See "Differentiated thyroid cancer: Clinicopathologic staging".)
●TNM staging system – Formal disease staging is based upon applying the
individual TNM descriptors in the American Joint Commission on Cancer
(AJCC) staging scheme (table 2). (See "Differentiated thyroid cancer:
Clinicopathologic staging", section on 'TNM system'.)
●ATA risk stratification system – We use the ATA initial risk stratification
system to estimate the risk of persistent/recurrent disease. This system is
designed to stratify patients as having either low (papillary thyroid cancer
confined to thyroid), intermediate (regional metastases, worrisome
histologies, extrathyroidal extension, or vascular invasion), or high (gross
extrathyroidal extension, distant metastases, or postoperative serum Tg
suggestive of distant metastases) risk of recurrence, primarily based upon
clinicopathologic findings (table 1) [1]. The risk of recurrence, however,
follows a continuum across the three discrete risk categories (low,
intermediate, and high). Additional prognostic variables (eg, extent of lymph
node involvement, degree of vascular invasion in follicular thyroid cancer)
were included in a modified version of the risk stratification system, although
the additional variables have not been rigorously evaluated. This topic is
reviewed in more detail elsewhere. (See "Differentiated thyroid cancer:
Clinicopathologic staging", section on 'ATA risk stratification'.)
Serum-specific molecular profiles (eg, BRAF, TERT) may be used to predict risk
of extrathyroidal extension, lymph node metastases, and even distant
metastases. While these observations need further validation, it is likely that
the specific molecular profile of the primary tumor may have significant
prognostic value that could be incorporated into the stratification systems.

55
 (See "Differentiated thyroid cancer: Clinicopathologic staging", section on
'Molecular characteristics'.)
While initial risk stratification can be used to guide initial therapeutic and
diagnostic follow-up strategy decisions, it is important to recognize that initial
risk estimates may need to change as new data are accumulated during
follow-up. (See 'Dynamic risk stratification' below.)
SUBSEQUENT MANAGEMENT BASED ON RISK
CLASSIFICATIONPostoperative management includes treatment with thyroid
hormone suppressive therapy (most patients) and radioiodine (high-risk and
selected intermediate-risk patients). Postoperative management depends upon
the risk of recurrence/persistent disease (table 1). (See 'Risk classification' above.)
Thyroid hormone suppression — After initial thyroidectomy, whether or not
radioiodine therapy is administered, thyroid hormone (T4 [levothyroxine]) therapy
is required in most patients to prevent hypothyroidism and to minimize potential
TSH stimulation of tumor growth.
Our approach for initial thyroid hormone suppression is based upon risk of disease
recurrence (table 1):
●American Thyroid Association (ATA) low risk – For patients with low-risk
disease treated with thyroidectomy who have detectable serum thyroglobulin
(Tg) levels (with or without remnant ablation), the serum TSH initially can be
maintained between 0.1 and 0.5 mU/L. For similar patients who have
undetectable serum Tg levels (with or without remnant ablation) or who were
treated with lobectomy, TSH can be maintained in the mid to lower half of the
reference range (0.5 to 2.0 mU/L). In the latter setting, thyroid hormone
treatment may be unnecessary if a patient can maintain their TSH in this
range.
●ATA intermediate risk – For patients with intermediate-risk disease, the
serum TSH initially can be maintained between 0.1 and 0.5 mU/L.
●ATA intermediate or high risk – For patients with high-risk disease, the
serum TSH initially should be less than 0.1 mU/L.
TSH goals for long-term follow-up are based on response to therapy assessments
further modified by comorbid conditions that increase the potential risks of
prolonged TSH suppression (such as menopause, tachycardia, osteopenia, older
age, osteoporosis, or atrial fibrillation) (figure 1) [1]. The dose also may be
decreased to allow the TSH to rise into the normal range in intermediate-risk
patients who demonstrate an excellent response to therapy. (See 'Monitoring
response to therapy' below.)
The hypothesis that reduction of serum TSH concentrations to below the normal
range decreases morbidity and mortality in all patients with differentiated thyroid
56
cancer has not been proven, but at least one study suggested improved relapse-
free survival when serum TSH concentrations were undetectable during follow-up
[11]. In another report from a multicenter prospective tumor registry, greater TSH
suppression was associated with improved progression-free survival in high-risk
papillary cancer patients [12]. The follow-up report from that registry indicated
that lowering TSH levels aggressively was associated with improved overall
survival in high-risk differentiated cancer patients, whereas milder degrees of TSH
suppression were still associated with excellent outcomes in patients with
intermediate-risk features, eg, less than 45 years of age at diagnosis with primary
tumors greater than 4 cm or gross extrathyroidal invasion and in patients older
than 45 years at diagnosis with primary tumor sizes between 1 and 4 cm,
multifocal disease, or microscopic extrathyroidal invasion [13].
On the other hand, in a randomized trial of suppressive versus replacement
therapy in 433 Japanese patients with papillary thyroid cancer [14], with achieved
mean TSH levels of 0.07 and 3.19 mU/L, respectively, disease-free five-year
survival, recurrence rates, and sites of recurrence were not significantly different
between the two groups. However, these data might not be generalizable, since
the majority of the participants had lobectomies and prophylactic central neck
dissections and some had prophylactic lateral neck dissections, forms of surgery
generally not done in most Western countries.
These findings, combined with the risks of overly aggressive T4 therapy, including
the potential for acceleration of bone loss [15-17], atrial fibrillation [18], and
cardiac dysfunction [19-21], emphasize the importance of tailoring the T4 dose to
the extent of the disease and the likelihood of recurrence [22]. These decisions can
be based in part upon staging by the tumor, node, metastases (TNM) system (table
2) in conjunction with the proposed ATA risk of recurrence system (table 1) [1].
(See 'Risk classification' above and "Differentiated thyroid cancer: Clinicopathologic
staging".)
Radioiodine therapy — Radioiodine is administered after thyroidectomy in
patients with differentiated thyroid cancer to ablate residual normal thyroid tissue
(remnant ablation), provide adjuvant therapy of subclinical micrometastatic
disease, and/or provide treatment of clinically apparent residual or metastatic
thyroid cancer. (See "Differentiated thyroid cancer: Radioiodine treatment", section
on 'Goals'.)
The decision to treat with radioiodine depends upon the risk of
recurrence/persistent disease (table 1). (See "Differentiated thyroid cancer:
Radioiodine treatment", section on 'Indications'.)

57
We routinely administer radioiodine after total thyroidectomy in high-risk patients
and in selected intermediate-risk patients, depending upon specific tumor
characteristics (eg, clinically significant lymph node metastases outside of the
thyroid bed, or other higher-risk features).

●ATA low-risk disease – In the absence of a proven benefit on either disease-

free survival or recurrence, we do not routinely administer radioiodine for
remnant ablation to patients with low-risk disease, especially patients with
unifocal tumors <1 cm without other high-risk features or multifocal cancer
when all foci are <1 cm in the absence of other high-risk features, even in the
presence of small-volume regional lymph node metastases (less than five
lymph nodes measuring less than 2 mm).
●ATA intermediate-risk disease – We suggest postoperative radioiodine
ablation to selected intermediate-risk patients, including those with clinically
significant lymph node metastases outside of the thyroid bed; vascular
invasion; or more aggressive histologic subtypes such as tall cell, columnar
cell, insular, or poorly differentiated histologies.
●ATA high-risk disease – We recommend postoperative radioiodine ablation
to patients with high-risk disease, including patients with distant metastases,
macroscopic tumor invasion, and/or incomplete tumor resection with gross
residual disease.
The data to support these recommendations, patient preparation, dosing,
monitoring, and complications of radioiodine treatment are reviewed in detail
separately. (See "Differentiated thyroid cancer: Radioiodine treatment".)
Role of adjuvant external beam radiation therapy — External beam
radiotherapy (EBRT) can be used as adjuvant therapy after macroscopically
complete surgical excision to prevent recurrence, particularly for older patients
with gross extrathyroid extension at the time of surgery or selected younger
patients with extensive disease and poor histologic features (eg, insular or poorly
differentiated histology) whose disease is resected but in whom there is a high
likelihood of residual microscopic disease. This topic is reviewed in detail
separately. (See "Differentiated thyroid cancer: External beam radiotherapy".)
MONITORING RESPONSE TO THERAPYMonitoring strategies are based
upon the patient's American Thyroid Association (ATA) risk of recurrence (table 1)
and the reassessment of response to therapy at each follow-up visit. This strategy
is in keeping with the ATA guidelines for the management of patients with thyroid
nodules and differentiated thyroid cancer [1].
Dynamic risk stratification — While initial staging systems can be used to guide
initial therapeutic and diagnostic follow-up strategy decisions, it is important to

58
recognize that initial risk estimates may need to change as new data are
accumulated during follow-up [23]. In our practice, we restratify patients on each
follow-up visit using a reclassification system that emphasizes the response to
therapy for each individual patient. The response to therapy is assessed primarily
with ultrasonography and measurements of serum thyroglobulin (Tg). (See 'Initial
monitoring during year 1' below.)
As originally conceived, these clinical outcomes described the best response to
initial therapy during the first two years of follow-up [23,24], but are now being
used to describe the clinical status at any point during follow-up.
(See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'Dynamic
risk stratification'.)
At each follow-up visit, patients are classified as having one of the following clinical
outcomes (table 3) [24,25]:
●Excellent response – No clinical, biochemical, or structural evidence of
disease.
●Biochemical incomplete response – Abnormal Tg or rising Tg antibody
values in the absence of localizable disease.
●Structural incomplete response – Persistent or newly identified
locoregional or distant metastases.
●Indeterminate response – Nonspecific biochemical or structural findings
that cannot be confidently classified as either benign or malignant. This
includes patients with stable or declining antithyroglobulin (anti-Tg) antibody
levels without definitive structural evidence of disease.
The precise definition of type of response is dependent on the extent of initial
therapy (table 3).
Reclassification at each follow-up visit allows clinician to tailor ongoing
management recommendations to the current clinical status (rather than the
initial risk stratification estimates) (table 4 and table 5). (See "Differentiated thyroid
cancer: Clinicopathologic staging", section on 'Dynamic risk stratification'.)
Initial monitoring during year 1 — For the detection of possible
persistent/recurrent disease during the first year after thyroidectomy or
lobectomy, we monitor [1,2,26]:
●Neck ultrasound
●TSH
●Serum Tg levels on thyroid hormone suppression
Serum Tg on thyroid hormone suppression is generally measured every three to
six months for the first year, with ultrasound at 6- to 12-month intervals depending
on initial risk assessment (table 4). (See "Overview of the clinical utility of
ultrasonography in thyroid disease", section on 'Thyroid cancer follow-up'.)

59
Additional imaging (cross-sectional or function imaging [eg, magnetic resonance
imaging (MRI), computed tomography (CT), fludeoxyglucose-positron emission
tomography (FDG-PET)]) is usually reserved only for (table 4) (see 'Imaging' below):
●ATA high-risk patients (table 1) who typically have either a biochemical or
structural incomplete response to therapy
●ATA low/intermediate-risk patients who demonstrate a structural or
biochemical incomplete response to therapy during the first year of follow-up
These patients require further evaluation to identify residual disease, with
consideration for additional therapies. In general, gross residual disease
(structural incomplete response) in cervical lymph nodes identified by physical
examination or ultrasound should be confirmed by fine-needle aspiration (FNA)
and surgical resection considered. (See 'Management of persistent or recurrent
disease' below.)
Diagnostic whole-body radioiodine scanning may still have a role in the follow up
of higher-risk patients. (See 'Diagnostic whole-body scan' below.)
Serum thyroglobulin measurements — Serum Tg levels are used to monitor
patients with differentiated thyroid cancer for persistent or recurrent disease after
initial therapy (lobectomy, thyroidectomy with or without radioiodine ablation)
(table 4). (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section
on 'Clinical application'.)
In the first year after treatment of differentiated thyroid cancer, we measure
thyroid hormone-suppressed serum Tg and Tg antibodies every three to six
months. Serial Tg measurements should be performed using the same assay. Use
of an assay with a functional sensitivity of 0.05 to 0.1 ng/mL is preferable. Anti-Tg
antibodies, present initially in approximately 25 percent of patients with thyroid
cancer, interfere with all assays for Tg. As a result, we measure anti-Tg antibodies,
using the same assay over time, with each measurement of serum Tg. Tg assays
are reviewed in detail elsewhere. (See "Differentiated thyroid cancer: Role of serum
thyroglobulin", section on 'Thyroglobulin assay'.)
Serum Tg can be measured while taking suppressive doses of thyroid hormone
(TSH suppressed) or with TSH stimulation (after thyroid hormone withdrawal or
after administration of recombinant human TSH [rhTSH (thyrotropin alfa)]).
Stimulated Tg measurements are generally not necessary in ATA low-risk patients
who do not receive radioiodine to ablate thyroid remnants, or in ATA
intermediate/high-risk patients who have a detectable Tg on suppression (ie,
evidence of biochemical incomplete response to therapy). Stimulated Tg values are
useful in ATA intermediate- and high-risk patients with an undetectable
suppressed Tg to document an excellent response to therapy or, conversely, to
identify the presence of persistent/recurrent disease [27].

60
In the newer, more sensitive Tg assays (functional sensitivity <0.05 ng/mL), serum
Tg concentrations (measured while receiving T4 [levothyroxine] suppression
therapy) correlate with rhTSH-stimulated Tg concentrations and, therefore, may
decrease the need for rhTSH-stimulated measurements [28-32].
The interpretation of the serum Tg level depends upon the initial therapy (table 3).
Thyroidectomy with 131-I ablation — For patients who had a total thyroidectomy
and radioiodine remnant ablation, an excellent response is a nonstimulated Tg
<0.2 ng/mL (or TSH-stimulated Tg <1 ng/mL) (table 3).
Thyroidectomy without 131-I ablation — For patients who have had total or
near-total thyroidectomy without radioiodine ablation, an excellent response is a
nonstimulated Tg <0.2 ng/mL (or TSH-stimulated Tg <2 ng/mL). The interpretation
of serum Tg levels may be difficult in this subset of patients as it depends upon the
size of the thyroid remnant [33]. Many patients do have undetectable basal Tg
levels (<0.2 ng/mL), and basal serum Tg (along with anti-Tg antibodies) should be
measured in such patients as rising values over time are suspicious for growing
thyroid tissue or cancer (table 3). (See "Differentiated thyroid cancer: Role of serum
thyroglobulin", section on 'Predictor of clinical outcomes'.)
Lobectomy — Periodic measurement of serum Tg should also be performed in
patients who were treated with lobectomy. Although specific criteria for
distinguishing normal residual thyroid tissue from persistent or recurrent thyroid
cancer have not been defined, most patients with an excellent response should
have a serum Tg level <30 ng/mL (table 3) [34,35]. Previously, a rising Tg value over
time was considered to be a reliable marker of recurrent disease. However,
subsequent studies have demonstrated that changes in serum Tg over time are
not reliable indicators of recurrent disease and that rising Tg levels are more likely
to be related to residual thyroid tissue/nodules than to a true structural disease
recurrence [36-38].
Thyroglobulin antibodies — In patients with anti-Tg antibodies, serum Tg
concentrations alone cannot be used as a marker to detect persistent or recurrent
disease after thyroidectomy and ablation of residual normal thyroid tissue.
Nevertheless, we measure serum Tg and anti-Tg antibodies as we do in patients
without anti-Tg antibodies because disease recurrence can be heralded by a rise in
Tg antibodies with or without a corresponding rise in serum Tg, and conversely, a
significant fall in these titers suggests future recurrence is unlikely [39].
(See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on
'Surrogate tumor marker'.)

61
In high-risk patients with persistent positive anti-Tg antibodies, imaging in
addition to neck ultrasound (including neck and chest CT and/or PET-CT) may be
warranted to detect structural disease.

Imaging — Neck ultrasound is performed at 6- to 12-month intervals depending

on risk assessment (table 4). Ultrasonography has been particularly useful at
identifying malignant cervical lymph nodes, the most common site of recurrent
papillary thyroid cancer. Ultrasonographic lymph node characteristics most
consistent with malignancy are a cystic appearance, microcalcifications, loss of the
normal fatty hilum, and peripheral vascularization (image 1) [40]. (See "Overview of
the clinical utility of ultrasonography in thyroid disease", section on 'Thyroid
cancer'.)
If there is biochemical or ultrasound evidence of recurrence, other tests that may
be indicated to identify the sites of disease include a diagnostic whole-body scan
(radioiodine imaging on a low-iodine diet with TSH stimulation), CT or MRI, skeletal
radiographs, or skeletal radionuclide imaging [41]. In patients with evidence of
distant metastases, FDG-PET scanning may provide useful prognostic information
[42]. This was illustrated in a study of 125 patients with well-differentiated thyroid
cancer who underwent FDG-PET scanning; uptake of FDG in a large volume of
tissue correlated with poor survival, predicting outcome better than uptake of
radioiodine.
In most studies, T4 therapy was not withdrawn before FDG-PET scanning was
done, but in one small study, more lesions were identified after therapy was
withdrawn [43]. The use of rhTSH before FDG-PET scan significantly increases the
number of lesions detected, but treatment changes due to true positive lesions are
uncommon (6 percent in one study of 63 patients) [44].
FDG-PET may complement iodine-131 (131-I) scanning [45]. In a study of 239
patients with metastases and high Tg, the sensitivity of FDG-PET was 49 percent,
the sensitivity of 131-I was 50 percent, and the combined sensitivity was 90
percent. FDG-PET was more likely to be positive in 131-I negative patients [46].
Diagnostic whole-body scan — Diagnostic whole-body radioiodine scanning may
have a role in the follow-up of patients with high or intermediate risk (with higher-
risk features) of persistent disease (table 1). However, we are in agreement with
the ATA guidelines that routine follow-up diagnostic whole-body scanning one
year after radioiodine ablation is not required in low- and intermediate-risk (with
lower-risk features) patients (table 4) [1].
Two studies [47,48], but not a third [49], suggested that whole-body scanning is
unnecessary if rhTSH-stimulated serum Tg concentrations are less than 2 ng/mL.
Another study reported that a combination of rhTSH-stimulated Tg and neck

62
ultrasound has a better predictive value than either rhTSH-stimulated Tg alone or
in combination with radioiodine scanning [50].
When diagnostic radioiodine scanning is performed, we suggest using rhTSH
stimulation for radioactive iodine scanning when the likelihood of requiring
additional radioactive iodine therapy is low. If the patient is very likely to need
additional radioiodine therapy (high-risk patients), thyroid hormone withdrawal is
the preferred approach. This topic is reviewed in more detail separately.
(See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Choice of
method for increasing TSH' and "Differentiated thyroid cancer: Radioiodine
treatment", section on 'Pretreatment scanning'.)
Ongoing monitoring after year 1 — Ongoing follow-up (neck ultrasound, serum
Tg) is guided by assessment of the individual patient's response to therapy during
the first one to two years of follow-up (table 5). Most recurrences of differentiated
thyroid cancer occur within the first five years after initial treatment, but
recurrences may occur many years or even decades later, particularly in patients
with papillary cancer [51]. Nonetheless, continued routine use of surveillance neck
ultrasound in ATA low- to intermediate-risk patients with no biochemical or clinical
evidence of disease is more likely to identify false-positive findings than true
structural disease recurrence [52,53].
A serum TSH is measured annually and six to eight weeks after any dose
adjustments of T4. Although the serum TSH should be maintained <0.1 mU/L in
patients with a structurally incomplete response (table 3), patients with a better
response to therapy can have their TSH goal raised [1]. As examples:
●For patients who initially presented with high-risk disease but who have an
excellent or indeterminate clinical response to therapy, a TSH goal of 0.1 to
0.5 mU/L for up to five years is acceptable, after which time the degree of
suppression can be further relaxed (with continued surveillance for
recurrence).
●For patients who initially presented with low-risk disease and who have an
excellent clinical response to therapy, a TSH goal of 0.5 to 2 mU/L is
acceptable.
●For patients with a biochemically incomplete response, the serum TSH
should be maintained between 0.1 and 0.5 mU/L.
MANAGEMENT OF PERSISTENT OR RECURRENT DISEASERecurrent
tumor in the neck may be detected by clinical examination or rising serum
thyroglobulin (Tg) concentrations, but ultrasonography is the most sensitive
technique for localization (image 1) [33,54]. (See 'Imaging' above and "Overview of
the clinical utility of ultrasonography in thyroid disease", section on 'Thyroid cancer
follow-up'.)
63
Highly sensitive detection tools (such neck ultrasonography, computer
tomography [CT] scans, magnetic resonance imaging [MRI], and highly sensitive
serum thyroglobulin assays) can identify very small volume persistent or recurrent
disease that may not demand immediate intervention. Thus, we differentiate
"detectable findings" from "actionable findings" [55]. The key factors that
differentiate detectable from actionable findings include:
●Tumor size (volume)
●Tumor location
●Tumor growth rate (biochemical or structural doubling time)
●Symptoms
●Patient preference
Minimal disease — Although many patients will still have abnormal serum Tg
levels after surgery, indicating a persistence of detectable disease, surgery is not
always indicated.

Surgical resection is typically reserved for patients with clinically significant, low-
volume metastatic disease, eg, central neck lymph nodes at least >0.8 cm in
diameter or, possibly, larger nodes in the lateral compartments (>1.5 to 2 cm),
especially if they are increasing in size (more than 3 to 5 mm in any dimension) or
are significantly fludeoxyglucose-positron emission tomography (FDG-PET) positive
(standardized uptake value [SUV] 5 to 10). However, we recognize that aggressive
surgical resection of small-volume disease in the central or lateral neck does not
have a proven benefit in terms of improving overall survival. Therefore, it is
important to ensure that the risk of persistent low-level disease outweighs the risk
of surgical resection in patients with potentially stable low-volume disease.

Surgery is usually followed by a reevaluation of the clinical status, which always

includes serum Tg determinations, may include radioiodine scanning, and, if there
is persistent radioiodine uptake, radioiodine therapy. However, if the patient had a
recombinant human thyroid-stimulating hormone (rhTSH [thyrotropin alfa])-
stimulated radioiodine scan before such surgery and if gross recurrent disease
failed to concentrate radioiodine before surgery, there is likely no role for
postoperative imaging and radioiodine therapy. Recurrent disease that is FDG avid
(positive on FDG-PET scanning) is unlikely to respond to even high-dose
radioiodine therapy [56]. (See 'High serum thyroglobulin and negative radioiodine
scan' below.)
Extensive disease — Recurrence within the thyroid bed may be associated with
soft-tissue, laryngeal, tracheal, or esophageal invasion, which may require more
extensive resection; imaging studies with contrast-enhanced computed
tomography (CT) or magnetic resonance imaging (MRI) may be valuable to detect
64
such locally extensive disease. (See 'Imaging' above and "Differentiated thyroid
cancer: Surgical treatment", section on 'Surgery for invasive disease'.)
Patients who develop distant metastases during long-term follow-up are treated
like those with metastases found at the time of initial treatment; however,
radioiodine therapy may be less effective in these patients [57]. (See 'Subsequent
management based on risk classification' above.)
Other options for treating recurrent/metastatic disease include the following [58-
61]:
●Radioiodine, if scans demonstrate uptake.
●Systemic chemotherapy (eg, kinase inhibitors).
●External radiotherapy.
●Percutaneous ethanol injection of cervical nodal metastases.
●Radiofrequency ablation of cervical, osseous, and pulmonary metastases –
This is an alternative for patients who are poor surgical candidates and
whose metastases do not concentrate radioiodine, but expertise in this
treatment modality is not widely available.
●Palliative embolization of bone metastases – Palliative embolization may
reduce symptoms or be used prior to surgery.
Surgery may be considered for patients with single distant metastases, including
patients with a single bone metastasis [62], brain metastases [63], or limited
pulmonary metastases [64]. The five-year survival for 31 patients with papillary
cancer after thoracic metastasectomy was 64 percent [64], and radical surgical
extirpation of isolated bone metastases is associated with improved survival [65].
Pamidronate may reduce bone pain from skeletal metastases and improve quality
of life, and in one study, resulted in partial radiologic improvement in 2 of 10
patients [66]. Zoledronic acid can also be used, although its greater potency may
increase risk of hypocalcemia and osteonecrosis of the jaw (ONJ) (although this
remains a rare complication) [67,68]. (See "Risks of therapy with bone
antiresorptive agents in patients with advanced malignancy", section on
'Osteonecrosis of the jaw'.)
Denosumab (a receptor activator of nuclear factor kappa-B [RANK] ligand inhibitor)
is also available for the prevention of skeletal related events (pathologic fracture,
need for surgery or external beam irradiation to a bone metastasis, or spinal cord
compression) in patients with bone metastases from solid tumors. Thus,
denosumab is an alternative to bisphosphonate therapy in the management of
thyroid cancer patients with bone metastases [69]. (See "Osteoclast inhibitors for
patients with bone metastases from breast, prostate, and other solid tumors",
section on 'Denosumab'.)

65
Systemic chemotherapy or palliative external radiotherapy may be considered for
patients with either local or distant recurrence or when radioiodine fails to control
local growth and spread of disease. (See "Differentiated thyroid cancer refractory
to standard treatment: Systemic therapy" and "Differentiated thyroid cancer:
External beam radiotherapy".)
High serum thyroglobulin and negative radioiodine scan — It is not uncommon
to identify patients who have abnormal serum Tg values after total thyroidectomy
and radioiodine ablation with no evidence of radioiodine avidity on diagnostic and,
often, post-therapy radioiodine scans [70,71]. These false-negative scans may
reflect inadequate TSH stimulation, iodine contamination, the presence of tumor
deposits too small to be detected by a scintillation camera, or loss of iodine uptake
through tumor dedifferentiation.
The management of such patients is controversial, and there are insufficient data
to determine optimal therapy [72].

Our approach to patients with radioiodine-negative, serum Tg-positive disease is

as follows:

●Measurement of 24-hour urinary iodine excretion to exclude exogenous

iodine excess causing a false-negative scan.
●Neck ultrasound and neck and chest CT (without iodinated contrast).
●In high-risk patients or those in whom the basal or stimulated Tg is ≥10
ng/mL, additional imaging studies should be performed to include whole-
body FDG-PET scan (preferably combined with CT imaging).
In various studies, ultrasonography [73,74], CT [73], MRI [75], or scintigraphy
with 111-indium-penetreotide, 99m-technetium-sestamibi, or 99m-
technetium-tetrafosmin [76-78] detected foci of cancer in from 25 to 50
percent of patients with negative diagnostic radioiodine scans. Distant
metastases can also be identified by chest and bone radiographs [79]. In
addition, FDG-PET may be useful. In a review of PET imaging in scan-negative
patients that summarized 12 studies, sensitivity ranged from 60 to 95 percent
and specificity from 25 to 90 percent [80]. Metastatic lesions with high avidity
for glucose in PET imaging, measured by elevated standard uptake values,
are associated with resistance to radioiodine therapy and worse prognosis
[56,81].
●We agree with the American Thyroid Association (ATA) guidelines that
radioiodine is usually not necessary in patients with nonstimulated Tg values
<5 ng/mL (or stimulated Tg values less than 10 ng/mL) in the absence of
structurally evident disease. However, we will consider empiric radioiodine
administration (100 to 200 mCi) in patients with radiographically detectable
66
 micrometastatic pulmonary metastases that do not concentrate FDG on PET
imaging or with progressively rising Tg levels. (See "Differentiated thyroid
cancer: Radioiodine treatment".)
●External radiotherapy for patients with critically placed bone metastases.
(See "Differentiated thyroid cancer: External beam radiotherapy".)
●Patients with progressive macrometastatic disease unresponsive to
radioiodine should be considered for systemic therapy or an appropriate
clinical trial.
Studies show 42 to 75 percent of patients with high serum Tg and negative
diagnostic radioiodine scans had demonstrable uptake, most often in the neck and
mediastinum, after administration of a high dose (therapeutic dose) of radioiodine
(eg, 150 mCi [5550 MBq]) [73,82,83]. Distant metastases were more often identified
in patients with higher serum Tg concentrations (>200 ng/mL) [82]. In a study of 27
patients with negative diagnostic scans and positive post-treatment scans, 56
percent had progressive disease that did not respond to radioiodine, while 44
percent had stable disease that did not regress after radioiodine [84].
In some [70,82,83,85], but not all [86], studies, radioiodine administration resulted
in reductions in serum Tg concentrations in patients with high serum Tg and
negative diagnostic radioiodine scans, but there is no evidence that the treatment
affects prognosis. Furthermore, when there is no structural evidence of disease,
observation with T4 (levothyroxine) suppression is often associated with a slow
decline in Tg levels over many years. These observations question whether empiric
radioiodine therapy for scan-negative, Tg-positive patients has any significant
clinical benefit beyond improved disease localization [48,72,87,88].
PROGNOSISMost patients with papillary cancer do not die of their disease.
However, a number of factors have been identified that are associated with a
higher risk for tumor recurrence and cancer-related mortality. The most important
prognostic factors are age at diagnosis, size of the primary tumor, and the
presence of soft tissue invasion or distant metastases (table 2). (See "Papillary
thyroid cancer: Clinical features and prognosis", section on 'Prognostic features'.)
When compared with papillary thyroid cancer, follicular cancer typically occurs in
older patients. In addition, it is more commonly associated with an aggressive
clinical course, distant metastases, and higher mortality than papillary thyroid
cancer. Women may have a better prognosis than men. (See "Follicular thyroid
cancer (including Hürthle cell cancer)", section on 'Prognostic features'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)

67
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Thyroid cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS
●The primary therapy for differentiated (papillary and follicular) thyroid
cancer is surgery. All patients should have a preoperative ultrasound
evaluation of the central and lateral neck lymph nodes in order to plan the
surgical procedure. Additional imaging beyond routine preoperative neck
ultrasound should be obtained in patients presenting with locally advanced
disease. (See 'Preoperative imaging' above and "Differentiated thyroid
cancer: Surgical treatment", section on 'Importance of preoperative
imaging'.)
●Surgical options include total/near-total thyroidectomy and unilateral
lobectomy with isthmusectomy. The operative approach depends upon the
extent of the disease (eg, primary tumor size and the presence of
extrathyroidal extension or lymph node metastases), the patient's age, and
the presence of comorbid conditions. Subtotal thyroidectomy is an
inadequate procedure for patients with thyroid cancer. (See 'Choice of
surgical procedure' above and "Differentiated thyroid cancer: Surgical
treatment", section on 'Choice of procedure'.)
●After thyroid surgery, all patients (except selected low-risk patients
undergoing lobectomy) require postoperative thyroid hormone therapy (T4
[levothyroxine]) to replace normal hormone production and/or to suppress
regrowth of tumor. Thyroid-stimulating hormone (TSH) is measured four to
six weeks postoperatively, and the initial dose is adjusted as needed to
achieve goal TSH. (See 'Postoperative thyroid hormone' above.)

68
●In order to determine the need for additional treatment (in particular,
radioiodine therapy) after surgery, we use the American Thyroid Association
(ATA) initial risk stratification system to estimate the risk of
persistent/recurrent disease. This system is designed to stratify patients as
having either low (papillary thyroid cancer confined to thyroid), intermediate
(regional metastases, worrisome histologies, extrathyroidal extension, or
vascular invasion), or high (gross extrathyroidal extension, distant
metastases, or postoperative serum thyroglobulin [Tg] suggestive of distant
metastases) risk of recurrence primarily based upon clinicopathologic
findings (table 1). (See 'Postoperative evaluation' above.)
●Postoperative management includes treatment with thyroid hormone-
suppressive therapy (most patients) and radioiodine (high-risk and selected
intermediate-risk patients). (See 'Radioiodine therapy' above
and "Differentiated thyroid cancer: Radioiodine treatment", section on
'Indications'.)
The degree of TSH suppression is individualized based upon the extent of the
disease and the likelihood of recurrence (table 1). For most patients with
high-risk disease, we recommend an initial serum TSH goal of <0.1 mU/L
(Grade 1B). For patients with intermediate-risk disease, or low-risk disease
treated with thyroidectomy who have detectable serum Tg levels, we suggest
an initial serum TSH goal between 0.1 and 0.5 mU/L (Grade 2C). For other
low-risk patients who have undetectable serum Tg levels (with or without
remnant ablation) or who were treated with lobectomy, TSH can be
maintained in the mid to lower half of the reference range (0.5 to 2.0 mU/L).
TSH goals for long-term follow-up are based on response to therapy
assessments further modified by comorbid conditions that increase the
potential risks of prolonged TSH suppression (such as menopause,
tachycardia, osteopenia, older age, osteoporosis, or atrial fibrillation) (figure
1). (See 'Thyroid hormone suppression' above.)
●Ongoing monitoring strategies are based upon the patient's ATA risk of
recurrence (table 1) and the reassessment of response to therapy at each
follow-up visit (table 3). (See 'Dynamic risk stratification' above.)
●For the detection of possible persistent/recurrent disease during the first
year after thyroidectomy or lobectomy, we monitor neck ultrasound, TSH,
and serum Tg levels on thyroid hormone suppression. The timing, frequency,
and type of additional testing used to detect recurrent disease is based on
both ATA initial risk stratification and ongoing response to therapy
evaluations (table 4 and table 5). (See 'Initial monitoring during year 1' above
and 'Ongoing monitoring after year 1' above.)

69
●Options for treating recurrent/metastatic disease include surgery,
radioiodine (if scans demonstrate uptake), chemotherapy, and external
radiotherapy. (See 'Management of persistent or recurrent disease' above
and "Differentiated thyroid cancer: External beam
radiotherapy" and "Differentiated thyroid cancer refractory to standard
treatment: Systemic therapy".)

70
Differentiated thyroid cancer: Radioiodine
treatment
Author:
R Michael Tuttle, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jun 24, 2020.
INTRODUCTIONRadioiodine therapy has been used in the management of
patients with well-differentiated (papillary or follicular) thyroid cancer since the
1940s. Thyroid tissue has a unique ability to take up iodine from blood. Like iodine,
radioiodine is taken up and concentrated in thyroid follicular cells because they
have a membrane sodium-iodide transporter [1]. Compared with normal thyroid
follicular cells, thyroid cancer cells have reduced expression of the transporter,
which may account for the low iodine-131 (131-I) uptake in thyroid cancer tissue.

131-I causes acute thyroid cell death by emission of short path-length (1 to 2 mm)
beta particles. The uptake of 131-I by thyroid tissue can be visualized by scanning
to detect the gamma radiation that is also emitted by the isotope. 131-I must be
taken up by thyroid tissue to be effective. As a result, it is of no value in patients
whose thyroid cancers do not concentrate iodide (ie, patients with medullary
cancer, lymphoma, or anaplastic cancer).

Radioiodine therapy for differentiated thyroid cancer will be reviewed here.

Surgery, the primary therapy for differentiated thyroid cancer, and an overview of
the management of thyroid cancer are discussed separately. (See "Differentiated
thyroid cancer: Surgical treatment" and "Differentiated thyroid cancer: Overview of
management".)
GOALSIn an effort to standardize terminology, an intersocietal working group
with representatives from the American Thyroid Association (ATA), the European
Thyroid Association, the European Association of Nuclear Medicine, and the
Society of Nuclear Medicine and Molecular Imaging reached the following
consensus regarding the goals of iodine-131 (131-I) therapy in differentiated
thyroid cancer [2]:

71
 ●Remnant ablation – The primary goal of remnant ablation is destruction of
presumably benign thyroid tissue after total thyroidectomy, to facilitate initial
staging and follow-up studies. This will, in turn:
•Improve the specificity of measurements of serum thyroglobulin (Tg) as a
tumor marker
•Increase the specificity of 131-I scanning for detection of recurrent or
metastatic disease by eliminating uptake by residual normal tissue
●Adjuvant treatment – The primary goal of adjuvant treatment is
destruction of subclinical tumor deposits that may or may not be present
after surgical resection of all known primary tumor tissue and metastatic foci.
Since adjuvant treatment is given based on the risk of having
persistent/recurrent disease without definitive evidence of biochemical or
structural evidence of disease, it is accepted that some patients selected for
adjuvant treatment might already have been treated sufficiently by their
primary surgery. Thus, the decision to recommend adjuvant treatment
requires balancing oncological risk (risk of persistent/recurrent disease and
disease-specific mortality) and the risks associated with adjuvant treatment
(short- and long-term risks of 131-I) with the potential benefit of adjuvant
treatment (potential to decrease recurrence, improve progression-free
survival, and/or improve disease-specific mortality). Thus, in properly selected
patients, the potential benefits of 131-I adjuvant treatment could include:
•Destruction of subclinical, microscopic foci of disease remaining after
surgery
•Decreased risk of recurrence
•Improved disease-specific survival
•Improved progression-free survival
●Treatment of known disease – The primary goal in the treatment of known
disease is destruction of clinically apparent macroscopic disease (evidenced
by either abnormal thyroglobulin values or structural findings) that is not
amenable to surgical therapy. Radioiodine treatment of residual disease and
metastatic disease may reduce the risk of recurrence and mortality, especially
in small-volume disease that is radioiodine avid. (See 'High risk' below.)
INDICATIONSThe decision to administer radioiodine after thyroidectomy in
patients with differentiated thyroid cancer is based upon the clinicopathologic
features of each case (table 1). The efficacy of radioiodine depends upon tumor-
specific characteristics, sites of disease, patient preparation, and dose. Because of
the careful risk stratification used in some studies, it is possible to identify specific
patient and tumor characteristics which suggest that radioiodine may be
beneficial. Our approach outlined below is in agreement with the American
72
Thyroid Association (ATA) guidelines on the role of postoperative radioiodine
ablation (table 2) [3].
Low risk — We do not routinely administer radioiodine after lobectomy or total
thyroidectomy to low-risk patients with differentiated thyroid cancer (table 1). This
includes patients with:
●Unifocal cancer <1 cm without other high-risk features (eg, without distant
metastases, vascular invasion, gross extrathyroidal extension, worrisome
histologic subtypes), even in the presence of small-volume regional lymph
node metastases (less than five lymph nodes measuring less than 2 mm)
●Multifocal cancer when all foci are <1 cm and there are no other high-risk
features
●Intrathyroidal cancer in the 1 to 4 cm range without other high-risk features

Individual tumor- and patient-specific features may warrant radioiodine ablation in

selected low-risk patients. As an example, we administer low-dose radioiodine
ablation (30 mCi) in low-risk patients with intrathyroidal tumors greater than 4 cm.

Systematic reviews and meta-analyses of the effectiveness of radioiodine in low-

risk patients have failed to find a benefit with regard to either overall recurrence
rate or disease-specific mortality [4-6]. As an example, in a retrospective analysis of
1129 patients who underwent total thyroidectomy for differentiated thyroid cancer
and received radioiodine based upon risk assessment, the majority of patients with
low-risk local disease (age <45 years, papillary cancer <4 cm without extrathyroidal
extension, and without distant metastases) had low rates of recurrence and high
rates of survival when managed without radioiodine (five-year recurrence-free
survival >97 percent) [7]. Another retrospective study similarly showed no benefit
of radioiodine ablation on disease recurrence in patients with papillary thyroid
microcarcinoma (unifocal or multifocal) [8]. In this study, there was no disease-
related mortality.
Intermediate risk — We administer radioiodine after total thyroidectomy in
selected intermediate-risk patients depending upon specific tumor characteristics,
including microscopic invasion into the perithyroidal soft tissue, clinically
significant lymph node metastases outside of the thyroid bed, or other higher-risk
features (eg, vascular invasion, more aggressive histologic subtypes such as tall
cell, columnar cell, insular, or poorly differentiated histologies) when the
combination of age, tumor size or multifocality, lymph node status, and individual
histology predicts an intermediate to high risk of recurrence (table 1) or death
(table 3) from thyroid cancer. In the absence of evidence supporting survival
benefit for all of the factors listed, clinical judgment and an individualized
approach to care are important.
73
There are limited data showing a benefit of radioiodine in intermediate-risk
patients [3,9]. In a study using the National Cancer Database registry, which
included 21,870 patients with intermediate-risk papillary thyroid cancer who had
total thyroidectomy with or without radioiodine, patients who received radioiodine
had improved overall survival (hazard ratio [HR] 0.71, 95% CI 0.62-0.82) [9].
In the National Thyroid Cancer Treatment Cooperative Study Group, a multicenter
thyroid cancer registry that has analyzed the outcomes of nearly 5000 patients
with differentiated thyroid cancer, multivariate analysis showed that radioiodine
ablation was associated with improvement in overall survival in stage II patients
(table 4), but this did not reach statistical significance (relative risk [RR] 0.67, 95% CI
0.36-1.28) [10].
High risk — We routinely treat high-risk patients with radioiodine after total
thyroidectomy (table 2), including patients with distant metastases, macroscopic
tumor invasion, and/or incomplete tumor resection with gross residual disease
(table 1).
In the National Thyroid Cancer Treatment Cooperative Study Group, radioiodine
was associated with improved overall survival in stage III patients (RR 0.66, 95% CI
0.46-0.98), with similar but nonsignificant improvement in stage IV (RR 0.70, 95% CI
0.46-1.10) (table 4) [10].
In addition, data prospectively collected from the Surveillance, Epidemiology, and
End Results (SEER) database showed benefit from radioiodine in patients older
than 45 years with primary tumors >2 cm, with disease in the lymph nodes at initial
diagnosis, and with distant metastatic disease [11].
The benefits and dose limits of iodine-131 (131-I) therapy for metastatic disease
were evaluated in a retrospective analysis of 444 patients treated between 1953
and 1994 (analysis of whole-body iodine scans and conventional radiographs) [12].
Forty-three percent of the 295 patients with radioiodine uptake achieved
resolution of radioiodine-avid metastases on iodine scan and negative
conventional radiographs. Additional features of patients in this group included
the following:
●They were more likely to be younger, with differentiated tumors
●96 percent of these patients were given cumulative doses of 100 to 600 mCi
(3700 to 22,000 MBq)
●7 percent had a recurrence
●10-year survival was 92 percent in this group, compared with only 19
percent in patients who did not achieve resolution of the radioiodine-avid
metastatic lesions
CONTRAINDICATIONSPregnancy and breastfeeding are absolute
contraindications to radioiodine therapy [13]. Fetal thyroid tissue is functional by
74
10 to 12 weeks and could be destroyed by the radioiodine, resulting in cretinism.
Radioiodine should only be administered if a woman has a negative pregnancy
test 72 hours before treatment is given or if the possibility of pregnancy is
excluded by a history of surgical sterilization in the patient.
There is increased sodium iodide symporter activity in estrogenized breast tissue,
resulting in breast uptake of radioiodine. Breastfeeding should be stopped at least
six to eight weeks prior to radioiodine therapy so as to reduce uptake of
radioiodine by breast tissue. There are reports of utilization of dopamine agonist
drugs such as cabergoline to decrease serum prolactin and hence shorten the time
that is required before iodine-131 (131-I) can be administered safely to lactating
women [14].
PATIENT PREPARATIONRadioiodine causes cytotoxicity by the emission of
short path-length (1 to 2 mm) beta radiation. Radioiodine uptake is dependent
upon adequate stimulation by thyroid-stimulating hormone (TSH) and is reduced
by the presence of excess stable iodide. Therefore, whenever radioiodine imaging
and treatment are planned, the patient should be instructed to avoid all iodine-
containing medications and to limit dietary intake of iodine for at least one week
(table 5). (See 'Low-iodine diet' below.)
In addition, the intravenous contrast used for computed tomography (CT) scans
contains a large iodine load and may interfere with radioiodine scanning and
therapy for several months. (See 'Recent iodine exposure' below.)
Choice of method for increasing TSH — Radioiodine uptake by thyroid tissue is
stimulated by TSH. There are two methods for increasing TSH, thyroid hormone
withdrawal or administration of recombinant human TSH (rhTSH [thyrotropin
alfa]). We prefer:
●rhTSH for routine radioiodine remnant ablation (destruction of residual
normal thyroid tissue) and follow-up scanning.
●rhTSH when radioiodine is given as adjuvant treatment (destruction of
microscopic residual disease) in low- and intermediate-risk patients.
●Thyroid hormone withdrawal when radioiodine is given as therapy for
known gross residual disease or as adjuvant treatment in high-risk patients.
However, we use rhTSH for such patients in whom severe hypothyroidism
might be relatively contraindicated (eg, older adults, patients with
depression, congestive heart failure, or severe sleep apnea), allowing them to
remain on thyroid hormone therapy.
This approach is consistent with the American Thyroid Association (ATA) guidelines
[3].
There are no long-term randomized trial data on recurrence and disease-specific
survival to guide choice of preparation. In randomized trials and a meta-analysis,
75
short-term rates of successful remnant ablation were similar after withdrawal of
thyroid hormone or after administration of rhTSH (91 to 100 percent) [15-22]. Two
of the larger randomized trials in the meta-analysis compared thyroid hormone
withdrawal versus rhTSH and low- and high-dose radioiodine:
●In a multicenter trial, 752 patients with low-risk differentiated thyroid cancer
(papillary or follicular; tumor, node, metastases [TNM] stage T1 [<1 cm] and
N1 or NX, T1 >1 to 2 cm with any N, or T2N0; absence of distant metastases
[M0]) were randomly assigned in a two-by-two factorial design to low- or
high-dose iodine-131 (131-I) (30 versus 100 mCi [1.1 versus 3.7 GBq]) and to
ablation with thyroid hormone withdrawal versus administration of rhTSH
[20]. The rates of complete ablation at 6 to 10 months were similar (89.1 and
88.9 percent in patients receiving rhTSH and in those undergoing thyroid
hormone withdrawal, respectively). The results did not change when the
analysis was restricted to the 684 patients who received radioiodine and
could be evaluated (91.7 and 92.9 percent, respectively). The efficacy was also
equivalent with either dose. (See 'Radioiodine dose (activity)' below.)
After a median follow-up of 5.4 years, 98 percent of the patients had no
evidence of persistent/recurrent disease, while structural disease was
identified in 0.6 percent and biochemical evidence of persistent disease in 0.7
percent. Neither the method of preparation (rhTSH versus thyroid hormone
withdrawal), nor the administered activity (30 versus 100 mCi [1.1 versus 3.7
GBq]), was associated with short-term biochemical or structural disease
recurrence [23].
●In a similar multicenter trial, 438 patients with low-risk differentiated thyroid
cancer (TNM stage T1 to T3 with possible lymph node involvement [N0, NX,
N1] but no distant metastases [M0] and no microscopic residual disease)
were randomly assigned to low- or high-dose radioiodine (30 versus 100 mCi
[1.1 versus 3.7 GBq]) each combined with rhTSH or thyroid hormone
withdrawal [21]. The rates of successful ablation were similar (87.2 and 86.8
percent for those who received rhTSH versus thyroid hormone withdrawal).
The results did not change when the analysis was restricted to the 421
patients who received radioiodine and could be evaluated (87.1 versus 86.7
percent). The efficacy was also equivalent with either dose. (See 'Radioiodine
dose (activity)' below.)
Few studies have evaluated the long-term outcomes of patients treated with
adjuvant radioiodine with one preparative regimen compared with another. In one
prospective study reporting 10-year follow-up data, outcomes were similar in
patients treated with radioiodine (30 mCi [1.1 GBq]) after stimulation by rhTSH
versus thyroid hormone withdrawal [24]. Similarly, a retrospective study with

76
median follow-up of nine years demonstrated similar effectiveness of rhTSH and
thyroid hormone withdrawal in low-, intermediate-, and high-risk patients [25].
In addition, two small prospective studies suggest that rhTSH-stimulated
radioiodine therapy is effective in destroying microscopic metastatic disease,
typically in cervical nodes or pulmonary micrometastases [26], and is associated
with a similar five-year survival as thyroid hormone withdrawal in the setting of
macroscopic radioiodine-avid distant metastases [27].
Thyroid hormone withdrawal — In the setting of 131-I treatment of residual
tumor or metastatic disease, thyroid hormone withdrawal remains the standard
approach to raising TSH levels for adequate radioiodine uptake. Thyroid hormone
should be withdrawn three to four weeks prior to radioiodine therapy [3]. After
thyroidectomy or cessation of T4 (levothyroxine) therapy, the patient's serum
thyroxine (T4) concentration must decline sufficiently to allow the serum TSH
concentration to rise to above 25 to 30 mU/L [28].
To minimize hypothyroid symptoms for patients withdrawing from thyroid
hormone, our approach is to reduce the dose of oral T4 by 50 percent for four
weeks and then discontinue the T4 for one week prior to administration of
radioiodine. Serum TSH should be measured immediately before any 131-I is given
to confirm that the concentration is high. One study found that with this approach,
the majority of patients taking half-dose T4 achieved a serum TSH concentration of
25 to 30 mU/L by five weeks [29]. In addition, their hypothyroid symptoms were
milder than a group of patients undergoing T3 (liothyronine) withdrawal.
Another strategy is to give the shorter-acting hormone T3 in doses of 25 mcg two
to three times per day for the first two weeks after stopping T4 [30]. Lower doses
(eg, 10 to 12.5 mcg two or three times per day) should be used in older patients
and those with ischemic heart disease. After cessation of T3, the serum TSH
concentration should rise to 25 to 30 mU/L within one to two weeks. Thus, the
interval during which the patient receives no thyroid hormone is shortened.
One randomized trial comparing administration of placebo or T3 for three weeks
following T4 withdrawal found no symptomatic benefit of T3 during thyroid
hormone withdrawal and confirmed that a two- to three-week period of
withdrawal was adequate time duration to see a sufficient rise in TSH to allow
radioiodine ablation [31].
Recombinant human TSH — For patients treated with radioiodine for thyroid
remnant ablation, hypothyroidism can be avoided altogether by administering
rhTSH before administration of 131-I.

With this method, the patient continues their usual dose of T4; rhTSH (0.9 mg) is
administered by intramuscular injection on two consecutive days, followed by

77
administration of radioiodine on the day following the second injection (ie, the
third day). Serum thyroglobulin (Tg) levels are obtained 72 hours after the second
rhTSH injection (the fifth day) and a posttreatment whole-body scan is performed
two to seven days after the radioiodine administration.

In patients in whom pretreatment (diagnostic) scanning is performed, the

scanning dose is administered on the afternoon of the second rhTSH dose, and the
diagnostic scan and therapy, if needed, are performed the next day.
(See 'Pretreatment scanning' below.)
Rarely, the high serum TSH concentrations that occur after withdrawal of thyroid
hormone stimulate rapid growth of persistent or metastatic thyroid cancer. Such
rapid growth has also been described in patients given rhTSH [32]. (See 'Tumor
swelling' below.)
rhTSH has no adverse cardiovascular effects [33]. If it is used, a two-dose regimen
is preferable to a three-dose regimen for ease of administration and lower cost.
Low-iodine diet — To maximize uptake of radioiodine into thyroid cells, we
suggest that patients follow a low-iodine diet for 7 to 10 days before and for one to
two days after 131-I is administered (table 5) [34-36]. This suggestion is consistent
with ATA guidelines [3].
In a systematic review of eight observational studies, dietary iodine restriction (<50
mcg daily) lasting anywhere from four days to four weeks prior to radioiodine
administration compared with a normal diet reduced urinary iodine
concentrations and increased 131-I uptake or lesional uptake [37]. In one
retrospective study that assessed clinical outcomes, patients prescribed a low-
iodine diet (24-hour urine iodine excretion 27±12 mcg) compared with controls (24-
hour urine excretion 159±9 mcg) were more likely to have negative radioiodine
uptake and Tg values <2 mcg/L when assessed six months after radioiodine
treatment [38]. On the other hand, a subsequent retrospective study (not included
in the meta-analysis) showed no relationship between urinary iodine excretion
(range 25 to 1890 mcg/L, mean 132 mcg/L) and ablation success rates in a group
of patients who were not routinely given a low-iodine diet [39]. Remnant ablation
was unsuccessful in another retrospective study only when urinary iodine
concentration was greater than 250 mcg iodine/g creatinine [40].
Recent iodine exposure — Radioiodine uptake by the thyroid remnant is reduced
by the presence of excess circulating stable iodide. Thus, patients who have been
exposed to high iodine loads (eg, iodinated contrast materials or medications high
in iodine content, such as amiodarone) cannot have diagnostic radioiodine scans
or receive radioiodine treatment until the iodine load is excreted.

78
Iodinated contrast is cleared from the blood after one month [41], but radioiodine
treatment is usually delayed for two to three months to be certain that there is no
interference with iodine-avid cancer. Twenty-four-hour urinary iodine
measurements (or estimated 24-hour measurements based on spot urine iodine
measurements corrected for urine creatinine) can be used to document depletion
of excess iodine loads in such patients. Once the 24-hour urine iodine content falls
to approximately 100 mcg/24 hours, patients can proceed with diagnostic
radioiodine scans and radioiodine therapies.
The iodine load associated with amiodarone administration can persist for months
to years after discontinuation of the drug. Plasma exchange has been used to
decrease whole-body iodine content in select patients who have persistent iodine
contamination for months to years after discontinuation of amiodarone [42].
Patients with distant metastases in whom the amiodarone cannot be discontinued
should be treated as if they have radioiodine refractory metastatic disease.
(See "Differentiated thyroid cancer: Overview of management", section on
'Management of persistent or recurrent disease'.)
Other strategies to increase uptake — Each of the strategies listed below have
the potential to increase radioiodine uptake into thyroid cancer cells in properly
selected patients but can be associated with risks that need to be carefully
managed. Thus, these approaches are not recommended for routine clinical
practice and are probably best considered and implemented for highly selected
individual patients within the context of an experienced multidisciplinary thyroid
cancer management team.
●Regimens to deplete body stores of iodine, such as the use of loop diuretics,
or mannitol with strict low-iodine diets may increase uptake by tumor;
however, there may also be a concomitant increase in total body irradiation
[43].
●Lithium can prolong 131-I retention by thyroid tissue. In a small study of
patients who had diagnostic 131-I scans before and then again after
receiving lithium for one to two days, 131-I retention was higher and more
prolonged during lithium administration in metastatic lesions and the thyroid
remnants in most patients, so that the estimated 131-I dose to the
metastases was higher [44]. Whether these findings will result in improved
eradication of metastases remains to be determined.
●Inhibition of the mitogen-activated protein kinase (MEK) pathway with MEK
inhibitors (selumetinib, trametinib, cobimetinib) or BRAF inhibitors
(dabrafenib, or vemurafenib) have been reported to restore radioiodine
sensitivity in 40 to 60 percent properly selected patients with radioactive
iodine refractory thyroid cancer [45]. Ongoing studies are trying to define

79
 precisely which patients would be most likely to achieve a significant clinical
benefit from these redifferentiation therapies based on clinical
characteristics, histologic findings, and molecular characterization of the
tumors. (See "Differentiated thyroid cancer refractory to standard treatment:
Systemic therapy", section on 'Assess for restoration of radioiodine uptake'.)
Pretreatment scanning
When to obtain — Diagnostic (pre-radioiodine treatment) whole-body scans for
localization of uptake before remnant ablation, adjuvant treatment, or treatment
of metastatic thyroid cancer are usually performed when the extent of residual
disease cannot be determined from surgery and neck ultrasonography and when
the presence of residual disease may alter the decision to treat with radioiodine or
the administered activity [3]. However, even if the patient has no known persistent
or metastatic disease, almost all patients have thyroid remnants (image 1), and
therefore, an alternative approach is to omit the pretreatment diagnostic scan,
administer empiric therapeutic doses of 131-I therapy, and obtain only a
posttreatment scan [46]. (See 'Posttreatment scanning' below.)
No studies have demonstrated superior outcomes following one or another
approach. The disadvantage of omitting the pretreatment scan is that those
patients with metastases may be undertreated by a strategy that gives all patients
the same initial dose of radioiodine. Furthermore, there are occasional patients
whose thyroidectomy is so complete that there is no uptake seen on the
pretreatment scan and who, therefore, would not benefit from radioiodine
therapy. In one study of 355 scans, 53 percent of patients had findings on the
pretreatment scan that might have altered management [47]. Omitting the
pretreatment scan may be reasonable for patients with a very low risk of
metastases in whom the goal is to ablate remnants.
Scanning dose — When pretreatment whole-body scanning is performed, low-
dose, orally-administered activities of 2 to 5 mCi (74 to 185 MBq) 131-I should be
used with whole-body imaging 48 to 72 hours later to identify thyroid tissue and
metastases [48]. Alternatively, a 1.3 to 5 mCi (48 to 185 MBq) iodine-123 (123-I)
scan can be performed with whole-body imaging 6 to 24 hours later. If present,
the degree of uptake should be quantitated. Greater sensitivity for the detection of
residual or metastatic tumor can be attained with the use of higher activities
[49,50], but higher amounts (>5 to 10 mCi 131-I) could lead to "stunning," in which
there is reduced uptake of the subsequent therapeutic radioiodine due to
sublethal radiation delivered by the diagnostic dose [51,52]. Stunning may be the
result of radiation-induced decrease in DNA synthesis as well as transcription of
the sodium iodide symporter gene, as suggested by in vitro studies of porcine
thyrocytes [53,54].

80
The importance of stunning may be overstated; one study found no difference in
the success of subsequent treatment in patients who received 3 to 5 mCi (111 to
185 MBq) 131-I for scanning as compared with those not scanned before
treatment [55]. A second study found no difference in the success rate of remnant
ablation (negative iodine scan six to eight months later and undetectable Tg) when
patients were scanned with 2 mCi (74 MBq) of 131-I versus 0.5 mCi (14.8 MBq) of
123-I before treatment [56]. The use of 123-I may be associated with a lower risk of
stunning [57].
Scanning technique — Between one and seven days after administration of the
diagnostic dose, whole-body scans are performed with a large field-of-view
gamma-scintillation camera fitted with a high-energy parallel hole collimator. Spot
images of the neck and other areas of uptake can be obtained using either the
same equipment or a rectilinear scanner. In some institutions, quantitative
dosimetry is performed to determine lesion uptake and to predict effective tumor
radiation dose; however, this requires specialized equipment and software [58].

Because of the higher cost and shorter half-life of 123-I, most centers use 131-I
(approximately 4 to 5 mCi) as the primary isotope for follow-up whole-body scan 6
to 12 months later. At our center, the initial diagnostic scan done prior to rhTSH
ablation is done using 2 to 4 mCi of 123-I, while all other routine follow-up scans
are done using 5 mCi of 131-I.

When rhTSH is used to ablate remnants, the standard protocol is either (1) to
obtain only a posttreatment scan, or (2) to obtain a 24-hour 123-I scan on day 3
prior to administration of radioiodine ablation [59]. (See 'Recombinant human
TSH' above.)
131-I SPECT/CT — As one might expect, initial reports suggest an advantage of
single-photon emission computed tomography/computed tomography (SPECT/CT)
scanning with radioiodine over traditional, planar whole-body scan imaging
[60,61]. As an example, in one study of 81 inconclusive lesions on planar images,
localization or characterization of the lesions was achieved by 83 to 85 percent of
the 131-I SPECT/CT images [60]. In another study, SPECT/CT significantly altered
the initial assessment of risk with a resultant impact on initial clinical management
[62].
123-I — Iodine-123 (123-I) may be superior to 131-I for diagnostic scans. In one
study of 14 patients following thyroidectomy, images obtained five hours after
administration of 1.3 to 1.5 mCi (48 to 56 MBq) of 123-I detected more thyroid
remnants than images obtained 48 hours after 3 mCi (111 MBq) of 131-I [63].
Another study evaluated 12 patients, previously treated with radioiodine, who had
high Tg concentrations and negative 131-I diagnostic scans. Eleven of the 12
81
patients had positive images 2 and 24 hours after administration of 5 mCi (185
MBq) 123-I; 10 of these 11 patients had concordant posttherapy (150 to 216 mCi
[5.6 to 8.1 GBq]) 131-I scans [64]. Since 123-I is primarily a gamma emitter, it does
not impair cellular function and should not cause stunning, but it is considerably
more expensive than 131-I.
Findings — Between 75 and 100 percent of patients with thyroid cancer have 131-I
uptake in the thyroid bed after thyroidectomy (image 2) [65]. Most often, this
represents remnants of normal thyroid tissue rather than residual thyroid cancer
[66]. In contrast, only approximately 50 percent of metastatic lesions in the lungs
or bones concentrate 131-I (image 3) [67].
Combining results from multiple studies, there is probably no significant
difference between papillary and follicular carcinomas in the frequency of
detectable uptake by recurrent or metastatic disease [48]. However, certain
histologic subtypes, such as oxyphilic follicular cancer (commonly called Hürthle
cell cancer), the tall cell variant of papillary cancer, and poorly differentiated
carcinomas, concentrate 131-I less often in metastatic sites. Older patients may
also be less likely to have adequate uptake in metastases [58,67].
Scans performed during follow-up that show apparent distant metastases must be
interpreted with caution. A few are false-positive scans due to physiologic uptake
of the 131-I in the breast, salivary glands, or thymus [68]; false-positive scans can
also occur with pathologic exudates, dilated hepatic ducts [69], or nonthyroid
benign tumors [70].
RADIOIODINE DOSE (ACTIVITY)
●When the primary goal is to ablate residual normal thyroid tissue (remnant
ablation), administered activities of 30 mCi (1.1 GBq) are typically used.
Higher doses may be necessary for patients who have had less than a total
thyroidectomy where a larger remnant is suspected [3].
●When the primary goal is to provide adjuvant treatment of subclinical
micrometastatic disease, administered activities of 75 to 150 mCi are used,
based on assessment of the individual's risk of having clinically significant
microscopic residual disease.
●When the primary goal is to provide treatment of clinically apparent residual
or metastatic thyroid cancer, administered activities of 100 to 200 mCi are
typically used.
Remnant ablation — Radioiodine is administered using a fixed-activity (fixed-
dose) regimen, typically 30 mCi (1.1 GBq) for remnant ablation [71-74]. Consistent
with the 2015 American Thyroid Association (ATA) guidelines, we choose the
iodine-131 (131-I) dose based upon the goals of radioiodine administration and
risk of recurrence/disease-specific mortality (table 2) [3].
82
Many studies have attempted to determine an optimal dose of radioiodine for
remnant ablation. In a 2013 meta-analysis of nine randomized trials, there was no
difference between low activity (30 mCi [1.1 GBq]) and high activity (100 mCi [3.7
GBq]) for successful thyroid remnant ablation [75]. There were fewer adverse
effects in the low-dose group. Other meta-analyses have reported similar findings
[76-78]. These analyses are confounded by differences in the definition of
successful ablation used in the various studies, the method of TSH stimulation, the
adherence to a low-iodine diet, and the length of time between ablation and the
follow-up diagnostic scan.

Two of the larger trials in the meta-analyses are reviewed in more detail below:

●In a multicenter trial, 752 patients with low-risk differentiated thyroid cancer
(papillary or follicular; tumor, node, metastases [TNM] stage T1 [<1 cm] and
N1 or NX, T1 >1 to 2 cm with any N, or T2N0; absence of distant metastases
[M0]) were randomly assigned in a two-by-two factorial design to low- or
high-dose 131-I (30 versus 100 mCi [1.1 versus 3.7 GBq]) and to ablation with
thyroid hormone withdrawal versus administration of recombinant human
TSH (rhTSH) [20]. Successful ablation was defined as a negative thyroid
ultrasound (normal postoperative thyroid bed and no suspicious lymph
nodes) and an rhTSH-stimulated thyroglobulin (Tg) ≤1 ng/mL, or in patients
with detectable Tg antibodies, a negative 131-I total-body scan (<0.5 percent
uptake in the thyroid bed). In the intention-to-treat analysis, complete
ablation rates in the low- and high-dose groups were identical (89 percent).
Similar compete ablation rates were found in an analysis limited to the 684
patients who received radioiodine and were evaluated 6 to 10 months later
(91.1 and 93.5 percent for low- and high-dose groups, respectively). The rates
of complete ablation were also similar in patients receiving rhTSH versus
thyroid hormone withdrawal. (See 'Recombinant human TSH' above.)
●In another multicenter trial, 438 patients with low-risk differentiated thyroid
cancer (TNM stage T1 to T3, with possible lymph node involvement [N0, NX,
N1] but no distant metastases [M0] and no microscopic residual disease)
were randomly assigned to low- or high-dose radioiodine (30 versus 100 mCi
[1.1 versus 3.7 GBq]), each combined with rhTSH or thyroid hormone
withdrawal [21]. Successful ablation was defined as both a negative scan
(<0.1 percent uptake) and an rhTSH-stimulated Tg level <2 ng/mL at six to
nine months. Only the scan result was considered for ablation success or
failure for patients with Tg antibodies and discordant Tg measurements on
immunometric and radioimmunoassays, unknown antibody status, or
unavailable serum sample. The rates of successful ablation were similar
83
 between the low- and high-dose groups (85 versus 88.9 percent). Success
rates were also similar in those who received rhTSH versus thyroid hormone
withdrawal. (See 'Recombinant human TSH' above.)
There are no randomized trials that evaluate long-term outcomes of patients
treated with low or high radioiodine dose (activity). In retrospective studies, there
was no difference in thyroid cancer recurrence after 5 and 14.7 years of follow-up
in patients treated with low versus high radioiodine activity [79,80].
The controversy about the role of 131-I remnant ablation in general, particularly in
patients with low-risk disease (ie, no soft tissue invasion and no distant
metastases), is reviewed above. (See 'Low risk' above.)
Adjuvant treatment — Patients with intermediate-risk differentiated thyroid
cancer are treated with 131-I to destroy both remnant normal thyroid tissue
remaining after total thyroidectomy (remnant ablation), and subclinical
microscopic foci of disease remaining after surgery (adjuvant treatment).

For patients with intermediate-risk differentiated thyroid cancer who are treated
with radioiodine to provide adjuvant treatment of subclinical microscopic residual
disease, we administer between 75 and 150 mCi, usually between 75 and 100 mCi
(2.8 to 3.7 GBq).

In retrospective analyses of patients with intermediate-risk differentiated thyroid

cancer (microscopic extrathyroidal extension, lateral neck lymph node metastases,
or other higher-risk features [eg, vascular invasion, more aggressive histologic
subtypes such as tall cell, columnar cell, insular, or poorly differentiated
histologies]), there was no significant difference in the rate of successful
radioiodine ablation in patients receiving high (100 to 150 mCi [3.7 to 5.6 GBq])
versus low (30 mCi [1.1 GBq]) activities [81,82]. Another retrospective analysis
compared 100, 150, and 200 mCi radioiodine adjuvant treatment and found that
the administration of more than 100 mCi radioiodine was unlikely to improve
response to therapy [83]. In another study, higher doses of radioiodine (>54 mCi)
were associated with improved cause-specific survival in a cohort of patients older
than age 45 years [84].
Macroscopic residual or metastatic disease — Patients with macroscopic
residual postoperative disease in the thyroid bed or in local regional lymph nodes
are usually treated with higher administered activities of 131-I.
Since rhTSH is not US Food and Drug Administration (FDA) approved as an adjunct
to radioiodine therapy in the setting of gross residual disease, these patients are
usually prepared with thyroid hormone withdrawal unless there are medical
contraindications to iatrogenic hypothyroidism. (See 'Choice of method for
increasing TSH' above.)
84
We suggest the following activities for patients with macroscopic residual or
metastatic disease in patients less than 70 years old with normal renal function:

●150 mCi (5.6 GBq) 131-I to treat uptake in lymph nodes in the neck and
mediastinum.
●150 to 200 mCi dose (5.6 to 7.5 GBq) for patients with pulmonary
metastases. Repeated dose of 131-I over several years has been shown to be
highly effective in the treatment of younger patients with small-volume
pulmonary metastases [12].
●200 mCi (7.5 GBq) for patients with skeletal or other distant metastatic
disease.
●Higher activities may be given to patients who have recurrent disease after
previous therapy but should be based on dosimetry to ascertain their safety.
Empiric dosing regimens may exceed the maximum tolerable doses as predicted
by dosimetry, especially in older adults [85,86]. As an example, in one study, a dose
of 200 mCi (7.5 GBq) exceeded the maximum tolerable dose in only 8 percent of
younger patients and over 22 percent of patients over age 70 years [85].
Therefore, doses should seldom exceed 150 mCi in patients 70 years or older
unless guided by dosimetry studies. For patients with diffuse pulmonary
metastases in whom pulmonary fibrosis could be a complication of radioiodine
therapy, dosimetry can be used to limit the whole-body radioiodine retention to 80
mCi at 48 hours, which will minimize pulmonary damage [87].
In patients with renal failure or on hemodialysis, there are two dosing approaches
to radioiodine therapy: a substantially lower dose of radioiodine followed by the
patient's usual dialysis schedule, or a standard radioiodine dose followed by more
frequent dialysis [88,89].
MONITORING AFTER RADIOIODINE
Posttreatment scanning — Tumor uptake of the treatment dose of radioiodine
should be confirmed by performing a whole-body scan two to eight days after
radioiodine treatment. In approximately 6 to 13 percent of these posttreatment
scans, foci of uptake that were not seen on the corresponding low-dose iodine-131
(131-I) pretherapy scan are seen [52,90,91]. However, in only 10 percent of cases
does the posttreatment scan reveal new sites of uptake that significantly alter the
patient's prognosis and were not known to exist by other means, such as
radiography or surgery [52].
Similarly, in a comparison of diagnostic iodine-123 (123-I) scans with
posttreatment scans, additional areas of uptake were found in 6 percent of
patients scanned for the first time, 18 percent of patients scanned for the second
time, and 44 percent of patients with high serum thyroglobulin (Tg) concentrations

85
and negative diagnostic scans; however, treatment was altered in few patients
[92].
Repeat scanning and treatment — In the absence of evidence for possible or
proven persistent disease (abnormal serum thyroglobulin, rising antithyroglobulin
antibodies, indeterminate/suspicious structural findings), we seldom recommend
routine follow-up whole-body radioactive iodine scans for routine surveillance.
Rather, follow-up radioactive scans (usually 131-I) are used to localize and
characterize radioiodine avidity in patients with biochemical or structural findings
that could indicate persistent/recurrent disease (see "Differentiated thyroid cancer:
Overview of management", section on 'Monitoring response to therapy'). If
significant uptake is seen within the thyroid bed (>1 percent), one more treatment
with 100 to 150 mCi (3.7 to 5.6 GBq) of 131-I may be given to complete the
ablation; generally, we are reluctant to repeat treatment of minor thyroid bed
uptake (<1 percent) in the absence of clear evidence of residual cancer by other
imaging techniques, such as ultrasound.
If there is uptake outside of the thyroid bed, we give doses of 131-I appropriate to
the site of uptake. Prior to incorporating stimulated Tg testing into diagnostic
algorithms, a common approach was to continue scanning to obtain two
successive negative 131-I scans, which predicted a 97 percent 10-year relapse-free
survival compared with 91 percent after only one negative scan [93].
For each scan, the patient's serum TSH concentration must be high enough to
maximize the uptake of 131-I by any residual thyroid tissue. This may be achieved
with thyroid hormone withdrawal or by administration of rhTSH [94]. (See 'Choice
of method for increasing TSH' above.)

We suggest using rhTSH support in all patients who require radioiodine scanning,
unless they are thought to be likely in need of subsequent radioiodine therapy that
is preferably done using thyroid hormone withdrawal. Imaging is usually done at
48 hours using the rhTSH approach or at 48 to 72 hours following thyroid
hormone withdrawal.

COMPLICATIONSAcute and chronic complications of radioiodine can limit the

usefulness of this treatment. In the short term, radiation thyroiditis, painless neck
edema, sialadenitis, and tumor hemorrhage or edema occur in 10 to 30 percent of
patients, particularly when higher doses are given [48,95]. Nausea after iodine-131
(131-I) administration can be treated with oral prochlorperazine (10 mg). To
promote more rapid clearance of radioiodine from the urinary bladder, patients
are encouraged to drink large volumes [96].

86
Laxatives that do not contain iodine should be given if the patient has not had a
bowel movement within 12 to 24 hours after administration of the radioiodine (to
purge radioiodine from the colon). Some clinicians routinely give laxatives to
everyone to reduce colonic exposure.

Sialadenitis — Most patients treated with 131-I experience dose-related

reductions in salivary flow [97], and some experience transient decreased or
altered sense of taste. Although previously thought to reduce the risk of
sialadenitis, the use of lemon candies in the first 24 hours was associated with
higher rates of sialadenitis, hypogeusia, and xerostomia due to increased
hematogenous delivery of radioiodine to salivary gland tissue [98,99]. Therefore,
the use of lemon candies or other sialogogues as a means to reduce radiation
sialadenitis remains controversial [98-100]. Since radioiodine is washed out rapidly
after the administration of lemon juice [100], additional studies are needed to
determine optimal timing of administration to reduce delivery of radioiodine to the
salivary glands and provide optimal washout.
Nonsteroidal antiinflammatory drugs (NSAIDs) are usually adequate for relieving
symptoms of acute sialadenitis; glucocorticoids are rarely required but are
effective in more severe cases. Small series have demonstrated a potential
therapeutic role for sialoendoscopy in patients with chronic parotid sialadenitis
caused by ductal stenosis, mucous plugs, and fibrosis in Stensen duct following
radioactive iodine therapy [101,102].
Amifostine, which functions as a radioprotectant by scavenging radiation-induced
free radicals in nonmalignant tissue, has been advocated to reduce the frequency
and severity of sialadenitis after radioiodine therapy [103,104]. However, it is
possible that amifostine would protect normal thyroid tissue from radiation-
induced damage [105], and therefore, its use should probably be limited to the
occasional patient who requires multiple radioiodine administrations for
metastatic disease rather than for adjuvant remnant ablation. Fewer side effects
have been reported with subcutaneous administration (500 mg) before radioiodine
ingestion [104].
In a related observation, dental caries and teeth extraction were markedly higher
in patients who developed postradioiodine xerostomia [106], and patients should
be advised about proper oral hygiene and regular dental care. (See "Management
of late complications of head and neck cancer and its treatment", section on
'Salivary gland damage and xerostomia'.)
Secondary malignancy — An excess risk of secondary malignancies has been
reported after radioiodine therapy for thyroid cancer [95,107,108], although the
data is heterogeneous [109]. Given the presence of sodium iodide symporters in

87
salivary glands and estrogenized breast tissue and the gastrointestinal and urinary
routes of excretion of radioiodine, salivary gland, breast, bladder, and
gastrointestinal cancers can be plausibly hypothesized to occur more frequently in
thyroid cancer patients treated with radioiodine [110-114]. The risk of leukemia is
also increased [109,115]. The cumulative incidence per 100,000 person-years is
approximately 20 to 30. The risk is considerably lower when the total blood dose
per treatment is less than 100 mCi [115].
In a report of 6840 patients treated for thyroid cancer in Sweden, Italy, and France,
62 percent received radioiodine therapy (mean cumulative activity 162 mCi [6.0
GBq]) [116]. Secondary malignancies that occurred with significantly increased risk
included bone and soft tissue (relative risk [RR] 4), female genital organs (RR 2.2),
central nervous system (RR 2.2), and leukemia (RR 2.5). A dose-response
relationship was seen between the administered activity and the risk for solid
malignancies as well as leukemia. Although breast cancer was more commonly
diagnosed in women treated for thyroid cancer, no relationship was identified
between radioiodine and breast disease. Another retrospective cohort study also
did not show a significant increase in the incidence of breast cancer among
women treated with radioiodine therapy [117].
In an analysis of patients in the National Cancer Institute (NCI)'s Surveillance,
Epidemiology, and End Results (SEER database) who had low-risk (T1N0) well-
differentiated thyroid cancer, the excess absolute risk was 4.6 cases of secondary
malignancies per 10,000 person-years [118]. Secondary malignancies with
significantly elevated risk due to radioiodine were salivary gland malignancies and
leukemia (standardized incidence ratios 11.13 and 5.68, respectively). During the
35-year study period, the rate of radioiodine use in patients with low-risk well-
differentiated thyroid cancer increased from 3.3 to 38.1 percent.
Because of the known relationship between ionizing radiation and myelodysplastic
syndromes (MDS) and myeloproliferative neoplasms (MPN), the relationship
between initial therapies and the risk of subsequently being diagnosed with
MDS/MPN was examined in 148,215 well-differentiated thyroid cancer patients in
the SEER database (54 percent thyroidectomy and 46 percent thyroidectomy and
radioactive iodine therapy). Radioiodine therapy was associated with a statistically
significant increase in MDS and MPN diagnosed two to three years after treatment
[119,120]. While data on administered radioiodine activities were not available,
patients with clinical features more likely to have received higher activities of
radioiodine demonstrated an increased risk of MDS, suggesting that a dose-
response effect could be present.

88
It is important to note that while high cumulative doses of radioiodine may be
associated with a statistically significant increase in second malignancies (RR), the
magnitude of this risk (absolute risk) is quite small. However, any risk of secondary
malignancy requires a careful analysis of the risk versus benefit of radioiodine for
patients with low-risk disease and additional radioiodine therapies in patients with
persistent or recurrent thyroid cancer.

Also of note is the lower total body radiation exposure in patients prepared with
recombinant human TSH (rhTSH) versus thyroid hormone withdrawal due to the
more rapid clearance of radioiodine from euthyroid versus hypothyroid patients.
In one study, the frequency of translocations in peripheral lymphocytes after
radioiodine was higher in patients prepared by withdrawal compared with those
prepared with rhTSH [121].
Gonadal function and fertility — Transient oligospermia and decreases in
ovarian function may occur, but subsequent infertility is rare except after high
doses [122-127]:
●In a study of men receiving less than 150 mCi (5.5 GBq) of radioiodine, there
was a transient rise in follicle-stimulating hormone (FSH) but no oligospermia
or change in serum testosterone levels [123]; one-third of men who received
350 to 750 mCi (13 to 27.7 GBq) developed transient oligospermia. A
systematic review concluded that biochemical evidence of gonadal damage
can be seen for up to 18 months after radioiodine treatment, but effects on
fertility and offspring were not identified [128].
●Transient amenorrhea for one to four months occurs in roughly 10 to 25
percent of women treated with radioiodine [125]. In a study of women who
had received 131-I therapy for thyroid cancer before age 45 years,
menopause occurred on average 1.5 years earlier than in women with
nodular goiter treated with equivalent doses of T4 (levothyroxine) [124].
In a subsequent study of 2360 women diagnosed with differentiated thyroid
cancer at ages 15 to 39 years, there was no difference in the cumulative
incidence of birth (maximum follow-up 14.5 years) in women who did or did
not receive radioiodine (30 versus 29 percent, respectively) [127]. Several
studies now demonstrate that radioiodine therapy is associated with a
statistically significant and sustained decline in anti-müllerian hormone
(AMH), a measure of ovarian reserve [129-134]. Even though AMH levels were
somewhat lower, pregnancy-related outcomes did not differ between
patients treated with radioiodine and either normal controls or thyroid
cancer patients managed without radioiodine, indicating that infertility is
uncommon despite the reduction in AMH levels [130,131].

89
 ●Genetic and chromosomal abnormalities in children due to parental
exposure to 131-I probably occur in only 1 percent of live births after
cumulative administered doses of 500 mCi (18.500 GBq) and even less
frequently after lower doses [125,126,135].
Nasolacrimal duct obstruction — Nasolacrimal duct obstruction, presenting as
epiphora (excessive tearing), has been reported to occur after as low an
administered activity as 100 mCi [136] and can be a cause of a false-positive
radioiodine scan in the orbit [137].
Tumor swelling — As noted above, tumor swelling can occur due to significant
serum TSH elevations after thyroid hormone withdrawal. After rhTSH
administration, tumor swelling resulting in airway obstruction, bone pain, or
neurologic symptoms may occur within hours. When patients with known or
suspected lesions in confined spaces are exposed to TSH increases, whether after
thyroid hormone withdrawal or rhTSH, meticulous clinical attention is
necessary. Dexamethasone 8 mg twice a day or prednisone 60 mg daily for one to
two days before and tapering over several weeks has been shown to prevent
adverse reactions related to tumor swelling [138].
RADIATION SAFETYIn 2011, the American Thyroid Association (ATA) published
recommendations on radiation safety for patients, families, caregivers, and the
public after radioiodine therapy [13]. The recommendations are based upon
clinical experience and available data. However, data on long-term outcomes are
limited. The recommendations are in keeping with Nuclear Regulatory Commission
(NRC) regulations and the principle of reducing radiation exposure to levels that
are as low as reasonably achievable.
Patient release criteria — According to NRC regulations, a patient treated with
iodine-131 (131-I) may be released from the care of the treating clinician as long as
the radiation exposure to another individual caring for the patient will not exceed
5 millisieverts (mSv, 500 mrem) per year and the exposure to the public, a child, or
a pregnant woman will not exceed 1 mSv (100 mrem) in one year [139,140].
Radiation exposure can be calculated in mrem or mSv using dose rate meters or a
total effective dose equivalent (TEDE) table. The calculation of the TEDE takes into
account patient-specific information such as the administered 131-I activity, the
physical and biological half-life of the 131-I, and the projected duration of
exposure time for family members or caregivers. Dose rates are established for a
distance of 1 m (approximately three feet) from the radiation source (ie, the
patient). Patients receiving a dose of 150 mCi (5550 MBq) for thyroid cancer can
typically be released without exceeding dose limits [13,141]. When the TEDE
exceeds NRC regulations and/or when patients are unable to comply with

90
posttreatment precautions, inpatient 131-I dosing is necessary. A Radiation Safety
Officer will generally oversee radiation safety calculations and precautions.
Posttreatment precautions — Patients who receive radioiodine have the
potential to expose their home and household contacts to very low levels of
radiation via saliva, urine, or radiation emitting from their body. To ensure the
safety of family members, caregivers, and other individuals, several precautions
are recommended. We agree with ATA guidelines as described below [13].
Safety for the general public and household members — Treated patients
should be given patient-specific advice on the necessary precautions to reduce
radiation exposure (table 6). The treated patient should remain ≥1.8 m (6 feet)
away from family members, caregivers, and the general public as much as possible
for approximately 24 hours after treatment. Adult caregivers may be closer than 1
m (3 feet) for brief intervals. In general, the treated patient should be instructed to
avoid public transportation and extended time in public places and should not stay
overnight in a hotel or motel within 24 hours of 131-I treatment.

To protect household members from radiation exposure, the treated patient

should avoid the following during the restricted period:

●Sleeping in the same bed with another adult, pregnant woman, infant, or
child
●Sexual contact
●Kissing
●Sharing cups, utensils, towels, razors, toothbrushes
The duration of the restricted period depends upon the dose received, amount of
thyroid tissue, and rate of clearance. As an example, treated patients should avoid
sleeping in the same bed with an adult for four days and for up to three weeks
with a pregnant partner, infant, or child after treatment with 200 mCi (7400 MBq).
The restricted period is calculated individually for each treated patient (table 7).
There are few long-term data to assess the protective benefits of these
precautions. In a study of 30 patients with thyroid cancer who received 75 to 150
mCi (2.775 to 5.550 GBq) of 131-I as outpatients, exposure of family members was
minimal when precautions were followed [142]. Patients were instructed to sleep
alone, drink fluids liberally, and avoid prolonged close personal contact with family
members for two days after treatment. Surveillance of family members and pets
demonstrated that doses to household members were well below the limit (5 mSv)
mandated by NRC regulations.
Personal hygiene — 131-I is renally excreted, and excretion is maximal during the
first 48 hours after treatment. Patients should stay well hydrated (3 to 4 L of fluid
daily) and void frequently. To avoid personal or caregiver contamination, patients
91
should be meticulous in their personal hygiene, wiping any surfaces that may
become contaminated with urine, stool, vomitus, blood, or perspiration for 48
hours after treatment (table 6). For 48 hours after therapy, men should sit when
urinating. Exercise equipment should be wiped with flushable or disposable wipes.
Exercise and bed clothes can be laundered in a washing machine. Dishes and
utensils can be washed by hand or in a dishwasher. Flushable waste can be flushed
down the toilet. Non-flushable waste (ie, incontinence pads) should be disposed of
in a plastic trash bag devoted to radiation waste. Caregivers should wear
disposable plastic gloves during clean-up. Radiation waste bags can be returned to
the nuclear medicine facility one to two weeks after treatment or stored in the
household (6 feet away from people or animals) for 80 days. After 80 days,
radiation-related trash can be disposed of with regular household trash.
International travel — Low levels of 131-I activity (0.0003 mCi [0.01 MBq]) can be
picked up by radiation detection systems at airports or international borders.
Treated patients may trigger alarms for as long as 95 days posttherapy. Thus,
patients who are traveling within three to four months of receiving 131-I require
documentation specifying the date of treatment, type and dose of radionuclide,
the treating facility, and contact information for the treating clinician.
Future pregnancy — In female thyroid cancer patients, pregnancy should
generally be delayed for at least six months after radioiodine therapy to ensure
that additional diagnostic imaging or additional radiation treatment is not
required. In men, it seems reasonable to delay attempts to produce pregnancy for
a period of three to four months to allow recovery of the transient oligospermia
that may follow radioiodine therapy. However, in some men, full fertility may not
be restored until one year or more after treatment, especially in men receiving
high cumulative doses of radioiodine (>350 mCi) [128].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
●Radioiodine is administered after thyroidectomy in patients with
differentiated thyroid cancer to provide remnant ablation (primary goal is
destruction of residual presumably benign thyroid tissue to facilitate initial
staging and follow-up studies), adjuvant treatment (primary goal is
destruction of subclinical tumor deposits that may or may not be present
after surgical resection of all known primary tumor tissue and metastatic
foci), or treatment of known disease (primary goal is destruction of known
disease evidenced by either abnormal thyroglobulin values or structural
findings). (See 'Goals' above.)
92
●For all at high risk (table 1 and table 2), including patients with distant
metastases, macroscopic tumor invasion, and/or incomplete tumor resection
with gross residual disease, we recommend postoperative radioiodine
therapy (Grade 1B). (See 'High risk' above.)
●For selected intermediate-risk patients (microscopic invasion into the
perithyroidal soft tissue; documented lymph node metastases outside of the
thyroid bed; vascular invasion; more aggressive histologic subtypes, such as
tall cell, columnar cell, insular, or poorly differentiated histologies) (table 1),
we suggest postoperative radioiodine as remnant ablation or adjuvant
treatment (Grade 2C). (See 'Intermediate risk' above.)
●In the absence of a proven benefit on either disease-free survival or
recurrence, we recommend against routine radioiodine ablation or adjuvant
treatment for patients with unifocal tumors <1 cm without other high-risk
features (Grade 1B). (See 'Low risk' above.)
●Recommendations for radioiodine dose (activity) are reviewed above.
(See 'Radioiodine dose (activity)' above.)
●To prepare for radioiodine remnant ablation or diagnostic (pretreatment
imaging), we suggest recombinant human thyroid-stimulating hormone
(rhTSH [thyrotropin alfa]) for most patients to raise serum TSH levels for
adequate radioiodine uptake (Grade 2B). (See 'Recombinant human
TSH' above.)
●We suggest that patients follow a low-iodine diet for 7 to 10 days before
radioiodine is given for remnant ablation (Grade 2C). (See 'Low-iodine
diet' above.)
●To protect household members from radiation exposure, the treated patient
should avoid sleeping in the same bed with another adult, pregnant woman,
infant, or child; sexual contact; kissing; and sharing cups, utensils, towels,
razors, and toothbrushes during the restricted period (table 7). The duration
of the restricted period depends upon the dose received, amount of thyroid
tissue, and rate of clearance. (See 'Radiation safety' above.)

93
Differentiated thyroid cancer: Role of serum
thyroglobulin
Author:
R Michael Tuttle, MD
Section Editors:
David S Cooper, MD
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jul 15, 2021.
INTRODUCTIONThyroglobulin (Tg) is a storage form of thyroxine (T4) and
triiodothyronine (T3). It is synthesized only by thyroid follicular cells and released
into serum along with the thyroid hormones. Given the cellular specificity of Tg, its
detection in biopsy specimens provides proof of the thyroid origin of the tissue. In
addition, measurements of serum Tg provide important information about the
presence or absence of residual, recurrent, or metastatic disease in patients with
differentiated thyroid cancer. This topic review will describe the methods for
measuring serum Tg and the use of serum Tg measurements in patients with
differentiated thyroid cancer. Other aspects of the management of thyroid cancer
are reviewed separately. (See "Differentiated thyroid cancer: Overview of
management".)
THYROGLOBULIN ASSAYTesting of serum thyroglobulin (Tg) should be done
using a sensitive assay, ideally using the same assay for each sample.
Methodology — Serum Tg is now generally measured by two-antibody "sandwich"
immunometric assays (the antigen is sandwiched between the two antibodies) in
which the capture antibody is bound to a solid support and the detection antibody
is labeled with either an isotopic (immunoradiometric assay, IRMA) or non-isotopic
(usually immunochemiluminescent assay, ICMA) marker. The values in normal
subjects in most laboratories range from 1 to approximately 30 ng/mL. These
immunometric assays are quicker, readily automated, and have greater sensitivity
(0.1 to 1 ng/mL) than most radioimmunoassays [1].
Interassay variation — We recommend that serial Tg measurements in thyroid
cancer patients be done using the same assay.
Despite a trend toward assay standardization, serum Tg values obtained with
different assays cannot be directly compared, as interassay variability remains
substantial [2-4]. The variability in assay results is due to [1,5-7]:
94
 ●Variations in the anti-Tg antibodies used.
●The heterogeneity of Tg, a consequence of alternative processing and
differences in iodination of Tg.
●Tg produced by thyroid cancer cells can be even more heterogeneous
(because of dysregulation of the enzymatic glycosylation and iodination
within malignant thyroid cells) and occasionally has enough conformational
difference that it may not be recognized by a standard Tg assay.

The net effect can be widely variable antigen (Tg) detection among different
assays.

Intraassay variation — Even using the same assay, between-run variability can

affect the comparability of serial determinations over time [2,8]. While these
differences are far less than the between-assay differences, they can be
responsible for small fluctuations in Tg measurements over time within the same
patient.
Functional sensitivity — Functional sensitivity is defined as the lowest Tg
concentration that an assay can reliably and consistently measure under clinically
relevant conditions with less than 20 percent coefficient of variation. For many
years, the functional sensitivity of most Tg assays had been approximately 0.9
ng/mL. However, several assays with functional sensitivities of ≤0.2 ng/mL are
commercially available [4,9].
To further enhance the sensitivity of serum Tg in the detection of
persistent/recurrent thyroid cancer, serum Tg levels can be measured during
thyroid stimulating hormone (TSH) stimulation (either thyroid hormone withdrawal
or with recombinant human TSH [rhTSH, thyrotropin alfa] administration) [10].
When using the less sensitive assays (functional sensitivities of approximately 1
ng/mL), TSH stimulation will result in a previously undetectable serum Tg value
becoming measurable in as many as 20 to 25 percent of patients [11].
In the newer, more sensitive Tg assays, serum Tg concentrations (measured while
receiving levothyroxine [T4, thyroxine] suppression therapy) correlate with rhTSH-
stimulated Tg concentrations and, therefore, decrease the need for rhTSH-
stimulated measurements [4,9,12-15]. This was illustrated in a study of 849 Tg
antibody-negative patients being monitored after treatment for differentiated
thyroid cancer [9]. Patients with a TSH-suppressed serum Tg concentration <0.1
ng/mL (measured with an assay with a functional sensitivity of 0.05 ng/mL) were
unlikely to have an rhTSH stimulated Tg above 2.0 ng/mL. Similar findings were
noted in a study of 178 low-risk patients that compared basal and post thyroid
hormone withdrawal Tg levels. Basal serum Tg levels were <0.1 ng/mL in 130
patients. After withdrawal of thyroid hormone, 5 of 130 (3.8 percent) had a Tg >1
95
ng/mL and recurrence was diagnosed in only one patient. Among the 48 patients
with Tg >0.1 ng/mL, 42 percent had Tg >1 ng/mL after withdrawal and 11 percent
had recurrences [14].
Hook effect — Occasionally, immunometric assays may fail to detect very high
serum Tg concentrations due to the so-called "hook effect," in which extremely
high concentrations of Tg bind to each antibody, preventing the formation of the
two-antibody sandwich upon which the assay depends [16]. If this effect is
suspected, the sample should be reanalyzed after dilution to obtain a reliable Tg
measurement.
Heterophilic antibodies — False-positive Tg results have been reported as a
result of interference by heterophilic anti-mouse antibodies (HAMA) in an
immunometric assay [17]. In this report, approximately 3 percent of the 1100
blood specimens tested had substantial differences in the measured Tg value
before and after the specimens were treated to block potential heterophile
antibody interference.
While an uncommon clinical problem, the presence of HAMA antibody interference
should be considered in patients in whom an elevated Tg does not seem
appropriate for their clinical condition [18]. Since radioimmunoassay is very
unlikely to be affected by HAMA antibodies, repeat determination with a
radioimmunoassay technique is likely to reveal the true serum Tg level [19].
Potential assay interference with biotin — Some automated assays utilizing a
biotin-streptavidin separation system report falsely low or falsely high Tg levels. As
an example, in one report, biotin (10 mg/day) was associated with a falsely lower
Tg value, with maximal biotin interference observed two hours after ingestion of
the biotin [20]. While additional studies are needed to clarify the likelihood of
biotin interference associated with various biotin doses commonly being used as
over-the-counter products in an effort to improve hair and joint health, repeating
Tg values in the absence of biotin supplementation for at least two days can be
considered if the measured Tg value is not consistent with the clinical scenario.
THYROGLOBULIN ANTIBODIESWe recommend measuring
antithyroglobulin (anti-Tg) antibodies with each measurement of serum Tg. Anti-Tg
antibodies are detectable in as many as 10 percent of the general population [21]
and 20 percent of thyroid cancer patients [1,22]. These antibodies represent a
challenge, because thyroglobulin (Tg) values obtained in the presence of anti-Tg
antibodies may not be clinically reliable. Just as with serum Tg measurements, anti-
Tg antibody levels are dependent upon the assay used, and serial values need to
be compared within the same assay.
In patients with anti-Tg antibodies, serum Tg concentrations alone cannot be used
as a marker to detect persistent or recurrent disease after thyroidectomy and
96
ablation of residual normal thyroid tissue (see 'Clinical application' below).
Nevertheless, serum Tg and anti-Tg antibodies should be measured as in patients
without Tg antibodies because disease recurrence can be heralded by a rise in Tg
antibodies with or without a corresponding rise in serum Tg. (See 'Surrogate
tumor marker' below.)
Impact on Tg assay — Because anti-Tg antibodies can have a major impact on the
measurement of serum Tg, all laboratories that measure serum Tg should test for
anti-Tg antibodies in any serum sample submitted for Tg assay [23].
By binding with the circulating serum Tg, anti-Tg antibodies may decrease the
amount of unbound (free) Tg available for detection. Since immunometric assay
systems appear to detect only the unbound (free) Tg, this effect can result in
falsely low values. The magnitude of the interference is most noticeable at low Tg
levels where the immunometric assays can falsely report an undetectable serum
Tg if the anti-Tg antibodies are competing for the low-level circulating Tg
molecules. This effect is not abrogated by use of monoclonal antibodies directed
against epitopes of Tg that do not react with the autoantibodies [24]. Even very low
anti-Tg antibody levels can interfere with the Tg assay performance. There does
not appear to be a threshold value of anti-Tg antibodies that is predictive of
antibody interference [1]. In some anti-Tg antibody assays, more reliable results
are obtained if any level above the analytic sensitivity of the assay is considered to
be Tg antibody-positive rather than using the manufacturer recommended cut-off
levels [25].
Conversely, radioimmunoassays tend to report falsely high Tg values in the
presence of anti-Tg antibodies. This is probably because, unlike the immunometric
assay, the radioimmunoassay detects both unbound (free) Tg and bound Tg
(complexed to anti-Tg antibodies). As a result, the Tg value reported may be higher
than the actual "free" Tg circulating in the blood stream but is much less likely to
be false low value. Because of this discordance between radioimmunoassay and
immunometric assays, some experts have recommended that in the presence of
anti-Tg antibodies, radioimmunoassays should be used to measure the serum Tg
(recognizing the possibility of a false high result) but assuming a low value is likely
to be real and reflect the clinical situation [19]. While this approach appears to be
valid, radioimmunoassays are not widely available and still need to be interpreted
with caution in this setting.
In an attempt to determine whether a circulating anti-Tg antibody is causing assay
interference, several commercial labs offer Tg measurements by recovery assays,
using standard immunometric assays to determine serum Tg levels before and
after addition of a known amount of Tg. If 80 to 120 percent of the added quantity
of Tg is detected, the antibodies are not considered to be interfering and a Tg

97
value is reported. If the value falls outside that range, antibody interference is
assumed and no Tg value is reported. While these assays have gained popularity in
both the United States and Europe, many experts feel strongly that recovery
assays are not reliable [19].
Assays using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for
the measurement of serum Tg are currently being evaluated. This technology uses
trypsin to digest Tg bound to Tg antibody in order to release a specific target Tg
peptide that can be enriched and subsequently detected by LC-MS/MS. While this
assay was reported to detect Tg in the presence of anti-Tg antibodies [26], another
study found that LC-MS/MS failed to detect Tg in at least 40 percent of Tg antibody-
positive patients with known structural disease [27]. In addition, functional
sensitivity (0.5 to 1.0 ng/mL) remains inferior to radioimmunoassays [27,28]. The
cause for an undetectable MS Tg reading in the setting of known structural disease
has not been determined but could be related to a wide variety of factors,
including suboptimal functional sensitivity, poor Tg secretion by some tumors,
tumor Tg polymorphisms, or enhanced metabolic clearance of serum Tg-anti-Tg
antibody complexes [27-30].
Surrogate tumor marker — Following total thyroidectomy and radioiodine
ablation, serum anti-Tg antibodies usually fall to undetectable levels over three to
five years, while patients with persistent disease typically maintain detectable or
rising anti-Tg. The decline in anti-Tg antibody levels has prognostic significance as
a >50 percent decline during the first three years of follow-up is associated with a
<3 percent risk of recurrence [29,31]. Stable values are associated with an
approximately 20 percent risk of recurrence and rising values with approximately
40 percent risk of recurrence.
In two studies of thyroid cancer patients with undetectable serum Tg
concentrations, 18 and 49 percent of patients with serum anti-Tg antibody
concentrations >100 units/mL had a recurrence, compared with only 1 and 3
percent of patients with serum anti-Tg antibody concentrations <100 units/mL
[31,32]. Even in patients previously documented to be free of anti-Tg antibodies,
disease recurrence can be heralded by a rise in Tg antibodies with or without a
corresponding rise in serum Tg [19,32,33]. However, in a subsequent study
evaluating 812 patients with undetectable Tg antibodies on at least three serial
assays over a minimum of three years of follow-up, 5 percent (n = 40) of patients
converted to having detectable Tg antibodies, which was not associated with an
increased risk of structural disease recurrence when compared with the group that
were consistently Tg antibody undetectable (n = 772 patients) [34].
Just as with serum Tg measurements, anti-Tg antibody levels are dependent upon
the assay used, and serial values need to be compared within the same assay [35].

98
In patients with coexistent autoimmune thyroid disease at the time of surgery,
anti-Tg antibodies may persist far longer. In a study of 116 patients with anti-Tg
antibodies prior to thyroidectomy, antibodies remained detectable for up to 20
years in some patients without detectable thyroid tissue, and the median time to
disappearance of antibodies was three years [36].
CLINICAL APPLICATIONThe three major determinants of the serum
thyroglobulin (Tg) concentration are [19]:
●The mass of thyroid tissue present (both normal and malignant thyroid cells)
●The presence of injury to the thyroid (eg, after fine-needle aspiration [FNA],
thyroidectomy or radioactive iodine therapy, or during thyroiditis)
●The degree of thyroid-stimulating hormone (TSH) receptor stimulation (eg,
endogenous TSH, recombinant human TSH [rhTSH, thyrotropin alfa], serum
human chorionic gonadotropin [hCG], TSH receptor antibodies associated
with autoimmune thyroid disease)
Serum Tg levels are used to monitor patients with differentiated thyroid cancer for
persistent or recurrent disease after initial therapy (thyroidectomy with or without
radioiodine ablation). Serum Tg can be measured while taking suppressive doses
of thyroid hormone (TSH-suppressed) or with TSH stimulation (after thyroid
hormone withdrawal or after administration of rhTSH). An important caveat
pertains to patients in whom rhTSH, instead of withdrawal, is used for remnant
ablation. In that protocol, radioiodine is given 48 hours before the measurement
of the "stimulated" Tg, which may cause release of Tg from the remnants,
potentially causing spuriously higher values [37].
A suggested schedule for long-term monitoring of patients with differentiated
thyroid cancer, including serum Tg measurements, is found separately.
(See "Differentiated thyroid cancer: Overview of management", section on
'Monitoring response to therapy'.)
Marker of persistent disease — Serum Tg measurements (post thyroidectomy)
are useful for detecting persistent disease. Serum Tg measured before
thyroidectomy is a reflection of both the normal and malignant thyroid cells and
therefore is not a reliable predictor of thyroid cancer. Serum Tg is cleared with a
half-life of approximately 30 hours following thyroidectomy [38]. After total
thyroidectomy and radioiodine ablation, serum Tg levels would be expected to be
very low (<1 to 2 ng/mL), both during thyroxine (T4, levothyroxine) therapy and
after it is discontinued or stimulated by rhTSH, if the patient is cured [39].
However, 10 to 50 percent of patients will have persistent biochemical evidence of
disease as manifested by a detectable TSH-suppressed or TSH-stimulated serum
Tg [40-42]. A stimulated Tg value of at least 2 ng/mL or higher suggests that
disease is present and more extensive evaluation is indicated [39].
99
In patients with metastatic thyroid cancer, the serum Tg appears to be influenced
by the volume of disease, the specific histology of the lesion, and the anatomic
location of the metastasis. As an example, in a retrospective study of 417 thyroid
cancer patients, basal Tg concentrations (TSH-suppressed) correlated with the
volume and location of metastases (higher with bone and/or lung than cervical
metastases), and with the histologic type of cancer (higher levels in follicular and
Hürthle cell cancers compared with papillary cancers) [40]. Stimulated Tg
concentrations (in response to recombinant TSH) correlated only with histologic
type of cancer (highest in papillary and lowest in Hürthle cell cancers).
A meta-analysis found that the sensitivity and specificity of Tg measurement to
detect persistent thyroid cancer was 96 and 95 percent, respectively, after thyroid
hormone withdrawal; 93 and 88 percent, respectively, after rhTSH; and 78 and 98
percent, respectively, when measured while taking suppressive doses of thyroid
hormone [43]. Combining rhTSH stimulation with cervical ultrasound improved
sensitivity and negative predictive value to 93 and 99 percent, respectively, in a
study of 340 consecutive patients [44]. These data indicate that neck
ultrasonography will occasionally identify structural disease even when the Tg is
undetectable.
Detecting recurrent thyroid cancer — Because serum Tg concentration is
dependent on the mass of thyroid tissue present (both normal and malignant),
serum Tg values have the highest sensitivity and specificity for detection of
recurrent disease after the patient has had a total thyroidectomy and radioiodine
ablation of any microscopic residual normal thyroid cells remaining after total
thyroidectomy [45-47]. In addition, because Tg production and release from the
cell are significantly influenced by the degree of TSH stimulation, it is not
surprising that Tg measurements are likely to be more sensitive for detection of
recurrent disease following TSH stimulation (endogenous TSH or rhTSH) than
when measured during TSH suppression (on T4). Nevertheless, others have utilized
T4-suppressed Tg measurements along with ultrasound to assess for disease
recurrence. In one such study of 495 patients, a detectable Tg while taking T4
indicated recurrence in 23 of 44 patients, while the addition of ultrasound detected
42 of the 44 recurrences [48].
Although initial measurement of rhTSH-stimulated Tg is useful, repeat rhTSH-
stimulated Tg testing in patients whose first stimulated Tg is undetectable may not
be helpful. As an example, in one study of 68 patients with an rhTSH-stimulated Tg
that was initially <1 ng/mL at the time of remnant ablation, only 1 of 67 patients
had a detectable stimulated value two to three years later [49].
Predictor of clinical outcomes — Serum Tg concentrations may predict disease-
free remission at various times in the patient's course. The serum Tg concentration

100
in low-risk patients after initial surgery while hypothyroid, just prior to
administration of radioiodine for remnant ablation, has been correlated with
patient outcomes [50-52]. As an example, in a meta-analysis of 15 studies (3947
patients with differentiated thyroid cancer) evaluating TSH-stimulated (thyroid
hormone withdrawal) Tg prior to radioiodine ablation, the negative predictive
value of a serum Tg below a threshold of 10 ng/mL was 94.2 percent for the
absence of disease recurrence [42].
In a study that assessed Tg levels months after remnant ablation and with up to
five years of follow-up, recurrent tumor was identified in 1.6 percent of patients
with initial Tg after rhTSH <0.5 ng/mL, 5.5 percent of patients with Tg 0.6 to 2.0
ng/mL, and 80 percent of patients with Tg greater than 2.0 ng/mL [53].
It has become increasingly apparent that the results of repeated measurements of
serum Tg over time are often more useful than a single measurement [54,55]. A
progressive increase in serum Tg concentrations strongly suggests progressive
disease and should lead to a search for the disease, usually starting with a chest
radiograph, neck ultrasonography, and radioiodine scanning. Serum Tg doubling
time of less than one year was associated with significantly higher rates of 10-year,
disease-specific mortality, locoregional metastases, and identification of distant
metastases than Tg doubling times of one to three years or greater than three
years [56]. (See "Differentiated thyroid cancer: Overview of management", section
on 'Monitoring response to therapy'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
●Thyroglobulin (Tg) is a storage form of thyroxine (T4) and triiodothyronine
(T3). It is synthesized only by thyroid follicular cells and released into serum
along with the thyroid hormones. Given the cellular specificity of Tg, its
detection in biopsy specimens provides proof of the thyroid origin of the
tissue. (See 'Introduction' above.)
●Limitations to serum Tg assays include interassay variability and the high
prevalence of antithyroglobulin (anti-Tg) antibodies, which interfere with Tg
assay results. However, in spite of these limitations, measurements of serum
Tg provide important information about the presence or absence of residual,
recurrent, or metastatic disease in patients with differentiated thyroid cancer.
In addition, serum Tg concentrations may predict disease-free remission at
various times in the patient's course. (See 'Thyroglobulin assay' above
and 'Thyroglobulin antibodies' above and 'Clinical application' above.)

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●Testing of serum Tg should be done using a sensitive assay, ideally using the
same assay for each sample. Tg antibodies should always be measured, also
using the same assay over time, with each sample. (See 'Thyroglobulin
assay' above and 'Thyroglobulin antibodies' above.)
●In patients with anti-Tg antibodies, serum Tg concentrations alone cannot
be used as a marker to detect persistent or recurrent disease after
thyroidectomy and ablation of residual normal thyroid tissue. Nevertheless,
serum Tg and anti-Tg antibodies should be measured as in patients without
Tg antibodies because disease recurrence can be heralded by a rise in Tg
antibodies with or without a corresponding rise in serum Tg. (See 'Surrogate
tumor marker' above and "Differentiated thyroid cancer: Overview of
management", section on 'Thyroglobulin antibodies'.)
●A suggested schedule for long-term monitoring of patients with
differentiated thyroid cancer, including serum Tg measurements, is found
separately. (See "Differentiated thyroid cancer: Overview of management",
section on 'Monitoring response to therapy'.)

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Differentiated thyroid cancer: Surgical treatment
Author:
R Michael Tuttle, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Mar 09, 2020.
INTRODUCTIONThe primary therapy for differentiated (papillary and follicular)
thyroid cancer is surgery. Considerable controversy exists about how much thyroid
tissue should be removed at the initial operation, and there are no prospective
randomized clinical trials to provide guidance for selection of the optimal
operation.

This topic will review the rationale behind selection of the most appropriate type of
operation for these patients, the basic approaches to the operation, and
management of the medical complications of surgery, particularly
hypoparathyroidism. The technique of thyroidectomy and staging of thyroid
cancer, as well as an overview of the management of differentiated thyroid cancer,
radioiodine treatment, and external radiotherapy, are discussed separately.

●(See "Thyroidectomy".)
●(See "Differentiated thyroid cancer: Clinicopathologic staging".)
●(See "Differentiated thyroid cancer: Overview of management".)
●(See "Differentiated thyroid cancer: Radioiodine treatment".)
●(See "Differentiated thyroid cancer: External beam radiotherapy".)

IMPORTANCE OF PREOPERATIVE IMAGINGWe suggest preoperative

ultrasound evaluation of the central and lateral neck lymph nodes for all patients
with malignant cytological findings on the fine-needle aspiration (FNA).
Preoperative ultrasonography of the central and lateral neck identifies abnormal
lymph nodes in as many as 20 to 30 percent of patients [1,2]; these ultrasound
findings may alter the planned surgical procedure in up to 20 percent of patients
[3,4]. However, ultrasonography can miss as many as 50 percent of the involved
lymph nodes in the central neck because the overlying thyroid gland hinders
adequate visualization [5].
While ultrasonography is the preferred modality for evaluation of the thyroid and
cervical lymph nodes, alternative imaging modalities such as magnetic resonance
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imaging (MRI), computed tomography (CT) with contrast, laryngoscopy, and
endoscopy may be required in patients with potentially more advanced local
disease in order to accurately define the extent of tracheal, nodal, esophageal,
laryngeal, or vascular involvement [6]. Additional imaging beyond routine
preoperative neck ultrasonography should be obtained in patients presenting with
locally advanced disease, as manifested by:
●Clinically palpable metastatic lymphadenopathy or other evidence of
extensive lymph node involvement identified preoperatively, as these
patients may have nodal involvement in regions inadequately evaluated with
ultrasound (mediastinal, infraclavicular, retropharyngeal, or parapharyngeal
lymph node chains)
●Signs or symptoms of locally invasive disease:
•Dysphagia
•Respiratory compromise
•Hemoptysis
•Rapid tumor enlargement
•Changes in voice
•Vocal cord paralysis
•Tumor fixed to surrounding structures
•Ultrasonographic evidence of macroscopic extrathyroidal extension

In these locally advanced cases, we routinely obtain preoperative CT of the neck

and chest with intravenous contrast to evaluate these lymph node chains and
optimize surgical planning. In such cases, the benefit of accurate surgical planning
outweighs the delay in radioiodine administration that is necessary after the use of
iodinated contrast. Fludeoxyglucose-positron emission tomography (FDG-PET)
scanning is seldom used in preoperative surgical planning.

APPROACH TO THYROIDECTOMY
Types of procedures — There are two potential surgical approaches to
differentiated thyroid cancer: total (or near-total) thyroidectomy and unilateral
lobectomy and isthmusectomy. A third option, subtotal thyroidectomy, is
considered to be an inadequate procedure and is not recommended.
●Total thyroidectomy involves removal of all thyroid tissue while attempting
to identify and preserve the recurrent laryngeal nerve (RLN), the superior
laryngeal nerve (SLN), and the vascular supply to the parathyroid glands.
Near-total thyroidectomy is identical except for a slightly more conservative
approach to preserving the posterior thyroid capsule of the lobe contralateral
to the thyroid tumor.

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 ●A unilateral lobectomy and isthmusectomy involves removal of one entire
lobe and the isthmus, without entering the contralateral neck.
The difference between total and near-total thyroidectomy procedures is primarily
a semantic one because most patients who undergo radioiodine imaging after
total thyroidectomy have thyroid-bed uptake consistent with residual normal
thyroid tissue. Whether there is a clinically important difference between total
thyroidectomy and near-total thyroidectomy is uncertain. This was illustrated by
the results of an analysis of 23,605 patients from the National Cancer Institute
(NCI) Surveillance, Epidemiology, and End Results (SEER) database with median
follow-up of 6.6 years [7]. In a multivariate analysis adjusted for prognostic
variables (ie, older age, larger tumors with extrathyroidal extension), the absolute
difference in 10-year overall (0.9 percent) and cause-specific (0.2 percent) survival
favored total thyroidectomy, but the difference, although statistically significant,
was small and of uncertain clinical significance.
If total thyroidectomy is indicated, an experienced thyroid surgeon is unavailable,
and it is impossible to refer the patient elsewhere, then the slightly more
conservative "near-total" procedure should be performed. In addition, a surgeon
intending to perform a total thyroidectomy for more extensive disease may choose
to stop with a unilateral lobectomy and isthmusectomy if the RLN has been
damaged or intentionally sacrificed during the resection of the initial lobe. The
patient should subsequently be referred to a specialist for completion of
thyroidectomy [8].
Subtotal thyroidectomy, in which several grams of thyroid tissue are preserved
along the posterior capsule bilaterally, is an inadequate procedure for patients
with thyroid cancer. It is associated with a higher complication rate if subsequent
surgery is required, and we do not recommend it [9-11].
Choice of procedure — Given access to an experienced thyroid surgeon, we
suggest the following procedures for patients with papillary or follicular cancer.
●Tumor <1 cm without extrathyroidal extension and no lymph nodes –
When surgery is planned for unilateral intrathyroidal differentiated thyroid
cancer <1 cm, a thyroid lobectomy is the preferred approach unless there are
clear indications to remove the contralateral lobe (eg, clinically evident
thyroid cancer in the contralateral lobe, previous history of head and neck
radiation, strong family history of thyroid cancer, or imaging abnormalities
that will make follow-up difficult).
●Tumor 1 to 4 cm without extrathyroidal extension and no lymph nodes –
For intrathyroidal tumors between 1 and 4 cm, the initial surgical procedure
can either be a total thyroidectomy or thyroid lobectomy. Total
thyroidectomy would be chosen either based on patient preference, the

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presence of ultrasonographic abnormalities in the contralateral lobe
(nodules, thyroiditis in the contralateral lobe, or nonspecific
lymphadenopathy, which will make follow-up difficult), or on a decision by the
treatment team that radioiodine therapy may be beneficial either as adjuvant
therapy or to facilitate follow-up.
●Tumor ≥4 cm, extrathyroidal extension, or metastases – Total
thyroidectomy is recommended if the primary tumor is 4 cm in diameter or
greater, there is extrathyroidal extension of tumor, or there are metastases
to lymph nodes or distant sites.
●Any tumor size and history of childhood head and neck radiation – Total
thyroidectomy should also be performed in all patients with thyroid cancer
who have a history of exposure to ionizing radiation of the head and neck,
given the high rate of tumor recurrence with lesser operations in these
patients [12]. (See "Radiation-induced thyroid disease".)
●Multifocal papillary microcarcinoma (fewer than five foci) – Unilateral
lobectomy and isthmusectomy is an appropriate procedure for patients
whose pathology reports subsequently show multifocal papillary
microcarcinomas with fewer than five foci.
●Multifocal papillary microcarcinoma (more than five foci) – When
multifocal papillary cancer is appreciated preoperatively, particularly when a
large number of microcarcinoma are suspected (eg, greater than five foci,
especially if the foci are in the 8 to 9 mm size range), we are more likely to
perform a total thyroidectomy.
For patients whose initial procedure was a lobectomy and in whom pathology
shows multifocal papillary microcarcinomas with more than five foci,
especially if the foci are in the 8 to 9 mm range, we typically refer patients for
completion thyroidectomy.
●Indeterminate or suspicious thyroid nodules – For patients with a
cytologically indeterminate nodule (Bethesda III or IV), a unilateral lobectomy
and isthmusectomy is usually performed unless mutational testing suggests
the nodule is likely to be benign. Because as many as 60 percent of these
patients may prove to have benign disease, total thyroidectomy is usually not
required as the initial procedure [13]. If the final pathologic diagnosis is
cancer and if a completion thyroidectomy is needed (for example, to
administer radioiodine), it can be performed without significant increased
risk because the second surgery would avoid the first operative field [14,15].
This occurs most commonly in patients with follicular cancer or follicular
variant papillary cancer [15].

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 For patients with a cytologically suspicious nodule (Bethesda V), the choice
between a lobectomy and a total thyroidectomy is less clear, since the risk of
malignancy may exceed 80 percent, especially if mutational testing is
positive. Additional clinical characteristics and patient preference should help
determine the extent of surgery. (See "Diagnostic approach to and treatment
of thyroid nodules", section on 'Management'.)
Most patients with clinically significant (tumor >4 cm, extrathyroidal extension,
clinically apparent metastatic disease to nodes) papillary and follicular thyroid
cancer are best served by total (or near-total) thyroidectomy. The benefit of total or
near-total thyroidectomy in this subset of patients comes from the National
Thyroid Cancer Treatment Cooperative Study Group in 2006 [16]. In a multicenter
analysis of outcomes of nearly 3000 patients with differentiated thyroid cancer,
significantly worse overall survival was reported in the following groups of patients
who underwent less-than-total or near-total thyroidectomy (with risk ratios for all-
cause mortality in subgroups ranging from 1.36 to 1.76):
●Papillary cancer under age 45 years, with tumor greater than 4 cm, or in the
presence of macroscopic extrathyroidal extension or extracervical
metastases
●Papillary cancer at age ≥45 years, with tumor of at least 1 cm, or in the
presence of multifocal tumors, extrathyroidal extension, or metastases to
locoregional nodes or distant sites
●Follicular cancer under age 45 years, with tumor greater than 4 cm, or in the
presence of macroscopic multifocality, macroscopic invasion of either the
tumor capsule or extrathyroidal tissues, poor differentiation, or extracervical
metastases
●Follicular cancer at age ≥45 years
Additional data from the 2009 National Thyroid Cancer Treatment Cooperative
Study Group demonstrated a lower recurrence rate in patients with multifocal,
microscopic papillary cancer who had a total or near-total thyroidectomy (6 versus
18 percent in those undergoing less than near-total thyroidectomy) [17].
In properly selected patients with low-risk disease, however, thyroid lobectomy is
an acceptable alternative to total thyroidectomy [6,18]. While the National
Comprehensive Cancer Network (NCCN) guidelines have accepted lobectomy for
intrathyroidal low-risk differentiated thyroid cancers up to 4 cm in size for many
years [18], the American Thyroid Association (ATA) guidelines have previously
recommended total thyroidectomy for all tumors greater than 1 cm. However, the
2015 ATA guidelines endorsed thyroid lobectomy as sufficient initial treatment in
properly selected patients with intrathyroidal primary tumors as large as 4 cm,

107
provided that the patient and clinical team agree that a more extensive surgery is
not required for adjuvant therapy or to facilitate follow-up [6].
This renewed interest in thyroid lobectomy is the result of newer observational
data [7,19-23] reexamining the survival benefit previously attributed to total
thyroidectomy [24-28] in patients with intrathyroidal tumors. In properly selected
patients, clinical outcomes are very similar following unilateral or bilateral thyroid
surgery. As an example, in an analysis from the NCI SEER database, patients
treated with lobectomy had a 10-year overall survival (90.8 percent) and cause-
specific survival (98.6 percent) that was nearly identical to patients selected to
receive total thyroidectomy (90.4 and 96.8 percent, respectively) [7]. A greater
proportion of patients who were treated with lobectomy had smaller tumor size ≤2
cm (65 versus 53 percent) without extrathyroidal extension, suggesting that the
appropriate selection of candidates for lobectomy is important for achieving good
outcomes. In addition, there are fewer complications with unilateral surgery, even
among high-volume surgeons [8].

Additional support for thyroid lobectomy in patients with intrathyroidal tumors is

related to:

●The marked increase in diagnosis and treatment of very-low-risk thyroid

cancers
●A trend toward a risk-adapted, individual management approach in thyroid
cancer
●Recommendations calling for more selective use of radioiodine as ablation
or adjuvant therapy in intrathyroidal tumors (<4 cm)
●A decrease in the use of radioiodine scanning as a routine test in follow-up
●Routine use of neck ultrasonography as the primary follow-up imaging
modality
●A better understanding of how serum thyroglobulin (Tg) can be used in
follow-up of patients that did not undergo radioiodine ablation
As a result of these changes, clinicians will be evaluating an increasing number of
thyroid cancer patients that will be potential candidates for thyroid lobectomy. It is
important for patients to understand that even if the preoperative decision is to
proceed with a thyroid lobectomy, there are intraoperative findings (eg,
identification of metastatic lymph nodes, invasion into surrounding structures)
that could necessitate immediate conversion to a total thyroidectomy. Thus,
patients are encouraged to empower the surgeon to make the decision to proceed
with total thyroidectomy if clinically indicated. Furthermore, findings on the final
histology examination obtained several days after lobectomy may necessitate a
completion thyroidectomy in 5 to 20 percent of patients, depending on the
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preferences of the patient and treatment team with regard to need for radioactive
iodine therapy, additional staging information, or highly sensitive follow-up
studies [22,29-35].
Surgical technique — Knowledge of the surgical technique of thyroidectomy
allows the referring clinician to interpret operative reports and findings,
understand the particular risks of thyroidectomy, and explain to the patient what
lies ahead [10,11]. The technique of thyroidectomy is reviewed in detail elsewhere.
(See "Thyroidectomy".)
Preservation recurrent laryngeal nerve — Identification and preservation of the
RLN and SLN are the major technical challenges of this procedure (figure 1).
Indications for preoperative laryngeal exam and intraoperative nerve monitoring
are reviewed elsewhere. (See "Thyroidectomy", section on 'Laryngeal
examination' and "Thyroidectomy", section on 'Intraoperative nerve monitoring'.)
Parathyroid glands — In addition to identifying the RLN and SLN, normal
variations in the location and number of the parathyroid glands must be
appreciated to avoid postoperative hypoparathyroidism (figure 2). (See "Surgical
anatomy of the parathyroid glands" and "Thyroidectomy", section on 'Parathyroid
preservation'.)
●Most superior parathyroid glands are located within 1 cm of the intersection
of the RLN and the inferior thyroid artery, usually within the thyroid fascia.
Approximately 15 percent are located within the thyroid capsule, and the
remainder are located in the retropharyngeal or retroesophageal spaces.
●The location of the inferior glands is far more variable, although they are
usually anterior and lateral to the recurrent nerves. They may be just below
the superior glands, posterolateral to the lower pole of the thyroid;
immediately inferior or posterior to the thyroid; within or below the thymus;
or in the posterior mediastinum.
●The arterial supply for the parathyroid glands is usually provided by
branches of the inferior thyroid artery; compromise of these vessels is the
most common cause of postoperative hypoparathyroidism.
APPROACH TO LYMPH NODE DISSECTIONThe indications for central and
lateral compartment lymph node dissection are reviewed below. The surgical
approach, intraoperative challenges, and operative complications are reviewed
separately. (See "Neck dissection for differentiated thyroid cancer".)
Nomenclature — A frequently used nomenclature defines level I nodes as
submental and submandibular; level II, III, and IV nodes as upper, middle, and
lower jugular, respectively; level V nodes as posterior; and level VI nodes as
anterior central compartment (figure 3) [36].

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Therapeutic neck dissection refers to lymph node dissection when nodal disease is
identified or suspected based upon clinical examination or ultrasound evaluation,
whereas prophylactic dissection refers to lymph node dissection when nodal
disease is not identified preoperatively.

Our approach — In patients with differentiated thyroid cancer, we perform a

preoperative assessment of nodal status with ultrasound. A neck dissection for
differentiated thyroid cancer (papillary and follicular) should be performed as a
therapeutic procedure when nodal disease is identified or suspected based upon
the clinical examination or ultrasound evaluation.
A prophylactic central neck dissection (level VI) for patients with thyroid cancer is
controversial. It is not necessary for small, noninvasive papillary and most follicular
cancers. However, for patients with advanced primary tumors (>4 cm and/or with
extrathyroidal invasion), clinically involved lateral lymph nodes, or if the
information will contribute to the planning of further therapy, we perform
prophylactic central lymph node dissection. (See 'Therapeutic lymph node
dissection' below and 'Prophylactic lymph node dissection' below.)
Therapeutic lymph node dissection — Therapeutic lymph node dissection should
be performed if there is clinical evidence (on exam or ultrasound) of central or
lateral node metastases due to the increased risk of neck recurrence and mortality
[27]. This approach is consistent with the National Comprehensive Cancer Network
(NCCN) and American Thyroid Association (ATA) guidelines, which recommend
central and/or lateral neck dissection only in the presence of grossly positive
metastases [6,18].

During the operation, the lymph nodes should be inspected, and any suspected of
containing cancer should be biopsied.

●If nodes in the central compartment (level VI, the region bounded by the
jugular veins, the hyoid bone, and the upper mediastinum) are found to
contain cancer, dissection of all lymphatic and surrounding tissue in that
compartment should be performed (figure 4).
●If any nodes in the upper, middle, or lower jugular nodal groups (levels II,
III, IV) are found to contain cancer, complete dissection of nodal tissue along
the jugular and carotid vessels should be done. Radical dissection, with
removal of the internal jugular vein, spinal accessory nerve, and
sternocleidomastoid muscle, is rarely necessary.
There is general agreement that therapeutic node dissection should be performed
in patients with papillary cancer who have visibly involved nodes [6,37]. We
perform lateral node dissection based upon intraoperative gross involvement or
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preoperative ultrasound detection [38]. Preoperative cervical ultrasound can
detect clinically nonpalpable, metastatic nodes in up to 20 percent of patients with
papillary cancer, including those with primary tumors <1 cm in diameter [4,39].
Lateral compartment nodes containing metastases detectable by ultrasound are
associated with a shortened relapse-free survival, whereas those only found by
histologic examination do not predict altered outcomes [39].
Although cervical nodal metastases are rare in patients with follicular cancer,
patients with the Hürthle cell variant may have nodal disease (which predicts a
worse outcome) and should have a therapeutic neck dissection if metastatic lymph
nodes are identified [38].
Prophylactic lymph node dissection — We agree with the ATA guidelines, which
suggest prophylactic central compartment neck dissection (ipsilateral or bilateral)
for advanced primary tumors (>4 cm and/or with extrathyroidal invasion), clinically
involved lateral lymph nodes, or if the information will contribute to the planning
of further therapy, but is not necessary for small, noninvasive papillary and most
follicular cancers [6]. There are no data to show that routine
prophylactic lateral neck dissection benefits patients' long-term survival [40,41],
and therefore, we do not perform this procedure.
Microscopic regional lymph node metastases of papillary cancer occur in up to 80
percent of patients. However, only approximately 35 percent have cervical or
mediastinal node metastases that are detected at the time of initial surgery.
Because microscopic nodal disease is rarely of clinical importance or subsequent
radioiodine administration ablates these occult foci, and observational studies
have not shown a clear benefit in reducing locoregional recurrence rates, many
authors argue that prophylactic neck dissection of microscopic lymph node
metastases that are not clinically identifiable at the time of surgery may not
improve long-term outcome and could subject patients to more risk than benefit
[42-45].
However, the precise role of prophylactic neck dissection for well-differentiated
thyroid cancer remains controversial because in experienced hands, this
procedure can be done with minimal additional risk [46], and some observational
studies have suggested a survival benefit in selected patients [47-50]. Since thyroid
cancers harboring the BRAF mutation have the potential to be more clinically
aggressive and less responsive to radioiodine adjuvant therapy, some authors
have suggested that prophylactic central neck dissection be considered for these
patients [51]. However, until additional data are available demonstrating a clinical
benefit to this approach, we are not advocating prophylactic neck dissection on the
basis of the molecular profile of the tumor at the current time.

111
Others who routinely perform prophylactic central neck dissection argue that the
absence of involved nodes and adverse pathological features modifies the
indication for radioiodine therapy in many patients. In a retrospective study of 115
patients with papillary thyroid cancers under 2 cm (without ultrasound evidence of
cervical nodes) undergoing neck dissection, 13 of 115 patients were identified (11
percent) who were expected to receive adjunctive radioiodine therapy but did not
because of the surgical findings [52]. Follow-up in this study was only one year,
and any benefit of avoiding radioiodine therapy has to be balanced against the risk
of complications of neck dissection.
SURGERY FOR INVASIVE DISEASEThe primary tumor or local and regional
metastases may invade the strap muscles, trachea, recurrent laryngeal nerves
(RLNs), larynx, esophagus, thoracic duct, or carotid sheath. Careful preoperative
and intraoperative evaluation, including laryngoscopy and symptom-guided
imaging studies, is essential [11].
Conservative procedures, such as vertical hemilaryngectomy for unilateral
laryngeal cartilage invasion or circumferential tracheal resection for subglottic
invasion, may allow maintenance of function [53]. However, extensive intraluminal
invasion may occasionally necessitate total laryngectomy. While attempting to
preserve normal organ function is important, gross resection of all visible tumor, if
possible, should be the goal of surgical intervention.
COMPLICATIONSThyroid surgery is associated with risk for metabolic
complications, of which hypoparathyroidism is the most common, and anatomic
complications, including damage to the laryngeal nerves. Both complications are
more likely to occur after total thyroidectomy combined with lymph node
dissection [54]. (See "Thyroidectomy", section on 'Complications'.)
Postoperative hypoparathyroidism is rare following lobectomy because a
unilateral procedure avoids the contralateral neck. Similarly, although hoarseness
may result from damage to one recurrent laryngeal nerve (RLN) in approximately 1
percent of cases, a unilateral procedure avoids the possibility of bilateral paralysis
[55].
Hypoparathyroidism — Hypoparathyroidism is the most frequent complication of
total or near-total thyroidectomy. Transient hypoparathyroidism occurs in up to 20
percent of patients after surgery for thyroid cancer [56,57], and permanent
hypoparathyroidism occurs in 0.8 to 3 percent of patients after total thyroidectomy
[54,56,58-60] and is more common when anatomic landmarks are displaced and
obscured.
The hallmark of acute hypocalcemia is tetany, which is characterized by
neuromuscular irritability. The symptoms of tetany may be mild (peri-oral
numbness, paresthesias of the hands and feet, muscle cramps) or severe
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(carpopedal spasm, laryngospasm, and focal or generalized seizures, which must
be distinguished from the generalized tonic muscle contractions that occur in
severe tetany). Chvostek's and Trousseau's signs are indicative of neuromuscular
irritability due to hypocalcemia. (See "Clinical manifestations of hypocalcemia",
section on 'Tetany'.)
Current requirements for short hospital stays argue for early treatment of
hypocalcemia. We generally use the following regimen (table 1):
●Patients with symptomatic hypocalcemia (circumoral and distal extremity
paresthesias) or a serum calcium concentration below 7.8 mg/dL (2 mmol/L,
with correction for any abnormality in the serum albumin concentration)
should be treated with calcitriol 0.5 mcg twice daily and calcium
carbonate 500 mg four times daily. For patients who absorb calcium
carbonate poorly, calcium citrate may be used. Calcium glubionate is
available as a liquid, although calcium carbonate can be crushed and mixed
with water to form a drinkable slurry.
●Patients with more severe symptoms (muscle cramps) or a serum calcium
concentration below 7.5 mg/dL (1.9 mmol/L) should also receive calcium
gluconate by continuous intravenous drip for 24 to 36 hours or until the
serum calcium concentration rises and is maintained above 8 mg/dL (2
mmol/L). Details on preparing the intravenous calcium solution are found
elsewhere. (See "Treatment of hypocalcemia", section on 'Intravenous
calcium dosing'.)
●Emergency therapy is indicated in patients with tetany, seizures,
laryngospasm, or markedly prolonged QT intervals on the electrocardiogram.
Treatment is initiated with the intravenous administration of one 10 mL
ampule of 10 percent calcium gluconate over 5 to 10 minutes, followed by
calcium gluconate by continuous intravenous drip for 24 to 36 hours or until
the serum calcium concentration rises and is maintained above 8 mg/dL (2
mmol/L). (See "Treatment of hypocalcemia", section on 'Intravenous calcium
dosing'.)
●If oral vitamin D and calcium carbonate cannot be tapered and then
discontinued over the next two to eight weeks, the hypoparathyroidism may
be permanent. Measurement of serum parathyroid hormone (PTH)
concentrations when serum calcium is low can confirm the permanent need
for treatment. (See "Hypoparathyroidism", section on 'Management'.)
An alternative approach is to treat all patients undergoing thyroidectomy
with calcitriol and calcium carbonate starting the day before surgery, in an effort
to avoid the postoperative hypocalcemia, with a plan to taper and eventually
discontinue these medications over the next few weeks.

113
Hypoparathyroidism is reviewed in more detail separately.
(See "Hypoparathyroidism", section on 'Postsurgical hypoparathyroidism'.)
Recurrent and superior laryngeal nerve injury — Occasionally, the RLN must be
sacrificed intentionally due to direct tumor invasion into the nerve or surrounding
tissues. As a postoperative complication, unilateral paresis of the RLN has been
reported in approximately 3.9 percent of patients and bilateral in 0.2 percent [61].
However, after six months, the incidence of nerve paresis was only 1 percent,
suggesting that injury may be temporary.

Endotracheal intubation or laryngeal mask airway ventilation can cause RLN injury
as well as arytenoid dislocation, vocal cord edema, and other causes of
postoperative hoarseness. High division of the vagus nerve near the carotid bulb
will paralyze both the superior laryngeal nerve (SLN) and the RLN, resulting in both
sensory and motor deficits with significant risk for aspiration. Injury to the SLN
results in voice weakness or fatigue as well as changes to both voice quality and
pitch. Injury to the RLN may result in paresis or paralysis of the true vocal cord to a
paramedian or lateral position.

Intraoperative monitoring of RLN function may reduce this complication, but data
are conflicting. Intraoperative neuromonitoring and nerve injury following
thyroidectomy are reviewed in more detail separately. (See "Thyroidectomy",
section on 'Nerve injury/vocal cord paresis or paralysis'.)
POSTOPERATIVE THYROID HORMONE THERAPYAfter thyroid surgery,
patients require postoperative thyroid hormone therapy both to replace normal
hormone production and to suppress regrowth of tumor. Thyroid hormone
therapy, including goals for thyroid hormone suppression, is reviewed in detail
separately. (See "Differentiated thyroid cancer: Overview of management", section
on 'Postoperative thyroid hormone' and "Differentiated thyroid cancer: Overview
of management", section on 'Thyroid hormone suppression'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
●We suggest preoperative ultrasound evaluation of the central and lateral
neck lymph nodes for all patients with malignant cytological findings on the
fine-needle aspiration (FNA) and additional imaging in patients with locally
advanced disease. (See 'Importance of preoperative imaging' above.)
●The primary therapy for differentiated (papillary and follicular) thyroid
cancer is surgery. Surgical options include total/near-total thyroidectomy or

114
unilateral lobectomy with isthmusectomy. The operative approach depends
upon the extent of the disease (eg, primary tumor size and the presence of
extrathyroidal extension or lymph node metastases), the patient's age, and
the presence of comorbid conditions. Subtotal thyroidectomy is
an inadequate procedure for patients with thyroid cancer. (See 'Types of
procedures' above.)
●For patients with papillary or follicular cancer with a primary tumor >4 cm in
diameter, extrathyroidal extension of tumor, or metastases to lymph nodes
or distant sites, we recommend total thyroidectomy (Grade 1B). (See 'Choice
of procedure' above.)
●For patients with 1 to 4 cm intrathyroidal tumors, either thyroid lobectomy
or total thyroidectomy can be performed depending on the preference of the
patient and the treatment team. We usually reserve thyroid lobectomy for
tumors less than 3 cm confined to the thyroid without evidence of aggressive
histologies or vascular invasion. Total thyroidectomy is preferred for tumors
greater than 3 cm or if there are ultrasonographic findings in the
contralateral lobe or in cervical lymph nodes that would make follow-up
difficult. (See 'Choice of procedure' above.)
However, it is recognized that if an experienced thyroid surgeon is
unavailable and the patient cannot be referred elsewhere, a near-total
thyroidectomy or a lobectomy may be preferable to a more complete
operation complicated by bilateral nerve damage.
●For patients with intrathyroidal unilateral differentiated thyroid cancer <1
cm, we suggest a thyroid lobectomy and isthmusectomy rather than total
thyroidectomy (Grade 2B). The 30-year survival rate for this subgroup of
patients approaches 100 percent. If there are clear indications to remove the
contralateral lobe (eg, microcalcifications or small [3 to 4 mm] nodules with
suspicious characteristics in the contralateral lobe, previous history of head
and neck radiation, strong family history of thyroid cancer, or imaging
abnormalities that will make follow-up difficult), total thyroidectomy is
preferred. (See 'Choice of procedure' above.)
●For patients with thyroid cancer with clinical evidence (on exam or
ultrasound) of central or lateral node metastases, we recommend therapeutic
regional lymph node dissection (Grade 1B). For patients with large primary
tumors (>4 cm), high-risk features for recurrence (extrathyroidal invasion), or
if the information will contribute to the planning of further therapy, we
suggest prophylactic central compartment lymph node dissection (Grade 2C).
Prophylactic central lymph node dissection is not necessary for small,

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noninvasive papillary and most follicular cancers. (See 'Approach to lymph
node dissection' above.)
●Because of the high risk of hypocalcemia after thyroidectomy, serum
calcium concentration should be measured the evening and first morning
after thyroidectomy. Treatment of postoperative hypocalcemia should be
tailored to the severity and expected duration of parathyroid deficiency (table
1). (See 'Hypoparathyroidism' above.)

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Exogenous hyperthyroidism
Author:
Douglas S Ross, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Aug 13, 2021.
What's New
Dietary supplements and exogenous hyperthyroidism (August 2021)
Accidental overdose of thyroid hormone has been described in adults taking
dietary supplements that claimed to contain only herbs but also contained
significant (unlabeled) amounts of 3,5,3'-triiodothyronine (T3), thyroxine (T4),
and/or animal thyroid tissue [1]. In one report, 11 of 19 thyroid glandular products
purchased on the internet (made from animal tissue, purportedly without added
hormone) had up to 210 mcg T4 or 32 mcg T3 [2]. Discontinuation of the
supplement may be the only treatment needed. Symptomatic patients can be
treated with a short course of beta blockers. (See "Exogenous hyperthyroidism",
section on 'Causes'.)
Read more

INTRODUCTIONExogenous hyperthyroidism is the term used to describe

hyperthyroidism caused by ingestion of excessive amounts of thyroid hormone. It
may be intentional (ie, suppressive doses of thyroxine to treat thyroid cancer) or
inadvertent (ie, contamination of dietary supplements). When exogenous
hyperthyroidism is due to the surreptitious ingestion of thyroid hormone, it is
termed thyrotoxicosis factitia.
The clinical manifestations, diagnosis, and treatment of exogenous
hyperthyroidism will be reviewed here. An overview of disorders that cause
hyperthyroidism is found elsewhere. (See "Disorders that cause hyperthyroidism".)
CAUSESExogenous hyperthyroidism is caused by the ingestion of excessive
amounts of thyroid hormone. Levothyroxine (T4) is the most widely used thyroid
hormone preparation, but the hormone is also available as liothyronine (T3)
and thyroid extract (desiccated thyroid). Symptoms from exogenous
hyperthyroidism frequently occur at doses in excess of 200 mcg for T4, 50 mcg for

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T3, and 120 mg for desiccated thyroid. However, most patients are taking
considerably higher doses.
Exogenous hyperthyroidism can occur in several clinical settings [1]. As examples:
●Patients with thyroid cancer prescribed suppressive doses of thyroxine to
minimize potential thyroid-stimulating hormone (TSH) stimulation of tumor
growth.
●Patients with goiter prescribed excessive doses in an attempt to shrink the
thyroid gland.
●Patients with a psychiatric disorder who may intentionally be prescribed
excessive doses of thyroid hormone.
●Other patients, with or without the help of a clinician, may take excessive
doses to treat obesity, menstrual disorders, depression, or infertility.
●Patients who intentionally or accidentally (particularly children) take an
overdose of thyroid hormone. Accidental overdose has been reported due to
errors made by compounding pharmacies [2].
Accidental overdose has also been described in adults taking weight-reducing
dietary supplements (purchased over the internet) that claimed to contain
only herbs but also contained significant amounts of both T3 and T4 or
animal thyroid tissue [3-7]. Eleven of 19 glandular thyroid products
purchased on the internet had up to 210 mcg T4 or 32 mcg T3 [6]. In one
report, two individuals taking a Mexican weight loss supplement (consumed
at the recommended dose) developed T3 thyrotoxicosis; the supplement
contained 75 mcg T3 per tablet [7].
A novel form of exogenous hyperthyroidism is the ingestion of thyroid tissue
inadvertently removed and ground up with neck muscle in slaughterhouses to
prepare hamburger; this has resulted in at least two community outbreaks of
thyrotoxicosis [8,9]. The terms hamburger thyroiditis and hamburger
hyperthyroidism were applied to these outbreaks because the clinical presentation
mimicked that of painless thyroiditis (see "Painless thyroiditis"). Patients who ate
large quantities of "thyroid burgers" became thyrotoxic for several weeks to
months until their freezers were depleted, after which they had transient
hypothyroidism. Subsequent case reports have described similar findings after
ingestion of beef or sausage [10,11].
CLINICAL FEATURES
Clinical manifestations — The symptoms and signs in patients who take
excessive doses of thyroid hormone are similar to those in patients with
hyperthyroidism from other causes, such as Graves' disease. The classic symptoms
include weight loss, heat intolerance, tremor, palpitations, anxiety, increased

118
frequency of bowel movements, and shortness of breath. (See "Overview of the
clinical manifestations of hyperthyroidism in adults".)

There are, however, two important exceptions:

●Exophthalmos (ophthalmopathy) occurs only in patients with Graves'

hyperthyroidism because it is not caused by thyroid hormone per se.
However, lid lag and lid retraction, signs of catecholamine excess, do occur.
(See "Clinical features and diagnosis of Graves' orbitopathy
(ophthalmopathy)".)
●There is usually no goiter because exogenous thyroid hormone in amounts
sufficient to cause hyperthyroidism inhibits TSH secretion, resulting in thyroid
atrophy. In patients with goiter given thyroid hormone in an attempt to
reduce goiter size, however, the goiter may persist despite exogenous
hyperthyroidism.
Acute levothyroxine (T4) overdose can cause acute hyperthyroidism. Myocardial
infarction also can occur, especially in older adult patients, and seizures have
rarely been described in children [12-14]. In most cases, however, particularly in
children (who ingested a parent's medication), accidental ingestion of many
milligrams of T4 and the accompanying transient marked elevation in serum
thyroxine (T4) concentrations cause few symptoms and signs of hyperthyroidism
[14].
Chronic T4 overdose can cause chronic overt (low serum TSH, high free thyroxine
[T4] and/or triiodothyronine [T3]) or subclinical (low serum TSH with normal free
T4) hyperthyroidism. The skeleton and the cardiovascular system are the major
target tissues adversely affected by chronic overt and subclinical hyperthyroidism,
although abnormalities in other systems have been reported (table 1). Overt
hyperthyroidism is most clearly associated with accelerated bone remodeling,
reduced bone density, osteoporosis, and an increase in fracture rate, especially in
postmenopausal women. In some, but not all studies, even subclinical
hyperthyroidism is also associated with low bone density in postmenopausal
women. In addition, the frequency of atrial fibrillation is increased in older patients
with subclinical hyperthyroidism, as it is in patients with overt hyperthyroidism.
These topics are reviewed in detail elsewhere. (See "Bone disease with
hyperthyroidism and thyroid hormone therapy", section on 'Exogenous thyroid
hormone therapy' and "Cardiovascular effects of hyperthyroidism", section on
'Atrial fibrillation'.)
Laboratory and imaging — All patients with exogenous hyperthyroidism have
low serum TSH concentrations. Serum T4 and/or T3 may be elevated or normal,
depending upon the degree of hyperthyroidism and which thyroid hormone
119
preparation was ingested. Serum thyroglobulin (Tg) is suppressed and 24-hour
radioiodine uptake is low due to suppression of TSH secretion. Thyroidal artery
blood flow on Doppler is also reduced.
DIAGNOSISThe diagnosis of exogenous hyperthyroidism is based upon the
clinical features, laboratory findings, and 24-hour radioiodine uptake. Patients with
exogenous hyperthyroidism have classic biochemical findings (low TSH, elevated
or normal free T4 and/or T3). The absence of goiter, a low serum thyroglobulin (Tg)
concentration, and a low or undetectable 24-hour radioiodine uptake differentiate
exogenous hyperthyroidism from other causes of hyperthyroidism.
The serum concentrations of T4 and T3 may be useful in identifying the type of
thyroid hormone ingestion [1,2]. As an example, patients taking excessive
amounts of liothyronine (T3) have high serum T3 and low serum T4
concentrations. Those taking levothyroxine (T4) have high serum T4 and T3
concentrations, but the T4/T3 ratio is higher than that in most patients with
spontaneously occurring hyperthyroidism. Conversely, patients taking thyroid
extract have higher than normal serum T3/T4 ratios, like most patients with
Graves' hyperthyroidism, toxic nodules, and toxic nodular goiter, since thyroid
extracts contain a higher ratio of T3 to T4 than is present in euthyroid patient
blood.
Diagnostic evaluation — In the setting of thyroid cancer or goiter, intentional
intake of exogenous thyroid hormone is easily identified. A careful history may
also reveal intentional intake of excessive doses of thyroid hormone to treat
psychiatric disorders. In such cases, further evaluation is not necessary to
diagnose exogenous hyperthyroidism. (See "Differentiated thyroid cancer:
Overview of management", section on 'Thyroid hormone
suppression' and "Thyroid hormone suppressive therapy for thyroid nodules and
benign goiter" and "Unipolar depression in adults: Augmentation of
antidepressants with thyroid hormone", section on 'Long-term treatment'.)

Accidental ingestion of thyroid hormone (diet pills, contaminated meat) or

surreptitious use of thyroid hormone (thyrotoxicosis factitia) is usually more
difficult to detect. In these cases, further evaluation is needed to confirm the cause
of hyperthyroidism. The initial evaluation typically includes measurement of
radioiodine uptake. The findings on 24-hour radioiodine uptake can distinguish
hyperthyroidism due to de novo synthesis of thyroid hormone (normal or high
uptake) from either inflammation and destruction of thyroid tissue with release of
preformed hormone into the circulation or an extrathyroidal source of thyroid
hormone (nearly absent uptake). For patients with nearly absent uptake, we
measure serum Tg to distinguish exogenous hyperthyroidism (low Tg) from all

120
other causes of hyperthyroidism with nearly absent uptake (high Tg). Whenever
serum Tg is measured, a test for anti-Tg antibodies should be performed at the
same time (good laboratories do the latter first) because serum Tg measurements
are falsely low in immunometric assays in the presence of anti-Tg antibodies.

●Nearly absent radioiodine uptake – The 24-hour radioiodine uptake in the

thyroid is less than 1 percent in patients with exogenous hyperthyroidism
due to the suppression of TSH secretion, except in patients with some
autonomously functioning thyroid tissue. In addition to exogenous
hyperthyroidism, other causes of hyperthyroidism with low or nearly absent
24-hour radioiodine uptake values include any of the different types of
thyroiditis associated with release of preformed hormone from an inflamed
gland, struma ovarii, and sometimes iodine-induced hyperthyroidism.
(See "Overview of thyroiditis" and "Struma ovarii" and "Iodine-induced
thyroid dysfunction", section on 'Iodine-induced hyperthyroidism'.)
●Tg – Serum Tg concentrations are low in patients with exogenous
hyperthyroidism in the absence of goiter or thyroid cancer [15]. In contrast,
they are high in hyperthyroid patients with endogenous hyperthyroidism,
including functional metastatic thyroid cancer, struma ovarii, thyroiditis, and
iodine-induced hyperthyroidism.
In difficult cases where thyrotoxicosis factitia is suspected and Tg is either not
suppressed potentially because of a goiter, or Tg is undetectable potentially
because of anti-Tg antibodies, fecal T4 measurement may be useful. In one study,
fecal T4 values were approximately 0.8 mcg/g (1 nmol/g) in normal subjects and
were increased twofold in patients with Graves' hyperthyroidism and 12- to 24-fold
in patients with exogenous hyperthyroidism [16].
TREATMENTDiscontinuation or reduction in the dose of thyroid hormone is
usually the only treatment needed. When therapy is stopped in patients
taking levothyroxine (T4), serum T4 concentrations fall approximately 50 percent in
seven days. T3 is cleared more rapidly (serum half-life approximately one day).
However, very symptomatic patients may benefit from additional therapy.
●Beta-adrenergic antagonist drugs will relieve many of the symptoms of
hyperthyroidism promptly. (See "Beta blockers in the treatment of
hyperthyroidism".)
●In patients taking T4 (or thyroid extract), the radiographic contrast agents
ipodate or iopanoic acid can be given to inhibit T4 conversion to T3 (these
drugs are presently not available in the United States) [1]. The usual dose is
500 mg once daily; treatment is rarely needed for longer than seven days.
(See "Iodinated radiocontrast agents in the treatment of hyperthyroidism".)

121
 ●Cholestyramine can be given to bind T4 and T3 in the intestine, thereby
interrupting the normal enterohepatic circulation of the two hormones [17].
The usual dose is 4 g four times a day.
●Patients (usually children) seen shortly after accidental ingestion of very
large doses of thyroid hormone may be treated by induced emesis, gastric
lavage, and intragastric instillation of charcoal.
●While plasmapheresis and exchange transfusion have been used to treat
massive thyroid hormone overdose [1,2], most patients, especially children,
have few symptoms and signs of hyperthyroidism, and conservative
management is usually satisfactory [14].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Hyperthyroidism".)
SUMMARY AND RECOMMENDATIONS
●Causes – Exogenous hyperthyroidism is the term used to describe
hyperthyroidism caused by ingestion of excessive amounts of thyroid
hormone. It may be intentional or inadvertent. It can occur in several clinical
settings, including ingestion of excessive doses to treat thyroid cancer or to
shrink the thyroid gland in patients with goiter, or through ingestion of
weight-reducing dietary supplements
containing levothyroxine (T4), liothyronine (T3), or animal thyroid tissue.
(See 'Causes' above.)
●Clinical features – The symptoms and signs in patients who take excessive
doses of thyroid hormone are similar to those in patients with
hyperthyroidism from other causes and include weight loss, heat intolerance,
tremor, palpitations, anxiety, increased frequency of bowel movements, and
shortness of breath. Unless underlying thyroid disease is present, there is no
goiter or ophthalmopathy. (See 'Clinical features' above and "Overview of the
clinical manifestations of hyperthyroidism in adults".)
●Diagnosis – The diagnosis of exogenous hyperthyroidism is based upon
clinical manifestations (presence of hyperthyroid symptoms, absence of
goiter), abnormal thyroid function tests (low TSH, elevated or normal free
thyroxine [T4] and/or triiodothyronine [T3]), a low serum thyroglobulin (Tg)
concentration, and a low or undetectable 24-hour radioiodine uptake.
(See 'Diagnosis' above.)
●Treatment – Discontinuation or reduction in the dose of thyroid hormone is
usually the only treatment needed for most patients. When therapy is
stopped in patients taking thyroxine, serum T4 concentrations fall

122
approximately 50 percent in seven days. T3 is cleared more rapidly (serum
half-life approximately one day). (See 'Treatment' above.)
Beta-adrenergic antagonist drugs can be used briefly to immediately relieve
many of the symptoms of hyperthyroidism. (See "Beta blockers in the
treatment of hyperthyroidism".)

123
Medullary thyroid cancer: Clinical manifestations,
diagnosis, and staging
Author:
R Michael Tuttle, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jul 13, 2020.
INTRODUCTIONMedullary thyroid cancer (MTC) is a neuroendocrine tumor of
the parafollicular or C cells of the thyroid gland. MTC accounts for approximately 1
to 2 percent of thyroid cancers in the United States [1]. The production of
calcitonin is a characteristic feature of this tumor.

Most medullary thyroid carcinomas are sporadic. However, approximately 25

percent are familial as part of the multiple endocrine neoplasia type 2 (MEN2)
syndrome. The clinical manifestations, diagnosis, evaluation, and clinical staging of
MTC will be covered in this topic review. Treatment of this disorder is discussed
separately. MEN2 is reviewed in detail elsewhere.

●(See "Medullary thyroid cancer: Surgical treatment and prognosis".)

●(See "Classification and genetics of multiple endocrine neoplasia type 2".)
●(See "Clinical manifestations and diagnosis of multiple endocrine neoplasia
type 2".)
●(See "Approach to therapy in multiple endocrine neoplasia type 2".)

CLINICAL PRESENTATION
Sporadic MTC — Sporadic medullary thyroid cancer (MTC) accounts for
approximately 75 percent of all cases of the disease (table 1). The typical age of
presentation is in the fourth and sixth decades of life [1].
●Symptoms and signs – The most common presentation of sporadic MTC is
that of a solitary thyroid nodule, which occurs in 75 to 95 percent of patients
[2-5]. The C cells are predominantly located in the upper portion of each
thyroid lobe; thus, most tumors are located in this region. In most patients
with MTC, the disease has already metastasized at the time of diagnosis.
Approximately 70 percent of patients have clinically detectable cervical lymph
node involvement, up to 15 percent have symptoms of upper aerodigestive
124
tract compression or invasion such as dysphagia or hoarseness, and
approximately 5 to 10 percent have distant metastatic disease [1,6]. Distant
metastases may occur in the liver, lung, bones, and, less often, brain and
skin. Nodal metastases are more common in patients with multifocal disease
[7]. However, as calcitonin screening results in the identification of more
"micro" medullary cancers, the number of patients with metastases at
presentation appears to be decreasing [8-10]. Calcitonin screening for MTC in
patients with thyroid nodules is controversial. (See 'Diagnosis' below
and "Diagnostic approach to and treatment of thyroid nodules", section on
'Serum calcitonin concentration'.)
Systemic symptoms may occur due to hormonal secretion by the tumor.
Tumor secretion of calcitonin, calcitonin gene-related peptide, or other
substances can cause diarrhea or facial flushing in patients with advanced
disease. In addition, occasional tumors secrete corticotropin (ACTH), causing
ectopic Cushing's syndrome.
●Biochemical tests – Basal serum calcitonin concentrations usually correlate
with tumor mass but also reflect tumor differentiation, and they are almost
always high in patients with a palpable tumor [6]. Most MTCs also secrete
carcinoembryonic antigen (CEA), which, like calcitonin, can be used as a
tumor marker [11,12]. In addition, the expression of CEA on MTC cells has led
to the use of anti-CEA antibodies for immunotherapy. (See "Medullary thyroid
cancer: Systemic therapy and immunotherapy", section on 'Immunotherapy'.)
Thyroid function tests are normal in patients with MTC.
●Imaging – There are several ultrasound features of thyroid nodules (eg,
hypoechoic, microcalcifications) that are associated with thyroid cancer risk.
However, there are no ultrasound features that are pathognomonic for
thyroid cancer. Furthermore, the majority of studies evaluating suspicious
ultrasound characteristics of nodules focused on papillary thyroid cancer
(see "Overview of the clinical utility of ultrasonography in thyroid disease",
section on 'Criteria for identifying cancer'). In a small retrospective study
examining the ultrasound characteristic of nodules that were histologically
proven to be MTC and papillary thyroid cancer, 50 percent of MTCs were solid
and hypoechoic and 16 percent showed microcalcifications, compared with
69.2 and 69.2 percent, respectively, for papillary thyroid cancers [13]. The
presence of at least one suspicious ultrasound feature was almost equal in
patients with MTC (58.3 percent) and controls with benign nodules (55.5
percent), whereas it was significantly more frequent in patients with papillary
thyroid cancer (100 percent). In other series, hypoechogenicity was present in
50 to 89 percent and microcalcifications in 30 to 70 percent [14-16], and there

125
 was no difference in echogenicity or the presence or type of calcifications
between MTC and papillary thyroid cancer [15,16]. Large areas of calcification
(macrocalcification) were noted in 16 to 30 percent [13,15,16].
Rarely, the diagnosis of MTC is suggested by the presence of dense
calcifications seen on radiographs or imaging of the anterior neck.
Inherited MTC — Multiple endocrine neoplasia type 2 (MEN2) is subclassified into
two distinct syndromes (MEN2A and MEN2B) (table 2), each of which is transmitted
in an autosomal dominant fashion and is associated with MTC. These syndromes
result from different mutations in the RET proto-oncogene. In the past, familial
MTC (FMTC, an inherited syndrome characterized by the presence of only MTC
without hyperparathyroidism or pheochromocytoma) was considered a separate
entity but is now considered a variant of MEN2A [1]. Hereditary MTC is typically
bilateral and multicentric (see "Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2"):
●Classical MEN2A is associated with MTC, pheochromocytoma, and primary
parathyroid hyperplasia. While the penetrance of MTC is nearly 100 percent,
there is inter- and intrafamily variability in the specific pattern of the other
disease manifestations.
●MEN2B shares the inherited predisposition to MTC and pheochromocytoma
present in classical MEN2A, but does not include hyperparathyroidism. MTC
occurs in almost all patients. The tumor develops at an earlier age and may
be more aggressive than in MEN2A. Patients typically have a marfanoid
habitus (but do not have Marfan syndrome), mucosal neuromas, and
intestinal ganglioneuromatosis.
In the index case, the clinical presentation and manifestations of MEN2-associated
MTC are similar to those of sporadic MTC. The most common presentation is that
of a solitary thyroid nodule or cervical lymphadenopathy. Early diagnosis (prior to
any clinical manifestations) by screening of "at-risk" family members in MEN2
kindreds is important because MTC is a life-threatening disease that can be cured
or prevented by early thyroidectomy. (See "Classification and genetics of multiple
endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2", section on 'Screening of family members in MEN2
kindreds' and "Approach to therapy in multiple endocrine neoplasia type 2".)
DIAGNOSISThe diagnosis of medullary thyroid cancer (MTC) is usually made
after fine-needle aspiration (FNA) biopsy in a patient who has a solitary thyroid
nodule (or a dominant nodule within a multinodular goiter) (picture 1). The
sensitivity of FNA is 50 to 80 percent, although higher sensitivity can be obtained
by the addition of immunohistochemical staining for calcitonin [17,18]. If the
clinical suspicion for MTC is high (eg, patient with diarrhea, flushing, and a thyroid
126
nodule), calcitonin can be measured in the washout of the FNA biopsy needle [19],
although this may not be readily available in many commercial laboratories.
In some cases, the diagnosis of MTC is made after thyroid lobectomy for a
suspicious or indeterminate FNA biopsy. Surgical specimens from patients with
MTC show spindle-shaped and frequently pleomorphic cells without follicle
development because these cells originate from the calcitonin-producing
parafollicular C cells of the thyroid (picture 2).
The use of serum calcitonin screening to complement ultrasound and FNA in the
routine diagnosis of thyroid nodules is controversial in the United States [20].
Measurement of serum calcitonin has not been a part of the routine evaluation of
patients with thyroid nodules in the United States. The high frequency of falsely
high serum calcitonin values, the inability to confirm the high calcitonin by
pentagastrin stimulation in the United States, and the accuracy of FNA biopsy
would argue against a change in this recommendation. Further, occasional
patients with locoregional metastases or locally invasive MTC will have normal
unstimulated serum calcitonin concentrations [2]. In some countries (eg, European
countries) where pentagastrin is available, however, serum basal and stimulated
calcitonin levels are routinely used in the evaluation of thyroid nodules to facilitate
the preoperative diagnosis of MTC. This topic is discussed in detail separately.
(See "Diagnostic approach to and treatment of thyroid nodules", section on 'Serum
calcitonin concentration'.)
DIFFERENTIAL DIAGNOSISThe differential diagnosis in a patient presenting
with a neck mass is extensive and varies with the age of the patient at
presentation. The majority of these masses represent benign thyroid nodules and
cysts (see "Diagnostic approach to and treatment of thyroid nodules"). Neck
masses that are not of thyroidal origin may be from congenital (ie, vascular
anomaly), inflammatory (lymph node enlargement), or other neoplastic (primary or
metastatic disease) disorders. The differential diagnosis of a neck mass is reviewed
separately. (See "Differential diagnosis of a neck mass".)
In addition to medullary thyroid cancer (MTC), elevated calcitonin results may also
be seen in patients with hypercalcemia, hypergastrinemia, neuroendocrine
tumors, renal insufficiency, papillary and follicular thyroid carcinomas, goiter, and
chronic autoimmune thyroiditis [21,22]. Furthermore, prolonged treatment
with omeprazole (greater than two to four months), beta blockers, and
glucocorticoids has been associated with hypercalcitoninemia [23]. In addition, the
presence of heterophilic antibodies to calcitonin can falsely elevate serum
calcitonin levels [24].

127
Elevated carcinoembryonic antigen (CEA) levels can also occur in patients with
heterophilic antibodies, gastrointestinal tract inflammatory disease, benign lung
disease, and nonthyroid malignancies [1]. Cigarette smoking may also elevate CEA.
EVALUATIONFor patients diagnosed with medullary thyroid cancer (MTC) on
the basis of cytologic evaluation of a thyroid nodule, evaluation should include
measurement of serum calcitonin, carcinoembryonic antigen (CEA),
ultrasonography of the neck (if not already performed), genetic testing for
germline RET mutations, and biochemical evaluation for coexisting tumors,
especially pheochromocytoma. Our approach outlined below is largely consistent
with National Comprehensive Cancer Network (NCCN) and American Thyroid
Association (ATA) Guidelines for Management of Medullary Thyroid Cancer
(algorithm 1) [1,25].
Serum calcitonin and CEA — The serum calcitonin and carcinoembryonic antigen
(CEA) concentrations should be measured in patients diagnosed with MTC on the
basis of cytologic evaluation of a thyroid nodule. These tests can establish that the
tumor is capable of hypersecreting the hormones and, if so, the values can be
compared with postoperative values. Postoperatively, results may provide a
prognostic factor or indicate biochemical cure [26].
In a study of 226 patients with MTC (50 percent sporadic MTC, 33 percent multiple
endocrine neoplasia [MEN] type 2A [MEN2A], 1 percent MEN type 2B [MEN2B], and
16 percent familial MTC [FMTC]), preoperative serum calcitonin concentrations
were significantly correlated with tumor size in both the sporadic and familial
cases [27]. In addition, among 45 patients who had a preoperative serum
calcitonin concentration of 50 pg/mL or less, 44 had normal concentrations after
surgery. In contrast, only 50 of 120 patients with preoperative serum calcitonin
concentrations higher than 50 pg/mL had normal concentrations after surgery. In
a second study of 224 patients with MTC, 28 of 45 patients (62 percent) without
nodal metastases had normal calcitonin postoperatively, while only 18 of 177 (10
percent) of node positive patients had normal postoperative calcitonin levels [28].
Assessment of calcitonin and CEA doubling times postoperatively provides
sensitive markers for progression and aggressiveness of metastatic MTC [29,30].
As an example, postoperative calcitonin doubling time was a prognostic factor for
survival in a study of 65 patients followed for 3 to 30 years [29]. Ten-year survival
was 8, 37, and 100 percent for doubling times under six months, between six
months and two years, and greater than two years, respectively.
Radiologic evaluation — MTC can spread by local invasion or metastasis within
the neck or distantly [4,6]. When MTC is diagnosed by fine-needle aspiration (FNA)
biopsy, ultrasonography of the neck is indicated to look for cervical lymph node
involvement.
128
For patients with local lymph node metastases on ultrasound or with preoperative
serum basal calcitonin >500 pg/mL (indicating high risk of local or distant
metastatic disease), additional imaging is required to assess for metastatic disease
[31]. In this setting, we suggest cross-sectional imaging including chest computed
tomography (CT), neck CT, three-phase contrast-enhanced liver CT or contrast-
enhanced liver magnetic resonance imaging (MRI), axial MRI, and bone
scintigraphy.
In patients suspected of having skeletal metastases, MRI may be superior to other
imaging modalities [32].
We do not recommend 18-fluoro-2-deoxyglucose positron emission tomography
(FDG-PET) imaging or somatostatin receptor imaging for routine initial screening
for metastatic disease. The sensitivity of FDG-PET scanning for detecting metastatic
disease is variable [33,34] but improves with higher calcitonin levels (sensitivity 78
versus 20 percent for basal calcitonin value greater than or less than 1000 pg/mL,
respectively) [35]. The use of radionuclide imaging with 111-In-octreotide or 99m-
Tc-DMSA [36,37] is not currently recommended for routine initial screening for
metastatic disease [38]. However, three patients have been described who had
regional and distant metastases of MTC detected by somatostatin receptor
scintigraphy but not by CT scan [39]. How to select patients with a negative CT scan
to undergo somatostatin receptor scintigraphy is not clear. Scanning may be more
useful in localizing residual or recurrent disease after primary therapy.
Genetic screening in sporadic MTC — We suggest germline RET testing in all
patients with newly diagnosed C cell hyperplasia or apparently sporadic MTC.
Initial germline testing in patients with C cell hyperplasia or apparently sporadic
MTC should include sequencing of exons 10, 11, and 13 through 16 of
the RET gene. Sequencing of the remaining exons in the RET gene should be
considered in patients with clinical features or family history highly suggestive of
hereditary medullary syndromes who demonstrate no mutations in exons 10, 11,
or 13 through 16 [40]. While it is possible for clinicians to directly order genetic
testing from reference laboratories, we strongly encourage consultation with
genetic counselors who are familiar with both the ethical issues and legal informed
consent requirements (which can vary significantly in different regions) that are
involved in germline testing [1].
When the index patient is positive for a germline mutation, family members should
be offered genetic counseling and genetic screening. (See "Clinical manifestations
and diagnosis of multiple endocrine neoplasia type 2", section on 'Screening of
family members in MEN2 kindreds'.)
An important question is what proportion of patients with apparently sporadic
MTC have unsuspected germline mutations in the RET proto-oncogene (the

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underlying defect in MEN2) and, therefore, have heritable disease. Studies of
unselected patients with MTC have found, on average, that approximately 6 to 7
percent (range 1.5 to 24 percent) have germline RET mutations [41-45]. In one
report, 35 of 482 patients (7.3 percent) with apparently sporadic MTC had
mutations, and in 18 of these 35, gene carriers were identified in relatives [45].
Seventy-five percent of the familial medullary cases had no prior family history.
A much higher percentage (approximately 60 percent) of patients with sporadic
MTC have somatic (acquired) mutations in the RET gene within the tumor cells
(table 1) [46-49]. These mutations are present only in the tumor cells and are not
detected by standard genetic testing, ie, using leukocyte DNA. The presence of
somatic RET mutations correlate with lymph node metastases, persistent disease,
and lower survival [50]. However, in one study, only mutations in exons 15 and 16
of the RET gene were associated with the worse prognosis, while those in other
exons had a more indolent course [48]. Since it is unclear how knowledge of a
specific somatic (acquired) RET mutation should impact initial clinical management
and follow-up, we do not routinely evaluate primary tumor samples for RET
mutational status. However, in patients with symptomatic or structurally
progressive disease being considered for a systemic therapy (multitargeted kinase
inhibitors or selective RET inhibitors in RET-mutated tumors), we routinely perform
somatic mutational profiling of tumor tissue.
Testing for coexisting tumors — Most patients require biochemical evaluation
for coexisting tumors (particularly pheochromocytoma and hyperparathyroidism)
prior to thyroidectomy. Even when genetic screening is performed preoperatively,
the results are rarely known prior to surgery.
For patients with unknown RET mutational status and for patients who have a
germline RET mutation, we measure:
●Serum calcium (to rule out hyperparathyroidism requiring concomitant
surgical intervention).
●Plasma fractionated metanephrines (as the initial screen for
pheochromocytoma).
Normal plasma fractionated metanephrines values exclude a symptomatic
catecholamine-secreting neoplasm, but mildly elevated values of
normetanephrine could be falsely positive, in which case additional
evaluations including 24-hour urinary fractionated metanephrines,
catecholamines, and adrenal imaging may be required to effectively rule in or
rule out pheochromocytoma prior to surgery. Adrenal imaging should not be
performed unless there is biochemical evidence suggesting a possible
pheochromocytoma. (See "Clinical presentation and diagnosis of
pheochromocytoma".)

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In a patient with negative RET proto-oncogene testing and no family history of
MEN2 syndrome, biochemical testing for coexisting tumors is typically not
required.
STAGING
TNM staging — The pathological tumor, node, metastasis (pTNM) criteria for
clinicopathologic tumor staging (eighth edition) adopted by the Union for
International Cancer Control (UICC) and the American Joint Committee on Cancer
(AJCC) are based upon tumor size and the presence or absence of extrathyroidal
invasion, local and regional nodal metastases, and distant metastases (table 3)
[51]:
●Stage I – Medullary thyroid cancers (MTCs) that are less than 2 cm in
diameter without evidence of disease outside of the thyroid gland
●Stage II – Tumors >2 cm confined to the thyroid or tumors of any size
without lymph node metastasis that demonstrate gross extrathyroidal
extension invading only the strap muscles (sternohyoid, sternothyroid,
thyrohyoid, or omohyoid muscles)
●Stage III – Tumors of any size demonstrating metastatic lymph node
involvement in the central neck (levels VI or VII; pretracheal, paratracheal, or
prelaryngeal/Delphian, or upper mediastinal lymph nodes) with or without
gross invasion into the strap muscles (sternohyoid, sternothyroid, thyrohyoid,
or omohyoid muscles)
●Stage IV – Any distant metastases, or lymph node involvement outside of
the central neck (level VI/VII), or gross invasion into other structures of the
neck (beyond just strap muscle involvement)
One study evaluated the prognostic significance of a previous TNM staging
scheme in patients with MTC, most of whom were treated by total thyroidectomy
and then followed for a median of four years [3]. Although the follow-up was short,
mortality due to MTC was 0 percent in patients with stage I disease, 13 percent in
stage II, 56 percent in stage III, and 100 percent in stage IV [3]. A subsequent
analysis of MTC patients using the National Cancer Database and the SEER
(Surveillance, Epidemiology, and End Results) data set demonstrated that the
seventh and eighth editions of the AJCC staging system were associated with five-
year overall survival rates of 95 percent in stage I, 91 percent in stage II, 89
percent in stage III, and 68 percent in stage IV. Furthermore, disease-specific
survival rates were 100 percent in stage I, 99 percent in stage II, 97 percent in
stage III, and 82 percent in stage IV [52].
Dynamic risk stratification — Using the same concepts that were initially
developed for differentiated thyroid cancer (see "Differentiated thyroid cancer:
Clinicopathologic staging", section on 'Dynamic risk stratification'), dynamic risk
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stratification for MTC allows clinicians to modify initial AJCC staging risk estimates
over time based on the biological behavior the tumor and the response to therapy
in individual patients [53,54]. For application in MTC, the definitions of the
response to therapy categories needed to be modified to utilize calcitonin and
carcinoembryonic antigen (CEA) as tumor markers (rather than thyroglobulin). At
each follow-up visit, patients are classified as having one of the following clinical
outcomes:
●Excellent response – An undetectable calcitonin and normal-range CEA in
the absence of structurally identifiable disease
●Biochemical incomplete response – A detectable calcitonin or elevated CEA
in the absence of structurally identifiable disease
●Structural incomplete response – The presence of recurrent or persistent
structurally identifiable disease
In two retrospective studies examining MTC patients with a median of 5 to 7 years
of follow-up, an excellent response to therapy was associated with a structural
disease recurrence rate of 1 to 4 percent and a biochemical recurrence rate of 11
to 15 percent, with a disease-specific mortality of <3 percent [55,56]. However,
patients with a biochemical incomplete response demonstrated a disease-specific
mortality of 11 percent with the vast majority demonstrating persistent
biochemical evidence of disease (51 to 53 percent) or structural evidence of
disease (32 to 37 percent). The poorest outcomes were seen in those patients with
a structural incomplete response to initial therapy with disease-specific mortality
rates of 38 to 56 percent.
As noted above, the calcitonin and CEA doubling times can also provide
meaningful insights into prognosis and expected course of disease progression
that can further refine these response to therapy assessments [29,30]. (See 'Serum
calcitonin and CEA' above.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Medullary thyroid cancer".)
SUMMARY AND RECOMMENDATIONS
●Medullary thyroid cancer (MTC) is a neuroendocrine tumor of the
parafollicular or C cells of the thyroid gland; it accounts for approximately 3
to 5 percent of thyroid carcinomas. The production of calcitonin is a
characteristic feature of this tumor. Most cases are sporadic (table 1).
(See 'Clinical presentation' above.)
●A solitary thyroid nodule is the most common presentation of sporadic MTC
(in 75 to 95 percent of patients). In most patients, the disease has already
metastasized at the time of diagnosis. Basal serum calcitonin concentrations
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usually correlate with tumor mass but also reflect tumor differentiation, and
they are almost always high in patients with a palpable tumor. (See 'Clinical
presentation' above.)
●The diagnosis of sporadic MTC is usually made after fine-needle aspiration
(FNA) biopsy in a patient who has a solitary thyroid nodule (or a dominant
nodule within a multinodular goiter) (picture 1). The sensitivity of FNA is
improved by the addition of immunohistochemical staining for calcitonin. The
routine use of serum calcitonin screening to complement FNA in the routine
diagnosis of thyroid nodules is controversial in the United States.
(See 'Diagnosis' above and "Diagnostic approach to and treatment of thyroid
nodules", section on 'Serum calcitonin concentration'.)
●For patients diagnosed with MTC on the basis of cytologic evaluation of a
thyroid nodule, evaluation should include measurement of serum calcitonin,
carcinoembryonic antigen (CEA), ultrasonography of the neck (if not already
performed), genetic testing for germline RET mutations, and biochemical
evaluation for coexisting tumors, especially pheochromocytoma (algorithm
1). For patients with local lymph node metastases on ultrasound or with
preoperative serum basal calcitonin >500 pg/mL (indicating high risk of local
or distant metastatic disease), additional imaging is required to assess for
metastatic disease. (See 'Radiologic evaluation' above.)
●Some patients with apparently sporadic MTC have unsuspected
germline RET mutations (the underlying defect in multiple endocrine
neoplasia type 2 [MEN2]) and, therefore, heritable disease. We suggest
germline RET testing to all patients with newly diagnosed C cell hyperplasia or
apparently sporadic MTC. (See 'Genetic screening in sporadic MTC' above.)
●Given the possibility that any patient with MTC may have MEN2, if results of
germline RET testing are unknown (or positive), preoperative testing must
also include measurement of serum calcium (to rule out hyperparathyroidism
requiring concomitant surgical intervention) and testing for
pheochromocytoma. We suggest plasma fractionated metanephrines as the
initial screen for pheochromocytoma. (See 'Testing for coexisting
tumors' above.)
●The management of MTC is discussed in detail separately. MEN2 is also
reviewed separately. (See "Medullary thyroid cancer: Surgical treatment and
prognosis" and "Clinical manifestations and diagnosis of multiple endocrine
neoplasia type 2" and "Classification and genetics of multiple endocrine
neoplasia type 2" and "Approach to therapy in multiple endocrine neoplasia
type 2".)

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Medullary thyroid cancer: Surgical treatment and
prognosis
Author:
R Michael Tuttle, MD
Section Editors:
David S Cooper, MD
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 26, 2021.
INTRODUCTIONPatients with medullary thyroid cancer (MTC) can be cured
only by complete resection of the thyroid tumor and any local and regional
metastases. For patients with residual or recurrent disease after primary surgery
or for those with distant metastases, the most appropriate treatment (surgery,
chemotherapy, or radiotherapy) is less clear.
This topic review will discuss the role of surgery as primary therapy and the
approaches to treating patients with persistent or recurrent MTC after surgery.
The approach outlined below is largely in agreement with American Thyroid
Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines
[1,2]. Recommendations for the timing of thyroidectomy in children
with RET mutations and the role of chemotherapy in the treatment of MTC are
reviewed elsewhere. (See "Approach to therapy in multiple endocrine neoplasia
type 2", section on 'Preventive surgery' and "Medullary thyroid cancer: Systemic
therapy and immunotherapy".)
PREOPERATIVE EVALUATIONNewly diagnosed patients with medullary
thyroid cancer (MTC) should be staged both biochemically and radiologically
(algorithm 1). This evaluation is reviewed briefly below and in more detail
elsewhere. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and
staging", section on 'Evaluation'.)

The following tests should be performed:

●Measurement of serum calcitonin and carcinoembryonic antigen (CEA) to

determine whether they are produced by the tumor, and if so, as a baseline
for comparison with results obtained after surgery. Among patients with
either sporadic or familial tumors, those with higher preoperative serum

134
 calcitonin concentrations have larger tumors and are less likely to have
normal serum concentrations after surgery than those with lower
preoperative values [3].
●Ultrasonography of the neck to assess for local and regional disease.
Additional imaging is necessary for patients with local lymph node
metastases or with preoperative serum basal calcitonin >500 pg/mL
(indicating high risk of local or distant metastatic disease).
●Germline RET mutation analysis, as some patients with apparently sporadic
MTC have unsuspected germline RET mutations (the underlying defect in
multiple endocrine neoplasia type 2 [MEN2]) and therefore heritable disease.
Germline mutational analysis may be performed pre- or postoperatively.
Even when performed preoperatively, the results are rarely known prior to
surgery. The presence or absence of a germline mutation has little impact on
the initial surgical approach.
●Measurement of serum calcium and either plasma fractionated
metanephrines or 24-hour urinary excretion of metanephrine and
catecholamines to assess for hyperparathyroidism and pheochromocytoma,
respectively. This testing should be performed in all patients who have either
unknown RET mutation status or a germline RET mutation. In patients with
negative RET mutation analysis and no family history of MEN2-related
diseases, such testing typically is not required.
SURGICAL APPROACH
MTC confined to the neck — Total thyroidectomy rather than unilateral
lobectomy is the preferred surgical approach. Up to 10 percent of patients with
sporadic medullary thyroid cancer (MTC) and all patients with inherited MTC have
bilateral or multifocal disease [1]; in addition, the latter all have premalignant
diffuse C cell hyperplasia. (See "Medullary thyroid cancer: Clinical manifestations,
diagnosis, and staging" and "Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2".)

The extent of cervical lymph node dissection depends on the findings on

preoperative ultrasound as well as intraoperative identification of lymph node
metastases.

The types of surgical procedures are described in detail elsewhere.

(See "Thyroidectomy" and "Differentiated thyroid cancer: Surgical treatment",
section on 'Approach to lymph node dissection'.)
No ultrasound evidence of cervical lymph node involvement — For most
patients with MTC confined to the neck and no evidence of involved cervical lymph
nodes on preoperative ultrasound, we routinely perform prophylactic bilateral
135
dissection of the central lymph node compartment without prophylactic lateral
neck dissection. Prophylactic central neck dissection is not required in patients
with small intrathyroidal MTCs with a preoperative calcitonin <20 pg/mL, as
metastatic lymph nodes are exceedingly rare in this circumstance [4].

For patients with intraoperative evidence of central cervical lymph node

involvement, dissection of the involved lateral neck compartment is also
performed.

●Central lymph node dissection – Prophylactic bilateral dissection of the

central lymph node compartment (from the hyoid bone to the innominate
veins and medial to the jugular veins) is the preferred initial treatment for
most patients [1]. MTC usually spreads to the central neck nodes. In one
study of 101 consecutive patients with MTC (and no previous surgery), lymph
node metastases to the central compartment were seen in approximately 50
percent of both sporadic (n = 54) and hereditary (n = 47) cases [5]. Metastatic
spread to central neck lymph nodes is exceedingly rare, however, if the
preoperative basal calcitonin is <20 pg/mL [4].
In a retrospective series, patients treated with total thyroidectomy with
central neck lymph node dissection required fewer reoperations than those
receiving lesser procedures [6-8].
●Lateral lymph node dissection – Whether or not to perform lateral neck
dissections in the absence of ultrasonographically identifiable lymph node
metastases as part of the primary surgery remains controversial. The lateral
jugular and mediastinal nodes should be carefully evaluated intraoperatively,
followed by modified neck and/or mediastinal dissections only if positive
nodes are identified. Although we do not routinely advise lateral neck
dissections in the absence of identifiable lymph node metastases (regardless
of the serum calcitonin level), dissection of the ipsilateral lateral lymph node
compartment is performed for patients with intraoperative evidence of
central lymph node involvement.
In one study, ipsilateral lateral lymph node metastases were found in 10
percent of patients with no central node involvement, 77 percent of patients
with one to three central nodes, and 98 percent of patients with more than
four central nodes; contralateral lateral lymph node metastases were found
in 4.9 percent of patients with no central nodes, 38 percent of patients with
one to nine central nodes, and 77 percent with more than nine central nodes
[9].
The American Thyroid Association (ATA) guidelines committee could not
achieve a consensus agreement on this topic but did recommend that
136
 prophylactic lateral neck dissections "may be considered based on serum
calcitonin levels" [1]. Some members recommended against routine
prophylactic lateral neck dissections if there was no evidence of disease on
preoperative neck ultrasound. Other members utilized preoperative
calcitonin values to guide the extent of prophylactic neck dissections by
recommending prophylactic ipsilateral central and ipsilateral lateral neck
dissection for patients with basal serum calcitonin values >20 pg/mL and
prophylactic dissection of uninvolved contralateral lateral neck
compartments for serum calcitonin >200 pg/mL [1].
The primary argument in favor of routine use of prophylactic lateral neck
dissection in patients with a preoperative basal calcitonin level of ≤1000
pg/mL is that at least one-half of them will achieve biochemical cure
(calcitonin <10 pg/mL) [4]. Since a biochemical cure is associated with 98
percent 10-year survival and approximately 3 to 4 percent recurrence rate,
proponents of prophylactic lateral lymph node dissection argue that the
benefits outweigh the additional risks and complications associated with
routine use of prophylactic lateral neck dissections when done by
experienced surgeons [10-12].
The counter argument is that long-term survival rates are also excellent in
patients with a biochemical incomplete response to initial therapy (abnormal
postoperative calcitonin in the absence of structural disease progression),
ranging from 90 to 100 percent at 10 years of follow-up, with the highest
survival rates seen in patients with intrathyroidal MTC without evidence for
local or distant metastases [10,13,14]. Thus, the excellent outcomes
attributed to more aggressive upfront resection of the lateral compartment
subclinical lymph nodes may be more related to the underlying biology of the
disease rather than to our therapeutic interventions. Furthermore, routine
use of prophylactic lateral neck dissections will expose patients to additional
morbidity, particularly knowing that most of these surgeries are not done by
high-volume, very experienced surgeons.
Thus, it remains unclear if there is truly a survival benefit from more
aggressive upfront lymph node dissection done in an effort to achieve an
initial excellent response to therapy as opposed to a more measured surgical
intervention, recognizing that some patients will have a biochemical
incomplete response that may or may not require additional therapy in the
future based on follow-up imaging and the trend in
calcitonin/carcinoembryonic antigen (CEA) values.
Ultrasound evidence of cervical lymph node involvement — For patients with
MTC involving the thyroid and known cervical lymph nodal involvement

137
preoperatively, total thyroidectomy with bilateral central compartment dissection
and dissection of the involved lateral neck compartment(s) is the preferred initial
treatment. In addition to compartment-oriented dissection of the clinically
involved ipsilateral neck, prophylactic neck dissection of uninvolved contralateral
neck compartments should also be considered in patients with a basal calcitonin
level greater than 200 pg/mL if there is no evidence of distant metastases [1].
Locally advanced or metastatic MTC — In patients with locally advanced or
metastatic disease, total thyroidectomy with resection of involved lymph node
compartments is recommended in most patients. Since the goals of surgery are
largely palliative in this setting, a less aggressive surgical approach to the thyroid
primary and to lymph node dissection in the central and lateral neck
compartments may be warranted in order not to impair speech, swallowing,
parathyroid function, and shoulder mobility [1]. In the presence of grossly invasive
disease, more extended procedures with resection of involved neck structures may
be appropriate in properly selected patients, but function-preserving (speech,
swallowing) approaches are preferred. Disfiguring radical neck dissections do not
improve prognosis and are not indicated. The surgical approach should be
individualized based upon the patient's wishes, life expectancy, and other medical
comorbidities [1].
MTC diagnosed after lobectomy — If medullary thyroid cancer (MTC) is
diagnosed postoperatively after a unilateral lobectomy, management options
include completion thyroidectomy (eg, removal of the remaining thyroid tissue) or
observation with monitoring of serum calcitonin levels. Because patients with
hereditary MTC uniformly have bilateral disease, all patients with hereditary MTC
should have a completion thyroidectomy.
The approach in patients with sporadic MTC is less certain, and there are few data
to guide management decisions. The incidence of bilateral disease in patients with
sporadic MTC is low, ranging from 0 to 9 percent [1,4,15]. Therefore, completion
thyroidectomy is not routinely indicated in patients without a
germline RET mutation. However, we do perform completion thyroidectomy in
sporadic MTC if the postoperative serum calcitonin is elevated above the upper
normal value of the reference range or if there is imaging evidence of persistent
disease in the thyroid or regional lymph nodes [1].
POSTOPERATIVE MANAGEMENT
Monitor for postoperative complications — Immediately after surgery, the
patient should be monitored closely for the development of hypoparathyroidism
or injury to either the recurrent or superior laryngeal nerves. These complications
are reviewed in detail elsewhere. (See "Differentiated thyroid cancer: Surgical

138
treatment", section on 'Complications' and "Thyroidectomy", section on 'Calcium
supplementation'.)
Thyroxine therapy — Thyroxine (levothyroxine, T4) therapy should be started
immediately after surgery; an appropriate initial dose is 1.6 mcg/kg of body weight
(ie, approximately 0.075 to 0.15 mg daily). The adequacy of therapy should be
evaluated clinically and by measurement of serum thyroid-stimulating hormone
(TSH) in six weeks. The goal of T4 therapy should be to restore and maintain a
euthyroid state; suppression of serum TSH concentrations is not indicated in
patients with medullary thyroid cancer (MTC), because C cells are not TSH
responsive. Similarly, adjuvant therapy with radioiodine is contraindicated because
the tumor cells do not concentrate iodine [16].
Assessment of tumor samples for somatic mutations — Somatic mutations
in RET, HRAS, KRAS, or, rarely, NRAS can be identified in tumors of patients with
sporadic MTC. In some [17-19], but not other [20], studies, tumors with an
identifiable RET mutation had a more aggressive course than those without a
mutation. Nonetheless, we agree that somatic mutational analysis of tumor
samples is not required as part of routine clinical care [1]. However, molecular
characterization of the primary tumor (or metastatic foci) is recommended in
patients with progressive metastatic disease that warrants systemic therapy in
order to identify tumors that harbor a somatic RET mutation (which would suggest
treatment with a specific RET inhibitor). (See "Medullary thyroid cancer: Systemic
therapy and immunotherapy", section on 'Mutation-selective kinase inhibitors'.)
SUBSEQUENT MANAGEMENTAfter thyroidectomy, it is important to
evaluate patients to determine if surgery was curative [10]. We measure serum
calcitonin and carcinoembryonic antigen (CEA) to assess for cure. Subsequent
management depends upon these values.
Serum calcitonin and CEA measurement — Serum calcitonin and
carcinoembryonic antigen (CEA) should be measured two to three months after
surgery to detect the presence of residual disease. Patients who have normal
serum CEA and undetectable serum calcitonin values are considered biochemically
cured and have the best prognosis [10,13,21,22]. Among those in one large series
who were biochemically cured, the five-year recurrence rate was only 5 percent
[11].
The timing of measurement of serum calcitonin after surgery is important because
the serum calcitonin concentration falls slowly in some patients, with the nadir not
being reached for several months [23]. However, in patients who are surgically
cured, calcitonin levels begin to rapidly decline within the first postoperative hour
[24], often achieving undetectable levels within the first few postoperative days in
patients destined to achieve a biochemical cure [25-29]. Therefore, serum
139
calcitonin measurements as early as a few days to weeks after surgery can provide
early evidence of biochemical remission in many patients, but elevated levels in
the immediate postoperative period do not necessarily indicate persistent disease.
Undetectable calcitonin and normal CEA — For patients with undetectable
calcitonin levels and carcinoembryonic antigen (CEA) values within the normal
reference range after surgery (ie, biochemically cured), subsequent follow-up
should include (algorithm 2):
●Physical examination twice yearly for two years and then yearly thereafter.
●Measurement of serum calcitonin and CEA levels twice yearly for two years
and then yearly thereafter.
●Neck ultrasound 3 to 12 months postoperatively (depending on the extent of
lymph node involvement prior to surgery) to establish a baseline.
Additional imaging is not required unless the calcitonin or CEA values rise
during follow-up.
Persistent hypercalcitoninemia — A high basal serum calcitonin value three or
more months after surgery is presumptive evidence of residual disease. Thirty to
55 percent of patients with palpable medullary thyroid cancer (MTC) or
nonpalpable but macroscopic MTC who undergo attempted curative resection
have persistently high serum calcitonin concentrations [5,6,11,30,31].
The prognosis for patients with postoperative hypercalcitoninemia depends
primarily upon the patient's age and the extent of disease at the time of initial
surgery [6,11,13,32-34]. In a series of 899 patients with MTC (57 percent sporadic),
the 10-year survival in the patients with postoperative hypercalcitoninemia (57
percent of the total group) was 70 percent compared with 98 percent in patients
who were biochemically cured [11]. Younger age at surgery and absence of lymph
node involvement were predictive of biochemical cure.
Further evaluation and management depend upon the magnitude of the elevation
in the serum calcitonin concentration (algorithm 2). In addition, for patients with
persistent elevation, assessment of calcitonin and CEA doubling times provides
sensitive markers for progression and aggressiveness of metastatic MTC [35,36].
(See 'Prognosis' below.)
●Calcitonin <150 pg/mL – Calcitonin values that are detectable but less than
150 pg/mL two to six months after surgery usually indicate persistent
locoregional disease in the neck. Therefore, neck ultrasound with or without
additional cross-sectional imaging (computed tomography [CT] or magnetic
resonance imaging [MRI] of the neck) should be performed to evaluate for
the presence of persistent macroscopic metastatic disease. Serum calcitonin
and CEA are measured every 6 to 12 months.

140
If imaging is positive, meticulous dissection of all cytologically confirmed local
and regional nodal tissue can be considered if there is no evidence of disease
outside of the neck or mediastinum. As in the primary surgical setting,
compartment-oriented neck dissections are recommended when surgery is
performed for cytologically confirmed locoregional disease. More focused
neck dissections may be appropriate in previously dissected neck
compartments. However, outside of centers experienced in managing these
patients, only those with overt disease in the neck and no distant metastases
should undergo neck dissection in this setting. (See 'Management of
persistent/recurrent disease' below.)
If imaging is negative and the serum calcitonin values measured every three
to six months remain stable, neck ultrasound is usually performed every 6 to
12 months for two to three years, then less often during long-term follow-up.
Additional imaging should be considered in patients with rising calcitonin and
CEA values, with the type and frequency of testing based on both the
magnitude and rate of rise of these biochemical markers. (See 'Small volume,
asymptomatic' below.)
●Calcitonin ≥150 pg/mL – Calcitonin values that remain ≥150 pg/mL two to
six months after surgery increase the likelihood that the patient may have
distant metastases [1,2]. Therefore, patients with postoperative calcitonin
levels that are ≥150 pg/mL should undergo neck ultrasound and additional
imaging (CT or MRI of neck, chest, and abdomen; bone scan or bone MRI in
patients suspected of having skeletal metastases) to identify possible distant
metastases. The liver is the most common site of metastases in patients with
MTC, occurring in approximately 45 percent of patients with advanced
disease [1]. Liver metastases are best identified with three-phase contrast-
enhanced liver CT or contrast-enhanced liver MRI. Other sites include bone,
brain, and lung.
If imaging is negative, monitoring with physical examination, measurement
of serum calcitonin and CEA, and evaluation of the neck with ultrasonography
should continue. The frequency of repeating imaging studies will be
dependent on the magnitude and rate of rise of the calcitonin and CEA
values. As an example, patients with stable postoperative serum calcitonin
values in the 150 to 300 pg/mL range are usually followed with yearly neck
ultrasound for several years, reserving repeat cross-sectional imaging (neck,
chest, abdomen) to look for distant metastases in those patients with rising
calcitonin or CEA values.
18-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) scans
are considered only when the serum calcitonin is higher than 500 to 1000

141
 pg/mL. In one report of 28 patients with MTC, PET had a sensitivity of 78
percent when calcitonin was >1000 pg/mL but failed to detect disease if
calcitonin was <500 pg/mL [37]. Alternative PET tracers such as fluorine-18-L-
dihydroxyphenylalanine (18F-DOPA) [38-41] and gallium-68 (68Ga)
radiolabeled somatostatin analogue peptides (DOTATATE, DOTATOC, and
DOTANOC) [41-47] have been studied and appear to be more sensitive for
disease detection than FDG PET scanning. The precise role for these
alternative tracers is being defined.
Radionuclide bone imaging can be helpful in selected cases when cross-
sectional imaging fails to identify the source of the persistent
hypercalcitoninemia [48-50]. Attempted localization of disease by
catheterization of the hepatic veins, both internal jugular veins, and the
innominate veins, with measurements of serum calcitonin before and after
calcium stimulation or laparoscopic examination of the liver, is rarely
considered and only if these findings would impact clinical management [51].
If imaging is positive, treatment depends upon the site of disease and may
include surgical resection and/or external beam radiation therapy (EBRT).
(See 'Management of persistent/recurrent disease' below.)
Management of persistent/recurrent disease — Treatment options for patients
with recurrent/residual disease include observation/active surveillance, surgical
resection, EBRT, and other directed therapies (such as radiofrequency ablation,
cryoablation, embolization) or systemic therapies. In the past, patients with
identifiable residual or recurrent MTC were operated on routinely. However,
despite routine lymphadenectomy or excision of palpable tumor, their serum
calcitonin concentrations often did not normalize after surgery [52]. This has led to
a more critical evaluation of the need for and timing of therapeutic interventions
and reevaluation of the role of cautious observation in properly selected patients.
The following approach to management of residual disease is based upon
observational studies and clinical experience.

The recommended treatment approach for persistent/recurrent disease depends

upon a variety of clinical factors, including:

●Whether or not the disease can be localized

●The volume of disease
●The precise location(s) of the metastatic disease
●Whether or not the disease is causing symptoms
●The rate (or likelihood) of clinically significant structural disease progression
●RET mutational status
Small volume, asymptomatic
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●Biochemical evidence of disease without structural correlate – Patients
with detectable calcitonin and/or abnormal CEA values without structurally
identifiable disease are best followed with observation. The extent and
frequency of cross-sectional imaging is dependent on the magnitude and
doubling time of calcitonin and CEA (see 'Persistent
hypercalcitoninemia' above). In the absence of structurally identifiable
disease, we do not suggest additional surgery or systemic therapies.
In the absence of gross residual disease, we also do not recommend routine
use of postoperative EBRT as adjuvant therapy, even if the postoperative
calcitonin and CEA values are abnormal. We reserve adjuvant EBRT for very
select patients with extensive preoperative gross extrathyroidal extension or
large-volume, multicompartment macroscopic lymph node involvement [1].
The lack of randomized trials makes it difficult to provide definitive
recommendations with regard to the use of EBRT as adjuvant therapy. We
feel that EBRT in this setting may improve locoregional control but are not
convinced that there is an overall survival benefit [53]. Furthermore, the
potential benefits of improved locoregional control must be weighed against
the wide range of acute and chronic toxicities associated with EBRT.
In a retrospective study of 51 patients with persistently elevated calcitonin
(ranging from 540 to 400,000 pg/mL) and no evidence of residual disease, the
local relapse rate was significantly lower in those who were treated with
radiation therapy because of advanced local disease at presentation (29
versus 59 percent) [54]. There was no difference in 10-year survival between
the two groups (72 versus 60 percent).
●Small-volume residual disease outside of cervical lymph nodes (thyroid
bed or soft tissue metastases) – Small-volume disease outside of cervical
lymph nodes is usually the result of gross extrathyroidal extension into major
structures in the neck, and it often reflects microscopic disease remaining
after all macroscopic disease has been surgically resected (R1 resection).
Usually, this is microscopic disease involving muscle, airway, esophagus, soft
tissues in the neck, or thyroid bed. As these patients are at high risk of
locoregional recurrence, we suggest EBRT as adjuvant therapy in this setting.
Structurally identifiable small-volume disease can also be a manifestation of
an early soft tissue recurrence of MTC, in which case the initial treatment
option would be surgical resection, usually followed by EBRT (or occasionally
EBRT alone if surgery is unlikely to be successful or likely to result in
unacceptable morbidity).
Retrospective analyses have suggested that radiotherapy may prolong the
interval until disease progression or recurrence in some patients. In one

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 retrospective series, as an example, the 10-year rate of control of local and
regional disease was 86 percent in patients with residual microscopic neck
disease who received postoperative radiotherapy versus 52 percent in those
who were not treated [53].
●Small-volume lymph node metastases – For most MTC patients with
persistent, asymptomatic small-volume locoregional disease (subcentimeter
lymph node metastases), we suggest active surveillance as the best
management option. Reoperation is frequently not curative and can be
associated with morbidity (ie, hypoparathyroidism, injury to recurrent
laryngeal nerve or accessory nerve). In addition, observation of
asymptomatic, stable lymph node metastases is nearly always recommended
if the basal serum calcitonin is >1000 pg/mL or if more than five metastatic
lymph nodes were removed with a previous surgery as reoperation is almost
never curative in these settings [1]. Patients are followed with serial cross-
sectional imaging at 6- to 12-month intervals, and surgical intervention is
reserved for patients that have documented structural disease progression.
●Small-volume distant metastases – Similar to asymptomatic small-volume
lymph node metastases, small-volume distant metastases (subcentimeter
metastatic foci) are usually followed with observation. It is not uncommon for
small pulmonary and liver metastases to remain asymptomatic and progress
very slowly (or not all) over many years.
Large volume or symptomatic
●Macroscopic gross residual disease in the thyroid bed or cervical soft
tissue metastases – If the gross residual disease is confirmed to be
unresectable or if the patient/treatment team agree that a complete surgical
resection would produce unacceptable morbidity, we suggest EBRT to
improve locoregional control. While systemic therapy (such as multitargeted
kinase inhibitors or selective RET inhibitors in RET-mutated tumors) can be
considered in this setting, our preference is to use EBRT to achieve local
regional control as the initial treatment unless there are other pressing
indications to begin systemic therapy [55].
●Symptomatic or large-volume locoregional lymph node disease –
Resection of large-volume locoregional lymph node disease may be
necessary to prevent invasion into surrounding major structures.
Occasionally, lymph node metastases can present as painful lesions that can
be readily palliated with surgical resection. However, since additional surgery
rarely achieves a biochemical cure if the basal serum calcitonin is >1000
pg/mL or if more than five metastatic lymph nodes were removed with a
previous surgery, cautious observation or systemic therapies (tyrosine kinase

144
 inhibitors) can be considered for asymptomatic large-volume lymph node
metastases detected in this setting.
●Symptomatic or large-volume distant metastasis – Rather than
immediately initiating systemic therapy, we prefer to treat individual (or a
few) isolated symptomatic or large-volume distant metastases with locally
directed therapies such as surgical resection, EBRT, embolization, or
radiofrequency ablation. For patients with symptomatic or progressive
metastatic disease that cannot be effectively treated by locally directed
therapies, systemic treatment with biologic response modifiers (ie,
multitargeted kinase inhibitors or selective RET inhibitors in RET-mutated
tumors) may improve progression-free survival. Molecular characterization of
the primary tumor or metastatic foci is recommended prior to initiating
systemic therapy in order to identify patients with sporadic MTC that may
harbor a somatic RET mutation, which would likely respond to specific RET
inhibitors. Kinase inhibitors are reviewed in more detail separately.
(See "Medullary thyroid cancer: Systemic therapy and immunotherapy",
section on 'Mutation-selective kinase inhibitors'.)
Locally directed therapies are recommended in the following clinical settings:
•Large-volume solitary metastatic lesions in the lung, liver, or brain should
be considered for surgical resection. Radiofrequency ablation may be an
option for smaller peripheral lung metastases.
•Oligometastatic lesions in the bone can be treated with surgical
resection, EBRT, embolization, and/or antiresorptive agents (eg,
bisphosphonates, denosumab). EBRT is often utilized to palliate painful
bone metastases or decrease the risk of fracture from progressive growth
of a bone metastasis. (See "Overview of therapeutic approaches for adult
patients with bone metastasis from solid tumors", section on 'General
approach to the patient'.)
•Multiple liver metastases may be amenable to localized therapies such as
transarterial chemoembolization or, less commonly, percutaneous
ethanol ablation or radiofrequency ablation.
•Skin metastases are usually treated with surgical resection or, less
commonly, with EBRT.
Palliation of the symptoms associated with hormonal excess — Diarrhea and
ectopic Cushing's syndrome, the most common hormonal excess syndromes, are
usually seen in the setting of large-volume persistent/recurrent disease.
●Diarrhea – Usually associated with large-volume liver metastases, the
diarrhea associated with MTC can have a major impact on quality of life.
Dietary measures such as avoiding alcohol intake and maintaining a diet that

145
 limits high-fiber foods can be augmented with antimotility agents
(loperamide, diphenoxylate/atropine, or codeine) as first-line therapy.
Somatostatin analogs may provide modest symptomatic improvement in
some patients. In selected patients, debulking of large tumor deposits with
surgery or chemoembolization may improve diarrhea.
●Ectopic Cushing's syndrome – We prefer vandetanib (prior to medical or
surgical adrenalectomy) as first-line therapy for ectopic Cushing's syndrome,
based on reports of a very rapid decline in serum cortisol levels in several
patients [56,57]. (See "Medullary thyroid cancer: Systemic therapy and
immunotherapy", section on 'Vandetanib'.)
Because Cushing's syndrome is associated with severe and debilitating side
effects, treatment should be strongly considered even in the setting of large-
volume persistent/recurrent disease. In our experience, medical therapy
(ketoconazole, metyrapone, mitotane, mifepristone) is generally suboptimally
effective and poorly tolerated. Tumor debulking is unlikely to be effective as
these patients usually have multiple sites of large-volume disease.
Conversely, we find that bilateral adrenalectomy is well tolerated and
effective but challenging, given the comorbidities associated with large-
volume MTC and hypercortisolism. (See "Overview of the treatment of
Cushing's syndrome", section on 'Nonresectable tumors'.)
PROGNOSISAge and stage of disease at the time of diagnosis have been shown
to be important factors that influences prognosis [1,6]; the 5- and 10-year disease-
free survival rates are higher among patients 40 years old or less as compared
with patients over age 40 years (95 versus 65 percent and 75 versus 50 percent,
respectively) [6,58]. However, another study found no effect of age if survival was
compared with the expected mortality rates in the general population [59]. The 10-
year survival rates for patients with stages I, II, III, and IV medullary thyroid cancer
(MTC) are 100, 93, 71, and 21 percent, respectively [1,11].
A nomogram that integrates age, sex, postoperative calcitonin, vascular invasion,
and TNM (tumor, node, metastasis) status has been developed that can be used to
easily predict cause-specific mortality [60]. Furthermore, using an approach
previously validated in non-MTC [61], a response to the therapy stratification
system was shown to have a higher proportion of variance explained for
predicting clinical outcomes than the TNM/American Joint Committee on Cancer
(AJCC) system [10,13].
Calcitonin and carcinoembryonic antigen (CEA) doubling times provide sensitive
markers for progression and aggressiveness of metastatic MTC. Calcitonin
doubling times less than 6 to 12 months are associated with poor survival, while
doubling times >24 months are associated with a very favorable prognosis [35,36].
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Furthermore, a tumor volume doubling time of ≤1 year in pulmonary metastases is
associated with poorer overall survival [62].
Controlling for the effect of age, the prognosis of patients with inherited disease is
probably similar to those with sporadic disease [63,64]. Specific germline
mutations in RET predict the aggressiveness of the tumor [1]. As an example,
patients with multiple endocrine neoplasia type 2B (MEN2B; germline RET mutation
codon 918) are more likely to have invasive disease and therefore a worse
prognosis than those with either classical multiple endocrine neoplasia type 2A
(MEN2A) or familial MTC [63]. In some [17-19], but not other [20], studies, tumors
with an identifiable RET mutation (ie, a somatic mutation) had a more aggressive
course than those without a mutation.
Other factors that may predict a poor prognosis include cellular heterogeneity,
paucity of tumor immunostaining for calcitonin [65], prominent tissue
immunostaining for galectin-3 [66] or immunostaining for CEA associated with
scant or absent tissue staining for calcitonin [67], high preoperative serum CEA
[68], a less than 10-fold increase in preoperative calcitonin levels after stimulation
with pentagastrin [69], an elevated procalcitonin-to-calcitonin ratio [70], and a
rising CEA level associated with a stable or declining calcitonin level.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Medullary thyroid cancer".)
SUMMARY AND RECOMMENDATIONS
●For patients with newly diagnosed medullary thyroid cancer (MTC),
preoperative evaluation should include measurement of serum calcitonin,
carcinoembryonic antigen (CEA), ultrasonography of the neck (if not already
performed), genetic testing for germline RET mutations (can be performed
pre- or postoperatively), and, in all patients who have either
unknown RET mutation status or a germline RET mutation, biochemical
evaluation for coexisting tumors (especially pheochromocytoma) (algorithm
1).
For patients with local lymph node metastases on ultrasound or with
preoperative serum basal calcitonin >500 pg/mL (indicating high risk of local
or distant metastatic disease), additional imaging is required to assess for
metastatic disease. (See 'Preoperative evaluation' above and "Medullary
thyroid cancer: Clinical manifestations, diagnosis, and staging", section on
'Evaluation'.)
●For patients with sporadic MTC, we recommend total thyroidectomy rather
than lobectomy for initial therapy (Grade 1B). Owing to the multicentric and
bilateral nature of hereditary MTC (and its precursor C cell hyperplasia), total
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thyroidectomy is the only way to cure hereditary MTC. (See 'Surgical
approach' above and "Approach to therapy in multiple endocrine neoplasia
type 2", section on 'Medullary thyroid cancer'.)
For patients with MTC confined to the neck and no evidence of involved
cervical lymph nodes on preoperative ultrasound, we routinely perform
bilateral dissection of the central lymph node compartment without
prophylactic lateral neck dissection. For patients with evidence of central
cervical lymph node involvement, dissection of the involved lateral neck
compartment is also performed.
For patients with locally advanced or metastatic disease, total thyroidectomy
with resection of involved lymph node compartments is performed in most
patients. However, since the goals of surgery are largely palliative in this
setting, a less aggressive approach to both the primary tumor and to
locoregional metastases may be warranted.
●Thyroxine (levothyroxine, T4) therapy should be started immediately after
surgery. The goal of T4 therapy is to restore and maintain euthyroidism.
Suppression of serum thyroid-stimulating hormone (TSH) concentrations is
not indicated in patients with MTC, because C cells are not TSH responsive.
Similarly, adjuvant therapy with radioiodine is not indicated, because the
tumor cells do not concentrate iodine. (See 'Thyroxine therapy' above.)
●Serum calcitonin and CEA should be measured two to three months after
surgery to detect the presence of residual disease. (See 'Serum calcitonin and
CEA measurement' above.)
●For patients with undetectable postoperative calcitonin levels, we measure
serum calcitonin and CEA levels twice yearly for two years and then yearly if
values are stable. We typically obtain a neck ultrasound 6 to 12 months
postoperatively to establish a baseline. Serial ultrasound evaluations are not
required in patients with undetectable postoperative calcitonin levels.
(See 'Undetectable calcitonin and normal CEA' above.)
●For patients with persistent hypercalcitoninemia, further evaluation depends
upon the magnitude of the elevation in the serum calcitonin concentration
and the calcitonin and CEA doubling times (algorithm 2). (See 'Persistent
hypercalcitoninemia' above.)
Patients with postoperative calcitonin levels that are detectable but less than
150 pg/mL (two to six months after surgery) should have neck imaging
(ultrasound with or without computed tomography [CT] or magnetic
resonance imaging [MRI]) to identify persistent locoregional disease.
Patients with postoperative calcitonin levels that are ≥150 pg/mL (two to six
months after surgery) should undergo additional imaging (CT or MRI of neck,

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chest, and abdomen; bone scan or bone MRI in patients suspected of having
skeletal metastases) to identify possible distant metastases.
●Treatment options for patients with recurrent/residual disease include
observation/active surveillance, surgical resection, external beam radiation
therapy (EBRT), and other directed therapies (such as radiofrequency
ablation, cryoablation, embolization) or systemic therapies. Choice of therapy
depends upon clinical factors, RET mutational status, and the potential
morbidities of therapy. (See 'Management of persistent/recurrent
disease' above.)

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Medullary thyroid cancer: Systemic therapy and
immunotherapy
Authors:
Steven I Sherman, MD
Andrew G Gianoukakis, MD, FACE
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 30, 2021.
INTRODUCTIONMedullary thyroid cancers (MTCs) are neuroendocrine tumors
of thyroid parafollicular cells that do not concentrate iodine. They occur both as
sporadic tumors and as components of multiple endocrine neoplasia (MEN) type 2.
They secrete calcitonin and carcinoembryonic antigen (CEA), both of which can
serve as tumor markers. (See "Medullary thyroid cancer: Clinical manifestations,
diagnosis, and staging".)
The primary treatment for MTC is extensive and meticulous surgical resection.
There is a limited role for external beam radiotherapy. Because the
neuroendocrine-derived MTC is not responsive to either radioiodine or thyroid-
stimulating hormone (TSH) suppression, these options are not appropriate for
treatment of progressive metastatic MTC. (See "Medullary thyroid cancer: Surgical
treatment and prognosis".)

Patients with progressive or symptomatic metastatic disease who cannot be

treated by surgery or radiotherapy should be considered candidates for systemic
therapy. New approaches based upon application of targeted chemotherapies are
now available as effective interventions for progressive disease, with additional
investigational options emerging. Alternatively, treatment with either cytotoxic
chemotherapy or biologic response modifiers may provide some benefit for
occasional patients who fail or are ineligible for targeted therapies.

Current and experimental chemotherapies for advanced medullary thyroid

carcinomas will be reviewed here. Chemotherapies for differentiated and
anaplastic thyroid carcinomas are discussed separately. (See "Differentiated
thyroid cancer refractory to standard treatment: Systemic therapy" and "Anaplastic
thyroid cancer".)

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SUGGESTED APPROACHThe availability of kinase inhibitors that can induce
tumor shrinkage or stabilize progressive metastatic disease is changing the
standard approach to treating metastatic MTC [1-5]. RET mutations are detected in
most MTCs, and in these RET-mutated tumors, treatment with an agent that
selectively targets RET (eg, selpercatinib, pralsetinib) is preferred [6]. Other potent
and selective RET inhibitors such as TPX-0046 and BOS172738 are being tested in
clinical trials. (See 'Mutation-selective kinase inhibitors' below.)
Antiangiogenic multikinase inhibitors (aaMKI) with nonselective RET inhibitory
activity (eg, vandetanib, cabozantinib) have been used to treat patients with MTC
with documented improvements in progression-free survival, although they are
generally less potent than selective RET inhibitors. RET-selective inhibitors appear
to be more effective and have a far more tolerable side-effect profile, but the data
supporting their US Food and Drug Administration (FDA) approvals are
considerably less robust than the phase III trials of either cabozantinib or
vandetanib. (See 'Multitargeted kinase inhibitors' below.)

Complete responses with these kinase inhibitors are uncommon, but these
therapies can potentially provide long-term disease stabilization and delay
progression in selected patients. However, no study has yet reported these agents'
effects to improve survival.

"Targeted therapies" have significant toxicities and, therefore, it is important to

limit the use of systemic treatments to patients at significant risk for morbidity or
mortality due to progressive metastatic disease. Patients treated with systemic
agents should have a baseline performance status sufficiently functional to
tolerate these interventions, such as being ambulatory at least 50 percent of the
day (Eastern Cooperative Oncology Group [ECOG] performance status 2 or better).

In the absence of sufficient clinical trial data comparing both efficacy and safety of
any individual drug or combination, the following treatment strategy is based
upon clinical experience and data from open label studies. Our approach is
consistent with the American Thyroid Association (ATA) Guidelines [3].
●For patients with asymptomatic metastatic tumors generally less than 1 to 2
cm in diameter, growing in diameter less than 20 percent per year, we
continue to monitor, treating symptoms like diarrhea with symptomatic
support. Known sites of metastatic disease should be imaged by computed
tomography (CT) or magnetic resonance imaging (MRI) every 6 to 12 months,
and screening for potential new sites of disease should be performed every
12 to 24 months. Scanning frequency within the range suggested can be

151
 guided by carcinoembryonic antigen (CEA) and calcitonin serial
measurements.
●For patients with metastatic tumors at least 1 to 2 cm in diameter, growing
by at least 20 percent per year, or for patients with symptoms related to
multiple metastatic foci that cannot be addressed with local intervention
(surgery or external beam radiotherapy), we prefer to administer systemic
treatment as part of a clinical trial. Increasingly, therapeutic selections are
dictated by the presence of specific gene mutations or signaling pathway
abnormalities that are the targets of approved or investigational therapies.
•For patients whose tumors bear somatic or germline RET mutations, we
suggest a selective RET kinase inhibitor (selpercatinib or pralsetinib),
based on high frequency of objective response in open-label,
nonrandomized trials and relatively lower levels of adverse effects
compared with aaMKIs. (See 'Mutation-selective kinase inhibitors' below.)
•For patients without RET mutations, we suggest an oral aaMKI, such
as cabozantinib or vandetanib. Sorafenib, sunitinib, or lenvatinib are
reasonable options for patients who fail either or both cabozantinib and
vandetanib. (See 'Multitargeted kinase inhibitors' below.)
•For patients who are unable to tolerate or who fail several attempts at
kinase inhibitor therapy, cytotoxic chemotherapy is an alternative. Among
the cytotoxic agents, dacarbazine-based regimens, such as
cyclophosphamide-vincristine-dacarbazine, may be preferable.
(See 'Cytotoxic agents' below.)
KINASE INHIBITORSAs in other tumors, constitutively activated tyrosine
kinases stimulate tumor proliferation, angiogenesis, invasion, and metastasis.
Small molecule inhibitors of select tyrosine kinases have been of interest for the
treatment of advanced MTC, given the oncogenic role of inherited and somatic
mutations in the tyrosine kinase RET, as well as the contributory roles of tyrosine
kinases in growth factor receptors such as the vascular endothelial growth factor
receptor (VEGFR) [7,8]. These agents are used for the treatment of symptomatic or
progressive MTC in patients with unresectable locally advanced or metastatic
disease. Most of the kinase inhibitors partially inhibit multiple kinases
(antiangiogenic multikinase inhibitors [aaMKIs]) at nanomolar concentrations and
often affect multiple signaling pathways. Selpercatinib is a RET-selective kinase
inhibitor, though it retains far weaker inhibitory activity against VEGFR that
contributes to toxicities. (See "Classification and genetics of multiple endocrine
neoplasia type 2" and "Overview of angiogenesis inhibitors", section on 'Small
molecule tyrosine kinase inhibitors'.)

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In randomized trials of aaMKIs, partial responses are reported in approximately 20
to 60 percent of patients; randomized trials of RET-selective inhibitors have not
been performed yet. Although complete responses are rare, kinase inhibitors can
potentially provide long-term disease stabilization. However, data on the ability of
any of these agents to improve survival are limited.

In the studies described below, the definitions of tumor response are based upon
the now-standard, Response Evaluation Criteria in Solid Tumors (RECIST), version 1
[9].
Mutation-selective kinase inhibitors — RET mutations are detected in most
MTCs, and in these RET-mutated tumors, treatment with an agent that selectively
targets RET (eg, selpercatinib, pralsetinib) is preferred
Selpercatinib — Selpercatinib is a US Food and Drug Administration (FDA)-
approved oral kinase inhibitor used to treat advanced or metastatic medullary
thyroid cancer and other types of thyroid cancers that have an alteration (mutation
or fusion) in the RET gene [10]. In the open-label LIBRETTO-001 trial of
selpercatinib in 143 patients with advanced or metastatic RET-mutant MTC,
previously treated or not treated with cabozantinib and/or vandetanib, the overall
response rate (ORR) was 69 and 73 percent, respectively [11]. Complete response
was reported in 9 percent of patients previously treated with an aaMKI and 11
percent in those who were treatment naive; partial response was 60 and 61
percent, respectively. Although median progression-free survivals have still not
been reached, 12-month rates were 82 and 92 percent, respectively. For patients
with disease-related symptoms such as diarrhea or Cushing's syndrome, therapy
with selpercatinib can lead to rapid palliation [12].
A phase III randomized trial (NCT04211337), comparing selpercatinib with the
physician's choice of cabozantinib or vandetanib, has been initiated. Due to the
rapid tumor shrinkage seen with selpercatinib, a trial of neoadjuvant therapy
(NCT04759911) is recruiting patients with locally advanced primary tumor or nodal
metastases.
The nature of the underlying RET mutation may also influence the choice of
therapy or outcome. Selpercatinib appears to have excellent inhibitory potential
against the "gatekeeper" mutation in RET codon 804, in contrast
with vandetanib or cabozantinib. However, "solvent front" mutations in codon 810
may yield resistance to selpercatinib, and such mutations have already been
reported to emerge in patients on therapy with RET-selective inhibitors in other
tumor types [13].
The most common grade 3 or 4 adverse events included hypertension (21
percent), increased alanine aminotransferase (11 percent), increased aspartate

153
aminotransferase (9 percent), hyponatremia (8 percent), and diarrhea (6 percent).
Common side effects occurring in ≥20 percent of patients included dry mouth,
diarrhea, constipation, nausea, abdominal pain, rash, hypertension, headache,
fatigue, and edema. Severe adverse effects included hypertension (18 percent) and
QT prolongation (4 percent). Hypersensitivity reactions occurred in approximately
4 to 5 percent of patients. (See "Chemotherapy hepatotoxicity and dose
modification in patients with liver disease: Molecularly targeted agents", section on
'Selpercatinib'.)
Pralsetinib — Pralsetinib is an FDA-approved oral kinase inhibitor used to treat
advanced or metastatic MTC and other types of thyroid cancers that have an
alteration (mutation or fusion) in the RET gene [14]. In preliminary results from the
open-label ARROW trial, 29 patients with RET-mutant MTC were treated with
pralsetinib [14]. The overall response rate was 66 percent (partial response 55
percent, and complete response 10 percent). In 55 patients previously treated
with cabozantinib and/or vandetanib, the overall response rate was 60 percent
(partial and complete responses 58 and 1.8 percent, respectively) [15,16]. The most
common grade 3 or 4 adverse events included hypertension (21 percent), fatigue
(6 percent), diarrhea (5 percent), fever (2.2 percent), and dyspnea (2.2 percent).
Multitargeted kinase inhibitors — We prefer that patients with progressive
advanced or symptomatic MTC participate in clinical trials of targeted therapies.
However, for those patients without a RET mutation, who are unwilling or unable
to participate in clinical trials, we suggest either cabozantinib or vandetanib as the
initial choice of oral aaMKI.
Vandetanib — Vandetanib is an oral inhibitor that targets VEGFR, RET, and the
epidermal growth factor receptor (EGFR) [17]. In a phase II trial limited to patients
with metastatic or unresectable hereditary MTC (either familial MTC or multiple
endocrine neoplasia type 2A [MEN2A]), vandetanib, 300 mg daily, was
administered to 30 patients [18]. Confirmed partial response was observed in six
(20 percent) patients, and another 16 (53 percent) patients had stable disease
lasting at least 24 weeks. The most common adverse events that occurred in more
than half of patients were diarrhea, rash, fatigue, and nausea.
An international, randomized phase III trial of vandetanib (300 mg daily) was
performed in over 300 patients with unresectable locally advanced or metastatic
sporadic or hereditary MTC. After a median follow-up of 24 months, progression-
free survival was significantly prolonged for patients randomly assigned to
vandetanib versus placebo (hazard ratio [HR] 0.46, 95% CI 0.31-0.69) [19,20]. The
median progression-free survival had not yet been reached for the vandetanib
group but was predicted to be 30.5 months compared with 19.3 months in the
placebo group. The objective response rate was significantly higher in the

154
vandetanib group (45 versus 13 percent). No difference has been observed in
overall survival between the two treatment arms despite the improvement in
progression-free survival, although the final survival analysis will be performed
when sufficient number of deaths have occurred. Patients with both progressive
and stable disease were eligible for enrollment, and outcomes were similar in the
two groups in a post hoc analysis [21]. However, patients with carcinoembryonic
antigen (CEA) doubling times greater than 24 months were unlikely to benefit from
treatment. The presence of a somatic RET M918T mutation predicted an improved
progression-free survival.
Common side effects occurring in ≥20 percent of patients included diarrhea/colitis,
rash, dermatitis, nausea, hypertension, headache, fatigue, anorexia, abdominal
pain, hypocalcemia, decreased glucose, and increased alanine aminotransferase
(ALT). Severe adverse effects (occurring in ≥5 percent) included diarrhea/colitis,
hypertension and hypertensive crisis, QT prolongation, fatigue, and rash. Torsades
de pointes and sudden death have been reported in patients
receiving vandetanib [22]. (See "Toxicity of molecularly targeted antiangiogenic
agents: Cardiovascular effects".)
Based upon the results from the phase III trial, vandetanib was made available in
the United States through a Risk Evaluation Mitigation Strategy (REMS) program
and in Europe, where it is monitored by the Commission on Human Medicines and
the Medicines and Healthcare products Regulatory Agency, for the treatment of
symptomatic or progressive MTC in patients with unresectable locally advanced or
metastatic disease [19,22-24]. In the United States, distribution is restricted to
prescribers and pharmacies participating in the REMS program. The
recommended starting daily dose is 300 mg orally. For patients with moderate
(creatinine clearance 30 to 50 mL/min) and severe (<30 mL/min) renal impairment,
the starting dose should be reduced to 200 mg daily. Electrocardiograms (ECGs)
and serum potassium, calcium, magnesium, and TSH should be obtained at two to
four weeks and 8 to 12 weeks after starting treatment and every three months
thereafter. Patients with diarrhea may require more frequent monitoring.
A randomized trial evaluated the relative efficacy and tolerability of starting with
the lower 150 mg daily dose compared with the approved 300 mg dose in 81
patients with progressive MTC [25]. The objective response rate was 29 percent
(95% CI 17.6-44.5 percent) in patients who started at 300 mg daily compared with
20 percent (95% CI 10.5-34.8 percent) in those who started at only 150 mg daily.
Side effects were typical of those previously reported with the drug, though more
commonly seen at the higher starting dose.
Cabozantinib — Cabozantinib is approved by the US Food and Drug
Administration (FDA) for the treatment of progressive, metastatic MTC [26].

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Cabozantinib is an oral, small molecule kinase inhibitor that targets VEGFRs 1 and
2, c-MET, and RET [27]. The inhibitory activity against c-MET, the cognate receptor
for the hepatocyte growth factor, may provide additional synergistic benefit in
MTC.
In a phase I, dose-escalation study, 10 of 35 MTC patients (29 percent) achieved a
confirmed partial response [28]. Stable disease of at least six months duration was
observed in 15 of 37 patients with MTC. The overall rate of partial responses and
six-month, progression-free survival was 68 percent. Responses were seen in
patients regardless of the RET mutation status of their tumors, indicating that the
drug is active in patients without RET activating mutations.
In a randomized trial, 330 patients with progressive, metastatic or unresectable
locally advanced MTC were randomly assigned to receive either cabozantinib (140
mg) or placebo once daily [26,29]. A significant prolongation in progression-free
survival was observed for cabozantinib treatment compared with placebo (11.2
versus 4.0 months; HR 0.28, 95% CI 0.19-0.40). Partial responses were observed in
27 versus 0 percent. Median overall survival was nonsignificantly improved by 5.5
months with cabozantinib therapy (26.6 versus 21.1 months; HR 0.85, 95% CI 0.64-
1.12) [30]. The most common side effects, occurring in ≥25 percent of patients,
were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome,
hypertension, and abdominal pain. Although uncommon, clinically significant
adverse events included fistula formation and osteonecrosis of the jaw. Significant
electrocardiographic abnormalities were not observed. In a subsequent analysis,
progression-free survival was markedly improved in the subset of patients treated
with cabozantinib compared with placebo whose tumors contained RET M918T
mutations (61 versus 17 weeks; HR 0.15, 95% CI 0.08-0.28), or whose tumors
contained RAS mutations (47 versus 8 weeks; HR 0.15, 95% CI 0.02-1.10) [31].
Although no improvement in progression-free survival was observed in patients
whose tumors lacked either a RET or RAS mutation, the partial response in that
cohort was 21 percent, indicating that there was still some degree of activity of the
drug regardless of known mutation status. In a post hoc analysis, overall survival
was significantly improved in patients with RET M918T mutations (44.3 months
with cabozantinib versus 18.9 months with placebo; HR 0.60, 95% CI 0.38-0.94)
[32].
The recommended starting dose of cabozantinib is 140 mg daily, with dose
reductions to adjust for tolerability. Lower starting doses, such as 60 mg used for
other malignancies, are also well tolerated but may be less effective. In a
preliminary report from the phase IV EXAMINER trial comparing two different
cabozantinib formulations (60 mg tablet versus 140 mg capsule) in patients with
progressive metastatic MTC, both dose regimens showed activity in advanced

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MTC. However, the 60 mg tablet did not meet prespecified noninferiority criteria
for progression-free survival versus the 140 mg capsule. The safety profile was
consistent with that observed previously with single-agent cabozantinib [33].
Although not mandated in its approval, safety monitoring during therapy should
include periodic assessment of electrolytes, calcium, and TSH.
Sorafenib — Sorafenib is an oral, small molecule aaMKI that targets VEGFR 2 and 3
and most mutant forms of RET [34]. It could be considered for use in selected
patients with advanced MTC who are unable to participate in clinical trials as a
second- or third-line therapy.
In a pilot study, five patients with metastatic MTC were treated with sorafenib,
starting at 400 mg twice daily [35]. After six months of treatment, responses were
described in two (including one complete response) and symptomatic
improvement was seen in all, but most patients required a dose reduction due to
side effects.
In addition, preliminary results from a larger (n = 16), open-label, phase II study
of sorafenib in patients with metastatic MTC showed a partial response in one
patient with sporadic MTC and a median progression-free survival of nearly 18
months [36]. Partial response (n = 3) or durable stable disease (n = 3) was also
reported in six of eight MTC patients participating in a phase I study of
combination sorafenib and tipifarnib [37].
In addition to differentiated thyroid cancer, sorafenib is approved in the United
States for treatment of advanced renal cell carcinoma and unresectable
hepatocellular carcinoma.
Sunitinib — Sunitinib is an oral, small molecule aaMKI that targets all three
VEGFRs and RET [38]. It could be considered for use in highly selected patients with
advanced MTC who are unable to participate in clinical trials as a second- or third-
line therapy.

Limited results in patients with MTC include the following:

●A prolonged partial response was described in one patient with MTC treated
with sunitinib, 50 mg daily for 28 days followed by 14 days of no treatment
per cycle [39].
●In an open-label, phase II trial in patients with progressive refractory thyroid
cancer (n = 7 with MTC) with a median follow-up of 15.5 months, three MTC
patients had a complete or partial response, and disease stabilization
occurred in two [40].
●Interim analysis from a second open-label, phase II trial reported partial
responses or stable disease for greater than 12 weeks in three of eight MTC
patients [41].
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Sunitinib is approved in the United States for treatment of advanced renal cell
carcinoma and also for refractory gastrointestinal stromal tumors.
Lenvatinib — Lenvatinib is an orally administered aaMKI that targets VEGFRs, RET,
and fibroblast growth factor receptors (FGFR) 1 to 4. It is approved in the United
States to treat progressive, metastatic, radioiodine-refractory differentiated
thyroid cancer. (See "Differentiated thyroid cancer refractory to standard
treatment: Systemic therapy", section on 'Mutation not identified'.)
In a phase II trial, 59 patients with surgically unresectable, progressive MTC were
treated with lenvatinib, starting at 24 mg daily [42]. The best overall response rate
was 35 percent (95% CI 24-49 percent), all partial responses. Another 44 percent
had stable disease. Identical response rates were observed in the cohorts
previously treated and never treated with prior VEGFR-targeted therapies. Median
progression-free survival and overall survival were 9.0 months (95% CI 7.0-not
estimable) and 16.6 months (95% CI 14.0-not estimable), respectively. Typical side
effects were observed, including diarrhea, hypertension, and decreased appetite.
(See 'Side effects and their management' below.)
Given evidence of similar response rates in patients previously
treated, lenvatinib may be considered as a second- or third-line aaMKI therapy for
patients with progressive, metastatic MTC who have failed other anti-VEGFR
therapies.
Side effects and their management — Side effects that are common to all of the
VEGF-targeted aaMKIs include hypertension, renal toxicity, bleeding,
myelosuppression, arterial thromboembolism, cardiotoxicity, thyroid dysfunction
(typically hypothyroidism), cutaneous toxicity including hand-foot skin reaction,
delayed wound healing, hepatotoxicity, and muscle wasting. These side effects and
their management are discussed in detail elsewhere. (See "Toxicity of molecularly
targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of
molecularly targeted antiangiogenic agents: Cardiovascular
effects" and "Cutaneous adverse events of molecularly targeted therapy and other
biologic agents used for cancer therapy".)
Other investigational tyrosine kinase inhibitors — Numerous other kinase
inhibitors have been studied in clinical trials during the past several years, but
these drugs remain investigational at this time and are not available for routine
clinical use. In general, the results of these studies are consistent with the findings
described above, supporting the concept that antiangiogenic kinase inhibitors and
those that target the mutated RET kinase are useful treatments for advanced
metastatic MTC. Rarely, oncogenic mutations other than in the RET  or RAS genes
can be observed with extended genomic testing, such as activating

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rearrangements of the ALK gene; in these instances, more selective kinase
inhibitors may be considered targeting the rare mutated gene [43,44].
CYTOTOXIC AGENTSWe do not consider traditional cytotoxic agents a first-
line therapy for patients with persistent or recurrent MTC. We reserve these agents
for patients who are unable to participate in clinical trials or cannot tolerate or fail
selective RET kinase inhibitors and aaMKIs. In patients with progressive metastatic
MTC, treatment with traditional cytotoxic agents provides limited benefit. Partial
responses are reported in approximately 10 to 20 percent of patients, but long-
term responses are uncommon. The availability of kinase inhibitors that can
stabilize progressive metastatic disease has changed the standard approach to
treating these patients, further limiting the role of cytotoxic agents.
Most regimens for patients with MTC combine dacarbazine with other agents,
including vincristine, fluorouracil, cyclophosphamide, streptozocin, or doxorubicin,
without significant advantage of one combination compared with another [45]. In
one widely cited report, the combination of cyclophosphamide (750 mg/m 2),
vincristine (1.4 mg/m2), and dacarbazine (600 mg/m2 daily for two days in each
cycle) every three weeks was administered to seven patients with metastatic MTC
[46]. Two patients experienced >50 percent shrinkage in tumor dimensions lasting
more than one year, and two others had stable disease.
A more complex regimen (repeating cycles of doxorubicin 60 mg/m2 on day one,
and streptozocin 500 mg/m2 daily for five consecutive days, followed four weeks
later with fluorouracil 400 mg/m2 and dacarbazine 200 mg/m2 daily for five
consecutive days) was given to 20 patients with progressing distant metastases
[47]. Three patients (15 percent) had partial responses lasting more than 18
months, and 10 (50 percent) were stable for at least eight months. Toxicities of
dacarbazine include neutropenia, thrombocytopenia, nausea, vomiting, and
hepatotoxicity.
Doxorubicin (60 to 75 mg/m2 every three weeks, or 15 mg/m2 weekly) is approved
by the US Food and Drug Administration (FDA) for the treatment of all histologies
of metastatic thyroid carcinoma including MTC, but fewer than 30 percent of
patients have an objective response, none are complete, and the duration is
generally short [48,49].
Doxorubicin is administered as a continuous intravenous infusion for 48 to 72
hours to minimize the risk of cardiac toxicity. Common adverse events can include
granulocytopenia with accompanying infections, nausea, vomiting, and alopecia.
INVESTIGATIONAL THERAPY
Immunotherapy — Immunotherapy of thyroid cancer holds some promise but as
yet has had little clinical application. One approach is to induce host immunity to
the tumor by administering tumor-derived vaccines or inoculations of tumor-cell
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transfectants expressing specific cytokines. Another is to administer monoclonal
antibodies coupled to radioisotopes to deliver radiotherapy. These therapies have
been tried more often for patients with MTC than for other types of thyroid cancer.
However, they remain investigational. (See "Principles of cancer immunotherapy".)
Tumor vaccines — A novel approach to targeted immunotherapy is the use of
tumor vaccines. Dendritic cells, which are derived from bone marrow antigen-
presenting cells, are capable of presenting tumor-associated antigens, thereby
generating cytotoxic T-cells targeting tumor cells.

In preliminary studies in patients with metastatic MTC, treatment with stimulated

dendritic cells was promising, as illustrated by the following:

●In one study, dendritic cells were obtained from each of seven patients and
stimulated in the presence of both calcitonin and carcinoembryonic antigen
(CEA) [50]. Following periodic intracutaneous injections of the stimulated
dendritic cells, one patient experienced a partial response, including
complete regression of hepatic metastases, which was associated with a 70
percent reduction in serum tumor markers. Two other patients had mixed
responses.
●In another study, dendritic cells were stimulated using lysates of each
individual patient's surgically resected primary tumor [51]. Three of 10
patients had partial responses, including one with complete resolution of
radiographic evidence of disease.
Toxicities in both of these trials were minor, including low-grade fever and
asymptomatic transient autoantibody development. Further small studies are
underway, refining the procedures to enhance the potency of the dendritic cell
vaccines [52,53].
Radioimmunotherapy — The expression of CEA on MTC cells led to the
exploitation of radiolabeled anti-CEA monoclonal antibodies for
radioimmunotherapy. In the initial trials, antitumor effects were noted using anti-
CEA/anti-diethylenetriamine pentaacetic acid (DTPA)-indium recombinant bispecific
antibody (BsMAb), followed four days later by a 131I-labeled bivalent hapten [54].
In a subsequent nonrandomized trial in patients with progressive metastatic MTC
(defined as a calcitonin doubling time less than two years), median overall survival
after administration of this therapy was 110 months [55]. This compared favorably
with a contemporaneous untreated cohort's median survival of only 60 months.

Significant toxicities included grade 4 neutropenia and thrombocytopenia, lasting

up to three weeks, and one patient (who had received previous radiotherapies)
developed myelodysplasia.
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Radiolabeled octreotide — In a phase II trial in 31 patients with progressive
metastatic MTC, treatment with radiolabeled octreotide, (90)Yttrium-1,4,7,10-tetra-
azacyclododecane N,N',N'',N'''-tetraacetic acid [(90)Y-DOTA]-Tyr(3)-octreotide (TOC)
resulted in decreases in calcitonin levels in nine patients (29 percent) [56].
Responders had a significantly longer median survival (109 months from time of
diagnosis compared with 80 months in nonresponders). Hematologic and renal
toxicities occurred in four and seven patients, respectively.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Medullary thyroid cancer".)
SUMMARY AND RECOMMENDATIONS
●Medullary thyroid cancers (MTCs) are neuroendocrine tumors of thyroid
parafollicular cells that do not concentrate iodine. The primary treatment for
MTC is extensive and meticulous surgical resection. There is a limited role for
external beam radiotherapy. (See "Medullary thyroid cancer: Surgical
treatment and prognosis".)
●For patients with asymptomatic metastatic tumors generally less than 1 to 2
cm in diameter, growing in diameter less than 20 percent per year, we
continue to monitor for disease progression. Known sites of metastatic
disease should be imaged by computed tomography (CT) or magnetic
resonance imaging (MRI) every 6 to 12 months, and screening for potential
new sites of disease should be performed every 12 to 24 months. Scanning
frequency within the range suggested can be guided by carcinoembryonic
antigen (CEA) and calcitonin serial measurements. (See 'Suggested
approach' above.)
●For patients with metastatic tumors at least 1 to 2 cm in diameter, growing
by at least 20 percent per year, or for patients with symptoms related to
multiple metastatic foci that cannot be addressed with local intervention
(surgery or external beam radiotherapy), we prefer to administer systemic
treatment as part of a clinical trial where available. (See 'Suggested
approach' above.)
●For patients with metastatic tumors at least 1 to 2 cm in diameter, growing
by at least 20 percent per year, or for patients with symptoms related to
multiple metastatic foci who cannot participate in a clinical trial, we suggest
an oral kinase inhibitor rather than traditional cytotoxic chemotherapy
(Grade 2C). (See 'Suggested approach' above.)
•For initial therapy in patients with RET-mutated tumors, we suggest
either selpercatinib or pralsetinib (Grade 2C). (See 'Suggested
approach' above and 'Selpercatinib' above.)
161
 •For patients without RET germline or somatic mutations, we
suggest cabozantinib or vandetanib (Grade 2C). Sorafenib, sunitinib,
or lenvatinib are reasonable options for patients who fail either or both
cabozantinib and vandetanib. (See 'Suggested approach' above
and 'Vandetanib' above and 'Cabozantinib' above.)
●Complete responses with these kinase inhibitors are uncommon, but these
therapies can potentially provide long-term disease stabilization and delay
progression in selected patients; no study has yet reported these agents'
effects to improve survival. Toxicities of many of these new therapies,
although probably less life-threatening than cytotoxic chemotherapies, are
common and can be dose limiting, and clinicians must be familiar with
recognizing and managing the side effects if they intend to use these agents.
(See "Toxicity of molecularly targeted antiangiogenic agents: Non-
cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic
agents: Cardiovascular effects" and "Cutaneous adverse events of
molecularly targeted therapy and other biologic agents used for cancer
therapy".)
●Cytotoxic chemotherapy, of which dacarbazine-based regimens such as
cyclophosphamide-vincristine-dacarbazine are preferable, is an alternative
option for patients who cannot tolerate or who fail multiple kinase inhibitors.
(See 'Suggested approach' above.)

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Papillary thyroid cancer: Clinical features and
prognosis
Author:
R Michael Tuttle, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 01, 2020.
INTRODUCTIONThyroid follicular epithelial-derived cancers include papillary,
follicular, and anaplastic cancer. Papillary and follicular cancers are considered
differentiated cancers, and patients with these tumors are often treated similarly
despite numerous biologic differences. The general pathogenetic, pathologic, and
prognostic features of papillary thyroid cancer and its variants will be discussed
here. The staging and treatment of well-differentiated thyroid cancers as well as
an overview of follicular thyroid cancer are discussed separately.
(See "Differentiated thyroid cancer: Clinicopathologic staging" and "Differentiated
thyroid cancer: Overview of management" and "Follicular thyroid cancer (including
Hürthle cell cancer)".)
INCIDENCEIn a report based upon the Surveillance, Epidemiology, and End
Results (SEER) database from 1975 to 2012, the incidence of papillary cancer
increased from 4.8 to 14.9 per 100,000 (figure 1) [1]. The age- and gender-adjusted
incidence of thyroid cancer increased faster than that of any other malignancy in
recent years, with the increased incidence seen in both genders and all ethnic
backgrounds (figure 2 and figure 3) [2,3]. In a subsequent review of the SEER
database from 2013 to 2016, the incidence of thyroid cancer plateaued [4]. In
addition, the annual rate of increase in women fell from 4.2 percent per year from
1992 to 1999, and 6.9 percent per year from 1999 to 2009, to 2.2 percent per year
from 2009 to 2011 [5].
The use of head and neck external beam radiation, commonly used to treat benign
childhood conditions between 1910 and 1960, led to an increased incidence of
thyroid cancer in the second half of the last century [6] (see "Radiation-induced
thyroid disease"). However, since radiation therapy for benign childhood
conditions was largely abandoned in the 1950s to 1960s, it is unlikely that the

163
increasing incidence in thyroid cancer seen in the last 10 to 15 years is associated
with childhood radiation exposure.
The increase in thyroid cancer in the United States and elsewhere may be primarily
due to an increased detection of small papillary cancers secondary to more
widespread use of neck ultrasonography and fine-needle aspiration (FNA) of very
small thyroid nodules [7-9]. Although the increased incidence probably partially
reflects earlier detection of subclinical disease (ie, small papillary cancers), an
analysis of the National Cancer Institute's SEER database found an increase in the
rates of differentiated thyroid cancer of all sizes, including tumors greater than 4
cm [10]. In addition, incidence-based mortality increased between 1974 and 2013,
from 0.40 to 0.46 per 100,000 person-years. These two findings suggest a true
increase in the incidence of papillary thyroid cancer.
The usual female-to-male ratio of papillary thyroid cancer is approximately 2.5:1,
with most of the female preponderance occurring during the fourth and fifth
decades of life. Although the incidence of thyroid cancer is rising, death rates (0.5
per 100,000 men and women per year) have not changed significantly between
2003 and 2012 [1].
RISK FACTORS
Radiation exposure — Radiation exposure of the thyroid during childhood is the
most clearly defined environmental factor associated with benign and malignant
thyroid tumors [11]. Potential sources of radiation exposure include therapeutic
uses of radiation (eg, treatment of childhood malignancies), environmental
exposure secondary to fallout from atomic weapons (eg, Nagasaki/Hiroshima,
Japan), or nuclear power plant accidents (eg, Chernobyl). In the past, ionizing
radiation was used to treat a wide variety of benign conditions of the head and
neck, although this practice essentially ceased in the late 1950s to early 1960s due
to increased appreciation of the carcinogenic effects of radiation on the thyroid.
(See "Radiation-induced thyroid disease".)
Family history — A history of thyroid cancer in a first-degree relative or a family
history of a thyroid cancer syndrome (eg, familial polyposis, Carney complex,
multiple endocrine neoplasia type 2 [MEN2], Werner syndrome, or Cowden
syndrome) increases the risk that a nodule may be malignant. In one study, there
was a 10-fold increased risk of thyroid cancer in relatives of thyroid cancer patients
[12]. In a second report, the standardized incidence ratio for papillary cancer was
3.2 with an involved parent, 6.2 with an involved sibling, and 11.2 for a female with
an involved sister [13]. (See "PTEN hamartoma tumor syndromes, including
Cowden syndrome" and "Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2".)

164
Other — A number of other possible (but not proven) risk factors have been
reported. Their relative importance appears to be small but not completely
defined. Potential risk factors include the following:
●Occupational and environmental exposures [14,15]
●Hepatitis C-related chronic hepatitis (odds ratio [OR] 12.2 in one report) [16]
●Increased parity and late age at first pregnancy [17]
●Obesity or overweight [18]

PATHOGENESISMutations or rearrangements in the genes encoding for the

proteins in the mitogen-activated protein kinase (MAPK) pathway are critical to the
development and progression of differentiated thyroid cancer (figure 4) [19,20].
The importance of this pathway is emphasized by the finding of exclusive,
nonoverlapping activation mutations in RET/PTC, NTRK1, RAS, or BRAF in as many as
70 percent of well-differentiated thyroid cancers [21]. Furthermore, thyroid-
targeted activation of either RET/PTC [22] or BRAF [23] has been shown to result in
development of thyroid cancer in transgenic mice. (See "Oncogenes and tumor
suppressor genes in thyroid nodules and nonmedullary thyroid cancer", section on
'Papillary thyroid cancer'.)
CLINICAL FEATURES
Clinical presentation — Thyroid cancer typically presents as a thyroid nodule.
Thyroid nodules come to clinical attention when noted by the patient; during
routine physical examination; or when incidentally noted during a radiologic
procedure, such as carotid ultrasonography, neck computed tomography (CT),
magnetic resonance imaging (MRI), or positron emission tomography (PET)
scanning. Nonpalpable nodules (incidentalomas) have the same risk of malignancy
as palpable nodules of the same size.
A history of rapid nodular growth, fixation of the nodule to surrounding tissues,
new-onset hoarseness or vocal cord paralysis, or the presence of ipsilateral
cervical lymphadenopathy all raise the suspicion that a nodule may be malignant.
Regardless of how thyroid nodules are discovered, the diagnosis of thyroid cancer
is usually made by fine-needle aspiration (FNA) biopsy (picture 1). (See "Diagnostic
approach to and treatment of thyroid nodules", section on 'History and physical
examination' and "Diagnostic approach to and treatment of thyroid nodules",
section on 'Evaluation'.)
Histology
Classic form — Papillary cancers are typically unencapsulated and may be partially
cystic. Microscopically, most are characterized by the presence of papillae
consisting of one or two layers of tumor cells surrounding a well-defined
fibrovascular core; follicles and colloid are typically absent (picture 2).

165
The morphologic diagnosis is based upon an aggregate of typical cytologic
features (picture 1), none by itself pathognomonic of papillary cancer. The nuclei
are large, oval, and appear crowded and overlapping on microscopic sections.
They may contain hypodense powdery chromatin, cytoplasmic pseudoinclusions
due to a redundant nuclear membrane, or nuclear grooves.
Approximately one-half of papillary cancers contain calcified psammoma bodies,
the scarred remnants of tumor papillae that presumably infarcted (picture 3).
Inflammatory cells may surround or infiltrate areas of malignant growth, although
this does not usually indicate the presence of chronic autoimmune thyroiditis
(Hashimoto's disease).
Papillary thyroid cancer is often multifocal. In some cases, this represents
intraglandular metastases from the primary tumor [24]. However, in one study of
10 women with multifocal papillary cancer, individual tumor foci were shown to
have independent clonal origins in 5 of the 10 women [25]. In a second study,
discordant patterns of BRAF mutations were found in 40 percent of the multifocal
papillary cancers [26].
Variant forms — Variant forms of papillary cancer include the follicular variant;
tall cell variant (a more aggressive tumor accounting for approximately 1 percent
of papillary cancers); and insular, hobnail, and diffuse sclerosing variants.
Follicular variants — Follicular variant papillary thyroid cancer demonstrates a
follicular growth pattern but cytologically, the tumors display the typical features
of common-type papillary cancers, including large, overlapping nuclei with
hypodense chromatin, nuclear pseudoinclusions, and nuclear grooves; most also
contain psammoma bodies (picture 3) [27].
Of the several histologic subtypes of papillary carcinoma, the follicular variants are
probably the most common. The incidence of follicular variant papillary cancer has
been increasing, while that of the classical form has been decreasing. In a single-
center study, nearly 40 percent of the papillary cancers were follicular variants
[28], and in a multicenter study, 23 percent of papillary cancers were the
noninvasive, well-circumscribed subtype (noninvasive follicular thyroid neoplasm
with papillary-like nuclear features, NIFTP) [29].
According to the 2017 World Health Organization classification of endocrine
tumors, follicular variants of papillary thyroid cancer are subtyped as being either
(1) infiltrative or (2) encapsulated with invasion [30]:
●Infiltrative – The infiltrative subtype demonstrates invasive tongues of
tumor infiltrating into non-neoplastic thyroid parenchyma and lacks a well-
defined tumor capsule [31]. The infiltrative subtype has a biological behavior
and molecular profile that is more similar to classic papillary thyroid cancer
than follicular cancers [31,32]. For example, the infiltrative subtype is more

166
 likely to have lymph node metastases and BRAF V600E mutations, while being
less likely than follicular thyroid cancers to have distant metastases
or RAS  mutations.
●Encapsulated with invasion – The encapsulated with invasion subtype
demonstrates both a well-defined tumor capsule and either invasion of the
tumor capsule or invasion into vessels within or beyond the tumor capsule.
The encapsulated variants, particularly those with vascular invasion, have a
tumor biology (often RAS  mutation) and biological behavior (more likely to
have distant metastases, less likely to have lymph node metastases) that is
more similar to follicular thyroid cancer than to classical papillary thyroid
cancer. It is the presence of either vascular or tumor capsular invasion that
differentiates an encapsulated follicular variant of papillary thyroid cancer
(capsular and/or vascular invasion present) from noninvasive encapsulated
follicular variant of papillary thyroid cancer (NIFTP; no capsular or vascular
invasion present).
In the past, encapsulated follicular variant of papillary thyroid cancer without
evidence for either vascular or tumor capsule invasion were considered
noninvasive variants of papillary thyroid cancer [29,33,34]. However, noninvasive
encapsulated follicular variants of papillary thyroid cancer have a very low
malignant potential and are uniformly cured with lobectomy [35,36]. Because of
the very low malignant potential, this type was renamed noninvasive follicular
thyroid neoplasm with papillary-like nuclear features (NIFTP), emphasizing that
this tumor can be managed as a neoplasm rather than a malignancy [35,36]. Both
the American Thyroid Association [37] and the World Health Organization have
endorsed this change in nomenclature [30].
While thyroid surgery is required to distinguish NIFTP from the encapsulated with
invasive subtype, therapy beyond thyroid lobectomy is usually not required (ie,
thyroid-stimulating hormone [TSH] suppression and radioactive iodine ablation is
not required) [35,37,38]. Proper use of the NIFTP nomenclature requires
adherence to strict histopathological criteria, which means that tumors previously
classified as noninvasive encapsulated follicular variant of papillary thyroid cancer
cannot be assumed to be NIFTP tumors. Because the entire tumor capsule may not
have been sampled or preserved at the time of initial diagnosis, it is often not
possible to determine if an archived tumor sample meets all the diagnostic criteria
to be reclassified as an NIFTP tumor [36]. (See "Evaluation and management of
thyroid nodules with indeterminate cytology", section on 'Repeat FNA
indeterminate'.)
Tall cell variant — The tall cell variant form of papillary cancer has the potential to
be a more aggressive tumor than classical papillary cancer [39,40]. These tumors

167
account for approximately 1 percent of papillary cancers and are typically
associated with a V600E mutation in the BRAF gene (see 'Molecular
characteristics' below). They are characterized by tumor cells with eosinophilic
cytoplasm that are twice as tall as they are wide. The primary tumors tend to be
large, they are often invasive, and many patients have both local and distant
metastases at the time of diagnosis [39]. Most patients have evidence of disease
after initial therapy, and the five-year mortality rate is higher than in patients with
classical papillary cancers.
Other variants — Several other variant types of papillary cancer have been
described, also based upon histologic differences from classical papillary cancers
but considered to be papillary cancers because of the characteristics of the tumor
cell nuclei:
●The insular variant of papillary cancer is characterized histologically by solid
nests of tumor, often separated by fibrous bands, but the tumor cell nuclei
have the same characteristics as do the nuclei of classical papillary cancers.
●The columnar variant, which consists of elongated cells with palisading
nuclei.
●The Hürthle or oxyphilic variant, which has cellular features of Hürthle cell
carcinomas but cells that are arranged in papillary formations.
●The solid or trabecular variant.
●The clear cell variant, which must be distinguished from clear cell
carcinomas of other organs such as the kidney or colon that have
metastasized to the thyroid.
●The diffuse sclerosing variant, characterized by diffuse involvement of the
thyroid, stromal fibrosis, and prominent lymphocytic infiltration.
●The cribriform morular variant, which has a prominent cribriform pattern
with solid and spindle cell areas as well as squamous morules. This variant is
often associated with familial adenomatous polyposis.
●The hobnail variant frequently, which harbors BRAF V600E mutations and
appears to be associated with a high risk of distant metastases and an
increased disease-specific mortality [41,42].
These variants are all rare, and therefore, little information about their
characteristics is available. In general, however, they are thought to be more
aggressive than classical papillary cancers. As a result, patients with these tumors
are usually managed more aggressively than are those with classical papillary
cancer of the same stage (table 1). (See "Differentiated thyroid cancer: Overview of
management", section on 'Subsequent management based on risk
classification' and "Differentiated thyroid cancer: Radioiodine
treatment" and "Differentiated thyroid cancer: Surgical treatment".)

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Lymph node involvement — The incidence of nodal metastases in adults
depends upon the extent of surgery. Among patients who undergo a modified
radical neck dissection, up to 80 percent have lymph node metastases (half of
which are microscopic), and even among patients with papillary microcarcinomas
who have prophylactic central node dissection, microscopic metastases have been
reported in 37 to 64 percent [43]. At diagnosis, clinically detectable regional lymph
node metastases are more common in children (approximately 50 percent) than
adults.

Invasion of either the thyroid capsule or a lymph node capsule into surrounding
soft tissue has been reported in 5 to 35 percent of surgical specimens, whereas
vascular invasion is seen in only approximately 5 to 10 percent.

Metastases — From 2 to 10 percent of patients have metastases beyond the neck

at the time of diagnosis [1]. Among such patients, two-thirds have pulmonary and
one-fourth have skeletal metastases. Rarer sites of metastasis are the brain,
kidneys, liver, and adrenals.
Growth pattern — The growth pattern and biologic behavior of papillary cancer
are variable.
●At one end of the spectrum is the common microcarcinoma (formerly called
occult papillary cancer), defined as a tumor <1 cm in diameter. These
microcarcinomas are found in 15 to 30 percent of thyroid glands at autopsy.
This high frequency, coupled with the rarity of clinically detected papillary
cancer, suggests that the presence of a single focus of microcarcinoma in a
thyroidectomy specimen is likely to be an incidental finding of no clinical
importance.
●At the other end of the spectrum is a large, locally invasive cancer with
distant metastases noted at the time of diagnosis. These tumors are also far
more likely than microcarcinoma to metastasize through intrathyroidal
lymphatic channels and form multifocal tumors or involve regional lymph
nodes.
PROGNOSTIC FEATURESMost patients with papillary cancer do not die of
their disease. As an example, in one series of patients with a median follow-up of
16 years, the cancer-related mortality in patients without metastases at
presentation was only 6 percent [44].
While there are a wide variety of staging systems available to predict disease-
specific survival and risk of structural disease recurrence, there are a small set of
key factors that identify the relatively small group of patients that are likely to do
poorly [45]. Patients at highest risk of dying from thyroid cancer are older patients
(>55 years of age at diagnosis) presenting with distant metastases or gross
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invasion of the tumor into the airway, nerves, or major vessels of the neck (table 2)
[46]. Similarly, patients at highest risk of structural recurrence demonstrate gross
invasion into major neck structures, distant metastases, palpable metastatic lymph
node metastases, extensive microscopic vascular invasion, or inappropriately
elevated serum thyroglobulin after initial therapy (table 1) [45].
The extent of initial surgery and the use of radioiodine therapy in advanced
papillary cancers are associated with improved outcomes. (See "Differentiated
thyroid cancer: Surgical treatment", section on 'Choice of
procedure' and "Differentiated thyroid cancer: Radioiodine treatment", section on
'Indications'.)
Age — Thyroid cancer mortality increases progressively with advancing age,
without a specific age cutoff that stratifies mortality risk [47]. This was illustrated in
an analysis of 53,581 patients in the Surveillance, Epidemiology, and End Results
(SEER) database, in which the five-year survival rate decreased with increasing age
at diagnosis (stratified in five-year categories from 20 to 84 years) [48]. There was a
continuum of disease-specific mortality with increasing age. Survival remained
above 90 percent for patients <65 years at diagnosis.
Tumor size — The prognosis is poorer in patients who have large tumors [49,50].
In one series, as an example, 20-year cancer-related mortality rates were 6, 16, and
50 percent for patients whose primary tumor diameters were 2 to 3.9 cm, 4 to 6.9
cm, or 7 cm or larger, respectively [49].
While small tumors usually have an excellent prognosis, clinically evident
recurrences are not infrequently detected. A survey of 299 patients with thyroid
cancers less than 1.5 cm found no deaths over a mean follow-up of 45 months, but
14.4 percent had evidence of persistent/recurrent disease. Persistent or recurrent
disease was associated with nonincidental cancer, lymph node metastases at
presentation, or bilateral tumor but not size [51]. This study only compared tumors
greater or less than 1 cm. In another study of 3965 patients with thyroid cancer (65
percent with tumors ≤2 cm), 10-year recurrence rates to the thyroid, lymph nodes,
and distant organs for tumors ≤2 cm were 0.3, 1.9, and 0.4 percent, respectively
[52]. Recurrence rates increased with tumor size (for tumors >4 cm 1.9, 8.1, and 3.4
percent, respectively). Mortality was low in both groups (0.04 and 0.4 percent,
respectively).
Soft-tissue invasion — When present, soft-tissue invasion increases the risk of
death fivefold. It can also cause substantial morbidity if there is involvement of the
trachea, esophagus, recurrent laryngeal nerves, or the spinal cord. It is important
to note that it is gross soft-tissue invasion (usually described as extrathyroidal
extension) identified on clinical examination, intraoperatively, or on imaging that
conveys an increased risk of mortality. Extrathyroidal extension that is only

170
identified on histopathologic examination is not a major factor for mortality, as
reflected in the changes in the eighth edition American Joint Committee on Cancer
(AJCC) tumor, node, metastasis (TNM) staging system where minor extrathyroidal
extension no longer upstages a patient to stage III (table 2). (See 'Staging' below.)
Distant metastases — The rate of survival in patients with distant metastases is
variable, depending upon the site of metastases. Among patients with small
pulmonary metastases but no other metastases outside of the neck, the 10-year
survival rate is 30 to 50 percent; even higher survival rates have been reported in
patients whose pulmonary metastases were detected only by radioiodine imaging
[53]. Conversely, the median survival of patients with brain metastases is only
approximately one year [54].
In multivariate analysis, fluorodeoxyglucose (FDG) positivity was the most powerful
predictor of death in a large cohort of patients with metastatic disease. Patients
with large-volume, intense FDG uptake had a three-year, disease-specific survival
less than 50 percent from the time of the positron emission tomography (PET) scan
[55]. This may be due in part to lower radioiodine avidity in papillary cancers
demonstrating a high FDG uptake.
Histologic subtype — Several studies have demonstrated a poorer prognosis for
specific subtypes of papillary thyroid cancers, including tall cell, insular, and
hobnail variants [41,56]. (See 'Variant forms' above.)
In one study of 62 patients with the tall cell variant of papillary cancer without
extrathyroidal extension at presentation, prognosis was still worse compared with
classic papillary cancer; 6.4 percent developed distant metastases versus none of
the patients in a comparison group with classic papillary cancer [56]. However,
among patients without initial lymph node metastases or extrathyroidal invasion,
no one developed metastatic disease.
Patients with aggressive histologic subtypes are usually treated more aggressively
than are those with common-type papillary cancer of the same stage (table 1).
(See "Differentiated thyroid cancer: Overview of management", section on 'Risk
classification'.)
Molecular characteristics — In addition to the traditional histopathologic risk
factors, specific molecular profiles (eg, BRAF, telomerase reverse transcriptase
[TERT]) may be used to predict risk of extrathyroidal extension, lymph node
metastases, and even distant metastases [57-59]. While these observations need
further validation, it is likely that the specific molecular profile of the primary
tumor may have significant prognostic value that could be incorporated into
stratification systems.

As examples:

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 ●In a cohort of low-risk patients with intrathyroidal papillary thyroid cancer
(<4 cm, N0, M0; 33 percent with BRAF mutation), the overall risk of having
structural disease recurrence over five years of follow-up was 3 percent [60].
However, BRAF V600E mutated tumors had a recurrence rate of 8 percent (8
of 106) compared with only 1 percent (2 of 213) in BRAF-negative tumors.
Furthermore, in multivariate analysis, the only clinicopathologically
significant predictor of persistent disease after five years of follow-up was the
presence of mutated BRAF V600E.
●TERT mutations have been described in 7 to 22 percent of papillary and 14 to
17 percent of follicular thyroid cancer but with a significantly higher
prevalence in aggressive thyroid cancer [61-64]. In the largest reported series
(332 papillary and 70 follicular thyroid cancer followed on average for eight
years), TERT mutation was an independent predictor of persistent disease
(odds ratio [OR] 4.68, 95% CI 1.54-14.27) and mortality (hazard ratio [HR]
10.35, 95% CI 2.01-53.24) for well-differentiated thyroid cancer [61].
●Expression of vascular endothelial growth factor (VEGF, a potent stimulator
of endothelial cell proliferation) in thyroid cancer specimens may help predict
the presence of metastases. As an example, in a retrospective study of 19
patients with papillary cancer, a high level of immunostaining for VEGF
correlated with a high risk of metastatic disease [65]. In a second report,
elevated preoperative serum VEGF-C concentrations were an independent
risk factor for nodal metastases and advanced tumor stages [66].
A broader genetic analysis may provide more accurate tumor prognostication.
Specifically, a growing body of data suggest that a more aggressive clinical course
can be expected in tumors that carry: (1) BRAF V600E in combination with other
driver oncogenic mutations such as PIK3CA, TP53, AKT1, or RET/PTC mutation [67-
69]; (2) TERT mutations, isolated or in combination with BRAF [61,70]; or
(3) TP53 mutations [71].
These results, although pending confirmation in other studies, suggest that
specific molecular profiles may eventually prove to be a useful adjunct to risk
stratification. (See "Oncogenes and tumor suppressor genes in thyroid nodules
and nonmedullary thyroid cancer" and "Differentiated thyroid cancer:
Clinicopathologic staging", section on 'Other prognostic factors'.)
Whether the presence of BRAF independently predicts mortality is uncertain.
Although in a retrospective analysis, the presence of a BRAF V600E mutation was
associated with thyroid cancer mortality (overall mortality 5.3 versus 1.1 percent
in BRAF V600E-positive versus mutation-negative patients), the association was no
longer significant after adjusting for clinical and histopathologic features,
including lymph node metastases, extrathyroidal invasion, and distant metastasis

172
[72,73]. However, BRAF V600E mutation does appear to have a significant
interaction with important clinicopathologic risk factors as the risk of mortality was
higher in BRAF mutated versus BRAF wild-type tumors in the setting of lymph node
metastases, distant metastases, and age greater than 45 years at diagnosis [72].
Other factors — Other factors associated with a minor increase in the risk of
either recurrence or death are [74,75]:
●Multicentricity of intrathyroidal tumor
●Bilateral or mediastinal lymph node involvement
●Greater than 10 nodal metastases
●Nodal metastases with extranodal extension
●Male gender
●Delay in primary surgical therapy of more than one year after detection of a
thyroid nodule
STAGINGPostoperative staging, based upon the clinicopathologic features of
each case, is important for providing prognostic information. We use both the
tumor, node, metastasis (TNM) classification scheme for prediction of disease-
specific mortality (table 2) and the American Thyroid Association (ATA) risk of
recurrence staging system for initial assessment of risk of recurrence (table 1).
While initial risk stratification can be used to guide initial therapeutic and
diagnostic follow-up strategy decisions, it is important to recognize that initial risk
estimates may need to change as new data are accumulated during follow-up for
each individual patient. Staging is reviewed in more detail elsewhere.
(See "Differentiated thyroid cancer: Clinicopathologic staging".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Thyroid cancer (The Basics)")

173
SUMMARY
●The incidence of papillary thyroid cancer in the United States increased
dramatically between 1975 and 2012 and then subsequently plateaued. The
increase appears to be due in part to an increased detection of small
papillary cancers (figure 1). (See 'Incidence' above.)
●Risk factors for papillary thyroid cancer include a history of radiation
exposure during childhood, a history of thyroid cancer in a first-degree
relative, or a family history of a thyroid cancer syndrome. (See 'Risk
factors' above.)
●Mutations or rearrangements in the genes encoding for the proteins in the
mitogen-activated protein kinase (MAPK) pathway are critical to the
development and progression of differentiated thyroid cancer. Mutations
in RET/PTC, NTRK1, RAS, or BRAF occur in as many as 70 percent of well-
differentiated thyroid cancers. (See 'Pathogenesis' above.)
●Thyroid cancer typically presents as a thyroid nodule. Thyroid nodules come
to clinical attention when noted by the patient; during routine physical
examination; or when incidentally noted during a radiologic procedure, such
as carotid ultrasonography, neck computed tomography (CT), magnetic
resonance imaging (MRI), or positron emission tomography (PET) scanning.
Nonpalpable nodules (incidentalomas) have the same risk of malignancy as
palpable nodules of the same size. (See 'Clinical presentation' above
and "Diagnostic approach to and treatment of thyroid nodules".)
●Clinical and pathologic features associated with a somewhat higher risk for
tumor recurrence and cancer-related mortality include older age at
diagnosis, size of primary tumor, and the presence of soft-tissue invasion or
distant metastases. (See 'Prognostic features' above.)
●Variant forms of papillary cancer include follicular, tall cell, insular, and
hobnail variants. Of the several histologic subtypes of papillary carcinoma,
the follicular variants are probably the most common. According to the 2017
World Health Organization classification of endocrine tumors, follicular
variants of papillary thyroid cancer are subtyped as being either (1) infiltrative
or (2) encapsulated with invasion. (See 'Follicular variants' above.)
●Noninvasive follicular thyroid neoplasm with papillary-like nuclear features
(NIFTP, formerly called noninvasive follicular variant of papillary thyroid
cancer, but subsequently reclassified as a nonmalignant variant because it
does not have either vascular or tumor capsule invasion) has an excellent
prognosis. While thyroid surgery is required to distinguish NIFTP from the
encapsulated with invasion subtype, therapy beyond thyroid lobectomy is
usually not required. (See 'Follicular variants' above.)
174
●Other variant forms of papillary cancer are thought to be more aggressive
than common-type papillary cancers. As a result, patients with these tumors
are usually managed more aggressively than are those with common-type
papillary cancer of the same stage. (See 'Tall cell variant' above and 'Other
variants' above and "Differentiated thyroid cancer: Overview of
management", section on 'Risk classification'.)
●The management of differentiated thyroid cancer is discussed separately.
(See "Differentiated thyroid cancer: Overview of management".)
Use of UpToDate is subject to the Subs

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Radiation-induced thyroid disease
Authors:
Arthur B Schneider, MD, PhD
R Michael Tuttle, MD
Section Editors:
David S Cooper, MD
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 04, 2021.
INTRODUCTIONRadiation exposure of the thyroid during childhood is the
most clearly defined environmental factor associated with benign and malignant
thyroid tumors. The risk of thyroid nodules and thyroid cancer following irradiation
is related to radiation dose and age (greater for children exposed early in life), and
the risk persists throughout life. Radiation exposure also increases the risk of
benign thyroid nodules and hypothyroidism.
This topic will review radiation-related thyroid disease and the evaluation of a
patient with a history of thyroid radiation exposure. Radiation injury to other
organs is reviewed separately. (See "Clinical manifestations, evaluation, and
diagnosis of acute radiation exposure".)
RADIATION EXPOSURE
Tumorigenesis
●Thyroid – Available data make the relationship between thyroid radiation
and thyroid tumorigenesis incontrovertible. Pooled analyses of studies with a
wide range of exposures (atomic bomb survivors, children treated for tinea
capitis or enlarged tonsils, infants irradiated for an enlarged thymus gland,
children treated for cancer) have shown the following [1-4]:
•Thyroid nodules of all types and sizes, including small ones only detected
by screening methods, are increased by radiation exposure.
•The thyroid is among the most radiation-sensitive tissues in the body,
with excess cancers occurring at doses as low as approximately 40 mGy.
•After low-dose exposure, there is a linear dose-response curve with
essentially no evidence of a threshold.
•The risk of thyroid cancer is higher with younger age at exposure.

176
 •The effects of radiation persist for several decades and then eventually
wane. It is still elevated at 45 years, and data from studies of atomic bomb
survivors show persistent effects at >50 years [2,5].
•The association between thyroid radiation and thyroid cancer may be
enhanced in individuals who receive chemotherapy in addition to
radiation [2].
●Other radiation-related tumors – Radiation exposure is also associated
with increases in:
•Parathyroid adenomas – The association between head and neck
radiation and hyperparathyroidism has been confirmed by studies
establishing a dose-response relationship. Patients with radiation-related
thyroid cancer should have a measurement of serum calcium prior to
surgery as some patients may require concomitant parathyroidectomy
and thyroidectomy. Occasionally, a nonfunctioning parathyroid adenoma
is discovered during thyroid surgery. Whether these adenomas are
related to radiation or have any clinical importance is not known.
(See "Pathogenesis and etiology of primary hyperparathyroidism", section
on 'Radiation exposure'.)
•Salivary gland tumors. (See "Salivary gland tumors: Epidemiology,
diagnosis, evaluation, and staging".)
•Schwannomas and meningiomas. (See "Vestibular schwannoma (acoustic
neuroma)", section on 'Pathogenesis and risk factors' and "Epidemiology,
pathology, clinical features, and diagnosis of meningioma", section on
'Ionizing radiation'.)
Type of exposure — Radiation exposure may be external or internal.
●External – The predominant types of external radiation are diagnostic
radiographs, therapeutic radiation for the treatment of cancer, and historical
use of external radiation to treat a wide variety of nonmalignant conditions.
External radiation also includes brachytherapy, whereby a sealed radiation
source is placed adjacent to a treatment area.
●Internal – Internal radiation exposure includes ingestion of foods or liquids
contaminated with radioactivity or by inhalation of radioactive gases or
particles. Internal radiation occurs after exposure to nuclear fallout (from
testing and accidents at operating nuclear power plants or above ground
nuclear explosive testing) or after ingestion of radioiodine for therapy of
hyperthyroidism. (See "Radioiodine in the treatment of hyperthyroidism",
section on 'Cancer'.)

177
External or internal radiation exposure may result in thyroid nodules, thyroid
cancer, and hypothyroidism. (See 'Approach to the patient with a history of thyroid
radiation exposure' below.)
Magnitude of exposure — The risk of radiation-induced thyroid neoplasms is
more common after childhood than adult radiation exposure and is, in part,
related to radiation dose [1,2]. In this topic, radiation exposure is categorized as
very low dose, low dose, and high dose, as follows.
●Very low dose – Ionizing radiation from medical imaging (ie, diagnostic
radiology)
●Low dose – Exposure from nuclear fallout (from testing, accidents, or in
Japanese survivors of atomic bombing) or from radiation for nonmalignant
conditions
●High dose – Therapeutic radiation for the treatment of cancer
Very low-dose exposure — Diagnostic radiology is an ever-increasing source of
radiation exposure, including to the thyroid gland. Ionizing radiation from medical
imaging now accounts for nearly one-half of the radiation exposure experienced
by the population in the United States.
Concern has been raised about a potential increase in risk of thyroid cancer in
children receiving frequent diagnostic radiographs, particularly computed
tomography (CT) scans. Thus far, the potential risk has been calculated assuming a
linear extrapolation dose-response model. However, due to the difficulty of
performing studies at the very low-dose range, it is largely unknown whether this
extrapolation is appropriate. The results of ongoing, large epidemiologic studies
are needed to determine if there is a risk of thyroid cancer from radiographs [6-8].
(See "Radiation-related risks of imaging", section on 'Children and adolescents'.)
Low-dose exposure — After low-dose exposure in childhood, there is a linear
dose-response curve for thyroid cancer, with essentially no evidence of a threshold
at low doses (approximately 40 mGy) [1,4]. There is inconclusive evidence for a risk
of thyroid cancer, albeit a small one, after low-dose exposure in adulthood.
The risk of thyroid nodules and cancer has been investigated in many radiation-
exposed groups, including children irradiated for benign diseases (enlarged
thymus glands or tonsils, hemangiomas of the face and neck, tinea capitis of the
scalp) [9]; survivors of atomic bombing in Japan [5]; Marshall Islanders exposed to
nuclear test fallout [10]; and children living in the area of Chernobyl, Three Mile
Island, or Fukushima, sites of a nuclear accident [11,12]. Virtually all of the previous
indications for external radiation treatments in this range (eg, to shrink an
"enlarged" thymus gland) have been abandoned [13]. However, environmental
exposures largely due to accidents remain possible.

178
 ●Childhood – Exposure of a cohort of children to low doses of iodine 131 (I-
131; estimated mean thyroid dose of 174 mGy) over a prolonged period of
time (13 years as a result of releases from the Hanford nuclear facility) was
not associated with an increased risk of thyroid disease in one study [14]. On
the other hand, children exposed to radiation, predominantly I-131, after the
Chernobyl accident have developed thyroid cancer [15-19]. Additionally,
among 1494 subjects aged 16 to 20 years who were exposed to I-131 fallout
from the Chernobyl accident in utero, there was an increase in thyroid
cancer; this is consistent with other data, but the risk estimate was based on
only eight cases and was not statistically significant [20]. It is not clear how
far the Chernobyl experience can be extrapolated, because other factors,
such as iodine deficiency [15], which may increase the uptake of radioiodine
by the thyroid gland, as well as exposure to other short-lived higher energy
iodine isotopes, may come into play.
●Adult – Assessment of the possible risk for thyroid cancer in exposed adults
largely comes from pooled analyses, atomic bomb survivor studies, and
Chernobyl liquidator studies.
•In the pooled analyses described above, there was a decrease in risk of
thyroid cancer with increasing age of exposure, with no demonstrable risk
found above an exposure age of approximately 20 years [2,3].
•In adult survivors exposed to atomic bomb fallout, the risk appears to
depend on the endpoint used for the estimate. For thyroid cancers ≥10
mm, no statistically significant risk was evident [5]. For papillary
microcarcinomas (<10 mm) identified in autopsy specimens, a dose-
response relationship was found (estimated excess odds ratio/Gy 0.57,
95% CI 0.01-1.55) [21,22].
•Some evidence of a risk from adult exposure comes from a study of 107
thyroid cancer cases and 423 controls among Chernobyl liquidators. The
median thyroid dose was estimated to be 69 mGy, and the observed,
excess relative risk (RR) at 100 mGy was 1.38 (95% CI 1.10-2.09) [23].
However, studies of Chernobyl liquidators are susceptible to
ascertainment bias.
High-dose exposure — High-dose exposure in childhood increases the risk of
thyroid nodules and thyroid cancer [3]. There appears to be much less risk (if any)
when exposure occurs after age 30 years [24].
High-dose head and neck radiation also increases the risk of hypothyroidism.
(See 'Surveillance for functional thyroid abnormalities' below and "Disorders that
cause hypothyroidism", section on 'External neck

179
irradiation' and "Endocrinopathies in cancer survivors and others exposed to
cytotoxic therapies during childhood".)
The increasing success of treating children for a variety of malignancies, often
using radiation, has resulted in studies of their risk for developing thyroid cancer
[25,26].
●Childhood – Studies in childhood cancer survivors have shown an increased
risk of thyroid cancer after radiotherapy (head/brain, neck, spine, total body
irradiation) [3,27-32], as illustrated by the findings of a pooled analysis of four
observational studies of childhood cancer survivors (16,757 patients with 187
developing primary thyroid cancer) [3]:
•The risk of thyroid cancer after radiotherapy:
-Increased with radiation dose (RRs of 6.8 for 2 to 4 Gy and 14.9 for 5
to 9 Gy)
-Plateaued between a dose of 10 and 30 Gy (RRs of 14.8 at 10 to 19 Gy
and 15.2 at 20 to 29 Gy)
-Declined with the highest doses (RRs 9.3 at 30 to 39 Gy and 5.1 at >40
Gy), presumably due to cell destruction (figure 1)
•The pooled excess absolute risk at 10 Gy was 12.4 per 10,000 patient-
years.
•The risk increased significantly with decreasing age at exposure (RR 17.5
and 3.9 for age at exposure <5 years and >15 years, respectively).
The risk of thyroid cancer does not appear to decrease over time [3,29].
●Adult – Thyroid cancer following high-dose adult exposures have not been
studied as extensively as childhood exposures.
•In a study of patients treated with hematopoietic cell transplantation
(including total body irradiation), compared with nonirradiated patients,
the risk of developing a second cancer was higher among patients
irradiated at <30 years of age, whereas there was no difference between
nonirradiated and irradiated patients when treatments were given at >30
years [24,33]. The majority of second cancers, including thyroid, occurred
among children <17 years at the time of hematopoietic cell
transplantation. (See "Second malignancies after treatment of classic
Hodgkin lymphoma", section on 'Thyroid cancer' and "Malignancy after
hematopoietic cell transplantation", section on 'Solid tumors'.)
In adults, a small increase in the absolute risk of secondary malignancies has
been reported after radioiodine therapy for thyroid cancer. This topic is
reviewed elsewhere. (See "Differentiated thyroid cancer: Radioiodine
treatment", section on 'Secondary malignancy'.)

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GENETICS OF RADIATION-INDUCED THYROID CANCERSomatic
mutations play a central role in the genesis of radiation-induced cancers. Even
though radiation can cause the entire range of possible mutations, those resulting
in breakage and rejoining of the DNA chain are most important [34,35].
These assumptions about radiation carcinogenesis are supported by work on the
papillary thyroid cancers found in children in the aftermath of the nuclear power
plant accident at Chernobyl in 1986 [35-37].
●In some papillary thyroid cancers, a translocation of the RET gene occurs,
resulting in its constitutive expression and activation; this gene is not
expressed in normal thyroid cells. The RET translocation has been found in a
higher proportion of Chernobyl-related cancers than those not associated
with radiation. Similarly, the frequency of RET translocations is increased in
thyroid cancer cases associated with external radiation treatment for benign
and malignant conditions [38,39].
●The specificity of RET and other translocations is illustrated by the
observation that point mutations in the BRAF gene, the other common
genetic driver in papillary thyroid cancer, are rarely found in radiation-related
cases [40,41]. (See "Oncogenes and tumor suppressor genes in thyroid
nodules and nonmedullary thyroid cancer", section on 'Papillary thyroid
cancer'.)
The effects of radiation on these alterations is more pronounced at younger ages
of exposure. Proliferative activity of normal human thyroid cells decreases with
increasing age [42]. This could explain, in part, the higher risk of radiation-related
thyroid cancer in children rather than adults. Some people may have increased
susceptibility to radiation effects related to a polymorphism upstream to
the FOXE1 (TTF-2) gene on chromosome 9q22 [43]. In a large study of people with
Chernobyl-related thyroid cancers, three polymorphisms have been tentatively
identified, including at 9q22, as associated with this susceptibility [35]. Thus far, it
is not clear whether radiation-related papillary thyroid cancers containing
translocations behave differently from cancers without them. Also, it is still not
possible to use patterns of somatic mutations to distinguish radiation-related from
sporadic thyroid cancers [35].
APPROACH TO THE PATIENT WITH A HISTORY OF THYROID
RADIATION EXPOSURE
Who might benefit from surveillance?
●Individuals with a childhood history of therapeutic radiation exposure to the
neck region (high dose) or environmental radiation exposure (low dose) are
candidates for long-term surveillance for thyroid cancer. They require regular
physical examination of the thyroid gland. Their medical records should be
181
 reviewed to determine, as best as possible, the dose and site of radiation, as
well as the age at the time of the radiation exposure. Such patients with high-
dose exposure should be monitored annually for hypothyroidism.
●Individuals with similar exposure as adults are at lower risk than those
exposed as children, and there is no convincing rationale for thyroid cancer
screening beyond routine medical care. Such patients with high-dose
exposure should be monitored annually for hypothyroidism.
It is possible that some people are genetically disposed to developing
radiation-induced thyroid cancer, but identifying them is not feasible or
advisable. Proving an effect of adult exposure would require very large
studies that avoid ascertainment bias and/or the ability to distinguish
radiation-related from sporadic thyroid cancer.
●The thyroid doses from diagnostic procedures (very low dose) are not high
enough to suggest that the benefit of surveillance would exceed the risks and
costs. However, it should be kept in mind that multiple radiograph
examinations may result in cumulative doses that reach the low-dose
category (≥100 mGy). (See 'Prevention of radiation-related thyroid
disease' below.)
General evaluation — Surveillance typically includes [32]:
●Annual history and physical examination of the neck, as part of routine
medical care (all individuals with a history of childhood low- or high-dose
radiation exposure to the thyroid)
●Assessment of thyroid function tests (all individuals with a history of high-
dose exposure)
The use of screening thyroid ultrasound to detect nonpalpable nodules in patients
with a history of childhood thyroid radiation exposure is controversial.
(See 'Surveillance for structural thyroid abnormalities' below.)
The increased risk of thyroid cancer resulting from radiation exposure during
childhood persists for at least four decades [4,44]. Thereafter, it begins to decline
but has not reached baseline for as long as observations have been made;
therefore, surveillance is continued indefinitely.
History — All patients who grew up in the era when radiation was used to treat a
wide variety of nonmalignant conditions, chiefly during the 1940s and 1950s,
should be asked about radiation exposure. For those who were exposed as a result
of such treatments, the actual records usually are not available. Nevertheless, a
few guidelines are helpful in obtaining and evaluating the history, remembering
that the goal is to determine the thyroid radiation dose.
●Confirmatory history is that the caregiver was asked to leave the room when
the treatment was administered. Contradictory history is memory of a purple

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 light (ultraviolet [UV] treatment) and the presence of the caregiver or other
personnel in the room during treatment.
●Dermatologists previously used radiation treatment to treat chronic cystic
acne. This should be distinguished from UV treatment and nonpenetrating
radiograph treatment (Grenz rays).
●Many doctors' offices were equipped with fluoroscope machines that were
used during routine examinations, as may be recalled by a patient or their
caregivers.
●Radium-tipped rods were placed through the nose into the posterior
pharynx to shrink the tonsils and adenoids of children. During this treatment,
only a very small amount of radiation reached the thyroid gland, and the risk
is proportionately smaller or absent [45,46].
Patients who have been exposed to nuclear fallout (from testing, accidents, or in
Japanese survivors of atomic bombing) are typically aware of the exposure and are
being followed as cohorts for radiation-related adverse effects [5,11,47].
Children exposed to therapeutic radiation typically have medical records detailing
the dose and site of radiation, as well as the age of radiation exposure. Cranial,
nasopharyngeal, oropharyngeal, neck, cervical spine, upper chest, mantle,
mediastinal, and total body irradiation increases the risk of thyroid cancer [32].
Physical examination — All individuals with a childhood history of low- or high-
dose radiation exposure to the thyroid should have a yearly thyroid examination
as part of routine medical care. The thyroid-related physical examination is no
different for radiation-exposed and nonexposed patients. The neck should be
palpated to assess the size of the thyroid gland, for the presence of firm or
dominant nodules, and for cervical adenopathy. In general, physical examination
has a low accuracy for predicting thyroid cancer. However, a fixed hard mass,
obstructive symptoms, cervical lymphadenopathy, or vocal cord paralysis all
suggest the possibility of cancer. (See "Diagnostic approach to and treatment of
thyroid nodules", section on 'History and physical examination'.)
The management of patients with a suspected palpable thyroid nodule is reviewed
briefly below and in more detail elsewhere. (See 'Management' below
and "Diagnostic approach to and treatment of thyroid nodules", section on
'Evaluation'.)
Surveillance for functional thyroid abnormalities
●Low and very low dose – The preponderance of evidence does not support
routine screening for hypothyroidism in individuals with a history of low- or
very low-dose radiation exposure. (See "Pathogenesis of Hashimoto's
thyroiditis (chronic autoimmune thyroiditis)", section on 'Radiation
exposure'.)

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 ●High dose – Thyroid function should be assessed annually in all patients
with a history of high-dose therapeutic irradiation exposure to the thyroid.
External irradiation of the neck (in doses of 25 Gy or more) causes
hypothyroidism [48]. The effect is dose dependent, the onset is gradual, and
many patients have subclinical hypothyroidism for several years before
developing overt disease. It is a reasonable hypothesis, although unproven,
that early intervention to avoid hypothyroidism could reduce the risk for
thyroid nodules and cancer. (See "Disorders that cause hypothyroidism",
section on 'External neck irradiation' and "Endocrinopathies in cancer
survivors and others exposed to cytotoxic therapies during childhood".)
•For patients with a history of cranial or nasopharyngeal irradiation (who
are at risk for central hypothyroidism), both thyroid-stimulating hormone
(TSH) and free thyroxine (T4) should be measured. (See "Central
hypothyroidism", section on 'Diagnosis'.)
•For patients with radiation confined to the neck area alone, measurement
of TSH is sufficient. If the serum TSH concentration is elevated, the TSH
measurement should be repeated along with a serum free T4 to make the
diagnosis of hypothyroidism. (See "Diagnosis of and screening for
hypothyroidism in nonpregnant adults", section on 'Diagnosis'.)
Testing should be initiated no later than the first year and is then repeated
annually. Lifelong replacement therapy with levothyroxine is indicated for
patients with hypothyroidism. Serum TSH should be monitored to assess
dosing adequacy and medication compliance. (See "Treatment of primary
hypothyroidism in adults", section on 'Dose and monitoring'.)
Surveillance for structural thyroid abnormalities — As part of routine clinical
care, physical examination of the neck is recommended for all patients previously
exposed to radiation during childhood, usually on a yearly basis. In addition,
ultrasonographic evaluation is useful in patients in whom the thyroid is difficult to
palpate on physical examination (eg, obesity, short neck), or in whom a structural
abnormality is suspected.
The use of thyroid ultrasound to screen for nonpalpable nodules in radiation-
exposed patients is controversial since it has not been shown to improve
outcomes [49,50]. In the absence of data supporting routine screening of all
exposed individuals, we suggest that the use of surveillance ultrasonography be
individualized, guided by shared clinical decision-making with patients [51]. The
discussion should include an assessment of each patient's risk factors, including
dose of radiation to the thyroid (when it is available) and age of exposure, as well
as a discussion of the potential harms and benefits of ultrasound surveillance [52].

184
(See 'Risk assessment' below and 'Potential benefits and harms of routine
ultrasound screening' below.)
Guidelines (Children's Oncology Group and American Thyroid Association [ATA]) do
not recommend or equivocate (neither recommending for nor against) ultrasound
screening in childhood cancer survivors with high-dose exposure [32,53,54]. The
absence of data showing a benefit of thyroid ultrasound over neck palpation
suggests the need for individualized decision-making.
Risk assessment — The authors consider the following risk factors when
assessing an individual's risk for the development of radiation-induced thyroid
nodules [3,4,55,56]:
●Age – Given the steep decline in risk with increasing age of exposure, being
exposed before age 18 years is a reasonable threshold to include in the risk
assessment.
●Dose – All patients who had radiation treatments during childhood, whether
for malignant or benign conditions, that included the neck area should be
considered at risk. The pooled analyses showed that the relative risk (RR) is
proportional to the radiation dose and continues to increase up to 10 to 30
Gy [2]. There was a significantly elevated risk starting at doses as low as 40
mGy [1,2]. Based on these analyses, when it can be estimated, a dose of 40
mGy is a reasonable threshold above which confers increased risk. With some
exceptions, usually when multiple examination are required, this excludes
patients with exposure limited to diagnostic radiology.
●Female sex – While the radiation-associated RR is not demonstrably
different for males and females, the absolute risk is higher for females
because of their higher baseline risk.
In an attempt to identify patients at highest risk for the development of thyroid
cancer, one group combined data from three childhood cancer survivor databases
to develop risk prediction models that project the absolute thyroid cancer risk
among five-year survivors of childhood cancer [57]. The model that included sex,
birth after 1970, age <15 years when diagnosed with a childhood cancer, prior
diagnosis of a thyroid nodule, history of radiation therapy including the neck, and
history of treatment with an alkylating agent had the best overall discriminatory
performance. This model performed as well as one that included a reconstructed
radiation absorbed dose to the thyroid gland [57]. Further validation is required
before this risk prediction tool can be used to guide clinical monitoring for thyroid
cancer.
Potential benefits and harms of routine ultrasound screening — Many patients
with a history of radiation exposure during childhood have nonpalpable thyroid
nodules (figure 2) [58]. Ultrasound can detect small nodules not apparent on

185
physical examination, which may or may not be related to the previous radiation
exposure, as structural thyroid abnormalities are very common. Baseline
ultrasounds, performed in children who lived near the Fukushima plant and in
children who lived in distant areas of Japan, showed many small, solid nodules,
cysts, and other findings such as ectopic thymus tissue inclusions [59-61]. There is
still no evidence that thyroid cancer is more prevalent in individuals living closer to
the reactor with higher levels of radiation exposure, compared with those living
further away with background exposure levels [62].
In prospective studies of children exposed to high-dose radiation for the treatment
of cancer, ultrasound surveillance beginning five years after radiation therapy and
repeated every one to three years for 12 to 15 years showed thyroid nodules >1
cm in approximately 36 to 42 percent [63,64]. Ultimately, thyroid cancer was
diagnosed in approximately 7 percent of patients in the cohorts. Cancer cases
ranged from 8 to 24 years after the exposure.
In general, the outcome of thyroid cancer is better when diagnosed at an earlier
stage, although the evidence is stronger for adults than for children [65]. For
children exposed to radiation, there are insufficient data to determine whether the
detection of thyroid cancer by screening ultrasound prior to a palpable
abnormality impacts long-term outcomes [53,66]. Any potential benefit of earlier
disease detection must be balanced against potential risks associated with
excessive evaluations and treatments for ultrasonographically detected thyroid
nodules and indolent thyroid cancers that may never have become clinically
apparent.

The arguments for screening thyroid ultrasound are:

●Ultrasonography is the most sensitive method of imaging the thyroid, does

not involve further radiation exposure, and is performed without stopping
thyroid hormone therapy
●Nodules sized 1.0 to 1.5 cm, and even larger ones, are not always palpable
but are easily detected by ultrasonography

The opposing arguments are:

●Most, but not all, clinically important nodules will be detected by physical
examination, either in the initial examination or during follow-up
●Detection of small nodules may result in anxiety and inappropriate
evaluation and treatment, and the complications of unneeded therapy may
be greater than the potential risk from the nodules
●The cost of screening patients is high

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Optimal timing and duration if ultrasound surveillance initiated
●Initial imaging – If surveillance ultrasound is obtained, based on the
expected time course for the development of thyroid nodules after radiation
exposure [1,2], we suggest that the initial surveillance ultrasound be done no
sooner than 5 to 10 years after exposure. Thereafter, the frequency and
method of follow-up of irradiated patients depends upon their estimated risk
and the clinical findings at the initial evaluation.
●Subsequent imaging – If the initial examination is normal and the level of
risk is low, then annual palpation is reasonable. When low-dose exposure
occurred years earlier (presumably in the 1940 to 1960 era when such
exposures were common), usually based on an estimate of a dose at least of
100 mGy at a young age, we consider a single normal ultrasound at least 5 to
10 years after exposure as sufficient. For others, an interval of every three to
five years in addition to annual palpation is preferred, especially if there are
small and/or fine-needle aspiration (FNA)-benign nodules. (See "Diagnostic
approach to and treatment of thyroid nodules", section on 'Benign nodules
(Bethesda II)'.)
Even if the potential benefit of ultrasonographic examination of the neck is
expected to outweigh the potential risk for an individual patient, data are lacking
to provide definitive recommendations with regard to the optimal timing of the
initial and follow-up surveillance ultrasonographic examinations. The absence of
thyroid nodules on a single thyroid ultrasound examination does not predict the
absence of nodular growth and thyroid cancer development in the future.
Therefore, thyroid ultrasound would have to be repeated over time. In addition,
the increased risk of thyroid cancer resulting from radiation exposure during
childhood persists for at least four decades [3]. Thereafter, it begins to decline but
does not return to baseline for as long as observations have been made.
In a prospective study of ultrasound examination in 2637 atomic-bomb survivors
during an average follow-up of 13.3 years, six thyroid cancer cases were found
among 68 subjects who had a solid thyroid nodule (7.3 percent) on baseline
screening, one case among 121 subjects who had a thyroid cyst (0.8 percent), and
seven cases among 2434 (0.3 percent) patients who did not have any nodules on
baseline examination [67]. In 140 subjects in a Chernobyl-related study with
confirmed nodules, approximately 10 to 25 percent of the nodules were present
on follow-up that were not diagnosed on earlier imaging [68].
Management
Thyroid nodules — The initial evaluation of a thyroid nodule (detected by physical
examination or imaging) is not different from the evaluation of thyroid nodules in
nonirradiated patients, and it includes measurement of TSH (if not previously

187
obtained) and thyroid ultrasound (if not previously obtained). (See "Diagnostic
approach to and treatment of thyroid nodules", section on 'Evaluation'.)
If the nodule meets sonographic criteria for sampling, the next step in the
evaluation of a thyroid nodule is a palpation or ultrasound-guided FNA biopsy.
(See "Diagnostic approach to and treatment of thyroid nodules", section on
'Sonographic criteria for FNA'.)
The sensitivity of FNA appears to be similar for nodules in the general population
and in patients exposed to radiation [69]. In patients with thyroid nodules,
however, a history of radiation exposure increases the likelihood that the nodule is
a thyroid cancer [67,70].
Although there is no evidence that subcentimetric nodules are more aggressive in
irradiated patients, certain suspicious ultrasound features in high-risk patients
may warrant FNA biopsy of subcentimeter nodules. Thus, in select patients, FNA
should be performed in nodules <1 cm with suspicious sonographic features (eg,
TR5 using American College of Radiology-Thyroid Imaging Reporting and Data
System [ACR-TIRADS] sonographic risk stratification system), and, in addition,
other concerning characteristics, such as subcapsular locations adjacent to the
recurrent laryngeal nerve or trachea, extrathyroidal extension, or metastatic
cervical lymphadenopathy. (See "Diagnostic approach to and treatment of thyroid
nodules", section on 'Sonographic criteria for FNA'.)
In a retrospective analysis of 4296 patients who received external radiation
treatment before age 16 years for a variety of benign conditions, 1059 patients
underwent thyroid surgery due to the presence of a suspicious thyroid lesion
(detected either by physical examination or imaging) [71]. There were 612
malignant nodules in 358 patients and 2037 benign nodules in 930 patients:
●A solitary nodule had the same risk of malignancy as one of multiple
nodules (18.8 versus 17.3 percent).
●Patients with multiple nodules were more likely to have cancer than those
with a solitary nodule (30.7 versus 18.7 percent).
●FNA of the two largest nodules in each patient missed micropapillary
cancers in 17 percent of patients.
●More than one-half of the patients had multifocal cancers.
Papillary thyroid cancer is the most common radiation-related histologic type [3,4].
Increasingly, molecular diagnostic tests are being applied to indeterminate FNAs.
So far, none of these tests have been evaluated for radiation-related thyroid
nodules. Because these nodules are more likely to be malignant, it is probable that
the negative predictive value of these tests will be adversely affected.
(See "Evaluation and management of thyroid nodules with indeterminate
cytology", section on 'Molecular markers'.)

188
Thyroid cancer — Patients with radiation-related thyroid cancer should be treated
in the same way as nonexposed patients with thyroid cancer. (See "Differentiated
thyroid cancer: Overview of management".)
Thyroid-specific outcomes appear to be similar in patients with and without a prior
history of external radiation exposure [72-74]. As examples:
●In a study of 296 patients with radiation-related thyroid cancers, although
multicentricity was frequent, the risk factors for recurrence were similar to
those for thyroid-cancer patients in general [72].
●In a study of 3664 patients with differentiated thyroid cancers (116 patients
with a previous history of head and neck irradiation and 3509 patients
without), there was no difference in five-year, disease-specific or recurrence-
free survival [74].
In addition, in studies of patients exposed to radiation as a result of the Chernobyl
accident, recurrence rates were not higher in radiation-exposed patients versus
patients with sporadic thyroid cancer, even though their thyroid cancers tended to
have aggressive histologic features [75-77]. After an average clinical follow-up of
10 years, the disease-specific mortality rate in these thyroid cancer cases was <1
percent, and short-term recurrence rates range from 7 to 28 percent (mean 17
percent) [77].
All-cause mortality was not increased in individuals who developed thyroid cancer
after they were irradiated for benign conditions during childhood compared with
individuals who were similarly irradiated but did not develop thyroid cancer, a
reassuring finding [78]. However, in childhood cancer survivors who develop
thyroid cancer as a secondary primary malignancy mortality may be increased [79].
Several factors may contribute to overall mortality outcomes in childhood cancer
survivors, including cardiovascular comorbidities and other chronic health
conditions.
Benign nodules
●Benign based upon FNA results – The follow-up of patients with biopsy-
proven benign nodules should include at least annual palpation and repeat
ultrasonography, initially at 12 months, and then at increasing intervals over
time. (See "Diagnostic approach to and treatment of thyroid nodules", section
on 'Benign nodules (Bethesda II)'.)
●Benign based upon surgical pathology – In patients with surgically
confirmed benign nodules after a thyroid lobectomy (ie, nodule with
suspicious cytology on FNA, which, when resected, had benign pathology),
thyroid hormone administration aiming either for minimal TSH suppression
or a low-normal TSH is a reasonable intervention. (See "Thyroid hormone

189
 suppressive therapy for thyroid nodules and benign goiter", section on
'Irradiated patients'.)
Postoperative thyroid hormone treatment, even if only one lobe was
removed, appears to reduce recurrences. As an example, in a nonrandomized
study of 632 adults who were treated prior to age 16 years with conventional
radiation for nonmalignant conditions and who subsequently had benign
thyroid nodules removed surgically, patients who were treated with thyroid
hormone had a lower incidence of recurrent nodules than those who were
not (14 versus 34 percent, RR 0.69, 95% CI 0.47-1.01) [80]. Histologic analysis
of 91 tissue samples from patients with recurrent nodules showed that 18
percent were malignancies and that thyroid hormone treatment had no
effect on the rate of malignancy. Thus, thyroid hormone reduced the risk of
new nodules, but it did not reduce the risk of thyroid cancer.
Prevention of radiation-related thyroid disease
Medical radiation exposure — While radiation exposure of the thyroid during the
treatment of benign medical conditions has decreased, exposure from diagnostic
procedures (eg, computed tomography [CT]) is increasing rapidly, particularly
among children [6]. In many cases, the exposure is greater than necessary. Efforts
to minimize exposure include the "image gently" campaign initiated by
radiologists. In addition, clinicians providing direct patient care should evaluate
the risks and benefits of any procedure, explain them to the patient or caregiver,
and consider strategies to reduce radiation risks to the thyroid gland.
(See "Radiation-related risks of imaging", section on 'Children and adolescents'.)
Routine dental radiography (intraoral, panoramic) has not been shown to increase
the risk of thyroid cancer; however, it is sensible to reduce thyroid radiation
exposure (eg, thyroid collar, reduction in frequency of imaging), especially in
children, as long as the dental examination is not compromised [81].
Potassium iodide for thyroid protection in a nuclear accident — In the event of
a nuclear accident, potassium iodide tablets can decrease thyroid uptake of
radioactive iodine. Potassium iodide can almost completely protect the thyroid if
administered within 12 hours before radioactive iodine exposure or up to two
hours after; after two hours, the degree of protection declines (80, 40, and 7
percent after 2, 8, and 24 hours, respectively) [82,83]. (See "Management of
radiation injury".)
One effect of potassium iodide is to "dilute" internal radioactive iodine so less
enters the thyroid. Another is the reduction of organification by way of the Wolff-
Chaikoff effect so that radioactive iodine that enters the thyroid is not retained. By
a less well understood mechanism, the sodium-iodide symporter (NIS) is
downregulated [84].

190
Potassium iodide is well tolerated, as shown by the experience of administering it
to a large population in Poland after the Chernobyl accident [85]. In older people,
especially those with goiters, one might expect rare cases of iodine-induced hyper-
or hypothyroidism. It has been estimated that for the fetus, the newborn, children,
and adolescents, the benefit of preventing radiation-induced thyroid cancer in the
event of an accidental exposure outweighs the potential risk of hypothyroidism. In
older adults, arbitrarily taken as above 40 years, the potential benefits of
potassium iodide prophylaxis probably do not outweigh the risks, except for
exposure levels that threaten to produce hypothyroidism [86]. Thus, in the event of
an accident, iodine prophylaxis should be given, with the possible exception of
older adults. Treatment should begin as soon as possible after exposure and
continue daily for the duration of the exposure [87].
Potassium iodide tablets and a solution designed for children are available
commercially without a prescription. Alternatively, for children, potassium iodide
tablets may be dissolved according to directions found at the US Food and Drug
Administration (FDA) website and the American Thyroid Association (ATA) website.
Following the Fukushima accident, potassium iodine was not widely distributed (it
had not been predistributed into households and schools) and few received it. In
retrospect, this was in keeping with guidelines for its use as the thyroid radiation
doses were almost universally below the threshold levels. In large part, this was
due to keeping radioactive iodine out of the food chain, in contrast with Chernobyl.
This substantial mitigation of the dose has led to a reconsideration of when and
how to use potassium iodide following an accident [88,89].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
●Radiation exposure – External or internal radiation exposure may result in
thyroid nodules, thyroid cancer, and/or hypothyroidism. (See 'Radiation
exposure' above.)
•External radiation – External radiation includes therapeutic radiation for
the treatment of cancer or historical use of external radiation to treat a
wide variety of nonmalignant conditions. Cranial, nasopharyngeal,
oropharyngeal, neck, cervical spine, upper chest, mantle, mediastinal, and
total body irradiation expose the thyroid to sufficient radiation to increase
the risk of radiation-related disease.
•Internal radiation – Internal radiation exposure may be due to ingestion
of foods or liquids contaminated with radioactivity or by inhalation of
radioactive gases or particles. Exposure may be due to nuclear fallout
191
 from testing and accidents at operating nuclear power plants, or above
ground nuclear explosive testing.
●Magnitude of exposure – The risk of thyroid cancer is related to age
(greater for children exposed early in life) and radiation dose to the neck
(figure 1). (See 'Magnitude of exposure' above.)
•Low dose – Environmental exposure or radiation for nonmalignant
conditions
•High dose – Therapeutic radiation for the treatment of cancer
●Thyroid surveillance, childhood exposure – Individuals with a childhood
history of radiation exposure to the neck region are candidates for
surveillance, as follows. (See 'Approach to the patient with a history of thyroid
radiation exposure' above.)
•Physical examination – Annual thyroid examination as part of routine
clinical care for all patients with low-dose or high-dose exposure during
childhood. (See 'Physical examination' above.)
•Thyroid function tests – Annual thyroid function testing for all patients
with high-dose exposure during childhood. For patients with radiation
confined to the neck area alone, measurement of thyroid-stimulating
hormone (TSH) is sufficient. For patients with a history of cranial or
nasopharyngeal irradiation (who are at risk for both thyroid nodules and
central hypothyroidism), we measure TSH and free thyroxine (T4).
(See 'Surveillance for functional thyroid abnormalities' above.)
•Thyroid ultrasound – Use of thyroid ultrasound to detect nonpalpable
nodules in radiation-exposed patients is controversial. In the absence of
data, the use of surveillance ultrasonography should be individualized,
guided by shared clinical decision-making after an assessment of each
patient's risk factors, as well as a discussion regarding the harms and
benefits of ultrasound screening. (See 'Surveillance for structural thyroid
abnormalities' above.)
●Thyroid surveillance, adult exposure – Individuals with high- or low-dose
exposure as adults are at lower risk of thyroid cancer than those exposed as
children, and there is no convincing rationale for thyroid cancer screening
beyond routine medical care. Such patients with high-dose exposure should
be monitored annually for hypothyroidism. (See 'Who might benefit from
surveillance?' above and 'Surveillance for functional thyroid
abnormalities' above.)
●Management – The clinical characteristics, evaluation, and management of
radiation-related thyroid nodules (discovered by palpation or through
ultrasound screening) are similar to those of thyroid nodules in nonexposed

192
patients. Patients with radiation-related thyroid cancer should be treated in
the same way as nonexposed patients with thyroid cancer.
(See 'Management' above and "Diagnostic approach to and treatment of
thyroid nodules".)
●Prevention of radiation-related thyroid disease – In the event of a nuclear
accident, potassium iodide tablets can decrease thyroid uptake of radioactive
iodine. Potassium iodide can almost completely protect the thyroid if
administered within 12 hours before radioactive iodine exposure or up to
two hours after; after two hours, the degree of protection declines (80, 40,
and 7 percent after 2, 8, and 24 hours, respectively). It can be taken once
daily as long as high levels of environmental radioactive iodine persist.
(See 'Potassium iodide for thyroid protection in a nuclear accident' above.)

193
Struma ovarii
Author:
Douglas S Ross, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Aug 16, 2021.
INTRODUCTIONStruma ovarii is a specialized or monodermal teratoma
predominantly composed of mature thyroid tissue [1]. Thyroid tissue must
comprise more than 50 percent of the overall tissue to be classified as a struma
ovarii. Struma ovarii accounts for approximately 5 percent of all ovarian teratomas
[2-4]. Depending on the histologic features, struma ovarii can be classified as
benign or malignant [5]. The clinical presentation, diagnosis, and management of
struma ovarii will be reviewed here. Ovarian teratomas are reviewed in detail
elsewhere. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical
manifestations, and diagnosis", section on 'Teratomas'.)
CLINICAL MANIFESTATIONSWomen with struma ovarii usually present with
pain and/or a pelvic mass and less frequently with ascites. Clinical and biochemical
features of hyperthyroidism are uncommon in women with struma ovarii,
occurring in less than 5 to 8 percent of cases [3,5-8]. The clinical manifestations of
struma ovarii are based upon single case reports and small case series [2-5,9,10].
General findings — Struma ovarii is most common between the ages of 40 and 60
years, but has been reported in patients as young as 10 years old [11]. In case
series of 20 to 30 patients with histologically confirmed struma ovarii, abdominal
or pelvic pain was present in 17 patients and a palpable lower abdominal mass in
22 [4,8]. In one series, no definite symptoms were present in 14 of 34 patients, in
whom the presence of an ovarian tumor was incidentally noted on
ultrasonography performed for other reasons [4]. Ascites was present in 4
patients. CA-125 was elevated in 4 of 13 women in whom it was measured (one of
three who were found to have malignant struma ovarii).
Hyperthyroidism — Clinical and biochemical features of hyperthyroidism are
uncommon in women with struma ovarii. In hyperthyroid patients, the serum
thyroid-stimulating hormone (TSH) is low and free thyroxine (T4) and/or
triiodothyronine (T3) are elevated. The thyroid gland typically is not enlarged, but
serum thyroglobulin is elevated. Radioiodine uptake is low or absent in the thyroid
194
gland but present in the pelvis. Rarely, women with struma ovarii and
hyperthyroidism also have a goiter [7]. There are at least two possible explanations
for this association:
●The coexistence of Graves' disease and struma ovarii, which has been
reported rarely in the literature [12,13]. Serum thyroid-stimulating
immunoglobulins (thyrotropin-receptor antibodies [TRAb]) would be
expected to stimulate function of thyroid tissue in the ovary as well as in the
neck.
●A toxic nodular goiter with parallel formation of thyroid autonomy in an
ovarian teratoma.

These women would have radioiodine accumulation in both locations.

Imaging — On ultrasound, struma ovarii appears as a heterogeneous solid mass

[14,15]. There are no distinguishing ultrasound features unique to struma ovarii.
Ascites is occasionally present.
Histology — Most women undergo surgical resection for diagnostic purposes. The
histologic pattern may show microfollicular, macrofollicular, or oxyphil adenoma,
with or without papillary hyperplasia [2,16]. As in follicular tumors of the thyroid
gland, the thyroid epithelium in the teratoma may be organized in a solid,
embryonal, or pseudotubular pattern, rather than thyroid follicles [7] (see "Atlas of
thyroid cytopathology"). Immunohistochemical staining for thyroglobulin may be
required to identify the cells as being of thyroid origin [17].
Histologic features of thyroid cancer are found in 5 to 37 percent of struma ovarii
[3,4,9]. One study evaluated 96 patients with struma ovarii [18]. Sixteen patients
had malignant struma; 10 had cytologic features of papillary cancers, one follicular
cancer, and five well-differentiated neuroendocrine stromal tumors. Features
indicative of malignancy include nuclear grooves, ground-glass appearance of the
nuclei, and vascular invasion [19]. Cancer is more likely in larger tumors (75
percent of tumors greater than 16 cm) and rare in tumors under 5 cm [7]. The
tumor can spread to the contralateral ovary and adjacent pelvic structures [20]. In
one review, distant metastases were reportedly uncommon, occurring in 5 percent
[8]. When present, the predominant sites of metastases are the lung, bone, liver,
and brain [14].
Rarely, seeding of the peritoneum by a benign tumor, a condition called strumosis,
occurs [6].
DIAGNOSIS
Struma ovarii — In women presenting with a pelvic mass, struma ovarii is typically
diagnosed postoperatively based upon histologic findings of thyroid follicles in the
resected ovary.
195
In women presenting with hyperthyroidism (elevated free T4 and/or T3, low TSH),
the diagnosis of struma ovarii should be considered in a woman with persistent
hyperthyroidism (>3 to 6 months), no goiter, absent radioiodine uptake in the
neck, and a detectable serum thyroglobulin level. However, even among women
with hyperthyroidism, without goiter, and with minimal or absent thyroid uptake
of radioiodine, struma ovarii is rare. If struma ovarii is suspected, pelvic ultrasound
should be obtained, and if pelvic ultrasound reveals an ovarian mass, pelvic
radioimaging (using iodine-123 [123-I] or iodine-131 [131-I]) is performed to
confirm the presence of functional thyroid tissue within the mass [21,22]. Because
the bladder concentrates radioiodine, single-photon emission computed
tomography (SPECT) images using any of the iodine radioisotopes may provide
better clarity than planar imaging [23].
Malignant struma ovarii — The diagnostic criteria for malignant struma ovarii
are similar to those for differentiated thyroid cancer. A definite diagnosis of
carcinoma requires tumor invasion, metastases, or recurrence (for follicular
cancer) or the typical cytopathologic features of papillary thyroid cancer.
(See "Atlas of thyroid cytopathology", section on 'Papillary cancer'.)
The diagnosis of follicular thyroid cancer in an ovarian teratoma (malignant struma
ovarii) may be difficult and parallels the difficulty in distinguishing benign thyroid
microfollicular adenomas from differentiated follicular thyroid cancer [7].
(See "Atlas of thyroid cytopathology", section on 'Follicular neoplasm or suspicious
for follicular neoplasm'.)
DIFFERENTIAL DIAGNOSIS
Pelvic mass — The differential diagnosis of a pelvic mass is extensive and is
reviewed elsewhere (see "Types of adnexal masses"). Thyroid cancer metastatic to
the ovary can be confused with true struma ovarii [24], but primary thyroid cancer
rarely metastasizes to the ovary [25]. In such cases, the ovarian tissue does not
have teratomatous features. (See "Ovarian germ cell tumors: Pathology,
epidemiology, clinical manifestations, and diagnosis", section on 'Teratomas'.)
Hyperthyroidism — Among women with hyperthyroidism, without goiter, and
with minimal or absent thyroid uptake of radioiodine, likely causes include
exogenous thyroid hormone administration and lymphocytic (painless) thyroiditis.
(See "Disorders that cause hyperthyroidism", section on 'Hyperthyroidism with a
near absent radioiodine uptake'.)
In most patients with thyroiditis, thyroid function normalizes within several weeks.
Patients with persistent hyperthyroidism (>3 to 6 months) are unlikely to have
thyroiditis. (See "Painless thyroiditis" and "Subacute thyroiditis" and "Postpartum
thyroiditis".)

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Serum thyroglobulin concentrations are low in patients with exogenous
hyperthyroidism in the absence of goiter or thyroid cancer. Thyroglobulin should
be measured to exclude factitious use of thyroid hormone in patients with
persistent hyperthyroidism, without goiter, and with minimal or absent thyroid
uptake of radioiodine. In contrast, thyroglobulin is high in hyperthyroid patients
with endogenous hyperthyroidism, including functional metastatic thyroid cancer,
struma ovarii, and thyroiditis. Whenever serum thyroglobulin is measured, a test
for antithyroglobulin antibodies should be performed at the same time (many
laboratories do the latter first) because serum thyroglobulin measurements are
unreliable if antithyroglobulin antibodies are present. (See "Exogenous
hyperthyroidism" and "Overview of thyroiditis".)
Patients with Graves' disease typically have a goiter and elevated radioiodine
uptake in the neck. The uptake may be lower than expected if iodine-rich drugs
(amiodarone) or contrast agents used for angiography or computed tomography
(CT) were recently administered. An exogenous iodine load will dilute the
administered radioiodine tracer, and the uptake will be lowered depending upon
the amount of the exogenous iodine load, whether the exposure is continuous (eg,
amiodarone), and the interval since the iodine exposure. However, a single iodine
load (eg, radiocontrast for a CT scan) may transiently reduce the radioiodine
uptake in patients with Graves' disease to less than 10 percent for up to two to
four weeks but rarely reduces the uptake to less than 1 percent as occurs in
patients with painless thyroiditis or struma ovarii. (See "Diagnosis of
hyperthyroidism", section on 'Radioiodine uptake' and "Iodine-induced thyroid
dysfunction".)
TREATMENTThe initial treatment of struma ovarii is oophorectomy. Patients
with malignant struma ovarii may need therapy in addition to oophorectomy,
particularly in the presence of metastatic disease. (See 'Malignant struma
ovarii' below.)
For patients with struma ovarii and newly discovered overt hyperthyroidism,
surgery should be postponed until the patient has achieved adequate control of
their thyroid condition (usually three to eight weeks). (See 'Control of
hyperthyroidism before nonthyroid surgery' below.)
Benign struma ovarii — The treatment of benign struma ovarii is surgical
resection of the ovarian tumor, typically unilateral oophorectomy. However, some
patients undergo total hysterectomy with unilateral or bilateral salpingo-
oophorectomy (BSO) because of the preoperative concern for ovarian cancer.
Malignant struma ovarii — There is no consensus on the optimal treatment of
women with malignant struma ovarii. Treatment recommendations are based
upon reports of single cases or case series [5,19,26-29]. The optimal ovarian
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surgical procedure (eg, unilateral or BSO, with or without hysterectomy) is
reviewed separately. (See "Treatment of malignant germ cell tumors of the ovary",
section on 'Surgical staging and primary cytoreduction'.)
Patients with malignant struma ovarii may need therapy in addition to
oophorectomy, such as radioactive iodine, particularly in the presence of
metastatic disease. Radioiodine has been used to treat women with functional
metastatic struma ovarii [3,8,30], analogous to its use in the treatment of
metastatic differentiated thyroid cancer. After ovariectomy but before radioiodine
scanning is performed, the woman must have a near-total thyroidectomy so that
radioiodine uptake by the cancer can be detected and high-dose radioiodine
therapy can be given. The decision to perform a thyroidectomy and administer
radioiodine after oophorectomy should be based upon the presence of
metastatic disease and the risk of recurrence. An extremely high thyroglobulin
suggests metastatic disease. The risk of recurrence is higher in patients with:
●Gross extraovarian extension of the tumor
●Large lesions (>4 cm, corresponding to thyroid T3 lesions)
●Presence of a BRAF mutation
●Histology other than classic papillary cancer
BRAF and RAS mutations have been reported in tumors of patients with malignant
struma ovarii and may prove useful in the diagnosis and management of difficult
cases [31-33]. BRAF-positive papillary cancer is more aggressive, and presumably,
this mutation in a malignant struma ovarii also indicates the potential for more
aggressive disease. However, in a review of 178 cases from the literature between
1983 and 2020, histology other than classic papillary cancer was the only
independent adverse prognostic factor in multivariate analysis (hazard ratio [HR]
3.30, 95% CI 1.12-9.75) [34]. (See "Oncogenes and tumor suppressor genes in
thyroid nodules and nonmedullary thyroid cancer", section on 'BRAF mutations'.)
In a review of 24 cases of malignant struma ovarii, 4 of 24 patients with initial
complete response were treated with adjuvant thyroidectomy and radioiodine
after ovarian surgery; none of these patients had a recurrence [8]. There were
eight recurrences (after an initial complete response to surgery), all of which
occurred in the 16 patients treated conservatively after initial surgery (ie, followed
clinically with or without serum thyroglobulin levels). The median time to
recurrence among those patients was 48 months. Seven of eight women with
recurrences were treated with radioiodine at the time of recurrence (along with
thyroidectomy). Four patients had no evidence of disease at 3, 5, 6, and 324
months following radioiodine. Three patients recurred after radioiodine (at one,
three, and six months). One patient did not receive further therapy and died of
disease six months after recurrence.

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Low risk of recurrence and no metastatic disease — Women with malignant
struma ovarii confined to the ovary typically do not require radioiodine therapy
after oophorectomy. We suggest T4 (levothyroxine) to suppress TSH to the lower
limit or just below normal. We measure serum thyroglobulin annually.
In one case series, four patients with malignant struma ovarii confined to the
ovary (ie, no extraovarian extension or distant metastases) were reviewed [19].
Surgical procedures included unilateral and BSO (one patient each) and total
abdominal hysterectomy (TAH)-BSO (two patients). Only one patient had a
thyroidectomy and treatment with radioactive iodine. This patient was found to
have a synchronous papillary thyroid cancer. After a median follow-up of nine
years, all patients remained without evidence of disease. In a review of a total of 57
cases of malignant struma ovarii confined to the ovary, 50 of whom did not
undergo thyroidectomy-radioactive iodine therapy, the pooled recurrence rate was
7.5 percent at 25 years [19].
High risk of recurrence or metastatic disease — For patients with known distant
metastases, gross extraovarian extension of the tumor, large lesions (>4 cm,
corresponding to thyroid T3 lesions), the presence of a BRAF mutation, or
synchronous primary thyroid cancer, we suggest thyroidectomy followed by
radioiodine treatment. These patients also require T4 therapy. The goal of T4
therapy is to maintain the TSH at levels corresponding to those for conventional
thyroid cancer, with TSH values maintained in the 0.1 to 0.5 mU/L range for the
first five years and then in the normal range thereafter in patients with no
evidence of disease. Patients with persistent disease following initial therapy
require maintenance of a serum TSH <0.1 mU/L.
Equivocal risk — In patients with a malignant struma ovarii and equivocal
indications for radioiodine therapy based upon the ovarian findings, we obtain a
thyroid ultrasound to evaluate for synchronous primary thyroid gland
abnormalities. Fine-needle aspiration (FNA) of detected thyroid nodules is
warranted. Assessment of the ovarian tumor for the presence of a BRAF mutation
may also be helpful.
Control of hyperthyroidism before nonthyroid surgery — There are no
published studies evaluating the risks of nonthyroid surgery in hyperthyroid
patients. In patients with untreated or poorly controlled overt hyperthyroidism
(low TSH, high free T4 and/or T3), an acute event such as surgery can precipitate
thyroid storm, a potentially life-threatening condition (see "Thyroid storm"). Thus,
surgery should be postponed in patients with newly discovered overt
hyperthyroidism until the patient has achieved adequate control of their thyroid
condition (usually three to eight weeks). Treatment of hyperthyroidism in
preparation for nonthyroid surgery is reviewed in detail elsewhere and briefly

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below. (See "Nonthyroid surgery in the patient with thyroid disease", section on
'Hyperthyroidism'.)
In women with struma ovarii and symptomatic or substantial biochemical
hyperthyroidism, we administer a beta blocker (typically atenolol 25 to 50 mg daily,
with the dose increased as needed to maintain the pulse rate below 80) and a
thionamide (typically methimazole, 10 mg two to three times daily or 20 to 30 mg
once daily) for four to six weeks before surgery. Beta blockers should be continued
until the patient's thyroid disease is under control, and then tapered. Thionamides
can be discontinued immediately after surgery. If hyperthyroidism is severe and
the need for surgery is urgent, potassium iodide solution (SSKI, one to five drops
three times daily) can be added one hour after thionamide administration. Iodine
blocks release of T4 and T3 from the gland (and presumably the ovarian tumor)
and thereby shortens the time to achieving a euthyroid state. (See "Thionamides in
the treatment of Graves' disease" and "Thionamides: Side effects and
toxicities" and "Beta blockers in the treatment of hyperthyroidism".)
Patients with subclinical hyperthyroidism (low TSH, normal free T4 and T3) can
typically proceed with elective surgeries. Unless contraindicated, we administer a
beta blocker preoperatively to older patients (>50 years) or younger patients with
cardiovascular disease and taper after recovery. (See "Nonthyroid surgery in the
patient with thyroid disease", section on 'Hyperthyroidism'.)
MONITORINGPatients with malignant struma ovarii require long-term (at least
10 years) follow-up [5,14]. Annual monitoring of stimulated serum thyroglobulin is
reasonable for the first two years postoperatively and, if negative, unstimulated
levels annually thereafter. Patients with biochemical evidence of persistent disease
should have pelvic imaging with computed tomography (CT), with single-photon
emission CT (SPECT) imaging using radioiodine when appropriate, or ultrasound.
(See "Differentiated thyroid cancer: Overview of management", section on
'Monitoring response to therapy'.)
For women with low risk of recurrence (no extraovarian extension or distant
metastases), we suggest T4 (levothyroxine) to suppress TSH to the lower limit or
just below normal and monitoring with yearly serum thyroglobulin.
SUMMARY AND RECOMMENDATIONS
●Struma ovarii is a specialized or monodermal teratoma predominantly
composed of mature thyroid tissue. Thyroid tissue must comprise more than
50 percent of the overall tissue to be classified as a struma ovarii.
(See 'Introduction' above.)
●Women with struma ovarii usually present with pain and/or a pelvic mass
and less frequently with ascites. Clinical and biochemical features of
hyperthyroidism are uncommon in women with struma ovarii, occurring in
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less than 5 to 8 percent of cases. On ultrasound, struma ovarii appears as a
heterogeneous solid mass. The histologic pattern may show microfollicular,
macrofollicular, or oxyphil adenoma, with or without papillary hyperplasia.
Histologic features of thyroid cancer are found in 5 to 37 percent of women
with struma ovarii. (See 'Clinical manifestations' above.)
●In women presenting with a pelvic mass, struma ovarii is typically diagnosed
postoperatively based upon histologic findings of thyroid follicles in the
resected ovary. The diagnostic criteria for malignant struma ovarii are similar
to those for differentiated thyroid cancer. A definite diagnosis of carcinoma
requires tumor invasion, metastases, or recurrence (for follicular cancer) or
the typical cytopathologic features of papillary thyroid cancer.
(See 'Diagnosis' above.)
In women presenting with hyperthyroidism (elevated free thyroxine [T4]
and/or triiodothyronine [T3], low thyroid-stimulating hormone [TSH]), the
diagnosis of struma ovarii should be considered in a woman with persistent
hyperthyroidism (>3 to 6 months), no goiter, absent radioiodine uptake in the
neck, and a detectable serum thyroglobulin level. In such women, pelvic
ultrasound should be obtained, and if pelvic ultrasound reveals an ovarian
mass, pelvic radioimaging (using iodine-123 [123-I] or iodine-131 [131-I] with
single-photon emission computed tomography [SPECT]) is performed to
confirm the presence of functional thyroid tissue within the mass.
(See 'Diagnosis' above.)
●Even among women with hyperthyroidism, without goiter, and with minimal
or absent thyroid uptake of radioiodine, struma ovarii is rare; the more likely
causes of these findings are exogenous thyroid hormone administration and
lymphocytic (painless) thyroiditis. Thyroid cancer metastatic to the ovary can
be confused with true struma ovarii. Primary thyroid cancer rarely
metastasizes to the ovary. In such cases, the ovarian tissue does not have
teratomatous features. (See 'Differential diagnosis' above and "Types of
adnexal masses".)
●The treatment of benign struma ovarii is surgical resection of the ovarian
tumor. (See 'Benign struma ovarii' above.)
●Patients with malignant struma ovarii may need therapy in addition to
oophorectomy, particularly in the presence of metastatic disease. The
optimal ovarian surgical procedure (eg, unilateral or bilateral salpingo-
oophorectomy [BSO], with or without hysterectomy) is reviewed elsewhere.
(See "Treatment of malignant germ cell tumors of the ovary", section on
'Surgical staging and primary cytoreduction'.)

201
●For women with low risk of recurrence (no extraovarian extension or distant
metastases), we suggest T4 (levothyroxine) to suppress TSH to the lower limit
or just below normal (Grade 2C). We measure serum thyroglobulin annually.
(See 'Malignant struma ovarii' above.)
●For patients with known distant metastases, gross extraovarian extension of
the tumor, large lesions (>4 cm, corresponding to thyroid T3 lesions), the
presence of a BRAF mutation, or a synchronous primary thyroid cancer, we
suggest thyroidectomy followed by radioiodine treatment (Grade 2C).
These patients also require T4 therapy. The goal of T4 therapy is to maintain
the TSH at levels corresponding to those for conventional thyroid cancer, with
TSH values maintained in the 0.1 to 0.5 mU/L range for the first five years and
then in the normal range thereafter in patients with no evidence of disease.
(See 'High risk of recurrence or metastatic disease' above.)
●In patients with untreated or poorly controlled overt hyperthyroidism, an
acute event such as surgery can precipitate thyroid storm, a potentially life-
threatening condition. Thus, we suggest postponing surgery in patients with
newly discovered overt hyperthyroidism until the patient has achieved
adequate control of their hyperthyroidism (usually three to eight weeks)
(Grade 2C). (See 'Control of hyperthyroidism before nonthyroid
surgery' above.)
●In women with struma ovarii and symptomatic or substantial biochemical
hyperthyroidism, we administer a beta blocker (typically atenolol 25 to 50 mg
daily, with the dose increased as needed to maintain the pulse rate below 80)
and a thionamide (typically methimazole, 10 mg two to three times daily or
20 to 30 mg once daily) for four to six weeks before surgery. (See 'Control of
hyperthyroidism before nonthyroid surgery' above and "Nonthyroid surgery
in the patient with thyroid disease", section on 'Hyperthyroidism'.)
●In our experience, patients with subclinical hyperthyroidism (low TSH,
normal free T4 and T3) can typically proceed with elective surgeries. Unless
contraindicated, we administer a beta blocker preoperatively to older
patients (>50 years) or younger patients with cardiovascular disease and
taper after recovery. (See 'Control of hyperthyroidism before nonthyroid
surgery' above and "Nonthyroid surgery in the patient with thyroid disease",
section on 'Hyperthyroidism'.)
●Patients with malignant struma ovarii require long-term (at least 10 years)
monitoring of serum thyroglobulin and, if there is biochemical evidence of
persistent or recurrent disease, appropriate imaging, which should also
include the pelvis. (See 'Monitoring' above and "Differentiated thyroid cancer:
Overview of management", section on 'Monitoring response to therapy'.)

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Approach to therapy in multiple endocrine neoplasia
type 2
Authors:
Cornelis J Lips, MD, PhD
Douglas W Ball, MD
Section Editor:
Marc K Drezner, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 11, 2021.
INTRODUCTIONMultiple endocrine neoplasia type 2 (MEN2) is subclassified into
two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B) (table 1). Affected patients
have germline mutations in the RET proto-oncogene.
●MEN2A is a heritable predisposition to medullary thyroid cancer (MTC),
pheochromocytoma, and primary parathyroid hyperplasia. There are four variants
of MEN2A.
●MEN2B shares the inherited predisposition to MTC and pheochromocytoma
found in MEN2A, but there is no parathyroid gland involvement. Patients with
MEN2B tend to have, in addition, mucosal neuromas, intestinal ganglioneuromas,
and a Marfanoid habitus.
In both syndromes, there is an occurrence of multicentric tumor formation in all organs
where the RET proto-oncogene is expressed. This topic will review the therapy of these
endocrine tumor syndromes. The classification, genetics, clinical features, diagnosis,
and evaluation of MEN2 are discussed separately. (See "Classification and genetics of
multiple endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of
multiple endocrine neoplasia type 2".)
Treatment of sporadic MTC is also discussed in more detail elsewhere. (See "Medullary
thyroid cancer: Surgical treatment and prognosis".)
MEDULLARY THYROID CANCER
Established disease — Among patients with multiple endocrine neoplasia type 2
(MEN2), virtually all develop clinically apparent medullary thyroid cancer (MTC), often
early in life [1]. Patients with MTC can be cured only by complete resection of the
thyroid tumor and any local and regional metastases. We recommend total
thyroidectomy for patients with hereditary forms of MTC (MEN types 2A [MEN2A] and
2B [MEN2B]).
The American Thyroid Association (ATA) has published guidelines on the management
of patients with either the inherited or sporadic forms of MTC [1]. Our recommendations
are largely in keeping with these guidelines. The treatment of hereditary MTC is
discussed briefly below and in more detail separately. (See "Medullary thyroid cancer:
Surgical treatment and prognosis".)
Preoperative evaluation — When the biochemical diagnosis of MEN2-related MTC is
established, preoperative thyroid and neck ultrasound are important to determine the
appropriate extent of surgery. Additional imaging based upon the elevation in serum
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basal calcitonin is reviewed in more detail separately. (See "Medullary thyroid cancer:
Clinical manifestations, diagnosis, and staging", section on 'Radiologic evaluation'.)
Preoperative evaluation should also include testing for coexisting tumors. We measure
serum calcium (to rule out hyperparathyroidism requiring concomitant surgical
intervention) and plasma fractionated metanephrines (as the initial screen for
pheochromocytoma). If pheochromocytoma is found, it should be removed first.
(See "Clinical presentation and diagnosis of
pheochromocytoma" and 'Pheochromocytoma' below and "Treatment of
pheochromocytoma in adults".)
If the initial screening tests for coexisting tumors are negative, it is important to evaluate
for pheochromocytoma (MEN2A and 2B) and hyperparathyroidism (MEN2A) regularly
(table 2). In addition, family members should undergo RET mutation screening.
(See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2",
section on 'Screening for MEN2-associated tumors' and "Clinical manifestations and
diagnosis of multiple endocrine neoplasia type 2", section on 'Genetic screening'.)
Thyroidectomy — We recommend total thyroidectomy as the minimal operation for
patients with hereditary forms of MTC. The multicentric and bilateral nature of MTC (and
its precursor C-cell hyperplasia) in all the MEN2 syndromes means that total
thyroidectomy is the only way to cure MEN2-related MTC [2-4]. MTC in patients with
MEN2B is more aggressive than in MEN2A, and total thyroidectomy is often not curative
[5,6]. In such cases, surgery can lead to a reduction in tumor burden or effective
palliation. In one large follow-up study published in 1985, death from MTC occurred in
50 percent of those with MEN2B but only 9.7 percent of those with MEN2A [5].
Cervical nodal metastases are common in patients with palpable MTC or higher
calcitonin levels [7]. Prophylactic dissection of nodal tissue in the central compartment
from the hyoid bone to the innominate veins and medial to the jugular veins is routinely
performed except in patients with very low levels of calcitonin, where total thyroidectomy
alone may be preferred (see 'Preventive surgery' below). The lateral jugular and
mediastinal nodes should be carefully evaluated, followed by modified neck and/or
mediastinal dissections if positive nodes are identified. (See "Medullary thyroid cancer:
Surgical treatment and prognosis", section on 'Surgical approach' and "Thyroidectomy".)
Postoperative management — Immediately after surgery, the patient should be
monitored closely for the development of hypoparathyroidism or injury to either the
recurrent or superior laryngeal nerves. (See "Differentiated thyroid cancer: Surgical
treatment", section on 'Complications'.)
Postoperative management and the longer-term monitoring of patients with MEN2-
associated MTC are essentially the same as for sporadic MTC (see "Medullary thyroid
cancer: Surgical treatment and prognosis", section on 'Postoperative
management' and "Medullary thyroid cancer: Surgical treatment and prognosis", section
on 'Persistent hypercalcitoninemia'):
●Thyroid hormone therapy to restore/maintain euthyroidism; suppressive doses
are not necessary, as C cells are not thyroid-stimulating hormone (TSH)
responsive
●Serial monitoring of serum calcitonin and carcinoembryonic antigen (CEA)
concentrations
●Periodic physical exams

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 ●Neck ultrasound, especially if serum calcitonin is elevated
●Additional imaging (computed tomography [CT] or magnetic resonance imaging
[MRI] of neck, chest, and abdomen; bone scan or bone MRI in patients suspected
of having skeletal metastases) if calcitonin is greater than 150 pg/mL
Neither postoperative radioactive iodine nor TSH-suppressive therapy with T4
(levothyroxine) is recommended for patients with MTC in the absence of concomitant
epithelial cell-derived differentiated thyroid cancer [1].
Management of residual or recurrent disease — The management options for
patients with persistent or recurrent locoregional MTC include one or more repeat neck
operations, external beam radiotherapy (EBRT), or active surveillance. Although data
are limited, EBRT may be beneficial in minimizing local recurrences in patients with
extensive extrathyroid extension. Palliative radiation therapy may be used to diminish
the tumor burden in the neck and to prevent local recurrence. Whether morbidity or
mortality is improved remains questionable. The management of residual or recurrent
disease is reviewed in more detail elsewhere. (See "Medullary thyroid cancer: Surgical
treatment and prognosis", section on 'Management of persistent/recurrent disease'.)
Patients with progressive metastatic disease who cannot be treated by surgery or
radiotherapy should be considered candidates for systemic therapy. Newer, target-
directed drug therapies are promising, including highly selective RET inhibitors [8]. The
germline RET genotype may influence the response to drug therapy. This topic is
discussed in detail elsewhere. (See "Medullary thyroid cancer: Systemic therapy and
immunotherapy".)
Preventive surgery — In patients with MEN2, there is predictable progression from
multicentric hyperplasia of the parafollicular C cells of the thyroid gland to MTC, with a
penetrance approaching 100 percent [2]. The goal in patients with
known RET mutations (but without clinically apparent disease) is to perform a
prophylactic thyroidectomy before MTC develops or when it is still confined to the
thyroid gland [1]. Children with certain RET mutations can develop clinically apparent
MTC at an early age (table 3).
In observational studies, the 10-year survival of MTC ranges from 61 to 76 percent
[3,9,10]. The important prognostic factors that predict adverse outcome include older
age at diagnosis, extent of primary tumor, nodal disease, and distant metastases [9-12].
In children identified as carrying a RET mutation by genetic screening, MTC can be
cured or prevented by early thyroidectomy. In some studies of children with MEN2
mutations undergoing preventive surgery, there were no lymph node metastases or
postoperative residual MTC when the basal serum calcitonin levels were <30 to 40
pg/mL [13-15].
Timing of surgery — Although there is not universal agreement, our approach to
determining the optimal timing of thyroidectomy is based upon the specific DNA
mutation in the RET proto-oncogene occurring in the family and, in some cases, serum
calcitonin levels (table 4) [16]. In an analysis of 50 children identified through genetic
screening who had undergone a previous total thyroidectomy, 88 percent had
undetectable stimulated serum calcitonin levels 5 to 10 years later; children with
undetectable levels had undergone their surgery before age eight years [17].
Although some RET mutations (eg, RET codons 634 and 918) are uniformly associated
with more aggressive and earlier onset MTC, there is heterogeneity in presentation with

205
other RET mutations, even among different families with the same mutation or within an
individual family having the same RET mutation. Therefore, measurement of serum
calcitonin (basal or stimulated) may be helpful for establishing the timing of
thyroidectomy. This approach is consistent with clinical practice guidelines published by
the ATA [1].
RET mutations can be categorized as highest, high, and moderate risk, referring to the
potential risk for local and distant MTC metastases at an early age (table 4) [1,16]. The
suggested timing of thyroidectomy is based upon evidence of age-dependent and
codon-specific progression of early MTC [18-20].
●Highest risk – For children with a predisposition for MEN2B, most commonly
associated with a germline mutation in codon 918, we suggest thyroidectomy
during the first year of life [21-27]. Total thyroidectomy and central neck dissection
during the first year of life is advocated, given that metastatic disease has been
reported in one-year-old children [6] and that later surgery is often not curative
[6,28]. Typical physical features are not necessarily present in an affected neonate
within an MEN2B family [5], so the absence of such features does not obviate the
need for early diagnosis.
●High risk – For children with mutations in codons 634 or 883, we suggest
thyroidectomy at or before age five years, with the exact timing based on detection
of an elevated serum calcitonin level (above the upper limit of normal).
●Moderate risk – For patients with MTC and RET mutations other than M918T,
C634, and A883F in codons 609, 611, 618, 620, 630, 666, 768, 790, 804, 891,
and 912, we suggest total thyroidectomy during childhood or young adulthood,
based on detection of an elevated serum calcitonin level (above the upper limit of
normal) [29-32].
Patients with a single mutation on codon 804 are thought to have atypical MEN2B
[23,33,34]. This mutation has low penetrance. While initially thought to be associated
with late onset of MTC and an indolent course, compared with the codon 918 and 634
mutations [35], early onset with metastatic disease has been reported, and these MTCs
are associated with a second germline or somatic (tandem) mutation [27]. We therefore
recommend that these individuals undergo surgery by an age depending on the identity
of this second (tandem) mutation.
Fewer than 1 percent of MEN2 families have no detectable RET mutation [5,27]. If no
genetic information is available to show a specific germline RET mutation from an
affected individual in a known MEN2 family, prophylactic thyroidectomy should be
performed when a pentagastrin stimulation test reveals a peak calcitonin level >200
pg/mL. There are few data using the calcium stimulation as a confirmatory test in
patients with elevated basal calcitonin levels, and cut points for the discrimination of
normal, C-cell hyperplasia, and MTC have not been standardized. These tests are
reviewed in detail separately. (See "Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2", section on 'Choice of biochemical test for MTC'.)
Surgical approach — In addition to total thyroidectomy, prophylactic central lymph
node dissection should also be performed in patients with a germline mutation in codon
918 who are undergoing preventive operations, and in other patients if the baseline
calcitonin level is already elevated (>40 pg/mL). In very young children, the parathyroid
glands may be difficult to identify intraoperatively, thus increasing the risk of

206
postsurgical hypoparathyroidism. If the parathyroid glands cannot be identified and
there are no suspicious lymph nodes on preoperative ultrasound or intraoperative
inspection, the surgeon may reasonably forgo central neck dissection [1].
A more limited central node dissection, taking care to avoid disrupting the parathyroid
glands or laryngeal nerves, has yielded good results in children who were regularly
screened biochemically for MTC with a calcium infusion test and operated on when the
test first became positive [4]. One would expect similarly good results from this surgical
approach in patients who carry the gene for MTC and are operated on before they have
any clinical or biochemical evidence of MTC.

Given the rarity of this disease and the potential complications of a total thyroidectomy
in young children, all patients should be referred to academic centers with expertise in
MEN2, where an experienced pediatric or endocrine surgeon can perform the required
surgery.

PHEOCHROMOCYTOMAPheochromocytoma occurs in approximately 40 percent

of patients with multiple endocrine neoplasia type 2A (MEN2A) and in approximately 50
percent of those with type 2B (MEN2B) [2,6]. There is, however, large variability in the
penetrance of pheochromocytoma among different reported kindreds, depending upon
the specific RET germline mutation [2].
The disease tends to progress slowly from its precursor, adrenal medullary hyperplasia.
There is an increased likelihood of bilateral pheochromocytoma in patients with MEN2
versus the unilateral and unicentric tumors that are almost always found in patients with
sporadic pheochromocytoma [36]. Extraadrenal pheochromocytoma is rare in MEN2 but
does occur [37].
Surgical approach — For patients with bilateral pheochromocytomas, bilateral
adrenalectomy is necessary. It should also be considered in a patient with unilateral
disease when other family members have had unusually aggressive bilateral adrenal
medullary disease. For most other patients with a unilateral pheochromocytoma,
unilateral adrenalectomy is the treatment of choice. Prior to unilateral or bilateral
adrenalectomy, patients should be treated with alpha blockade and counselled
regarding volume expansion. (See "Treatment of pheochromocytoma in adults", section
on 'Alpha-adrenergic blockade'.)
Bilateral adrenalectomy has been advocated for MEN2 patients with apparently
unilateral pheochromocytomas [38-40]. However, we and others think unilateral
adrenalectomy in those patients who have a normal-appearing contralateral gland is
more appropriate [37]. The rationale for this approach includes the following:
●Approximately one-third of patients undergoing unilateral surgery eventually
require surgery for pheochromocytoma in the remaining adrenal [37]. However,
the second tumor may not appear for many years, and initial unilateral surgery
obviates the need for glucocorticoid and mineralocorticoid replacement (with its
attendant risks and morbidity) in the interim.
●No deaths from catecholamine crisis have been reported in patients with MEN2
who underwent unilateral adrenalectomy, were followed, and then developed
contralateral disease [37].
●Metastatic pheochromocytoma has not been reported in a patient with MEN2
after unilateral adrenalectomy [37].
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If a bilateral adrenalectomy is planned preoperatively, the patient should receive
glucocorticoid stress coverage while awaiting transfer to the operating room. Peri- and
postoperative management of patients undergoing adrenalectomy are reviewed
separately. (See "Treatment of pheochromocytoma in adults", section on
'Adrenalectomy' and "Treatment of adrenal insufficiency in adults".)
One technique that has been used in an attempt to avoid causing adrenal insufficiency
from bilateral adrenalectomy is to perform adrenal-sparing surgery (partial or cortex-
sparing adrenalectomy). However, because of the diffuse medullary disease in MEN2
patients, many groups advise complete bilateral adrenalectomy when bilateral disease
is evident on imaging. The choice of cortex-sparing adrenal surgery should be balanced
by the consideration that this will increase the risk of recurrence. This topic is reviewed
in detail elsewhere. (See "Treatment of pheochromocytoma in adults", section on
'Familial pheochromocytoma'.)
PRIMARY HYPERPARATHYROIDISMPrimary hyperparathyroidism occurs in
10 to 25 percent of patients with multiple endocrine neoplasia type 2A (MEN2A) and is
almost always multiglandular [2]. The hyperparathyroidism in MEN2A is often clinically
occult. Primary hyperparathyroidism is not a feature of MEN type 2B (MEN2B) (table 1).
Some centers have described a markedly diminished incidence of hyperparathyroidism
in patients with MEN2A who have undergone early total thyroidectomy for cure or
prevention of medullary thyroid cancer (MTC) [41,42]. In one report, as an example,
hyperparathyroidism developed in none of 22 patients treated with early thyroidectomy
[42]. Why this might occur is not known. (See "Clinical manifestations and diagnosis of
multiple endocrine neoplasia type 2", section on 'Primary hyperparathyroidism'.)
Whether or not there is a decreased incidence of hyperparathyroidism after successful
treatment or prevention of MTC, the already low penetrance of hyperparathyroidism in
MEN2A and the success of treatment if it develops argue strongly against prophylactic
total parathyroidectomy at the time of thyroidectomy. This approach would have a
substantial risk of hypoparathyroidism with a low likelihood of benefit [43].
Once the biochemical diagnosis of primary hyperparathyroidism is confirmed in a
patient known or presumed to have MEN2A, the indications for surgical intervention are
similar to those in patients with sporadic primary hyperparathyroidism [44].
(See "Primary hyperparathyroidism: Management".)
Management of asymptomatic disease — For patients with MEN2A-related
hyperparathyroidism who are asymptomatic, it is acceptable to defer surgery. If surgery
is not performed, then it is appropriate to recommend supportive-preventive measures
with adequate monitoring. Asymptomatic patients who do not undergo surgery require
long-term monitoring for worsening hypercalcemia, renal impairment, and bone loss.
The development of any of these findings indicates disease progression and the need
for surgical intervention. Similar to the periodic monitoring performed in patients with
asymptomatic sporadic primary hyperparathyroidism, we monitor serum calcium and
creatinine annually and bone density (hip, spine, and forearm) every one to two years.
(See "Primary hyperparathyroidism: Management", section on 'Preventive
measures' and "Primary hyperparathyroidism: Management", section on 'Monitoring'.)
Symptomatic disease — Patients with symptomatic primary hyperparathyroidism
(nephrolithiasis, symptomatic hypercalcemia) should have parathyroid surgery, which is
the only definitive therapy. Other indications for surgery include marked hypercalcemia,
208
major hypercalciuria, and evidence of bone loss. (See "Primary hyperparathyroidism:
Management", section on 'Candidates for surgery'.)

Evidence of pheochromocytoma should be sought before parathyroidectomy and, if

present, the pheochromocytoma(s) should be removed before the parathyroid surgery.

Preoperative localization — Because of the polyglandular nature of

hyperparathyroidism in MEN2A, preoperative localization studies are not indicated in
patients with MEN2A who have not had previous neck surgery. However, we
recommend preoperative localization studies (such as ultrasonography, sestamibi scan,
and/or neck and chest computed tomography [CT]) in patients who have had previous
neck surgery for MTC and for those with recurrent or persistent disease.
(See "Preoperative localization for parathyroid surgery in patients with primary
hyperparathyroidism".)
Surgical approach — Bilateral neck exploration in an attempt to find all glands should
always be performed in patients with known or suspected MEN2A. Beyond that,
controversy exists as to the ideal surgical approach. Options include [1]:
●Resection of the visibly enlarged glands only, with intraoperative monitoring of
serum parathyroid hormone (PTH) levels to document removal of hyperfunctioning
parathyroid tissue
●Subtotal parathyroidectomy (usually removal of three and one-half glands, often
with cervical thymectomy) leaving one gland or a piece of one gland in situ or with
forearm grafting
●Total parathyroidectomy, which carries a higher risk of hypoparathyroidism, with
forearm grafting

We typically prefer the first option. However, in patients with four-gland enlargement, we
prefer subtotal parathyroidectomy. In patients who require repeated neck surgeries for
MTC, early forearm parathyroid gland autografting may reduce the risk of subsequent
permanent hypoparathyroidism.

When performed in centers with major experience in parathyroid surgery, as surgery for
MEN2 patients should be, results utilizing the different approaches are equivalent and
complication rates are low [45,46]. In such instances, institutional preferences should be
followed.
The recurrence rate after apparently successful subtotal parathyroidectomy, performed
by expert parathyroid surgeons, appears to be low; in one report, as an example, none
of 18 patients had recurrent disease after a mean follow-up of 5.8 years [45]. In
comparison, a retrospective study noted recurrence in two of eight patients treated with
subtotal parathyroidectomy at a mean of 11.5 years after surgery; however, the initial
surgery was not necessarily performed at a specialized center [41].
Medical therapy — Certain medications, particularly estrogen plus progestin and
bisphosphonates, inhibit bone resorption and can increase bone density and possibly
lower serum calcium concentrations in patients with hyperparathyroidism. Others, such
as calcimimetics or vitamin D analogues, suppress PTH release or counteract the
effects of hyperparathyroidism at the level of the PTH receptor. None of these medical
therapies have been rigorously studied in patients with MEN2. Medical therapy in
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patients with sporadic primary hyperparathyroidism is discussed elsewhere.
(See "Primary hyperparathyroidism: Management", section on 'Poor surgical
candidates'.)
OTHER ASSOCIATED DISEASESThe treatment of Hirschsprung disease (HD)
and cutaneous lichen amyloidosis (CLA; lichen planus amyloidosis [LPA]) are reviewed
separately. (See "Congenital aganglionic megacolon (Hirschsprung disease)", section
on 'Management' and "Acquired hyperpigmentation disorders", section on 'Primary
cutaneous amyloidosis'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Medullary thyroid cancer".)
SUMMARY AND RECOMMENDATIONS
●Among patients with multiple endocrine neoplasia type 2 (MEN2), virtually all
patients develop clinically apparent medullary thyroid cancer (MTC), often early in
life. Patients with hereditary forms of MTC (MEN types 2A [MEN2A] and 2B
[MEN2B]) should undergo total thyroidectomy. The multicentric and bilateral
nature of MTC (and its precursor C-cell hyperplasia) in the MEN2 syndromes
means that total thyroidectomy is the only way to cure MEN2-related MTC.
(See 'Established disease' above.)
Patients with MTC should be evaluated for possible
pheochromocytoma before thyroidectomy; if one is found, it should be removed
first. (See 'Preoperative evaluation' above and "Clinical presentation and diagnosis
of pheochromocytoma".)
●After surgery, the patient should be monitored closely for the development of
hypoparathyroidism or injury to either the recurrent or superior laryngeal nerves.
(See "Differentiated thyroid cancer: Surgical treatment", section on
'Complications'.)
●Postoperative management and the longer-term monitoring of patients with
MEN2-associated MTC are essentially the same as for sporadic MTC.
(See "Medullary thyroid cancer: Surgical treatment and prognosis", section on
'Postoperative management' and "Medullary thyroid cancer: Surgical treatment
and prognosis", section on 'Management of persistent/recurrent
disease' and "Medullary thyroid cancer: Systemic therapy and immunotherapy".)
●The goal in patients with known RET mutations (but without clinically apparent
disease) is to perform a prophylactic thyroidectomy before MTC develops or when
it is still confined to the thyroid gland. We time prophylactic thyroidectomy in family
members based upon the specific DNA mutation in the RET proto-oncogene
occurring in the family (table 4). (See 'Preventive surgery' above.)
●These mutations can be categorized as highest, high, and moderate risk,
referring to the potential risk for local and distant metastases at an early age, as
follows:
•Highest risk – For children with a predisposition for MEN2B, most commonly
associated with a germline mutation in codon 918, we suggest thyroidectomy
during the first year of life (Grade 2C).
•High risk – For children with RET mutations in codons 634 or 883, we suggest
total thyroidectomy at or before age five years (Grade 2C).
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 •Moderate risk – For patients with MTC and RET mutations other than M918T,
C634, and A883F in codons 609, 611, 618, 620, 630, 666, 768, 790, 804, 891,
and 912, we suggest total thyroidectomy during childhood or young adulthood,
based on detection of an elevated serum calcitonin level (above the upper limit
of normal) (Grade 2C).
●For patients with bilateral pheochromocytomas, bilateral adrenalectomy is
necessary. It should also be considered in a patient with unilateral disease when
other family members have had unusually aggressive bilateral adrenal medullary
disease. For most other patients with a unilateral pheochromocytoma, we
recommend unilateral adrenalectomy as the treatment of choice (Grade 1C).
(See 'Pheochromocytoma' above and "Treatment of pheochromocytoma in
adults".)
●For patients with mild hyperparathyroidism who are asymptomatic, it is
acceptable to defer surgery. If surgery is not performed, then it is appropriate to
recommend supportive-preventive measures with adequate monitoring.
(See 'Management of asymptomatic disease' above.)
●Once the biochemical diagnosis of primary hyperparathyroidism is confirmed in a
patient known or presumed to have MEN2A, the indications for surgical
intervention are similar to those in patients with sporadic primary
hyperparathyroidism. These include symptomatic or marked hypercalcemia,
nephrolithiasis, major hypercalciuria, and evidence of bone loss. (See "Primary
hyperparathyroidism: Management".)
Evidence of pheochromocytoma should be sought before parathyroidectomy and,
if present, the pheochromocytoma(s) should be removed before the parathyroid
surgery.

211
Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2
Authors:
Cornelis J Lips, MD, PhD
Douglas W Ball, MD
Section Editor:
Marc K Drezner, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 11, 2021.
INTRODUCTIONMultiple endocrine neoplasia type 2 (MEN2) is an autosomal
dominant disorder with an estimated prevalence of 1 per 30,000 in the general
population. MEN2 is subclassified into two distinct syndromes: types 2A (MEN2A)
and 2B (MEN2B). Within MEN2A, there are four variants: classical MEN2A, MEN2A
with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HD),
and familial medullary thyroid cancer (FMTC) (table 1) [1].
The genetic defect in these disorders involves the RET proto-oncogene on
chromosome 10. MEN2A and 2B are inherited in an autosomal dominant pattern
with very high penetrance. In both syndromes, there is an occurrence of
multicentric tumor formation in all organs where the RET proto-oncogene is
expressed. The thyroid, parathyroid, and adrenal glands are at risk for developing
tumors that may reduce life expectancy and quality of life. The excellent prognosis
for medullary thyroid cancer (MTC) diagnosed at its earliest stage underscores the
importance of early diagnosis for sporadic and hereditary MTC [2].

This topic will review the clinical manifestations, diagnosis, and evaluation of
MEN2. The genetics and treatment of this disorder are discussed separately.
Sporadic MTC is also discussed separately.

●(See "Classification
and genetics of multiple endocrine neoplasia type 2".)
●(See "Approach to therapy in multiple endocrine neoplasia type 2".)
●(See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and
staging".)
●(See "Medullary thyroid cancer: Surgical treatment and prognosis".)

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CLINICAL FEATURESMultiple endocrine neoplasia type 2 (MEN2) is
subclassified into two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B) (table
1) [3-6].
MEN2A is characterized by medullary thyroid cancer (MTC), pheochromocytoma,
and primary parathyroid hyperplasia (see 'MEN2A' below). MEN2B is characterized
by MTC and pheochromocytoma but not hyperparathyroidism. It is associated with
additional clinical features (eg, mucosal neuromas) not seen in MEN2A.
(See 'MEN2B' below.)
MEN2A — Within multiple endocrine neoplasia type 2A (MEN2A), there are four
variants (table 1) [1] (see "Classification and genetics of multiple endocrine
neoplasia type 2"):
●Classical MEN2A
●MEN2A with cutaneous lichen amyloidosis (CLA)
●MEN2A with Hirschsprung disease (HD)
●Familial MTC (FMTC)
The clinical manifestations of MEN2A depend upon which organs are involved,
which in turn is dependent upon the specific RET mutation. While the penetrance
of MTC is nearly 100 percent, there is much inter- and intrafamily variability in the
other manifestations of MEN2A.

FMTC is a variant of MEN2A in which there is a strong predisposition to MTC but

not the other clinical manifestations of MEN2A (or MEN2B).

Medullary thyroid cancer — MTC is a neuroendocrine tumor of the parafollicular

or C cells of the thyroid gland. Most cases of MTC (75 percent) are sporadic, but as
many as 25 percent of all MTCs are familial (table 2) [7]. Among patients with
MEN2, virtually all patients develop clinically apparent MTC, often early in life [1]. In
MEN2A-associated MTC, the peak incidence of index cases is in the third decade of
life, and it is usually earlier in MEN2B. Specific RET mutations are associated with
characteristic age-specific penetrance of MTC (table 3), as well as characteristic
prevalence of the extrathyroidal manifestations. MTCs in patients with MEN2 are
multicentric and concentrated in the upper third of the thyroid gland, reflecting
the normal distribution of parafollicular cells (picture 1).
If diagnosed as an index case, the clinical presentation and manifestations of
MEN2-associated MTC are similar to those of sporadic MTC, except that sporadic
MTC typically presents later in life. The most common presentation is that of a
solitary thyroid nodule or cervical lymphadenopathy. Fine-needle aspiration (FNA)
biopsy shows eccentrically placed nuclei that are larger and more pleomorphic
than those of normal follicular cells. The cytoplasm may be slightly granular and is
usually configured as a tear drop or cytoplasmic tail. If the diagnosis is suspected,
213
immunocytologic staining for calcitonin should be performed. (See "Medullary
thyroid cancer: Clinical manifestations, diagnosis, and staging", section on
'Diagnosis'.)
Less common presentations specific to MEN2-associated MTC include recognition
during a search initiated after an associated disease (such as pheochromocytoma
or hyperparathyroidism) becomes apparent, diarrhea caused by gastrointestinal
secretion of fluid and electrolytes, and flushing due to the secretion of other
peptides by the tumor. In rare cases, MTC causes Cushing's syndrome due to
ectopic production of corticotropin (ACTH). (See "Causes and pathophysiology of
Cushing's syndrome".)
In asymptomatic patients identified through calcitonin or DNA testing, initiated
due to the presence of an associated disease or to a family history of MEN2, MTC is
often diagnosed in its preneoplastic state, C-cell hyperplasia. Basal serum
calcitonin concentrations usually correlate with tumor mass and are almost always
high in patients with a palpable tumor. In patients with small tumors and those
with C-cell hyperplasia, the values may be normal but rise excessively after calcium
or pentagastrin infusion [8]. (See 'Choice of biochemical test for MTC' below.)
The presence of C-cell hyperplasia is defined based upon microscopy criteria: the
presence of an increased number of diffusely scattered C cells (≥7 per thyroid
follicle), complete follicles surrounded by C cells, or distribution of C cells beyond
the normal anatomical location [1,9]. C-cell hyperplasia can occur in a reactive
(secondary) form or a neoplastic form (precursor to MTC in MEN2). Neoplastic C-
cell hyperplasia is diagnosed when nests of C cells appear to extend beyond the
basement membrane and to infiltrate and destroy thyroid follicles (picture 2) [10].
Reactive C-cell hyperplasia is considered to be caused by a stimulus from outside
the C cell and probably is not premalignant (picture 3). Hyperparathyroidism,
chronic renal insufficiency, chronic lymphocytic thyroiditis, and follicular thyroid
tumors have been associated with reactive C-cell hyperplasia [11].
Pheochromocytoma — Pheochromocytoma occurs in approximately 50 percent
of patients with MEN2. The frequency of pheochromocytoma depends upon the
specific underlying RET mutation [1,12]. Some RET mutations are associated with a
higher penetrance of pheochromocytoma. As an example, in one study, the
penetrance of pheochromocytoma was 25 percent by age 30 years, 52 percent by
age 50 years, and 88 percent by age 77 years in patients with RET codon 634
mutations [13].
As with MTC, pheochromocytomas in MEN2 occur earlier than sporadic forms.
Although they may develop as early as 8 to 12 years of age, the mean age of
presentation is 25 to 32 years, depending on the RET mutation [14-16]. It is unusual
for pheochromocytoma to precede the development of MTC and be the initial

214
manifestation of MEN2. In patients who have undergone regular screening,
pheochromocytomas have usually become evident approximately 10 years later
than C-cell hyperplasia or MTC [17]. Thus, pheochromocytomas in MEN2 are
usually identified during screening or through heightened vigilance for symptoms
in patients with known or suspected MEN2.
Rarely, pheochromocytoma may be the first manifestation of MEN2 [18,19]. In
such patients, symptoms are similar to those in patients with sporadic
pheochromocytomas and may include attacks (paroxysms) of anxiety, headache,
diaphoresis, palpitations, or tachycardia. However, in one report, only
approximately one-third had hypertension at the time of diagnosis [20]. The
severity of symptoms may depend upon the specific RET mutation [21]. The
diagnosis of pheochromocytoma includes biochemical testing and, once a
diagnosis of pheochromocytoma is established, imaging studies. The clinical
manifestations and diagnosis of pheochromocytoma are reviewed in detail
separately. (See "Clinical presentation and diagnosis of pheochromocytoma".)
Sporadic pheochromocytomas are almost always unilateral [22,23]. In contrast,
pheochromocytomas in MEN2 have been reported to be bilateral in approximately
30 to 100 percent of patients [14,20,23]. Thus, once the diagnosis of
pheochromocytoma in MEN2 is established, the possibility of bilateral disease
must be carefully evaluated. Extraadrenal pheochromocytoma is rare in MEN2 but
does occur, especially in accessory adrenal glands (picture 4 and picture 5) or in
extraadrenal chromaffin cells (paragangliomas) [24,25]. (See "Paragangliomas:
Epidemiology, clinical presentation, diagnosis, and histology", section on 'MEN2'.)
In most studies, the percentage of MEN2A-associated pheochromocytomas that
are malignant is considerably less than the 10 percent rate of malignancy reported
for sporadic pheochromocytomas [7,24]. (See "Clinical presentation and diagnosis
of pheochromocytoma".)
Other heritable syndromes associated with pheochromocytoma include von
Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1, and paraganglioma
syndromes. This topic is reviewed in more detail elsewhere.
(See "Pheochromocytoma in genetic disorders".)
Primary hyperparathyroidism — Primary hyperparathyroidism in MEN2A is
almost always multiglandular. It has been reported in 10 to 25 percent of patients
with MEN2A, depending upon the specific RET mutation [1,7,26,27]. The
hyperparathyroidism in MEN2A is often mild and asymptomatic. In patients who
have undergone regular screening, the diagnosis is established by finding high (or
inappropriately normal) serum parathyroid hormone (PTH) concentrations in the
presence of hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis,
differential diagnosis, and evaluation".)

215
The recurrence rate after apparently successful subtotal parathyroidectomy is less
than that in multiple endocrine neoplasia type 1 (MEN1) [28,29] and is similar to
the excellent long-term results seen in patients with nonfamilial primary
hyperparathyroidism.
There has been a suggestion that parathyroid disease in MEN2A may somehow be
a consequence of the C-cell abnormalities, based upon a low reported incidence of
parathyroid disease in patients in whom C-cell hyperplasia was detected early and
treated by total thyroidectomy [30,31]. In one report, as an example, none of 22
patients who underwent thyroidectomy developed hyperparathyroidism after
more than 10 years of follow-up [30]. Why this might occur and whether the risk is
indeed lower after thyroidectomy is not clear. It seems unlikely that
hypercalcitoninemia per se is the stimulus for the parathyroid tumors for the
following reasons:
●Hyperparathyroidism is not associated with MEN2B, FMTC, or sporadic MTC,
all of which can be characterized by sustained hypercalcitoninemia.
●The RET gene is expressed in MEN2A-associated parathyroid tumors [32].
●A particular RET mutation, Cys to Arg at codon 634, may be preferentially
found in MEN2 families that have hyperparathyroidism [3,33].
●Primary hyperparathyroidism rarely may be the first manifestation of MEN2
[34].
These data imply that the initial stimulus to parathyroid cell proliferation in
MEN2A, while often mild, is probably related to expression of the mutant RET
protein within parathyroid tissue. It is interesting in this context, although not of
direct clinical importance, that calcium suppression testing in normocalcemic
patients has suggested that mild abnormalities in parathyroid function may be
common in MEN2A [35].
Other associated diseases
Cutaneous lichen amyloidosis — CLA, also termed lichen planus amyloidosis
(LPA), is a rare skin condition and can occur both sporadically and as a familial
disease. The hereditary forms are transmitted in an autosomal dominant fashion,
and an association between CLA and MEN2A has been established in some families
[36].
The skin lesion is usually described as pruritic, scaly, papular, pigmented, and
located in the interscapular region or on the extensor surfaces of the extremities
(picture 6A-B) [35]. Amyloid deposition has been documented histologically [37,38].
Keratin-like peptides have been found in the amyloid deposits but not calcitonin-
like peptides [36]. CLA is thought to result from a primary neuropathy [38-40]. This
is an attractive hypothesis with respect to CLA being a rare manifestation of

216
MEN2A since RET is expressed in the peripheral and central nervous system [41-
43].
Several different RET codon 634 mutations have been described in MEN2A/CLA
families [44,45], and both dermal and nondermal manifestations segregate with
the mutation [44]. These same RET mutations are also found in MEN2A families
without evidence of CLA, suggesting the influence of "modifying genes" or other
factors cooperating with the RET mutation in the expression of the CLA phenotype.
CLA was also reported in a patient with a RET codon 804 mutation [46]. CLA
kindreds without MEN2A have not had demonstrable germline RET mutations [45].
Hirschsprung disease — HD is characterized by the absence of autonomic
ganglion cells within the distal colonic parasympathetic plexus, resulting in chronic
obstruction and megacolon. (See "Congenital aganglionic megacolon
(Hirschsprung disease)".)
HD is a heterogenic disorder, occurring both in a familial and in a sporadic form. In
approximately 50 percent of familial and 15 to 35 percent of sporadic HD patients,
mutations in the RET gene are involved. In one study, HD was found in 50 percent
of children in families with a C620 mutation [47]. Most HD cases arise from loss-of-
function mutations, RET haploinsufficiency, RET polymorphisms, or haplotypes of
the RET promotor region. RET proto-oncogene testing in infants presenting with
HD is useful and may identify new MEN2A kindreds [48,49]. (See "Classification and
genetics of multiple endocrine neoplasia type 2", section on 'Germline mutations
causing Hirschsprung disease'.)
MEN2B — Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal
dominant disorder characterized by MTC and pheochromocytoma but not
hyperparathyroidism. MTC occurs in almost all patients. The tumor develops at an
earlier age and is more aggressive than in MEN2A [7]. Surgery is often not
curative. In one large study, death from MTC occurred in 50 percent of patients
with MEN2B versus 9.7 percent of those with MEN2A [50]. Thus, early diagnosis
and prevention are crucial. Thyroidectomy as early as the neonatal period may be
indicated in patients with MEN2B identified by genetic screening. (See "Approach
to therapy in multiple endocrine neoplasia type 2", section on 'Timing of surgery'.)
Pheochromocytoma occurs in approximately 50 percent of patients with MEN2B
[1,51]. Pheochromocytomas in MEN2B occur earlier than sporadic forms. However,
it is unusual for pheochromocytoma to precede the development of MTC and be
the initial manifestation of MEN2.
The syndrome of MEN2B also includes mucosal neuromas, typically involving the
lips and tongue, and intestinal ganglioneuromas. Patients with MEN2B also have
development abnormalities, a decreased upper/lower body ratio, skeletal
deformations (kyphoscoliosis or lordosis), joint laxity, Marfanoid habitus, and

217
myelinated corneal nerves. Disturbances of colonic function are common,
including chronic constipation and megacolon [51]. Unlike patients with Marfan
syndrome, MEN2B patients do not have ectopia lentis or aortic abnormalities [7].
DIAGNOSISMultiple endocrine neoplasia type 2 (MEN2) should be suspected in
any patient with medullary thyroid cancer (MTC) or pheochromocytoma,
particularly when the tumors occur at a young age (<35 years), are multicentric, or
when more than one family member is affected. The diagnosis of MEN2 is based
upon the presence of the classical clinical features, family history, and genetic
testing.
MEN2 — In an index patient with one or two of the classical clinical features,
identification of a germline RET mutation or the identification of the clinical
features of multiple endocrine neoplasia type 2 (MEN2) in other first-degree
relatives is required to make the diagnosis of MEN2 [26].
In the absence of an autosomal dominant familial inheritance pattern
or RET mutation, at least two of the classical clinical features of MEN type 2A
(MEN2A) (MTC, pheochromocytoma, primary hyperparathyroidism) are required to
make a clinical diagnosis of MEN2A.
In the absence of an autosomal dominant familial inheritance pattern
or RET mutation, the majority of classical clinical features of MEN type 2B (MEN2B)
(MTC, pheochromocytoma, mucosal neuromas, Marfanoid habitus, intestinal
ganglioneuromas, myelinated corneal nerves) are required to make a clinical
diagnosis of MEN2B [26].
Although a patient with the classical clinical features of MEN2 and similar clinical
features in one or more first-degree relatives does not need RET mutation analysis
for diagnosis, genetic testing (where available) is performed in all patients with
clinical MEN2 in order to identify the specific RET mutation and facilitate family
screening (table 4). There are rare families, however, with clinical features of
MEN2A in the absence of an identifiable RET mutation. (See 'Screening of family
members in MEN2 kindreds' below.)
●Genetic testing – For the index patient with suspected MEN2A, all exons
should be sequenced, starting with the most commonly mutated codons in
exons 10 and 11 and then, if negative, sequentially proceeding to exons 8, 13,
14, 15, and 16 [1]. If no germline mutation is found, only a small risk of
hereditary MTC remains. In this case, sequencing the entire RET coding
region is an option to identify a RET mutations.
For the index patient with the MEN2B phenotype, initial testing should be for
the RET codon M918T mutation in exon 16 and, if negative, for the A883F
mutation in exon 15. If no mutations are identified, the entire RET coding
region should be sequenced [1].
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 Once a germline RET mutation is identified in an index case, RET mutation
analysis should also be performed in first- and second-degree family
members. The screening of family members is discussed below.
(See 'Screening of family members in MEN2 kindreds' below.)
Occasionally, older patients with MTC, a negative family history, and no
clinical features of MEN2 may nonetheless harbor a cryptic
germline RET mutation. Evaluation of patients with apparently sporadic MTC
should include genetic testing for germline RET mutations as
germline RET gene mutations are detected in approximately 4 to 6 percent of
apparently sporadic cases [52]. The indications for genetic testing for the
detection of unsuspected heritable MEN2 in patients with apparently
sporadic MTC or pheochromocytoma (eg, unilateral disease, a negative family
history, and no other signs or symptoms of MEN2) is reviewed separately.
(See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and
staging", section on 'Genetic screening in sporadic
MTC' and "Pheochromocytoma in genetic disorders", section on 'Genetic
screening'.)
Familial medullary thyroid cancer variant — The familial MTC (FMTC) variant of
MEN2A is characterized by the presence of a RET germline mutation in families
with MTC, or an individual with MTC, who do not develop pheochromocytoma or
primary hyperparathyroidism. Distinguishing the FMTC variant from classical
MEN2A may be difficult in small families, and therefore, rigorous criteria for FMTC
should be used in order not to miss a pheochromocytoma [53]. There should be:
●More than 10 carriers in the kindred
●Multiple carriers or affected members over the age of 50 years
●An adequate medical history, particularly in older family members

EVALUATION
RET mutation analysis — For patients diagnosed with multiple endocrine
neoplasia type 2 (MEN2) based upon the classical clinical features and family
history (typically medullary thyroid cancer [MTC] and a family member with MTC),
evaluation should include RET mutation analysis (if not already performed) in order
to identify the specific RET mutation to facilitate family screening (table 4).
(See 'Diagnosis' above and "Medullary thyroid cancer: Clinical manifestations,
diagnosis, and staging", section on 'Genetic screening in sporadic
MTC' and 'Genetic screening' below.)
If a family member is positive for the RET mutation, prophylactic thyroidectomy is
indicated. The timing of thyroidectomy is based upon the specific RET mutation
and, in some cases, serum calcitonin levels. (See "Approach to therapy in multiple
endocrine neoplasia type 2", section on 'Preventive surgery'.)
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Screening for MEN2-associated tumors — Patients with multiple endocrine
neoplasia type 2 (MEN2) (and their affected family members) also require
screening for MEN2-associated tumors. In all patients diagnosed with MEN2, we
measure plasma fractionated metanephrines (as the initial screen for
pheochromocytoma) and serum calcium (to rule out hyperparathyroidism
requiring concomitant surgical intervention). For patients with MEN2 who present
with pheochromocytoma rather than MTC, we measure serum calcitonin and
obtain a thyroid and neck ultrasound to assess for the presence of MTC.
Screening for MEN2-associated tumors in families of the index patient is reviewed
below. (See 'Monitoring for MEN2-associated tumors' below.)
Pheochromocytoma — Screening for pheochromocytoma is mandatory in all
patients with inherited MTC syndromes. If pheochromocytoma is found, it should
be removed prior to thyroidectomy.
For the index patient with MTC, we measure plasma fractionated metanephrines
as the initial screen for pheochromocytoma. If biochemical results are positive,
adrenal imaging with computed tomography (CT) or magnetic resonance imaging
(MRI) is the next step. (See "Clinical presentation and diagnosis of
pheochromocytoma", section on 'Additional evaluation after biochemical
diagnosis'.)
If the initial screening tests for pheochromocytoma are negative, it is important to
evaluate for pheochromocytoma yearly (table 5). Details of biochemical screening
to detect pheochromocytomas, including in MEN2 patients, is reviewed elsewhere.
(See "Clinical presentation and diagnosis of pheochromocytoma", section on 'High
risk for pheochromocytoma'.)
Hyperparathyroidism — When the diagnosis of MEN type 2A (MEN2A)-related
MTC is established, we measure serum calcium to rule out hyperparathyroidism
requiring concomitant surgical intervention. Hyperparathyroidism is not part of
the MEN type 2B (MEN2B) syndrome, and therefore, patients with MEN2B do not
require evaluation for hyperparathyroidism.
If the serum calcium is elevated, we measure intact parathyroid hormone (PTH).
The diagnosis is established by finding high (or inappropriately normal) serum PTH
concentrations in the presence of hypercalcemia. (See "Primary
hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
If the serum calcium is normal, we measure serum calcium yearly to detect the
development of hyperparathyroidism (table 5).
Medullary thyroid cancer — Most index patients with MEN2 present with MTC
and, therefore, do not require monitoring for its development. For patients with
MEN2 who present with pheochromocytoma, we measure serum calcitonin and

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obtain a thyroid and neck ultrasound to assess for the presence of MTC. If there is
no evidence of MTC, we continue to screen annually (table 6).
Additional evaluation of patients who have been diagnosed with MEN2-related
MTC is similar to that in sporadic MTC and should include measurement of serum
calcitonin, carcinoembryonic antigen (CEA), and ultrasonography of the neck (if not
already performed). (See "Medullary thyroid cancer: Clinical manifestations,
diagnosis, and staging", section on 'Evaluation'.)
SCREENING OF FAMILY MEMBERS IN MEN2 KINDREDSOnce a
germline RET mutation is identified in an index case, RET mutation analysis should
be performed in first- and second-degree family members. Affected family
members also require screening for multiple endocrine neoplasia type 2 (MEN2)-
associated tumors. (See 'Genetic screening' below and 'Monitoring for MEN2-
associated tumors' below.)
Advances in the molecular genetics underlying the MEN2 syndromes have resulted
in DNA testing becoming the optimal test for their detection. The role of RET DNA
testing in MEN2 kindreds is better established than testing for MEN1 mutations in
multiple endocrine neoplasia type 1 (MEN1) families. This is because identification
of specific RET mutations predicts particular phenotypes (age of onset,
aggressiveness of medullary thyroid cancer [MTC], and presence or absence of
other endocrine neoplasms) and, thus, guides surveillance and management (table
3 and table 5 and table 6) [2].
In the past, pentagastrin and calcium stimulation tests were used to stimulate
calcitonin secretion by thyroid C cells and assess for the diagnosis of MTC in family
members. However, RET mutation screening is available for MEN2, and therefore,
these tests have lost their clinical significance with respect to diagnosis of MEN2
[54]. Genetic testing in known MEN2 families has several clinically important
advantages over the pentagastrin or calcium tests:
●It provides clinical benefit that should accrue from earlier surgery for known
MEN2 gene carriers as the genotype correlates with the age at initial
diagnosis of MTC (table 3).
●It definitively establishes that an individual does not carry the MEN2
mutation and eliminates the need for biochemical testing.
●It avoids unnecessary thyroidectomy in genetically normal subjects in MEN2
families. It is now clear, from retrospective DNA testing, that such subjects
can have falsely positive pentagastrin tests [55,56].
However, biochemical tests are still used in families who meet the clinical criteria
for MEN2 but have negative sequencing of the entire RET coding region or for
families who refuse genetic testing. (See 'When RET mutation is unknown' below.)

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Genetic screening — In general, the primary and most compelling purpose of
genetic screening in human tumor predisposition syndromes is to prevent disease-
related morbidity and mortality that would otherwise occur [2,26,57,58]. Genetic
counseling and genetic testing for RET germline mutations should be offered to
the following groups [1]:
●First-degree relatives of a patient with proven germline RET mutation
●Parents whose infants or young children have the clinical characteristics of
MEN type 2B (MEN2B)
●Patients with cutaneous lichen amyloidosis (CLA)
●Families whose infants or young children have Hirschsprung disease (HD)
In an MEN2 family, a sample from one subject already known to be affected should
be tested in order to determine the specific RET mutation for that family. All
subjects of unknown status in that family should then be definitively
genotyped. RET genotyping requires only a small blood sample and can therefore
be performed at birth or soon thereafter. At the latest, genotyping should be done
before the time at which prophylactic thyroidectomy would be performed in the
event of a positive result.
●Known RET mutation present – For those with RET mutations, prophylactic
thyroidectomy in family members is timed based upon the specific DNA
mutation in the RET proto-oncogene occurring in the family (table 6). The risk-
benefit equation is strengthened by the ease of thyroid hormone
replacement after thyroidectomy and the relatively low morbidity of the
surgery, even in children, when performed by high-volume surgeons [59].
The timing of prophylactic thyroidectomy is reviewed separately.
(See "Approach to therapy in multiple endocrine neoplasia type 2", section on
'Preventive surgery'.)
●Known RET mutation absent – A family member who has not inherited the
specific RET mutation that causes that family's MTC needs no further
evaluation.
Thus far, family screening efforts appear to be suboptimal, as a high proportion of
patients continue to receive less than optimal initial surgical treatment. According
to the population-based Surveillance, Epidemiology, and End Results (SEER)
registry, there has been no change in stage at diagnosis or significant
improvement in survival noted over the last 30 years [60,61]. Although the SEER
registry does not contain information regarding hereditary or biochemical results,
an estimated 50 percent had a familial form of MTC (FMTC). This suggests that
many MEN2/FMTC patients underwent surgery that was less than optimal for the
stage of the disease. Summary information concerning MEN2 may be useful for

222
counseling patients and affected families. Family alliances can provide such
information: Genetic Testing Registry (GTR) or EndocrineWeb.
Sensitivity/specificity — One potential problem relates to the rare MEN2 families
with no detectable RET mutation. In addition, as with any genetic test, other
potential sources of error exist such as sample mix-up, cross-contamination of the
polymerase chain reactions used in the tests, and DNA polymorphisms that would
prevent amplification of one RET allele, a situation that could result in a false-
negative screening test. To date, however, neither false-negative nor false-
positive RET tests have been described in MEN2 families in which a
specific RET mutation was detected in an index case.
Availability of genetic diagnosis — Genetic diagnosis of MEN type 2A (MEN2A),
FMTC, and MEN2B is readily available commercially. A list of testing laboratories is
available at the MD Anderson Cancer Center website and through the genetic
testing resource Genetic Testing Registry (GTR). In Europe, a listing of commercial
laboratories can be found at the European Directory of DNA Diagnostic
Laboratories.
Clinicians should inquire as to the protocol and methodology of the
offered RET DNA test. One important issue is whether all relevant exons (exons 10,
11, and 16, and, if those are negative, exons 8, 13, 14, and 15) will be sequenced if
the RET mutation in that family is unknown.
Counseling — Before blood samples are taken for DNA analysis, detailed
information about the consequences of DNA analysis must be provided to the
family. Psychological support may well be needed before DNA test results are
disclosed and during follow-up after diagnosis to minimize distress. Written
consent must be obtained [62]. Given the rarity of this disease and the potential
complications of a total thyroidectomy in young children, patients should be
referred to academic centers with expertise in MEN2.
Reproductive options — Patients with MEN2 and a known familial RET mutation
should be counseled that prenatal testing and preimplantation genetic testing are
available options if they choose to pursue fertility [26]. Prenatal testing is
performed in the first or second trimester via chorionic villus sampling or
amniocentesis, respectively. Preimplantation genetic diagnosis (PGD) is done as
part of in vitro fertilization (IVF); single embryonic cells are tested for
the RET mutation. Only embryos without a RET mutation are then transferred to
the uterus. The various reproductive options available to prospective parents
require thoughtful discussion and genetic counseling.
Monitoring for MEN2-associated tumors — Affected family members require
screening for multiple endocrine neoplasia type 2 (MEN2)-associated tumors.

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When RET mutation is known — When the RET mutation is known, monitoring for
MEN2-associated tumors is based upon the specific mutation and degree of risk it
confers for MTC, pheochromocytoma, and primary hyperparathyroidism.
Medullary thyroid cancer — Children with certain RET mutations can develop
clinically apparent MTC at an early age. The goal in patients with
known RET mutations (but without clinically apparent disease) is to perform a
prophylactic thyroidectomy before MTC develops or when it is still confined to the
thyroid gland (table 6). (See "Approach to therapy in multiple endocrine neoplasia
type 2", section on 'Preventive surgery'.)

Children with the highest risk mutation (codon 918) should have thyroidectomy
within the first year of life and, therefore, do not require monitoring.

For children with high-risk mutations (codons 634, 883), we begin monitoring at
age three years, and for children with moderate risk mutations, we begin
monitoring at age five years. We monitor with an annual physical examination,
neck ultrasound, and measurement of serum calcitonin. The detection of a serum
calcitonin level (basal or stimulated) above the upper limit of normal is an
indication for surgery.

Pheochromocytoma — The risk of developing pheochromocytoma is variable

depending upon genotype [63-65]. For children in the highest and high-risk
categories, screening for pheochromocytoma should begin by age 11 years (table
5). For children in the moderate-risk category, we begin screening by age 16 years.
Patients should be screened yearly by measuring plasma fractionated
metanephrines or 24-hour urinary metanephrines and normetanephrines. If
biochemical results are positive, adrenal imaging with computed tomography (CT)
or magnetic resonance imaging (MRI) is the next step. (See "Clinical presentation
and diagnosis of pheochromocytoma", section on 'Additional evaluation after
biochemical diagnosis'.)
There is large variability in the penetrance of pheochromocytoma among different
reported kindreds, depending upon the specific RET germline mutation. These
findings help guide screening and therapy for MEN2 patients [66-70]. As an
example, compared with families with mutations in codons 634 and 918,
pheochromocytomas are rare in families with mutations in codons 533, 609, 611,
618, 620, 630, 633, 666, 768, 790, 791, 804, and 891, although they do still occur.

Due to screening programs, pheochromocytomas may be diagnosed at a young

age and before symptoms are present.

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Hyperparathyroidism — The hyperparathyroidism in MEN2A is often mild and
asymptomatic. In one study, the mean age at diagnosis was 33 years, but children
diagnosed as young as two years of age has been reported [1,27,71,72].
Biochemical screening for hyperparathyroidism should be performed yearly
beginning at age 11 years in high-risk patients and 16 years in moderate-risk
patients (patients in the highest risk category [MEN2B] are not at risk for
developing hyperparathyroidism) (table 5) [1]. We measure serum calcium
(corrected for albumin). If it is elevated, we measure intact parathyroid hormone
(PTH). The diagnosis is established by finding high (or inappropriately normal)
serum PTH concentrations in the presence of hypercalcemia. (See "Primary
hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
When RET mutation is unknown
Biochemical testing — For closely related MEN2 family members who refuse DNA
analysis for themselves or their children, or for families who meet the clinical
criteria for MEN2 but have negative sequencing of the entire RET coding region,
biochemical testing can be performed to detect MEN2-related tumors. If
biochemical testing is used, yearly testing starting at age five and continuing until
at least age 35 years (or until a positive test occurs) is necessary [7]. For families
with a clinical diagnosis of MTC prior to age five years, biochemical screening for
MTC should begin at the youngest age of first diagnosis.

Either a pentagastrin or a calcium stimulation test can be used to screen for C-cell
hyperplasia/MTC. Where available (not in the United States), pentagastrin is the
preferred stimulation test. Testing should also include plasma fractionated
metanephrines or 24-hour urinary metanephrines and normetanephrines (to
screen for pheochromocytoma) and serum calcium (to screen for
hyperparathyroidism).

Choice of biochemical test for MTC — Owing to the unavailability of pentagastrin

in many countries, there is growing interest in the calcium stimulation test.
However, there are few data using the calcium stimulation as a confirmatory test
in patients with elevated basal calcitonin levels, and cutpoints for the
discrimination of normal, C-cell hyperplasia, and medullary thyroid cancer (MTC)
have not been standardized [73]. In one study, basal and stimulated calcitonin
levels were measured in over 100 patients with thyroid disease (MTC in remission
or persistence, RET gene mutation carriers, nodular goiter) and in 16 healthy
volunteers [74]. In all groups, the levels of calcitonin stimulated by either
pentagastrin or calcium were significantly correlated. In this study, calcium
stimulated calcitonin levels above 32.6 pg/mL (females) and 192 pg/mL (males) had
the best accuracy to differentiate normal subjects from patients with C-cell
225
hyperplasia or MTC [74]. Criteria for abnormal calcitonin values may vary in local or
commercial laboratories [75].
●Pentagastrin stimulation test – The pentagastrin stimulation test uses a
slow intravenous injection of pentagastrin (0.5 mcg/kg body weight) over
three minutes. Blood samples for calcitonin are obtained at baseline and two
and five minutes after pentagastrin infusion [76,77]. If stimulated calcitonin
values are ≥200 pg/mL, MTC is likely and thyroidectomy and
lymphadenectomy are required. If values are <100 pg/mL, the risk of MTC is
low and periodic monitoring of basal and stimulated serum calcitonin levels
is recommended. If the stimulated calcitonin values are between 100 and 200
pg/mL, the risk is uncertain. Such values could be indicative of C-cell
hyperplasia or micro MTC. Some advise surgery [78,79], while others
observation (following calcitonin levels) [80].
Side effects of pentagastrin include abdominal cramping, extremity
paresthesia, and feeling of warmth, lasting up to one to two minutes [77].
Pentagastrin is not available in many countries, including the United States.
●Calcium stimulation test – The calcium stimulation test uses an infusion
of calcium gluconate (2.5 mg elemental calcium/kg body weight over 30
seconds) administered in a fasting state (no food after midnight) [55,77].
Blood samples for calcitonin are obtained at baseline and two and five
minutes after the stimulus. In one study, calcium-stimulated calcitonin levels
above 32.6 pg/mL (females) and 192 pg/mL (males) had the best accuracy to
differentiate normal subjects from patients with C-cell hyperplasia or MTC
[74].
The most common side effects are temporary flushing and feeling of warmth
(98 percent) [77]. Facial paresthesias are less common (20 percent).
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Medullary thyroid cancer".)
SUMMARY AND RECOMMENDATIONS
●Multiple endocrine neoplasia type 2 (MEN2) is subclassified into two distinct
syndromes: types 2A (MEN2A) and 2B (MEN2B) (table 1). Within MEN2A, there
are four variants. The genetic defect in MEN2 involves the RET proto-
oncogene on chromosome 10. MEN2A and 2B are inherited in an autosomal
dominant pattern with very high penetrance. (See 'Introduction' above.)
●MEN2A is characterized by medullary thyroid cancer (MTC),
pheochromocytoma, and primary parathyroid hyperplasia. While the lifetime
penetrance of MTC is nearly 100 percent, there is much inter- and intrafamily

226
variability in MTC onset and in the other manifestations of MEN2A.
(See 'Clinical features' above.)
●MEN2B is characterized by MTC and pheochromocytoma but not
hyperparathyroidism. MTC occurs in almost all patients. The tumor develops
at an earlier age and is more aggressive than in MEN2A; as a result, early
diagnosis and prevention are crucial. The syndrome also includes mucosal
neuromas, typically involving the lips and tongue, intestinal
ganglioneuromas, and a Marfanoid habitus. Disturbances of colonic function
are common, including chronic constipation and megacolon. (See 'Clinical
features' above.)
●MEN2 should be suspected in any patient with MTC or pheochromocytoma,
particularly when the tumors occur at a young age (<35 years), are
multicentric, or when more than one family member is affected. The
diagnosis of MEN2 is based upon the presence of the classical clinical
features, family history, and genetic testing. (See 'Diagnosis' above.)
●In an index patient with one or two of the classical clinical features,
identification of a germline RET mutation or the identification of the clinical
features of MEN2 in other first-degree relatives is required to make the
diagnosis of MEN2. (See 'MEN2' above.)
In the absence of an autosomal dominant inheritance pattern
or RET mutation, at least two of the classical clinical features of MEN2A (MTC,
pheochromocytoma, primary hyperparathyroidism) are required to make the
diagnosis.
In the absence of an autosomal dominant familial inheritance pattern
or RET mutation, the majority of classical clinical features of MEN2B are
required to make a clinical diagnosis of MEN2B.
●Familial MTC (FMTC) is characterized by the presence of a RET germline
mutation in families with MTC, or an individual with MTC, who do not develop
pheochromocytoma or primary hyperparathyroidism. Distinguishing the
FMTC variant from classical MEN2A may be difficult in small families, and
therefore, rigorous criteria for FMTC should be used in order not to miss a
pheochromocytoma. (See 'Familial medullary thyroid cancer variant' above.)
●For patients diagnosed with MEN2 based upon the classical clinical features
and family history (typically MTC and a family member with MTC), evaluation
should include RET mutation analysis (if not already performed) in order to
identify the specific RET mutation to facilitate family screening (table 4).
(See 'RET mutation analysis' above.)
●Patients with MEN2 also require screening for MEN2-associated tumors. In
all patients diagnosed with MEN2-related MTC, we measure plasma

227
fractionated metanephrines (as the initial screen for pheochromocytoma in
patients with MEN2A or 2B) and serum calcium (to rule out
hyperparathyroidism requiring concomitant surgical intervention in patients
with MEN2A). For patients with MEN2 who present with pheochromocytoma
rather than MTC, we measure serum calcitonin and obtain a neck ultrasound
to assess for the presence of MTC. (See 'Screening for MEN2-associated
tumors' above.)
If pheochromocytoma is found, it should be removed prior to thyroidectomy.
If the initial testing for coexisting tumors is negative, it is important to
evaluate the index patient for pheochromocytoma (MEN2A and 2B) and
hyperparathyroidism (MEN2A) yearly (table 5).
●Once a germline RET mutation is identified in an index case, RET mutation
analysis should also be performed in first- and second-degree family
members. Affected family members require screening for MEN2-associated
tumors. (See 'Genetic screening' above and 'Monitoring for MEN2-associated
tumors' above.)
Early diagnosis by screening of "at-risk" family members in MEN2 kindreds is
important because identification of specific RET mutations predicts particular
phenotypes (age of onset, aggressiveness of MTC, and presence or absence
of other endocrine neoplasms) and, thus, guides surveillance for MEN2-
associated tumors and management (table 3 and table 5 and table 6).
(See 'Screening of family members in MEN2 kindreds' above.)
●For those with RET mutations, prophylactic thyroidectomy in family members
is timed based upon the specific DNA mutation in the RET proto-oncogene
occurring in the family (table 6). (See "Approach to therapy in multiple
endocrine neoplasia type 2", section on 'Timing of surgery'.)

228
Multiple endocrine neoplasia type 1: Clinical
manifestations and diagnosis
Author:
Andrew Arnold, MD
Section Editor:
Marc K Drezner, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Aug 30, 2021.
INTRODUCTIONMultiple endocrine neoplasia type 1 (MEN1) is an autosomal
dominant predisposition to tumors of the parathyroid glands (which occur in the
large majority of patients by age 50 years), anterior pituitary, and enteropancreatic
endocrine cells; hence, the mnemonic device of the "3 Ps" [1]. However, the clinical
spectrum of this disorder has been expanded. The duodenum is a common site of
tumors (gastrinomas) in these patients, and carcinoid tumors, adrenal adenomas,
and lipomas are more common than in the general population (table 1).
The clinical manifestations and diagnosis of MEN1 will be reviewed here. The
genetics of this disorder, its distinction from other multiple endocrine neoplasia
(MEN) syndromes, and its treatment are discussed separately. (See "Multiple
endocrine neoplasia type 1: Definition and genetics" and "Multiple endocrine
neoplasia type 1: Treatment" and "Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2".)
DEFINITION OF MEN1Multiple endocrine neoplasia type 1 (MEN1) is a rare
heritable disorder classically characterized by a predisposition to tumors of the
parathyroid glands, anterior pituitary, and pancreatic islet cells [1,2]. The presence
of MEN1 is defined clinically as the occurrence of two or more primary MEN1
tumor types, or in family members of a patient with a clinical diagnosis of MEN1,
the occurrence of one of the MEN1-associated tumors (table 1). It should be noted
that these are clinical definitions and do not necessarily indicate that mutation of
the MEN1 gene will be identifiable or responsible (see "Multiple endocrine
neoplasia type 1: Definition and genetics"). In addition, for diagnosis of MEN1,
there are situations where genetic criteria can be used. (See 'Diagnosis' below.)
CLINICAL MANIFESTATIONS
Primary hyperparathyroidism — Multiple parathyroid tumors causing
hyperparathyroidism are the most common manifestation of multiple endocrine

229
neoplasia type 1 (MEN1), displaying almost 100 percent penetrance overall and at
least 75 percent penetrance by age 50 years [1-3]. In most cases, it is the initial
manifestation of MEN1. Reliable incidence figures do not exist, but it has been
estimated that the incidence of MEN1 ranges from 1 to 18 percent in patients with
primary hyperparathyroidism [1] and probably much closer to the lower end of
this range [4].
Primary hyperparathyroidism in the setting of familial MEN1 has a number of
different features from the common sporadic (non-familial) form of the disease
[1,5]:
●The male-to-female ratio is even in MEN1 in contrast to the female
predominance in sporadic hyperparathyroidism.
●Hyperparathyroidism in MEN1 typically presents in the second to fourth
decade of life, approximately two decades earlier than in sporadic
hyperparathyroidism.
●Multiple gland disease is typical in MEN1 and, given sufficient time, perhaps
universal. In comparison, approximately 80 to 85 percent of patients with
sporadic disease have single parathyroid adenomas. There can be marked
asymmetry in size among the distinct glands and, upon initial neck
exploration, some parathyroid glands in MEN1 may appear to be grossly
normal. However, even the smaller glands will generally exhibit
hypercellularity on histologic examination.
●A strong and seemingly inexorable proliferative drive in parathyroid cells
appears to exist in classical MEN1, as indicated by the high rate of recurrent
hyperparathyroidism after apparently successful subtotal parathyroidectomy.
One report from the National Institutes of Health (NIH), as an example, found
a recurrence rate above 50 percent at 12 years [6]; most other studies have
had shorter follow-up periods. The high recurrence rate clearly distinguishes
the hyperparathyroidism of MEN1 from that seen in sporadic disease. It has
also resulted in differences of opinion with respect to optimal surgical
management of this disorder. (See "Multiple endocrine neoplasia type 1:
Treatment".)
Similar to sporadic primary hyperparathyroidism, the majority of patients are
asymptomatic or minimally symptomatic, and hypercalcemia is detected by
routine or surveillance-driven biochemical screening. If clinical manifestations of
primary hyperparathyroidism are present, they may include decreased bone
mineral density, kidney stones, and symptoms of hypercalcemia (eg, polyuria,
polydipsia, constipation). The biochemical diagnosis of primary
hyperparathyroidism is based, as it is in other patients, on the demonstration of
hypercalcemia with inappropriately high serum parathyroid hormone (PTH)

230
concentrations. (See "Primary hyperparathyroidism: Clinical
manifestations" and "Primary hyperparathyroidism: Diagnosis, differential
diagnosis, and evaluation".)
Pituitary adenomas — Clinically apparent pituitary adenomas have been found in
approximately 15 to 20 percent of patients with MEN1 when sought by computed
tomography (CT) or magnetic resonance imaging (MRI) [7] and 42 percent in a
multicenter study of 324 MEN1 patients [8]. The pathological prevalence in one
series was over 60 percent [9]. Pituitary tumors have been reported to be the first
manifestation of MEN1 in 13 percent of patients [10]. The range of pituitary cell
types is similar to that found in sporadic pituitary adenomas. Thus, the most
common type of pituitary adenoma in MEN1 is lactotroph, but somatotroph,
corticotroph, gonadotroph, and clinically nonfunctioning tumors can also occur
(table 1). Multiple pituitary tumors are rarely present in MEN1.
The phenotypic presentation of pituitary disease is variable. In one large kindred,
as an example, lactotroph adenomas predominated, and none of the 165 patients
had acromegaly [7,11]. Furthermore, the distribution of lactotroph adenomas was
not even; the prevalence was more than 50 percent in some branches of the
kindred and very low in others [12].
A multicenter study of 324 MEN1 patients (42 percent of whom had pituitary
tumors), compared with 110 non-MEN patients with pituitary adenomas, revealed
that [8]:
●Of the 136 MEN1 patients with pituitary adenomas, 85 percent had
macroadenomas (versus 42 percent in non-MEN1 patients).
●In the same patients, hormonal hypersecretion was normalized in 42
percent after treatment versus 90 percent in non-MEN1 patients, reflecting
the finding that the MEN1 patients had adenomas that were larger and more
aggressive than those in non-MEN patients.
In contrast, another study, which examined the results of systematic
presymptomatic screening for pituitary adenomas over a significant follow-up
period (median 6 years), showed that such screening primarily detected
nonfunctioning microadenomas that grew only occasionally and without clinical
consequence; detected prolactinomas responded well to medical treatment [13].

Whether a program of routine and lifelong surveillance by imaging would

decrease morbidity from pituitary disease in MEN1 remains unknown.

The clinical manifestations, approach to diagnosis, and therapy of pituitary

adenomas in patients with MEN1 is similar to that in patients with sporadic
adenomas. (See "Causes, presentation, and evaluation of sellar masses", section
on 'Pituitary adenomas'.)
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Pancreatic islet cell/gastrointestinal endocrine tumors — Effective treatment is
usually available for the hyperparathyroidism and pituitary disease in MEN1; as a
result, the malignant potential of enteropancreatic neuroendocrine tumors is now
the primary life-threatening manifestation of MEN1.
Functioning pancreatic islet cell or gastrointestinal endocrine cell tumors become
clinically apparent in one-third to two-thirds of patients with MEN1 (table 1). The
most common cause of symptomatic disease is the Zollinger-Ellison (gastrinoma)
syndrome (ZES), leading to multiple peptic ulcers or diarrhea. It has been
estimated that 60 percent of patients with MEN1 have either ZES or asymptomatic
elevation in serum gastrin concentrations; on the other hand, MEN1 is present in
approximately 25 percent of patients with ZES [14,15]. Symptomatic insulinomas
also occur with moderate frequency, while VIPomas and glucagonomas are rare
(table 1). (See "VIPoma: Clinical manifestations, diagnosis, and
management" and "Glucagonoma and the glucagonoma syndrome".)
The prevalence of radiographically confirmed, nonfunctioning tumors is similar to
that of gastrinomas, ranging from 30 to 80 percent [16-19]. Like hormonally active
enteropancreatic tumors in MEN1, clinically "nonfunctioning" pancreatic
neuroendocrine tumors may be malignant and capable of causing liver
metastases. (See 'Nonfunctioning pancreatic tumors' below.)
Zollinger-Ellison syndrome — Historically, attempts at surgical cure of the
hypergastrinemia in ZES in patients with MEN1 were uniformly unsuccessful. It is
now apparent that the basis for the failure of these approaches, namely resection
of palpable tumors and/or partial pancreatectomy, is due to the biological nature
and characteristics of the tumors in MEN1. In contrast to sporadically occurring
gastrinomas, the gastrinomas in MEN1 patients are multifocal, often exceedingly
small, and easily overlooked. In addition, the duodenum is a common site of
gastrinomas both in MEN1 and in sporadic gastrinoma [14,20,21]; in comparison,
in MEN1, the tumors that are found in the pancreas do not usually secrete gastrin
[14].
The risk of death from malignant spread of MEN1-associated gastrinoma appears
to be less than that for sporadic gastrinoma. Local lymph node metastases are
common but are not necessarily associated with a poor prognosis or a high
likelihood that clinically important metastases will occur [22].
In one large series, investigators at the NIH prospectively followed 107 patients
with MEN1 and ZES and reviewed 1009 cases from the literature [23]. Their
findings were as follows:
●Approximately 25 percent of MEN1/ZES patients had no family history of
MEN1.

232
 ●ZES was the initial clinical manifestation of MEN1 in only 8 percent of
patients with MEN1/ZES if careful testing was done.
●The onset of ZES symptoms preceded the diagnosis of hyperparathyroidism
in 45 percent of patients.
●The diagnosis of ZES was delayed for three to six years after its onset.
●Pituitary disease occurred in 60 percent of patients.
●In patients without a family history of MEN1, ZES and other MEN1
manifestations occurred later and were less severe.
Hypersecretion of gastrin in ZES in MEN1 may be suspected clinically by the
presence of multiple peptic ulcers (image 1) or symptoms like diarrhea. The
diagnosis is confirmed by the same biochemical and gastric acid output criteria as
are used in the sporadic cases [22,24,25] (see "Zollinger-Ellison syndrome
(gastrinoma): Clinical manifestations and diagnosis"). Hypercalcemia from
coexisting hyperparathyroidism can significantly exacerbate the symptoms of ZES,
and parathyroidectomy to correct hypercalcemia can reduce fasting
and secretin stimulated gastrin levels and basal acid secretion [26].
The incidence of Cushing's syndrome has been reported to be increased in
patients with ZES. When Cushing's syndrome occurs in patients with nonfamilial
gastrinoma, the usual cause is ectopic corticotropin (ACTH) release from the islet-
cell tumor. These cases are associated with severe symptoms. In contrast, patients
with familial MEN1 and ZES who develop Cushing's syndrome usually have a
corticotroph adenoma of the pituitary and relatively mild symptoms of cortisol
excess [27].
Insulinoma — Insulin-producing pancreatic islet cell adenomas in MEN1 are often
small, may be multiple, and may be associated with the simultaneous presence of
other islet cell tumors. Insulinoma in MEN1 typically presents in the second to
fourth decade of life, earlier than in sporadic insulinoma, which usually occurs in
individuals older than 40 years [1]. The diagnosis of insulinoma depends, as in
nonfamilial causes, upon the documentation of hypoglycemia with characteristic
symptoms that are rapidly reversed by the administration of glucose, and
inappropriately high serum insulin concentrations. (See "Insulinoma".)
Nonfunctioning pancreatic tumors — It is important to recognize that pancreatic
neuroendocrine tumors in MEN1 often synthesize multiple hormones. But
hormone synthesis does not always have clinical consequences, suggesting that
many such tumors may be defective in their peptide hormone processing
apparatus or have an inefficient secretory mechanism [28]. Like hormonally active
enteropancreatic tumors in MEN1, clinically "nonfunctioning" pancreatic
neuroendocrine tumors may be malignant and can metastasize to the liver.

233
Nonfunctioning pancreatic neuroendocrine tumors have been detected as early as
ages 12 to 14 in asymptomatic children with MEN1 [29,30].
Nonfunctioning pancreatic neuroendocrine tumors are among the most common
tumor of the pancreaticoduodenal region in patients with MEN1 [16-19]. In a
report of 579 MEN1 patients, 108 patients with isolated nonfunctioning pancreatic
neuroendocrine tumors were identified with the following clinical characteristics
and course [17]:
●The penetrance of nonfunctioning pancreatic neuroendocrine tumors was
34 percent at age 50 years.
●The risks of metastasis and death were low for patients with tumors ≤20
mm.
●Average life expectancy for patients with nonfunctioning pancreatic
neuroendocrine tumors was similar to that for gastrinoma patients (69 to 70
years) and shorter than that for patients without pancreatic tumors (77
years).
The best way to detect these nonfunctioning tumors is unclear. Assays for tumor
markers like chromogranin A have low value [31,32]. A limited amount of data
suggests that endoscopic ultrasound (EUS) outperforms CT scanning in this
setting, and a combination of MRI plus EUS has been recommended
[2,30]. 68Gallium-DOTATATE PET/CT scanning has been reported to have especially
high sensitivity for detecting neuroendocrine tumors in MEN1, at times leading to
a change in management [33]. Such sensitive imaging methods increase detection
of indolent tumors as well as potentially aggressive lesions. In a retrospective
study, 18F-FDG PET/CT imaging was useful for predicting the malignant potential of
pancreatic neuroendocrine tumors in MEN1 [34]. (See "Classification,
epidemiology, clinical presentation, localization, and staging of pancreatic
neuroendocrine neoplasms", section on 'Endoscopic ultrasonography'.)
Other tumors — A number of other tumors also occur with increased frequency in
MEN1. These include carcinoid, cutaneous tumors, adrenal tumors (especially
nonfunctional adrenocortical adenomas), gastric enterochromaffin-like cell
carcinoids, pheochromocytoma (very rarely), angiomyolipomas, meningiomas, and
spinal cord ependymomas (table 1).
Carcinoid tumors — Thymic carcinoid tumors occur with increased frequency in
MEN1 (2.6 to 8 percent in retrospective series of patients with MEN1), mostly in
men [35-37]. Heavy smoking may be a risk factor [35]. Carcinoids in women with
MEN1 are most often bronchial [38].
Thymic carcinoids, the most common cause of anterior mediastinal masses in
MEN1, are typically nonfunctional (in contrast to the substantial incidence of

234
ectopic Cushing's syndrome in patients with sporadic thymic carcinoid) and tend to
be aggressive. (See "Pathology of mediastinal tumors".)
A prospective study of thymic carcinoids in 85 patients with MEN1 evaluated for
pancreatic endocrine tumors and followed for a mean of eight years (with serial
chest CT, MRI, and somatostatin receptor scintigraphy [SRS]) reported the
following results [39]:
●Seven patients (8 percent) developed thymic carcinoids, all of which were
hormonally inactive.
●All seven patients were male, and ZES was present in six.
●Five of the seven were asymptomatic, one had cough, and one had chest
pain.
●CT and MRI were more sensitive than SRS for detecting the tumors initially
or with recurrence.
●All patients underwent surgical resection. All four patients followed for more
than one year postoperatively had tumor recurrence.
Some have recommended regular screening, by chest imaging studies, for this
tumor in men with MEN1 [1,35,37]. Given the rarity of these tumors and the
unproven survival benefits of this approach, we consider such routine surveillance
reasonable but not mandatory. Certainly, it seems prudent to strongly advise men
with definite or possible MEN1 against smoking, to take into consideration a
strong family history of carcinoid tumors, and to perform prophylactic
thymectomy in patients undergoing parathyroidectomy, although even this
measure does not fully prevent subsequent development of thymic neoplasia
[36,40]. (See "Multiple endocrine neoplasia type 1: Treatment".)
Gastric carcinoids and enterochromaffin-like cell proliferation (a precursor lesion
of gastric carcinoid) occur with substantial frequency in patients with MEN1 and
ZES. In a prospective study of 57 patients with MEN1 and ZES, advanced
enterochromaffin-like cell proliferation and gastric carcinoid were detected in 53
and 23 percent, respectively [41]. Long duration of ZES, long duration of medical
treatment, high fasting serum gastrin levels, and the presence of gastric nodules
on gastroscopy were associated with a higher risk of gastric carcinoid. Such
patients may benefit from regular monitoring for gastric carcinoid. (See "Clinical
characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in
the gastrointestinal and genitourinary tracts", section on 'Stomach' and "Multiple
endocrine neoplasia type 1: Treatment".)
Cutaneous tumors — Cutaneous tumors are common in MEN1 (table 1) [1,2,42];
their presence in patients with pancreatic endocrine tumors suggest the diagnosis
of MEN1. This was illustrated in a prospective study of 110 consecutive patients

235
with gastrinoma (48 with MEN1 and 62 without MEN1) with the following findings
[43]:
●Angiofibromas and collagenomas were more common in MEN1 patients
than in those without MEN1 (64 versus 8 percent, and 62 versus 5 percent,
respectively).
●These cutaneous tumors were multiple in 77 to 81 percent of MEN1 patients;
lipomas were present in 17 percent.
●The combination criterion of more than three angiofibromas and any
collagenomas had a sensitivity of 75 percent and a specificity of 95 percent
for the diagnosis on MEN1. The sensitivity and specificity of this criterion
compares favorably to the finding of hyperparathyroidism in patients who
present initially with gastrinomas [23].
Similarly, the presence of angiofibromas or collagenomas can be helpful clinically
in suggesting the diagnosis of MEN1 in selected patients with primary
hyperparathyroidism. Melanoma and hibernoma have also been reported in MEN1
patients [2], but this association and potential menin-related pathogenesis require
further investigation.
Breast cancer — The risk of breast cancer in female patients with MEN1 has been
reported to be almost double, and with earlier mean onset, compared with the
general population [44,45]. Early screening (eg, beginning age 40) has been
reasonably suggested but evidence for effectiveness remains to be demonstrated.
DIAGNOSISThe clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1)
is based upon the occurrence of two or more primary MEN1 tumor types
(parathyroid gland, anterior pituitary, and enteropancreatic). In family members of
a patient with a clinical diagnosis of MEN1, the occurrence of one of the MEN1-
associated tumors is consistent with familial MEN1 [1].
The diagnosis of MEN1 (or at least a determination that an individual is genetically
predisposed to developing MEN1 clinically) can also be made by identifying a
germline MEN1 mutation in an individual in whom the clinical diagnosis of MEN1 is
not clearly established or in an asymptomatic family member who has not yet
developed the serum biochemical or radiological abnormalities associated with
tumor development. (See 'Confirming the diagnosis of MEN1' below
and 'Screening of family members in MEN1 kindreds' below.)

Given the complexity of decision-making and specialized skills needed in the

diagnosis, management, and treatment of MEN1, it is strongly recommended that
this be done in centers with established multidisciplinary teams experienced in the
care of MEN1 patients.

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MEN1 MUTATIONAL ANALYSIS
Potential benefits — The optimal role of DNA testing in the context of multiple
endocrine neoplasia type 1 (MEN1) is not clear cut [1,46]. In large part, this is due
to a dearth of solid data showing that preclinical detection of MEN1-related tumors
leads to interventions that improve morbidity or mortality. This situation contrasts,
for example, with the established value of RET DNA testing in multiple endocrine
neoplasia type 2 (MEN2) kindreds (table 2) (see "Clinical manifestations and
diagnosis of multiple endocrine neoplasia type 2"). Nonetheless, there are
circumstances in which DNA testing for MEN1 can be helpful, and this option
should be seriously considered. We make determinations regarding MEN1 DNA
testing on a case-by-case basis.
Direct DNA testing for MEN1 gene mutations is available in academic and
commercial laboratories (ie, Genetic Testing Registry). Generally speaking, DNA
testing can have utility in several linked ways including [46,47]:
●Confirming the clinical diagnosis of the syndrome in a proband
●Examining a clearly affected proband to determine if mutation-specific
carrier testing can be offered to relatives in that family
●Definitively determining whether or not asymptomatic or other relatives of a
proband carry the mutant gene
●Prenatal/preimplantation diagnosis
Based upon these potential benefits, guidelines from an international group of
endocrinologists recommend offering MEN1 mutational analysis to [1]:
●Any index patient with clinical MEN1 (two or more primary MEN1 tumor
types)
●All first-degree relatives of known MEN1 mutation carriers
●Individuals with suspicious or atypical MEN1 (eg, multiple parathyroid
tumors, gastrinoma, or multiple pancreatic neuroendocrine tumors)
Confirming the diagnosis of MEN1 — We make determinations regarding
multiple endocrine neoplasia type 1 (MEN1) DNA testing on a case-by-case basis,
but discussions with patient and genetic counselor more often than not lead to
pursuit of such testing. Situations in which DNA testing can be helpful may arise
when the diagnosis of MEN1 is unable to be clearly established on clinical grounds
and would alter management. Examples may include some patients with a
suggestive family history who present with isolated primary hyperparathyroidism
[46] or those with apparently sporadic Zollinger-Ellison syndrome (ZES), some of
whom will have MEN1 mutation and would therefore be managed differently.
(See "Multiple endocrine neoplasia type 1: Treatment".)
Relevant factors to consider in these situations include the expected yield of
testing, or likelihood of a positive result, which can vary markedly depending on
237
the specific clinical presentation. For example, while MEN1 gene mutation is
detectable in approximately 70 percent of kindreds with classic familial MEN1, the
yield of testing drops to 7 percent in individuals with a sporadic presentation of
combined hyperparathyroidism and pituitary adenoma [48]. Approximately 10
percent of kindreds with familial isolated hyperparathyroidism have a
detectable MEN1 mutation, and yields can be even lower when less stringent
criteria are selected, such as sporadic isolated hyperparathyroidism with age
under 40 [49].
Cost-benefit considerations can importantly influence decision-making.
Sequencing costs have generally dropped but can remain substantial in some
settings (and are variably covered by insurance in the United States). It is also
important to recognize that a negative result (mutation not detected) does not rule
out the diagnosis of MEN1 nor the possibility that unidentified pathologic
disruption of the MEN1 gene is responsible. Beyond assessing whether detection
of an MEN1 mutation would impact a patient's immediate clinical management,
factors influencing the decision to test include an examination of the potential
utility of a positive finding for the purposes of family screening and one's approach
to the prospective surveillance for MEN1-related tumors in the proband and
family. (See 'Monitoring for MEN1-associated tumors' below.)
Screening of family members in MEN1 kindreds
Candidates for screening — We have a discussion about DNA testing with the
index patient and appropriate family members, making decisions on a case-by-
case basis. Involvement of a genetic counselor can be very helpful. Proper
informed consent must be obtained for each individual to be tested.

When a patient is diagnosed as having MEN1, the issue of screening family

members who are at risk often arises. In general, the primary and most compelling
purpose of such screening in human tumor predisposition syndromes is to prevent
disease-related morbidity and mortality that would otherwise occur. However,
there is at present little evidence that early, preclinical detection actually reduces
overall morbidity or mortality in MEN1. Nonetheless, because benefit seems likely
in some instances and because other helpful information can potentially result,
screening may be pursued and DNA-based testing merits serious consideration.

Screening approach — If DNA-based family screening is to be pursued, the initial

step is to test the MEN1 gene, usually from a sample of peripheral blood or buccal
cells, from the affected index case, if not already performed. If MEN1 sequencing
of the affected patient does reveal a pathologic mutation, the presence or absence
of this family-specific mutation can then be determined in at-risk relatives. Thus, a
significant potential benefit of such testing is the identification of family members
238
who do not have the mutation and therefore do not need regular surveillance. The
value of this benefit is enhanced to the extent that the clinician tends to opt for
one of the more costly or intensive approaches to surveillance to detect MEN1-
associated conditions in at-risk individuals. (See 'Monitoring for MEN1-associated
tumors' below.)

The presence of the mutation in an asymptomatic family member does not

indicate the need for a major intervention but does focus the need for regular
surveillance (eg, assessment of symptoms, signs, biochemical/imaging tests) on
these individuals. It is possible that asymptomatic individuals’ knowledge that they
definitely carries the disease gene may increase compliance with surveillance visits
and testing. Other issues include genetic discrimination, which, in the United
States, remains a potential concern, despite certain protections in the Genetic
Information Nondiscrimination Act of 2008. Approaches to DNA testing and
screening can vary in different nations.

Finally, knowledge of a family's specific MEN1 mutation can resolve the small

potential for diagnostic confusion attributable to rare MEN1 phenocopies within
MEN1 kindreds, namely individuals who can initially be classified as having the
syndrome when they develop a typical tumor (eg, prolactinoma) but may then be
proven by DNA testing to have not inherited the pathologic mutation [50].
Alternative to DNA screening — If DNA testing is not employed for screening
asymptomatic family members in known or suspected MEN1 kindreds, one low-
cost option is measurement of serum calcium [7]. This approach exploits the high
penetrance of hyperparathyroidism in MEN1. In addition, adding measurements of
serum parathyroid hormone (PTH) and/or ionized calcium and assuring the
absence of vitamin D deficiency may improve sensitivity and specificity of
screening. Also, as noted above, the presence of angiofibromas or collagenomas
can be useful in this context.
MONITORING FOR MEN1-ASSOCIATED TUMORSFor patients with
multiple endocrine neoplasia type 1 (MEN1), known MEN1 carriers, and family
members whose risk has not been eliminated by DNA testing, we monitor for
MEN1-associated tumors as follows:
●We maintain clinical vigilance for symptoms or signs that could be due to
MEN1-associated tumors. These include symptoms of nephrolithiasis,
amenorrhea, galactorrhea, growth abnormalities, cushingoid changes,
headache, vision issues, cough, erectile dysfunction, peptic ulcer disease,
diarrhea, and neuroglycopenic or sympathoadrenal symptoms from
hypoglycemia.

239
 ●We typically measure serum calcium, PTH, and prolactin annually to detect
asymptomatic hyperparathyroidism and prolactinoma, respectively.
●We tend toward conservatism in performing imaging studies, given the
absence of prospective evidence for improved survival outcomes, and taking
patient preferences into account regarding the frequency and nature of such
imaging is reasonable. Often we will initially perform an imaging study for
enteropancreatic neoplasia, favoring modalities and subsequent intervals
that minimize radiation exposure (eg, endoscopic ultrasound and magnetic
resonance imaging [MRI]), with a follow-up study one or two years later, and
address factors like patient anxiety.
The extent to which additional surveillance for endocrine tumors, employing
biochemical and/or radiographic methods, should be used can be debated since
evidence for their efficacy in improving outcomes is not strong [1,51].
Nevertheless, some published guidelines have opted for pointing the clinician to a
more aggressive screening protocol for MEN1-associated risks beginning at very
early ages [1,48]. A 2012 paper, for example, while acknowledging weaknesses in
available supporting data, suggested routine annual measurement of serum
calcium, parathyroid hormone (PTH), gastrin, fasting glucose, insulin, insulin-like
growth factor-1 (IGF-1), prolactin, and chromogranin-A, starting in childhood and
continuing for life. Imaging tests (magnetic resonance imaging [MRI] of the
pituitary and MRI/computed tomography [CT] scan/endoscopic ultrasound (EUS) to
evaluate for enteropancreatic tumors) were suggested every one to three years
[1]. Others have recommended more limited biochemical testing and somewhat
different imaging approaches [13,51].
We believe that cost-effectiveness and risk-benefit considerations (including those
related to diagnostic radiation exposure) can be taken into account in determining
the prospective preclinical surveillance program of an individual with MEN1 or a
family member at risk, beyond the maintenance of disease-focused clinical
vigilance. For example, annual measurement of serum calcium offers the
opportunity to inexpensively detect asymptomatic hyperparathyroidism, which
might be treated surgically. Other combinations of biochemical and imaging
surveillance, including those in published protocols, can reasonably be used but
are not mandatory given the absence of support by high-quality evidence [1]. The
surveillance approach will also be reasonably informed by one's potential use of
tumor size criteria in the decision to operate on enteropancreatic endocrine
tumors (see "Multiple endocrine neoplasia type 1: Treatment"). New advances in
treatment could dramatically alter these recommendations; for example, a future
demonstration that an aggressive surgical approach to gastrinoma clearly
improves disease-related mortality would provide a rationale for intensive

240
biochemical and anatomic screening, which is capable of detecting gastrointestinal
or pancreatic disease in asymptomatic family members [16].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●General principles – Given the complexity of decision-making and
specialized skills needed in the diagnosis, monitoring, and treatment of
multiple endocrine neoplasia type 1 (MEN1), it is strongly advised that
patients are evaluated and managed in centers with established
multidisciplinary teams experienced in the care of MEN1 patients.
(See 'Diagnosis' above.)
●MEN1 diagnosis – The clinical diagnosis of MEN1 is based upon the
occurrence of two or more primary MEN1 tumor types (parathyroid gland,
anterior pituitary, and enteropancreatic). In family members of a patient with
a clinical diagnosis of MEN1, the occurrence of one of the MEN1-associated
tumors is consistent with familial MEN1 (table 1). (See 'Definition of
MEN1' above and 'Diagnosis' above.)
The diagnosis of MEN1 (or at least a determination that an individual is
genetically predisposed to developing MEN1 clinically) can also be made by
identifying a germline MEN1 mutation in an individual in whom the clinical
diagnosis of MEN1 is not clearly established or in an asymptomatic family
member who has not yet developed the serum biochemical or radiological
abnormalities associated with tumor development.
●Primary hyperparathyroidism – In most cases, multiple parathyroid
tumors causing primary hyperparathyroidism are the initial manifestation of
MEN1, and they are found in the large majority of patients by age 50 years
(table 1). Similar to sporadic adenomas causing primary
hyperparathyroidism, most patients are asymptomatic or minimally
symptomatic, and hypercalcemia is detected by routine (or surveillance-
based) biochemical screening. The biochemical diagnosis of primary
hyperparathyroidism is based, as it is in all patients with primary
hyperparathyroidism, upon the demonstration of hypercalcemia with
inappropriately high serum parathyroid hormone (PTH) concentrations.
(See 'Primary hyperparathyroidism' above.)
●Pituitary adenomas – The most common type of pituitary adenoma in
MEN1 is a lactotroph adenoma, but somatotroph, corticotroph, gonadotroph,
and clinically nonfunctioning adenomas can also occur. The approach to
241
diagnosis and therapy of pituitary adenomas in patients with MEN1 is similar
to that in patients with sporadic adenomas. (See 'Pituitary adenomas' above
and "Causes, presentation, and evaluation of sellar masses", section on
'Evaluation of a sellar mass'.)
●Pancreatic islet cell/gastrointestinal endocrine tumors – Functioning
pancreatic islet cell or gastrointestinal endocrine tumors become clinically
apparent in approximately one-third of patients with MEN1. The most
common cause of symptomatic disease is the Zollinger-Ellison (gastrinoma)
syndrome (ZES) (table 1). (See 'Pancreatic islet cell/gastrointestinal endocrine
tumors' above.)
●Screening of family members – DNA testing for MEN1 gene mutations is
available commercially and can provide valuable information in specific
situations, although its results generally do not dictate use of a major
intervention established to improve morbidity or mortality. We make
determinations regarding MEN1 DNA testing on a case-by-case basis, but
discussions with patient and genetic counselor more often than not lead to
pursuit of such testing. Biochemical screening (ie, serum calcium) of family
members can be considered as a less costly alternative to genetic screening,
given the high penetrance of primary hyperparathyroidism in MEN1,
although its negative predictive value at younger ages is limited. (See 'MEN1
mutational analysis' above and 'Screening of family members in MEN1
kindreds' above.)
●Monitoring for MEN-1 associated tumors – We carefully monitor all
patients with MEN1, known MEN1 mutation carriers, and at-risk family
members with unknown carrier status for symptoms or signs of MEN1-
associated tumors, such as nephrolithiasis, amenorrhea (women),
galactorrhea, erectile dysfunction (men), peptic ulcer disease, diarrhea, and
neuroglycopenic or sympathoadrenal symptoms from hypoglycemia. We
typically measure serum calcium, PTH, and prolactin annually to detect
asymptomatic hyperparathyroidism and prolactinoma, respectively. Often,
we perform additional surveillance using biochemical and imaging
modalities. Others routinely use more aggressive screening protocols for
MEN1-associated risks, beginning at very early ages. Differences in
approaches to surveillance in large part relate to the poor quality of
supportive evidence in this area. (See 'Monitoring for MEN1-associated
tumors' above.)

242
Multiple endocrine neoplasia type 1: Definition
and genetics
Author:
Andrew Arnold, MD
Section Editor:
Benjamin A Raby, MD, MPH
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Aug 30, 2021.
INTRODUCTIONThe multiple endocrine neoplasia (MEN) syndromes are rare,
but recognition is important both for treatment and for evaluation of family
members.
This topic will review the classification and genetics of the MEN type 1 (MEN1)
syndrome (OMIM ID #131100). The clinical manifestations, diagnosis, and therapy
of MEN type 1 and the MEN type 2 (MEN2) syndromes are discussed separately.
(See "Multiple endocrine neoplasia type 1: Clinical manifestations and
diagnosis" and "Multiple endocrine neoplasia type 1:
Treatment" and "Classification and genetics of multiple endocrine neoplasia type
2" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type
2" and "Approach to therapy in multiple endocrine neoplasia type 2".)
DEFINITIONMultiple endocrine neoplasia type 1 (MEN1) is a rare heritable
disorder classically characterized by a predisposition to tumors of the parathyroid
glands, anterior pituitary, and pancreatic islet cells (table 1) [1,2]. The presence of
MEN1 is defined clinically as the occurrence of two or more primary MEN1 tumor
types, or in family members of a patient with a clinical diagnosis of MEN1, the
occurrence of one of the MEN1-associated tumors. Multiple parathyroid tumors
causing primary hyperparathyroidism are the most common component of MEN1,
occurring in the large majority of patients by age 50 years, and is the initial
manifestation of the disorder in most patients [2-4]. In one series of 220 patients
with MEN1, parathyroid, pituitary glands, and pancreatic islet cell tumors occurred
in 95, 30, and 41 percent of affected patients, respectively [3].
The prevalence of MEN1 is approximately 2 per 100,000 [2]. The incidence ranges
from 1 to 18, 16 to 38, and less than 3 percent in patients with parathyroid
adenomas, gastrinomas, and pituitary adenomas, respectively [1].

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Patients with MEN1 may have tumors other than those in the parathyroid and
pituitary, and pancreatic islet cells. The duodenum is a common site of tumors
(gastrinomas) in these patients, and thymic or bronchial carcinoid tumors,
enterochromaffin cell-like gastric tumors, adrenocortical adenomas, and lipomas
are more frequent than in the general population. Other associated tumors
include angiofibromas, angiomyolipomas, spinal cord ependymomas (table 1), and
an increased risk of breast cancer has been reported [5].
GENETICS
MEN1 gene — The inheritance of classical multiple endocrine neoplasia type 1
(MEN1) follows an autosomal dominant pattern, indicating that Mendelian
inheritance of a single mutant gene is responsible for transmitting the tumor
predisposition within a given family. In 1988, genetic linkage analysis implicated a
region on the long arm of chromosome 11 (11q13) as the site of the "MEN1 gene"
[6]. A decade later, the critical gene in this region was identified, given the gene
symbol designation MEN1, and its protein product termed "menin" [7]. Across
multiple studies, mutations in the MEN1 gene have been detected in 70 to 90
percent of unrelated MEN1 kindreds [8-11], although this figure is variable across
studies and is sensitive to the mode of case selection. It has been reasonably
hypothesized that most typical MEN1 kindreds without detectable MEN1 gene
mutations nonetheless have inactivating germline mutations in (or near and in
"cis" with) the same gene but outside the coding region that is typically sequenced
in diagnostic and research labs. Somatic mosaicism of pathogenic MEN1 mutations
in tumor-prone tissues could be occurring in some cases as well. However, it is
clear that mutations in the MEN1 gene are not responsible for all individuals, or
even kindreds, with an MEN1 phenotype (see 'Other genes' below). Furthermore,
rare phenocopies have been reported, ie, individuals within MEN1 kindreds who
were initially classified as having the syndrome when they developed a typical
tumor (eg, prolactinoma) but were then proven by DNA testing to have not
inherited the pathologic mutation [12].
Much has been learned about the biochemical and cellular functions of menin, but
the precise way(s) in which these functions relate to tumorigenesis is still not well
established. However, it is clear that most of the pathogenic MEN1 gene mutations
found in MEN1 patients would be expected to inactivate or disrupt menin function.
Typical of a classical tumor suppressor gene, the spectrum of reported
germline MEN1 mutations occur throughout the gene and yield no strong
genotype/phenotype relationships [11]. The genotype-phenotype correlations are
often unclear, even within a family [13]. In addition, biallelic somatic mutations
within this gene have been found in 12 to 17 percent of typical nonfamilial
parathyroid adenomas [14-16] and some sporadic gastrinomas and insulinomas
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[17], sporadic neuroendocrine tumors of the foregut [18], sporadic carcinoid
tumors of the lung [19], and sporadic pituitary tumors [20], further supporting the
relationship between the mutations and tumorigenesis (see "Pathogenesis and
etiology of primary hyperparathyroidism"). However, the large majority of non-
MEN1-associated pituitary tumors, whether sporadic or familial, do not have
an MEN1 mutation [21,22].
Other genes — Syndromes clinically related to but genetically distinct from MEN1
do exist. At least one family with an unusual expression of MEN1 (eg, a lower than
expected incidence of hyperparathyroidism and higher than expected incidence of
pituitary tumors) was reported to have a predisposing gene at a location distinct
from the chromosome 11q13 site [23,24]. Germline AIP mutation, in the absence
of MEN1 gene mutation, has been reported in the setting of pituitary plus
parathyroid neoplasia [25]. Furthermore, mutations in the MEN1 gene are
infrequent in kindreds with familial isolated hyperparathyroidism [26,27] and were
not found in three kindreds with familial pituitary adenoma [28] and one with
isolated familial acromegaly [29].
Cyclin-dependent kinase inhibitor genes — An inherited mutation of the p27
cyclin-dependent kinase (CDK) inhibitor gene, CDKN1B, was reported in one
kindred whose proband had hyperparathyroidism and acromegaly due to a
growth hormone-producing pituitary tumor; the proband's father had acromegaly,
and the sister had a renal angiomyolipoma [30]. Germline CDKN1B mutation was
also reported in a few other cases of MEN1 that collectively exhibited features
including hyperparathyroidism, Cushing's disease, cervical carcinoid tumor,
bilateral nonfunctioning adrenal masses, and Zollinger-Ellison syndrome with
duodenal and pancreatic masses [31,32]. MEN1-like disease caused by
germline CDKN1B mutation has been termed MEN4 (OMIM ID #610755) and may
account for 1 to 3 percent of unrelated MEN1-like cases without
identifiable MEN1 mutations [32-34].
Rare germline mutations in three other CDK inhibitor genes, CDKN2B, CDKN2C,
and CDKN1A, encoding the p15, p18, and p21 proteins, respectively, have also been
identified in this setting and may collectively account for another 1 to 2 percent of
MEN1-like cases without detectable MEN1 mutations [32].
Overall, because patients presenting with the combination of sporadic parathyroid
plus pituitary tumor have a much lower yield of detectable MEN1 mutation than in
typical MEN1 kindreds or in sporadic cases of parathyroid plus pancreatic tumor
[35], it seems likely that this phenotype may often be due to mutation in a gene
other than MEN1, or possibly the coincidental presence of sporadic tumors absent
any major genetic predisposition. However, as noted above, the extent to which
mutation in CDKN1B or other CDK inhibitor genes is responsible for MEN1-like

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phenotypes, sporadic or familial, in the absence of MEN1 mutation appears to be
small [32,34,36].
DNA testing — Direct DNA testing for MEN1 mutation is available for clinical use,
has a useful role in certain settings, and should be considered on an individual
basis [1]. However, in contrast to testing for RET gene mutations in MEN2,
presymptomatic DNA diagnosis has not been shown to yield equally clear benefit
in preventing morbidity and mortality in individuals at risk for MEN1. (See "Multiple
endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on
'MEN1 mutational analysis' and "Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2", section on 'Evaluation'.)
PATHOGENESISPatients with classical multiple endocrine neoplasia type 1
(MEN1) have often inherited one inactivated copy of the MEN1 gene from an
affected parent [7,9]. The actual outgrowth of a tumor is thought to require the
subsequent somatic inactivation, often by gross deletion, of the remaining normal
copy of the gene in one cell (so-called "two-hit" effect described by Knudson). Such
a parathyroid cell, as an example, would then be devoid of the MEN1 gene's
normal tumor suppressor function, and could gain a selective advantage over its
neighbors, resulting in a clonal proliferation (figure 1). The high incidence of
endocrine tumors in MEN1 (which has over 90 percent penetrance) and the
common multiplicity of these tumors implies that somatic inactivation of the
remaining normal copy of the gene occurs at an appreciable frequency and
contributes importantly to tumorigenesis in the clinically affected tissues. This
model also appears to apply to some of the nonendocrine tumors that occur in
patients with MEN1.
Further functional studies of the MEN1 gene and its product are certain to shed
light on these processes. In addition, the identification and analysis of other genes
whose somatic alteration is also important in the emergence of clonal tumors in
this syndrome should further clarify the relationship between genotype and
phenotype in MEN1.
SUMMARY
●Definition – Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal
dominant disorder with a prevalence of approximately 2 per 100,000. MEN1
is defined clinically as the presence of two of the three main MEN1 tumor
types (parathyroid, enteropancreatic endocrine, and pituitary tumors), or in
family members of a patient with a clinical diagnosis of MEN1, the occurrence
of one of the MEN1-associated tumors. In addition, patients with MEN1 may
have tumors other than those in the parathyroid, pituitary glands, and in the
pancreatic islet cells, including duodenal gastrinomas, thymic or bronchial
carcinoid tumors, enterochromaffin cell-like gastric tumors, adrenocortical
246
adenomas, lipomas, angiofibromas, angiomyolipomas, and spinal cord
ependymomas (table 1). (See 'Definition' above.)
●MEN1 gene – The MEN1 tumor suppressor gene is located on the long arm
of chromosome 11 (11q13). Its protein product is termed "menin." Over
1000 MEN1 gene mutations have been detected that inactivate or disrupt
menin function. Inactivation of menin results in loss of tumor suppression.
Families with the same types of mutations do not necessarily have the same
clinical phenotype. (See 'MEN1 gene' above.)
●Other genes – Syndromes clinically related to but genetically distinct from
MEN1 do exist, and mutations in the MEN1 gene are not responsible for all
individuals, or even kindreds, with an MEN1 phenotype. (See 'Other
genes' above.)

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Multiple endocrine neoplasia type 1: Treatment
Author:
Andrew Arnold, MD
Section Editor:
Peter J Snyder, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: May 18, 2021.
INTRODUCTIONMultiple endocrine neoplasia type 1 (MEN1) is an autosomal
dominant disorder classically characterized by predisposition to tumors of the
parathyroid glands (which occur in the large majority of patients by age 50 years),
anterior pituitary, and pancreatic islet cells (table 1). MEN1 also includes a
predisposition to gastrinomas in the duodenum, carcinoids, adrenal adenomas,
angiofibromas, lipomas, and other tumors (table 2). The most common types of
tumors in MEN1 are generally benign, but malignancy of some carcinoid, islet cell,
and gastrointestinal tract tumors are important causes of mortality in MEN1.
Treatment of MEN1 can differ markedly from that of more common sporadic
forms of the relevant endocrine tumors, and referral to centers with major
experience and multidisciplinary expertise in MEN1 is strongly recommended.
This topic will review the treatment of MEN1. The classification, genetics, clinical
manifestations, and diagnosis are reviewed separately. (See "Multiple endocrine
neoplasia type 1: Definition and genetics" and "Multiple endocrine neoplasia type
1: Clinical manifestations and diagnosis".)
PARATHYROID TUMORSMultiple parathyroid tumors causing primary
hyperparathyroidism are the most common manifestation of MEN1, with over 90
percent penetrance by age 50 to 70 years [1-3]. Pathologic hypercellularity of
multiple glands is common in these patients and, given sufficient time, perhaps
universal. Patients with classical MEN1 are at high risk of recurrent
hyperparathyroidism after apparently successful subtotal parathyroidectomy.
Indications for surgery — Once the biochemical diagnosis of primary
hyperparathyroidism is confirmed in a patient with known or presumed MEN1, the
indications for surgical intervention are similar to those in patients with sporadic
primary hyperparathyroidism. These include symptomatic or marked
hypercalcemia, nephrolithiasis, and evidence of bone disease such as diminished
bone density or fracture [4]. Bone density of the lumbar spine and hip can improve
after parathyroidectomy in patients with hyperparathyroidism associated with
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MEN1, as it does in patients with sporadic hyperparathyroidism [5] or perhaps to a
lesser degree [6]. (See "Primary hyperparathyroidism: Management", section on
'Candidates for surgery'.)
An additional indication for parathyroidectomy in patients with MEN1 is the
presence of severe peptic ulcer disease or other symptoms caused by a
gastrinoma (the Zollinger-Ellison syndrome) that are difficult to control with
medications. Hypercalcemia typically worsens hypergastrinemia, and
parathyroidectomy may markedly reduce gastrin secretion in patients with a
gastrinoma [7,8]. The typical high success of pharmacologic therapy for
hypergastrinemia makes this a rare indication for operation.
Management of asymptomatic disease — Surgery or no therapy can be
acceptable alternatives for patients with MEN1 who have asymptomatic or
minimally symptomatic hyperparathyroidism, as they are for patients with
sporadic hyperparathyroidism (see "Primary hyperparathyroidism: Management").
Whether early treatment of hyperparathyroidism reduces mortality or morbidity in
patients with MEN1 is not known, but many clinicians lean toward surgery in
young patients because of their long life expectancy (and years at risk for
developing bone disease). In addition, kidney function has been reported to
improve after parathyroidectomy in MEN1 patients with hyperparathyroidism and
reduced glomerular filtration rate [9]. On the other hand, other clinicians defer
surgery as long as possible, in the hope that fewer operations for recurrent
hyperparathyroidism (which may be more difficult than the initial surgery) will be
needed during the patient's lifetime.
The clinician's threshold for recommending surgery for patients with
asymptomatic hyperparathyroidism bears importantly on the decision to screen
asymptomatic persons at risk (see "Multiple endocrine neoplasia type 1: Clinical
manifestations and diagnosis", section on 'Screening of family members in MEN1
kindreds'). Such decisions must also take into account the level of surgical
expertise available at one's institution, an important consideration because of the
likelihood of recurrent hyperparathyroidism and need for another operation in the
future.
We tend to defer surgery in young MEN1 patients with asymptomatic
hyperparathyroidism who lack any specific indications for surgery, such as
nephrolithiasis. In such patients, periodic monitoring should be performed for
disease progression and development of indications for surgery. (See "Primary
hyperparathyroidism: Management", section on 'Monitoring'.)
We do, however, tend to recommend surgery for asymptomatic patients with
reduced bone density or declining renal function for the reasons mentioned above
and, therefore, find it reasonable to regularly screen individuals with MEN1 for

249
biochemical hyperparathyroidism. (See "Multiple endocrine neoplasia type 1:
Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated
tumors'.)
Preoperative localization — Most patients with MEN1 have multiple parathyroid
tumors so bilateral exploration of previously unoperated patients should be
planned, regardless of the outcome of preoperative localization studies, such as
ultrasonography, sestamibi imaging, or four-dimensional (4D)-computed
tomography (CT). However, the surgeon may find these studies to be anatomically
helpful and may therefore order them. We recommend localization studies before
reoperation in patients with recurrent or persistent disease. (See "Preoperative
localization for parathyroid surgery in patients with primary
hyperparathyroidism".)
Surgical approach — In observational studies, persistent disease is more
common among patients who were treated with less than subtotal
parathyroidectomy [2,8,10-13]. Thus, for patients with MEN1 and indications for
parathyroidectomy, we generally recommend subtotal (three and one-half gland)
parathyroidectomy rather than removal of fewer glands.
Still, patients with classical MEN1 are at high risk of recurrent hyperparathyroidism
after initially successful subtotal parathyroidectomy; this finding reflects the strong
and seemingly inexorable proliferative drive in parathyroid cells in this disorder.
One report from the National Institutes of Health, for example, found a recurrence
rate of greater than 50 percent at 12 years [1]; in another report, the recurrence
rate was 67 percent at eight years [14].

Bilateral neck exploration should be performed to attempt to find all glands in

patients with known or suspected MEN1. The optimum extent of the
parathyroidectomy procedure remains controversial. Some favor a more extensive
procedure to reduce the risk of persistent or recurrent disease, while others favor
a less extensive procedure to decrease the risk of hypoparathyroidism:

●Most commonly, initial surgery is subtotal parathyroidectomy, involving

removal of three and one-half parathyroid glands (or all but one-half gland, if
supernumerary glands are found), together with thymectomy. Surgery is
repeated if hypercalcemia and specific indications recur [2,15-17].
●A more aggressive initial surgical approach involves complete
parathyroidectomy and placement of a small parathyroid autograft in the
muscles of the forearm or neck [18-21]. Recurrent hyperparathyroidism due
to growth of the autograft can then be treated by graft removal under local
anesthesia. If, however, the autograft does not function, the patient may

250
 have the extremely undesirable outcome of long-term or permanent
hypoparathyroidism.
There are no randomized trials comparing the two approaches. In a review of 18
reports of 2 to 73 patients with MEN1 followed for 4 to 12 years after subtotal
parathyroidectomy (three and one-half glands resected) with or without cervical
thymectomy, persistent hyperparathyroidism was reported in 0 to 33 percent,
recurrent hyperparathyroidism in 0 to 36 percent, and persistent
hypoparathyroidism in 0 to 35 percent [10]. In the same review, there were 10
reports of 4 to 36 patients with MEN1 who had complete parathyroidectomy with
cervical thymectomy and autologous placement of a small parathyroid autograft.
After a mean follow-up of 6 to 10 years, persistent hyperparathyroidism was
reported in 0 to 3 percent, recurrent hyperparathyroidism in 0 to 55 percent, and
hypoparathyroidism in 0 to 46 percent. In these observational studies, the more
aggressive approach was associated with lower rates of persistent
hyperparathyroidism but higher rates of hypoparathyroidism.
When performed by a surgeon who has extensive experience in either approach,
as surgery for MEN1 patients should be, results should be good and complication
rates low [22]. Overall, however, we view subtotal parathyroidectomy as the
generally preferable approach in large part because of its lesser likelihood of
causing long-term hypoparathyroidism [2,17].
Cervically accessible thymectomy during initial parathyroidectomy in MEN1 is
generally recommended, acknowledging that high-quality evidence from
randomized trials is lacking [17,23-25]. The rationales for thymectomy relate to the
substantial frequency with which intrathymic parathyroid tissue is found as a
present or future source of pathologic parathyroid hormone (PTH) production [23],
and to the risk in MEN1 for developing thymic carcinoid, a rare but often-
aggressive tumor [24]. Since only part of the thymus is accessible cervically, this
measure will not completely neutralize these risks. Still, we think the expected
benefit of preventing some thymic carcinoids and lessening the risk of recurrent
hyperparathyroidism outweighs the potential risk of this procedure in the hands of
an expert surgeon, so we generally favor thymectomy in this setting [22,26].
Medical management — Calcimimetic agents (eg, cinacalcet) activate the calcium-
sensing receptor in the parathyroid gland, thereby inhibiting PTH secretion.
Although not typically used in the United States for the treatment of sporadic
benign primary hyperparathyroidism, cinacalcet reduces serum calcium in the
majority of affected patients. (See "Primary hyperparathyroidism: Management",
section on 'Calcimimetics'.)
Cinacalcet also appears to decrease the serum calcium concentration in patients
with primary hyperparathyroidism due to MEN1 [27], although the data are

251
limited. In a case report of a patient with MEN1 and recurrent
hyperparathyroidism five years after parathyroidectomy, treatment with cinacalcet
reduced serum calcium and PTH levels to normal [28]. During one year of
treatment, levels remained normal. Similarly, in a one-year study of MEN1-
associated hyperparathyroidism, cinacalcet reduced serum calcium levels (but not
PTH) and was generally well tolerated; bone mineral density (BMD) at the spine
and femur (no distal radius data) were unchanged, as was urinary calcium
excretion [29]. Thus, cinacalcet may be beneficial for patients with MEN1 and
recurrent symptomatic primary hyperparathyroidism who are not candidates for
or refuse repeated surgical procedures. However, there are no long-term data
evaluating the effect of cinacalcet on clinically important outcomes (eg, bone
density, fracture, nephrolithiasis, mortality) in patients with MEN1.
PITUITARY ADENOMASApproximately 15 to 20 percent of patients with
MEN1 have clinically apparent pituitary adenomas, or approximately 40 percent if
one includes microadenomas detected via systematic screening of asymptomatic
individuals [30]. The characteristics of these adenomas in terms of hormonal
activity and other features are similar to those in patients with sporadic pituitary
adenomas. The most common pituitary adenoma in MEN1 is a lactotroph
adenoma, but all other types of adenomas can occur (table 1). Multiple pituitary
tumors are rarely present in MEN1. (See "Multiple endocrine neoplasia type 1:
Clinical manifestations and diagnosis".)
Individuals with MEN1 who have pituitary adenomas should generally be treated
in the same way as patients with sporadic adenomas [2,17]. (See "Management of
hyperprolactinemia" and "Treatment of gonadotroph and other clinically
nonfunctioning adenomas" and "Primary therapy of Cushing's disease:
Transsphenoidal surgery and pituitary irradiation" and "Treatment of
acromegaly".)
PANCREATIC ISLET CELL/GASTROINTESTINAL TUMORSBecause of
the efficacy of therapy for hyperparathyroidism and pituitary tumors in patients in
MEN1, malignant pancreatic islet cell and gastrointestinal tumors are the primary
life-threatening components of the disorder. Endocrine cell tumors at these sites
become clinically apparent in approximately one-third of patients with MEN1.
However, subclinical involvement is more common; anatomic or intensive
biochemical studies reveal evidence of pancreatic tumors in up to 80 percent of
patients with MEN1.

The most common cause of symptoms is the Zollinger-Ellison (gastrinoma)

syndrome. Approximately 40 percent of patients with MEN1 have either the
Zollinger-Ellison syndrome or asymptomatic elevation in serum gastrin
252
concentrations. Symptomatic insulinomas are also fairly common, but tumors that
are symptomatic due to secretion of vasoactive-intestinal polypeptide, glucagon,
or pancreatic polypeptide are rare. Given the complexity of decision-making and
specialized skills needed for treating duodenopancreatic endocrine tumors in
MEN1, it is strongly recommended that this be done in centers with established
multidisciplinary teams experienced in the care of MEN1 patients.

Zollinger-Ellison syndrome
General therapeutic considerations — Early attempts to treat the Zollinger-
Ellison syndrome surgically in patients with MEN1 involved resection of palpable
tumors or partial pancreatectomy, but historically, this approach typically failed to
cure the hypersecretion of gastrin [31,32]. The recognition that patients with MEN1
often have small, multifocal tumors in the duodenum, not infrequently
accompanied by lymph node metastases [33,34], is consistent with these failures
and led to reexamination of the role of surgery. In a controversial area with a
dearth of prospective studies to provide guidance, some surgeons are less inclined
to operate, while some now regularly operate on MEN1 patients with the Zollinger-
Ellison syndrome that persists after correction of hyperparathyroidism or if
imaged tumors in the pancreaticoduodenal region exceed a certain size threshold
(eg, 2 cm) [34-38]. If surgery is undertaken, one recommended approach includes
duodenotomy and resection of detectable duodenal wall tumors, often preceded
by endoscopic ultrasound or accompanied by intraoperative ultrasonography,
combined with subtotal/distal pancreatectomy and enucleation of tumors in the
pancreatic head [39-41]. Even more aggressive resections, with increased risk of
short- and long-term complications, are sometimes performed, subject to
modification based upon the individual situation, including complete
pancreatoduodenectomy, eg, in the setting of large pancreatic head tumors
[2,17,36,42].
Given the impressive efficacy of proton pump blockers in controlling symptoms
and the fact that surgery for primary gastrinoma in MEN1 is unlikely to result in
cure [43], the primary benefit to be sought from surgery is a decrease in mortality
from metastatic gastrinoma. While results of modern surgical approaches seem
promising [38,39,41,44-46], longer follow-up studies are needed because the
likelihood of developing hepatic metastases and death may be low even in
unoperated patients [34,41]. Currently, no definitive evidence exists that surgery
decreases the mortality of the disease in MEN1 or the likelihood that clinically
important metastases will develop, although nonrandomized evidence suggests
that it may [35].

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Pharmacologic treatment — Medical therapy for patients with a MEN1-
associated gastrinoma is administration of a proton pump inhibitor, such
as omeprazole or lansoprazole (see "Management and prognosis of the Zollinger-
Ellison syndrome (gastrinoma)"). When given once or twice daily, these drugs
effectively inhibit acid secretion and relieve acid-peptic symptoms in these patients
for prolonged periods [38,47]. A nine-year prospective study of the safety and
efficacy of omeprazole revealed no tachyphylaxis or important toxicity [48].
Surgery — The question of whether or not to recommend duodenal-pancreatic
surgery in patients with MEN1 who have pharmacologically controllable Zollinger-
Ellison syndrome and no other clinically evident hormonal excess syndrome or
imaged tumors is an especially difficult one. Because clinical outcome data are not
definitive, we extensively discuss potential advantages and risks of both options
with the patient. While we do not strongly advocate for surgery, we do not
discourage a patient who wishes to have surgery for MEN1-associated Zollinger-
Ellison syndrome, as long as the individual recognizes that solid proof of improved
mortality is lacking and the surgeon is experienced and knowledgeable.
Furthermore, if such a patient requires abdominal surgery for another reason
(such as insulinoma), it seems appropriate to include duodenotomy in the
procedure.
For patients with pharmacologically controlled Zollinger-Ellison who do not have
surgery, we monitor symptoms and perform periodic imaging studies (computed
tomography [CT]/magnetic resonance imaging [MRI], endoscopic ultrasound
[EUS]), with a preference toward minimizing radiation exposure in younger
patients. As clinicians who favor pancreaticoduodenal surgery when a tumor
exceeds the often used 2-cm size threshold, we generally use published guidance
[4] for their timing, but it should be kept in mind that data favoring the use of such
specific triggers in improving outcomes (eg, preventing metastases, mortality) are
very limited [34,38].
The best course for patients with hepatic metastases is unclear, and multiple
options exist. The considerations are very similar to those with non-MEN1
advanced gastroenteropancreatic endocrine tumors, discussed in detail elsewhere.
(See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)",
section on 'Therapy of metastatic disease' and "Metastatic well-differentiated
gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging,
and biochemical monitoring".)
Insulinoma — Approximately 10 percent of patients with MEN1 have an
insulinoma (table 2). Approximately 4 to 10 percent of patients with insulinomas
have MEN1, and in most, but not all, the MEN1 is known or suspected. Treatment
is complicated by the possible presence of multiple insulinomas and/or other

254
pancreatic neuroendocrine tumors, the likelihood that preoperative or
intraoperative localization techniques may miss small tumors, and the continuing
risk for pancreatic tumors after surgery. As a result, some experienced surgeons
recommend excision of any tumors found in the head of the pancreas plus a distal
subtotal pancreatectomy [49]. This approach differs from that in patients with
sporadic insulinomas, who typically have a solitary tumor and in whom localization
and local excision alone are usually successful. Functional techniques for
preoperatively distinguishing an insulinoma from other pancreatic lesions are
under investigation, notably use of 68-Ga-exendin 4 positron emission
tomography (PET)/computed tomography (CT) imaging, which exploits the high-
density expression of the glucagon-like peptide 1 (GLP-1) receptor in benign
insulinomas [17,50]. (See "Insulinoma".)
Clinically nonfunctional pancreatic endocrine tumors — In the absence of
metastatic disease, the management of nonfunctional pancreatic neuroendocrine
tumors in MEN1 is controversial [2,17]. In an emerging consensus (albeit not based
on randomized, controlled approaches), many experienced clinicians have been
using a tumor size threshold of 2 cm in the decision to surgically resect the lesions
[51-53], and corresponding surveillance recommendations have been made [4,54-
58]. Generally speaking, tumors under 1 cm appear to have a very low risk for
substantial growth and metastasis, and avoiding surgery with continued
surveillance seems reasonable. Again, we try to individualize surveillance protocols
to minimize lifetime radiation exposure in younger individuals. Available data offer
less guidance for tumors between 1 to 2 cm size. Clearly, further study of risks,
benefits, and alternative approaches would benefit the field [53,59,60].
PROGNOSISThe long-term mortality of patients with MEN1 is increased
compared with the general population or unaffected members of their families
[2,17,61]. In a retrospective review of 233 patients with MEN1 treated at the Mayo
Clinic, the overall 20-year survival of MEN1 patients was significantly lower than
that of an age, sex, and geographically matched-population (64 versus 81 percent)
[62]. Among those in whom a cause of death could be reliably obtained (60 of 69
patients), 28 percent died of causes related to MEN1, most commonly metastatic
islet cell tumors. Similarly, in European populations, the mean ages at death for
patients with MEN1 was significantly lower than in the average population [63].
Compared with nonaffected patients, those with thymic tumors and
duodenopancreatic neuroendocrine or nonfunctioning tumors had a higher risk of
death [64]. Because effective treatment is available for hyperparathyroidism and
pituitary disease in MEN1, the malignant potential of pancreatic endocrine tumors
and carcinoids are the primary life-threatening manifestations of MEN1. These
tumors are often present at initial assessment [24,65]. Whether earlier detection
255
through radiographic screening improves mortality remains uncertain [38].
(See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis",
section on 'Monitoring for MEN1-associated tumors'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●The indications for parathyroidectomy in patients with multiple endocrine
neoplasia type 1 (MEN1) are similar to those in patients with sporadic
adenomas causing primary hyperparathyroidism and include symptomatic
hypercalcemia, nephrolithiasis, and evidence of bone disease, such as
diminished bone density or fracture. (See 'Indications for surgery' above
and "Primary hyperparathyroidism: Management", section on 'Candidates for
surgery'.)
●For patients with MEN1 and indications for initial parathyroidectomy, we
typically recommend subtotal (three and one-half gland) parathyroidectomy
rather than removal of fewer glands (Grade 1B). We generally favor including
cervical thymectomy in this setting. Surgery should only be performed by
surgeons highly experienced in parathyroid surgery. (See 'Surgical
approach' above.)
●Pituitary adenomas in patients with MEN1 should be treated in the same
way as sporadic pituitary adenomas. (See "Management of
hyperprolactinemia" and "Treatment of acromegaly" and "Primary therapy of
Cushing's disease: Transsphenoidal surgery and pituitary
irradiation" and "Treatment of gonadotroph and other clinically
nonfunctioning adenomas".)
●Active Zollinger-Ellison syndrome as part of the MEN1 syndrome should be
treated primarily by proton pump therapy to limit the clinical manifestations
and complications of peptic ulcer disease. The role of duodenal-pancreatic
surgery to prevent metastatic disease is uncertain and controversial but
could prove beneficial and requires further study. (See 'Zollinger-Ellison
syndrome' above and "Management and prognosis of the Zollinger-Ellison
syndrome (gastrinoma)", section on 'Medical management'.)
●Surgery is indicated for patients with MEN1 and insulinoma. Because
patients with MEN1 often have additional pancreatic tumors that may include
other insulinomas, local excision of any tumors in the head of the pancreas
plus a distal subtotal pancreatectomy is frequently performed.
(See 'Insulinoma' above and "Insulinoma".)
256
●The management of metastatic gastroenteropancreatic neuroendocrine
tumors is reviewed separately. (See "Metastatic well-differentiated
gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis,
imaging, and biochemical monitoring" and "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control
tumor growth and symptoms of hormone hypersecretion".)

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Carcinoid heart disease
Author:
Heidi M Connolly, MD, FACC, FASE
Section Editor:
Catherine M Otto, MD
Deputy Editor:
Susan B Yeon, MD, JD, FACC
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 11, 2022.
INTRODUCTIONCarcinoid tumors are rare, arising in 1.2 to 2.1 per 100,000 people
in the general population per year [1]. They can arise anywhere in the body, but are
most commonly found in the gastrointestinal tract (midgut carcinoids) and bronchus
(foregut carcinoids) (table 1). Primary midgut carcinoid tumors metastasize to the liver
or regional lymph nodes and may present with bowel obstruction. In 20 to 30 percent of
patients, the initial presentation occurs as a result of hormone production, called the
carcinoid syndrome. (See "Clinical characteristics of well-differentiated neuroendocrine
(carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
The most common manifestations of the carcinoid syndrome are vasomotor changes
(flushing) (picture 1), gastrointestinal hypermotility (secretory diarrhea), bronchospasm,
and hypotension (table 2). These symptoms are caused by the release of vasoactive
substances, including serotonin (5-hydroxytryptamine), 5-hydroxytryptophan, histamine,
bradykinin, tachykinins, and prostaglandins (table 3). The diagnosis of carcinoid
syndrome is usually suspected by the clinical features and confirmed by identification of
the primary tumor, localization of metastatic lesions, and detection of increased urinary
excretion of the by-product of serotonin metabolism, 5-hydroxyindoleacetic acid (5-
HIAA) (figure 1). (See "Clinical features of carcinoid syndrome" and "Diagnosis of
carcinoid syndrome and tumor localization".)
Progress in the medical and surgical management of patients with carcinoid disease
has resulted in improved symptoms and survival. (See "Staging, treatment, and post-
treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract
neuroendocrine (carcinoid) tumors".)
However, carcinoid heart disease, which eventually occurs in up to 50 percent of
patients with carcinoid syndrome and may be the initial presentation of carcinoid
disease in as many as 20 percent of patients [2,3], remains a major cause of morbidity
and mortality among patients with carcinoid syndrome [4,5].
PATHOPHYSIOLOGY
Pathologic findings — Carcinoid heart disease is characterized by pathognomonic
plaque-like deposits of fibrous tissue. These deposits occur most commonly on the
endocardium of valvular cusps, leaflets, papillary muscles and cords, cardiac chambers,
and occasionally on the intima of the pulmonary arteries or aorta (figure 2) [6,7].
The affected cardiac valves in carcinoid heart disease have a white appearance with
thickened leaflets and subvalvular apparatus with fused and shortened chordae and
thickened papillary muscles [8]. Microscopic examination demonstrates deposits of
fibrous tissue. The carcinoid plaque is composed of smooth muscle cells,
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myofibroblasts, and an overlying endothelial cell layer. Smooth muscle cells and
myofibroblasts are surrounded by an extracellular matrix composed of microfibrils, acid
mucopolysaccharides, basement membrane, and collagen fibers [7]. The morphology of
the valve leaflet is not disrupted and the carcinoid plaque generally affects the
ventricular aspect of the tricuspid valve leaflets and the arterial aspect of the pulmonic
valve cusps [6,9].
The valves and endocardium of the right side of the heart are most often affected by
carcinoid disease [2,3]; it is postulated that the left-sided valves are usually spared due
to inactivation of humoral substances by the lung (picture 2). Carcinoid plaques are
observed along either endocardial surface of the tricuspid leaflets with alterations
ranging from mild disease (stiff thickened leaflets with trivial or mild tricuspid
regurgitation) to severe disease (fixed, retracted leaflets with severe tricuspid
regurgitation with or without accompanying mild or moderate tricuspid stenosis) [8].
Carcinoid plaques also commonly affect the pulmonic valve (particularly the arterial
aspect) with consequent regurgitation, stenosis, or both. In patients with advanced
disease, carcinoid plaque may also involve the endocardial lining of the right heart
chambers.
Left-sided valvular pathology occurs in less than 10 percent of patients with cardiac
involvement [2]. It is almost always associated with an atrial level right-to-left shunt (as
with a patent foramen ovale) [2,8,10,11]. These conditions permit serotonin-rich blood to
enter the left heart chambers without passing through the pulmonary capillaries. The
degree of right-to-left shunting may correlate with the degree of valve involvement and
associated valve regurgitation [8]. Infrequently, left-sided valve disease occurs in
patients without a right-to-left shunt. This is usually related to severe, poorly controlled
carcinoid syndrome with high levels of circulating serotonin. Carcinoid valve disease
affecting the aortic or mitral valve generally manifests as valve thickening and pure
regurgitation [7].
An additional rare cardiac complication is metastasis to the heart, identified by
echocardiography in 2 (4 percent) of 252 patients with carcinoid syndrome in one series
[8]. In a review of 11 such patients, the small bowel was the source of the primary tumor
in nine and all had the carcinoid syndrome and hepatic metastases [4]. Transthoracic
echocardiography detected nine tumors ≥1 cm in size in 5 of 11 patients, revealing a
well circumscribed, noninfiltrating, and homogeneous mass.
Role of serotonin — Evidence suggests a role for serotonin in the pathogenesis of
carcinoid heart disease. Alterations in serotonin metabolism, its associated receptors,
and transporter gene have been proposed as likely mechanisms for development of
carcinoid related valvular heart disease [12,13]. It is thought that high circulating
serotonin concentration is the major effector of carcinoid heart disease and of the
similar valve lesions that may be induced by the ergot-alkaloid derivatives, the anorectic
drugs fenfluramine (alone or in combination with phentermine) and dexfenfluramine and
the dopamine receptor agonist pergolide and cabergoline used for Parkinson's disease.
The data supporting the role of serotonin in the pathogenesis of valve disease are
presented elsewhere. (See "Valvular heart disease induced by drugs", section on
'Pathogenesis'.)
In nearly all patients with carcinoid syndrome, tryptophan metabolism is altered so that
70 percent or more of dietary tryptophan is converted to serotonin, as compared with

259
approximately 1 percent in normal subjects. Serotonin is metabolized to 5-
hydroxyindoleacetic acid (HIAA) (figure 1). (See "Clinical features of carcinoid
syndrome", section on 'Tryptophan metabolism'.)
Indirect evidence in support of the role of serotonin in the carcinoid syndrome in
humans comes from a study that compared 19 patients with carcinoid heart disease
(diagnosed by echocardiography or cardiac catheterization) with 585 carcinoid patients
without heart disease [14]. The patients with heart disease had much higher (two- to
fourfold) values for serum and plasma serotonin, platelet serotonin, and urinary 5-HIAA
excretion. They were also three times as likely to have typical carcinoid symptoms.
Similarly, in a report in 23 patients with carcinoid syndrome, urinary 5-HIAA values
averaged 356 mg/day in those with heart disease compared with only 99 mg/day in
those without cardiac involvement [15].
Urinary 5-HIAA excretion may also predict progression of carcinoid heart disease. In a
report from Mayo Clinic, which included 71 patients in whom serial echocardiograms
were performed more than one year apart, a "cardiac score" was developed to define
the severity of cardiac involvement (including grading scales for tricuspid and pulmonic
valve abnormalities as well as right ventricular size and function). Urinary 5-HIAA levels
were significantly higher in those with a >25 percent increase in cardiac score than in
those with lesser evidence of progression (265 versus 189 mg/day) [16].
Liver disease, usually due to hepatic metastases, is thought to play a permissive role by
allowing large quantities of tumor products such as serotonin to reach the right heart
without being inactivated [17,18]. Rarely, patients with a primary ovarian carcinoid
develop carcinoid heart disease in the absence of hepatic metastases because the liver
is bypassed by direct venous drainage of the ovary into the inferior vena cava [19,20].
Despite the likely pathogenic link between serotonin and carcinoid heart disease, it is
not known if medical therapy to reduce serotonin secretion can prevent the
development of cardiac lesions. In an uncontrolled observational series, patients treated
with somatostatin analogs, which decrease serotonin secretion, did not demonstrate
absent or delayed development of valve disease. (See 'Treatment of carcinoid
syndrome' below.)
CLINICAL MANIFESTATIONS
Symptoms — The clinical manifestations of carcinoid heart disease are often subtle
early in the course of the disease. In addition, moderate to severe tricuspid and
pulmonary valve disease may be well tolerated for many months. Early symptoms of
right-sided valvular heart disease include fatigue and dyspnea on exertion. Right-sided
heart failure with worsening dyspnea, edema, ascites, and eventual cardiac cachexia
occur with progressive disease.
Physical examination — The major findings on physical examination include an
elevated jugular venous pressure with a prominent "v" wave; this is often the earliest
clinical finding (see "Examination of the jugular venous pulse"). Additional clinical
features include a palpable right ventricular impulse, and murmurs of tricuspid and
pulmonic valve regurgitation [21]. Less frequently, a systolic murmur of pulmonary
stenosis or a diastolic murmur of tricuspid stenosis is audible. Right-sided cardiac
murmurs are accentuated by inspiration. (See "Auscultation of cardiac murmurs in
adults".)

260
The auscultatory findings may be subtle, as the murmurs of tricuspid and pulmonary
valve disease may be difficult to detect due to the low pressure in the pulmonary
circulation. As an example, the murmur of pulmonic regurgitation in the absence of
pulmonary hypertension does not have the high-pitched, blowing quality heard with
higher pulmonary pressures.

As the valve disease progresses, the physical features generally become readily
apparent with progressive peripheral edema, ascites, and pulsatile hepatomegaly.
(See "Etiology, clinical features, and evaluation of tricuspid regurgitation".)

Aggressive metastatic carcinoid disease with active carcinoid syndrome may cause
relatively acute severe tricuspid regurgitation.

Initial test findings

Electrocardiogram — An electrocardiogram is not required for the diagnosis of
carcinoid heart disease but is commonly included as a component of the cardiac
evaluation. Electrocardiographic findings are nonspecific, with many cases lacking any
electrocardiographic abnormalities (eg, 32 percent normal in one series [2]). Nonspecific
electrocardiographic findings may include ST-T wave abnormalities, sinus tachycardia,
and prolonged PR interval [2]. The electrocardiogram in advanced carcinoid heart
disease demonstrates low QRS voltage [2]. The cause of the low voltage is not clear but
may be related to decreased conduction of the electrical signal to the body surface.
Chest radiograph — A chest radiograph is not required for diagnosis of carcinoid heart
disease but is commonly included as a component of evaluation of this condition. The
chest radiograph is often normal (46 percent in one series) [2]. A common radiographic
finding is cardiomegaly with prominence of the right-sided cardiac chambers. Pulmonary
congestion, if present, is mild. Pleural effusions and metastatic pleural plaque formation
occur late in the course of the disease.
DIAGNOSIS AND EVALUATIONDiagnosis of carcinoid syndrome, including
biochemical testing, is discussed separately. (See "Diagnosis of carcinoid syndrome
and tumor localization" and "Overview of tumor biomarkers in gastroenteropancreatic
neuroendocrine tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-
HIAA)'.)
When and how to initially test for carcinoid heart disease
Patients with carcinoid syndrome — We recommend that all patients with carcinoid
syndrome undergo 6 to 12 monthly clinical evaluations for symptoms and signs of valve
disease or heart failure and have a serum N-terminal brain natriuretic peptide (NT-
proBNP) level measured. It is particularly important to screen for carcinoid heart disease
in patients with carcinoid syndrome scheduled to undergo liver or abdominal surgery
given the risk of hemorrhage related to liver or abdominal surgery in patients with
carcinoid syndrome with elevated right atrial pressures [22]. Guidelines for screening
and diagnosis of carcinoid heart disease are evolving, with differing recommendations in
various major society guidelines [23,24].
After this initial evaluation, echocardiography should be performed in patients with signs
and/or symptoms of valvular heart disease or heart failure, in patients with NT-proBNP
level greater than 260 ng/mL (or 31 pmol/l) [24], as well as in patients who are
scheduled to undergo liver or abdominal intervention. Some experts use a urinary 5-
261
hydroxyindoleacetic acid (5-HIAA) level >300 micromol/24 hours to help identify
individuals at risk for carcinoid heart disease. However, we do not use 5-HIAA levels to
help identify candidates for echocardiographic screening, since there is evidence that
NT-proBNP levels correlate better with carcinoid heart disease severity. (See 'Role of
biomarkers' below.)
In addition, a follow-up echocardiogram is recommended in patients who later develop
new or worsening signs and symptoms of valve disease or heart failure or elevation of
NT-proBNP above 260 ng/mL [25].
Role of biomarkers — As noted above, we suggest annual measurement of serum NT-
proBNP levels in all patients with carcinoid syndrome without known carcinoid heart
disease to screen for carcinoid heart disease. This recommendation is based upon
studies suggesting that NT-proBNP is a sensitive and specific marker for carcinoid heart
disease [25,26]. Based on two studies, an NT-proBNP level >260 pg/mL has a
sensitivity of 69 to 92 percent and specificity of 80 to 91 percent for detection of
carcinoid heart disease [25,26]. NT-proBNP and plasma 5-HIAA levels are both
sensitive and specific markers for the presence of carcinoid heart disease, but NT-
proBNP correlated moderately with severity of carcinoid heart disease while plasma 5-
HIAA correlated only weakly [25].
Biochemical testing for carcinoid syndrome is discussed separately. Urinary levels of 5-
HIAA are significantly elevated in patients with carcinoid heart disease, and higher
levels are associated with greater risk of progression of carcinoid heart disease [27]. A
study identified an association between plasma 5-HIAA and carcinoid heart disease
progression and death [28]. (See "Diagnosis of carcinoid syndrome and tumor
localization" and "Overview of tumor biomarkers in gastroenteropancreatic
neuroendocrine tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-
HIAA)'.)
Chromogranin A (CgA) is another potential nonhormonal marker for carcinoid heart
disease, but its specificity for detection of severe carcinoid heart disease is low (eg, 30
percent [29]); we do not recommend its use to screen for carcinoid heart disease. In a
study of 102 patients with neuroendocrine tumors, levels of CgA and NT-proBNP were
independently associated with carcinoid heart disease and with overall mortality [29].
Survival at five years was 81 percent in patients with normal CgA levels, 44 percent in
those with elevated CgA but normal NT-proBNP levels, and 16 percent in those with
elevations in both CgA and NT-proBNP. (See "Overview of tumor biomarkers in
gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A (CgA)'.)
Patients with tricuspid and/or pulmonic valve disease — Acquired valvular heart
disease involving the tricuspid and/or pulmonary valves, in the absence of left-sided
valve disease, is uncommon and when detected clinically or echocardiographically
should prompt consideration of carcinoid heart disease with clinical cardiovascular
evaluation (as described above), evaluation for carcinoid syndrome, and
echocardiography. (See "Diagnosis of carcinoid syndrome and tumor
localization" and "Clinical features of carcinoid syndrome".)
Approach to diagnosis and evaluation — Transthoracic echocardiography (TTE) is
the main modality for diagnosis and evaluation of carcinoid heart disease as it enables
identification and assessment of valve disease and right heart chamber size and
function. If the TTE evaluation is inadequate to assess valve structure and function and

262
right heart size and function, transesophageal echocardiogram (TEE), cardiovascular
magnetic resonance (CMR), or computed tomography (CT) (image 1) may be helpful,
particularly for assessing the right heart.
Echocardiography — Characteristic echocardiographic features of advanced carcinoid
heart disease include thickening and retraction of immobile tricuspid valve leaflets with
associated tricuspid regurgitation, which is severe at the time of identification in 90
percent of patients (movie 1A-B) [2]. Less commonly, tricuspid valve stenosis is noted.
(See "Echocardiographic evaluation of the tricuspid valve".)

Pulmonary valve involvement usually coexists with tricuspid valve disease. The major
finding on echocardiography is immobility of the pulmonary valve cusps. However, the
pulmonary valve cusps may be difficult to visualize by echocardiography due to cusp
retraction. Pulmonary annular constriction may also occur, resulting in predominant
pulmonary outflow tract obstruction.

Left-sided valve involvement (characterized by diffuse thickening of valve leaflets) is

much less common and usually less severe than right-sided valve disease due to
vasoactive peptide inactivation within the pulmonary circulation [5,30]. Left-sided valve
disease may be caused by right-to-left shunting (eg, through a patent foramen ovale), or
high levels of circulating vasoactive substances. An agitated saline contrast injection
(bubble study) is recommended at the time of initial echocardiogram to assess for a
patent foramen ovale. This does not generally need to be repeated in follow-up studies.
(See "Patent foramen ovale", section on 'Diagnosis'.)
Although bronchopulmonary carcinoid has been postulated as an additional potential
cause of left-sided valve involvement [5,30], a series of patients with bronchopulmonary
carcinoid identified no cases of left-sided valve involvement attributable solely to this
tumor location [31]. In a series of 186 patients with bronchopulmonary carcinoid, only
two patients (1 percent) had echocardiographic features of carcinoid heart disease: one
patient had clinical features more consistent with diet-drug related valve disease and
the other had tricuspid, pulmonary and aortic valve disease, liver metastases, and a
patent foramen ovale [31]. Thus, no carcinoid heart disease was identified in patients
with bronchopulmonary carcinoid without liver metastases, and no left-sided valve
involvement was found in the absence of a patent foramen ovale.
The frequency with which these and other findings occur was illustrated in a report in
which comprehensive echocardiography was performed in 74 patients with carcinoid
heart disease [2]. The following distribution of lesions was noted:
●All patients had tricuspid regurgitation, which was moderate to severe in 90
percent.
●Pulmonic stenosis was present in 53 percent, and some degree of pulmonic
regurgitation was present in 81 percent.
●Left-sided valvular involvement was noted in five patients (7 percent).
●A small pericardial effusion was seen in 14 percent; these effusions are rarely
hemodynamically significant.
Long-standing tricuspid and pulmonary valve regurgitation result in progressive right
ventricular volume overload and right ventricular diastolic pressure elevation [2].
Metastatic carcinoid tumors in the myocardium are uncommonly detected, but larger
tumors (eg, 1.0 cm or greater) may be identified by echocardiography in the left
263
ventricle, right ventricle, or interventricular septum and may protrude into the ventricular
cavity as sessile masses [6].
Three-dimensional echocardiography may play an incremental role for the preoperative
assessment of the pulmonary valve in patients with carcinoid heart disease [32]. The
impact of 3D echocardiography on assessment of the tricuspid valve has not been
assessed.
Transesophageal echocardiography — TEE is primarily used intraoperatively to
image the patient with carcinoid heart disease during valve replacement surgery. In
addition, for patients with features of carcinoid heart disease in whom incomplete data
are obtained by TTE, TEE is used as a complementary imaging test. TEE may provide
incremental assessment of the degree of cardiac valve involvement and the atrial septal
anatomy in patients with carcinoid heart disease. Since the right-sided valves are in the
far field, assessment by TEE is less reliable than assessment of left-sided valves, but
an experienced examiner is usually able to obtain diagnostic images of the right-sided
valves.
CMR and CT — CMR or CT are used as complementary imaging tests for patients with
features of carcinoid heart disease where incomplete data are obtained by
echocardiography. Features of carcinoid valve disease, including valve dysfunction and
right ventricular size and function, can be evaluated by CMR or CT (image 1) [33,34].
CT is helpful to assess coronary anatomy prior to planned intervention. These
modalities are also helpful for quantification of right ventricular volumes and ejection
fraction. There is no specific right heart size and function threshold that is used as an
indication for valve intervention, so we do not perform routine serial CT or CMR.
MANAGEMENT
Approach to management — Valve surgery is the only current effective therapy for
carcinoid heart disease. Early diagnosis of carcinoid heart disease and regular cardiac
follow-up are recommended for timely identification of patients likely to benefit from
surgery. Diuretics are generally only temporarily effective in reducing edema, and they
may reduce cardiac output. Therapies that reduce circulating serotonin levels (such as
somatostatin analogs and antitumor therapy) have not been demonstrated to reverse
valve disease.
Diuretic therapy — Diuretics temporarily improve symptoms related to edema but may
result in a further reduction in cardiac output, which in turn worsens fatigue.
Telotristat ethyl — Telotristat ethyl is an oral tryptophan hydroxylase inhibitor that has
been approved in the United States for use in combination with somatostatin analog for
control of diarrhea associated with the carcinoid syndrome. There is no evidence that
this agent prevents development of carcinoid heart disease. However, given that
carcinoid heart disease is thought to be related to high levels of circulating serotonin, it
may be reasonable to consider telotristat therapy in select patients with active
metastatic carcinoid disease, high levels of circulating serotonin, and no or early
carcinoid heart disease to try to prevent carcinoid heart disease progression.
(See "Treatment of the carcinoid syndrome", section on 'Telotristat'.)
Other — The role of peptide receptor radionuclide therapy (PRRT), a radioisotope
therapy used to treat neuroendocrine tumors, in preventing or delaying development of
carcinoid heart disease has not been determined. This treatment is approved by the US
Food and Drug Administration for management of patients with metastatic
264
neuroendocrine tumors. (See "Metastatic well-differentiated gastrointestinal
neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth",
section on 'Peptide receptor radioligand therapy'.)
Monitoring — Early diagnosis of carcinoid heart disease and regular clinical follow-up
are recommended to enable identification of the most appropriate timing of surgical
intervention for each patient. Cardiac follow-up should include clinical assessment,
echocardiography, and exercise testing. Additional imaging may be suggested in select
patients. (See 'CMR and CT' above.)
Valve intervention — Surgical valve replacement is the current standard of care when
intervention is indicated for carcinoid heart disease and should be considered for
symptomatic patients with severe native valve involvement whose metastatic carcinoid
disease and symptoms of carcinoid syndrome are well controlled [35]. Transcatheter
valve replacement to treat carcinoid native pulmonic valve disease has been reported
[36,37]. Catheter-based valve interventions have also been reported in the setting of
carcinoid prosthetic valve disease [38].
Indications for valve intervention include symptomatic valve dysfunction (with symptoms
such as impaired exercise capacity, progressive fatigue, or symptoms and signs of right
heart failure such as edema, pleural effusions, or ascites) or progressive decline in right
ventricular function with valve dysfunction. Valve surgery should be considered only for
patients whose metastatic carcinoid disease and symptoms of carcinoid syndrome are
well controlled. For patients with symptomatic tricuspid or pulmonic valve disease, valve
replacement is the procedure of choice. Determining the best approach to the individual
patient requires a multidisciplinary approach, with the neuroendocrine specialist,
cardiologist, and surgical team optimizing carcinoid disease activity and recognizing the
best selection and order of advanced treatment options. (See "Management and
prognosis of tricuspid regurgitation", section on 'Indications' and "Natural history and
treatment of pulmonic stenosis in adults", section on 'Indications for
intervention' and "Pulmonic regurgitation", section on 'Intervention'.)
When pulmonary valve disease is present, valve replacement is preferable to valve
resection [39]; double (tricuspid and pulmonic) or multiple valve replacement can be
undertaken simultaneously [35,40,41]. Balloon valvuloplasty is not recommended for
pulmonic stenosis given the presence of concurrent tricuspid and pulmonary valve
regurgitation. Transcatheter valve replacement has been reported for carcinoid-related
pulmonic valve disease, but experience is lacking for transcatheter tricuspid valve
replacement.
Surgical resection of cardiac metastases is not routinely indicated since these do not
generally cause complications, but surgical resection can be performed at the time of
valve surgery if only one or two such lesions are present [6]. Patients with severe
unoperated carcinoid cardiac disease are not candidates for hepatic surgery due to the
risk of hepatic hemorrhage, induced by the elevated right-sided cardiac pressures, at
the time of surgery. In occasional patients, cardiac surgical intervention is carried out
despite minimal cardiac symptoms, in anticipation of hepatic surgical resection of
metastatic disease [42]. (See "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Surgical resection'.)

265
Choice of surgical valve prosthesis — The choice of surgical valve prosthesis
requires meticulous discussion and individual selection in patients with carcinoid heart
disease. In a series of 195 patients with carcinoid heart disease referred for valve
replacement, no difference in survival or reoperation rate was noted related to
prosthesis valve type [35].
With the use of bioprosthetic valves, premature degeneration may be induced by the
carcinoid process [43-45]. The risk of valve degeneration may be offset by aggressive
carcinoid tumor intervention and somatostatin therapy [40,46,47].
Bioprosthetic valve dysfunction may be related to thrombosis [35,48], carcinoid plaque
deposition, or degeneration. If bioprosthetic valve dysfunction is identified, a
comprehensive review of the potential causes and treatment options is needed [47]. For
patients with bioprosthetic valve dysfunction that might be caused by valve thrombosis,
a trial of anticoagulation with warfarin should generally be attempted (unless the
potential risks outweigh the potential benefits) prior to considering surgical or
percutaneous valve replacement. (See "Diagnosis and management of bioprosthetic
valve thrombosis and obstruction".)
Mechanical prostheses are not ideal for patients with carcinoid heart disease since
subsequent surgical procedures for tumor control are often required and are
complicated by anticoagulation management. In addition, the risk of mechanical
tricuspid prosthesis thrombosis is approximately 4 percent per year [49].
(See "Diagnosis of mechanical prosthetic valve thrombosis or obstruction".)
Anesthesia management — Anesthesia can precipitate carcinoid crisis in patients with
carcinoid syndrome [50,51]. This syndrome, which is characterized by profound
flushing, extreme changes in blood pressure related to vasodilatation,
bronchoconstriction, arrhythmias, and confusion or stupor, can be fatal. Thus, control of
carcinoid symptoms by an octreotide analog should be attained prior to anesthesia, and
meticulous anesthetic care is required during the procedure. Large doses of
somatostatin are often required in the perioperative and postoperative periods [51-53].
(See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors:
Systemic therapy options to control tumor growth".)
Treatment of carcinoid syndrome — Management of carcinoid syndrome with
somatostatin-analogs, antitumor therapies, and other therapies is discussed separately.
(See "Treatment of the carcinoid syndrome".)

Given evidence of a pathogenic role for serotonin or its metabolites in the development
of carcinoid heart disease, it is likely that somatostatin analogs and other therapies that
reduce circulating serotonin levels can reduce the risk of developing carcinoid heart
disease, and they may inhibit progression of existing disease. However, there is no
evidence that such therapy can reverse valvular damage.

Treatment of the tumor itself does not typically result in regression of valvular disease,
as illustrated by the following observations [2,15,17]:
●In a study of 23 patients, serial echocardiography was used to examine the
association of urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion with the
appearance or worsening of valvular lesions after treatment with a somatostatin
analog, presumably octreotide [15]. Despite major declines in 5-HIAA excretion in
most patients, existing valvular lesions did not regress. However, the post-
266
 treatment levels of 5-HIAA independently predicted the development or
progression of valvular abnormalities, with a threshold of approximately 100
mg/day.
●In the report of 71 patients from Mayo Clinic cited above, all patients received
treatment with a somatostatin analogue, hepatic dearterialization, and/or
chemotherapy [17]. None of these therapies, which had a variable effect on
urinary 5-HIAA excretion, were associated with a reduction in the risk of
progressive valvular disease; to the contrary, chemotherapy was statistically
correlated with a higher rate of progression, possibly because this form of therapy
is typically reserved for patients with more aggressive carcinoid tumors.
Rarely, an ovarian carcinoid tumor can cause carcinoid heart disease without liver
metastases. Because the ovarian veins bypass the portal circulation and enter the
systemic venous circulation directly, cardiac involvement can occur without liver
metastases. Tumor resection in such patients can be curative [20]. Even in such cases,
however, the cardiac manifestations do not typically regress after curative surgery [54].
PROGNOSISWithout treatment, the median duration of survival with malignant
carcinoid syndrome ranges from 12 to 38 months from the onset of systemic symptoms
[55,56]. Carcinoid heart disease with advanced symptoms (New York Heart Association
class III or IV) portends a particularly poor prognosis and the median survival is only 11
months; most die within one year because of progressive heart failure [46].
Cardiac surgery, chiefly tricuspid valve replacement and pulmonic valve replacement,
has been successful in reducing or relieving the cardiac symptoms of many patients
with carcinoid heart disease. However, surgical series from the Mayo Clinic noted an
overall surgical mortality of 10 percent, which is higher than expected for other valve
disease patients, but lower than in prior series; the operative mortality rate after 2000
was 6 percent [35,46,57]. Cardiac surgery was primarily performed on patients with
advanced right heart failure manifested by edema and ascites. Despite the high surgical
mortality, the survival among surgically treated patients was better than that in medically
treated patients with similar symptoms. By multivariate analysis, the operative mortality
was related to era of operation (higher mortality rate before 2000) and need for
intravenous loop diuretic therapy [35]. Overall mortality was associated with older age,
preoperative cytotoxic chemotherapy, and preoperative tobacco use. Incomplete
symptom resolution was noted among surgical survivors; 75 percent of survivors had
symptomatic improvement at follow-up [35].
In a series of 200 patients with carcinoid heart disease treated medically and surgically
at the Mayo Clinic (partially overlapping with the cohorts in the studies above), cardiac
surgery was associated with significant risk reduction (hazard ratio 0.44; 95% CI 0.29-
0.61) in a multivariate analysis [58]. An increasing number of mildly symptomatic
patients with severe valve dysfunction were offered surgery over time. In an updated
series of 240 patients treated with surgical valve replacement for carcinoid heart
disease at the Mayo Clinic between 1985 and 2018, lower 30-day mortality was
observed during the most recent era (2005 to 2018, 5 percent) compared to earlier
experience (1995 to 2004, 7 percent and 1985 to 1994, 29 percent) [47].
Other modalities such as somatostatin analogs for carcinoid syndrome, hepatic artery
embolization, or chemoembolization for hepatic metastases improve symptoms but not

267
survival. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Cardiac valve disease".)
SUMMARY AND RECOMMENDATIONS
●Carcinoid heart disease eventually occurs in up to 50 percent of patients with
carcinoid syndrome and may be the initial presentation in up to 20 percent of
patients. (See 'Introduction' above.)
●Carcinoid heart disease is characterized by plaque-like deposits of fibrous tissue,
most frequently affecting the right heart valves (most commonly tricuspid
regurgitation and commonly pulmonic stenosis or regurgitation) and endocardium.
Left-sided valve disease occurs in less than 10 percent of patients with cardiac
involvement and is almost always associated with an atrial right-to-left shunt (as
with a patent foramen ovale). (See 'Pathophysiology' above
and 'Echocardiography' above.)
●Evidence suggests a role for serotonin in the pathogenesis of carcinoid heart
disease. (See 'Role of serotonin' above.)
●The clinical manifestations of carcinoid heart disease are often subtle early in the
course of the disease. Symptoms range from fatigue and dyspnea on exertion to
right heart failure with edema, ascites, and eventual cardiac cachexia with
progressive disease. (See 'Symptoms' above.)
●The major findings of carcinoid heart disease on physical examination include an
elevated jugular venous pressure, palpable right ventricular impulse, and murmurs
of tricuspid and pulmonary valve regurgitation. (See 'Physical
examination' above.)
●We recommend that all patients with carcinoid syndrome undergo annual clinical
evaluation for symptoms and signs of valve disease or heart failure and have an
annual serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level
measurement. (See 'When and how to initially test for carcinoid heart
disease' above.)
●An echocardiogram is recommended for all patients with carcinoid syndrome who
have symptoms or signs of carcinoid heart disease, an NT-proBNP level greater
than 260 ng/mL, or are undergoing liver or abdominal surgical intervention.
(See 'When and how to initially test for carcinoid heart disease' above.)
●Carcinoid heart disease with advanced symptoms (New York Heart Association
class III or IV) portends a poor prognosis and the median survival without
intervention is only 11 months. (See 'Prognosis' above.)
●Early diagnosis of carcinoid heart disease and regular cardiac follow-up are
recommended for timely identification of patients likely to benefit from valve
replacement surgery. Diuretics are generally only temporarily effective in reducing
edema, and they may reduce cardiac output. Therapies that reduce circulating
serotonin levels (such as somatostatin analogs and antitumor therapy) have not
been demonstrated to reverse valve disease. (See 'Management' above.)
●Valve replacement (tricuspid valve replacement with addition of pulmonary valve
replacement in patients with pulmonary valve disease) is the only effective
268
intervention for carcinoid heart disease. Standard indications for valve
replacement apply, including symptomatic valve disease (impaired exercise
capacity, progressive fatigue) or progressive decline in ventricular function. Valve
replacement should be reserved for patients whose metastatic carcinoid disease
and symptoms of carcinoid syndrome are well controlled, emphasizing the
importance of a multidisciplinary approach to these patients. Catheter-based
interventions have been reported in the setting of native and carcinoid prosthetic
valve disease. (See 'Valve intervention' above and "Management and prognosis of
tricuspid regurgitation", section on 'Indications' and "Natural history and treatment
of pulmonic stenosis in adults", section on 'Indications for
intervention' and "Pulmonic regurgitation", section on 'Intervention'.)
●In carcinoid patients with cardiac symptoms and controlled systemic disease,
cardiac valve replacement surgery alleviates otherwise intractable symptoms and
appears to improve survival. (See 'Valve intervention' above.)

269
Clinical characteristics of well-differentiated
neuroendocrine (carcinoid) tumors arising in the
gastrointestinal and genitourinary tracts
Author:
Jonathan R Strosberg, MD
Section Editors:
Kenneth K Tanabe, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Feb 02, 2021.
INTRODUCTIONWell-differentiated neuroendocrine tumors (NETs) most
commonly originate in the gastrointestinal tract and lung and rarely arise in the
genitourinary tract. The term "carcinoid" is still used to describe these tumors;
however, preferred terms include NET or neuroendocrine neoplasm (NEN). Well-
differentiated NETs that arise in the pancreas, while histologically similar to those
arising in the tubular portion of the gastrointestinal tract, are not referred to as
"carcinoids" but instead as pancreatic NETs (older term: islet cell tumors).
(See "Pathology, classification, and grading of neuroendocrine neoplasms arising
in the digestive system", section on 'Pathology, tumor classification, and
nomenclature'.)
"Carcinoid syndrome" is the term applied to a constellation of symptoms mediated
by various humoral factors that are elaborated by some well-differentiated NETs
arising in the gastrointestinal tract (table 1) [1]. Typical carcinoid syndrome,
consisting primarily of flushing and diarrhea (table 2), occurs predominantly in
patients with metastatic NETs originating in the small intestine. Carcinoid
syndrome is rare with lung or genitourinary well-differentiated NETs. (See "Clinical
features of carcinoid syndrome".)

Well-differentiated NETs are rare overall, but their age-adjusted incidence in the
United States has increased significantly, partly due to increased detection on
radiographic imaging and endoscopy.

This topic will cover the epidemiology, classification, and clinical features of
primary well-differentiated NETs (carcinoid tumors) arising in the gastrointestinal

270
and genitourinary systems. The pathology and nomenclature of digestive tract
NETs; clinical features and diagnosis of carcinoid syndrome; issues related to
tumor localization in well-differentiated NETs arising in the gastrointestinal tract;
features and management of high-grade gastroenteropancreatic neuroendocrine
carcinoma, bronchial NETs, and thymic NETs; and the management of patients
with non-metastatic and metastatic well-differentiated NETs arising in the
gastrointestinal tract are discussed separately.

●(See "Pathology, classification, and grading of neuroendocrine neoplasms

arising in the digestive system".)
●(See "Clinical features of carcinoid syndrome".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
●(See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors,
classification, histology, diagnosis, and staging".)
●(See "Thymic neuroendocrine (carcinoid) tumors".)
●(See "Staging, treatment, and post-treatment surveillance of non-metastatic,
well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)
EPIDEMIOLOGYWell-differentiated NETs are relatively rare tumors. In a series
of 35,618 NETs (which included pancreatic NETs as well as gastrointestinal NETs
[GINETs] at all sites) reported to the Surveillance, Epidemiology, and End Results
(SEER) program of the National Cancer Institute (NCI), the age-adjusted incidence
for nonpancreatic primaries was 4.7 per 100,000 [2]. The annual incidence rate for
African Americans was higher than for White Americans (6.46 versus 4.6 per
100,000), and the incidence for males was slightly higher than for females (4.97
versus 4.49 per 100,000). The median age at diagnosis for all patients with NETs
was 63 years.
Roughly similar incidence rates were found in a database study from a Swedish
registry that focused on 5184 GINETs tumors seen between 1958 and 1998 [3].
Incidence rates for men and women were 2.0 and 2.4 per 100,000, respectively.
Although clear risk factors have not been identified, a regression analysis of this
database suggested that risk was increased in the setting of a family history of a
GINET in a first-degree relative (relative risk 3.6).
The incidence of well-differentiated NETs has been rising over time in the United
States and elsewhere [4-7]. As an example, in an analysis of 64,971 NETs reported
to the SEER registry, the age-adjusted incidence rate for all NETs rose from 1.09 to
6.98 per 100,000 between 1973 and 2012 [7]. The increase is probably partly due to
increased detection on radiographic imaging and endoscopy.

271
Distribution — The distribution of NETs has shifted over time in the United States.
In a report from the SEER database of 11,427 cases treated between 1973 and
1997, the majority were located in the gastrointestinal tract (55 percent) and
bronchopulmonary system (30 percent) [8]. Within the gastrointestinal tract, most
NETs arose in the small intestine (45 percent, most commonly in the ileum),
followed by the rectum (20 percent), appendix (16 percent), colon (11 percent), and
stomach (7 percent). However, since the implementation of screening colonoscopy
(approximately in the year 2000), the proportion of patients diagnosed with rectal
NETs has been greater than the proportion of those diagnosed with small
intestinal NETs in 12 of 13 SEER registry reporting agencies [9]. The rising
incidence of rectal NETs over time, and in all age groups, including 20 to 29 year
olds, has been noted by others [10].
Distribution may differ in other geographic areas. As an example, colorectal NETs
may be more frequent in the Asia/Pacific region as compared with Europe, where
GINETs are more commonly found in the stomach and ileum [11,12]. An important
point is that the SEER database may be inconsistent in recording tumors that are
not considered "malignant" (ie, small gastric NETs that are encountered at
endoscopy in patients with chronic atrophic gastritis). (See "Staging, treatment,
and post-treatment surveillance of non-metastatic, well-differentiated
gastrointestinal tract neuroendocrine (carcinoid) tumors".)
PATHOLOGY AND GRADINGWell-differentiated NETs arising in the tubular
gastrointestinal tract, lung, and genitourinary tract were initially referred to as
"carcinoids" because they seemed morphologically different and clinically less
aggressive than the more common gastrointestinal tract adenocarcinomas [13].
NETs arise from enterochromaffin (neuroendocrine) cells of the aerodigestive
tract. The term enterochromaffin refers to the ability to stain with potassium
chromate (chromaffin), a feature of cells that contain serotonin.
While most NETs are relatively slow-growing neoplasms, some behave
aggressively. Histologic grade and differentiation correlate closely with clinical
behavior. Grade refers to the proliferative activity of tumors, commonly measured
by the mitotic rate (number of mitotic figures per 10 high-powered fields) or the Ki-
67 index. In contrast, differentiation refers to the extent to which neoplastic cells
resemble their non-neoplastic counterparts [14].
The World Health Organization (WHO) distinguishes two broad subgroups of
neuroendocrine neoplasms affecting the digestive tract (table 3) [15]:
●Well-differentiated NETs, which are further subdivided into low grade and
intermediate grade according to proliferative rate. Intermediate-grade NETs
arising in the lung (but not elsewhere) are referred to as atypical carcinoids.

272
 In general, clinical behavior is relatively indolent. (See "Pathology of lung
malignancies", section on 'Neuroendocrine tumors'.)
●Poorly differentiated neuroendocrine carcinomas, which are high-grade
carcinomas that resemble small cell or large cell neuroendocrine carcinoma
of the lung (picture 1) [16]. They generally behave in a biologically aggressive
fashion. (See "High-grade gastroenteropancreatic neuroendocrine
neoplasms".)
●While all poorly differentiated neuroendocrine carcinomas are high grade, it
is now recognized that there is a small subset of patients with NETs that
appear histologically well differentiated with high proliferation indexes that
fall into the high-grade range. The clinical behavior of these tumors is
somewhat worse than that of well-differentiated intermediate-grade tumors,
but it is better than that of bona fide poorly differentiated neuroendocrine
carcinomas. A more detailed discussion of the pathology and classification of
NETs arising in the digestive tract is presented elsewhere. (See "Pathology,
classification, and grading of neuroendocrine neoplasms arising in the
digestive system".)
EMBRYONIC CLASSIFICATIONNETs arising in the tubular gastrointestinal
tract, lung, and genitourinary tract have traditionally been classified based on their
origin from the embryonic divisions (foregut, midgut, or hindgut) of the alimentary
tract (figure 1) [17]. In general, midgut gastrointestinal tract NETs (distal small
intestine and proximal colon) produce serotonin and other vasoactive substances
that give rise to the typical carcinoid syndrome (table 4). In contrast, tumors
derived from the embryonic hindgut are rarely associated with a hormonal
syndrome. (See "Clinical features of carcinoid syndrome", section on
'Pathophysiology'.)

While this classification has some utility as a means of grouping together tumor
sites according to their likelihood of producing a hormonal syndrome, it is
increasingly evident that each specific primary site possesses its own unique
clinical characteristics.

FOREGUT TUMORSThe symptoms associated with foregut tumors vary with

the site.
Stomach — Gastric NETs are subdivided into three categories that have differing
biologic behavior and prognoses [18,19].
Type 1 — Type 1 tumors account for 70 to 80 percent of all gastric NETs [19-21].
They are associated with chronic atrophic gastritis and often pernicious anemia (65

273
percent in one series) [19]. The disease is more common in women [22-24].
(See "Metaplastic (chronic) atrophic gastritis".)
Endoscopically, the tumors are usually smaller than 1 cm, are often multiple, and
may appear as polypoid lesions with a small central ulceration (picture 2A-C). The
tumors are derived from enterochromaffin-like (ECL) cells.
The prevailing hypothesis is that ECL cells develop into NETs after chronic
stimulation by the high gastrin levels that occur in patients with atrophic gastritis.
This is supported by the observation that regression of gastric NETs can be
achieved by antrectomy, which is occasionally recommended. (See "Staging,
treatment, and post-treatment surveillance of non-metastatic, well-differentiated
gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Stomach'.)
The importance of gastrin in ECL transformation is supported by the observation
that NETs arising in the stomach develop in certain animals treated with high
doses of proton pump inhibitors (PPIs), which are associated with
hypergastrinemia, because of loss of feedback [25]. However, a link between PPI
use and development of gastric NETs in humans has not been established.
Patients with gastric NETs related to chronic atrophic gastritis are usually
diagnosed in their 60s or 70s during endoscopic evaluation for abdominal pain or
anemia [19]. They are usually nonfunctioning tumors. These tumors are usually
indolent and generally represent a benign condition. Metastases occur in less than
10 percent of tumors ≤2 cm but approximately 20 percent of larger tumors [26].
Type 2 — Type 2 gastric NETs occur in association with gastrinomas (Zollinger-
Ellison syndrome), often in the setting of multiple endocrine neoplasia type 1
(MEN1). They account for approximately 5 percent of gastric NETs. Similar to the
NETs that arise in the setting of atrophic gastritis, the tumors are thought to arise
from ECL cells stimulated by elevated serum gastrin levels. The hypergastrinemia
is produced by a gastrinoma in the pancreas or duodenum. (See "Multiple
endocrine neoplasia type 1: Treatment" and "Management and prognosis of the
Zollinger-Ellison syndrome (gastrinoma)".)
Type 2 tumors behave similarly to type 1 tumors; they are frequently multifocal
and usually indolent [27]. Management is addressed elsewhere. (See "Staging,
treatment, and post-treatment surveillance of non-metastatic, well-differentiated
gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Stomach'.)
Type 3 — Type 3 gastric NETs are known as sporadic NETs because they occur in
the absence of atrophic gastritis, Zollinger-Ellison syndrome, or MEN1 syndrome.
They account for 20 percent of gastric NETs and are the most aggressive; local or
hepatic metastases are present in up to 65 percent of patients who come to
resection [18,27]. Unlike type 1 and 2 tumors, the fasting serum gastrin is usually
normal in patients with type 3 gastric NETs.

274
Type 3 tumors often contain a variety of endocrine cells, and they may be
associated with atypical carcinoid syndrome (table 4). (See "Clinical features of
carcinoid syndrome", section on 'Gastric NET variant syndrome'.)
Lung — Well-differentiated bronchial NETs are classified among other pulmonary
neuroendocrine neoplasms, such as small cell and large cell neuroendocrine lung
cancer. (See "Pathology of lung malignancies", section on 'Neuroendocrine
tumors'.)
Patients with bronchial NETs rarely develop carcinoid syndrome, even in the
presence of liver metastases. They may have a variant carcinoid syndrome with
flushes or sweats that are severe and prolonged, lasting hours to days. These
flushes may be associated with disorientation, anxiety, and tremor. The clinical
features of bronchial NETs are discussed separately. (See "Clinical features of
carcinoid syndrome", section on 'Lung NET variant syndrome' and "Lung
neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification,
histology, diagnosis, and staging", section on 'Clinical features'.)
MIDGUT TUMORS
Jejunoileal small bowel tumors — Small bowel NETs have increased in frequency
in the last several decades, in part due to increased detection on endoscopy and
imaging studies [28]. In the year 2000, NETs surpassed adenocarcinomas as the
most common small bowel tumor reported to the National Cancer Database [29].
Patients usually present in their 60s or 70s. (See "Epidemiology, clinical features,
and types of small bowel neoplasms", section on 'Malignant tumors'.)
Small bowel NETs are thought to arise from intraepithelial endocrine cells, in
contrast to appendiceal NETs, which arise from subepithelial endocrine cells [30].
Small intestinal NETs are most commonly located in the ileum within 60 cm of the
ileocecal valve; they may arise from a Meckel's diverticulum [28,31-33].
Approximately 25 percent of patients will have more than one small bowel NET at
the time of discovery.
Some small bowel NETs are asymptomatic at presentation and are found
incidentally [34]. Among symptomatic patients, abdominal pain is the most
common initial symptom, occurring in approximately 40 percent [35]. The pain is
usually vague and nonspecific, and may be incorrectly assumed to represent
irritable bowel syndrome for years before the diagnosis is made. Intermittent
obstruction occurs in 25 percent of small intestinal NETs [35,36]. Duodenal NETs
may produce duodenal or biliary obstruction.
Abdominal pain may be due to intussusception, the mechanical effect of the
tumor, or mesenteric ischemia. Obstruction may be caused by intussusception or
intraluminal tumor bulk, but it often results from mesenteric kinking and
distortion brought on by tumor invasion, lymph node metastases, and/or a
275
secondary desmoplastic response (image 1) [37]. The last produces a characteristic
radiographic abnormality: a combination of abrupt angulation and a filling defect
in the small bowel (image 2).
Pain may also arise from ischemia that is due to local fibrosis or vascular
compromise [36]. Vascular compromise may be secondary to large, bulky
mesenteric nodal metastasis, mesenteric vascular invasion, and/or microvascular
metastasis [36]. Possibly contributing to the ischemic process is the vasospastic
effect of serotonin produced by the tumor.
Metastases to lymph nodes or the liver are common, even if the primary tumor is
<2 cm in size (table 5) [38,39]. Carcinoid syndrome is present in the majority of
patients who have a small bowel primary NET and liver metastases [38,40-42].
Staging, treatment, and prognosis of small bowel carcinoid NETs are addressed
elsewhere. (See "Staging, treatment, and post-treatment surveillance of non-
metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid)
tumors", section on 'Small intestine'.)
Appendix — Well-differentiated NETs are the most common neoplasms in the
appendix. In approximately 1 in 300 appendectomies, a NET is discovered
incidentally, most often in the tip of the appendix. (See "Well-differentiated
neuroendocrine tumors of the appendix", section on 'Terminology and
classification'.)
Appendiceal NETs are detected most commonly in the patients in their 40s or 50s,
which most likely reflects the younger age of patients who undergo
appendectomy. They are probably more common in women, although this
association has in part been attributed to the greater frequency of incidental
appendectomies in women who undergo pelvic surgery. (See "Well-differentiated
neuroendocrine tumors of the appendix", section on 'Terminology and
classification'.)
The majority are submucosal and located in the distal one-third of the appendix,
where they are unlikely to cause obstruction (picture 3A-B). As a result, most
patients are asymptomatic. Symptoms are more likely with large tumors and in the
rare patient with metastases beyond the regional lymph nodes. Approximately 10
percent of appendiceal NETs are located at the base of the appendix, where they
can cause obstruction leading to appendicitis.
The likelihood of regional and distant metastases is related to tumor size but is
generally lower than for small intestinal NETs (table 5). Features of carcinoid
syndrome may be present in patients with tumors that have metastasized to the
liver. (See "Clinical features of carcinoid syndrome".)
A rare type of appendiceal tumor, formerly referred to as "adenocarcinoid" or
"goblet cell carcinoid," is now more appropriately termed "goblet cell

276
adenocarcinoma" [43]. These cancers are staged and treated as epithelial tumors
of the appendix and are discussed in detail elsewhere. (See "Epithelial tumors of
the appendix", section on 'Goblet cell adenocarcinoma'.)
The staging, prognosis, and treatment of appendiceal NETs are discussed
separately. (See "Well-differentiated neuroendocrine tumors of the appendix",
section on 'Staging and prognosis' and "Well-differentiated neuroendocrine
tumors of the appendix", section on 'Treatment of localized disease'.)
HINDGUT TUMORSHindgut NETs (transverse and descending colon, rectum)
are usually nonsecretory and not associated with carcinoid syndrome, even when
metastatic (table 4). When symptoms do occur, they are the same as those of a
colorectal adenocarcinoma: changes in bowel habits, obstruction, or bleeding.
(See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on
'Clinical presentation'.)
Colon — Colonic NETs are usually detected in patients who are in their 70s during
evaluation for diarrhea, abdominal pain, anorexia, or weight loss [44,45]. The
incidence of functioning tumors is very low. Features of carcinoid syndrome were
present in only 1 of 36 patients in one series from the Alberta Cancer Registry [46].
The majority of colonic NETs are located in the right colon, particularly in the
cecum [44,46,47]. Most patients do not become symptomatic until the tumors are
large. In two series, the average size of the tumors was approximately 5 cm at
diagnosis [44,47], and approximately two-thirds were associated with local nodal,
or distant metastasis (table 5).
Staging, treatment, and prognosis are discussed elsewhere. (See "Staging,
treatment, and post-treatment surveillance of non-metastatic, well-differentiated
gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Colon'.)
Rectum — The vast majority of rectal NETs are asymptomatic and found
incidentally on endoscopy that is performed for another reason [45,48]. They are
most commonly diagnosed in patients in their 60s [49]. Uncommon manifestations
include rectal bleeding, change in bowel habits, or pain; carcinoid syndrome is rare
because most are nonsecretory.
The majority (75 to 85 percent) are localized at diagnosis [45]. However, size
correlates closely with the likelihood of metastases. Tumors smaller than 1 cm are
rarely metastatic [26,50], while approximately 6 percent of tumors between 1 and
1.9 cm, and 24 percent of those over 2 cm metastasize to the liver [31,50-52]. Other
poor prognostic features include deep invasion (into the muscularis propria or
deeper), lymphovascular invasion, and a high mitotic rate (≥2 per 50 high-power
fields) [52,53].

277
Staging, prognosis, and treatment are discussed in detail elsewhere. (See "Staging,
treatment, and post-treatment surveillance of non-metastatic, well-differentiated
gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Rectum'.)
Genitourinary — NETs rarely arise in the genitourinary system; however, both
renal and testicular primary tumors have been described in case reports and case
series [54-57]. In addition to primary tumors, renal and testicular NETs may
represent metastatic spread from another site [57,58]. These lesions commonly
present as an abdominal or testicular mass, but some have manifestations of
carcinoid syndrome. (See "Clinical features of carcinoid syndrome".)
OVARYOvarian NETs are rare neoplasms that may be primary or metastatic.
Primary ovarian NETs are usually unilateral, localized to the ovary, and composed
of gastrointestinal or respiratory epithelium; they often arise within a cystic
teratoma or dermoid tumor [59,60]. (See "Ovarian germ cell tumors: Pathology,
epidemiology, clinical manifestations, and diagnosis".)
The coexistence of an ovarian germ cell tumor may have prognostic implications.
In one report, 189 of 329 primary ovarian NETs (57 percent) coexisted with cystic
teratomas/dermoid tumors [60]. When compared with NETs without associated
germ cell tumors, these NETs were significantly smaller (45 versus 90 mm), less
likely to have liver metastases (2 versus 15 percent), and less likely to have
carcinoid syndrome (14 versus 23 percent), and the five-year survival rates were
modestly better (94 versus 84 percent).
Metastatic NETs to the ovaries occur most commonly in patients with intestinal
primary tumors [61]. Unlike primary ovarian NETs, which are typically unilateral,
metastatic NETs to the ovaries are usually bilateral, originate in the small intestine,
and are associated with peritoneal carcinomatosis [61].
Rarely, ovarian NETs can produce carcinoid syndrome without hepatic metastases
due to their direct drainage into the systemic circulation [62]. Some ovarian NETs
that produce peptide YY, a gastrointestinal hormone responsible for decreased gut
motility, have been associated with severe constipation [63]. (See "Pancreatic
polypeptide, peptide YY, and neuropeptide Y".)
OTHER RARE SITESPrimary well-differentiated NETs have rarely been
diagnosed at other sites, including the liver, gallbladder, cystic duct, thymus, and
middle ear. While many patients present with liver-only disease, it is debatable
whether some of these tumors are true liver primaries or represent metastases
from an occult primary site. (See "Neuroendocrine neoplasms of unknown primary
site".)
METASTATIC TUMORSRegardless of primary site, NETs are characterized by a
strong propensity to metastasize to the liver [41]. Patients with liver metastases
may experience symptoms related to tumor burden (eg, pain, jaundice, early
278
satiety) or hormonal symptoms (eg, flushing and diarrhea, the main symptoms of
carcinoid syndrome). Even when extensive, metastatic well-differentiated NETs can
often cause significant hepatomegaly without any abnormalities of liver function.
(See "Clinical features of carcinoid syndrome", section on 'Clinical features'.)
Other common metastatic sites associated with small intestinal (midgut) NETs
include the mesentery and peritoneum. Tumors in the root of the mesentery may
be unresectable and lead to recurrent bowel obstruction or ischemia. Likewise,
patients with peritoneal carcinomatosis may experience chronic obstruction,
weight loss, and malnutrition [40].
Bone metastases are observed increasingly commonly in patients with metastatic
NETs, particularly with the use of sensitive somatostatin-receptor-based imaging
modalities, such as integrated positron emission tomography (PET)/computed
tomography (CT) using gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC [64].
Other metastatic sites include the retroperitoneal lymph nodes, ovaries, breasts,
and supraclavicular lymph nodes. (See "Metastatic well-differentiated
gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging,
and biochemical monitoring", section on 'Somatostatin receptor-based imaging
techniques'.)
SUMMARY
●Well-differentiated neuroendocrine tumors (NETs) are rare neoplasms that
can arise at several body sites. The majority originate in the gastrointestinal
tract (55 percent) and bronchopulmonary system (30 percent); they rarely
arise in the genitourinary tract. (See 'Distribution' above.)
●NETs arise from enterochromaffin cells. They have traditionally been
classified based on their origin from the embryonic divisions of the
alimentary tract: the foregut (bronchial, stomach), midgut (small intestine,
appendix, cecum), or hindgut (distal colon, rectum, genitourinary).
(See 'Embryonic classification' above.)
●Histologically, NETs are classified based on histologic grade and
differentiation. (See 'Pathology and grading' above.)
•Well-differentiated NETs are further subdivided into low grade and
intermediate grade according to proliferative rate. In general, clinical
behavior is relatively indolent.
•Poorly differentiated neuroendocrine carcinomas are high-grade
malignancies that resemble small cell or large cell neuroendocrine
carcinoma of the lung. They generally behave in a biologically aggressive
fashion.
•There is a small subset of NETs that appear histologically well
differentiated with proliferation indexes that fall into the high-grade
279
 range. The clinical behavior of these tumors is somewhat worse than that
of well-differentiated intermediate-grade tumors, but it is better than that
of bona fide poorly differentiated neuroendocrine carcinomas.
●The metastatic potential of localized well-differentiated NETs correlates with
tumor size, location, and histologic grade.
●Clinical symptoms may be general, or they may correlate with the location of
the tumor and be organ related. Symptoms of carcinoid syndrome (eg,
flushing and diarrhea) typically occur in patients with metastatic NETs of the
small bowel. Rarely, carcinoid syndrome is observed in non-metastatic
tumors that can release hormones directly into the systemic circulation (eg,
lungs, ovaries). (See 'Lung' above and 'Ovary' above.)
●Gastric tumors are subclassified into three types that have different clinical
presentation and malignant potential. (See 'Stomach' above.)
●Small intestinal NETs often present with abdominal pain and/or intermittent
obstruction. (See 'Jejunoileal small bowel tumors' above.)
●Appendiceal NETs are the most common neoplasm found in the appendix;
they are most often discovered incidentally during appendectomy.
(See 'Appendix' above.)
●Transverse colon, descending colon, and rectal NETs may present with
changes in bowel habit, obstruction, or bleeding. (See 'Hindgut
tumors' above.)
●The great majority of rectal NETs are discovered incidentally at the time of
rectal examination or endoscopy.
●Ovarian NETs may be primary or metastatic. Primary ovarian NETs are often
associated with an ovarian germ cell tumor. They can produce carcinoid
syndrome without hepatic metastases due to their direct drainage into the
systemic circulation. (See 'Ovary' above.)

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Clinical features of carcinoid syndrome
Author:
Jonathan R Strosberg, MD
Section Editors:
Kenneth K Tanabe, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Nov 16, 2021.
INTRODUCTION"Carcinoid syndrome" is the term applied to a constellation of
symptoms mediated by various humoral factors elaborated by some well-
differentiated neuroendocrine tumors (NETs) of the digestive tract and lungs,
which synthesize, store, and release a variety of polypeptides, biogenic amines,
and prostaglandins (table 1). Some of these tumor products are responsible for
carcinoid syndrome, but the relative contributions of each and the specificity of
any for particular components of the syndrome are uncertain (table 2).
The pathophysiology and clinical manifestations of carcinoid syndrome will be
reviewed here. The diagnosis and treatment of this disorder are discussed
separately. (See "Diagnosis of carcinoid syndrome and tumor
localization" and "Staging, treatment, and post-treatment surveillance of non-
metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid)
tumors" and "Metastatic well-differentiated gastroenteropancreatic
neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical
monitoring".)
FREQUENCYNeuroendocrine tumors (NETs) may arise anywhere in the
gastrointestinal tract, in the lungs, and occasionally, elsewhere (table 3). Carcinoid
syndrome is most common in the setting of disseminated disease, particularly liver
metastases, but it can occur in apparently locoregional disease. One reason may
be understaging. Unappreciated hepatic metastases may be more common than
previously reported [1-3], especially in small bowel primaries.
The liver inactivates bioactive products secreted into the portal circulation. This
may explain why patients with gastrointestinal NETs most often develop carcinoid
syndrome if they have hepatic metastases, resulting in the secretion of tumor
products into the systemic circulation [4]. In the large majority of cases, carcinoid
syndrome is associated with metastatic tumors originating in the midgut (jejunum,
ileum, and cecum); however, the expression is variable in individual patients [5].

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Less often, carcinoid syndrome is caused by a NET arising in the lung or in the
distal colon or rectum (foregut and hindgut embryologic origin, respectively) [6].
Gastric and lung NETs may be associated with atypical carcinoid syndromes.
(See 'Variant syndromes' below.)
Approximately 1 percent of pancreatic NETs secrete excess serotonin and other
vasoactive substances that produce carcinoid syndrome. (See "Clinical
characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in
the gastrointestinal and genitourinary tracts".)
PATHOPHYSIOLOGYAs many as 40 secretory products have been identified in
various gastroenteropancreatic neuroendocrine tumors (NETs) [4]. The most
prominent of these are serotonin, histamine, tachykinins, kallikrein, and
prostaglandins (table 1).
Tryptophan metabolism — Altered metabolism of tryptophan occurs in almost all
patients with carcinoid syndrome. In normal subjects, approximately 1 percent of
dietary tryptophan is converted to serotonin; however, this value may increase to
70 percent or more in patients with carcinoid syndrome [7]. Serotonin is then
metabolized to 5-hydroxyindoleacetic acid (5-HIAA) (figure 1).
However, some foregut NETs (gastric, lung (figure 2)) lack the aromatic amino acid
decarboxylase that converts 5-hydroxytryptophan to serotonin [5]; these tumors
produce 5-hydroxytryptophan (and histamine) instead of serotonin. Hindgut NETs
(distal colon and rectum) rarely secrete serotonin or any other bioactive hormones
and are, therefore, unassociated with hormonal syndromes, even when metastatic
(table 3) [5].

These alterations in tryptophan metabolism can explain many of the findings in

carcinoid syndrome:

●The diversion of tryptophan to the synthesis of serotonin in patients with

widely metastatic tumors may result in niacin deficiency. This disorder may
be characterized by decreased protein synthesis and hypoalbuminemia, with
or without the clinical manifestations of pellagra (rough scaly skin, glossitis,
angular stomatitis, and mental confusion) [8].
●Tumor production of serotonin is the most likely cause of the diarrhea in
carcinoid syndrome. Serotonin stimulates intestinal secretion and motility
and inhibits intestinal absorption [9,10].
Serotonin may also stimulate fibroblast growth and fibrogenesis. These effects can
lead to the peritoneal and cardiac valvular fibrosis associated with carcinoid
syndrome [11]. (See 'Cardiac valvular lesions' below.)
Serotonin does not cause flushing [12]. Among the potential mediators are
bradykinins, prostaglandins, tachykinins, substance P, and/or histamine [13].
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Histamine — Primary gastric NETs can produce histamine, which may be
responsible for the atypical flushing and pruritus associated with these tumors
(see 'Gastric NET variant syndrome' below). The observation that such flushing can
be ameliorated by combined H1 and H2 antagonism is compatible with this
hypothesis [12].
Kallikrein — Some NETs produce kallikrein, a protein that cleaves kinin from
plasma kininogens. Bradykinin, a short-lived product of this cleavage, is a potent
vasodilator and may be responsible for flushing in some carcinoid patients [14].
Kinins also stimulate intestinal motility and increase vascular permeability [15].
Prostaglandins — Prostaglandins E and F stimulate intestinal motility and fluid
secretion in the normal gastrointestinal tract [16]. Although elevated serum
prostaglandin concentrations are found in patients with carcinoid syndrome, their
role in the symptomatology of this disorder is uncertain [17].
Tachykinins — Some NETs secrete tachykinins (substance P, neurokinin A,
neuropeptide K). Elevations in the serum concentrations of these latter
polypeptides may contribute to flushing and diarrhea [18-20].
CLINICAL FEATURES
Cutaneous flushing — Episodic flushing is the clinical hallmark of carcinoid
syndrome and occurs in 85 percent of patients. The typical flush associated with
midgut neuroendocrine tumors (NETs; jejunum, ileum, cecum, appendix) begins
suddenly and lasts from 30 seconds to as long as 30 minutes. It primarily involves
the face, neck, and upper chest, which become red to violaceous or purple, and is
associated with a mild burning sensation (picture 1). Severe flushes are
accompanied by a fall in blood pressure and rise in pulse rate. As the disease
progresses, the episodes may last longer, and the flushing may be more diffuse.
The differential diagnosis of flushing is listed in the table (table 4).
Most flushing episodes occur spontaneously, but they can be provoked by eating,
drinking alcohol, defecation, emotional events, palpation of the liver, and
anesthesia [21-23]. (See "Treatment of the carcinoid syndrome", section on
'Prevention and management of carcinoid crisis'.)
Venous telangiectasia — These purplish vascular lesions, similar to those seen in
acne rosacea, appear late in the course of carcinoid syndrome. They are due to
prolonged vasodilatation and most often occur on the nose, upper lip, and malar
areas.
Diarrhea — Secretory diarrhea occurs in 80 percent of patients and is often the
most debilitating component of the syndrome. Stools may vary from few to more
than 30 per day, are typically watery and nonbloody, and can be explosive and
accompanied by abdominal cramping. The abdominal cramps may be a
consequence of mesenteric fibrosis or intestinal blockage by the primary tumor.
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The diarrhea is usually unrelated to flushing episodes. Transit time through the
intestine may be extremely short [10].
Bronchospasm — Ten to 20 percent of patients with carcinoid syndrome have
wheezing and dyspnea, often during flushing episodes. Carcinoid wheezing should
not be mistaken for bronchial asthma because treatment with beta agonists can
trigger intense, prolonged vasodilation [24].
Cardiac valvular lesions — Carcinoid heart disease is characterized by
pathognomonic plaque-like deposits of fibrous tissue. These deposits occur most
commonly on the endocardium of valvular cusps, the cardiac chambers, and
occasionally, the intima of the pulmonary arteries or aorta (figure 3). The valves
and endocardium of the right side of the heart are most often affected because
inactivation of humoral substances by the lung protects the left heart. Left-sided
valve disease may be caused by right-to-left shunting (eg, through a patent
foramen ovale [PFO]) or with high levels of circulating vasoactive substances. The
clinical manifestations and treatment of carcinoid heart disease are discussed
separately. (See "Carcinoid heart disease".)
Minor manifestations — There are a number of minor manifestations associated
with carcinoid syndrome:
●As noted above, diversion of dietary tryptophan for synthesis of large
amounts of serotonin can very rarely result in the development of pellagra
[8], manifested by rough scaly skin, glossitis, angular stomatitis, and mental
confusion. Poor dietary intake, and diarrhea or malabsorption can augment
this process.
●Muscle wasting may occur as a result of poor protein synthesis.
●In addition to the mesenteric fibrosis associated with NETs, extensive
fibrosis can occur in the retroperitoneal area and other sites, causing ureteral
obstruction [25,26].
●Persistent brawny edema of the face and, to a lesser degree, of the
extremities may be an advanced manifestation of the syndrome in some
patients with severe flushing attacks. This is particularly true for those with
foregut NETs [27].
VARIANT SYNDROMESSome patients with functioning gastric or lung
neuroendocrine tumors (NETs) have clinical and biochemical variations from the
classic syndrome.
Gastric NET variant syndrome — In patients with the gastric NET variant, the
flushes may be patchy, sharply demarcated, serpiginous, and cherry red; they are
also intensely pruritic. Diarrhea or cardiac lesions are unusual. The tumors that
cause this variant syndrome secrete histamine [28,29].

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Lung NET variant syndrome — In patients with the lung NET variant, the flushes
can be very severe and prolonged, lasting hours to days [27]. They may be
associated with disorientation, anxiety, and tremor. Periorbital edema, lacrimation,
salivation, hypotension, tachycardia, diarrhea, dyspnea, asthma, edema, and
oliguria are other components of this variant. The specific hormone mediator of
flushing in patients with lung NETs is unclear, but it could be histamine. In some
cases, blood serotonin or urine 5-hydroxyindoleacetic acid (5-HIAA) levels are
normal. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors,
classification, histology, diagnosis, and staging".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Carcinoid syndrome (The Basics)")

SUMMARY
●At least seventy-five to 80 percent of patients with carcinoid syndrome have
small bowel primary neuroendocrine tumors (NETs); however, the
manifestations and severity vary in individual patients [5]. Gastric and lung
NETs are sometimes associated with atypical carcinoid syndromes (see
below).
●Among patients with NETs, carcinoid syndrome is most common in the
presence of liver metastases, but it can occur in locoregional disease. It is less
common overall with gastric and lung NETs, and almost never occurs in NETs
arising in the hindgut (distal colon and rectum). (See 'Frequency' above.)
●Episodic flushing is the clinical hallmark of carcinoid syndrome and occurs in
85 percent of patients. The typical flush associated with midgut NETs
(jejunum, ileum, cecum, appendix) begins suddenly and often lasts 20 to 30
seconds. It primarily involves the face, neck, and upper chest, which become

285
red to violaceous or purple, and is associated with a mild burning sensation
(picture 1). Severe flushes are accompanied by a fall in blood pressure and
rise in pulse rate. As the disease progresses, the episodes may last longer,
and the flushing may be more diffuse. The differential diagnosis of flushing is
listed in the table (table 4). (See 'Clinical features' above.)
●Diarrhea is a prominent complaint in the majority of patients with carcinoid
syndrome and is due to rapid intestinal transit time. Right-sided valvular
heart disease affects as many as 40 percent of patients. A minority may
experience bronchospasm.
●Some patients with functioning gastric or lung NETs have clinical and
biochemical variations from the classic syndrome.

286
Diagnosis of carcinoid syndrome and tumor
localization
Author:
Jonathan R Strosberg, MD
Section Editors:
Kenneth K Tanabe, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: May 17, 2021.
INTRODUCTIONThe term "carcinoid" has been generally applied to well-
differentiated neuroendocrine tumors (NETs) originating in the digestive tract,
lungs, or rare primary sites, such as the kidneys or ovaries. In modern use, the
term carcinoid is still used to refer to well-differentiated NETs arising in the lung
(typical or atypical carcinoids), but within the gastrointestinal tract, the term
carcinoid has fallen out of favor, and the World Health Organization (WHO)
preference is for the term "NET." Regardless of site, the term "neuroendocrine
carcinoma" is usually assigned to high-grade or poorly differentiated NETs.
(See "Pathology, classification, and grading of neuroendocrine neoplasms arising
in the digestive system", section on 'Pathology, tumor classification, and
nomenclature'.)

NETs can present in several different ways:

●As a result of carcinoid syndrome – Chronic flushing and/or diarrhea are

the typical manifestations of carcinoid syndrome, which is the result of
secretion of serotonin and other vasoactive substances into the systemic
circulation. Carcinoid syndrome is primarily associated with metastatic
tumors originating in the midgut (distal small intestine and proximal colon).
In contrast, hindgut (distal colorectal) and foregut (gastroduodenal, lung)
NETs uncommonly produce carcinoid syndrome. (See "Clinical features of
carcinoid syndrome" and "Lung neuroendocrine (carcinoid) tumors:
Epidemiology, risk factors, classification, histology, diagnosis, and staging",
section on 'Presenting signs and symptoms'.)
●As a result of tumor growth – Small bowel NETs may cause
chronic/recurrent abdominal pain, occasionally leading to bowel obstruction.

287
 Metastatic tumors in the liver can cause right upper quadrant pain,
hepatomegaly, and early satiety. (See "Clinical characteristics of well-
differentiated neuroendocrine (carcinoid) tumors arising in the
gastrointestinal and genitourinary tracts", section on 'Jejunoileal small bowel
tumors' and "Metastatic well-differentiated gastroenteropancreatic
neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical
monitoring", section on 'Clinical presentation'.)
●As an incidental finding – Many NETs are discovered during endoscopic or
radiographic procedures planned for other purposes; this is especially true of
NETs of the stomach and rectum.

This review will focus on the diagnosis of carcinoid syndrome and the
localization/staging of well-differentiated NETs. Clinical and pathologic
characteristics of NETs, treatment and prognosis of localized NETs, clinical
manifestations and treatment of carcinoid syndrome, and treatment options for
advanced metastatic gastrointestinal NETs are discussed separately:

●(See "Clinical characteristics of well-differentiated neuroendocrine

(carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
●(See "Pathology, classification, and grading of neuroendocrine neoplasms
arising in the digestive system".)
●(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring",
section on 'Clinical presentation'.)
●(See "Staging, treatment, and post-treatment surveillance of non-metastatic,
well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)
●(See "Clinical features of carcinoid syndrome".)
●(See "Treatment of the carcinoid syndrome".)
●(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone
hypersecretion".)
●(See "Metastatic well-differentiated gastrointestinal neuroendocrine
(carcinoid) tumors: Systemic therapy options to control tumor growth".)
BIOCHEMICAL TESTING FOR CARCINOID SYNDROMECarcinoid
syndrome is the result of secretion of serotonin and other vasoactive substances
into the systemic circulation in the setting of a neuroendocrine tumor, most often
a small bowel primary tumor with liver metastases. Hormone measurements in
the blood and/or urine can serve an important role in identifying and following
patients with carcinoid syndrome. In general, nonhormonal peptide biomarkers

288
(eg, chromogranin A [CgA]) markers are less useful. (See "Overview of tumor
biomarkers in gastroenteropancreatic neuroendocrine tumors".)
The presence of carcinoid syndrome is usually considered when a patient has
suggestive symptoms, such as otherwise unexplained chronic severe diarrhea
and/or flushing. Clinical features of carcinoid syndrome other than flushing and
diarrhea are presented elsewhere. (See "Clinical features of carcinoid syndrome".)
Differential diagnosis — Other conditions should be considered in the differential
diagnosis, however:
●The differential diagnosis for flushing, for example, includes physiologic
events, drugs, and a number of diseases other than carcinoid syndrome
(table 1). (See "Approach to flushing in adults".)
●The differential diagnosis for diarrhea is broad. (See "Approach to the adult
with chronic diarrhea in resource-rich settings".)
In addition to the well-differentiated neuroendocrine tumors (NETs) of the
gastrointestinal tract that cause carcinoid syndrome, other well-differentiated
NETs arising in the pancreas may cause severe diarrhea, including gastrinomas
and VIPomas. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical
manifestations and diagnosis" and "Management and prognosis of the Zollinger-
Ellison syndrome (gastrinoma)" and "VIPoma: Clinical manifestations, diagnosis,
and management".)

Assay of hormonal biomarkers can help in the differential diagnosis.

Hormonal markers
Blood serotonin concentration — We do not recommend measurement of blood
serotonin levels as a standard diagnostic test for carcinoid syndrome. Various
serotonin assays have been described in the literature, including whole blood
serotonin, platelet-rich plasma serotonin, and platelet-poor plasma serotonin
assays. However, the sensitivities and specificities of these assays are not well
established. In one report, the mean fasting blood serotonin concentration in
normal subjects ranged from 71 to 310 ng/mL (0.4 to 1.8 micromol/L). Ten patients
with carcinoid syndrome had markedly elevated values, from 790 to 4500 ng/mL
(4.5 to 25.5 micromol/L); of these, two had normal urinary 5-hydroxyindoleacetic
acid (5-HIAA) excretion [1]. Notably, false-positive serotonin tests may occur due to
release of platelet serotonin in stored blood samples, as well as from the ingestion
of tryptophan/serotonin-rich foods [2].
Urinary excretion of 5-HIAA — A preferred initial diagnostic test for carcinoid
syndrome is to measure 24-hour urinary excretion of 5-HIAA, which is the end
product of serotonin metabolism (figure 1). This test has a sensitivity of over 90

289
percent and a specificity of 90 percent for carcinoid syndrome [3]. Sensitivity is low
in patients with NETs without carcinoid syndrome [4].
False-positive results may be induced by the ingestion of certain drugs and
tryptophan/serotonin-rich foods (table 2). These foods should be avoided for three
days prior to urine collection [5].
Measurement of urinary excretion of 5-HIAA is generally most useful in patients
with primary midgut (jejunoileal, appendiceal, ascending colon) NETs, which
produce the highest levels of serotonin. Foregut (gastroduodenal, bronchus) and
hindgut (transverse, descending, and sigmoid colon, rectum, genitourinary) NETs
only rarely secrete serotonin; they lack the enzyme dopa decarboxylase and
cannot convert 5-hydroxytryptophan (5-HT) into serotonin and, therefore, into 5-
HIAA (figure 1) [6]. These tumors may produce 5-HT (and histamine) instead of
serotonin. However, there is no commercially available assay for urinary 5-HT.
The normal rate of 5-HIAA excretion ranges from 2 to 8 mg/day (10 to 42
micromol/day). Values of up to 30 mg/day (157 micromol/day) may be found in
patients with malabsorption syndromes, such as celiac and Whipple's disease, as
well as after the ingestion of large amounts of tryptophan- or serotonin-rich foods
(table 2). Although many patients with carcinoid syndrome have similar modest
elevations, some have values for urinary 5-HIAA excretion above 100 mg/day (523
micromol/day). In one study, for example, urinary 5-HIAA excretion in patients with
carcinoid syndrome ranged from 99 to 2070 mg/day (518 to 10,826 micromol/day)
[3].
Plasma 5-HIAA concentration — Plasma 5-HIAA measurement is a reasonable
option, particularly for patients who have difficultly providing 24-hour urine
specimens, although published experience with this assay is confined to a small
number of institutions, and this test has yet to be validated in large clinical series.
Plasma 5-HIAA levels can be obtained from several laboratories, and reportedly
correlate closely with urine 5-HIAA [7-9]. In one study of 115 NET patients, levels of
fasting plasma 5-HIAA correlated very closely with levels of urine 5-HIAA (p
<0.0001) [8].
Gastrin and VIP — As noted above, some functional pancreatic neuroendocrine
tumors (notably, gastrinomas and VIPomas) can be associated with severe
diarrhea. In such cases, assays to 5-HIAA may be negative, but serum levels of
gastrin and vasointestinal polypeptide (VIP) may be elevated, and aid in the
differential diagnosis. (See "Overview of tumor biomarkers in
gastroenteropancreatic neuroendocrine tumors", section on 'Hormones
associated with pancreatic NETs'.)
Nonhormonal markers

290
Chromogranin concentration — Due to its relatively low specificity, we do not
recommend the use of CgA as a screening test for the diagnosis of a NET or
carcinoid syndrome. CgA may be an appropriate tumor biomarker for patients
with an established diagnosis of advanced NET in order to assess disease
progression, response to therapy, or, in some cases, recurrence after surgical
resection. (See "Overview of tumor biomarkers in gastroenteropancreatic
neuroendocrine tumors", section on 'Chromogranin A (CgA)'.)
Chromogranins (designated as chromogranin A [CgA], chromogranin B [CgB], and
chromogranin C [CgC]) are proteins that are stored and released with peptides and
amines in a variety of neuroendocrine tissues. Well-differentiated NETs, including
carcinoids, are associated with elevated blood concentrations of chromogranins,
which increase with larger tumor burden [5,10-12]. CgB and CgC are less sensitive
indicators of NETs as compared with CgA [13].

Despite a high volume of published studies evaluating multiple circulating

nonhormonal tumor markers like CgA in NETs, consensus-based guidelines have
increasingly de-emphasized their role in clinical care for the following reasons:

●Levels of CgA secretion vary on a day-by-day basis in healthy subjects and

those with NETs.
●Food intake also increases CgA levels [14,15]. False-positive elevations of
CgA can be present in a number of other conditions, including atrophic
gastritis (table 3). They are especially common in patients who are taking a
proton pump inhibitor [16-18]. As a result, CgA is a relatively nonspecific
marker for NETs [4,5,19].
●A recognized international standard for CgA assay is not available, and
multiple CgA tests exist that use different assays, have widely divergent
normal thresholds, and varying degrees of accuracy [20].
Sensitivity is limited for localized disease. Test performance is better with
advanced disease and varies according to disease burden, and the specific cutoff
value [11,21]. In general, serial measurements of CgA and/or other nonhormonal
tumor markers are most useful in patients with metastatic NETs and highly
elevated levels of the marker, which are more likely to be true-positives than false-
positives. In such patients, serial assay of CgA levels may be a reasonable indicator
of disease activity and response to antitumor therapy. Whenever we do measure
tumor marker levels, we usually obtain them in conjunction with radiographic
imaging, typically every 6 to 12 months. (See "Overview of tumor biomarkers in
gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A
(CgA)' and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine

291
tumors: Presentation, prognosis, imaging, and biochemical monitoring", section
on 'Chromogranin A'.)
TUMOR LOCALIZATION AND STAGINGCarcinoid syndrome is primarily
associated with metastatic neuroendocrine tumors (NETs) that originate in the
small intestine or proximal colon. Vasoactive peptides that are produced by
localized intestinal NETs are inactivated in the portal circulation and, thus, do not
result in carcinoid syndrome. The liver is the most common distant metastatic site.
Imaging studies should, therefore, focus on the abdomen and pelvis. Computed
tomography (CT), magnetic resonance imaging (MRI), and diagnostic imaging
using radiolabeled somatostatin analogs (SSAs; indium-111 pentetreotide [111-In
pentetreotide; OctreoScan] and gallium Ga-68 DOTATATE [68-Ga DOTATATE]) are
the primary imaging modalities used to identify NETs.
Computed tomography — CT scans are noninvasive and readily available.
Multiphasic contrast-enhanced CT is recommended for evaluation of all patients
with NETs, with the exception of tumors with a very low probability of spread, such
as most type 1 and 2 gastric NETs or small (<1 to 2 cm) superficial (T1) rectal NETs
[22,23]. (See "Staging, treatment, and post-treatment surveillance of non-
metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid)
tumors", section on 'Staging and treatment of localized tumors'.)
Most NET liver metastases are highly vascular, but approximately 6 to 20 percent
are hypovascular [24]. Hypervascular metastases may appear isodense with the
liver on a noncontrasted study. Following the injection of intravenous contrast,
most NETs enhance with iodinated contrast during the early arterial phase
(approximately 20 seconds after contrast injection), with washout during the portal
venous imaging phase (approximately 70 seconds after contrast injection) [24,25].
Arterial phase and portal venous phase sequences maximize the conspicuity of
liver metastases compared with the surrounding normal liver parenchyma (image
1).

The ability of CT to localize the site of the primary tumor in patients with carcinoid
syndrome is variable:

●NETs originating in the jejunum and ileum are often difficult to identify on
CT because of their small size. However, multiphasic helical CT performed
with neutral oral contrast and multiplanar reformations can improve
detection [24]. Arterial phase imaging can aid in detection of these early
enhancing lesions. Small intestinal NETs often produce mesenteric masses
with dense desmoplastic fibrosis, either due to direct extension of primary
tumors into the mesentery or due to mesenteric lymph node metastases
(image 2). The classic finding on CT is a mass-like process with soft tissue
292
 "spokes" radiating into the mesenteric fat toward the small bowel, often
causing retraction of the bowel with angulation and tethering. The central
mass may or may not be calcified. The differential diagnosis includes
sclerosing mesenteritis. (See "Staging, treatment, and post-treatment
surveillance of non-metastatic, well-differentiated gastrointestinal tract
neuroendocrine (carcinoid) tumors", section on 'Small intestine'.)
●Appendiceal NETs may not be seen on CT because of their small size [24].
The scan may only show features of appendicitis, such as diffuse thickening
of the appendix or periappendiceal fat stranding. A larger tumor may present
as a soft tissue mass in the appendix, with or without calcification. (See "Well-
differentiated neuroendocrine tumors of the appendix", section on 'Staging
and prognosis'.)
●Colonic NETs tend to be large (>2 cm) and more frequently involve the
cecum and ascending colon. CT cannot differentiate a colonic NET from the
more common adenocarcinoma since both present as circumferential
thickening or polypoid masses and may have adjacent lymphadenopathy
[24]. (See "Staging, treatment, and post-treatment surveillance of non-
metastatic, well-differentiated gastrointestinal tract neuroendocrine
(carcinoid) tumors", section on 'Colon'.)
Magnetic resonance imaging — MRI may represent the most sensitive method
for detection of liver metastases. In one study of 64 patients with metastatic
gastrointestinal NETs, multiphasic MRI detected more hepatic lesions than either
CT or 111-In pentetreotide [26]. As a result of this greater sensitivity for liver
metastases, some clinicians prefer MRI over CT for assessing the status of the liver
in patients with NETs [27]. This subject is discussed in detail elsewhere.
(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring", section
on 'Cross-sectional imaging'.)
However, even MRI can significantly underestimate the total tumor burden,
especially when lesions are small. In a study comparing preoperative imaging with
thin-section pathology mapping, the accuracy for detecting liver metastases was
only 49 percent for MRI [28].
As with CT scans, early arterial phase imaging following the injection of contrast is
critical for the detection of small hypervascular liver metastases. In a study of 37
patients with liver metastases from gastroenteropancreatic NETs, the most
sensitive sequences for detection of liver metastases were hepatic arterial phase
and fast spin-echo T2-weighed images [29]. In another study comparing two MRI
contrast agents, the delayed hepatobiliary phase using gadoxetate (Eovist)

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contrast provided the highest contrast-to-noise ratio as well as the highest levels
of interobserver agreement on tumor diameter [30].
Somatostatin receptor imaging — Most well-differentiated NETs express high
levels of somatostatin receptors (SSTRs) and can therefore be imaged with
radiolabeled SSAs. These scans allow for whole body imaging. They also provide
information on SSTR expression, which has important therapeutic implications
regarding use of cold and radiolabeled SSAs. The first imaging technique to
visualize SSTR-expressing tumors used 111-In pentetreotide to produce a
scintigraphic image (OctreoScan). The accuracy of 111-In pentetreotide improved
with the addition of single-photon emission computed tomography (SPECT) to
planar imaging (image 3) [31,32]. More recently, several positron emission
tomography (PET) tracers for SSTR imaging have emerged (such as 68-Ga
DOTATATE and 68-Ga DOTATOC), which in combination with CT, improve the
detection and staging of NETs [33]. These novel PET modalities offer higher spatial
resolution than conventional 111-In pentetreotide scanning and are associated
with improved sensitivity for detection of small lesions, including occult primary
tumors (image 4). In our view (and that of others [34]), 68-Ga DOTATATE or 68-Ga
DOTATOC PET/CT, where available, is preferred over conventional 111-In
pentetreotide scanning for tumor localization. This subject is discussed in detail
elsewhere. (See "Neuroendocrine neoplasms of unknown primary site", section on
'Initial workup' and "Diagnosis and staging of small bowel neoplasms", section on
'Somatostatin receptor-based imaging'.)
Of note, poorly differentiated neuroendocrine carcinomas generally express fewer
SSTRs and are not routinely evaluated with SSTR imaging [35].
Endoscopy — Upper and lower endoscopy (with attention to the terminal ileum)
should be performed for the evaluation of metastatic NET with an unknown
primary site. Other options include CT enterography. Although video capsule
endoscopy has been used to detect the primary site in metastatic NETs, we do not
recommend this study given several reports of obstruction following ingestion of
the video capsule [36].
Lung neuroendocrine tumors — CT scans and diagnostic imaging with
radiolabeled SSAs can be used to localize well-differentiated lung NETs (bronchial
carcinoids). These tumors tend to be centrally located endobronchial lesions;
however, approximately 20 percent arise peripherally and present as a well-
circumscribed solitary pulmonary nodule (image 5). Uncommonly, lung NETs can
present with carcinoid syndrome, even in the absence of hepatic metastases.
(See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors,
classification, histology, diagnosis, and staging", section on 'Clinical syndromes
related to peptide production'.)

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SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Carcinoid syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS
●The presence of carcinoid syndrome may be suspected when a patient has
suggestive symptoms, such as otherwise unexplained diarrhea or flushing.
However, other diagnoses must be considered. The differential diagnosis of
flushing, for example, includes physiologic events, drugs, and a number of
diseases other than carcinoid syndrome (table 1). Moreover, other
neuroendocrine tumor (NET) types can cause severe chronic diarrhea.
(See 'Differential diagnosis' above.)
●The most useful initial diagnostic test for carcinoid syndrome is to measure
24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), which is the
end product of serotonin metabolism (figure 1). Depending on the cutoff
value used, this test has a high sensitivity and high specificity for carcinoid
syndrome but requires strict avoidance of foods containing serotonin and
tryptophan as well as certain drugs for three days prior to the urine collection
(table 2). (See 'Urinary excretion of 5-HIAA' above.)
Measurement of urinary 5-HIAA excretion is generally not useful in foregut
(gastroduodenal, lung) NETs, which often lack aromatic amino acid
decarboxylase. In this setting, we would pursue imaging studies to search for
a NET.

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Due to its relatively low specificity, we do not recommend the use of serum
chromogranin A (CgA) as a screening test for the diagnosis of carcinoid
syndrome. (See 'Chromogranin concentration' above.)
●Once the biochemical diagnosis of carcinoid syndrome is confirmed, usually
by an elevated 24-hour excretion of 5-HIAA, the tumor must be localized. Two
techniques, standard cross-sectional imaging and diagnostic imaging with
radiolabeled somatostatin analogs (SSAs), have a complementary role in
tumor localization. For the diagnostic workup of carcinoid syndrome, we
generally perform helical, contrast-enhanced, triple-phase computed
tomography (CT) scans of the abdomen and pelvis. (See 'Computed
tomography' above.)
Contrast-enhanced magnetic resonance imaging (MRI) of the abdomen and
pelvis is an acceptable alternative and is preferred by some clinicians because
of its greater sensitivity for liver metastases. (See 'Magnetic resonance
imaging' above.)
Uptake of radiolabeled SSAs can assist in identifying an otherwise occult
primary site. Where available, functional imaging with gallium Ga-68
DOTATATE positron emission tomography (PET)/CT is preferred over indium-
111 pentetreotide (OctreoScan) due to its greater sensitivity.
(See 'Somatostatin receptor imaging' above.)

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Staging, treatment, and post-treatment
surveillance of non-metastatic, well-differentiated
gastrointestinal tract neuroendocrine (carcinoid)
tumors
Authors:
Jonathan R Strosberg, MD
Alexandra Gangi, MD
Section Editors:
Kenneth K Tanabe, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jun 16, 2021.
INTRODUCTIONThe term "neuroendocrine tumor (NET)" refers to well-
differentiated neuroendocrine neoplasms, and "neuroendocrine carcinoma (NEC)"
refers to poorly differentiated neuroendocrine cancers. The term "carcinoid" has
been generally applied to well-differentiated neuroendocrine tumors (NETs)
originating in the digestive tract, lungs, or rare primary sites such as the kidneys or
ovaries. (See "Pathology, classification, and grading of neuroendocrine neoplasms
arising in the digestive system", section on 'Pathology, tumor classification, and
nomenclature' and "High-grade gastroenteropancreatic neuroendocrine
neoplasms".)
"Carcinoid syndrome" is the term applied to a constellation of symptoms mediated
by various humoral factors that are elaborated by some NETs (table 1) [1]. Two of
the most common manifestations are flushing and diarrhea (table 2). (See "Clinical
features of carcinoid syndrome".)
Most NETs are associated with carcinoid syndrome only when they have
metastasized to the liver (table 3).

In general, the basic principles of evaluation and management of patients with

NETs include:

●Radiographic staging and tumor localization – Common imaging

modalities include computed tomography (CT) or magnetic resonance
imaging (MRI) scans as well as somatostatin receptor-based diagnostic

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 imaging (Indium-111 pentetreotide imaging [OctreoScan] or gallium Ga-68
DOTATATE (or gallium Ga-68 DOTATOC or copper Cu-64 DOTATATE)
integrated positron emission tomography [PET]/CT scanning). Where
available, integrated PET/CT using one of the radiolabeled somatostatin
analogs is preferred over OctreoScan because of greater sensitivity.
Upper and lower endoscopy (with attention to the terminal ileum) should be
performed for the evaluation of metastatic NET with an unknown primary
site. CT enterography can also be used for this purpose. While video capsule
endoscopy allows for evaluation of the entire small intestine, routine use of
capsule endoscopy cannot be recommended due to the risk of bowel
obstruction from retention of the capsule at the site of an intestinal NET.
(See "Neuroendocrine neoplasms of unknown primary site", section on 'Well-
differentiated neuroendocrine tumor'.)
Mesenteric masses are usually indicative of a primary tumor located in the
small intestine. Radiographic staging and tumor localization of NETs is
addressed in detail elsewhere. (See "Diagnosis of carcinoid syndrome and
tumor localization".)
●Pathologic assessment of tumor differentiation and/or
grade (assessment of mitotic rate and/or Ki-67 index, presence/absence of
necrosis and pleomorphism) – This subject is addressed in detail elsewhere.
(See "Pathology, classification, and grading of neuroendocrine neoplasms
arising in the digestive system", section on 'Pathology, tumor classification,
and nomenclature'.)
●Removal of the tumor if all disease is surgically resectable, even if liver
metastases are present. (See "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and
symptoms of hormone hypersecretion", section on 'Surgical resection'.)
●Control of carcinoid symptoms, if present. (See "Treatment of the carcinoid
syndrome".)
●Judicious use of antitumor therapy for unresectable metastatic
disease – One of the key principles underlying selection of appropriate
therapy for advanced disease is the indolent nature of most well-
differentiated NETs and their prolonged natural history; this must be
weighed against the toxicity of available antitumor regimens.

This topic review will provide an overview of treatment of localized NETs, focusing
on treatment of digestive tract primary sites. Antitumor treatment, prognosis and
biochemical monitoring of patients with advanced or metastatic disease, diagnosis
and treatment of the carcinoid syndrome, radiologic staging, tumor localization

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and histologic assessment of gastroenteropancreatic NETs, management of
bronchial and thymic NETs, and evaluation and management of high-grade
neuroendocrine carcinomas are discussed in detail elsewhere.

●(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local

options to control tumor growth and symptoms of hormone
hypersecretion".)
●(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Treatment of the carcinoid syndrome".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms".)
●(See "Pathology, classification, and grading of neuroendocrine neoplasms
arising in the digestive system".)
●(See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors,
classification, histology, diagnosis, and staging".)
●(See "Thymic neuroendocrine (carcinoid) tumors".)
●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

STAGING AND TREATMENT OF LOCALIZED TUMORSThe treatment of

choice for a patient who has a localized well-differentiated neuroendocrine tumor
(NET) is usually surgery. The extent of the surgical resection depends on the site of
origin and size of the primary tumor. A detailed discussion of the clinical
presentation of NETs arising in specific organs is available elsewhere. (See "Clinical
characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in
the gastrointestinal and genitourinary tracts".)
Staging studies — Multiphasic contrast-enhanced computed tomography (CT) is
recommended for evaluation of all patients with NETs, with the exception of
tumors with very low probability of spread, such as most type 1 and 2 gastric NETs,
or small (<1 cm) superficial (T1) rectal NETs. (See "Diagnosis of carcinoid syndrome
and tumor localization", section on 'Tumor localization and staging'.)
The utility of other studies, including magnetic resonance imaging (MRI),
somatostatin receptor-based diagnostic imaging with either indium-111
pentetreotide scanning (OctreoScan) or integrated positron emission tomography
(PET)/CT using gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC or copper Cu-
64 DOTATATE, and biochemical markers, such as chromogranin A and urinary 5-
hydroxyindoleacetic acid (5-HIAA), are discussed in detail elsewhere.
(See "Diagnosis of carcinoid syndrome and tumor localization" and "Metastatic

299
well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation,
prognosis, imaging, and biochemical monitoring" and "Diagnosis and staging of
small bowel neoplasms", section on 'Neuroendocrine tumors' and "Overview of
tumor biomarkers in gastroenteropancreatic neuroendocrine tumors".)
Appendix — The prognosis of appendiceal NETs is best predicted by tumor size. In
many series, tumors less than 2 cm in diameter (found in approximately 95
percent of patients) have a low likelihood of metastases at diagnosis (table 4). In
contrast, up to 30 percent of larger tumors have already metastasized at
diagnosis, mostly to regional nodes. (See "Well-differentiated neuroendocrine
tumors of the appendix", section on 'Clinical presentation'.)
The current Tumor, Node, Metastasis (TNM) staging system (eighth edition, 2017)
for appendiceal NETs is distinct from the TNM staging system for NETs arising at
other sites within the gastrointestinal tract and lung (table 5) [2]. (See "Well-
differentiated neuroendocrine tumors of the appendix", section on 'Staging and
prognosis'.)

Optimal surgical management for appendiceal NETs is subject to some debate.

Because most are discovered incidentally in an appendectomy specimen done for
other reasons, a decision must be made whether or not to return the patient to
the operating room for a right colectomy. Unlike simple appendectomy, colectomy
removes the draining lymph nodes of the appendix and any residual disease that
might remain at the base of the appendix or in the mesoappendix.

Because of the association of tumor size with prognosis, a right hemicolectomy

has been traditionally recommended for tumors greater than 2 cm or those with
mesoappendiceal invasion [3]. On the other hand, whether or not a colectomy
should be performed in some patients with smaller tumors is unclear; there is
limited evidence on which to base clear indications for hemicolectomy. Some
clinicians pursue completion right colectomy for tumors <2 cm only if there is
evidence of mesoappendiceal invasion or positive or unclear margins, while others
disagree and consider that appendectomy alone is adequate for tumors <2 cm,
even with mesoappendiceal invasion. There is general agreement that tumors less
than 1 cm can usually be treated by simple appendectomy [3].
These issues are discussed in more detail elsewhere. (See "Well-differentiated
neuroendocrine tumors of the appendix", section on 'Treatment of localized
disease'.)
Small intestine — NETs of the small intestine are most commonly found in the
ileum within 60 cm of the ileocecal valve. Small intestinal NETs have the potential
to metastasize, irrespective of size (table 4). The current (eighth edition, 2017) TNM
staging system from the combined American Joint Committee on Cancer
300
(AJCC)/Union for International Cancer Control (UICC) has separate TNM
classifications and prognostic stage groupings for jejunoileal (table 6) [4] and
duodenal/ampullary tumors (table 7) [5]. (See "Epidemiology, clinical features, and
types of small bowel neoplasms", section on 'Well-differentiated gastrointestinal
neuroendocrine tumors'.)
Patients with non-metastatic tumors should be treated with resection of the
involved segment and small bowel mesentery [3] (see "Treatment of small bowel
neoplasms", section on 'Neuroendocrine tumors'). Because multiple NETs are
present in approximately 25 to 55 percent of cases, the remainder of the small
bowel should be examined at the time of surgery [6,7]. Although this is a
controversial area, resection of the primary tumor may be advised even in patients
with known distant metastases in order to reduce the potential for bowel
obstruction or bleeding, or to palliate abdominal pain related to the primary
tumor.
The prognosis depends upon disease stage [8]. (See 'Stage and site of
origin' below.)
However, even among patients with distant metastasis, five-year overall survival
rates range from 40 to 85 percent; 10-year survival rates of 40 to 60 percent are
reported [8-12]. Ten-year disease-specific survival rates stratified according to the
2010 AJCC/UICC stage groupings from a series of 6792 patients with small intestine
NETs diagnosed between 1988 and 2009 derived from the National Cancer
Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) registry were as
follows [12]:
●Stage I – 95 percent (95% CI 93-97 percent)
●Stage IIA – 95 percent (95% CI 90-96 percent)
●Stage IIB – 77 percent (95% CI 71-83 percent)
●Stage IIIA – 68 percent (95% CI 58-77 percent)
●Stage IIIB – 77 percent (95% CI 74-80 percent)
●Stage IV – 42 percent (95% CI 38-46 percent)
Limited data are available that stratify prognosis according to the most recent
eighth edition classification, which separates jejunoileal and duodenal/ampullary
tumors and condenses stages I to IV disease (eliminating the A and B substages)
(figure 1) [2].
Prognosis among surgically treated patients also depends on margin status
[11,13]. (See 'Residual disease' below.)
Ampulla of Vater — Ampullary NETs are rare. The most recent TNM classification
(eighth edition, 2017) has a distinct staging system for duodenal and ampullary
NETs that is separate from that used for jejunoileal primary sites (table 7) [5].

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There is a high likelihood of nodal metastases with ampullary NETs, even with
tumor size <2 cm [14-17]. Pancreaticoduodenectomy has been advocated for
resectable cases regardless of size due to relatively high risk of occult nodal
metastases. However, these recommendations are based on very small case
series, and treatment decisions may need to be individualized based on precise
location of tumors, histologic grade, depth of invasion, and patient suitability for
aggressive surgery.
Rectum — Most rectal NETs are small, localized, and mucosal or submucosal in
location [18,19]. As with rectal adenocarcinomas, transrectal endoscopic
ultrasound (TEUS) is often useful for assessment of tumor size, depth of invasion,
and lymph node involvement in rectal NETs [20,21]. (See "Clinical characteristics of
well-differentiated neuroendocrine (carcinoid) tumors arising in the
gastrointestinal and genitourinary tracts", section on 'Rectum' and "Endoscopic
ultrasound for evaluating patients with rectal cancer".)
The current (eighth edition, 2017) TNM staging system used for NETs of the colon
and rectum is outlined in the table (table 8) [22]. While many small rectal NETs
exhibit indolent behavior, certain risk factors predict for metastases. Traditionally,
tumor size and depth of invasion (T stage) have been the main determinants of
prognosis:
●According to one report [23], metastases were found in 2 percent of patients
with tumors <1 cm, 10 to 15 percent in patients with tumors measuring 1.0 to
1.9 cm, and 60 to 80 percent in tumors measuring >2 cm.
●Another report [24] indicated that in tumors <2 cm, the rate of metastasis
was 2 percent of patients if the tumor was confined to the submucosa, but as
high as 48 percent if the tumor invaded the muscularis propria.
●More recent reports [25,26] have identified additional prognostic factors,
including mitotic index and lymphovascular invasion (LVI), which could
portend a poorer prognosis even among patients with relatively small (<2 cm)
and superficial tumors [27].
Observation alone results in inferior outcomes, even for small tumors <1 cm [28].
Treatment options for localized rectal NETs include conventional endoscopic
resection (standard polypectomy or endoscopic mucosal resection [EMR]),
advanced endoscopic resection (endoscopic submucosal dissection, transanal
endoscopic microsurgery [TEM], cap-assisted EMR), transanal surgical resection, or
radical resection (low anterior resection [LAR], abdominoperineal resection [APR]).
Decisions about technique should be based on tumor size and other risk factors
for nodal metastases:
●Tumors smaller than 1 cm and confined to the mucosa or submucosa (T1)
can generally be treated by standard endoscopic resection [18,23,29-32],

302
 particularly if they lack other risk factors (ie, mitotic rate >2 per 10 high-
power fields [HPF] or LVI). A greater likelihood of negative resection margins
may be achievable with more advanced endoscopic techniques including
endoscopic submucosal dissection [33,34] and cap-assisted EMR (in which the
tumor is suctioned into a cap and then removed with a snare) [35]. However
it is unclear whether negative margins are necessary given the excellent
outcome of patients with low-grade T1 tumors, even with positive or
indeterminant margins [32].
●Large tumors (>2 cm) or those that invade the muscularis propria (≥T2) are
generally treated with radical surgical resection (LAR or APR) [36]. This
approach is endorsed by consensus-based guidelines from the National
Comprehensive Cancer Network and the European Neuroendocrine Tumor
Society [37,38]. Although some data suggest that local excision may be a
viable alternative for some subgroups of patients with lower-risk rectal
neuroendocrine tumors >2 cm, the optimal way to select these patients is not
established, and we do not endorse this approach unless patients refuse
radical resection [39].
●The management of intermediate-sized tumors (1 to 2 cm confined to
mucosa or submucosa) is somewhat controversial. Transanal resection or
advanced endoscopic resection techniques (such as TEM) may be appropriate
for tumors lacking risk factors, whereas radical resection may be more
appropriate for tumors with risk factors such as elevated mitotic rate (or Ki-67
index), LVI, or size >1.5 cm [25,40].
For well-differentiated NETs, prognosis is mainly dependent on tumor size and
depth of invasion, as reflected by the T-stage classification [10]. Prognosis
stratified according to disease stage is available from the following reports:
●In a SEER database series, the five-year survival rates for localized, regional,
or distant disease involving the rectum or rectosigmoid junction over the last
decade were 90, 49, and 26 percent, respectively [41].
●In another report of 258 well-differentiated rectal NETs reported to the
National Cancer Database between 1998 and 2002 that were stratified
according to stage, five-year overall survival rates were 92, 88, 59, and 15
percent for stage I, II, III, and IV disease, respectively [42].
●Similarly, in a series of 122 Korean patients treated for rectal NET between
1995 and 2010, and staged according to the seventh edition AJCC staging
system, five-year survival rates were 100, 80, 51, and 0 percent for stage I, II,
III, and IV disease, respectively [43].
Prognosis is significantly worse for high grade neuroendocrine carcinomas [27].
(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

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Colon — Colonic NETs are staged similarly to rectal NETs. (See 'Rectum' above.)
Colonic NETs tend to be more aggressive than those arising in the rectum. In one
large series derived from the SEER database, five-year survival rates were only 62
percent across all stages (compared with 88 percent for rectal NETs) [41]. In a
dataset of 5457 colorectal NETs reported to the National Cancer Database between
1998 and 2002, compared with rectal primaries, a colonic primary site was
associated with significantly poorer overall survival (hazard ratio [HR] for death
1.85, 95% CI 1.61-2.13) [42].
Well-differentiated colonic NETs have the worst prognosis of any gastrointestinal
tract well-differentiated NET [30,41,44,45]. One reason for more aggressive
behavior may be that colonic NETs are frequently right sided and may be clinically
occult until locally advanced; approximately two-thirds have evidence of nodal or
distant metastases at the time of diagnosis [46,47]. (See "Clinical characteristics of
well-differentiated neuroendocrine (carcinoid) tumors arising in the
gastrointestinal and genitourinary tracts", section on 'Colon'.)
Given that most tumors are >2 cm and/or invasive through the muscularis propria,
patients with non-metastatic well-differentiated NETs of the colon should be
managed with formal partial colectomy and regional lymphadenectomy, similar to
treatment of colonic adenocarcinomas [30]. (See "Overview of the management of
primary colon cancer", section on 'Surgical resection' and "Surgical resection of
primary colon cancer".)
Prognosis is dependent on stage (table 8) [10]. Five-year overall survival for a
series of 882 well-differentiated colonic NETs reported to the National Cancer
Database between 1998 and 2002 and stratified according to AJCC stage were 86,
79, 65, and 27 percent for stage I, II, III, and IV disease, respectively [42].
Prognosis is significantly worse for high-grade neuroendocrine carcinomas.
(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
Stomach — Gastric NETs are subdivided into three categories, with differing
biologic behavior and prognoses:
●Type 1 gastric NETs, which represent 70 to 80 percent of all gastric NETs, are
associated with chronic atrophic gastritis. In this condition, serum gastrin
rises in response to gastric achlorhydria. The elevated gastrin, in turn,
stimulates neuroendocrine cell hyperplasia in the stomach and development
of multifocal polypoid NETs. The clinical behavior of these tumors is usually
indolent. Most are grade 1 tumors with stage I disease and no mortality with
prolonged follow-up [48,49].
●Type 2 gastric NETs, which represent approximately 5 percent of gastric
NETs, also occur as a result of elevated serum gastrin levels stimulating
multifocal gastric NETs. The underlying cause of type 2 gastric NETs is a

304
 pancreatic or duodenal gastrinoma (Zollinger-Ellison syndrome). The clinical
behavior is usually indolent.
●Type 3 (sporadic) gastric NETs occur in the absence of atrophic gastritis or
the Zollinger-Ellison syndrome. They account for 20 percent of gastric NETs
and are the most aggressive; local or hepatic metastases are present in up to
65 percent of patients who come to resection.
Definitions and a more complete discussion of characteristics of the different types
of gastric NETs are discussed elsewhere. (See "Clinical characteristics of well-
differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal
and genitourinary tracts", section on 'Stomach'.)
The current (eighth edition, 2017) staging system is depicted in the table (table 9)
[50].

Management depends on the type of gastric NET:

●Type 3 (sporadic) gastric NETs are generally treated by partial or total

gastrectomy with local lymph node resection [51-53]. The risk of nodal
metastases is dependent on tumor size and depth. Some have suggested
that endoscopic resection alone may represent adequate therapy for
intraepithelial tumors <2 cm and perhaps for tumors <1 cm invading the
lamina propria or submucosa [54], while others suggest wedge resection or
endoscopic therapy alone only for those with a well-differentiated (grade 1)
gastric NET no larger than 1.5 cm and without lymphovascular invasion [55].
However, this is not a standard approach, and we generally advocate
gastrectomy/lymphadenectomy for all type 3 tumors, regardless of size and
histologic differentiation.
For type 1 and 2 gastric NETs smaller than 1 to 2 cm, endoscopic resection
represents adequate therapy [49,56,57]. Subsequent endoscopic surveillance
is needed every 6 to 12 months since these patients continue to exhibit
mucosal changes and hyperplasia of enterochromaffin-like cells (ECL) due to
sustained hypergastrinemia. (See 'Post-treatment follow-up' below.)
Progression to a malignant phenotype or disease-related death is rare with
small tumors [58]. Metastases occur in less than 10 percent of tumors ≤2 cm
[59].
Antrectomy is a controversial option for type 1 gastric NETs if there are
numerous progressive tumors. Antrectomy reduces hypergastrinemia by
reducing the gastrin-producing cell mass in the antrum of the stomach; in
most cases, this leads to tumor regression [56,60-63]. This approach was
used in a series of 51 patients with type I gastric NETs, 10 of whom had
antrectomy (eight in conjunction with endoscopic removal of the largest
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 tumor) [56]. Seven of the eight with residual disease became endoscopically
tumor-free, and one progressed and died of metastatic disease. In all, 9 of
the 10 patients treated with antrectomy remained tumor free for an average
of 65 months.
●More aggressive surgical therapy is rarely needed for type 1 gastric NETs
unless there is extensive tumor involvement of the gastric wall (which
increases the risk for a coexisting adenocarcinoma [64]), tumor size >2 cm
(which increases the risk for metastases [59]), poorly differentiated histology,
or emergent bleeding [65].
The role of medical rather than surgical therapy (anti-gastrin maneuvers such as
acidification by diet or dilute oral hydrochloric acid, or somatostatin analog
therapy) for type 1 tumors is debated [51,62,66,67]. Gastrin levels may or may not
decrease, and continued endoscopic surveillance is necessary.
Lung — The preferred treatment for bronchial NETs is surgical resection. The
clinical features, diagnosis, and treatment of bronchial NETs are discussed
separately. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk
factors, classification, histology, diagnosis, and staging".)
POST-TREATMENT FOLLOW-UPThere is limited evidence from which to
make recommendations for follow-up after resection of a well-differentiated
neuroendocrine tumor (NET). For all resected well-differentiated small intestinal
and colonic NETs and for rectal, gastric, and appendiceal NETs >2 cm, in our
practice we focus on long-term (rather than frequent) surveillance given the fact
that distant relapses can occur beyond five years after surgery, particularly with
small bowel primary tumors. As an example, in one study of 129 midgut NETs,
there was a fairly steady annual rate of recurrence for the first eight years after
surgery, followed by a decline in risk of recurrence after eight years [68]. For
patients with resected small intestinal NETs, we generally recommend surveillance
with triple-phase computed tomography (CT) scans or magnetic resonance
imaging (MRI) of the abdomen and pelvis every six months for the first year after
surgery, then roughly annually for approximately 10 years after surgery [69]. For
surveillance of NETs at other sites, we generally follow a similar strategy; however,
more frequent surveillance can be considered for more aggressive tumors, such as
grade 2, lymph node positive, gastric or rectal NETs. We do not recommend post-
treatment surveillance for low-grade appendiceal tumors <2 cm and superficial
low-grade rectal tumors <1 cm in size given the exceptionally low risks of
recurrence.
The role of nonhormonal biomarkers such as chromogranin A (CgA) in surveillance
is controversial as the contribution to detection of recurrent disease is limited
[68,70]. Furthermore, specificity is limited as a number of conditions and
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medications (especially proton pump inhibitors) can falsely elevate the CgA (table
10). Consensus-based guidelines have increasingly deemphasized the role of CgA
in clinical care. (See "Overview of tumor biomarkers in gastroenteropancreatic
neuroendocrine tumors", section on 'Role of nonhormonal tumor markers in
clinical practice'.)
In general, 24-hour measurements of urinary 5-hydroxyindoleacetic acid (5-HIAA)
are not recommended for postoperative surveillance of tumors that are unlikely to
produce serotonin (ie, well-differentiated NETs of the hindgut [distal colon and
rectum], or foregut [lungs, stomach, duodenum]). If serial assay of 24-hour urinary
5-HIAA is performed for the rare localized midgut tumor that was initially
associated with a significant elevation in 5-HIAA, measurement requires strict
adherence to dietary restrictions before and during urine collection.
(See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine
tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)'.)
Recommendations from expert groups — Our recommendations are consistent
with those of the National Comprehensive Cancer Network (NCCN) [71], which are
relatively non-specific after treatment of all resected small intestinal and colonic
NETs and for rectal, gastric, and appendiceal NETs >2 cm:
●3 to 12 months postresection: Abdominal or abdominopelvic multiphasic
CT or MRI scan for gastrointestinal NETs, chest CT with or without contrast
for lung/thymus NETs. Assay of biochemical markers as clinically indicated.
●>1 year postresection: Every 12 to 24 months abdominal or abdominopelvic
multiphasic CT or MRI scan for gastrointestinal NETs, chest CT with or without
contrast for lung/thymus NETs. Assay of biochemical markers as clinically
indicated.
●>10 years postresection: Continue surveillance as clinically indicated.

These recommendations are particularly applicable for low and low-intermediate

grade tumors (ie, ki-67 <10 percent). More frequent surveillance and scan intervals
may be appropriate for higher-grade NETs and particularly grade 3 NETs,
particularly during the first two to three years after surgery.

Post-treatment surveillance is not recommended by the NCCN [71] for appendiceal

tumors <2 cm and rectal tumors <1 cm in size given the exceptionally low risks of
recurrence. For T1 rectal tumors 1 to 2 cm in size, the only surveillance
recommended is endorectal ultrasound or rectal MRI at 6 and 12 months. We
agree with this position. (See "Well-differentiated neuroendocrine tumors of the
appendix", section on 'Posttreatment follow-up'.)

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The NCCN [71] guidelines for post-treatment surveillance of type I gastric NETs ≤2
cm include esophagogastroduodenoscopy (EGD) every one to two years. Routine
imaging studies are not recommended. We agree with this position.
Consensus-based follow-up guidelines are also available from a number of other
groups including the Commonwealth Neuroendocrine Tumour Collaboration
(CommNETs) [72], European Society for Medical Oncology (ESMO) [73], European
Neuroendocrine Tumor Society (ENETs) [74,75] and North American
Neuroendocrine Tumor Society (NANETS) [69,76]. These recommendations, which
are largely random, are compared with those of the NCCN in the table (table 11).
PROGNOSISPrognosis depends primarily on tumor stage, margin status,
histologic grade/differentiation, and site of origin.
Stage and site of origin — The prognostic validity of tumor stage for well-
differentiated neuroendocrine tumors (NETs) of the gastrointestinal tract is
supported by several studies [10,12,13,77,78]. However, at least some data
suggest that there are no significant differences in outcomes between stage I and
IIA midgut (jejunal and ileocecal) NETs (10-year overall survival 95 percent for both
[12]), and heterogeneous outcomes in patients with stage IIIB (node positive)
disease depending on whether disease was resected (five-year overall survival 95
percent) or unresectable (five-year overall survival 78 percent) [13].
(See "Pathology, classification, and grading of neuroendocrine neoplasms arising
in the digestive system", section on 'Staging system'.)
The impact of stage on 5-, 10-, and 15-year outcomes can be illustrated by the
results of a Swedish series of 135 surgically managed small intestine NETs (table
12) [11].
Site also determines prognosis. As a general principle, well-differentiated NETs
originating in the midgut (small intestine, proximal colon) are more prone to
metastasize than are well-differentiated tumors of the foregut (lung, stomach) or
hindgut (distal colon, rectum) (table 3). However, they also progress more slowly
once they do metastasize, and as a result, median survival durations are longer
among patients with metastatic (stage IV) NETs of the small intestine compared
with metastatic tumors originating in other sites [9]. Prognosis is particularly poor
for colonic NETs [30].
The differing prognosis according to stage and site of origin can be illustrated by
an analysis of the Surveillance, Epidemiology, and End Results (SEER) database that
evaluated the impact of primary tumor site and stage (localized, locally advanced,
metastatic) in 35,618 patients with well-differentiated gastrointestinal tract NETs
(table 13) [79].
Residual disease — Prognosis among surgically treated patients also depends on
whether or not the resection was complete [11,13]. The impact of residual disease
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on outcomes can be illustrated by the results of a Swedish series of 135 surgically
managed small intestine NETs (table 12) [11].
Tumor differentiation and grade — The World Health Organization (WHO)
classification system for neuroendocrine neoplasms of the digestive system
separates these tumors into two major categories (table 14) [80]:
●Well-differentiated NETs show a solid, trabecular, gyriform, or glandular
pattern of cellular arrangement, with fairly uniform nuclei, salt-and-pepper
chromatin, and finely granular cytoplasm.
●Poorly differentiated neuroendocrine carcinomas are high-grade
carcinomas that resemble small cell or large cell neuroendocrine carcinoma
of the lung (picture 1). (See "High-grade gastroenteropancreatic
neuroendocrine neoplasms".)
All poorly differentiated gastroenteropancreatic NETs are high grade (grade 3), but
it is now recognized that there is a subset of well- and moderately well-
differentiated tumors that have a proliferative index that places them in the high-
grade category; these are referred to as "NET, G3" tumors. Their clinical behavior is
in between poorly differentiated neuroendocrine carcinomas and intermediate-
grade well-differentiated NETs. (See "Pathology, classification, and grading of
neuroendocrine neoplasms arising in the digestive system", section on '2010 and
2019 World Health Organization classification' and "High-grade
gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade well-
differentiated tumors'.)
Multiple studies have evaluated the impact of tumor grade (defined primarily by
mitotic rate per 10 high-power fields [HPF] and/or Ki-67 labeling) on prognosis of
gastroenteropancreatic NETs. In one institutional study, five-year survival rates for
metastatic gastrointestinal NETs of low-, intermediate-, or high-grade histologic
differentiation were 87, 38, and 0 percent, respectively [81].
Issues related to grading of gastroenteropancreatic NETs are discussed in detail
elsewhere. (See "Pathology, classification, and grading of neuroendocrine
neoplasms arising in the digestive system", section on 'Issues related to assessing
grade'.)
Other prognostic factors
●Tumor burden – Among patients with liver metastases, tumor burden is an
important prognostic factor. In one institutional study of 301 patients with
metastatic NETs of the small intestine, five-year survival rates for those with
<5 and ≥5 metastases were 79 and 47 percent, respectively [82].
●Carcinoid heart disease – Presence of clinically significant valvular damage
represents an important adverse prognostic factor. In a report of 146
patients with metastatic midgut NETs, five-year survival rates were 75 percent

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 for the entire cohort, while they were only 45 percent among the 23 patients
(16 percent) with carcinoid heart disease [9]. (See "Carcinoid heart disease".)
●Hormone production – There is some evidence that, among patients with
metastatic small bowel NETs, functioning tumors (ie, those associated with
the carcinoid syndrome) have a worse prognosis than nonfunctioning tumors
[83,84]. However, this is probably attributable to tumor burden.
●Metastatic site – There is some evidence that site of metastasis correlates
with survival outcomes. A multivariate analysis of SEER data found that
patients with liver metastasis had worse survival than did those with brain
and bone metastasis [85].
Survival trends — Multiple studies, based upon population registries as well as
institutional data, have documented a trend towards improved survival for well-
differentiated NETs over the past three decades [45,86,87]. As an example, an
analysis of the SEER database observed a dramatic increase in survival among
patients diagnosed with a NET between 2009 and 2012 as compared with 2000 to
2004 (hazard ratio for death 0.79, 95% CI 0.74-0.85) [45]. These survival
improvements have been attributed to treatment advances, including long-acting
somatostatin analogs; however, earlier diagnosis may also be an explanatory
factor.
The prognosis of patients with carcinoid heart disease has also improved
significantly over the past 20 years, possibly due to increasing valve replacement
surgeries [88]. (See "Carcinoid heart disease", section on 'Prognosis'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●The basic principles of evaluation and management of patients with well-
differentiated neuroendocrine tumors (NETs) consist of localization and
staging of tumors, pathologic assessment of the histologic grade and
differentiation, surgical removal of the tumor(s) if the disease is surgically
resectable, control of symptoms of carcinoid syndrome if present, and
judicious use of antitumor therapy for unresectable metastatic disease. A key
principle underlying selection of appropriate therapy for advanced disease is
the indolent nature of most well-differentiated NETs and their prolonged
natural history. (See 'Introduction' above.)
●For most patients with a localized NET, we recommend resection, the extent
of which depends upon the site of origin and the size of the primary tumor
(Grade 1B). Resection of the primary tumor may be advised even in patients
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 with known distant metastases in order to reduce the potential for bowel
obstruction or bleeding, or to palliate abdominal pain related to the primary
tumor. This is a controversial area, and decision making must be
individualized. (See 'Staging and treatment of localized tumors' above.)
Management by site — The following represents our approach to specific sites:
●Simple appendectomy is usually sufficient for low-grade tumors <2 cm. A
right hemicolectomy has been traditionally recommended for tumors >2 cm.
It is unclear whether other potential risk factors, such as mesoappendiceal
invasion, should lead to recommendation for right hemicolectomy in patients
with a tumor size of 1 to 2 cm. In general, appendectomy alone is appropriate
for tumors <1 cm. (See 'Appendix' above.)
●Patients with small bowel NETs should undergo resection of the involved
segment and small bowel mesentery. (See 'Small intestine' above.)
●Ampulla of Vater NETs may be more aggressive than other duodenal NETs.
Pancreaticoduodenectomy has been advocated for resectable cases
regardless of size. However, these recommendations are based on very small
case series, and treatment decisions need to be individualized. (See 'Ampulla
of Vater' above.)
●Rectal NETs that are smaller than 1 cm and confined to the mucosa or
submucosa (T1) can be treated by local endoscopic excision. The
management of tumors between 1 and 2 cm that are confined to the mucosa
or submucosa is controversial, and treatment must be individualized based
upon size and the presence of risk factors such as lymphovascular invasion
and mitotic rate (or Ki-67 index). Tumors larger than 2 cm and those that
invade into or beyond the muscularis propria or have regional lymph node
metastases are treated by low anterior resection (LAR) or abdominoperineal
resection (APR). (See 'Rectum' above.)
●Most patients with non-metastatic colonic NETs should be managed with
formal partial colectomy and regional lymphadenectomy. (See 'Colon' above.)
●Local management for gastric NETs depends on the type
(see 'Stomach' above):
•Type 3 (sporadic) gastric NETs are treated by partial or total gastrectomy
with local lymph node resection.
•For type 1 and 2 gastric NETs smaller than 1 to 2 cm, endoscopic
resection is the treatment of choice.
•More aggressive surgical therapy is rarely needed for type 1 gastric NETs
unless there is extensive tumor involvement of the gastric wall (which
increases the risk for a coexisting adenocarcinoma), tumor size >2 cm, or
emergent bleeding.

311
Post-treatment follow-up
●Given the long natural history and the propensity for small bowel NETs to
metastasize, we recommend surveillance with triple-phase computed
tomography (CT) scans or magnetic resonance imaging (MRI) of the abdomen
or abdomen and pelvis 3 to 12 months after surgery, then roughly annually
for approximately 10 years. A similar surveillance strategy can be pursued for
rectal, gastric, and appendiceal NETs >2 cm, although more frequent
surveillance should be considered for more aggressive tumors, such as grade
2 gastric or rectal NETs. (See 'Post-treatment follow-up' above.)
●Post-treatment surveillance generally is not recommended for appendiceal
tumors <2 cm and T1 low-grade rectal tumors <1 cm in size.
●For type 1 gastric NETs ≤2 cm, we recommend
esophagogastroduodenoscopy (EGD) roughly once a year, and imaging
studies only as clinically indicated.

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Treatment of the carcinoid syndrome
Author:
Jonathan R Strosberg, MD
Section Editors:
Kenneth K Tanabe, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 28, 2021.
INTRODUCTIONCarcinoid tumors are neuroendocrine tumors (NETs) that
originate in the digestive tract, lungs, or rare primary sites, such as kidneys or
ovaries. The term "carcinoid" usually implies a well-differentiated histology and is
rarely used to describe high-grade or poorly differentiated neuroendocrine
cancers. (See "Pathology, classification, and grading of neuroendocrine neoplasms
arising in the digestive system", section on 'Pathology, tumor classification, and
nomenclature'.)
Carcinoid syndrome is the term applied to a constellation of symptoms that are
mediated by various hormones that are secreted by some NETs (table 1) [1]. Two of
the most common manifestations are flushing and diarrhea (table 2). Symptoms
are associated with elevations in serum serotonin or its metabolite urinary 5-
hydroxyindoleacetic acid (5-HIAA). (See "Clinical features of carcinoid syndrome".)

Carcinoid crisis is a life-threatening form of carcinoid syndrome that results from

the release of an overwhelming amount of biologically active compounds from the
tumor that may be triggered by tumor manipulation (biopsy or surgery) or by
anesthesia.

More than 90 percent of patients with the carcinoid syndrome have metastatic
disease, typically involving the liver, with primary tumors in the distal small
intestine or proximal colon (midgut). Rare exceptions are bronchial and ovarian
NETs, which can release hormones directly into the systemic circulation, thereby
producing symptoms without metastases. When it does occur, carcinoid syndrome
associated with bronchial NETs is often atypical; episodes of flushing and/or
diaphoresis may be accompanied by other symptoms, such as tremor, periorbital
edema, lacrimation, salivation, and edema. (See "Clinical features of carcinoid
syndrome", section on 'Lung NET variant syndrome'.)

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This topic provides an overview of treatment for patients with symptoms of the
carcinoid syndrome. Diagnosis of the carcinoid syndrome, radiologic staging,
tumor localization, histologic assessment of NETs arising at different sites, and
presentation, treatment, prognosis, and posttreatment surveillance of patients
with localized and metastatic NETs are discussed in detail elsewhere.
(See "Diagnosis of carcinoid syndrome and tumor localization" and "Pathology,
classification, and grading of neuroendocrine neoplasms arising in the digestive
system", section on 'Pathology, tumor classification, and
nomenclature' and "Staging, treatment, and post-treatment surveillance of non-
metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid)
tumors" and "Metastatic well-differentiated gastroenteropancreatic
neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical
monitoring" and "Metastatic gastroenteropancreatic neuroendocrine tumors:
Local options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Surgical resection'.)
SOMATOSTATIN-ANALOG THERAPYSomatostatin is a 14-amino acid
peptide that inhibits the secretion of a broad range of hormones. It acts by binding
to somatostatin receptors, which are expressed on the majority of neuroendocrine
tumors (NETs) [2]. Nearly 80 percent of well-differentiated gastrointestinal NETs
express somatostatin receptors, as determined using somatostatin receptor-based
diagnostic imaging with a radiolabeled form of the somatostatin
analog octreotide (indium-111 [111-In] pentetreotide [OctreoScan]) or gallium Ga-
68 DOTATATE (or gallium Ga-68 DOTATOC) positron emission tomography
(PET)/computed tomography (CT). However, whether imaging with any of these
modalities is necessary before a trial of somatostatin analog therapy for patients
who are symptomatic from carcinoid syndrome is controversial. (See "Metastatic
well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation,
prognosis, imaging, and biochemical monitoring", section on 'Somatostatin
receptor-based imaging techniques'.)
Because the somatostatin analogs octreotide and lanreotide bind to somatostatin
receptors on the tumor cells, they are highly effective at inhibiting the release of
serotonin and other vasoactive substances. Flushing and diarrhea are significantly
improved in over 80 percent of patients with the carcinoid syndrome [3].
Treatment for symptomatic carcinoid syndrome may be initiated with short-
acting octreotide, administered subcutaneously. An octreotide pen (2500 mcg/mL)
for self- or caregiver administration of short-acting octreotide has been approved
for initial treatment of severe diarrhea/flushing episodes associated with carcinoid
syndrome. However, unless patients are severely symptomatic, we generally
initiate therapy with octreotide long-acting release (LAR) rather than short-acting
314
subcutaneous octreotide. We typically initiate depot octreotide (Sandostatin LAR)
at a dose of 20 to 30 mg intramuscularly every four weeks [4].
Escalation of the dose or frequency of a somatostatin analog, or supplementation
with doses of short-acting octreotide may be necessary for patients with refractory
symptoms [4,5]. For example, patients who complain of exacerbation of symptoms
at the end of their four-week somatostatin analog cycle may benefit from drug
administration every three weeks. It is unclear whether there is benefit to
escalation of dose beyond double the label dose. Typical doses of short-acting
octreotide range from 200 to 500 mcg up to three times a day. Short-acting
octreotide is also available in a prefilled pen at a concentration of 2500 mcg/mL.
A long-acting formulation of lanreotide (Somatuline Depot) is also available for
monthly injections at doses ranging from 60 to 120 mg every four weeks [6].
Lanreotide appears to have similar clinical efficacy and tolerability as octreotide for
treatment of the carcinoid syndrome [7-14]. In a randomized phase III trial of
depot lanreotide versus placebo in patients with carcinoid syndrome, lanreotide
significantly reduced the need for short-acting somatostatin analog injections
compared with placebo [13,14].
Both octreotide and lanreotide are usually well tolerated. Rarely, patients may
develop nausea, abdominal discomfort, bloating and/or steatorrhea, often during
the first several weeks of therapy, after which the symptoms subside. Pancreatic
malabsorption may be a contributing factor, which can be alleviated with
pancreatic enzyme supplementation. Another effect of somatostatin analogs is
inhibition of gallbladder contractility, which can lead to gallstones or sludge. For
that reason, a prophylactic cholecystectomy is sometimes recommended for
patients who are undergoing abdominal surgery for other reasons [15].
Antiproliferative effects — The somatostatin
analogs octreotide and lanreotide were initially developed for control of the
carcinoid syndrome. Both drugs have also been proven to inhibit tumor growth in
randomized phase III trials [16,17]. This subject is addressed elsewhere.
(See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid)
tumors: Systemic therapy options to control tumor growth", section on
'Somatostatin analogs' and "Metastatic well-differentiated gastrointestinal
neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor
growth".)
LIVER-DIRECTED THERAPIESHepatic resection is often considered for the
treatment of potentially resectable liver metastases in the absence of diffuse
bilobar involvement, compromised liver function, or widespread extrahepatic
metastases. Hepatic resection can also provide palliation for patients who are
symptomatic from tumor bulk or the carcinoid syndrome. Preoperative and
315
intraoperative octreotide therapy are essential to protect against carcinoid crises
that can arise from anaesthesia and/or tumor manipulation. (See 'Prevention and
management of carcinoid crisis' below.)
Hepatic resections are generally restricted to patients in whom 90 percent or more
of the disease bulk can be successfully resected or ablated. These issues are all
addressed in more detail elsewhere. (See "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and symptoms of
hormone hypersecretion", section on 'Surgical resection'.)
Hepatic transarterial embolizations are often performed for patients with
surgically unresectable liver-dominant metastases. In patients with widespread
liver metastases, the embolizations are often lobar rather than highly selective.
Embolization of the entire liver can usually be undertaken in two to three separate
procedures. In uncontrolled trials, up to 75 percent of patients with
neuroendocrine tumor hepatic metastases have marked symptomatic
improvement in flushing and diarrhea [18-21]. Embolizations can be performed
using microparticles alone (bland embolization) or with admixed chemotherapy
(chemoembolization). There is no evidence that chemoembolization results in
superior outcomes compared with bland embolization, particularly in the
treatment of metastases from midgut NETs, which are generally chemoresistant
(as compared with pancreatic NETs). Short-term side effects of liver embolization
include abdominal pain, fever, nausea/vomiting, and fatigue. Patients with the
carcinoid syndrome should receive prophylactic octreotide pre- and
postembolization in order to reduce risk of carcinoid crisis.
Experience with radioembolization using yttrium-90 (90Y)-labeled resin or glass
microspheres is limited but growing. Radioembolization using 90Y-labeled resin or
glass microspheres reduces symptoms in approximately one-half of patients with
functioning NETs [22,23]. However, in the absence of randomized trials, it is
difficult to know when to choose this technique over other embolization
techniques. In particular, the risk of long-term radioembolization-induced liver
disease (REILD) has not been well-characterized. (See "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control tumor
growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial
embolization'.)
MANAGEMENT OF REFRACTORY SYMPTOMS
Telotristat — The carcinoid syndrome is thought to be caused in large part by
secretion of serotonin. A rate-limiting step in the conversion of the amino acid
tryptophan to serotonin is mediated by the enzyme tryptophan hydroxylase (figure
1). An oral tryptophan hydroxylase inhibitor, telotristat ethyl, can be used in
combination with somatostatin analog therapy in order to control diarrhea
316
associated with the carcinoid syndrome. Approval was based on the TELESTAR
trial, a three-arm study evaluating two doses of oral telotristat (250 mg and 500
mg, each taken three times daily) against placebo over a 12-week period) that was
conducted in 135 patients with history of carcinoid syndrome who were receiving
treatment with a somatostatin analog and who had uncontrolled diarrhea (≥4
bowel movements daily) [24]. Treatment with telotristat at either dose was
associated with a statistically significant reduction in bowel movement frequency
over time compared with placebo. At week 12, the arithmetic mean reduction in
daily bowel movement frequency from baseline was -1.7 and -2.1 with telotristat
250 and 500 mg, respectively, compared with -0.9 for placebo. Urinary 5-
hydroxyindoleacetic acid (5-HIAA; a metabolite of serotonin) was also significantly
decreased with telotristat; by week 12, mean urinary 5-HIAA levels decreased by 40
and 57.7 mg per 24 hours with telotristat 250 and 500 mg, respectively, while
levels increased in the placebo group by 11.5 mg per 24 hours in this same time
period. Too few patients had flushing or abdominal discomfort to ascertain
changes in these endpoints. Overall, the drug was well tolerated. There was a
higher incidence of nausea with the 500 mg dose of telotristat as compared with
either the lower 250 mg dose or placebo (31 versus 13 and 11 percent,
respectively), and depression-related adverse events were also more frequent at
the higher dose (16 versus 7 percent each for the telotristat 250 mg and placebo
groups, respectively).
Largely based upon these results, telotristat has been approved in the United
States in combination with somatostatin analog therapy for the treatment of
adults with diarrhea related to carcinoid syndrome that is inadequately controlled
by somatostatin analog therapy alone [25]. The recommended dose is 250 mg
three times daily with food [26].
Flushing in patients with carcinoid syndrome is associated with production of
multiple vasoactive substances, and it is unclear whether telotristat has a
significant impact upon this symptom. On the other hand, carcinoid heart disease
is thought to be directly related to high levels of circulating serotonin. Although
evidence of inhibition of carcinoid heart disease with telotristat is purely anecdotal
at this time, use of the drug in patients with early evidence of carcinoid heart
disease and high levels of circulating serotonin is reasonable, even if their diarrhea
is otherwise controlled.
Interferon — Another option for control of refractory symptoms of the carcinoid
syndrome in patients treated with somatostatin analogs is interferon alfa (IFNa)
[27]. Interferons can exert antitumor effects via stimulation of T cells, induction of
cell cycle arrest, and inhibition of angiogenesis.

317
In retrospective series, low-dose IFNa alone (ie, 3 to 5 million units up to three to
five times weekly) reduces symptoms of hormonal hypersecretion (flushing,
diarrhea) in 40 to 50 percent of patients who are refractory to somatostatin
analogs [28]. Objective tumor regression is rare [29]. Unfortunately, the benefits of
IFNa for neuroendocrine tumors (NETs) are counterbalanced by sometimes
debilitating toxicities, which can include fatigue, depression, and flu-like
symptoms. As a result, IFNa is rarely used and typically only for otherwise
refractory NETs. (See "Metastatic well-differentiated gastrointestinal
neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor
growth", section on 'Interferon'.)
Antidiarrheal therapy — Antidiarrheal agents, such
as loperamide and/or diphenoxylate-atropine (Lomotil), can be used for control of
refractory diarrhea. For more severe diarrhea, the opiates paregoric (where
available) and tincture of opium may be prescribed. Paregoric has been
discontinued in the United States but is available in other countries. A few reports
demonstrate that serotonin receptor antagonists, such as ondansetron, can
alleviate diarrhea in patients with the carcinoid syndrome in whom treatment with
somatostatin analogs is not successful [30-32].
Other causes of diarrhea should be considered. As noted above, symptomatic fat
malabsorption and steatorrhea from chronic somatostatin analog therapy may
respond to pancreatic enzyme supplementation. (See 'Somatostatin-analog
therapy' above.)
Patients who have undergone resection of the distal small bowel frequently
develop bile malabsorption and bile salt-induced diarrhea that can be treated with
bile acid sequestrants, such as cholestyramine or colestipol [33]. A trial of a bile
acid sequestrant is reasonable in any patient who has refractory diarrhea after
right hemicolectomy.
Systemic therapies
Everolimus — There are few data addressing the benefit of everolimus, a
mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitor,
for control of symptoms related to carcinoid syndrome. Most of the information
comes from small retrospective series and case reports [34,35]. It is important to
note that diarrhea is a frequent side effect of everolimus.
In the phase III RADIANT 2 study comparing everolimus plus octreotide long-
acting release (LAR) with placebo plus octreotide LAR in patients with metastatic
NETs and a history of carcinoid syndrome, improvements in urinary excretion of 5-
HIAA occurred at a slightly higher frequency in the everolimus arm of this study
(61 versus 54 percent), but information was not provided on symptoms attributed
to carcinoid syndrome [36]. The study fell short of meeting its primary endpoint,

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which was a significant improvement in progression-free survival with everolimus.
(See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid)
tumors: Systemic therapy options to control tumor growth", section on
'Molecularly targeted therapy'.)
177-Lutetium (Lu) dotatate (Peptide receptor radioligand
therapy) — Radiolabeled somatostatin analogs can be used to deliver targeted
radiation to somatostatin receptor-expressing tumors. Single-arm studies of the
radiolabeled somatostatin analogs have demonstrated high symptomatic
response rates in patients with carcinoid syndrome who were refractory
to octreotide [37].
The phase III NETTER-1 study randomized 231 patients with progressive metastatic
midgut NETs to receive 177-Lu-dotatate plus octreotide LAR 30 mg versus high-
dose octreotide (60 mg every four weeks). Analysis of health-related quality of life
(HRQOL) outcomes based on European Organisation for Research and Treatment
of Cancer (EORTC) questionnaires demonstrated clinically and statistically
significant delays in time to deterioration of HRQOL in global health, physical
functioning, role functioning, and in clinically relevant symptoms, notably diarrhea
[38]. No significant change was seen in time to deterioration of flushing.
(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring", section
on 'Somatostatin receptor-based imaging techniques' and "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options to
control tumor growth and symptoms of hormone hypersecretion", section on
'Radiolabeled somatostatin analogs' and "Metastatic well-differentiated
gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to
control tumor growth", section on 'Radiolabeled somatostatin analogs'.)
PREVENTION AND MANAGEMENT OF CARCINOID
CRISISProphylactic and intraoperative octreotide should be administered to all
patients with carcinoid syndrome and/or elevated urinary 5-hydroxyindoleacetic
acid (5-HIAA) levels in the absence of carcinoid syndrome. Patients with tumors
that do not produce serotonin (eg, rectal NETs, most pancreatic NETs, or localized
midgut NETs) do not require prophylactic octreotide.
Carcinoid crisis is a life-threatening form of the carcinoid syndrome that may be
triggered by tumor manipulation (eg biopsy, surgery) or by anesthesia [39]. It is
less commonly reported after chemotherapy, hepatic arterial embolization, or
radionuclide therapy, mostly in patients with extensive tumor bulk [40-47].
Carcinoid crisis results from the release of an overwhelming amount of biologically
active compounds from the tumor (table 1). The predominant symptom is wide
blood pressure fluctuations with a predominance of hypotension.
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Octreotide should be readily available during any surgical procedure, particularly
the resection of hepatic metastases. Administration of octreotide prior to resection
(300 to 500 mcg intravenously or subcutaneously) reduces the incidence of
carcinoid crisis and is often recommended for patients with a history of carcinoid
syndrome who require surgical procedures [48-51]. (See "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control tumor
growth and symptoms of hormone hypersecretion", section on 'Prevention and
management of carcinoid crisis'.)
However, intraoperative complications can still occur in patients with hepatic
metastases despite the use of preoperative prophylactic octreotide. Octreotide
doses should be repeated as needed during the procedure to protect against
hypotension due to release of bioactive mediators from carcinoid
tissue. Adrenergic agents to support blood pressure should be avoided as a first-
line measure because of their paradoxical effect in these patients (see below).
Whether prophylactic octreotide is needed prior to surgical resection in
patients without carcinoid syndrome is unclear. At least two published guidelines
regarding octreotide prophylaxis recommend treatment in patients with
functioning neuroendocrine tumors (NETs), suggesting that patients with clinically
nonfunctional tumors are not at risk and do not require prophylactic octreotide
[50,51].
On the other hand, this recommendation has been called into question by other
reports suggesting that crises can still occur in the absence of carcinoid syndrome
[52,53].
In our view, urinary 5-HIAA levels should be assayed before surgery in all patients
with metastatic midgut NETs who do not have symptoms consistent with carcinoid
syndrome. Prophylactic and intraoperative octreotide should be administered to
all patients with carcinoid syndrome and/or elevated urinary 5-HIAA levels.
Patients with tumors that do not produce serotonin (eg, rectal NETs, most
pancreatic NETs, or localized midgut NETs) do not require prophylactic octreotide.
When it occurs, treatment for carcinoid crisis differs from that for other causes of
acute intraoperative hypotension. Symptoms are generally refractory to fluid
resuscitation alone [40,54,55]. Calcium and catecholamines may provoke release of
mediators from the tumor and worsen, rather than ameliorate, the syndrome [45].
The blood pressure should be supported by infusion of octreotide (500 to 1000
mcg intravenously; a continuous intravenous drip of octreotide at a rate of 50 to
200 mcg/hour may also be used) [40,56].
CARCINOID HEART DISEASECarcinoid heart disease occurs in fewer than
one-half of patients with the carcinoid syndrome. High-circulating concentrations
of serotonin are thought to be the major underlying factor. Among patients with
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the carcinoid syndrome, individuals with carcinoid heart disease exhibit higher
levels of serum serotonin and urinary 5-hydroxyindoleacetic acid (5-HIAA)
excretion than do those without heart disease. (See "Carcinoid heart disease",
section on 'Pathophysiology'.)
Carcinoid heart lesions are characterized by plaque-like fibrous endocardial
thickening that classically involves the right side of the heart, and often causes
retraction and fixation of the leaflets of the tricuspid and pulmonary valves (picture
1). Tricuspid regurgitation is a nearly universal finding; tricuspid stenosis,
pulmonary regurgitation, and pulmonary stenosis may also occur. The resulting
right-sided heart failure produces significant morbidity and mortality.
(See "Carcinoid heart disease", section on 'Clinical manifestations'.)

Left-sided heart disease, which occurs in less than 10 percent of patients, is almost
always associated with an atrial right-to-left shunt (such as with a patent foramen
ovale). This permits serotonin-rich blood to enter the left heart chambers without
passing through the pulmonary capillaries.

Because evidence suggests a pathogenic role for serotonin or one of its

metabolites in the development of carcinoid heart disease, it is likely that
somatostatin analogs and other therapies that reduce circulating serotonin levels
can reduce the risk of developing carcinoid heart disease, and they may inhibit
progression of existing disease. However, there is no evidence that medical
therapy can reverse valvular damage. (See "Carcinoid heart disease", section on
'Treatment of carcinoid syndrome'.)

All patients with carcinoid syndrome should undergo at least an annual clinical
evaluation for symptoms and signs of valvular heart disease or heart failure. In our
view, all patients with signs or symptoms of right heart valvular disease or heart
failure should undergo echocardiography. Echocardiograms should also be
performed prior to surgery in patients with carcinoid syndrome.

Guidelines for screening for carcinoid heart disease in at-risk patients without
valvular heart disease or heart failure are evolving, with differing
recommendations in various major society guidelines [57]. For most patients with
carcinoid syndrome, we suggest periodic echocardiography, although the optimal
frequency is not established. Another alternative is monitoring of serum levels of
N-terminal brain natriuretic peptide (NT-proBNP). Some guidelines suggest that
levels be measured every six months and that an echocardiogram be obtained for
those with an elevated level >260 ng/mL [58]. This subject is discussed in detail

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elsewhere. (See "Carcinoid heart disease", section on 'When and how to initially
test for carcinoid heart disease'.)
Importantly, carcinoid heart disease is rare in patients with mild elevations in
blood serotonin or urine 5-HIAA, and we generally perform screening on an annual
basis only in patients with carcinoid syndrome and significant elevations in
serotonin or 5-HIAA (ie, >5 times the upper limit of normal [ULN]). (See "Carcinoid
heart disease", section on 'Echocardiography'.)
Among patients with carcinoid heart disease, valve replacement surgery (typically
bivalvular replacement of tricuspid and pulmonary valves) can prevent progression
to frank heart failure. (See "Carcinoid heart disease", section on 'Valve
intervention'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Carcinoid syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS
●Carcinoid syndrome is the term applied to a constellation of symptoms
mediated by various hormones that are elaborated by some neuroendocrine
tumors (NETs) (table 1) [1]. Two of the most common manifestations are
flushing and diarrhea (table 2). More than 90 percent of patients with the
carcinoid syndrome have metastatic disease, typically to the liver, and
primary tumors in the midgut. (See "Clinical features of carcinoid
syndrome" and 'Introduction' above.)

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 ●Carcinoid crisis is a life-threatening form of carcinoid syndrome that results
from the release of an overwhelming amount of biologically active
compounds from the tumor; it may be triggered by tumor manipulation (eg,
biopsy, embolization, surgery) or anesthesia, and occurs mostly in patients
with markedly elevated serum serotonin or urine 5-hydroxyindoleacetic acid
(5-HIAA).
Treatment
●The somatostatin analogs octreotide and lanreotide are highly effective in
controlling the symptoms associated with NETs. For patients who are
symptomatic from carcinoid syndrome, we recommend initiating treatment
with a somatostatin analog (Grade 1A). (See 'Somatostatin-analog
therapy' above.)
We usually begin therapy with octreotide long-acting release (LAR) 30 mg
every four weeks or depot lanreotide 120 mg every four weeks; however,
lower starting doses can be considered (eg, octreotide 20 mg or lanreotide 90
mg).
●Liver-directed therapies, including surgical resection or hepatic
embolization, can be highly palliative for patients with carcinoid syndrome
and liver-dominant disease. (See 'Liver-directed therapies' above.)
●Patients with persistence or recurrence of flushing and/or diarrhea may
benefit from higher doses or more frequent administration of long-acting
somatostatin analogs. (See 'Management of refractory symptoms' above.)
●For patients with carcinoid syndrome diarrhea that is refractory to
somatostatin analog therapy, we suggest telotristat (Grade 2A).
(See 'Telotristat' above.)
●While the addition of interferon may palliate refractory symptoms related to
carcinoid syndrome, the benefits are counterbalanced by sometimes
debilitating toxicities. (See 'Interferon' above.)
●The radiolabeled somatostatin analog 177-Lutetium dotatate is associated
with significant delay in time to progression of diarrhea as well as other
quality of life metrics compared with high-dose octreotide. (See '177-Lutetium
(Lu) dotatate (Peptide receptor radioligand therapy)' above.)
●Everolimus can reduce levels of urinary 5-HIAA. However, its effect on
symptoms of carcinoid syndrome has only been described in small series and
case reports, and diarrhea is a common side effect of the drug.
(See 'Everolimus' above.)
●Patients with refractory diarrhea may benefit from use of an antidiarrheal
agent, such as loperamide. (See 'Antidiarrheal therapy' above.)

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●For patients undergoing surgery for metastatic NET who have a history of
carcinoid syndrome or elevated urinary levels of 5-HIAA in the absence of
carcinoid syndrome, we recommend prophylactic subcutaneous or
intravenous administration of octreotide prior to the procedure to reduce the
incidence of carcinoid crisis (Grade 1B). We also recommend the use of
prophylactic octreotide for patients with carcinoid syndrome and extensive
tumor bulk prior to hepatic artery embolization (Grade 1B). (See 'Prevention
and management of carcinoid crisis' above.)
●Carcinoid heart disease can occur in patients with severe, longstanding
elevations of circulating serotonin and is typically characterized by fibrosis of
the right-sided (tricuspid and pulmonary) heart valves. While some guidelines
advocate echocardiograms in all patients with carcinoid syndrome, we
recommend that echocardiographic evaluation be reserved for patients with
significant elevations of serum serotonin/urine 5-HIAA (>5 times the upper
limit of normal [ULN]), clinical signs/symptoms of carcinoid heart disease, or
if major surgery is being planned. (See 'Carcinoid heart disease' above.)

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Causes and clinical manifestations of acromegaly
Authors:
Shlomo Melmed, MD
Laurence Katznelson, MD
Section Editor:
Peter J Snyder, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: May 29, 2020.
INTRODUCTIONAcromegaly is the clinical syndrome that results from excessive
secretion of growth hormone (GH) [1]. Its annual incidence is six to eight per million
people [2]. The mean age at diagnosis is 40 to 45 years.
The causes and clinical features of acromegaly will be reviewed here. The laboratory
diagnosis and treatment of acromegaly are discussed separately. (See "Diagnosis of
acromegaly" and "Treatment of acromegaly".)
CAUSESThe most common cause of acromegaly is a somatotroph (growth hormone
[GH]-secreting) adenoma of the anterior pituitary. These adenomas account for
approximately one-third of all hormone-secreting pituitary adenomas (table 1). GH
excess that occurs before fusion of the epiphyseal growth plates in a child or adolescent
is called pituitary gigantism. (See "Pituitary gigantism".)
An activating mutation of the alpha subunit of the guanine nucleotide stimulatory protein
(Gs-alpha) gene is found in approximately 40 percent of somatotroph adenomas [3-5].
These mutations result in constitutive activation of adenylyl cyclase, which may play a
role in both cell division in and excessive GH secretion by these adenomas.
The pituitary tumor transforming gene is also overexpressed in most human
somatotroph adenomas [6]. It also appears to play a role in tumor invasiveness since
expression is increased in tumors that invade the sphenoid bone.
Microduplications on chromosome Xq26.3 have been associated with excessive GH in
children with gigantism and in adults with acromegaly. In a study of 43 patients with
gigantism due to GH excess, microduplications in the Xp26.3 region that includes
the GPR101 (G protein-coupled receptor 101) gene were identified in 13 patients
(termed X-linked acrogigantism [X-LAG]) [7]. All patients identified with this
microduplication had disease onset before five years of age, and the G protein-coupled
receptor was overexpressed in the patients' pituitary lesions (see "Pituitary
gigantism" and "Sex chromosome abnormalities", section on 'Xq26.3 microduplication').
In the same study, a recurrent mutation in GPR101 was found in 11 of 248 adult
patients with acromegaly (mostly in pituitary tumors). Other known causes of
acromegaly, all very rare, are excess secretion of GH-releasing hormone (GHRH) by
hypothalamic tumors, ectopic GHRH secretion by neuroendocrine tumors such as
carcinoid tumors or small-cell lung cancers, and ectopic secretion of GH by
neuroendocrine tumors [8-10].
CLINICAL MANIFESTATIONS

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 ●The clinical features of acromegaly are attributable to high serum concentrations
of both growth hormone (GH) and insulin-like growth factor-1 (IGF-1), which is GH
dependent. Excess GH and IGF-1 have both somatic and metabolic effects. The
somatic effects include stimulation of growth of many tissues, such as skin,
connective tissue, cartilage, bone, viscera, and many epithelial tissues.
●The metabolic effects include nitrogen retention, insulin antagonism, and
lipolysis.

In addition, the somatotroph adenoma itself may cause symptoms due to its size.

Insidious onset — The onset of acromegaly is insidious, and its progression is usually

very slow. The average interval from the onset of symptoms until diagnosis is
approximately 12 years [11], but determining the onset, which is usually done from old
photographs, is very difficult. At diagnosis, most patients have macroadenomas (tumor
diameter 10 mm or greater) [12], and some of the adenomas extend to the parasellar or
suprasellar regions [13]. Overall, approximately 60 percent of patients eventually have
headaches, and 10 percent have visual symptoms [1,14,15].
Direct effects of pituitary tumor
Headache/vision loss — Some patients with acromegaly and large tumors have
symptoms due to direct compressive effects of the tumor mass, such as headache,
visual field defects (classically bitemporal hemianopsia), and cranial nerve palsies. In a
series of 310 patients with acromegaly, headache and visual defects were reported as
the presenting features in 8 and 3 percent of patients, respectively [13]. However,
approximately 60 percent of patients eventually develop headaches and 10 percent
develop visual symptoms [1,14]. Headache, however, may be the direct result of the
elevated serum GH concentration, as well as of the mass effect. (See "Causes,
presentation, and evaluation of sellar masses", section on 'Clinical manifestations'.)
Pituitary function — A somatotroph macroadenoma, due to its size, can cause
decreased secretion of other pituitary hormones, most commonly gonadotropins [14].
Many women with acromegaly have menstrual dysfunction, with or without galactorrhea,
and some have hot flashes and vaginal atrophy as a result of estrogen deficiency. In a
study of 47 women of reproductive age who had acromegaly, 29 (62 percent) had
amenorrhea and seven (15 percent) had oligomenorrhea [16]. Men may have erectile
dysfunction, loss of libido, decreased facial hair growth, and a decrease in testicular
volume.

Hyperprolactinemia occurs in approximately 30 percent of patients. In some patients, it

is due to cosecretion of prolactin and GH by a somatomammotroph adenoma, in which
case the serum prolactin concentration may be over 200 ng/mL. In other patients, the
cause is likely interference with hypothalamic-pituitary blood flow, in which case the
serum prolactin concentration will likely be less than 200 ng/mL.

In a pilot study from a multicenter acromegaly registry (363 patients), hypogonadism

was present in 53 percent of patients (49 percent of men and 57 percent of women)
[17]. Prevalence of hypogonadism was similar in those with macroadenomas and
microadenomas (54 and 38 percent, respectively). In macroadenoma patients,
hypogonadism was more common in those with coexisting hyperprolactinemia. The
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cause of the hypogonadism in patients with microadenomas and normal serum prolactin
concentrations is unknown. (See "Causes of secondary hypogonadism in males".)
Thyroid-stimulating hormone (TSH) and corticotropin (ACTH) deficiency occur less
commonly than other pituitary hormonal deficiencies [18].
Effects of GH/IGF-1 excess — Long-term growth hormone (GH) and insulin-like
growth factor-1 (IGF-1) excess results in overgrowth of many tissues, including
connective tissue, cartilage, bone, skin, and visceral organs. Other systemic
complications include cardiovascular disease, sleep apnea, metabolic disorders, and
colon neoplasia.
Soft tissue and skin — Virtually all patients with acromegaly have acral and soft tissue
overgrowth and skin thickening. The characteristic findings are an enlarged jaw
(macrognathia) and enlarged, swollen hands and feet, which result in increasing shoe
and glove size and the need to enlarge rings.
The facial features become coarse, with enlargement of the nose and frontal bones as
well as the jaw, and the teeth become spread apart (picture 1A-B). Despite the
prominence of these findings at the time of diagnosis, the rate of change is so slow that
few patients seek care because their appearance had changed or for other symptoms
related to acral enlargement (eg, only 13 percent of 256 patients in one series [13]).
Manifestations of soft tissue overgrowth include macroglossia, deepening of the voice,
and paresthesias of the hands (eg, carpal tunnel syndrome in around 20 percent).
Magnetic resonance imaging (MRI) studies suggest that the pathology of median
neuropathy in acromegaly is increased edema of the median nerve, which resolves
rapidly with reduction of serum GH and IGF-1 concentrations [19]. Other patients have a
symmetric sensorimotor peripheral (rarely hypertrophic) neuropathy unrelated to
entrapment.
Macroglossia and enlargement of the soft tissues of the pharynx and larynx lead to
obstructive sleep apnea in approximately 50 percent of patients. (See 'Sleep
apnea' below.)
The skin thickens, making it hard to puncture, and skin tags may appear. Hyperhidrosis
is common (present in around 50 percent of patients), often making the patient
malodorous. Hair growth increases, and some women have hirsutism (56 percent in one
series) [16].
Bone and joints — When excess GH secretion occurs in children, eg, before the
epiphyses of the long bones are fused, linear growth does increase; the result is
pituitary gigantism. In contrast, adults with acromegaly do not become taller.
(See "Pituitary gigantism".)
Synovial tissue and cartilage enlarge, causing hypertrophic arthropathy of the knees,
ankles, hips, spine, and other joints [20]. Joint symptoms are a common presenting
feature of the disease, and back pain (and kyphosis) is common (image 1A-B). Back
pain may also be due to osteoporosis caused by concurrent gonadal insufficiency due
to the enlarging pituitary tumor. (See "Rheumatologic manifestations of acromegaly".)
Bone density may be increased in both the spine and hip in acromegaly, at least in
women [21], but not if the women are estrogen deficient. A meta-analysis of 41 studies
reported a high prevalence of vertebral fractures in patients with active acromegaly [22].
A detailed discussion concerning bone disorders associated with acromegaly is located
elsewhere. (See "Rheumatologic manifestations of acromegaly".)

327
Visceral enlargement — Many visceral organs are enlarged in acromegaly, including
the thyroid, heart, liver, lungs, and kidneys. Reversible prostatic enlargement is also
common, even in men with hypogonadism [23].
Thyroid — The thyroid enlargement may be diffuse or multinodular. In one study of 37
patients with acromegaly, 34 (92 percent) had an enlarged thyroid gland when
assessed by ultrasonography; the mean thyroid size was more than five times normal
[24]. In another report, 39 of 45 patients (87 percent) had palpable diffuse or
multinodular goiter [25]. In one systematic review, 4 percent or patients with acromegaly
also had thyroid cancer [26], higher than rates in the general population. It is unclear
whether this association is due to increased GH/IGF-1 levels or enhanced
ascertainment by the treating endocrinologists. Thyroid function is usually normal, but
some patients with goiter have subclinical hyperthyroidism. A few patients have central
hypothyroidism caused by their pituitary tumor. Thyroid function is usually normal in
these patients.
Salivary gland enlargement has been described [27,28].
Cardiovascular disease — Cardiovascular abnormalities include hypertension, left
ventricular hypertrophy, and cardiomyopathy [29,30].
The cardiomyopathy is characterized by diastolic dysfunction and arrhythmias [31]. The
abnormalities are due both to hypertension (present in 43 percent of patients with active
disease in one report) and to the acromegaly itself [32]. Reducing GH secretion
improves some of the abnormalities of cardiac function [33-35]. A high plasma
fibrinogen concentration occurs in acromegaly and is reduced when serum GH
concentrations are lowered with octreotide [36].
Heart failure occurs in 3 to 10 percent of patients [37,38]. Compared with patients with
acromegaly without heart failure, these patients had an increase in left ventricular mass
index that was largely due to chamber dilation, a reduction in left ventricular ejection
fraction (42 versus 66 percent), and a significant elevation in cardiac index (4.3 versus
3.5 L/min per m2) [37].
An increased prevalence of valvular heart disease has also been reported. In a series of
40 patients with acromegaly, echocardiography demonstrated significant aortic
regurgitation in 30 percent and mitral regurgitation in 5 percent; the comparable values
in a control group matched for age, sex, hypertension, and left ventricular systolic
function were 7 and 0 percent, respectively [39]. The risk increased with the duration of
GH excess, including inadequate therapy.
Sleep apnea — Obstructive sleep apnea may represent an additional risk factor for
cardiovascular complications and excess mortality in patients with acromegaly.
(See 'Cardiovascular disease' above and 'Mortality' below.)
The overall frequency of sleep apnea in patients with acromegaly is approximately 40 to
50 percent [40-42]. In most cases, craniofacial deformities, macroglossia, and
enlargement of the soft tissues of the pharynx and larynx result in obstructive sleep
apnea. Less commonly, patients develop central sleep apnea, which is thought to be
due to altered respiratory control [40,43]. (See "Clinical presentation and diagnosis of
obstructive sleep apnea in adults".)
Predictive factors for the development of sleep apnea include the severity of GH
excess, duration of disease, obesity, older age, and male sex [41,42].

328
Sleep apnea symptoms gradually improve in some, but not all, patients after correction
of the underlying GH excess with transsphenoidal surgery or medical therapy
[41,42,44,45]. Thus, specific therapies for sleep apnea are necessary in many patients,
although some require only transient therapy as the anatomic abnormalities induced by
GH excess recede. (See "Treatment of acromegaly" and "Management of obstructive
sleep apnea in adults".)
Metabolic — In addition to high serum GH and IGF-1 concentrations, uncontrolled
acromegaly is also associated with hyperinsulinism, insulin resistance, overt diabetes in
10 to 15 percent of cases, and impaired glucose tolerance in a further 50 percent [46-
49]. Some patients have hypertriglyceridemia or hypercalciuria.
Hyperphosphatemia occurs in approximately 70 percent of patients with acromegaly
and is presumably due to direct stimulation of renal tubular phosphate reabsorption by
IGF-1 [50]. The serum phosphate concentration usually does not exceed 5.5 mg/dL (1.8
mmol/L).
Colonic effects
Neoplasia — Conflicting evidence suggests that acromegaly is associated with an
increased risk of colonic neoplasia [51-56]. However, colon cancer mortality does
appear to be increased with uncontrolled GH or IGF-1 levels. Mechanisms thought to be
involved in the apparent excess risk include a trophic IGF-1 effect on the proliferation of
epithelial cells [57] and reduced expression of the peroxisome proliferator-activated
receptor (PPAR) gene [58] (see "Molecular genetics of colorectal cancer", section on
'Modifier genes'). Many of these studies are confounded by the observed bowel loop
complexity and increased length and megacolon [59,60].
A number of individual studies have reported an increased risk of adenomatous colonic
polyps in patients with acromegaly [51-53,61]. As an example, a prospective
colonoscopy study evaluated 103 patients with acromegaly and 138 nonacromegalic
controls [51]. Adenomatous polyps were found in 22 percent of patients compared with
8 percent of controls. Patients with acromegaly who are over age 50 years, male, have
three or more skin tags, or have a family history of colon cancer are more likely to
develop polyps [61].
An excess risk of colon cancer has also been observed, but the magnitude of risk
compared with controls has been highly variable, ranging from 2- to 14-fold [51-
54,61,62]. The best estimate of risk in patients with acromegaly comes from a meta-
analysis of nine studies that compared colon adenoma and cancer rates in 701
acromegalic patients and 1573 control subjects [55]. Results included the following:
●In the eight studies with colon adenoma data, the frequency of adenomas was
2.5-fold higher in acromegaly patients than controls (23 versus 12 percent, pooled
odds ratio [OR] 2.5, 95% CI 1.9-3.2).
●In the three studies with colon cancer data, the frequency of cancer was
increased more than fourfold in acromegaly patients (5 versus 1 percent, pooled
OR 4.4, 95% CI 1.5-12.3).
Based upon these observations, we suggest that colonoscopy be performed at baseline
and then every three to four years thereafter in patients over age 50 years, especially
when GH levels are not strictly controlled. This recommendation is consistent with the
2009 guidelines from the Acromegaly Consensus Group [63].

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Diverticula — Acromegaly also appears to be associated with an increased prevalence
of colonic diverticula, as illustrated by a case-control study comparing 107 patients with
cured or biochemically controlled acromegaly and 214 age- and sex-matched controls
[64]. Diverticula were present on colonoscopy in 39 and 19 percent of patients with
acromegaly and controls, respectively. Patients with the longest duration of active
disease (>11 years), after adjustment for pretreatment concentrations of GH and IGF-1
(standard deviation scores), were the most likely to develop diverticula (OR 4.2).
Other tumors — In addition to an excess risk of colon polyps and cancer, acromegaly
may be associated with other tumors [65-67]. In men, an excess number of malignant
tumors including adenocarcinomas of the colon, stomach, esophagus, and melanoma
were observed in a cohort of 1041 men with acromegaly (table 2) [65]. An increased
frequency of thyroid cancers [68] and uterine leiomyomata have been reported in
women [66].
Nonspecific symptoms — Fatigue and weakness can be prominent symptoms. They
may result from sleep apnea, cardiovascular dysfunction, neuropathy, hypogonadism,
hyperglycemia, or some combination of these factors as described in this section.
MORTALITYThe mortality rate of patients with acromegaly appears to be increased.
Death is primarily from cardiovascular disease, a risk that may be reduced by strict
biochemical control of the disease (table 3) [1,2,31,69-75].
The best estimate of all-cause mortality risk in patients with acromegaly and the effect
of treatment comes from a meta-analysis of 16 studies published between 1970 and
2005 that compared mortality rates in acromegalic patients with those in the general
population [70]. The mortality risk was reduced by therapy and may have been
eliminated by cure, as illustrated by the following findings:
●The overall weighted mean standard mortality ratio (SMR) was 1.72, which
represents a 72 percent increase in mortality in acromegalic patients compared
with the general population. Some studies have reported an average reduction in
survival of as much as 10 years [31].
●When only studies in which over 80 percent of patients underwent
transsphenoidal surgery as primary therapy were included, there was a smaller
increase in weighted mean SMR (1.32). However, transsphenoidal surgery is not
synonymous with cure, as the cure rate is only 80 to 90 percent when performed
by the most experienced surgeons. (See "Treatment of acromegaly", section on
'Transsphenoidal surgery'.)
●There were four studies with postoperative biochemical data that could assess
for surgical cure (serum growth hormone [GH] and insulin-like growth factor-1
[IGF-1]). When only patients considered to be cured were analyzed, there was no
significant increase in mortality (weighted SMR 1.09, 95% CI 0.81-1.46).
●Independent, yet significant, determinants of mortality in acromegaly include age,
hypertension, GH levels, IGF-1 levels, history of prior irradiation, and coexisting
corticotropin (ACTH) deficiency [76].
Although mortality is still increased in patients with acromegaly compared with control
populations, rates have declined over time [77]. This is thought to be related to the more
frequent use of pituitary surgery, more experienced pituitary surgeons, a decreased
prevalence of hypopituitarism, and the availability of more medical treatment options.
(See "Treatment of acromegaly", section on 'Medical therapy'.)
330
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of acromegaly".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient education
materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces
are written in plain language, at the 5th to 6th grade reading level, and they answer the
four or five key questions a patient might have about a given condition. These articles
are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated,
and more detailed. These articles are written at the 10 th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you
to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of
interest.)

●Basics topics (see "Patient education: Acromegaly (The Basics)")

●Beyond the Basics topics (see "Patient education: Acromegaly (Beyond the
Basics)")
SUMMARY
●Acromegaly is the clinical syndrome that results from excessive secretion of
growth hormone (GH). Its annual incidence is six to eight per million people. The
mean age at diagnosis is 40 to 45 years.
●The most common cause of acromegaly is a somatotroph (GH-secreting)
adenoma of the anterior pituitary. These adenomas account for approximately
one-third of all hormone-secreting pituitary adenomas. An activating mutation of
the alpha subunit of the guanine nucleotide stimulatory protein (Gs-alpha) gene is
found in approximately 40 percent of somatotroph adenomas. These mutations
result in constitutive activation of adenylyl cyclase, which may play a role in both
cell division and excessive GH secretion by these adenomas.
(See 'Causes' above.)
●The clinical features of acromegaly are attributable to high serum concentrations
of both pituitary-derived GH and liver-derived insulin-like growth factor-1 (IGF-1),
which is GH dependent. Excess GH and IGF-1 have both somatic and metabolic
effects. In addition, the somatotroph adenoma itself may cause local symptoms.
(See 'Clinical manifestations' above.)
●The onset of acromegaly is insidious, and its progression is usually very slow.
The interval from the onset of symptoms until diagnosis is approximately 12 years.
At diagnosis, approximately 75 percent of patients have macroadenomas (tumor
diameter 10 mm or greater) and some of the adenomas extend to the parasellar or
suprasellar regions. (See 'Insidious onset' above.)
●Some patients with acromegaly and large tumors have symptoms due to
compressive effects of the tumor, such as headache, visual field defects
(classically bitemporal hemianopsia), and cranial nerve palsies. Overall,
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approximately 60 percent of patients eventually have headaches, and 10 percent
have visual symptoms. Macroadenomas can also cause decreased secretion of
other pituitary hormones, most commonly gonadotropins. (See 'Direct effects of
pituitary tumor' above.)
●Virtually all patients with acromegaly have acral and soft tissue overgrowth, and
skin thickening. The characteristic findings are an enlarged jaw (macrognathia)
and enlarged, swollen hands and feet, which result in increasing shoe and glove
size and the need to enlarge rings. (See 'Soft tissue and skin' above.)
●Cardiovascular abnormalities include hypertension, left ventricular hypertrophy,
and cardiomyopathy. (See 'Cardiovascular disease' above.)
●In addition to high serum GH and IGF-1 concentrations, uncontrolled acromegaly
is also associated with hyperinsulinism, insulin resistance, overt diabetes in 10 to
15 percent of cases, and impaired glucose tolerance in a further 50 percent.
(See 'Metabolic' above.)
●Patients with acromegaly appear to be at increased risk for colon polyps, colon
cancer, and other tumors. (See 'Colonic effects' above.)
●The mortality rate of patients with acromegaly appears to be increased,
especially if strict biochemical control is not achieved. Death is primarily from
cardiovascular disease. However, mortality rates have begun to decline with
improvements in therapy. (See 'Mortality' above.)

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Causes, presentation, and evaluation of sellar
masses
Author:
Peter J Snyder, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 21, 2021.
INTRODUCTIONSellar masses typically present in one or more ways:
●With neurologic symptoms, such as visual impairment, diplopia, or
headache
●As an incidental finding on magnetic resonance imaging (MRI) or computed
tomographic (CT) scanning performed for some other reason
●With hormonal abnormalities
This topic will review the causes, clinical manifestations, and evaluation of sellar
masses. The clinical presentation and management of individual pituitary tumors
and of hypopituitarism are discussed separately. (See "Clinical manifestations and
evaluation of hyperprolactinemia" and "Clinical manifestations and diagnosis of
gonadotroph and other clinically nonfunctioning pituitary adenomas" and "Clinical
manifestations of hypopituitarism" and "Diagnostic testing for hypopituitarism".)
CAUSESPituitary adenomas are the most common cause of sellar masses from
the third decade on, accounting for up to 10 percent of all intracranial neoplasms
[1-3]. Other disorders, which are often difficult to distinguish from pituitary
adenomas by imaging, include physiologic enlargement of the pituitary and
benign and malignant tumors (table 1).
Pituitary adenomas — Pituitary adenomas are benign tumors of the anterior
pituitary, but they are true neoplasms, as shown by clonality studies [4,5].
Incidence and prevalence — There are few population studies of the incidence
and prevalence of pituitary adenomas. However, a population-based study in
Northern Finland, where all patients within a health care district are referred to a
predetermined medical center, found the following standardized incidence rates
per 100,000 (cases diagnosed between 1992 and 2007) [6]:
●All pituitary adenomas – 4.0
●Lactotroph adenomas – 2.2

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 ●Clinically nonfunctioning adenomas – 1.0
●Somatotroph adenomas – 0.34
●Corticotroph adenomas – 0.17
Past studies of pituitary adenomas in the population are thought to have
underestimated their true prevalence. In a current report from a single community
of over 80,000 inhabitants in England, the prevalence of pituitary adenomas per
100,000 was fourfold higher than previous estimates [7]:
●All adenomas – 77.6
●Lactotroph adenomas – 44.4
●Nonfunctioning adenomas – 22.2
●Somatotroph adenomas – 8.6
●Corticotroph adenomas – 1.2
Genetics — Classic oncogene mutations are rarely found in pituitary adenomas,
but mutations in the following genes may play a role in the development of one or
more types of pituitary adenomas:
●MEN1 – Loss-of-function mutations of this tumor suppressor gene appear to
be responsible for the tumors that occur in the parathyroids, pancreatic
islets, and pituitary glands of patients who have multiple endocrine neoplasia
type 1 (MEN1) syndrome [8]. However, mutations in this gene do not appear
to cause sporadic pituitary adenomas [9]. (See "Multiple endocrine neoplasia
type 1: Definition and genetics".)
●Gs-alpha – An activating mutation of the alpha subunit of the guanine
nucleotide stimulatory protein (Gs-alpha) gene is found in approximately 40
percent of somatotroph adenomas [10,11]. These mutations result in
constitutive activation of adenylyl cyclase, which may play a role in both cell
division and excessive growth hormone secretion by these adenomas.
(See "Causes and clinical manifestations of acromegaly".)
●AIP – Mutations in the aryl hydrocarbon receptor-interacting protein (AIP)
are associated with familial pituitary adenomas, usually somatotroph or
somatomammotroph adenomas, that present in adolescence or early
adulthood and are relatively aggressive [12].
Classification — Adenomas are classified by size and the cell of origin. Lesions
smaller than 1 cm are classified as microadenomas, and lesions larger than 1 cm
are classified as macroadenomas. Adenomas can arise from any type of cell of the
anterior pituitary and may result in increased secretion of the hormone(s)
produced by that cell and/or decreased secretion of other hormones due to
compression of other cell types [13].
●Gonadotroph adenomas usually present as clinically nonfunctioning sellar
masses, but rarely cause symptoms due to hormonal hypersecretion.

334
 (See "Clinical manifestations and diagnosis of gonadotroph and other
clinically nonfunctioning pituitary adenomas".)
●Thyrotroph adenomas may present as clinically nonfunctioning sellar
masses that secrete only alpha or TSHB subunits or may cause
hyperthyroidism due to increased secretion of intact thyroid-stimulating
hormone (TSH). (See "TSH-secreting pituitary adenomas".)
●Corticotroph adenomas usually cause Cushing's disease, but a significant
minority are "clinically silent" or totally silent. (See "Establishing the cause of
Cushing's syndrome" and "Clinical manifestations and diagnosis of
gonadotroph and other clinically nonfunctioning pituitary adenomas".)
●Lactotroph adenomas usually cause hyperprolactinemia, which leads to
hypogonadism in both females and males. (See "Clinical manifestations and
evaluation of hyperprolactinemia".)
●Somatotroph adenomas typically cause acromegaly due to increased growth
hormone secretion, but a significant minority are "clinically silent."
(See "Causes and clinical manifestations of acromegaly" and "Clinical
manifestations and diagnosis of gonadotroph and other clinically
nonfunctioning pituitary adenomas".)
●Lactotroph/somatotroph adenoma combinations that secrete both prolactin
and growth hormone [14] are well recognized and cause the clinical
syndromes of both hormones. Other mixed cell adenomas, sometimes called
plurihormonal adenomas, can involve any combination of cells but are
uncommon.
Pituitary hyperplasia — There are several recognized causes of hyperplasia of the
pituitary. These may present as sellar masses and be misdiagnosed as pituitary
adenomas:
●Lactotroph hyperplasia during pregnancy. (See "Causes of
hyperprolactinemia".)
●Thyrotroph and gonadotroph hyperplasia due to longstanding primary
hypothyroidism and primary hypogonadism, respectively [15-19].
●Somatotroph hyperplasia due to ectopic secretion of growth hormone-
releasing hormone, a rare condition [20].
Other benign tumors — Several other benign tumors can occur in or near the
sella, including craniopharyngiomas, meningiomas, and, less commonly,
pituicytomas.
Craniopharyngioma — Craniopharyngiomas are solid or mixed solid-cystic
benign tumors that arise from remnants of Rathke's pouch along a line from the
nasopharynx to the diencephalon. Most are either intrasellar or suprasellar.
Approximately 50 percent present clinically during childhood and adolescence, the

335
other 50 percent present after age 20 years, some not until age 70 or 80 years. The
major presenting symptoms are growth retardation in children and abnormal
vision in adults. In addition, pituitary hormonal deficiencies, including diabetes
insipidus, are common. (See "Craniopharyngioma".)
Meningioma — A meningioma is a usually benign tumor arising from the
meninges anywhere within the head. Some arise near the sella, causing visual
impairment and hormonal deficiencies. (See "Epidemiology, pathology, clinical
features, and diagnosis of meningioma".)
Pituicytoma — This is an uncommon, low-grade (World Health Organization
[WHO] grade 1), indolent glioma arising from the pituicytes of the posterior
pituitary. It presents as a sellar mass, which is usually mistaken for a pituitary
adenoma, and has no known hormonal secretory function.
Malignant tumors — Some malignant tumors arise within or near the sella, and
others metastasize to this site.
Primary — Malignancies that arise in the parasellar region include germ cell
tumors, sarcomas, chordomas, and lymphomas. Pituitary carcinomas are rare [21].
●Germ cell tumors – Germ cell tumors, also called ectopic pinealomas, usually
occur through the third decade of life and may present with headache,
nausea, vomiting, and lethargy (from increased intracranial pressure in
patients with pineal lesions); diplopia, hypopituitarism, or diabetes insipidus
(with suprasellar tumors); and paralysis of upward conjugate gaze (Parinaud
syndrome). Imaging shows a mass in the third ventricle. Serum
concentrations of human chorionic gonadotropin-beta (B-hCG) and/or alpha
fetoprotein (AFP) may be increased. Although these lesions are highly
malignant and metastasize readily, they are also highly radiosensitive.
(See "Intracranial germ cell tumors".)
●Chordomas – Chordomas usually are locally aggressive tumors that can
metastasize. They often arise in the clivus and present with headaches, visual
impairment, and anterior pituitary hormonal deficiencies. (See "Chordoma
and chondrosarcoma of the skull base".)
●Primary lymphoma – Primary central nervous system (CNS) lymphoma
sometimes involves the pituitary and hypothalamus. A review of 13 patients
with pituitary involvement noted neurologic symptoms (headaches and visual
and oculomotor impairment) and/or deficiencies of anterior pituitary
hormones and antidiuretic hormone [22]. Magnetic resonance imaging (MRI)
shows a sellar mass with variable extrasellar extension.
Metastatic disease — Metastases to the hypothalamus and pituitary gland
account for 1 to 2 percent of sellar masses [1,23]. They occur most commonly with
breast cancer in women and lung cancer in men but can be seen with many other

336
cancers [24,25]. Symptoms, which occur in approximately 7 percent of patients,
include diabetes insipidus, anterior pituitary dysfunction, visual field defects,
retroorbital pain, and ophthalmoplegia [23]. Survival in 36 patients in one series
averaged six months [25].
Cysts — Several types of cysts can occur in the sellar and/or suprasellar area,
including Rathke's cleft [26,27], arachnoid [28], and dermoid cysts. Rathke's cleft
cysts, the most common, are benign cysts derived from remnants of Rathke's
pouch, the same structure from which craniopharyngiomas arise
(see "Craniopharyngioma"). The clinical characteristics of all are similar.

Most cysts are small and discovered incidentally by MRI. The MRI characteristics
include a sellar and/or suprasellar, symmetrical, round or ovoid mass that
enhances on either T1 or T2-weighted images but does not concentrate
gadolinium. Larger cysts may cause headaches, visual impairment, and/or anterior
pituitary hormonal deficiencies. Rarely, they bleed, causing apoplexy, or rupture,
causing aseptic meningitis.

The natural history is variable. Of 75 patients with Rathke's cleft cysts followed for
a median of 24 months, 57 percent had no change in size, 28 percent increased,
and 15 percent decreased [27].
Abscess — Pituitary abscesses, which are rare, can occur in a normal or diseased
pituitary gland. In a series of 24 patients, 16 (67 percent) presented with symptoms
and physical findings consistent with a pituitary mass, while only eight had
features suggestive of infection (fever, leukocytosis, meningismus) [29]. Imaging
studies, including computed tomography (CT) and MRI, were unable to distinguish
between pituitary abscess and pituitary adenoma. As a result, most patients were
diagnosed at the time of surgical exploration.
Arteriovenous fistula of the cavernous sinus — Arteriovenous fistulae of the
cavernous sinus can cause modest enlargement of the pituitary gland. Pituitary
size returns toward baseline after the fistula is blocked [30].
Hypophysitis — Several types of hypophysitis can enlarge the pituitary early in
their course. Lymphocytic infiltration of the pituitary usually occurs in late
pregnancy or the postpartum period, but can also be seen in women at other
times and infrequently in men [31] and increasingly due to anti-cytotoxic T-
lymphocyte antigen (CTLA)-4 treatment of malignancies [32-34]. It is characterized
by headaches of an intensity out of proportion to the size of the lesion and
hypopituitarism, in which adrenal insufficiency is unusually prominent.
(See "Causes of hypopituitarism", section on 'Hypophysitis' and "Toxicities
associated with checkpoint inhibitor immunotherapy", section on 'Hypophysitis'.)

337
CLINICAL MANIFESTATIONSSellar masses can present with neurologic
symptoms, abnormalities related to under- or oversecretion of pituitary hormones,
or as an incidental finding on radiologic examination performed for some other
reason.
Visual defects — Impaired vision is the most common symptom that leads a
patient with a nonfunctioning adenoma, of which over 80 percent are
gonadotroph adenomas, to seek medical attention [35]. (See "Clinical
manifestations and diagnosis of gonadotroph and other clinically nonfunctioning
pituitary adenomas".)

Visual impairment is caused by suprasellar extension of the adenoma, leading to

compression of the optic chiasm. The most common complaint is diminished vision
in the temporal fields (bitemporal hemianopsia). One or both eyes may be affected
and, if both, to variable degrees. Diminished visual acuity occurs when the optic
chiasm is more severely compressed. Other patterns of visual loss can also occur.
Thus, an intrasellar lesion should be suspected when there is any unexplained
pattern of visual loss.

The onset of the visual deficit is usually so gradual that many patients do not seek
ophthalmologic consultation for months or even years. Even at this time, the
reason for the deficit may not be recognized, unless a visual field examination is
performed, further delaying the diagnosis.

Other neurologic symptoms — Other neurologic symptoms that may cause a

patient with a sellar mass to seek medical attention include:
●Headaches, presumably caused by expansion of the sella. The quality of the
headache is not specific.
●Diplopia, induced by oculomotor nerve compression resulting from lateral
extension of the mass.
●Pituitary apoplexy induced by sudden hemorrhage into an adenoma,
causing excruciating headache and diplopia.
●Cerebrospinal fluid rhinorrhea, caused by inferior extension of the mass, an
extremely uncommon presentation.
●Parinaud syndrome, a constellation of neuro-ophthalmologic findings (most
often paralysis of upward conjugate gaze), that result from ectopic
pinealomas. (See "Supranuclear disorders of gaze in children", section on
'Parinaud syndrome'.)
Hormone deficiencies — At the time of initial presentation with a neurologic
symptom, many patients with sellar masses, when carefully questioned, admit to

338
symptoms of pituitary hormone deficiencies. However, these symptoms are not
usually the reason that the patient seeks medical attention.

The most common pituitary hormone deficiencies are of gonadotropins, resulting

in hypogonadism in both males and females.

EVALUATION OF A SELLAR MASSSellar masses should be evaluated both

radiologically and hormonally.
Radiologic procedures
MRI — Magnetic resonance imaging (MRI) with gadolinium is the single best
imaging procedure for most sellar masses, and there is usually no need to perform
any other imaging study. Certain MRI findings suggest a greater likelihood of
some kinds of sellar masses than others [36]. As an example, a mass that is
separate from the pituitary gland generally indicates that the mass is not a
pituitary adenoma (image 1). However, no finding is usually pathognomonic of any
one kind of mass (image 1 and image 2 and image 3). In situations in which the
use of gadolinium is contraindicated, such as renal impairment or pregnancy, MRI
without gadolinium may still be helpful.
Unenhanced image — Normal pituitary tissue and most sellar lesions, pituitary
adenomas, and other tumors, have a signal that is similar to or slightly greater in
intensity than that of central nervous system (CNS) tissue. Cystic lesions, such as
Rathke's cleft cysts, often have a low-intensity signal on T1-weighted images;
however, craniopharyngiomas and even pituitary adenomas may be partially cystic
and, therefore, have low-intensity signals. Furthermore, the signal intensity on T1-
weighted images will be high if the protein or lipid concentration of the cyst fluid is
high. On T2-weighted images, cystic lesions may have a high-intensity signal.
Hemorrhage into the pituitary gland results in a high-intensity signal on both T1-
and T2-weighted images.
Meningiomas typically have a brighter and more homogeneous signal than
pituitary adenomas. They also have a suprasellar rather than a sellar epicenter and
a dural-based attachment best seen after contrast enhancement [37].
Gadolinium-enhanced image — Normal pituitary tissue takes up gadolinium to a
greater degree than CNS tissue and therefore has a higher-intensity signal than
the surrounding CNS. Both micro- and macroadenomas of the pituitary (as well as
other sellar masses such as craniopharyngiomas and meningiomas) usually take
up gadolinium to a lesser degree than the normal pituitary but more than the CNS.
Therefore, the degree of gadolinium enhancement does not distinguish one kind
of sellar mass from another. The postcontrast enhancement of meningiomas is
usually homogeneous. If a sellar lesion can be seen as separate from the normal

339
pituitary, whether on unenhanced or, more commonly, enhanced images, the
lesion is usually not a pituitary adenoma.
Among patients with moderate to advanced renal failure (dialysis-dependent or
estimated glomerular filtration rate [eGFR] less than 30 mL/min), the
administration of gadolinium has been associated with the potentially severe
syndrome of nephrogenic systemic fibrosis. In such patients, gadolinium-based
imaging should be avoided if possible. This issue, as well as the role of
hemodialysis after the procedure if gadolinium-based imaging must be
performed, is discussed separately. (See "Patient evaluation before gadolinium
contrast administration for magnetic resonance imaging", section on 'Approach to
preventing nephrogenic systemic fibrosis' and "Nephrogenic systemic
fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease", section
on 'Prevention'.)
CT scan — Calcification in a craniopharyngioma or meningioma is seen better by
computed tomography (CT) scan than by MRI (image 4).
(See "Craniopharyngioma".)
Hormonal evaluation — We recommend evaluation of hypothalamic-pituitary
hormonal function whenever a sellar mass is encountered. Hormonal
hypersecretion is caused only by pituitary adenomas. Consequently, the
demonstration of hormonal hypersecretion identifies the sellar mass as a pituitary
adenoma and also identifies the type of adenoma.

We therefore suggest measurements of serum prolactin (lactotroph adenomas),

insulin-like growth factor-1 (IGF-1) (somatotroph adenomas), and plasma
corticotropin (ACTH) and 24-hour urinary free cortisol (corticotroph adenomas).

Additional endocrine testing is needed when a gonadotroph or thyrotroph

adenoma is suspected (luteinizing hormone [LH], follicle-stimulating hormone
[FSH], total or free thyroxine [T4], and thyroid-stimulating hormone [TSH],
respectively). Testing of alpha subunit is needed when either type of adenoma is
suspected. (See "Clinical manifestations and diagnosis of gonadotroph and other
clinically nonfunctioning pituitary adenomas" and "TSH-secreting pituitary
adenomas".)
Hormonal hypersecretion — Hypersecretion, with the exception noted below, is
caused only by pituitary adenomas. As a result, the demonstration of hormonal
hypersecretion identifies both the sellar mass as a pituitary adenoma and the kind
of adenoma:
●A serum prolactin concentration >200 ng/mL generally identifies a
lactotroph adenoma; values that are between 20 and 200 ng/mL could be due
to a lactotroph adenoma or to any other sellar mass or medications.
340
 (See "Clinical manifestations and evaluation of hyperprolactinemia", section
on 'Serum prolactin concentrations'.)
●The best single test for the diagnosis of acromegaly is measurement of
serum IGF-1. Among patients with equivocal values, serum growth hormone
levels can be measured after an oral glucose load. (See "Diagnosis of
acromegaly".)
●Elevated 24-hour urine cortisol excretion associated with a high-normal or
high ACTH concentration usually indicates a corticotroph adenoma.
(See "Establishing the diagnosis of Cushing's syndrome" and "Establishing the
cause of Cushing's syndrome".)
●Gonadotroph adenomas can be identified by characteristic patterns of basal
and thyrotropin-releasing hormone (TRH)-stimulated concentrations of
gonadotropins and their subunits; these patterns differ somewhat in males
and females. TRH is not currently available in the United States but is still
available in many other countries. (See "Clinical manifestations and diagnosis
of gonadotroph and other clinically nonfunctioning pituitary adenomas".)
●Thyrotroph adenomas are characterized by a clinically hyperthyroid patient
who has a diffuse goiter and elevations in serum free T4 and triiodothyronine
(T3) but an inappropriately normal or elevated serum TSH level. (See "TSH-
secreting pituitary adenomas".)
Hormonal hyposecretion — In addition to testing for hormonal hypersecretion,
the possibility of hormonal hyposecretion should be evaluated in all patients who
have a sellar mass >1 cm in order to identify and replace hormonal deficiencies
(see "Diagnostic testing for hypopituitarism"). The presence of hormonal
deficiencies, however, is not generally useful in the differential diagnosis of a sellar
mass, since any mass can cause these deficiencies. One exception to this
statement is that the spontaneous development of central diabetes insipidus
indicates that the lesion affects the hypothalamus or the stalk and is therefore not
a pituitary lesion. (See "Clinical manifestations and causes of central diabetes
insipidus".)
Pituitary incidentaloma — The extent of the evaluation in a patient with an
incidentally discovered intrasellar MRI signal abnormality depends upon its size. If
it is larger than 1 cm, it should be evaluated as described above. If the mass is
smaller than 1 cm, especially much smaller, and the patient has no clinical findings
of pituitary dysfunction, we usually measure only the serum prolactin
concentration, which, in one report, was much more cost effective than either
measurement of multiple hormones or performance of follow-up MRIs at 6 and 12
months [38]. One exception may be the patient who is quite anxious about the
presence of a small pituitary tumor. No evaluation for hormonal hyposecretion or

341
visual abnormalities is necessary. (See "Incidentally discovered sellar masses
(pituitary incidentalomas)".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Prolactinoma (The

Basics)" and "Patient education: Pituitary adenoma (The Basics)")
●Beyond the Basics topics (see "Patient education: High prolactin levels and
prolactinomas (Beyond the Basics)" and "Patient education: Acromegaly
(Beyond the Basics)" and "Patient education: Meningioma (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONSSellar masses usually present with
neurologic symptoms, hormonal abnormalities, or as an incidental finding on
magnetic resonance imaging (MRI). Pituitary adenomas are the most common
cause of sellar masses, but other causes include:
●Physiologic enlargement of the pituitary, most commonly during pregnancy,
but also in primary hypothyroidism and primary hypogonadism. (See "Causes
of hyperprolactinemia".)
●Other benign tumors, such as craniopharyngioma and meningioma.
(See "Craniopharyngioma" and "Epidemiology, pathology, clinical features,
and diagnosis of meningioma".)
●Malignant tumors, both primary (germ cell tumor, chordoma, primary
central nervous system [CNS] lymphoma) and metastatic (most commonly

342
from breast and lung cancer). (See "Intracranial germ cell
tumors" and "Chordoma and chondrosarcoma of the skull base".)
●Sellar masses may also be due to a cyst, abscess, or arteriovenous fistula of
the cavernous sinus. (See 'Cysts' above and 'Abscess' above
and 'Arteriovenous fistula of the cavernous sinus' above.)
●Hypophysitis, especially lymphocytic (lymphocytic infiltration of the
pituitary), occurs most commonly in postpartum women, but can also be
seen in women at other times, and rarely in men, but increasingly due to anti-
cytotoxic T-lymphocyte antigen (CTLA)-4 treatment of malignancies.
(See 'Hypophysitis' above and "Causes of hypopituitarism".)
●We recommend MRI with gadolinium as the single best and usually only
imaging procedure for most sellar masses. Certain MRI findings suggest a
greater likelihood of some kinds of sellar masses than others. As an example,
finding a mass that is separate from the pituitary gland generally indicates
that the mass is not a pituitary adenoma.
●We recommend evaluation of hypothalamic-pituitary hormonal function
whenever a sellar mass is encountered. Hormonal hypersecretion is caused
only by pituitary adenomas. Consequently, the demonstration of hormonal
hypersecretion identifies the sellar mass as a pituitary adenoma and also
identifies the type of adenoma. (See 'Hormonal evaluation' above.)
●The extent of the evaluation in a patient with an incidentally discovered
intrasellar MRI signal abnormality (pituitary incidentaloma) depends upon its
size. If it is larger than 1 cm, we recommend evaluating for hormonal
hypersecretion and hyposecretion as described above (see 'Hormonal
evaluation' above). If it is smaller than 10 mm and the patient has no clinical
findings of pituitary dysfunction, we recommend measuring only the serum
prolactin concentration. (See "Incidentally discovered sellar masses (pituitary
incidentalomas)".)
●Hormonal hyposecretion may be caused by any hypothalamic or pituitary
lesion and therefore usually has no value in the differential diagnosis of a
sellar mass. One exception to this statement is that the spontaneous
development of central diabetes insipidus indicates that the lesion affects the
hypothalamus or the stalk and is therefore not a pituitary lesion.
(See "Clinical manifestations and causes of central diabetes insipidus".)

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Clinical manifestations and diagnosis of
gonadotroph and other clinically nonfunctioning
pituitary adenomas
Author:
Peter J Snyder, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 30, 2021.
INTRODUCTIONMost patients with pituitary adenomas present with signs and
symptoms of hormone hypersecretion (eg, hyperprolactinemia, growth hormone
[GH] excess, or hypercortisolism). However, 25 to 35 percent of pituitary adenomas
are clinically nonfunctioning or "silent"; 70 to 90 percent of these are gonadotroph
adenomas, making them the most common type of pituitary macroadenoma.
Patients with clinically nonfunctioning adenomas most often present with
neurologic symptoms due to mass effects, while others may be completely
asymptomatic and be first detected on an imaging study done for reasons other
than pituitary symptoms or disease. By the time patients present, a high
percentage have biochemical evidence of hypopituitarism due to compression of
normal pituitary cells by the macroadenoma.
The clinical features, evaluation, and diagnosis of clinically nonfunctioning pituitary
adenomas are reviewed here. The treatment of these tumors and an overview of
incidentally discovered sellar masses (pituitary incidentalomas) are discussed
separately. (See "Treatment of gonadotroph and other clinically nonfunctioning
adenomas" and "Incidentally discovered sellar masses (pituitary incidentalomas)".)
OVERVIEWPituitary adenomas are classified by their cell of origin (lactotroph,
gonadotroph, somatotroph, corticotroph, and thyrotroph) and their size
(microadenomas <1 cm, macroadenomas ≥1 cm). Most adenomas (65 to 70
percent) secrete an excess amount of hormone including prolactin, growth
hormone (GH), corticotropin (ACTH), or thyroid-stimulating hormone (TSH).
(See "Causes of hyperprolactinemia" and "Causes and clinical manifestations of
acromegaly" and "Causes and pathophysiology of Cushing's syndrome" and "TSH-
secreting pituitary adenomas".)

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The remainder of pituitary adenomas (25 to 35 percent) are clinically
nonfunctioning or "silent." Of these, 70 to 90 percent are gonadotroph adenomas
[1]. There are also clinically nonfunctioning somatotroph [2,3], corticotroph, and
lactotroph adenomas [4], although these are less common.
The majority of gonadotroph adenomas are clinically "silent" and difficult to
identify because they are poorly differentiated and produce and secrete hormones
inefficiently. The gonadotropins, luteinizing hormone (LH) and follicle-stimulating
hormone (FSH), consist of a common alpha subunit and a unique beta subunit. TSH
and human chorionic gonadotropin (hCG) also consist of the common alpha
subunit and a unique beta subunit. The hormones secreted by gonadotroph
adenomas in order of decreasing frequency include: FSH, FSH-beta, alpha subunit,
LH, and LH-beta [5].
Alpha subunit is not biologically active and also does not result in a clinical
symptom due to its secretion. However, it is measured to evaluate patients with
sellar masses to determine if the mass is pituitary in origin and whether there is
accompanying hormonal hypersecretion. (See 'Hormone excess' below.)
EPIDEMIOLOGYEstimates of the prevalence of pituitary adenomas are variable
and are often based upon autopsy or magnetic resonance imaging (MRI) series. In
a report from a single community of over 80,000 inhabitants in England, the
prevalence of nonfunctioning pituitary adenomas (that had come to the attention
of a clinician) was 22 per 100,000 [6]. This is likely an underestimate of the true
prevalence, as many nonfunctioning pituitary adenomas go undiagnosed until
they are very large or are identified on an imaging study done for unrelated
reasons.
Gonadotroph adenomas are thought to be most common in men over age 50
years [1] and less common in similar aged women, but this could be due to
difficulty in recognizing gonadotroph adenomas in this population. High serum
gonadotropins would be unlikely to raise suspicion for a gonadotroph adenoma in
a woman over 50 years since she is likely to have elevated basal serum
gonadotropin concentrations from the normal menopause [7]. (See "Clinical
manifestations and diagnosis of menopause".)
PATHOGENESISGonadotroph adenomas, like other pituitary adenomas, appear
to be true clonal neoplasms [8,9], but the mutations that cause them are not
known. Genes that have been found to be overexpressed include the pituitary
tumor transforming gene, Ki-67, and FGF-R [10-12]. The maternally-expressed
gene 3 (MEG3) is underexpressed [13].
CLINICAL PRESENTATIONSNonfunctioning pituitary adenomas (including
the majority of gonadotroph adenomas) are difficult to recognize clinically until

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they are large enough to cause symptoms due to a mass effect. The three most
common presentations include the following (table 1) [14]:
●Neurologic symptoms – Most commonly, visual symptoms; less commonly,
headache
●A pituitary mass that is discovered as an incidental finding when an imaging
procedure is done for reasons other than pituitary symptoms or disease
●Pituitary hypofunction due to compression of normal pituitary tissue by the
adenoma
Less commonly, patients with gonadotroph adenomas may present with clinical
syndromes due to hypersecretion of follicle-stimulating hormone (FSH) or, less
commonly, luteinizing hormone (LH) (ovarian hyperstimulation or precocious
puberty). (See 'Hormone excess' below.)
Neurologic symptoms
Visual impairment — Impaired vision, caused by suprasellar extension of the
adenoma that compresses the optic chiasm, is the most common symptom that
leads a patient with a gonadotroph or other clinically nonfunctioning adenoma to
seek medical attention (image 1) [14-16].
●The most common type of vision impairment is visual field loss, typically
diminished vision in the temporal fields (superior temporal quadrantanopsia
or temporal hemianopsia). One or both eyes may be affected. In a review of
eight series of 1719 patients with clinically nonfunctioning pituitary
adenomas, visual field disturbances were present in 798 (46 percent) [14],
while in a single-center series of 295 patients, the frequency was even higher
(192 of 295, 65 percent) [15].
●Diminished visual acuity, which occurs when the optic chiasm is more
severely compressed [16], was reported in approximately 30 percent of
patients in one series [15]. Thus, an intrasellar lesion should be suspected
when there is any unexplained pattern of visual loss.
●The onset of visual deficits is usually so gradual that many patients do not
seek ophthalmologic consultation for months or even years.
●Diplopia, induced by oculomotor nerve compression resulting from lateral
extension of the adenoma, may occur, but it is less common, occurring in up
to 10 to 15 percent of patients in several large series [14].
Headache — Headaches, the second most common neurologic symptom, occur in
30 to 40 percent of patients [14,15] and are thought to be due to sellar expansion.
There is no distinguishing characteristic of the headaches, although they are
usually diffuse.
Other — Other less common neurologic symptoms include [16]:

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 ●Cerebrospinal fluid rhinorrhea, caused by inferior extension of the
adenoma, rarely occurs spontaneously [17].
●Pituitary apoplexy (sudden hemorrhage into a pituitary macroadenoma), is
also rare. It causes excruciating headache and visual impairment [18]. This
may occur spontaneously but has also been reported during pregnancy,
surgery, and with anticoagulant use [19]. It has been described less
commonly after thyrotropin-releasing hormone (TRH) and gonadotropin-
releasing hormone (GnRH) stimulation tests [20,21] and with gonadotropin-
releasing hormone (GnRH) agonist therapy for prostate cancer [22,23].
Incidental finding on imaging — The common use of magnetic resonance
imaging (MRI) to evaluate symptoms in the head or neck has resulted in the
incidental discovery of many intrasellar lesions. In two MRI series of 100 [24] and
52 [25] normal volunteers, 10 (10 percent) and 25 (38 percent), respectively, had
previously unsuspected sellar lesions, but almost all were <10 mm. However, in
one review of eight series of pituitary "incidentalomas" discovered on MRI, 68
percent were macroadenomas [14]. This percentage is much higher than other
imaging series, suggesting that patients likely had symptoms suggestive of a sellar
mass that led to the imaging study.
The evaluation and management of these adenomas are reviewed separately.
(See "Incidentally discovered sellar masses (pituitary incidentalomas)".)
Symptoms due to hormonal abnormalities — Clinically nonfunctioning
adenomas often present with evidence of hypopituitarism (usually biochemical).
On rare occasions, gonadotroph adenomas present with hormonal hypersecretion
causing a clinical syndrome such as ovarian hyperstimulation or precocious
puberty.
Gonadotroph adenomas, like all other types of pituitary adenomas, can occur as
part of the multiple endocrine neoplasia type 1 (MEN1) syndrome, a rare heritable
disorder classically characterized by a predisposition to tumors of the parathyroid
glands, anterior pituitary, and pancreatic islet cells. (See "Multiple endocrine
neoplasia type 1: Definition and genetics", section on 'MEN1 gene'.)
Hormone deficiencies — Patients who present with neurologic symptoms, when
carefully questioned, may acknowledge symptoms of pituitary hormone
deficiencies that are due to compression of nonadenomatous cells by the
macroadenoma. However, these symptoms tend to be nonspecific (fatigue and
lethargy) and are not usually the reason that the patient seeks medical attention.
The most common clinical hormone deficiency is impaired secretion of
gonadotropins resulting in hypogonadism. In a series of 295 patients with
nonfunctioning pituitary adenomas, 61 of 161 men (38 percent) had low serum
gonadotropins, resulting in low serum testosterone, decreased libido, and erectile

347
dysfunction [15]. In the same report, 33 percent of the women of reproductive age
had menstrual cycle disorders.
Higher percentages of hypopituitarism may be detected biochemically in patients
with clinically nonfunctioning adenomas. In a review of eight series of 1719
patients, 993 (58 percent) had laboratory evidence of pituitary hormone deficiency
[14]. The most common pituitary hormone deficiencies were:
●Growth hormone (GH) (87 percent, 220 of 252 tested). Testing for GH
deficiency was less common in older series because GH deficiency was not
thought to have important clinical consequences. (See "Growth hormone
deficiency in adults".)
●LH/FSH (hypogonadotropic hypogonadism; 1216 of 1699 patients tested, 72
percent).
●Corticotropin (ACTH) (secondary adrenal insufficiency; 514 of 1699, 30
percent).
●Thyroid-stimulating hormone (TSH) (central hypothyroidism; 402 of 1699, 24
percent).
Hormone excess
Gonadotroph adenomas — Although gonadotroph adenomas are considered to
be "nonfunctioning," most do produce intact gonadotropins or their subunits.
However, these adenomas are typically poorly differentiated and inefficient
producers/secretors and do not raise serum gonadotropin concentrations. Thus,
they are usually clinically "silent" and cannot be distinguished from other clinically
nonfunctioning adenomas until immunohistochemistry is performed after
pituitary surgery.
However, approximately 35 percent of gonadotroph adenomas secrete enough LH
or FSH to raise serum gonadotropin levels [26], but clinical syndromes due to
hypersecretion of intact gonadotropins are rare. However, several syndromes have
been recognized (table 2) [27]:
●Ovarian hyperstimulation has been reported in premenopausal women [28-
34] and, rarely, in prepubertal girls [35,36]. The slight, but persistently,
elevated serum FSH concentrations lead to recruitment of multiple dominant
follicles, high serum estradiol (E2) concentrations (>500 pg/mL), and
thickened endometrium on pelvic ultrasound (potentially suggestive of
endometrial hyperplasia). The clinical picture is similar to ovarian stimulation
with exogenous FSH when administered for fertility treatment (image 2).
Because the multiple follicles are not triggered to ovulate, women present
with amenorrhea or oligomenorrhea [28-34], and prepubertal girls present
with breast development, vaginal bleeding, and abdominal distension [35,36].
If pituitary surgery is successful in removing the adenoma but not removing

348
 the normal pituitary, gonadotropin secretion and ovarian function returns to
normal [33,37-40].
●An LH-secreting pituitary adenoma resulting in precocious puberty has been
reported in two boys [41,42].
The majority of gonadotroph adenomas that secrete intact gonadotropins occur in
middle-aged adults and do not result in a clinical syndrome. In postmenopausal
women, for example, a gonadotroph adenoma that secretes intact gonadotropins
would not result in a clinical syndrome, because gonadotropin levels are already
high and a postmenopausal ovary cannot be stimulated to produce follicles or E2.
However, in males, elevated serum testosterone concentration due to
hypersecretion of intact LH and testicular enlargement due to FSH hypersecretion
have been described [5,43,44].
Other pituitary adenomas
●Somatotroph adenomas – In 100 consecutive patients with pituitary
adenomas that were surgically excised, 24 had somatotroph adenomas by
immunochemical staining [3]. Of these, eight (one-third) had an elevated
insulin-like growth factor-1 (IGF-1) concentration but not even subtle
manifestations of acromegaly and could therefore be considered to be
clinically silent.
●Corticotroph adenomas – Clinically silent corticotroph adenomas might be
recognizable by higher plasma ACTH concentrations than other
macroadenomas [4].
Elevated prolactin — Macroadenomas often compress the pituitary stalk and
obstruct the normal inhibitory hypothalamic influence on the prolactin-producing
cells, resulting in modestly elevated serum prolactin concentrations (usually <100
ng/mL but sometimes as high as 200 ng/mL). Illustrated in one study of 226
patients with nonfunctioning macroadenomas, a serum prolactin concentration
>94 ng/mL reliably distinguished between lactotroph adenomas and
nonfunctioning adenomas [45]. Rarely, gonadotroph adenomas cosecrete
prolactin and gonadotropins.
Characteristic imaging features — As noted, gonadotroph adenomas are
generally hormonally inefficient; as a result, by the time a gonadotroph adenoma
produces supranormal serum concentrations of intact gonadotropins or their
subunits, it is a macroadenoma (>1 cm) by imaging (image 1). MRI in a patient with
neurologic symptoms usually shows a large intrasellar mass that is frequently
extending outside of the sella. Elevation of the optic chiasm or extension into the
cavernous sinuses or sphenoid sinus can also be detected. MRI with gadolinium is
preferred to computed tomography (CT) because it provides superior resolution of

349
the mass and its relation to surrounding structures. (See 'Pituitary imaging' below
and "Causes, presentation, and evaluation of sellar masses", section on 'MRI'.)
Aggressive pituitary adenomas — Although most pituitary adenomas are benign
and follow an indolent course, some are aggressive and partially or entirely
resistant to all forms of treatment. A meta-analysis found that 31 percent of
clinically silent corticotroph adenomas recurred, a similar frequency as other kinds
of clinically silent adenomas. The management of some types of aggressive
pituitary adenomas is discussed separately [46]. (See "Treatment of gonadotroph
and other clinically nonfunctioning adenomas", section on 'Aggressive tumors'.)
EVALUATION
General approach — Our approach to the patient whose presenting signs,
symptoms, or prior imaging suggests a sellar mass includes the following:
●Take a detailed history and perform a physical examination, recognizing that
any visual abnormalities or other neurologic symptoms could represent a
sellar mass. The history should also focus on possible symptoms of
hypopituitarism, including symptoms of hypogonadism in men (fatigue,
decreased libido, erectile dysfunction) and women
(amenorrhea/oligomenorrhea). (See 'Neurologic symptoms' above
and 'Hormone deficiencies' above.)
●Confirm the presence of a sellar mass by a magnetic resonance imaging
(MRI) dedicated to this region, if not already done. If a sellar mass is
confirmed, assess its size, relationship to chiasm, and cavernous sinuses.
●Visual field and visual acuity testing. (See 'Visual field testing' below.)
●Biochemical testing to detect other kinds of pituitary adenomas by their
excessive hormonal secretion (eg, lactotroph, somatotroph, and, less
commonly, corticotroph adenomas). (See 'Hormone excess' above.)
●Biochemical testing for excessive secretion of gonadotropins and their
subunits, as they are characteristic of gonadotroph adenomas. This includes
measurement of serum luteinizing hormone (LH), follicle-stimulating
hormone (FSH), and alpha subunit concentrations. (See 'Hormone
excess' above.)
●Biochemical testing also for pituitary hypofunction due to compression of
normal pituitary cells by the adenoma. (See 'Hormonal testing' below.)
We agree with the Endocrine Society Clinical Practice Guidelines on Pituitary
Incidentaloma and suggest MRI, visual field testing, and biochemical evaluation for
hormone hypersecretion and hypopituitarism for patients with pituitary
incidentalomas that are >1 cm in size [47]. (See "Incidentally discovered sellar
masses (pituitary incidentalomas)".)

350
Pituitary imaging — We suggest MRI for the initial imaging study for suspected
adenomas because of its superior resolution and its ability to demonstrate the
optic chiasm. MRI with gadolinium is preferred to computed tomography (CT)
because it provides superior resolution of the mass and its relation to surrounding
structures. MRI is also able to detect blood, thereby permitting recognition of
hemorrhage into the pituitary and distinction of an aneurysm from other
intrasellar lesions (image 1).
However, MRI will not distinguish adenomatous tissue from normal pituitary
tissue. MRI will also not distinguish a gonadotroph adenoma from other pituitary
macroadenomas and often not even from nonpituitary lesions. This topic is
reviewed in more detail separately. (See "Causes, presentation, and evaluation of
sellar masses", section on 'MRI'.)
Visual field testing — All patients with sellar masses >1 cm or elevating the optic
chiasm, including those who deny visual symptoms, should undergo baseline
Humphrey visual field testing and evaluation of visual acuity. A clinician
experienced in evaluating visual field abnormalities, such as a neuro-
ophthalmologist, should interpret the results.
Hormonal testing — Hypothalamic-pituitary hormonal function (both hyper- and
hypofunction) should be evaluated whenever a large sellar mass (>1 cm) is seen on
MRI to determine if it is a pituitary adenoma that can be recognized by hormonal
hypersecretion.
●Hypersecretion - The possibility of hormone excess should be evaluated to
detect the presence of functioning pituitary adenomas. We therefore suggest
measurements of:
•Serum LH, FSH, and alpha subunit (gonadotroph adenoma). In countries
where thyrotropin-releasing hormone (TRH) is available, the FSH and
alpha subunit response to TRH will also identify a gonadotroph adenoma
(table 2).
•Serum prolactin (lactotroph adenomas).
•Insulin-like growth factor-1 (IGF-1) (somatotroph adenomas).
•Plasma ACTH, 24-hour urine free cortisol (corticotroph adenomas)
●Hypopituitarism - Deficient secretion of other pituitary hormones often
occurs due to the mass effect of the typically large gonadotroph adenomas
and should always be investigated. Additional testing for hormone
deficiencies due to compression of the normal pituitary tissue includes
measurement of the serum concentrations of:
•8 AM cortisol
•Thyroxine (T4) (if elevated, measure thyroid-stimulating hormone [TSH] to
evaluate the possibility of a thyrotroph adenoma)

351
 •Testosterone in men
•Estradiol (E2) in women of premenopausal age with amenorrhea
The interpretation of pituitary tests and the diagnosis of hypopituitarism are
discussed separately. (See "Diagnostic testing for hypopituitarism".)
Gonadotroph adenomas — In postmenopausal women, a sellar mass can be
recognized as a gonadotroph adenoma biochemically by the combination of an
elevated FSH and/or alpha subunit and a suppressed LH (table 2) [16].
Alpha subunit values should be interpreted in the context of normal values for the
specific patient group and specific assay. The serum concentration of uncombined
alpha subunit is elevated in women in three physiologic conditions [48-50]:
●Menopause, in which the gonadotroph cells of the pituitary hypersecrete
intact FSH and LH and uncombined alpha subunit
●Pregnancy, in which the placenta secretes intact human chorionic
gonadotropin (hCG) and uncombined alpha subunit
●Ovarian stimulation with exogenous gonadotropins (hCG, human
menopausal gonadotropins [hMG], FSH) for the treatment of infertility
In men, a sellar mass can be recognized as a gonadotroph adenoma by a
supranormal basal serum FSH concentration (figure 1) [51]. An elevated
concentration of alpha subunit indicates a gonadotroph adenoma, thyrotroph
adenoma, or less differentiated glycoprotein adenoma. A supranormal response of
intact FSH or alpha subunit to TRH also indicates a gonadotroph adenoma.
Finding evidence for a gonadotroph adenoma will not influence the choice of
therapy (which is pituitary surgery), but recognizing that a sellar mass is a
gonadotroph adenoma and not a nonpituitary lesion could influence the route of
surgery and can be used as a tumor marker by which to evaluate the result of
surgery and for subsequent monitoring. Finding evidence for one of the other
types of clinically nonfunctioning adenomas could also open the possibility of
pharmacologic treatment. (See "Treatment of gonadotroph and other clinically
nonfunctioning adenomas".)
Somatotroph adenomas — Although somatotroph adenomas typically cause the
characteristic clinical syndrome of acromegaly, some are silent. They can result in
excessive hormonal secretion without even the subtlest clinical change ("clinically
silent") or no clinical or biochemical evidence of excessive hormonal secretion
("totally silent"). In 100 consecutive patients with pituitary adenomas that were
surgically excised, 24 had somatotroph adenomas by immunochemical staining
[3]. Of these, eight (one-third) had an elevated IGF-1 concentration but not even
subtle manifestations of acromegaly and could therefore be considered to be
clinically silent.

352
Corticotroph adenomas — Corticotroph macroadenomas, unlike
microadenomas, do not typically cause Cushing's syndrome. However, they may
be clinically silent and recognizable by elevated plasma corticotropin (ACTH)
concentrations [4].
Lactotroph adenomas — Most lactotroph macroadenomas produce very high
serum prolactin concentrations, but some are inefficient and do not. These may be
difficult to distinguish from other sellar lesions that compress the pituitary stalk
and obstruct the normal inhibitory hypothalamic influence on the prolactin
producing cells, resulting in modestly elevated serum prolactin concentrations
(usually <100 ng/mL but sometimes as high as 200 ng/mL). Illustrated in one study
of 226 patients with nonfunctioning macroadenomas, a serum prolactin
concentration >94 ng/mL reliably distinguished between lactotroph adenomas and
nonfunctioning adenomas [45]. Rarely, gonadotroph adenomas cosecrete
prolactin and gonadotropins.
DIAGNOSISA definitive diagnosis of a gonadotroph adenoma is made by
pathologic evaluation of the excised tissue. Pituitary adenomas typically show
effacement of the normal lobular pituitary architecture and instead show a
monomorphic population of cells and loss of the normal reticulin pattern.
Immunochemical staining is positive for follicle-stimulating hormone (FSH)-beta,
luteinizing hormone (LH)-beta, and/or alpha subunit.

However, the diagnosis of a gonadotroph adenoma can be made with a

reasonable degree of certainty preoperatively in a patient with a large sellar mass
in the following circumstances:

●Serum prolactin concentration less than 100 ng/mL. (See 'Elevated

prolactin' above.)
●No symptoms or signs of acromegaly and serum concentration of insulin-
like growth factor-1 (IGF-1) not elevated. (See "Causes and clinical
manifestations of acromegaly" and "Diagnosis of acromegaly".)
●No signs or symptoms of Cushing's syndrome and 24-hour urine cortisol
excretion not elevated. (See "Epidemiology and clinical manifestations of
Cushing's syndrome" and "Establishing the diagnosis of Cushing's
syndrome".)
●In men, elevated basal serum concentrations of intact FSH and/or of alpha
subunit (table 2). In countries where thyrotropin-releasing hormone (TRH) is
available, an FSH response to TRH. Rarely, elevated LH and testosterone.
Elevated FSH and LH and subnormal testosterone indicate primary
hypogonadism. (See 'Primary hypogonadism' below.)

353
 ●In premenopausal women, irregular menses, elevated FSH and estradiol
(E2), low LH, and on pelvic ultrasound, massive polycystic ovaries and
thickened endometrium.
●In postmenopausal women, elevated FSH and/or alpha subunit and low LH
(table 2). Elevation of both FSH and LH likely indicate only normal
postmenopausal gonadotropin secretion.
DIFFERENTIAL DIAGNOSISPituitary adenomas are the most common cause
of a large sellar mass, but other causes include craniopharyngioma, meningioma,
malignant tumors, Rathke's cleft cysts, and hypophysitis. Any sellar masses >1 cm
may present with neurologic symptoms similar to clinically nonfunctioning
pituitary adenomas. Evaluation of a large sellar mass includes imaging with
magnetic resonance imaging (MRI), and hormonal evaluation for pituitary hyper-
and hypofunction. (See "Causes, presentation, and evaluation of sellar masses",
section on 'Evaluation of a sellar mass' and "Incidentally discovered sellar masses
(pituitary incidentalomas)", section on 'Lesions 10 mm or larger'.)
Lactotroph macroadenoma — As noted above, a large sellar mass associated
with a prolactin concentration <100 ng/mL probably does not represent a
lactotroph adenoma. Large sellar masses compress the pituitary stalk and thereby
prevent dopamine from the hypothalamus from reaching the pituitary, thus
decreasing normal inhibition of prolactin secretion. The result is a mild elevation of
serum prolactin (>20 ng/mL [eg, higher than normal] but usually <100 ng/mL)
[45,52]. (See 'Elevated prolactin' above and "Clinical manifestations and evaluation
of hyperprolactinemia".)
Primary hypogonadism — Longstanding primary hypogonadism can cause
gonadotroph cell hypertrophy and therefore overall pituitary enlargement [53,54]
and, in this way, as well as in elevated gonadotropin concentrations, is similar to
gonadotroph adenomas. Primary hypogonadism differs from gonadotroph
adenomas in several ways:
●The degree of pituitary enlargement is much less
●Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are
elevated
●Neither intact gonadotropins nor their subunits respond to thyrotropin-
releasing hormone (TRH) [51,55]
Polycystic ovary syndrome — Women with polycystic ovary syndrome (PCOS)
have multiple follicles on pelvic ultrasound. However, they are small and arranged
in a peripheral pattern, unlike the follicles described in the cases of ovarian
hyperstimulation syndrome in women with gonadotroph adenomas (image 2) [28-
34]. In addition, serum FSH concentrations are low in PCOS, not normal or high as
they would be with a gonadotroph adenoma. Lastly, a serum estradiol (E2)
354
concentration >500 pg/mL should strongly raise the suspicion that the multiple
ovarian cysts are due to a gonadotroph adenoma (image 2) rather than PCOS.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pituitary adenoma (The Basics)")

SUMMARY
●Approximately 25 to 35 percent of all pituitary adenomas are clinically
nonfunctioning or "silent"; 70 to 90 percent of these are gonadotroph
adenomas. (See 'Overview' above.)
●Clinically nonfunctioning adenomas (including gonadotroph adenomas)
usually come to clinical attention when they become large enough to cause
neurologic symptoms such as impaired vision (diminished vision in the
temporal fields [bitemporal hemianopsia] and diminished visual acuity),
nonspecific headaches, diplopia, cerebrospinal fluid rhinorrhea, and pituitary
apoplexy. (See 'Neurologic symptoms' above.)
●Some are detected as an incidental finding when magnetic resonance
imaging (MRI) is done for other reasons. (See 'Incidental finding on
imaging' above.)
●Approximately 60 percent of patients at the time of diagnosis have
hypopituitarism due to compression by the macroadenoma, but the
hormonal deficiencies are usually not the presenting symptoms and not
detected until the patient undergoes biochemical testing. (See 'Hormone
deficiencies' above.)

355
●Gonadotroph adenomas are difficult to recognize because they secrete
variably and inefficiently, and the resulting products often do not cause a
clinical syndrome. Only 35 percent secrete enough intact follicle-stimulating
hormone (FSH) or alpha subunit to raise their serum levels. Uncommonly,
however, gonadotroph adenomas hypersecrete FSH in premenopausal
women and cause ovarian hyperstimulation and, rarely, some hypersecrete
luteinizing hormone (LH) in a boy or man and cause an increased serum
testosterone concentration. (See 'Hormone excess' above.)
●Evaluation of the patient who presents with neurologic symptoms
suggestive of a clinically nonfunctioning sellar mass should first include
pituitary MRI (see 'Evaluation' above). If a sellar mass >1 cm is detected on
pituitary MRI, the following should be performed:
•Visual field testing
•Biochemical testing for hormone hypersecretion (serum prolactin,
insulin-like growth factor-1 [IGF-1], and 24-hour urine free cortisol)
(see 'Hormone excess' above)
•Testing for hypopituitarism – 8 AM cortisol, thyroxine (T4) (plus TSH if the
T4 is high), testosterone in men and estradiol (E2) in women of
premenopausal age, FSH, LH, and alpha subunit (see 'Hormonal
testing' above)
●The diagnosis of a gonadotroph adenoma is likely if there is a large sellar
mass, no clinical or biochemical evidence of acromegaly or Cushing's
syndrome, the serum prolactin is <100 ng/mL, and the concentrations of
gonadotropins are characteristic (table 2). (See 'Diagnosis' above.)
•In men, characteristic patterns are an elevated serum FSH and/or alpha
subunit or, rarely, elevated LH and testosterone.
•In women of premenopausal age, characteristic patterns are an elevated
FSH, with or without alpha subunit, and E2.
•In postmenopausal women, the patterns are an elevated FSH and/or
alpha subunit but low LH. The diagnosis is confirmed if histologic
examination of the excised tissue shows a pituitary adenoma and
immunocytochemical staining shows staining for FSH, LH, and/or alpha
subunit.

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Diagnosis of acromegaly
Authors:
Shlomo Melmed, MD
Laurence Katznelson, MD
Section Editor:
Peter J Snyder, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 03, 2021.
INTRODUCTIONAcromegaly results from persistent hypersecretion of growth
hormone (GH). Excess GH stimulates hepatic secretion of insulin-like growth
factor-1 (IGF-1), which causes most of the clinical manifestations of acromegaly.

The clinical diagnosis is often delayed because of the slow progression of the signs
of acromegaly over a period of many years. GH excess that occurs before fusion of
the epiphyseal growth plates in a child or adolescent is called pituitary gigantism
and is discussed separately.

The diagnostic approach to acromegaly will be reviewed here. GH excess in

children and adolescents and the causes, clinical manifestations, and treatment of
acromegaly are discussed separately. (See "Pituitary gigantism" and "Causes and
clinical manifestations of acromegaly" and "Treatment of acromegaly".)
EPIDEMIOLOGYAcromegaly has been considered to be a rare disease, with an
estimated prevalence in Europe of 30 to 70 individuals per million [1,2]. However,
current estimates are considerably higher [2-4]. In one report, seven new cases of
acromegaly were identified among 6773 unselected adults in a primary care
population who underwent plasma insulin-like growth factor-1 (IGF-1) screening;
this suggests a population prevalence as high as 1000 per million individuals [5]. A
similar uncontrolled IGF-1 screening study in over 2000 individuals with type 2
diabetes found a prevalence of approximately 480 per million individuals [6].
WHO SHOULD BE TESTED FOR ACROMEGALY?
●The diagnosis of acromegaly should be suspected in individuals who present
with the typical clinical features of growth hormone (GH) excess, which
include the enlargement during adulthood of the jaw (macrognathia), hands,
and feet, which result in increasing shoe and glove size and the need to
enlarge finger rings. (See "Causes and clinical manifestations of acromegaly",
section on 'Effects of GH/IGF-1 excess'.)
357
 The facial features become coarse, with enlargement of the nose and frontal
bones as well as the jaw, and the upper incisors may become spread apart.
Despite the prominence of these findings at the time of diagnosis, the rate of
change is so slow that few patients seek care because their appearance had
changed.
●Other features include cardiovascular disease, sleep apnea, type 2 diabetes,
arthropathies, carpal tunnel syndrome, and problems directly related to the
pituitary tumor size (headache, visual loss).
However, because acromegaly is rare, we suggest against screening patients
with isolated sleep apnea, uncontrolled diabetes, arthropathy, or carpal
tunnel syndrome (unless there is a clinical suspicion of the disorder).
●We do suggest testing in patients who present with a cluster of the
following conditions, even if they do not have the typical manifestations of
acromegaly (eg, acral and facial features) [7]:
•Sleep apnea, uncontrolled diabetes, carpal tunnel syndrome, colon
polyps, cardiac failure with hypertension.
•Jaw prognathism or new-onset severe snoring or sleep apnea in a person
without obesity.
•Pituitary macroadenoma.
•The diagnosis should also be considered when a pituitary mass is
identified on an imaging study; 75 to 80 percent of somatotroph
adenomas are macroadenomas at the time of diagnosis. Some patients
may be asymptomatic in spite of raised GH and insulin-like growth factor-
1 (IGF-1) levels.
In the past, most patients had pituitary adenomas that caused visual field defects,
but this is less common now, presumably because of increased awareness of the
disease and earlier diagnosis. The percentage of patients with visual defects at
presentation is now estimated to be approximately 6 percent, down from 15 to 25
percent in 1975 [2].
DIAGNOSTIC EVALUATIONOnce a patient is suspected to have acromegaly,
the first step is biochemical testing to confirm the clinical diagnosis, followed by
imaging to determine the cause of the excess growth hormone (GH) secretion.
(algorithm 1)The cause is a somatotroph adenoma of the pituitary in over 95
percent of cases (table 1) [8]. (See 'Determining the source of excess GH' below.)
Biochemical testing — The diagnosis of acromegaly is a biochemical one and
does not require the presence of typical phenotypic features or the presence of a
pituitary tumor on magnetic resonance imaging (MRI). Therefore, biochemical
testing of anyone with a clinical picture suggestive of acromegaly (eg, pituitary

358
tumor of any size or signs and symptoms of acromegaly) is essential. (See 'Who
should be tested for acromegaly?' above.)
Serum IGF-1 concentration — The best single test for the diagnosis of
acromegaly is measurement of serum insulin-like growth factor-1 (IGF-1)
(algorithm 1) [7,9,10]. Unlike GH, serum IGF-1 concentrations do not vary from
hour to hour according to food intake, exercise, or sleep, but instead they reflect
integrated GH secretion during the preceding day or longer. Serum IGF-1
concentrations are elevated in virtually all patients with acromegaly and provide
excellent discrimination from normal individuals [11,12].
Our approach, which is similar to that of the Endocrine Society [7], includes
measurement of a serum insulin-like growth factor-1 (IGF-1) concentration as the
first step (algorithm 1).
●An unequivocally elevated serum IGF-1 concentration in a patient with
typical clinical manifestations of acromegaly confirms the diagnosis of
acromegaly.
●A normal serum IGF-1 concentration is strong evidence that the patient
does not have acromegaly.
●If the serum IGF-1 concentration is equivocal, serum GH should be
measured after oral glucose administration. Inadequate suppression of GH
after a glucose load confirms the diagnosis of acromegaly. (See 'Determining
the source of excess GH' below.)

Both serum GH concentrations and IGF-1 concentrations are increased in virtually

all patients with acromegaly. The increase in serum IGF-1 is often
disproportionately greater than that in GH for two reasons: GH secretion
fluctuates more, and GH stimulates the secretion of IGF-1-binding protein-3
(IGFBP-3), the major IGF-1 binding protein in serum.

The results must be interpreted, however, according to the patient's age. In

normal subjects, serum IGF-1 concentrations are highest during puberty and
decline gradually thereafter. Values are significantly lower in adults over the age of
60 years than in younger subjects. Thus, an apparently "normal" value in a patient
aged 70 years may in fact be elevated.

In addition, there are a number of conditions that are associated with lower serum
IGF-1 concentrations, including hypothyroidism, malnutrition, poorly controlled
type 1 diabetes, liver failure, renal failure, and oral estrogen use. In these
situations, it is possible that the diagnosis of acromegaly could be missed, and an

359
oral glucose tolerance test (OGTT) should also be performed if the disorder is
suspected [2].
A further caution is that values from one laboratory may not be comparable with
those from another laboratory. A major cause of this finding is a difference in the
calibration standards for the assay [13].

All patients with elevated age-adjusted IGF-1 levels should undergo testing for GH
hypersecretion (eg, measurement of serum GH after oral glucose administration).

Oral glucose tolerance test — The most specific dynamic test for establishing the
diagnosis of acromegaly is an OGTT. When performing the test, we measure
serum GH before and two hours after glucose administration; the criterion for the
diagnosis of acromegaly is a GH concentration greater than 1 ng/mL. In normal
subjects, serum GH concentrations fall to 1 ng/mL or less within two hours after
ingestion of 75 g glucose. In contrast, the post-glucose values are greater than 2
ng/mL in over 85 percent of patients with acromegaly.
OGTT is the gold standard for determining control of GH secretion after surgical
treatment, but it does not appear to be useful in assessing biochemical control in
patients receiving medical therapy with somatostatin analogs. In these patients,
both basal and post-glucose GH levels are highly discordant with serum IGF-1
concentrations [14]. (See "Treatment of acromegaly", section on 'Monitoring'.)
These results were obtained mainly with a radioimmunoassay method for the
measurement of GH. If one of the newer, highly sensitive immunoradiometric or
immunochemiluminescent GH assays is used, the serum GH concentration falls to
less than 0.3 ng/mL after oral glucose administration in normal subjects [15]. Thus,
the diagnosis of acromegaly can be made when the serum GH concentration
remains above 1 ng/mL using standard assays. More importantly, these more
sensitive assays may give better discrimination between those with and without
acromegaly [15].
Limitations of random serum GH measurements — Random serum growth
hormone (GH) measurements are not useful for the diagnosis of acromegaly. GH
secretion in normal subjects is pulsatile, diurnal, and stimulated by a variety of
factors, including short-term fasting, exercise, stress, and sleep; in addition, GH
clearance is rapid (plasma half-life of approximately 20 minutes) [16]. As a result,
serum GH concentrations fluctuate widely, ranging from less than 0.5 to 1 ng/mL
(less than 0.1 ng/mL using very sensitive assays [17]) during most of the day, to 2
to 5 ng/mL before the next meal or after exercise, to as high as 20 or 30 ng/mL at
night or after vigorous exercise [2]. Serum GH concentrations also may be high in
patients with uncontrolled diabetes mellitus, liver disease, and malnutrition.

360
All patients with acromegaly have increased GH secretion. However, the random
serum GH concentration is often in the range of 2 to 10 ng/mL during much of the
day, values that can be found in normal subjects. Unlike normal subjects, the
patient's serum GH concentrations change little during the day or night and, in
most patients, do not change in response to stimuli such as food or exercise.
Nevertheless, because of the variations in serum GH that occur in normal subjects
and in patients with other disorders, a high value cannot be interpreted without
knowing when the blood sample was obtained and something about the patient.
To obviate these problems, it is best not to obtain random measurements of
serum GH.
Other dynamic tests — Although rarely necessary, other dynamic tests can be
done. An example of when these might be performed would be a patient in whom
acromegaly is suspected clinically but whose IGF-1 and OGTT results are normal.
Thyrotropin-releasing hormone (TRH), in a dose of 500 mcg intravenously, raises
serum GH concentrations by 50 percent or more in approximately one-half of
patients with acromegaly, with peak values occurring at 20 to 30 minutes; serum
GH does not rise in normal subjects [18]. Conversely, L-DOPA (500 mg orally)
reduces serum GH concentrations by 50 percent or more in approximately one-
half of patients with acromegaly, while it raises the GH concentration in normal
subjects [2]. TRH is unavailable in the United States.
Serum IGFBP-3 concentration — Because IGF-1-binding protein-3 (IGFBP-3)
secretion is GH-dependent (as is IGF-1), serum IGFBP-3 concentrations are
elevated in patients with acromegaly [19]. There is, however, considerable overlap
of these values with those in normal persons, thereby limiting the utility of this
measurement [20].
Determining the source of excess GH
Pituitary MRI — Once GH hypersecretion has been confirmed, the next step is
magnetic resonance imaging (MRI) of the pituitary because a somatotroph
adenoma of the pituitary is by far the most common cause of acromegaly (table 1).
In one report of 39 patients undergoing pituitary MRI for suspected acromegaly, a
mass was identified in 27 of the 39 (69 percent) [21].
Pituitary tumors as small as 2 mm in diameter can be detected with this technique,
and the dimensions and anatomic extent of the tumor can be accurately identified
(image 1); computed tomography is less sensitive. In approximately 75 percent of
patients with somatotroph adenomas, the tumor is a macroadenoma (tumor
diameter 10 mm or more), and the tumor may extend to the parasellar or
suprasellar region. An occasional patient has an empty sella with the tumor
situated within the normal pituitary tissue lining the sella turcica.

361
It is important to remember that MRI does not distinguish between functioning
and nonfunctioning tumors; this distinction must be based upon biochemical
studies. This is an important concern because approximately 10 to 20 percent of
normal subjects have MRI or autopsy evidence of a pituitary microadenoma.
(See "Causes, presentation, and evaluation of sellar masses".)

When no clear mass is seen on a dedicated sella MRI, we consider additional

imaging, including chest and abdominal CT scans, and DOTATATE PET scan.
However, most of these patients have a somatotroph adenoma, just too small to
be detected by routine imaging.

Other studies — Other rare causes of acromegaly include pituitary somatotroph

carcinoma, a hypothalamic tumor secreting growth hormone-releasing hormone
(GHRH), a nonendocrine tumor secreting GHRH, ectopic secretion of GH by a
nonendocrine tumor, and excess growth factor activity (acromegaloidism) [22].
MRI of the head and pituitary should identify some of these other tumors. If the
MRI is normal, abdominal and chest imaging should be performed to look for an
ectopic source of hormone secretion, followed by catheterization studies in an
attempt to demonstrate an arteriovenous gradient of either GH or GHRH in the
region of the tumor [8].
Ectopic GHRH secretion accounts for only 0.5 percent of cases of acromegaly [22].
Serum GHRH is the only specific marker for this disorder, and concentrations are
usually quite elevated; special arrangements with a reliable laboratory must be
made for this assay. Pituitary MRI often reveals a normal-sized or enlarged gland,
but other patients appear to have an adenoma. GHRH should not be measured
routinely but should be if a clear-cut pituitary adenoma is not seen on MRI or
postoperatively if histologic and immunocytochemical examination of the excised
pituitary tissue reveals somatotroph hyperplasia rather than a somatotroph
adenoma.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of acromegaly".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are

362
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acromegaly (The Basics)")

●Beyond the Basics topics (see "Patient education: Acromegaly (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
●Acromegaly has been considered to be a rare disease, with an estimated
prevalence in Europe of 30 to 70 individuals per million [1,2]. However,
current prevalence estimates are considerably higher.
(See 'Epidemiology' above.)
●The diagnosis of acromegaly should be suspected in individuals who present
with the typical clinical features of growth hormone (GH) excess, which
include an enlarged jaw (macrognathia) and enlarged hands and feet, which
result in increasing shoe and glove size and the need to enlarge rings. The
facial features become coarse, with enlargement of the nose and frontal
bones as well as the jaw, and the teeth become spread apart.
We also suggest testing in patients who present with a cluster of the
following conditions, even if they do not have the typical manifestations of
acromegaly (eg, acral and facial features): sleep apnea, uncontrolled
diabetes, carpal tunnel syndrome, colon polyps, and cardiac failure with
hypertension. (See 'Who should be tested for acromegaly?' above.)
●The diagnosis should also be considered when a pituitary mass is identified
on an imaging study; 75 to 80 percent of somatotroph adenomas are
macroadenomas at the time of diagnosis. (See 'Who should be tested for
acromegaly?' above.)
●The first step in the diagnosis is measurement of a serum insulin-like growth
factor-1 (IGF-1) concentration (algorithm 1). An unequivocally elevated serum
IGF-1 concentration in a patient with typical clinical manifestations of
acromegaly confirms the diagnosis of acromegaly. A normal serum IGF-1
concentration is strong evidence that the patient does not have acromegaly.
If the serum IGF-1 concentration is equivocal, serum GH should be measured
after oral glucose administration. Inadequate suppression of serum GH after
a glucose load confirms the diagnosis of acromegaly. (See 'Diagnostic
evaluation' above.)
363
●Once the biochemical diagnosis is made, pituitary magnetic resonance
imaging (MRI) should be performed (algorithm 1); a pituitary adenoma is
found in the majority of cases. If the MRI is normal, then studies to identify a
growth hormone-releasing hormone (GHRH)- or GH-secreting tumor should
be undertaken. (See 'Other studies' above and 'Pituitary MRI' above.)

364
Diagnostic testing for hypopituitarism
Author:
Peter J Snyder, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Feb 10, 2020.
INTRODUCTIONThe diagnosis of hypopituitarism, defined as deficient
secretion of one or more pituitary hormones because of pituitary or hypothalamic
disease, is made by documenting subnormal secretion of these pituitary hormones
in defined circumstances. Each pituitary hormone must be tested separately since
there is a variable pattern of hormone deficiency among patients with
hypopituitarism. Diagnostic testing for hypopituitarism will be discussed here. The
causes, clinical manifestations, and treatment of hypopituitarism are reviewed
separately. (See "Causes of hypopituitarism" and "Clinical manifestations of
hypopituitarism" and "Treatment of hypopituitarism".)
INDICATIONS FOR TESTINGThe impetus to measure pituitary hormones is
the suspicion that the secretion of one or more may be subnormal [1]. This
suspicion can be based upon the knowledge that the patient has either a lesion
known to cause hypopituitarism or a symptom known to be caused by
hypopituitarism. The knowledge that the patient has a lesion that can cause
hypopituitarism, eg, a sellar mass, is by itself sufficient reason to test for
hypopituitarism because some patients with hypopituitarism have no symptoms.
(See "Causes, presentation, and evaluation of sellar masses" and "Incidentally
discovered sellar masses (pituitary incidentalomas)".)
CORTICOTROPIN
Evaluate for ACTH deficiency — For normal health, the basal secretion of
corticotropin (ACTH) must be sufficient to maintain the serum cortisol
concentration within the normal range. For survival, it must increase to raise
serum cortisol concentrations in times of physical stress.
Morning serum cortisol — To test basal ACTH secretion, we suggest measuring a
morning serum cortisol (at 8 to 9 AM), and the results should be interpreted as
follows:
Low — A serum cortisol value of ≤3 mcg/dL (83 nmol/L, normal range 5 to 25
mcg/dL [138 to 690 nmol/L]), confirmed by a second determination, is strong
365
evidence of cortisol deficiency, which in a patient with a disorder known to cause
hypopituitarism is usually the result of that disorder.
Such a finding in the absence of any known cause of hypopituitarism mandates
measurement of serum ACTH. A serum ACTH value not higher than normal is
inappropriately low and establishes the diagnosis of secondary adrenal deficiency
(ie, pituitary or hypothalamic disease). A value higher than normal documents
primary adrenal insufficiency (ie, adrenal disease). (See "Diagnosis of adrenal
insufficiency in adults".)
Normal — A serum cortisol value of ≥18 mcg/dL (497 nmol/L) indicates that basal
ACTH secretion is sufficient and also that it is probably sufficient for times of
physical stress.
Indeterminate — A serum cortisol value >3 mcg/dL (83 nmol/L) but <18 mcg/dL
(497 nmol/L) that is persistent on repeat determination is an indication to evaluate
ACTH reserve.
There are varying opinions among experts about  the best approach to evaluating
ACTH reserve in patients with an indeterminate morning serum cortisol. The
author of this topic suggests metyrapone testing when a test of ACTH reserve is
required. However, other experts use the cosyntropin stimulation test because of
its availability and ease of administration. (See 'Cosyntropin stimulation
test' below.)
Metyrapone test — The rationale for the administration of metyrapone is that it
blocks 11-beta-hydroxylase (CYP11B1), the enzyme that catalyzes the conversion of
11-deoxycortisol to cortisol, resulting in a reduction in cortisol secretion (figure 1).
The ensuing fall in serum cortisol should, if the hypothalamic-pituitary-adrenal axis
is normal, cause an increase in ACTH secretion and therefore an increase in
adrenal steroidogenesis up to and including 11-deoxycortisol.
●Normal subjects – In normal subjects, administration of 750 mg
of metyrapone orally every four hours for 24 hours results in a decline in 8
AM serum cortisol to less than 7 mcg/dL (172 nmol/L) and an elevation in 8
AM serum 11-deoxycortisol to ≥10 mcg/dL (289 nmol/L) at the end of the 24
hours (figure 2). Patients taking phenytoin metabolize metyrapone more
rapidly than normal; as a result, each metyrapone dose should be 1500 mg.
After the 8 AM blood sample is taken at the end of the 24 hours, 100 mg
of hydrocortisone should be administered intravenously to reverse the
cortisol deficiency caused by the metyrapone.
●Patients with hypothalamic-pituitary disease – In patients who have
decreased ACTH reserve due to hypothalamic or pituitary disease, the serum
11-deoxycortisol concentration will be less than 10 mcg/dL (289 nmol/L) and

366
 the serum cortisol <7 mcg/dL (172 nmol/L) at the end of 24 hours (figure 3)
[2].
Interpretation of the metyrapone test requires adequate inhibition of cortisol
production. If the serum 11-deoxycortisol concentration at the end of 24 hours is
<10 mcg/dL (289 nmol/L) but the serum cortisol concentration is ≥7 mcg/dL (193
nmol/L), the reason for the insufficient rise in 11-deoxycortisol may be insufficient
inhibition by metyrapone. In this case, reasons for insufficient inhibition should be
sought, such as failure to take all of the metyrapone, rapid metabolism, and
malabsorption. The test should be then be repeated using a double dose of
metyrapone. (See "Metyrapone stimulation tests".)
The advantages of the metyrapone test are that it can be administered to adults of
any age and the results correlate reasonably well with the serum cortisol response
to surgical stress. The principal disadvantage is that the patient must be observed
in an inpatient setting so that blood pressure and pulse can be measured lying and
standing before each four-hourly dose for 24 hours. If postural hypotension
occurs, the test should be terminated by administration of 100 mg
of hydrocortisone intravenously. Of note, other experts perform this test on an
outpatient basis based upon data in a number of studies suggesting its safety [3-
8]. One potential concern with this test is the declining number of clinical
laboratories that routinely perform serum 11-deoxycortisol testing.
A shorter version of this test involves the administration of a single 750 mg dose
of metyrapone at midnight and measurements of serum 11-deoxycortisol and
cortisol at 8 AM [9]. It may not, however, separate normal from abnormal as well
as the longer test.
Cosyntropin stimulation test — As noted, there is disagreement among experts
on the best approach to evaluating ACTH reserve in patients with an indeterminate
morning serum cortisol. While the author of this topic uses the metyrapone test,
Endocrine Society Clinical Practice Guidelines and many experts suggest the
cosyntropin stimulation test when a morning serum cortisol is indeterminate
[1,10,11]. The major advantages of the cosyntropin test over the metyrapone test
are drug availability and ease of administration.
The rationale for the administration of cosyntropin (ACTH) is that the adrenal
glands atrophy when they have not been stimulated for a prolonged period; as a
result, they do not secrete cortisol normally in response to a bolus dose of ACTH.
The test is usually performed by administering 0.25 mg (25 units) of cosyntropin
(synthetic ACTH 1-24) intramuscularly or intravenously and measuring serum
cortisol 60 minutes later. A serum cortisol concentration of ≥18 mcg/dL (497
nmol/L) is considered a normal response. (See "Initial testing for adrenal
insufficiency: Basal cortisol and the ACTH stimulation test".)

367
In practice, this test may be less useful because a patient who has such severe
ACTH deficiency that the adrenal glands do not respond normally to cosyntropin
will also probably have an 8 to 9 AM basal serum cortisol value that is ≤3 mcg/dL
(83 nmol/L) and therefore will not need a test of ACTH reserve. On the other hand,
a patient who has partial ACTH deficiency may have falsely normal results [12,13].
A low-dose cosyntropin stimulation test has been proposed as yielding fewer
falsely normal results [14], but several studies show that this test has the same
pitfalls as the standard dose test [8,15-18].
Insulin-induced hypoglycemia test — The rationale for this test is that
hypoglycemia induced by insulin administration is a sufficient stress to stimulate
ACTH and therefore cortisol secretion. The test is performed by administering 0.1
unit of insulin per kg of body weight and measuring serum glucose and cortisol
before and 15, 30, 60, 90, and 120 minutes after the injection [19]. In normal
subjects, serum cortisol increases to ≥18 mcg/dL (498 nmol/L) if the serum glucose
falls to <50 mg/dL (2.8 mmol/L). (See "Insulin-induced hypoglycemia test".)
The advantage of this test is that the results also correlate relatively well with the
serum cortisol response to surgical stress. The disadvantages are that
hypoglycemia can be dangerous in elderly patients and those with cardiovascular
or cerebrovascular disease or a seizure disorder and that constant monitoring is
required during the first hour after the administration of insulin. The monitoring is
necessary to detect neuroglycopenic symptoms, which should be treated with
intravenous glucose (see "Insulin-induced hypoglycemia test"). For these reasons,
we prefer the metyrapone test.
THYROTROPINHypothyroidism in patients who have pituitary or hypothalamic
disease is the result of thyrotropin (TSH) deficiency and, therefore, unlike in
patients who have thyroid disease, an elevated serum TSH concentration cannot
be used to make the diagnosis of hypothyroidism. The serum TSH concentration is
usually not low either, except when the hypothyroidism is treated. Screening for
hypothyroidism in patients with pituitary or hypothalamic disease is therefore
performed by measuring thyroxine, either total thyroxine (T4) and triiodothyronine
(T3) uptake or free T4. (See "Diagnosis of and screening for hypothyroidism in
nonpregnant adults", section on 'Secondary and tertiary (central) hypothyroidism'.)
GONADOTROPINSThe approach to the diagnosis of gonadotropin deficiency
in a patient with known hypothalamic or pituitary disease varies with the gender of
the patient.
Men — In a man with hypopituitarism, luteinizing hormone (LH) deficiency can
best be detected by measurement of the serum testosterone concentration. If it is
repeatedly low at 8 to 10 AM and the LH concentration is not elevated, the patient
has secondary hypogonadism. When the serum testosterone concentration is low,
368
the serum LH concentration is usually within the normal range, but low compared
with elevated values in primary hypogonadism. If fertility is an issue, the sperm
count should be determined. (See "Clinical features and diagnosis of male
hypogonadism".)
Women — In a woman of premenopausal age who has pituitary or hypothalamic
disease but normal menses, no tests of LH or follicle-stimulating hormone (FSH)
secretion are needed because a normal menstrual cycle is a more sensitive
indicator of intact pituitary-gonadal function than any biochemical test. If the
woman has oligomenorrhea or amenorrhea, serum LH or FSH should be
measured to be sure it is not high due to ovarian disease. In addition, the
following two tests should be obtained:
●Measurement of serum estradiol
●Administration of medroxyprogesterone, 10 mg daily for 10 days, to
determine if vaginal bleeding occurs after the 10-day course

A low serum estradiol concentration and/or absence of vaginal bleeding indicate

estradiol deficiency as a consequence of gonadotropin deficiency and warrant
consideration of estrogen treatment. Normal results, in association with
oligomenorrhea or amenorrhea, could indicate sufficient gonadotropin secretion
to maintain normal basal estradiol secretion but insufficient to cause ovulation and
normal progesterone secretion. This situation should prompt consideration of
intermittent progestin treatment.

The serum LH response to a single bolus dose of gonadotropin-releasing hormone

(GnRH) is not helpful in distinguishing secondary hypogonadism due to pituitary
disease from that due to hypothalamic disease, because patients who have
hypogonadism due to pituitary disease may have normal or subnormal serum LH
responses to GnRH, as may those who have hypothalamic disease.

GROWTH HORMONEThe availability of growth hormone for treatment of

abnormal body composition in adults who have growth hormone deficiency
increases the interest in testing growth hormone secretion in patients who have
hypothalamic or pituitary disease.
Measurement of basal serum growth hormone concentration does not distinguish
reliably between normal and subnormal growth hormone secretion in adults.
Three other criteria, however, are useful:
●Deficiencies of multiple other pituitary hormones – The likelihood that
the growth hormone response to all provocative stimuli will be subnormal in
patients who have organic pituitary disease, eg, a macroadenoma, and

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 deficiencies of corticotropin (ACTH), thyrotropin (TSH), and gonadotropins is
approximately 95 percent [20].
●Serum insulin-like growth factor-1 (IGF-1) – A serum IGF-1 concentration
lower than the age-specific lower limit of normal in a patient who has organic
pituitary disease confirms the diagnosis of growth hormone deficiency [21].
●Provocative tests of growth hormone secretion – Either insulin-induced
hypoglycemia or the combination of arginine and growth hormone-releasing
hormone (GHRH) is a potent stimulus of growth hormone release. Subnormal
increases in the serum growth hormone concentration (<5.1 ng/mL for the
former and <4.1 ng/mL for the latter) in a patient who has organic pituitary
disease confirms the diagnosis of growth hormone deficiency (figure 4) [21].
If a provocative test is necessary, we prefer the arginine-GHRH test because it
carries minimal risk, whereas the insulin tolerance test carries the risk of seizures
and angina, especially in the elderly, and neuroglycopenic symptoms in patients of
all ages. However, GHRH is no longer available in the United States. Other stimuli,
such as arginine alone, clonidine, L-DOPA, and the combination of arginine and L-
DOPA are much weaker and therefore more likely to give false-positive results [21].
All tests of growth hormone secretion are more likely to give false-positive results
in obesity. The provocative tests are reviewed in more detail separately.
(See "Growth hormone deficiency in adults", section on 'Provocative tests'.)
PROLACTINThe main physiologic role of prolactin is for lactation. Women who
have severe hypopituitarism due to hypothalamic or pituitary disease may, in the
postpartum period, have a serum prolactin concentration that is inappropriately
low and not be able to nurse. No commercially available prolactin preparation is
available for these women (see "Treatment of hypopituitarism", section on
'Prolactin deficiency'). No data are available about serum prolactin concentrations
in women without known pituitary disease who are unable to lactate.

Routine testing for prolactin deficiency is not currently performed, as it is difficult

to distinguish low from normal serum prolactin concentrations, and there is no
standardized test of prolactin reserve.

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)
SUMMARY AND RECOMMENDATIONSPituitary function should be tested
when a patient is found to have a disease that affects the hypothalamus or
pituitary (see "Causes of hypopituitarism"). Each pituitary hormone that the
clinician thinks is clinically important to a patient needs to be tested separately.

370
●Corticotropin (ACTH) secretion is tested by measuring serum cortisol at 8 to
9 AM on two or more occasions; if the value is <3 mcg/dL, the patient has
cortisol deficiency, and if >18 mcg/dL, the patient has cortisol sufficiency. If
the value is persistently intermediate, a test of ACTH reserve, such as
a metyrapone test or cosyntropin stimulation test, should be performed.
(See 'Evaluate for ACTH deficiency' above.)
●To evaluate thyrotropin (TSH) secretion, we measure either total thyroxine
(T4) and triiodothyronine (T3) uptake or free T4. The serum TSH concentration
should not be used to make the diagnosis, because it is usually within the
normal range, although sometimes low or even slightly high and, therefore,
it is not helpful. (See 'Thyrotropin' above.)
●Gonadotropin secretion in a man is tested by measuring the serum total
testosterone concentration on two or more occasions at 8 to 10 AM. A low
testosterone, assuming he is not obese (or free testosterone if he is obese),
and luteinizing hormone (LH) that is not elevated indicate secondary
hypogonadism. Gonadotropin secretion in a woman of premenopausal age
who has amenorrhea is tested by measuring estradiol. A low estradiol and
follicle-stimulating hormone (FSH) that is not elevated indicate secondary
hypogonadism. (See 'Gonadotropins' above.)
●Growth hormone secretion can be assumed to be subnormal if the patient
has: organic pituitary disease; deficiencies of ACTH, TSH, and gonadotropins;
and either an age-specific low serum insulin-like growth factor-1 (IGF-1)
concentration or a subnormal growth hormone response to a test of growth
hormone stimulation. (See 'Growth hormone' above.)

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Management of hyperprolactinemia
Author:
Peter J Snyder, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jul 20, 2020.
INTRODUCTIONLactotroph adenomas (prolactinomas) are more amenable to
pharmacologic treatment than any other kind of pituitary adenoma because of the
availability of dopamine agonists, which usually decrease both the secretion and
size of these tumors. For the minority of lactotroph adenomas that do not respond
to dopamine agonists, other treatments must be used. Hyperprolactinemia due to
nonadenoma causes should also be treated if it causes hypogonadism.
This topic will review the major issues concerning the therapy of
hyperprolactinemia due to lactotroph adenomas and other causes, with the
exception of treatment during pregnancy, which is discussed separately. The
causes, clinical manifestations, and diagnosis of hyperprolactinemia are also
discussed elsewhere. (See "Management of lactotroph adenoma (prolactinoma)
during pregnancy" and "Causes of hyperprolactinemia" and "Clinical
manifestations and evaluation of hyperprolactinemia".)
INDICATIONS FOR TREATMENTThere are two principal reasons why
patients with hyperprolactinemia may need to be treated: existing or impending
neurologic symptoms due to the large size of a lactotroph adenoma, and
hypogonadism or other symptoms due to hyperprolactinemia, such as
galactorrhea [1-3].
A third indication is in women with mild hyperprolactinemia and normal cycles
who are trying to conceive as they may have subtle luteal phase dysfunction
(see "Clinical manifestations and evaluation of hyperprolactinemia", section on
'Menstrual cycle dysfunction'). Our approach to management is similar to that
suggested by the Endocrine Society Guidelines [2].
Adenoma size — A lactotroph adenoma (prolactinoma) 1 cm or more in size is a
macroadenoma. Treatment is usually essential when the tumor is large enough to
cause neurologic symptoms, such as visual impairment or headache (see "Causes,
presentation, and evaluation of sellar masses", section on 'Clinical manifestations').
Treatment is usually desirable when the adenoma extends outside of the sella and
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abuts or elevates the optic chiasm, or invades the cavernous or sphenoid sinuses
or the clivus; lesions of this size are likely to continue to grow and eventually cause
neurologic symptoms.
Microadenomas are less than 1 cm in diameter. Studies of the natural history of
microadenomas show that 95 percent do not enlarge during four to six years of
observation [4,5]. The 5 percent that do enlarge should be treated because of the
increase in size alone. (See 'Withdrawal of dopamine agonists' below.)
Prolactin secretion by lactotroph adenomas is usually proportional to their size.
Adenomas <1 cm in diameter are typically associated with serum prolactin values
below 200 ng/mL (8.7 nmol/L), those approximately 1 to 2 cm in diameter with
values between 200 and 1000 ng/mL (8.7 to 43.48 nmol/L), and those greater than
2 cm in diameter with values above 1000 ng/mL (43.48 nmol/L) and as high as
50,000 ng/mL (2173.91 nmol/L) (figure 1). There are exceptions to this
generalization, however, as occasional patients have a large lactotroph adenoma
but only modest hyperprolactinemia. Such adenomas are generally less well
differentiated and respond less well to dopamine agonists than the more typical
adenomas.
In contrast to the extremely high serum prolactin concentrations that may be seen
with lactotroph macroadenomas, prolactin levels due to nonadenoma causes
rarely exceed 200 ng/mL (8.7 nmol/L). (See "Clinical manifestations and evaluation
of hyperprolactinemia", section on 'Serum prolactin concentrations'.)
Symptoms — Treatment of hyperprolactinemia is indicated when it causes
hypogonadism by suppressing gonadotropin secretion or when it causes
bothersome galactorrhea [1]. The clinical manifestations of hyperprolactinemia are
reviewed in detail separately. (See "Clinical manifestations and evaluation of
hyperprolactinemia".)
Premenopausal women
●In premenopausal women, serum prolactin concentrations >100 ng/mL
(4.35 nmol/L) are likely to be associated with amenorrhea and
low estradiol levels (which lead to eventual bone loss and osteoporosis if
untreated). The symptoms correlate with the magnitude of the
hyperprolactinemia. Moderate degrees of hyperprolactinemia (eg, serum
prolactin values of 50 to 100 ng/mL [2.17 to 4.35 nmol/L]) cause either
amenorrhea or oligomenorrhea, and milder degrees of hyperprolactinemia
(20 to 50 ng/mL [0.87 to 2.17 nmol/L]) may cause oligomenorrhea or not
affect menses but cause infertility due to insufficient luteal
phase progesterone secretion.

373
 ●Hyperprolactinemia in premenopausal women can also cause galactorrhea.
The presence of galactorrhea alone does not require treatment unless the
patient finds it bothersome.
Postmenopausal women
●Postmenopausal women have markedly low estradiol levels due to cessation
of ovarian function, and therefore, galactorrhea is rare. Hyperprolactinemia
in these women is clinically recognized only in the unusual situation when a
lactotroph adenoma becomes so large as to cause headaches or impair
vision.
Men
●In men, hypogonadism can cause decreased libido and energy and
eventually loss of sexual hair, loss of muscle mass, and osteoporosis.
Hyperprolactinemia in men may also be associated with erectile dysfunction,
even when the serum testosterone concentration is normal. The mechanism
is unknown, but the erectile dysfunction usually improves dramatically when
the hyperprolactinemia is corrected [6-8]. Gynecomastia and galactorrhea
may occur, but both are rare.
OVERVIEW OF DOPAMINE AGONISTSA dopamine agonist drug should
usually be the first treatment for patients with hyperprolactinemia of any cause,
including lactotroph adenomas (prolactinomas) of all sizes, because these drugs
decrease serum prolactin concentrations and decrease the size of most lactotroph
adenomas [9,10]. Other approaches must be considered for the minority of
patients whose adenomas are resistant to dopamine agonists or who cannot
tolerate these drugs, and for those who are taking a medication (such as an
antipsychotic drug) that cannot be discontinued. (See 'Intolerant or inadequate
response' below and 'Drug-induced hyperprolactinemia' below.)
Choice of drug — For most patients with hyperprolactinemia, cabergoline is our
first choice, and bromocriptine is our second. Pergolide had been used for
Parkinson disease and hyperprolactinemia, but it was withdrawn from the market
in the United States because of concerns about valvular heart
disease. Quinagolide is available in some countries, but not the United States.
(See 'Valvular heart disease' below.)
●Cabergoline – We suggest cabergoline as the first choice because of its
efficacy and favorable side-effect profile [2]. It is an ergot dopamine agonist
that is administered once or twice a week and has much less tendency to
cause nausea than bromocriptine [11,12]. It may also be effective in patients
resistant to bromocriptine [13]. At the high doses used for the treatment of
Parkinson disease, cabergoline is associated with an increased risk of valvular
heart disease [14,15], but at the lower doses generally used for the treatment
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 of hyperprolactinemia, cabergoline does not appear to be associated with
this risk or a lower risk. (See 'Valvular heart disease' below and "Initial
pharmacologic treatment of Parkinson disease", section on 'Limited role of
ergot dopamine agonists'.)
●Bromocriptine – Bromocriptine is an ergot derivative that has been used for
approximately three decades for treatment of hyperprolactinemia. It should
be given twice a day to have optimal therapeutic effect [9]. It is more likely to
cause nausea than cabergoline.
●Pergolide – Pergolide is an ergot derivative that had been used primarily for
the treatment of Parkinson disease [16]. At the high dose used for Parkinson
disease (>3 mg/day), pergolide was associated with an increased risk of
valvular heart disease [14,15]. It was withdrawn from the United States
market in 2007 [17], but it is still available in some countries. (See 'Valvular
heart disease' below and "Initial pharmacologic treatment of Parkinson
disease", section on 'Limited role of ergot dopamine agonists'.)
●Other – Quinagolide (CV 205-502), a non-ergot dopamine agonist that is
given once or twice a day, is available in some countries but not the United
States [18-20]. The starting dose is 0.075 mg once a day, which can be
increased to twice a day and a maximum total daily dose of 0.9 mg. It is
generally considered a second-line drug if cabergoline is available, but unlike
cabergoline, it is not an ergot derivative so valvular heart disease is not a
concern.
Efficacy — Dopamine agonists decrease prolactin secretion (figure 2) and reduce
the size of the lactotroph adenoma (image 1) in more than 90 percent of patients.
Both effects are mediated by the binding of the drug to cell-surface dopamine
receptors, leading to reductions in the synthesis and secretion of prolactin and in
adenoma cell size [21]. A review of 13 studies, as an example, showed
that bromocriptine reduced the serum prolactin concentration to normal in 229 of
280 women (82 percent) with hyperprolactinemia, and in 12 studies, in 66 of 92
patients (71 percent) with lactotroph macroadenomas [9].
Cabergoline may be superior to bromocriptine in decreasing the serum prolactin
concentration [11,13]. This was illustrated in a trial of 459 women with
hyperprolactinemia and amenorrhea who had microadenomas or no obvious
cause; the patients who were randomized to cabergoline were more likely to have
a reduction of serum prolactin to normal (83 versus 52 percent in the
bromocriptine group) (figure 2) [11]. In addition, a meta-analysis of three trials and
six observational studies reported that cabergoline was more effective than
bromocriptine in reducing the risk of persistent hyperprolactinemia, amenorrhea,
and galactorrhea (relative risk [RR] 2.88, 1.85, and 3.41, respectively) [10].

375
Overall, the greater the decrease in serum prolactin concentration, the greater the
decrease in adenoma size, although there is considerable variation from patient to
patient. The effect on adenoma size is most apparent in patients with lactotroph
macroadenomas (image 1) [22].
The therapeutic efficacy of dopamine agonists may be blunted by the concurrent
use of drugs known to raise serum prolactin concentrations, including neuroleptic
drugs, metoclopramide, sulpiride, domperidone, methyldopa, verapamil,
and cimetidine.
Quinagolide appears to have equivalent therapeutic effects to cabergoline in
reducing serum prolactin and adenoma size [19,23]. It is available in some
countries, but not the United States.
Time course of clinical response — The fall in serum prolactin typically occurs
within the first two to three weeks of therapy with a dopamine agonist (figure 2)
[11]; in patients with macroadenomas, it always precedes any decrease in
adenoma size [19]. The decrease in adenoma size can, in many patients, be
detected by imaging within six weeks after initiation of treatment; in some
patients, however, a decrease is not apparent for six months (image 1) [22]. These
benefits occur even in patients who have impaired visual fields before therapy,
occurring in 9 of 10 such patients in each of two reports [24,25].
Following the decrease in serum prolactin and adenoma size in patients with
macroadenomas, visual and pituitary function often return to normal. Vision
usually begins to improve within days after the initiation of treatment [22,24].
There is recovery of menses and fertility in women and of testosterone secretion,
sperm count, and erectile function in men [9,11,26-28]. Patients with
macroadenomas who are hypothyroid and/or hypoadrenal may also have a return
of these functions to normal [29].
Adverse effects
Typical — The principal side effects of dopamine agonist drugs are nausea,
postural hypotension, and mental fogginess. Less common side effects include
nasal stuffiness, depression, Raynaud phenomenon, alcohol intolerance, and
constipation. Nausea appears to be more common
with bromocriptine than cabergoline.
Side effects are more likely to occur when treatment is initiated or the dose is
increased. They can be avoided in most patients by starting with a small dose (eg,
one-half of the lowest strength pill of bromocriptine once a day or half a pill
of cabergoline twice a week) and by giving it with food or at bedtime. A small
percentage of patients have side effects even at the lowest doses. In women,
nausea can be avoided by intravaginal administration [30].

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Impulse control disorders — An uncommon but well-recognized adverse effect is
the onset or exacerbation of impulse control disorders, such as hypersexuality and
compulsive gambling, shopping, or eating. These behaviors had originally been
described in case reports. In a small, controlled study, 10 hyperprolactinemic
patients who were treated with cabergoline had a higher score on one scale of
impulsiveness than hyperprolactinemic patients not treated or 10 patients with a
normal prolactin [31]. In an uncontrolled study of 308 patients who had lactotroph
adenomas and were treated with cabergoline for at least three months, 17 percent
developed an impulse control disorder [32]. The increased risk of impulse control
disorders has also been described in up to 50 percent of patients taking dopamine
agonists for Parkinson disease (See "Initial pharmacologic treatment of Parkinson
disease", section on 'Impulse control disorders'.)
Valvular heart disease — Cabergoline and pergolide have been associated with
valvular heart disease in patients with Parkinson disease [14,15]. The association
appears to be dose dependent, and the pergolide doses used for Parkinson
disease were much higher than those used for hyperprolactinemia. In the United
States, pergolide was voluntarily withdrawn from the market in March 2007 due to
this risk [17]. (See "Initial pharmacologic treatment of Parkinson disease", section
on 'Limited role of ergot dopamine agonists'.)
In contrast to the excess risk of cardiac valvulopathy associated with high-
dose cabergoline use for Parkinson disease, most studies suggest that low-dose
cabergoline for hyperprolactinemia is probably not associated with excess risk [33-
42]. In one report of 50 patients with lactotroph adenoma treated with
cabergoline, moderate tricuspid regurgitation was more frequent (54 percent)
than in 50 age- and gender-matched subjects (18 percent) [35]. In a cross-sectional
study, 62 patients who were treated with cabergoline were more likely to have
valvular disease, primarily mild regurgitation, than patients who were treated
with bromocriptine (37.1 versus 17.5 percent, respectively) [43]. However, in a
review of nine studies published through 2008, the majority did not demonstrate
an increased risk of valvular regurgitation with cabergoline [33]. Most patients
were using standard doses of cabergoline for hyperprolactinemia (0.5 to 1.5
mg/week). Additional reassuring data come from a prospective study of 40
patients with newly diagnosed hyperprolactinemia treated with a median
cumulative dose of 149 mg over five years [44]. Patients were evaluated by
transthoracic echocardiography before initiating cabergoline and after 24 and 60
months of therapy; none of the patients developed significant valvulopathy.
One hundred and ninety-one of patients who were reported in one of the studies
above [42] were followed for an additional median time of 34 months, during
which time they took a median additional 232 mg of cabergoline and had a

377
transthoracic echocardiogram at the beginning and end of the additional
observation period. No association was found between the dose of cabergoline
and the prevalence of a valvular abnormality [45].
However, new onset of valvular heart disease has been reported in a few patients
taking cabergoline. In one patient who was treated with 6 mg of cabergoline a
week, serial echocardiograms showed no valvular disease when the cumulative
dose was 3272 mg, but a thickened and restricted aortic valve when the
cumulative dose was 4192 mg [46].
Based upon the available data, we suggest using the lowest dose
of cabergoline necessary to lower prolactin to normal. We also suggest ordering
cardiac ultrasonography approximately every two years in patients who take larger
than typical doses of cabergoline (eg, greater than 2 mg per week). There are no
available data for cabergoline use in patients with preexisting valvular heart
disease. However, for patients with a lactotroph adenoma and mild valvular heart
disease, we feel it is reasonable to use cabergoline therapy since the doses used in
this setting have not been associated with an increased risk of valvular heart
disease.
Withdrawal of therapy is discussed below. (See 'Withdrawal of dopamine
agonists' below.)
Cerebrospinal fluid rhinorrhea — Cerebrospinal fluid rhinorrhea may occur
during dopamine agonist treatment for very large lactotroph adenomas that
extend inferiorly and invade the floor of the sella [47,48]. Although uncommon,
early recognition and neurosurgical evaluation of this complication is important
because of the potential risk of bacterial meningitis.
MICROADENOMAS
Initial therapy (dopamine agonists) — Given the high rate of efficacy and low
rate of side effects with dopamine agonists, as well as the consequences of
hypogonadism, we recommend that these agents be used in patients with
lactotroph microadenomas who have any degree of hypogonadism. Decreasing
the size of the pituitary adenoma is not a treatment goal in these patients.
●Cabergoline is the best initial choice in most circumstances because it is
most likely to be effective and least likely to cause side effects. Our approach
is consistent with the Endocrine Society hyperprolactinemia clinical guidelines
[2]. The initial dose should be 0.25 mg twice a week or 0.5 mg once a week, if
a patient finds that more convenient. Giving the dose at dinner or at bedtime
reduces the chance of nausea or sleepiness.
●We now typically offer cabergoline to women who wish to become
pregnant. Bromocriptine might theoretically be a better first choice because
there is more evidence that it does not cause birth defects [49], However,
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 available data suggest that cabergoline is also safe in early pregnancy
[50,51], and it has the other advantages over bromocriptine described above.
(See "Management of lactotroph adenoma (prolactinoma) during
pregnancy".)
●If bromocriptine is used, we suggest a starting dose of 1.25 mg after dinner
or at bedtime for one week, then increase to 1.25 mg twice a day (after
breakfast and after dinner or at bedtime).
Response to therapy — After one month of therapy, the patient should be
evaluated for side effects and serum prolactin should be measured. Subsequent
treatment depends upon the response:
Prolactin normalized — If the serum prolactin concentration is normal and no
side effects have occurred, the initial dose should be continued. In this setting,
gonadal function will probably return within a few months. (See 'Long-term follow-
up' below.)

Of note, in some patients, dopamine agonist therapy may result in restoration of

normal gonadal function (eg, normal menstrual cycles in women) even if serum
prolactin levels remain slightly high. In this case, the reproductive outcome
(menstrual function) can be followed rather than the absolute prolactin level to
determine treatment dose.

Similarly, when treating women with bothersome galactorrhea, the goal of therapy
is to lower the serum prolactin low enough to resolve the galactorrhea. This may
not require lowering prolactin into the normal range for the galactorrhea to remit.

Prolactin improved but not normal

●If the serum prolactin concentration has not decreased to normal but no
side effects have occurred, the dose should be increased gradually to as
much as 1.5 mg of cabergoline two or three times a week or 5 mg
of bromocriptine twice a day. Whatever dose results in a normal serum
prolactin value should be continued. (See 'Prolactin normalized' above.)
●If the cabergoline dose is increased above 2 mg per week, we suggest
cardiac ultrasonography every two years in patients to monitor for valvular
heart disease.
Intolerant or inadequate response
●To initial therapy:
•If the serum prolactin concentration does not decrease sufficiently to
restore normal gonadal function in response to bromocriptine (if it was
chosen as initial therapy) and if compliance seems good, changing

379
 to cabergoline may be effective. The cabergoline dose should then be
adjusted until the serum prolactin concentration is normal. (See 'Prolactin
normalized' above.)
Approximately 25 percent of patients are resistant
to bromocriptine [11,13], and most (80 percent) can achieve normal
prolactin concentrations with cabergoline therapy [13,52]. It is estimated
that 10 percent of patients are resistant to cabergoline [2].
•If the patient cannot tolerate the first dopamine agonist administered
because of side effects, another can be tried. In women, nausea can be
avoided by vaginal administration [53], although other side effects cannot.
●To all dopamine agonists:
•Patients who do not respond to typical doses of dopamine agonists, eg,
up to 2 mg of cabergoline a week, may respond to higher doses [52], but
higher doses may be associated with higher risk of valvular heart disease.
•If dopamine agonists have been unsuccessful or the patient cannot
tolerate them, transsphenoidal surgery or ovulation induction
with clomiphene citrate can be considered (for women wishing to become
pregnant). For women not pursuing
pregnancy, estradiol and progesterone replacement can be considered;
men can consider testosterone therapy. (See 'Role of transsphenoidal
surgery' below and "Overview of ovulation induction" and 'Treatment of
women with estradiol' below.)
Treatment of women with estradiol — Estradiol, along with a progestin, can be
considered as sole therapy for the hypogonadism resulting from
hyperprolactinemia in women who have lactotroph microadenomas but who
cannot tolerate or do not respond to dopamine agonists and do not want to
become pregnant (see "Management of spontaneous primary ovarian insufficiency
(premature ovarian failure)", section on 'Estrogen therapy'). Estradiol is also a
reasonable option for women who have hypogonadism resulting from
hyperprolactinemia due to other causes, including antipsychotic agents.
(See "Clinical manifestations and evaluation of hyperprolactinemia" and 'Drug-
induced hyperprolactinemia' below.)
Since estradiol treatment might pose a slight risk of increasing the size of the
adenoma, the serum prolactin concentration should be measured periodically in
these patients. Estradiol should not be used as the sole treatment for lactotroph
macroadenomas.
Estradiol and progestin can be administered separately in low doses as they would
be for the treatment of hypogonadism of any etiology, or estrogen can be

380
administered in the form of an oral contraceptive. (See "Combined estrogen-
progestin oral contraceptives: Patient selection, counseling, and use".)
Treatment of men with testosterone — For men with hyperprolactinemia
causing hypogonadism who cannot tolerate or who do not respond to dopamine
agonists, testosterone treatment can be considered for those who are not
interested in fertility and human chorionic gonadotropin (hCG) for those who are.
(See "Testosterone treatment of male hypogonadism" and "Induction of fertility in
men with secondary hypogonadism".)
Transsphenoidal surgery — Transsphenoidal surgery should be considered in
patients with microadenomas when dopamine agonist treatment has been
unsuccessful in lowering the serum prolactin concentration, symptoms or signs
due to hyperprolactinemia persist even after several months of treatment, and
gonadal steroid replacement is not an option, eg, when pregnancy is desired. The
role of surgery in patients with macroadenomas is reviewed below. (See 'Role of
transsphenoidal surgery' below.)
Long-term follow-up — Patients with microadenomas who achieve normal serum
prolactin concentrations should be treated for at least one year. Serum prolactin
measurements should be obtained at least every 12 months [1,2].
After approximately one year of treatment (if prolactin is normal), the dose can
often be decreased. If the prolactin has been normal for two or more years and no
adenoma is seen on magnetic resonance imaging (MRI), discontinuation of the
drug can be considered. (See 'Withdrawal of dopamine agonists' below.)
Dopamine agonists should be stopped in women who become pregnant.
(See "Management of lactotroph adenoma (prolactinoma) during pregnancy".)
Withdrawal of dopamine agonists — We suggest considering decreasing
gradually and then discontinuing the dopamine agonist in the following situations:
●A patient who had idiopathic hyperprolactinemia (no pituitary mass at
baseline) and whose serum prolactin decreased to low normal in response to
dopamine agonist treatment. We suggest gradually decreasing the dose, as
long as the prolactin remains within the normal range. If a patient has a
normal prolactin for two years while taking a low dose (eg, 0.25 mg twice a
week) of cabergoline, we suggest a trial of discontinuation of the drug.
●A patient who had hyperprolactinemia and a microadenoma prior to
treatment in whom prolactin fell to normal and who has not had evidence of
an adenoma by MRI for at least two years.
●A patient had a macroadenoma prior to treatment, as long as the serum
prolactin has been normal and no adenoma has been detectable by MRI for
at least two years.

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Our approach is consistent with that of the Endocrine Society clinical guidelines [2].
If the drug is discontinued, prolactin should be measured after three months and
yearly thereafter. If the prolactin increases substantially (eg, to >100 ng/mL),
especially in a patient who originally had a macroadenoma, an MRI should be
performed.

We recommend not stopping the dopamine agonist if the prolactin increases

above normal while gradually decreasing the drug.

If serum prolactin increases after a withdrawal attempt, we suggest

resuming cabergoline therapy at the same dose that previously kept the prolactin
normal and decreased the adenoma size to undetectable.
Several studies have reported the consequences of discontinuation of dopamine
agonist treatment in patients who have hyperprolactinemia. Recurrence of
hyperprolactinemia and increase in adenoma size have been variable [54-59].
In one prospective study of 200 cabergoline-treated patients with
hyperprolactinemia (25 with idiopathic hyperprolactinemia, 105 with
microadenomas, and 70 with macroadenomas), therapy was withdrawn when
serum prolactin concentrations were normal and MRI showed no adenoma (or >50
percent reduction with no cavernous sinus invasion and >5 mm distance from the
optic chiasm) [54]. After two to five years of observation, the following results were
seen:
●Hyperprolactinemia recurred in 24, 31, and 36 percent of patients with
idiopathic hyperprolactinemia, microadenomas, and macroadenomas,
respectively (eg, a remission rate [persistent normoprolactinemia] of 64 to 76
percent).
●Adenoma regrowth was not seen in any patient.
●Hyperprolactinemia in patients with adenomas was more likely to recur if an
adenoma remnant was seen on MRI than if it was not when treatment was
stopped (78 versus 33 percent for macroadenomas, and 42 versus 26 percent
for microadenomas).
Most patients with a macroadenoma remnant had adenoma recurrence by seven
years of follow-up [60]. However, giant adenomas (>3 cm) may behave more
aggressively, as shown by case reports of rapid, substantial regrowth within weeks
of discontinuation of dopamine agonist medication [61,62].
In contrast, a number of other studies report higher rates of recurrent
hyperprolactinemia (eg, lower rates of remission) [55,58,62]. In a meta-analysis of
19 studies with a total of 743 patients, the overall rate of remission (persistent
normoprolactinemia) after withdrawal of dopamine agonist therapy was only 21
percent (32, 21, and 16 percent for idiopathic hyperprolactinemia,
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microprolactinomas, and macroprolactinomas, respectively) [59]. Other findings
included:
●Higher rate of remission in studies in which cabergoline was used (35
percent in four studies) than in those in which bromocriptine was used (20
percent in 12 studies).
●Higher rates of remission in studies with treatment duration longer than 24
months (34 percent) compared with studies with shorter treatment duration
(16 percent).
●Higher rate of remission in studies where a 50 percent tumor reduction was
achieved in all patients before stopping therapy (55 percent remission rate
was seen).

In summary, hyperprolactinemia may recur in a considerable number of patients

after stopping dopamine agonist therapy. The probability of remission is best the
longer the serum prolactin has been normal and no adenoma has been seen by
MRI, preferably for at least two years.

Menopause — After menopause, the drug can be discontinued and the serum

prolactin concentration can be allowed to rise. Imaging should be performed if the
value rises above 200 ng/mL to determine if the adenoma has increased to a
clinically important size. If so, drug therapy should be resumed.
MACROADENOMAS
Initial therapy — Treatment of patients with lactotroph macroadenomas, no
matter how large or how severe the neurologic sequelae, should also be initiated
with a dopamine agonist, starting with cabergoline [2], as described above for
patients with microadenomas. (See 'Microadenomas' above.) Patients whose
macroadenomas are largely cystic should also be treated initially with a dopamine
agonist since this treatment shrinks most of these [63]. We titrate the dose up on
the same schedule as for patients with microadenomas. Increasing the dose too
quickly can increase the risk of side effects and lead to the erroneous conclusion
that the patient is unable to tolerate the drug.
Titration of dose and monitoring — The serum prolactin should be measured
and the cabergoline dose should be increased every one to three months, if
necessary, until the serum prolactin concentration becomes normal.

If vision was abnormal before therapy, it should be reassessed within one month,
although improvement may occur within a few days. Magnetic resonance imaging
(MRI) should be repeated in 6 to 12 months to determine if the size of the
adenoma has decreased.

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In most patients with lactotroph macroadenomas:

●The size of the adenoma decreases to approximately the same degree as

the serum prolactin concentration, although the relationship varies from
patient to patient.
●The decrease in size usually cannot be demonstrated until weeks or months
after the prolactin secretion has decreased (image 1).
●The size of the adenoma can continue to decrease for years.

Once serum prolactin has normalized:

●If the clinical picture is stable (no evidence of adenoma growth on MRI and
no symptoms such as headaches or visual symptoms), serum prolactin
should be measured in six months, and if normal, it should then be measured
yearly.
●Serum prolactin should be measured at any point if there are recurrent or
new symptoms.
Candidates for stopping therapy — If the serum prolactin concentration has
been normal for at least one year and the adenoma has decreased markedly in
size, the dose of the dopamine agonist can be decreased gradually, as long as the
serum prolactin remains normal [64]. Discontinuation can be considered in those
patients who had macroadenomas of modest size (eg, 1.0 to 1.5 cm), whose serum
prolactin concentrations have been normal for more than two years, and whose
adenomas can no longer be visualized by MRI for more than two years.

If the drug is discontinued, the prolactin concentration and the size of the
adenoma by MRI must be monitored.

Discontinuation should probably not be considered if the adenoma was initially >2

cm, if it can still be visualized by MRI during treatment, or if the prolactin has not
become normal during treatment. The agonist should not be discontinued entirely,
even after menopause, because hyperprolactinemia will probably recur and the
adenoma may increase in size [54,61,62]. (See 'Withdrawal of dopamine
agonists' above.)
Inadequate response or drug intolerance — We recommend the following
approach in patients who do not have a complete response to dopamine agonist
therapy:
●If bromocriptine was tried first and the patient cannot tolerate it or the
adenoma does not respond to it, cabergoline should be tried.
●If the patient cannot tolerate or the adenoma does not respond to agonist
therapy, transsphenoidal surgery should be performed, and if a significant
384
 amount of adenoma tissue remains after surgery, radiation therapy should
be administered (see "Radiation therapy of pituitary adenomas", section on
'Lactotroph adenomas (prolactin-secreting adenomas)'). Surgery can also be
considered for the woman who has a giant adenoma and is contemplating
pregnancy. (See 'Role of transsphenoidal surgery' below.)
Role of transsphenoidal surgery — Transsphenoidal surgery should be
considered when:
●Dopamine agonist treatment has been unsuccessful in lowering the serum
prolactin concentration or size of the adenoma, and symptoms or signs due
to hyperprolactinemia or adenoma size persist after several months of
treatment at high doses.
●A woman has a giant lactotroph adenoma (eg, >3 cm) and wishes to become
pregnant even if the adenoma responds to a dopamine agonist. The rationale
for this approach is that if the patient becomes pregnant and discontinues
the agonist for the duration of pregnancy, the adenoma may increase to a
clinically important size before delivery.
Surgery is usually successful in substantially reducing serum prolactin
concentrations in patients with lactotroph adenomas, sometimes to normal [65-
68]. It is a safer procedure when performed by an experienced surgeon [69].
(See "Transsphenoidal surgery for pituitary adenomas and other sellar masses",
section on 'Lactotroph adenomas'.)

Surgery, however, has the following limitations:

●Not all of the adenoma tissue is excised in many patients, particularly those
with macroadenomas. (See "Transsphenoidal surgery for pituitary adenomas
and other sellar masses", section on 'Lactotroph adenomas'.)
●The adenoma and hyperprolactinemia may recur within several years after
surgery. (See "Transsphenoidal surgery for pituitary adenomas and other
sellar masses", section on 'Lactotroph adenomas'.)

Complications are the same as may occur during and after transsphenoidal
surgery for any kind of pituitary adenoma.

Postoperative radiation therapy — Radiation is primarily used to prevent

regrowth of residual tumor in a patient with a very large macroadenoma after
transsphenoidal debulking of lactotroph adenomas that are resistant
to cabergoline. It should not be used for the primary treatment of patients with
macroadenomas or at all for those with microadenomas. While radiation therapy
(single dose or multiple fraction) appears to be effective in controlling growth of

385
most pituitary macroadenomas, the effect on aggressive lactotroph adenomas
that do not respond to dopamine agonists and cannot be entirely resected
surgically is less well known. (See "Radiation therapy of pituitary adenomas",
section on 'Lactotroph adenomas (prolactin-secreting adenomas)'.)
Complications of radiation include transient nausea, lassitude, loss of taste and
smell, loss of scalp hair at the radiation portals during and shortly after the
treatment, and possible damage to the optic nerve and neurologic dysfunction [1].
There is also a 50 percent chance of loss of anterior pituitary hormone secretion
during the subsequent 10 years [70].
PREGNANCYThe management of lactotroph adenomas before, during, and
after pregnancy is reviewed in detail separately. (See "Management of lactotroph
adenoma (prolactinoma) during pregnancy".)
TREATMENT OF NONADENOMA CAUSESTreatment of
hyperprolactinemia due to an abnormality other than a lactotroph adenoma varies
depending on the cause:
Idiopathic hyperprolactinemia — In a substantial number of patients whose
serum prolactin concentration is between 20 and 100 ng/mL (100 mcg/L SI units),
no cause can be found; they are considered to have idiopathic hyperprolactinemia.
Although many of these patients may have microadenomas not visible on imaging
studies, in most of them, the serum prolactin concentrations change little during
follow-up for several years. Serum prolactin should be measured yearly.
(See "Causes of hyperprolactinemia".)
In patients with idiopathic hyperprolactinemia (no pituitary mass at baseline)
whose serum prolactin decreased to low-normal in response to dopamine agonist
treatment, we suggest attempting to decrease the dose gradually, as long as the
prolactin remains within the normal range. If a patient has a normal prolactin for
two years while taking a low dose (eg, 0.25 mg of cabergoline twice a week), we
suggest a trial of discontinuation of the drug. (See 'Withdrawal of dopamine
agonists' above.)
Hypothalamic and pituitary disease — Any disease in or near the hypothalamus
or pituitary that interferes with the secretion of dopamine or its delivery to the
hypothalamus can cause hyperprolactinemia, including tumors and infiltrative
diseases of the hypothalamus, section of the hypothalamic-pituitary stalk (eg, due
to head trauma or surgery), and adenomas of the pituitary other than lactotroph
adenomas. If removal of the adenoma or mass is not possible, the
hyperprolactinemia should be treated with a dopamine agonist.
Drug-induced hyperprolactinemia — A number of drugs, especially
antipsychotics and some antihypertensives (verapamil, methyldopa), can cause
hyperprolactinemia (table 1) (see "Causes of hyperprolactinemia", section on 'Drug
386
induced'). If the hyperprolactinemia is asymptomatic, no treatment is necessary. If
symptoms are present and the hyperprolactinemia is due to a drug other than an
antipsychotic agent, we suggest discontinuing the drug as a trial. If
discontinuation is not feasible, options include switching to a drug with a similar
action that does not cause hyperprolactinemia, adding estradiol or testosterone
for the hypogonadal symptoms and/or low bone mass, or cautious administration
of a dopamine agonist, as described in the following section.
Antipsychotic drug use — If an antipsychotic drug is causing hyperprolactinemia
and hypogonadism but cannot be discontinued because it is essential, several
possible treatment options can be considered:
●Addition of a dopamine agonist. This option should be
undertaken very cautiously in consultation with the treating psychiatrist
since it might counteract the dopamine antagonist property of the
antipsychotic drug.
●Change to an antipsychotic drug that does not raise prolactin, such
as quetiapine. This course should only be considered in conjunction with the
treating psychiatrist.
●Addition of the antipsychotic drug aripiprazole to the existing antipsychotic
drug. This drug has both dopamine agonist and antagonist properties and
dampens hyperprolactinemia when added to other antipsychotic drugs such
as risperidone [71].
●Addition of estradiol and progestin to treat the estradiol deficiency and
prevent bone loss in women and testosterone to treat testosterone
deficiency in men. This approach will not treat the hyperprolactinemia.
Hypothyroidism — If hyperprolactinemia is solely the result of hypothyroidism, it
will remit as the hypothyroidism is corrected, so no other treatment is necessary.
(See "Causes of hyperprolactinemia", section on 'Hypothyroidism' and "Treatment
of primary hypothyroidism in adults".)
Macroprolactinemia — Macroprolactinemia or "big prolactin" is a benign
condition that does not require treatment, as it does not result from a pituitary
adenoma or cause hypogonadism.

Macroprolactin is an umbrella term used to describe nonbioactive prolactin

isoforms, usually composed of a prolactin monomer and an immunoglobulin G
(IgG) molecule. These isoforms are clinically nonreactive and range in size from
approximately 150 to 170 kD (the most common form of native prolactin in serum
is 23 kD in size).

Macroprolactinemia is sometimes misdiagnosed and treated as ordinary

hyperprolactinemia. Misdiagnosis can be avoided by asking the laboratory to
387
pretreat the serum with polyethylene glycol to precipitate the macroprolactin
before the immunoassay for prolactin. (See "Causes of hyperprolactinemia",
section on 'Macroprolactinemia'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Hyperprolactinemia/prolactinoma".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Prolactinoma (The Basics)")

●Beyond the Basics topics (see "Patient education: High prolactin levels and
prolactinomas (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONSBased upon the treatments now
available, we make the following recommendations:
●For patients with lactotroph microadenomas and any degree of
hypogonadism, we recommend initial treatment with a dopamine agonist
(Grade 1B) (see 'Microadenomas' above). We also use dopamine agonist
therapy in women with hyperprolactinemia and normal menstrual cycles if
they have bothersome galactorrhea. (See 'Premenopausal women' above.)
●For women starting dopamine agonist therapy, we
suggest cabergoline over bromocriptine because it is more likely to be
effective and less likely to cause side effects (Grade 2B). (See 'Choice of
drug' above.)
●Because of the association between high-dose cabergoline use for
Parkinson disease and valvular heart disease, the lowest dose of cabergoline
necessary to lower prolactin to normal should be used. (See 'Valvular heart
disease' above.)

388
●For patients who require higher than usual doses of cabergoline (eg, greater
than 2 mg per week), cardiac ultrasonography should be performed every
two years. (See 'Valvular heart disease' above.)
●For patients whose serum prolactin decreases to low-normal in response to
dopamine agonist treatment, we typically decrease the dose gradually, as
long as the prolactin remains within the normal range. (See 'Long-term
follow-up' above.)
●For patients who had idiopathic hyperprolactinemia (negative magnetic
resonance imaging [MRI]) and have had a normal prolactin while taking a low
dose of dopamine agonist for at least two years, we suggest a trial of
stopping the drug (Grade 2C). We use a similar approach for patients who
had lactotroph adenomas and have also had no evidence of the adenoma by
MRI for at least two years. (See 'Withdrawal of dopamine agonists' above.)
●If the drug is discontinued, prolactin should be measured after three
months and yearly thereafter. If the prolactin increases substantially, eg, to
>100 ng/mL, especially in a patient who originally had a macroadenoma, an
MRI should be performed. (See 'Withdrawal of dopamine agonists' above.)
●If bromocriptine is used first and the patient cannot tolerate it or serum
prolactin concentrations do not normalize, we switch
to cabergoline (see 'Intolerant or inadequate response' above). Starting
doses and upward titration of dose based upon clinical response are
reviewed above. (See 'Microadenomas' above.)
●In women with lactotroph microadenomas seeking fertility whose serum
prolactin concentrations do not normalize with dopamine agonist therapy
(and who therefore do not ovulate), we proceed with ovulation induction
with clomiphene citrate or gonadotropin therapy. (See "Management of
lactotroph adenoma (prolactinoma) during pregnancy".)
●For patients with lactotroph macroadenomas, no matter how large or how
severe the neurologic consequences, we recommend initial treatment with a
dopamine agonist (Grade 1B). Dosing is the same as that for
microadenomas. (See 'Microadenomas' above.)
●Transsphenoidal surgery is a reasonable option for patients in whom
dopamine agonist treatment has been unsuccessful in reducing the serum
prolactin concentration or size of the macroadenoma, or when symptoms or
signs due to hyperprolactinemia or adenoma size do not improve. (See 'Role
of transsphenoidal surgery' above.)
●In patients with large macroadenomas who have undergone
transsphenoidal debulking and in whom considerable residual adenoma
remains in a location not readily accessible to surgery, we suggest radiation

389
therapy to prevent regrowth of residual adenoma (Grade 2C). We do not use
radiation therapy for the primary treatment of patients with macroadenomas
or at all for those with microadenomas. (See 'Postoperative radiation
therapy' above.)
●In premenopausal women who have lactotroph microadenomas causing
hyperprolactinemia and hypogonadism, but who cannot tolerate or do not
respond to dopamine agonists and do not want to become pregnant, we
suggest estradiol and progestin replacement to prevent bone loss (Grade 2C)
(see 'Treatment of women with estradiol' above). Similarly, we start
testosterone replacement for men whose lactotroph adenomas are causing
hypogonadism.
●We also use gonadal steroid replacement therapy in patients with
hyperprolactinemia and hypogonadism due to antipsychotic agents
(estradiol-progestin in women and testosterone in men) if addition of a
dopamine agonist is not possible or if a satisfactory antipsychotic regimen
that does not cause hyperprolactinemia cannot be found. (See 'Antipsychotic
drug use' above.)

390
Management of lactotroph adenoma
(prolactinoma) during pregnancy
Author:
Peter J Snyder, MD
Section Editors:
David S Cooper, MD
Charles J Lockwood, MD, MHCM
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 18, 2019.
INTRODUCTIONLactotroph adenomas (prolactinomas) usually cause infertility
because of the inhibitory effect of elevated prolactin, and sometimes because of
the mass effect of a macroadenoma, on gonadotropin secretion, resulting in
anovulation and decreased estradiol and progesterone secretion. However, our
ability to treat both of these abnormalities allows most women with this disorder
to become pregnant. Management during pregnancy is based on knowledge of
the risks to the mother and the fetus.
The management of women with lactotroph adenomas during pregnancy will be
reviewed here. Other aspects of hyperprolactinemia and lactotroph adenomas are
reviewed separately. (See "Clinical manifestations and evaluation of
hyperprolactinemia" and "Causes of hyperprolactinemia" and "Management of
hyperprolactinemia".)
OVERVIEWMost women with lactotroph adenomas have anovulatory infertility
and even frank hypogonadism but are able to conceive once the lactotroph
adenoma has been treated and the serum prolactin concentration has been
lowered to normal. Management should begin before lowering the prolactin
concentration with a discussion about the risks of adenoma growth during
pregnancy and the potential effects of exposure to dopamine agonists on the
fetus. Current data suggest that neither bromocriptine nor cabergoline use during
the first month of pregnancy harms the fetus. However, few data are available
about the risk of either drug later in pregnancy.
Goals of treatment — The main goals of treatment for women with lactotroph
adenomas considering pregnancy include:
●Women with microadenomas – Lower serum prolactin into the normal range
to allow spontaneous ovulation.

391
 ●Women with macroadenomas – Administer dopamine agonists or perform
transsphenoidal surgery to decrease adenoma size before attempting to
conceive.
●During pregnancy, monitor women for possible adenoma growth; growth
that affects visual function should be treated with dopamine agonists or, if
necessary, surgery (but only in the second trimester).
PATIENT COUNSELING BEFORE PREGNANCYManagement of a woman
with lactotroph adenoma who wants to conceive should begin with advice about
the potential risks of pregnancy to her and the fetus. The main concern for the
mother is adenoma growth, while the potential risk for the fetus is exposure
to dopamine agonists, which are used to permit ovulation. To date,
neither bromocriptine nor cabergoline, the dopamine agonists used for this
purpose, have been associated with adverse fetal outcomes when compared with
what is expected in the general population. (See 'Restoration of ovulation' below.)
Discuss risk of adenoma growth — The principal risk during pregnancy to a
mother with a lactotroph adenoma is an increase in adenoma size sufficient to
cause neurologic symptoms, most importantly visual impairment. The theoretical
basis for an increase in size is that the increased serum level of estradiol during
pregnancy causes lactotroph hyperplasia. As an example of the effect of the
increased level of estradiol in normal pregnancy, a study of 20 normal
nonpregnant women and 32 normal pregnant women showed a greater increase
in pituitary size, as assessed by magnetic resonance imaging (MRI), the later in
pregnancy, so that the volume during the third trimester was more than double
that in nonpregnant women (figure 1) [1]. Similarly, in women with lactotroph
adenomas who become pregnant, the higher levels of estradiol of pregnancy may
increase the size of the lactotroph adenoma.

The risk that the increase in size of a lactotroph adenoma will be clinically
important depends upon the size of the adenoma before pregnancy.

Microadenoma — For a microadenoma (<10 mm in diameter), the risk of growth

is very low [2-5]. A review of 14 studies reporting a total of 764 patients with
lactotroph microadenomas showed that only 2.4 percent exhibited a symptomatic
increase in the size of the adenoma during pregnancy [6].
Macroadenoma — The risk of growth of a lactotroph macroadenoma (≥10 mm)
during pregnancy is substantially higher. In the same review as above [6], only 4.8
percent of 148 women who had macroadenomas that had been treated by prior
surgery or radiation developed clinically significant enlargement during
pregnancy, but 22.9 percent of 214 women who had not had such treatment did.

392
Enlargement not accompanied by symptoms or visual field deficit was not
counted.
TREATMENT BEFORE PREGNANCY: MICROADENOMAS
Restoration of ovulation — Hyperprolactinemia suppresses pituitary
gonadotropin secretion, resulting in irregular menstrual cycles and anovulatory
infertility. Serum prolactin concentrations between 50 to 100 ng/mL (normal <15 to
20 ng/mL), typically cause either amenorrhea or oligomenorrhea, while levels
greater than 100 ng/mL result in deficient estradiol and progesterone secretion
and amenorrhea. (See "Clinical manifestations and evaluation of
hyperprolactinemia", section on 'Menstrual cycle dysfunction'.)
For women with lactotroph microadenomas, treatment with a dopamine agonist
usually normalizes prolactin and thereby removes the inhibition of gonadotropin
secretion and restores normal ovulation and fertility.
Dopamine agonist therapy — A dopamine agonist is the treatment of choice for
women with a lactotroph adenoma. A marked reduction in the serum prolactin
concentration often occurs within two to three weeks (figure 2). (See "Management
of hyperprolactinemia", section on 'Overview of dopamine agonists'.)

Dosing is as follows:

●For cabergoline, start at 0.25 mg twice a week. If the serum prolactin

concentration is not normal after one to two months, the dose can be
increased to 0.5 mg twice a week or, if necessary, 1 mg twice a week.
Sometimes, even higher doses are needed [7].
●For bromocriptine, start with 1.25 mg at bedtime for one week, then 1.25
mg twice a day for one to two months. If the serum prolactin concentration
does not fall to near normal or normal by then, the dose can be increased to
2.5 mg twice a day and, if necessary, to 5 mg twice a day. If nausea occurs or
if serum prolactin does not decrease to normal, consider changing
to cabergoline.
The occurrence of regular menstrual cycles during treatment indicates that the
woman is probably ovulating. Following correction of hyperprolactinemia,
approximately 80 percent of women will ovulate, and pregnancy rates of 70 to 80
percent can be achieved [8]. Neither cabergoline nor bromocriptine has been
associated with an increased risk of miscarriage, congenital malformations, or
pregnancy complications such as preterm deliveries.
We suggest stopping the dopamine agonist in women with either a micro- or
macroadenoma once pregnancy has been confirmed because the safety of
continued usage has not been established.

393
For women who do not ovulate or do not conceive with dopamine agonist
therapy, clomiphene citrate may be added [9]. If unsuccessful, gonadotropin
therapy may be needed, although this therapy is associated with high serum
estradiol concentrations during treatment and a significant risk of multiple
gestations. (See "Ovulation induction with clomiphene citrate" and "Overview of
ovulation induction", section on 'Gonadotropin therapy'.)
Risks to fetus — Although dopamine agonists are typically discontinued when
pregnancy is confirmed, pregnancy has usually progressed at least two weeks
before confirmation occurs and the drug discontinued, so the fetus is exposed to
the dopamine agonist during that time. Evidence to date does not suggest risk to
the fetus from this exposure.
Data from over 6000 pregnancies suggest that the administration
of bromocriptine during the first month of pregnancy does not harm the fetus [5].
In this series, the incidence of spontaneous abortions (9.9 percent), multiple births
(1.7 percent), and malformations (1.8 percent) was no higher than in the general
population. In addition, in a study of children followed for up to nine years after
exposure to bromocriptine in utero, no harmful effects were noted [10].
Rarely, dopamine agonist treatment is resumed during pregnancy if adenoma size
increases so much as to impair vision (see 'Treatment of enlarging
adenoma' below). Continuous use of bromocriptine during pregnancy has been
reported in approximately 100 women. Although the rate of congenital
malformations did not appear to be higher than nonexposed pregnancies, there
was one case of undescended testis and one of talipes deformity [5,11].
Although the number of pregnancies in women taking cabergoline at the time of
conception is much smaller (968), the evidence suggests that this drug is safe as
well. In one review of over 700 cases, the incidence of spontaneous abortions (7.5
percent), multiple births (2.4 percent), and malformations (2.4 percent) was no
higher than in the general population [6]. Patients with Parkinson disease treated
with high doses of cabergoline (eg, >20 mg per week) have an increased risk of
valvular heart disease, but this risk has not been demonstrated using the lower
doses used for lactotroph adenomas [12]. (See "Valvular heart disease induced by
drugs", section on 'Hyperprolactinemia'.)
Choice of drug — When a dopamine agonist is needed to lower the serum
prolactin concentration to permit ovulation, cabergoline has the advantage that it
is more likely to be tolerated and more likely to be effective in lowering the
prolactin, although bromocriptine has the advantage of the greater certainty that
it does not cause birth defects. We typically let women choose which dopamine
agonist they would like to try. Women who are more concerned about nausea
from bromocriptine often choose cabergoline, but women who are especially

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concerned about the possibility of birth defects may choose bromocriptine.
(See "Management of hyperprolactinemia", section on 'Overview of dopamine
agonists'.)
TREATMENT BEFORE PREGNANCY: MACROADENOMASFor a woman
with macroadenoma, adenoma size should be reduced and ovulation should be
restored before pregnancy is attempted. A dopamine agonist may do both, but
surgery may also be required.
Dopamine agonist to decrease size — A woman who has a lactotroph
macroadenoma should be advised of the relatively higher risk of clinically
important adenoma enlargement during pregnancy, as described above [5]
(see 'Discuss risk of adenoma growth' above). We recommend a dopamine agonist
as the initial treatment of a lactotroph adenoma, whether or not the adenoma is
elevating the optic chiasm. Once the adenoma size has decreased dramatically and
is well within the confines of the sella and ovulation has been restored, pregnancy
can be attempted. Reduction in size in this way should reduce the chance of
clinically important enlargement during pregnancy [2,13]. The dopamine agonist
should be discontinued when pregnancy has been confirmed.
Transsphenoidal surgery to decrease adenoma size — If the adenoma elevates
the optic chiasm and does not shrink substantially in response to
a dopamine agonist, we recommend transsphenoidal surgery to reduce adenoma
size. Prior surgery reduces the chance that symptomatic expansion will occur
during pregnancy [6], but it may still occur. (See "Radiation therapy of pituitary
adenomas", section on 'Lactotroph adenomas (prolactin-secreting adenomas)'.)
We also recommend surgery in a woman whose macroadenoma (≥10 mm) is
unresponsive to bromocriptine or cabergoline, even if it is not elevating the optic
chiasm, because medical treatment would not likely be effective if the adenoma
enlarges during pregnancy.
DURING PREGNANCYWomen with lactotroph adenomas, in particular those
with macroadenomas, should be monitored closely during pregnancy. The
approach outlined here is consistent with the 2011 Endocrine Society Clinical
Practice Guidelines on the diagnosis and treatment of hyperprolactinemia [14].
Monitoring — Patients should be seen at routine intervals and asked about
headaches and changes in vision (as indicators of potential adenoma growth).
●Women with microadenomas should be seen every three months.
●Women with macroadenomas should also be seen at least every three
months, and more often the larger the adenoma.
Serum prolactin — During normal pregnancy, serum prolactin concentrations
increase to as high as 400 ng/mL. Women with lactotroph adenomas may
experience an increase in serum prolactin to pretreatment levels (figure 3).
395
However, not all women with lactotroph adenomas experience a similar increase
[5].
The Endocrine Society guidelines recommend against measuring prolactin during
pregnancy, because it can be difficult to distinguish the normal pregnancy-
associated rise in prolactin from that associated with adenoma growth [14].
However, we do measure prolactin in women with both macro- and
microadenomas every three months during pregnancy because we find it
reassuring if the prolactin does not increase above 400 ng/mL. If the prolactin
does increase to >400 ng/mL, we obtain visual field testing.
Visual field testing — For most pregnant women with lactotroph adenomas,
routine visual field testing is not indicated. However, women who develop visual
symptoms during pregnancy should have visual field testing. In addition,
women whose macroadenomas extend above the sella should undergo visual
field testing before pregnancy and every three months during the pregnancy, even
if the patient has no visual symptoms. If a visual field defect consistent with a sellar
mass is found (diminished vision in the temporal fields [bitemporal hemianopsia]),
magnetic resonance imaging (MRI) without contrast should be performed.
Pituitary MRI — Routine pituitary magnetic resonance imaging (MRI) is not
indicated in women with lactotroph adenomas during pregnancy, because the risk
of adenoma growth is very low. However, if a patient develops severe headaches
or visual field abnormalities, pituitary MRI without contrast should be performed
to assess adenoma size. (See 'Discuss risk of adenoma growth' above.)
Treatment of enlarging adenoma — If the adenoma has enlarged to a degree
that could account for the headaches and/or visual field defect, the woman should
be treated with cabergoline or bromocriptine throughout the remainder of the
pregnancy, and she should be seen at least once a month to reevaluate symptoms
and visual fields. This treatment will usually decrease the size of the adenoma and
alleviate the symptoms [11,15].
We suggest using the same dopamine agonist the patient took and tolerated
previously. (See 'Choice of drug' above.)
If bromocriptine is used first and the adenoma does not
respond, cabergoline should then be tried because it is more effective for
decreasing adenoma size [16]. If cabergoline is not successful in alleviating
severely compromised vision after several weeks, we suggest transsphenoidal
surgery in the second trimester. In contrast, in the third trimester, surgery for
persistent visual symptoms should be deferred until after delivery, if possible.
Pituitary apoplexy — Pituitary apoplexy refers to sudden hemorrhage into the
pituitary, a rare event with potential serious neurologic and endocrine
consequences. Apoplexy can occur in patients with pituitary micro- or

396
macroadenomas, including women with lactotroph macroadenomas during
pregnancy. In its most dramatic presentation, apoplexy causes the sudden onset
of excruciating headache, diplopia due to pressure on the oculomotor nerves, and
hypopituitarism. All pituitary hormonal deficiencies can occur, but the sudden
onset of corticotropin (ACTH) and therefore cortisol deficiency is the most serious
because it can cause life-threatening hypotension. It should be treated with high-
dose hydrocortisone. (See "Causes of hypopituitarism", section on 'Pituitary
apoplexy'.)

Most patients who develop apoplexy were not known to have an adenoma
previously, and when tissue is excised surgically, it is necrotic, so the cell type
cannot be identified.

AFTER PREGNANCY
Breastfeeding and dopamine agonists — Breastfeeding increases serum
prolactin concentrations (figure 4) but does not appear to increase the risk of
lactotroph adenoma growth [17,18]. Therefore, breastfeeding is an option for
women with micro- and macroadenomas that remained stable in size during
pregnancy. Dopamine agonist therapy, which lowers serum prolactin and inhibits
lactation, should be withheld until breastfeeding is completed.
In contrast, breastfeeding is contraindicated in women who have visual field
impairment because they should be treated with a dopamine agonist.
Normalization of prolactin after pregnancy — To evaluate the need for
further dopamine agonist therapy after pregnancy, serum prolactin should be
measured approximately three months after delivery in women who do not
breastfeed and after cessation of breastfeeding in those who do. Serum prolactin
normalizes within 6 to 12 weeks postpartum in women who do not breastfeed.
(See "Causes of hyperprolactinemia", section on 'Nipple stimulation and breast
examinations'.)
●In a study of 143 pregnancies in 91 patients with hyperprolactinemia treated
with cabergoline prior to pregnancy, no further treatment was necessary to
maintain a normal serum prolactin concentration in 68 percent of the
patients for up to 60 months postpartum [19]. Breastfeeding did not affect
the results. Recurrence was slightly greater in those who had
macroadenomas than in those who had microadenomas.
●In a study of 104 pregnancies in 73 patients with lactotroph adenomas
treated with a dopamine agonist prior to pregnancy, 41 percent had a normal
serum prolactin concentration a median of 22 months after delivery or
cessation of lactation [20].

397
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Hyperprolactinemia/prolactinoma".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Prolactinoma (The Basics)")

●Beyond the Basics topics (see "Patient education: High prolactin levels and
prolactinomas (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Management of a woman with a lactotroph adenoma should begin before
conception with advice to her and her partner about the potential risks to her
and the fetus. The main concern for the mother is adenoma growth, while
the main concern for the fetus is exposure to a dopamine agonist.
(See 'Overview' above.)
●When a dopamine agonist is needed to lower the serum prolactin
concentration to permit ovulation, we suggest a dopamine agonist
(either cabergoline or bromocriptine) (Grade 2C). (See 'Restoration of
ovulation' above.)
Cabergoline has the advantage that it is more likely to be tolerated and more
likely to be effective in lowering the prolactin, but bromocriptine has the
advantage of the greater certainty that it does not cause birth defects.
(See 'Dopamine agonist therapy' above.)
●We suggest stopping dopamine agonist therapy (for women with either a
microadenoma or macroadenoma) once pregnancy has been confirmed
because the safety of continued usage throughout pregnancy has not been
established (Grade 2C). (See 'Dopamine agonist therapy' above.)

398
●For women with macroadenomas, we suggest treatment with
a dopamine agonist to decrease the size of the adenoma prior to pregnancy,
whether the adenoma elevates the optic chiasm or not (Grade 2C).
(See 'Dopamine agonist to decrease size' above.)
●We suggest transsphenoidal surgery prior to pregnancy when the
macroadenoma does not decrease to well within the sella in response to
a dopamine agonist (Grade 2C). We also suggest transsphenoidal surgery
when a macroadenoma is within the sella but does not respond at all to a
dopamine agonist because if it enlarges during pregnancy, use of a
dopamine agonist will not decrease the size. (See 'Transsphenoidal surgery to
decrease adenoma size' above.)
●During pregnancy, women with either a micro- or macroadenoma should be
seen every three months to evaluate for possible adenoma growth.
(See 'Monitoring' above.)
●For women with evidence of macroadenoma growth on pituitary magnetic
resonance imaging (MRI; performed for severe headaches or visual field
abnormalities), we suggest treatment
with cabergoline or bromocriptine throughout the remainder of the
pregnancy (Grade 2C). Transsphenoidal surgery is sometimes needed
if dopamine agonists are not successful and vision is severely compromised.
(See 'Treatment of enlarging adenoma' above.)
●Breastfeeding is not contraindicated in women who have lactotroph
adenomas, but dopamine agonists should not be used during breastfeeding,
because they impair lactation. An exception is a woman who has visual field
impairment, who should not breastfeed and should be treated with a
dopamine agonist. (See 'Breastfeeding and dopamine agonists' above.)
●Forty to 60 percent of women who were treated with dopamine agonists for
lactotroph adenomas prior to pregnancy do not require them afterwards.
Therefore, women should be reevaluated by measurement of the serum
prolactin concentration three months after delivery in women who do not
breastfeed or after cessation of breastfeeding. (See 'Normalization of
prolactin after pregnancy' above.)

399
TSH-secreting pituitary adenomas
Authors:
Roy E Weiss, MD, PhD
Samuel Refetoff, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 25, 2021.
INTRODUCTIONThyroid-stimulating hormone (TSH)-secreting pituitary
adenomas are a rare cause of hyperthyroidism [1]. They account for 0.5 to 3
percent of all functioning pituitary tumors [2] and much less than 1 percent of all
cases of hyperthyroidism. The incidence in Sweden is calculated to be 2.8 per 1
million, in which 0.85 per million had disease [1]. Nevertheless, the diagnosis
should be considered in all hyperthyroid patients, especially those with a diffuse
goiter and no extrathyroidal manifestations of Graves' disease.
This topic will review the clinical presentation, diagnosis, and treatment of TSH-
secreting pituitary tumors. Other causes of hyperthyroidism are reviewed
separately. (See "Disorders that cause hyperthyroidism" and "Diagnosis of
hyperthyroidism".)
PATHOPHYSIOLOGYTSH-secreting adenomas secrete biologically active TSH
in a more or less autonomous fashion. Thus, TSH secretion usually does not
increase much in response to thyrotropin-releasing hormone (TRH) and does not
decrease much in response to exogenous thyroid hormone administration. The
biological activity of the TSH that is secreted varies considerably; as a result, serum
immunoreactive TSH concentrations range from normal (albeit inappropriately
high in the presence of hyperthyroidism) to markedly elevated (>500 mU/L) [3].
Most TSH-secreting adenomas secrete only TSH. However, approximately 20 to 25
percent of the adenomas secrete one or more other pituitary hormones,
predominantly growth hormone or prolactin [2]. There have been no reported
instances of cosecretion of corticotropin (ACTH) and TSH.
Adenomas secreting TSH and growth hormone are equally common in men and
women, whereas cosecretion of TSH and prolactin is approximately five times
more common in women than in men. Hyperprolactinemia is not always due to
tumor secretion of prolactin; in some patients, it is caused by compression of the
pituitary stalk and interruption of tonic hypothalamic inhibition of prolactin

400
secretion. (See "Causes of hyperprolactinemia", section on 'Decreased
dopaminergic inhibition of prolactin secretion'.)

The molecular basis of TSH-secreting adenomas is not known. While somatic

mutations or abnormal oncogene expression could contribute to these tumors as
in the case of other pituitary tumors, no such mutations have been described.
Molecular analysis of TSH-secreting adenomas has shown:

●Overexpression of the pituitary-specific transcription factor-1 (Pit-1) in 14

patients [4-6].
●Somatic mutations of the thyroid hormone receptor beta (THRB) gene in two
of six TSH-secreting adenomas [7,8]. In the latter, the mutant thyroid
hormone receptor beta protein (TR-beta) did not bind thyroid hormone and
interfered with the function of the normal TR-beta, thus providing an
explanation for the nonsuppressible nature of at least some of the
adenomas.
●Aberrant expression of an isoform of TR-beta, TR-beta-4, which inhibited the
negative regulation of TSH-alpha mediated by TR-beta-1 or TR-beta-2 [9].
Activating mutations in the TRH-receptor gene have not been identified [10].
CLINICAL PRESENTATION
Symptoms and signs — Most patients have the typical symptoms and signs of
hyperthyroidism (eg, palpitations, tremor, heat intolerance), but a few patients
have mild or even no hyperthyroid symptoms [11,12] (see "Overview of the clinical
manifestations of hyperthyroidism in adults"). In addition, patients may have
symptoms related to the expanding tumor mass with compression of the normal
pituitary gland or the optic chiasm or from cosecretion of growth hormone or
prolactin.
In a review of 255 patients with TSH-secreting tumors, clinical features other than
hyperthyroidism included [3,13]:
●A diffuse goiter – 93 percent
●Visual field defects – 35 percent
●Menstrual disturbances – 33 percent
●Galactorrhea (women), with or without cosecretion of prolactin – 28 percent
●Headache – 21 percent
In cases of mixed TSH/growth hormone-secreting tumors, symptoms of
acromegaly may also occur, including macroglossia, deepening of the voice, carpal
tunnel syndrome, and hyperhidrosis. (See "Causes and clinical manifestations of
acromegaly".)

401
In a case series of 62 patients with TSH-secreting pituitary adenoma, three patients
had coexisting differentiated thyroid cancer, possibly due to long-term TSH
stimulation [14].
The characteristic signs of Graves' ophthalmopathy (proptosis and periorbital
edema) are absent, unless there is coexisting Graves' disease [15,16].
In two series, the mean age at presentation was 41 to 45 years and equal
incidence in males and females [3,17]. In contrast, Graves' disease and most other
causes of hyperthyroidism are much more common in women. Additional reports
of Graves' disease concurrent with a TSH-secreting adenoma [18,19] may reflect
presence of a common disease with a rare disease. The time from onset of
symptoms to diagnosis of the pituitary tumor has ranged from 1 to 27 years. Most
of the longstanding cases erroneously received ablative thyroid treatment at least
once and often several times before their adenomas were correctly diagnosed. In
such cases, patients whose thyroid glands were ablated may present as having
high serum TSH levels that do not respond to escalating doses of T4
(levothyroxine) replacement.
Thyroid function tests — The characteristic biochemical abnormalities in patients
with hyperthyroidism caused by a TSH-secreting adenoma are normal or high
serum TSH concentrations and high serum total and free thyroxine (T4) and
triiodothyronine (T3) concentrations.
Among 255 reviewed patients [3], the ranges of hormone values were:
●Serum TSH concentrations – <1.0 to 568 mU/L
●Serum total T4 concentrations – 11.6 to 53 micrograms/dL (150 to 678
nmol/L)
●Serum free T4 concentrations – 1.6 to 7.7 ng/dL (20 to 100 pmol/L)
●Serum total T3 concentrations – 195 to 1300 ng/dL (3 to 20 nmol/L)
●Serum free T3 concentrations – 5 to 26 pg/mL (8.0 to 40.2 pmol/L)
Approximately 30 percent of patients who had not had any thyroid ablation
therapy in the past had serum TSH values within the normal range; however,
"normal" values are inappropriately high in the presence of high serum T4 and T3
concentrations. Frequent measurements of serum TSH in four patients
demonstrated loss of the normal nocturnal surge in TSH secretion, a finding that is
compatible with autonomous TSH secretion [20]. Serum TSH concentrations do not
increase in response to thyrotropin-releasing hormone (TRH) in the majority of
patients [3,21].
Alpha subunit — Approximately 50 to 85 percent of patients with TSH-secreting
pituitary adenomas (particularly macroadenomas) have a high serum
concentration of the alpha subunit of glycoprotein hormones [3,12]. The relative

402
increase in serum alpha subunit is greater than that of serum TSH, resulting in a
high molar ratio of serum alpha subunit to TSH (mean 3.2) [3,21].

The ratio is calculated using the following formula:

[Alpha subunit (in micrograms/L) ÷ TSH (in mU/L)] x 10

In postmenopausal women, who have normally elevated serum alpha-subunit

levels accompanying their high serum gonadotropin levels, the cutoff which
suggests a TSH-secreting pituitary adenoma is higher than in premenopausal
women and men (as high as 29.1 compared with 0.3 in men) [2,22]. The ratio can
be normal in patients with microadenomas [12].
Imaging studies — The thyroid appearance on ultrasound and radioiodine
imaging is similar to that in Graves' disease (diffuse homogeneous enlargement,
normal or high radioiodine uptake, increased color Doppler flow).
Magnetic resonance imaging (MRI) of the pituitary more often shows a
macroadenoma than a microadenoma, and some are locally invasive [12]. In one
series of 18 patients, the mean macroadenoma size was 3.1 cm [23].
Indium-0111 octreotide scintigraphy may show focal uptake in the pituitary [24].
DIAGNOSISA TSH-secreting pituitary adenoma should be suspected in
hyperthyroid patients with diffuse goiter and no extrathyroidal manifestations of
Graves' disease, who have high serum free T4 and T3 concentrations and
unsuppressed (normal or high) serum TSH concentrations, particularly in the
presence of headache or clinical features of concomitant hypersecretion of other
pituitary hormones (eg, symptoms of acromegaly). The subsequent finding of a
pituitary macroadenoma by magnetic resonance imaging (MRI) is very strong
evidence that the patient has a TSH-secreting pituitary adenoma, particularly in the
presence of an elevated alpha subunit. (See 'Diagnostic evaluation' below.)
Differential diagnosis
Assay interference — Other conditions to be distinguished from TSH-secreting
adenomas are those in which there is methodological interference in the
measurement of total T4, total T3, or TSH. Serum total T4 and total T3
concentrations may be increased because of increased protein binding of the
hormones in serum. These conditions include elevations in serum T4-binding
globulin concentrations, familial dysalbuminemic hyperthyroxinemia (in which an
abnormal albumin with increased affinity for T4 is produced), and the presence of
anti-T4 antibodies. Patients with these conditions are euthyroid and have normal
serum TSH concentrations, elevated total T4, and elevated total T3 but usually

403
normal serum free T4 and free T3 concentrations when measured by appropriate
methods. (See "Euthyroid hyperthyroxinemia and hypothyroxinemia".)
The presence of heterophilic antibodies can interfere with TSH measurements in
immunometric assays. These human anti-mouse gamma globulins can bridge the
two mouse monoclonal antibodies (solid phase antibody and signal antibody) and
cause spuriously elevated readings for TSH [16,25]. Nonlinearity of TSH
measurements with serial dilution of the patient's serum strongly suggests assay
interference. Addition of nonimmune homologous mouse immunoglobulins has
reduced this type of assay interference. Commercial assays exist for detecting
human anti-mouse antibodies (HAMA).
In addition, autoantibodies to TSH have also been described which create TSH-anti-
TSH immunoglobulin G (IgG) complexes (also called macro-TSH), which lack
biologic activity but may be immunoreactive and cause spuriously high TSH values
(often >100 mU/L) [26-28]. Autoantibodies to TSH can be detected by removal of
the IgG-TSH complexes with polyethylene glycol or protein A or G, then repeating
the assay on the immunosubtracted sera.

Patients with substances interfering with TSH measurements are usually

euthyroid, not thyrotoxic, and have normal free T4 and T3. Thus, tests for
interference with the TSH measurement are rarely required.

Resistance to thyroid hormone — Patients with TSH-secreting adenomas and

hyperthyroidism must be distinguished from those with the syndrome of
resistance to thyroid hormone due to mutations in the THRB gene (RTH-beta).
Patients with RTH-beta have variable tissue hyporesponsiveness to thyroid
hormone due to a defect in the THRB gene [21]. Despite their RTH in many tissues
(including the pituitary gland), some patients with RTH-beta have symptoms and
signs of hyperthyroidism, particularly tachycardia, hyperactivity, and hyperreflexia,
and many have goiter. (See "Resistance to thyroid hormone and other defects in
thyroid hormone action", section on 'Resistance to thyroid hormone beta (RTH-
beta and nonTR-RTH)'.)

The following findings help to distinguish TSH-secreting adenomas from RTH-beta:

●A mutation in the THRB gene is present in patients with RTH-beta but usually

not in patients with TSH-secreting adenomas. There is one reported patient
with RTH-beta and a TSH-secreting adenoma [29].
●The serum alpha-subunit concentration is normal in RTH-beta but, as noted
above, often high in patients with TSH-secreting adenomas. (See 'Alpha
subunit' above.)

404
 ●The serum sex hormone-binding globulin (SHBG) concentration is high in
patients with TSH-secreting pituitary adenomas, whereas the values are
normal in RTH-beta. This difference reflects the expected action of excess T4
and T3 on hepatic SHBG production in hyperthyroidism and resistance to the
hormones' action in RTH-beta.
●The serum TSH concentration increases in response to thyrotropin-releasing
hormone (TRH) in patients with RTH-beta but not in most patients with TSH-
secreting adenomas.
●Patients with RTH-beta are more likely to have a fall in serum TSH
concentrations in response to administered T3 (90 versus 12 to 25 percent)
[3].
●Patients with RTH-beta are more likely to have a decrease in the velocity of
TSH suppression two hours after subcutaneous injection of a short-term
somatostatin analog [30].
The use of color flow Doppler sonography of the thyroid gland has also been
shown to distinguish between patients with TSH-secreting pituitary adenomas and
those with RTH-beta [31]. After a standard T3 suppression test, used for the
diagnosis of RTH-beta (50 micrograms/day for days 1 to 3, followed by 100
micrograms/day for days 4 to 6, and then 200 micrograms/day for days 7 to 9) [21],
the increased color flow Doppler sonography pattern and peak systolic velocity
normalized in 8 of 10 patients with RTH-beta but not in any of the eight patients
with a TSH-secreting pituitary adenoma.
Incidental pituitary adenomas may occur in patients with RTH-beta due
to THRB gene mutations. There is no evidence to suggest that THRB  gene
mutations cause pituitary adenomas, but the relatively common occurrence of
incidental pituitary adenomas, when they do occur in patients with THRB  gene
mutations, can make it difficult to distinguish one from the other.
Longstanding primary hypothyroidism — An occasional patient with
longstanding primary hypothyroidism has sufficient hyperplasia of the thyrotroph
cells to cause pituitary enlargement [32]. The hyperplasia may be mistaken for a
pituitary tumor, but the patients have clinical manifestations of hypothyroidism,
low serum T4 and T3 concentrations, and very high serum TSH concentrations.
These patients should not be confused with patients with TSH-secreting
adenomas. The enlarged pituitary in hypothyroidism shrinks with T4 therapy.
(See "Disorders that cause hypothyroidism".)
Diagnostic evaluation — A TSH-secreting pituitary adenoma should be suspected
in a hyperthyroid patient with high serum free T4 and T3 concentrations and
unsuppressed (normal or high) serum TSH concentration. In patients with these

405
thyroid function tests, we perform a combination of tests to confirm the diagnosis
as there is no single test that will absolutely diagnose this condition:

Initial assessment:

●Ask the patient to question other family members regarding abnormal

thyroid function tests. Take a careful history for other potential pituitary
abnormalities (eg, does the patient have amenorrhea or a visual field
defect?).
●Repeat the thyroid tests in another lab (TSH, free T4 and T3). Assay
interference is frequently dependent on the commercial kit used for
measuring the hormone. Another strategy is to ask the original lab to assay
the serum TSH in serial dilution; authentic TSH will dilute in parallel with the
serial dilutions (eg, a serum TSH of 10 mU/L will be 5 mU/L when the serum is
diluted 1:2).
●Measure alpha subunit, as approximately 50 to 85 percent of patients with
TSH-secreting pituitary adenomas have high serum concentrations. A normal
level makes the diagnosis less likely but does not exclude it.
●Measure serum SHBG. A normal value is evidence that the patient
is not hyperthyroid and argues for RTH-beta or spuriously elevated TSH
values.
●Measure other pituitary hormones. Approximately 20 to 25 percent of the
adenomas secrete one or more other pituitary hormones, predominantly
growth hormone or prolactin [2]. Therefore, we measure insulin-like growth
factor-1 (IGF-1) and prolactin in patients with suspected TSH-secreting
pituitary adenomas. Additionally, the presence of other hormonal
deficiencies suggests the possibility of a possible sellar mass (eg, measure
follicle-stimulating hormone [FSH] in a postmenopausal woman, testosterone
in a young man, etc).

Subsequent assessment:

●In the absence of any history or testing suggestive of a pituitary adenoma,

given the difficulty in distinguishing patients with TSH-secreting tumors from
RTH-beta, we perform an analysis for mutations in the THRB gene in patients
with elevated free T4, T3, and nonsuppressed TSH and normal serum alpha
subunit. In some countries, including the United States, this is now a rather
widely available test. Although 15 percent of patients with RTH-beta do not
have mutations in the TR-beta, the presence of a mutation rules out the
diagnosis of a TSH-secreting tumor (see 'Resistance to thyroid

406
 hormone' above) and may prevent the possible confounding discovery of a
pituitary incidentaloma.
●In the presence of history or testing suggestive of a pituitary adenoma, or
after exclusion of RTH-beta, we obtain an MRI of the pituitary with
gadolinium.
The presence of a macroadenoma on MRI is strong evidence of a TSH-
secreting tumor, particularly in the presence of an elevated alpha subunit.
The presence of a microadenoma on MRI is not specific for a TSH-secreting
tumor and can be seen as an incidental finding in 10 percent of normal
individuals [33].
Conversely, small pituitary tumors can be missed by MRI or computed
tomography (CT). In a few patients, radiolabeled pentetreotide has been
useful in detecting the adenomas [34]. Cases of ectopic TSH-secreting
adenomas have been reported in the nasopharynx [35,36] and in the
vomerosphenoidal junction [37].
●Rarely, radiolabeled pentetreotide and inferior petrosal sinus sampling may
be indicated when MRI of the pituitary shows a microadenoma or is normal.
(See "Incidentally discovered sellar masses (pituitary incidentalomas)".)
TREATMENTThe treatment approach outlined below is primarily based upon
case series and clinical experience [2].
Initial — The initial treatment of a TSH-secreting pituitary adenoma is medical
therapy (with somatostatin analogs) to restore euthyroidism prior to surgery. Once
euthyroid, transsphenoidal resection of the tumor is the most appropriate
definitive therapy for patients with TSH-secreting pituitary adenomas. With this
approach, most patients with microadenomas (≤10 mm) will be cured.
Approximately half of patients with macroadenomas will require additional
therapy for residual disease. (See 'Residual disease' below.)
Medical therapy — Medical therapy (typically somatostatin analogs) is used to
restore euthyroidism prior to definitive treatment with transsphenoidal surgery. In
addition, somatostatin analogs sometimes reduce the size of the tumor prior to
resection. The role of somatostatin analogs as a primary treatment (instead of
surgery) for TSH-secreting pituitary adenomas requires further investigation.
However, there may be a role for somatostatin analogs as primary treatment for
patients who refuse or are unable to undergo pituitary surgery. (See 'Primary
treatment' below.)
Restore euthyroidism prior to neurosurgery — Patients should be euthyroid
prior to neurosurgery. For medical therapy to restore euthyroidism, we suggest a
somatostatin analog.

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 ●We start first with a short-acting somatostatin analog in order to determine
if the patient can tolerate the medication and if it is effective in lowering the
TSH. A suitable initial dose of a short-acting somatostatin analog is 50
micrograms subcutaneously twice daily, increasing to three times daily and
then to 100 micrograms three times daily, with additional increments of 50
micrograms per injection as needed; serum TSH and free T4 concentrations
should be measured at two- to three-week intervals.
●If tolerated and efficacious, the medication can be switched to a long-acting
somatostatin analog, which is administered as 20 mg intramuscular (IM)
every four weeks.
Treatment with somatostatin analogs typically is continued for three to four
months in order to normalize thyroid hormone levels. In a review of 43 cases of
TSH-secreting pituitary adenomas, 26 patients received somatostatin analogs as
initial therapy [12]. A reduction of more than 50 percent in TSH occurred in 23 of
26 patients (88 percent) and normalization of free T4 in 22 of 26 (85 percent). The
side effects of somatostatin analogs include nausea, abdominal discomfort,
bloating, diarrhea, glucose intolerance, and cholelithiasis. In addition,
somatostatin analogs are very expensive. (See "Treatment of acromegaly".)
If somatostatin analogs are not tolerated, dopamine agonists
(bromocriptine, cabergoline) may be effective in select cases, particularly in
patients whose tumor cosecrete prolactin. However, in a series of 43 cases of TSH-
secreting pituitary adenoma, seven patients were treated with dopamine agonists,
and a significant reduction in TSH and prolactin occurred in only one of these
cases, a patient with a mixed TSH/prolactin-secreting adenoma [12].
In addition to somatostatin analogs, a beta blocker such as propranolol (80 to 160
mg daily) or atenolol (25 to 50 mg daily) can be given to ameliorate some of the
symptoms and signs of hyperthyroidism until more effective treatment is
administered. (See "Beta blockers in the treatment of hyperthyroidism".)
Antithyroid therapy of any type, radioiodine or drug (eg, thionamide),
is not indicated for the treatment of patients with TSH-secreting adenomas,
because sustained reductions in thyroid hormone secretion would be expected to
increase TSH secretion and stimulate tumor growth. However, if euthyroidism
cannot be achieved with somatostatin analogs or dopamine agonists, short-term
administration of a thionamide is necessary to restore euthyroidism prior to
neurosurgery. (See "Nonthyroid surgery in the patient with thyroid disease",
section on 'Hyperthyroidism'.)
Reduce tumor size prior to neurosurgery — Although the main goal of
somatostatin analogs is to restore euthyroidism prior to surgery to minimize the
risks of surgery, somatostatin analogs also may reduce the size of the adenoma

408
prior to transsphenoidal surgery. As an example, in a review of 43 cases of TSH-
secreting pituitary adenomas, 26 patients received somatostatin analogs as initial
therapy [12]. Tumoral shrinkage of more than 20 percent occurred in 5 of 13 (36
percent) treated for at least three months. In another study, 23 of 38 (61 percent)
of tumors shrank with octreotide after a mean of 33 days [38].
Primary treatment — The role of somatostatin analogs as a primary treatment
for TSH-secreting pituitary adenomas requires further investigation. For patients
receiving somatostatin analogs as primary therapy to control hyperthyroidism,
thyroid function (TSH, free T4, total T3) should be monitored after two to three
months, as somatostatin receptor analogs can induce TSH deficiency, necessitating
a reduction in the frequency of injections [39].
In a retrospective study of seven patients (three with microadenoma, four with
macroadenoma) who were treated with somatostatin analogs and followed for a
mean of 8.5 years, six patients achieved good biochemical control [40]. Adenoma
volume decreased in five of six patients for whom data were available. In another
report, a patient with a 1.5 cm macroadenoma was treated with octreotide for four
years, with complete resolution of hyperthyroidism and normalization of magnetic
resonance imaging (MRI) findings [41]. After withdrawal of octreotide, the patient
remained euthyroid and MRI scans have shown no recurrence during five years of
follow-up. These findings suggest a primary role for medical therapy in some
patients. However, in another case series, tumoral shrinkage was not observed in
three of seven patients treated with octreotide for 24 months [12].
Why some tumors shrink in response to octreotide and others do not may be
related to the expression of subtypes of somatostatin receptors (SSTRs) [42].
Octreotide may inhibit TSH secretion in all tumors that express SSTR2, and the
expression of the type 5 receptor may enhance the inhibitory effects of octreotide
[43].
Bromocriptine (10 to 20 mg/day orally) has proven effective as primary medical
therapy in occasional patients, usually those with concomitant hyperprolactinemia,
as has cabergoline, which is often better tolerated and need be given only once or
twice weekly in a dose of 0.25 or 0.5 mg orally [44]. Occasional patients have
responded to bromocriptine alone [45]. In three such patients, there was no
growth of the pituitary tumor over eight years of therapy [46].
Surgery — Transsphenoidal resection of the pituitary adenoma is the definitive
therapy of choice for patients with TSH-secreting adenomas. It results in cure in
the majority of patients with microadenoma and approximately 50 to 60 percent of
patients with macroadenoma [2,11,12]. In a review of 43 cases of TSH-secreting
pituitary adenoma, transsphenoidal surgery was performed in 36 patients [12].
After one year, 21 (58.3 percent) were cured. The remaining 15 patients were

409
treated with either radiotherapy (n = 8) or long-term somatostatin analogs.
Surgical remission rates in micro- versus macroadenomas were 6 of 7 and 15 of 29
cases, respectively. (See "Transsphenoidal surgery for pituitary adenomas and
other sellar masses".)
Criteria for cure — There are no well-established criteria for cure after
transsphenoidal surgery [2]. The following parameters should be taken into
account when assessing for cure:
●Clinical remission of symptoms of hyperthyroidism
●Normalization of thyroid function tests
●Absence of residual tumor on MRI

Somatostatin analogs and antithyroid drugs (if used) must be discontinued prior to
the assessment of thyroid function tests. We discontinue somatostatin analogs
three days prior to surgery and antithyroid drugs (thionamides, if used) on the day
of surgery. We taper and discontinue beta blockers in the early postoperative
period.

Thyroid function should be monitored carefully postoperatively. Assessment of

thyroid function requires measurement of TSH, free T4, and total T3 at frequent
intervals postoperatively, depending on the clinical scenario, until the patient's
status is ascertained and steady-state conditions are established. While there are
no published protocols, the first measurement of thyroid function tests should be
24 hours postoperatively, then weekly for four weeks, and then monthly for
several months until the outcome of the surgery is certain:

●Normal TSH, free T4, and T3 – Successful surgery will restore euthyroidism.
However, it may take months for thyroid function tests to return to normal.
In one small series, the finding of an undetectable TSH level seven days after
surgery was predictive of a successful outcome [47]. In another report, a TSH
below 0.6 mU/L (obtained 12 hours postoperatively) was a major predictor of
long-term remission [48].
●High TSH, free T4, and/or T3 – If the surgery is not successful, patients may
develop recurrent hyperthyroidism after medical therapy is discontinued.
However, if there was incomplete removal of the tumor, an apparent cure
may be transient, and recurrent hyperthyroidism may occur months or years
later with tumor regrowth.
●Low TSH and low free T4 – Surgery may damage the normal thyrotrophs (as
well as other pituitary cells), resulting in central hypothyroidism or
panhypopituitarism [49].

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 ●Recovery of the pituitary-thyroid axis may take as long as two to three
months, resulting in transient central hypothyroidism (low TSH and low free
T4).
If the patient is started on thyroid hormone replacement for central
hypothyroidism, especially in the absence of other pituitary deficiencies,
slightly lower than full replacement doses should be given for the first few
months to be certain that the central hypothyroidism is not transient.
(See "Central hypothyroidism", section on 'Treatment'.)
Four to six weeks after discharge from the hospital, we also assess hormonal
function of the nonadenomatous pituitary, regardless of whether it was normal or
abnormal prior to surgery. We measure an early morning serum cortisol and
either serum testosterone in men or serum estradiol and follicle-stimulating (FSH)
in premenopausal women. (See "Treatment of gonadotroph and other clinically
nonfunctioning adenomas" and "Diagnostic testing for hypopituitarism".)
An MRI should be obtained approximately 12 weeks postoperatively, and patients
should be monitored for tumor recurrence based on clinical impression of tumor
regrowth (headaches, visual changes) or recurrence of abnormal thyroid tests.
(See 'Long-term monitoring' below.)
Residual disease — Because of the relatively poor results of surgery, many
patients with macroadenomas need additional therapy [12]. For patients with
residual disease after transsphenoidal surgery, we prefer to treat with
somatostatin analogs rather than pituitary irradiation due to the more immediate
response with medication [12]. However, for patients who cannot tolerate
somatostatin analogs or who prefer to avoid long-term medical therapy, pituitary
radiation is an alternative option to control TSH secretion in patients with
persistent disease after transsphenoidal surgery [50].

The choice between long-term somatostatin analogs and pituitary radiation is

based upon discussion with the individual patient about the risks and benefits of
each therapy. The benefit of radiation therapy is the freedom from taking
medications long term. However, adverse effects of pituitary radiation in the long
term may include hypopituitarism, infertility, and, rarely, impaired cognitive
function. Long-acting somatostatin analogs are injected monthly. Adverse effects
include nausea, abdominal discomfort, bloating, diarrhea, glucose intolerance, and
cholelithiasis. In addition, somatostatin analogs are very expensive.

Somatostatin analogs — Somatostatin analogs are administered after

transsphenoidal surgery for long-term control of residual disease. As an example,
in a series of 73 patients treated with octreotide (50 to 750 micrograms given

411
subcutaneously two or three times daily), most of whom had already undergone
surgery, the following results were noted [3]:
●The serum TSH concentration fell by more than 50 percent in 92 percent of
patients and became normal in 79 percent.
●Serum T4 and T3 concentrations fell to normal in 95 percent of patients after
one year.
●The tumor decreased in size in 52 percent of patients after one year.
●Less than 10 percent of patients developed resistance to the action
of octreotide.
A slow-release formulation of a somatostatin analog, lanreotide, has proven
effective in patients with TSH-secreting pituitary adenomas [51]. In 16 patients (the
majority of whom had residual disease after transsphenoidal surgery), 30 mg
lanreotide given IM two to three times per month for six months resulted in
amelioration of hyperthyroid symptoms in all patients and normalization of serum
TSH and thyroid hormone concentrations in 13, but no change in tumor size was
observed. Thyroid tests (TSH, free T4, total T3) should be monitored as
somatostatin analogs can induce TSH deficiency, necessitating a reduction in
dosing frequency [39].
Pituitary irradiation — Radiation therapy may be effective in reducing the size of
TSH-secreting adenomas and decreasing TSH, free T4, and T3 concentrations.
There are few data on the efficacy of radiation therapy [11,12,50]. In one series, 22
patients had pituitary surgery for a TSH-secreting pituitary adenoma [11]. In the
absence of surgical cure, 11 patients received external radiation of the pituitary
(typical dose 4500 to 5500 cGy), and one patient received focused high-dose
irradiation with a Gamma Knife unit. Patients
received octreotide or bromocriptine until TSH secretion was controlled by
radiation therapy as the full effect of radiation requires months to years. After 1 to
14 years of follow-up, the majority of the patients were biochemically euthyroid
without requiring long-term treatment with somatostatin analogs, and 5 of 11 had
no evidence of tumor on MRI.
Thyroidectomy — Thyroid surgery should be reserved for patients with
symptomatic goiters in whom pharmacotherapy has failed. With the general
availability of somatostatin analogs, however, thyroid surgery is rarely required. In
patients with TSH-secreting pituitary tumors who undergo thyroidectomy either
due to goiter or in whom pharmacotherapy or surgery of the pituitary lesion have
failed, thyroid hormone replacement can be initiated at a dose which maintains
the serum free T4 concentration in the upper 50 percent of the normal range.
Serum TSH cannot be used to monitor therapy, since the TSH value may not be
suppressible.

412
The risk of reactive growth of the pituitary cells has not been reported in patients
with TSH-secreting pituitary tumors who receive normal replacement doses of
thyroid hormone. This may reflect the relative nonaggressive nature of these
tumors or the irrelevance of thyroid hormone feedback to tumor thyrotrophs.
However, in those patients in whom tumor growth occurs despite appropriate T4
treatment, irradiation of the tumor is recommended.

Long-term monitoring — Patients with TSH-secreting adenomas who appear to

be cured require monitoring of TSH, free T4, and free T3 two or three times in the
first postoperative year and less frequently (annually) thereafter [2]. MRI of the
pituitary should be performed one year postoperatively and then less frequently
(every two to three years and then even less frequently) if the MRI is normal and
there is no clinical or biochemical evidence of recurrence. For patients with mixed
tumors (ie, TSH/growth hormone-secreting tumors), this includes no evidence of
secretion of any components of the tumor. MRI should be repeated more often if
there are any indications of biochemical or clinical recurrence.
Outcome — While most patients do reasonably well, in one series of 25 patients
there were three deaths, including one from metastatic thyrotroph carcinoma [11].
An additional case of a metastatic TSH-secreting pituitary adenoma cosecreting
prolactin has been reported [52]. In a series of 43 cases followed for a mean of
eight years, two patients died (ages 75 and 86 years); 19 patients were cured after
pituitary surgery alone; 17 patients with residual disease after surgery were
controlled with somatostatin analogs, pituitary radiation, or both; and 7 were
controlled by somatostatin analogs alone (no surgery) [12].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)
SUMMARY AND RECOMMENDATIONS
●Thyroid-stimulating hormone (TSH)-secreting pituitary adenomas are a rare
cause of hyperthyroidism, accounting for much less than 1 percent of all
cases of hyperthyroidism. (See 'Introduction' above.)
●Most patients have the typical symptoms and signs of hyperthyroidism, but
a few patients have mild or even no symptoms. Other clinical features include
a diffuse goiter, visual field deficits, headache, and, in women, menstrual
disturbances and galactorrhea. (See 'Clinical presentation' above.)
●The characteristic biochemical abnormalities in patients with
hyperthyroidism caused by a TSH-secreting adenoma are normal or high
serum TSH concentrations, high serum total and free thyroxine (T4) and
triiodothyronine (T3) concentrations, and, in some cases, elevated serum
413
concentrations of the alpha subunit of glycoprotein hormones. (See 'Thyroid
function tests' above and 'Alpha subunit' above.)
●Other conditions to be distinguished from TSH-secreting adenomas are
those in which there is methodological interference in the measurement of
total T4, total T3, or TSH and the syndrome of resistance to thyroid hormone
beta (RTH-beta). (See 'Differential diagnosis' above and "Resistance to thyroid
hormone and other defects in thyroid hormone action" and "Euthyroid
hyperthyroxinemia and hypothyroxinemia".)
●In patients with high serum free T4 and T3 concentrations and
unsuppressed (normal or high) serum TSH concentration, we perform a
combination of tests (eg, repeat thyroid tests in another lab, alpha subunit,
other pituitary hormones) to confirm the diagnosis of TSH-secreting pituitary
adenoma as there is no single test that will absolutely diagnose this
condition. (See 'Diagnostic evaluation' above.)
●In the absence of any history or testing suggestive of a pituitary adenoma,
given the difficulty in distinguishing patients with TSH-secreting tumors from
RTH-beta, we perform (when available) an analysis for mutations in the
thyroid hormone receptor beta (THRB) gene in patients with elevated free T4,
T3, and nonsuppressed TSH and normal serum alpha subunit. Although 15
percent of patients with RTH-beta do not have mutations in the TR-beta, the
presence of a mutation rules out the diagnosis of a TSH-secreting tumor.
(See 'Diagnostic evaluation' above.)
●In the presence of history or testing suggestive of a pituitary adenoma, or
after exclusion of RTH-beta, we obtain magnetic resonance imaging (MRI) of
the pituitary with gadolinium. (See 'Diagnostic evaluation' above.)
●The presence of high serum free T4 and T3 concentrations and measurable
(normal or high) serum TSH concentrations in the presence of a
macroadenoma on MRI is strong evidence of a TSH-secreting tumor,
particularly in the presence of an elevated alpha subunit.
(See 'Diagnosis' above.)
●For definitive therapy of TSH-secreting pituitary adenomas, we recommend
transsphenoidal resection of the tumor performed by a neurosurgeon with
considerable experience (Grade 1B). The role of somatostatin analogs as a
primary treatment for TSH-secreting pituitary adenomas requires further
investigation. (See 'Treatment' above.)
●Medical therapy is used to restore euthyroidism prior to surgery. For
medical therapy, we suggest a long-acting somatostatin analog (Grade 2B).
Dopamine agonists are an alternative option for those who do not tolerate

414
somatostatin analogs, particularly in patients with cosecretion of prolactin.
(See 'Restore euthyroidism prior to neurosurgery' above.)
●A beta blocker such as propranolol (80 to 160 mg daily) or atenolol (25 to 50
mg daily) can be given to ameliorate some of the symptoms and signs of
hyperthyroidism. Long-term antithyroid drug therapy or thyroid ablation with
radioiodine or surgery is not indicated in patients with TSH-secreting
adenomas, because sustained reductions in thyroid hormone secretion
would be expected to increase TSH secretion and stimulate tumor growth.
However, if euthyroidism cannot be achieved with somatostatin analogs or
dopamine agonists, short-term administration of a thionamide is necessary
to restore euthyroidism prior to neurosurgery. (See 'Treatment' above
and "Beta blockers in the treatment of hyperthyroidism" and "Nonthyroid
surgery in the patient with thyroid disease", section on 'Hyperthyroidism'.)
●There are no well-established criteria for cure after transsphenoidal surgery.
The parameters that should be taken into account when assessing for cure
include clinical remission of symptoms of hyperthyroidism, normalization of
thyroid function tests, and absence of residual tumor on MRI. (See 'Criteria
for cure' above.)
●For patients with residual disease after transsphenoidal surgery, we prefer
to treat with somatostatin analogs rather than pituitary irradiation due to the
more immediate response with medication. The choice between long-term
somatostatin analogs and pituitary radiation is based upon discussion with
the individual patient about the risks and benefits of each therapy.
(See 'Residual disease' above.)

415
Treatment of acromegaly
Authors:
Shlomo Melmed, MD
Laurence Katznelson, MD
Section Editor:
Peter J Snyder, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 03, 2020.
INTRODUCTIONAcromegaly is almost always caused by a somatotroph
(growth hormone [GH]-secreting) adenoma of the pituitary gland and is associated
with increased morbidity and mortality. As a result, almost all patients should be
treated, even those who are asymptomatic and those in whom the disorder does
not seem to be progressing. One exception is a patient with a short life expectancy
who is not expected to live long enough to benefit from therapy.
The treatment of acromegaly will be reviewed here. The clinical manifestations and
diagnosis of acromegaly are discussed separately. (See "Causes and clinical
manifestations of acromegaly" and "Diagnosis of acromegaly".)
GOALS OF THERAPYThe goals of therapy in patients with acromegaly are to
lower the serum insulin-like growth factor-1 (IGF-1) concentration to within the
normal range for the patient's age and gender, control adenoma size and reduce
mass effects, improve symptoms, and reverse metabolic abnormalities such as
diabetes mellitus [1]. (See "Causes and clinical manifestations of acromegaly",
section on 'Metabolic'.)
●In addition to lowering IGF-1, another biochemical goal is to lower the
serum growth hormone (GH) concentration to <1 mcg/L as measured by
immunoradiometric or chemiluminescent assay, as this also correlates with
control of acromegaly. [2]. However, the IGF-1 criterion may be better since
some patients who appear to have active disease clinically and by elevated
IGF-1 concentration have serum GH values that suppress to <1 mcg/L [3,4].
Serum IGF-1 concentrations also correlate better than serum GH with insulin
sensitivity in patients with acromegaly [5]. (See 'Biochemical
outcomes' below.)
●When serum GH and IGF-1 concentrations decline to normal [6], the
characteristic soft tissue overgrowth and related symptoms gradually recede
and the metabolic abnormalities, such as diabetes mellitus, improve. In

416
 addition, life expectancy returns to that of the general population [7,8].
However, bony abnormalities generally do not regress and joint symptoms
persist. (See 'Amelioration of symptoms' below.)
●Another goal of treatment is to alleviate symptoms due to the direct effects
of the somatotroph adenoma (headaches, vision loss), without causing
hypopituitarism.
OVERVIEW OF APPROACHA summary of treatment effects is provided in the
table (table 1). The choice of initial treatment depends upon the size and location
of the adenoma, the presence of symptoms due to size (such as impairment of
vision), and the patient's ability to undergo surgery (algorithm 1). The approach
outlined here is similar to the Endocrine Society's 2014 Clinical Practice Guideline
[2].
Transsphenoidal surgery — For the majority of patients with acromegaly, we
recommend transsphenoidal surgery as the initial therapy (algorithm 1). This
includes patients with a microadenoma, a macroadenoma that appears to be fully
resectable, or a macroadenoma causing impairment of vision. We also recommend
that transsphenoidal surgery be performed by a neurosurgeon with considerable
experience in pituitary surgery [2]. (See "Transsphenoidal surgery for pituitary
adenomas and other sellar masses", section on 'Somatotroph adenomas
(acromegaly)'.)
We suggest surgical debulking for patients with macroadenomas abutting or
adjacent to the chiasm (followed by medical therapy) (algorithm 1). Medical
treatment may be more effective after surgical debulking. (See 'Somatostatin
analogs' below.)
Potential complications — The perioperative mortality rate is less than 1 percent
in patients with large, invasive adenomas and negligible in patients with smaller
ones. Long-term deficiency of one or more pituitary hormones has been reported
in up to 70 percent of patients [8,9]. Patients treated with both surgery and
radiation are particularly prone to develop pituitary hormonal deficiencies,
including growth hormone (GH) deficiency [10]. (See 'Should GH deficiency be
treated?' below.)
Other major complications of surgery occur in approximately 8 percent of patients.
These include central diabetes insipidus (2 percent), cerebrospinal fluid rhinorrhea
(2 percent), and meningitis (2 percent) [8,11]. All are more common in patients with
macroadenomas.
These complication rates reflect results from neurosurgeons with the most
experience with transsphenoidal surgery. Rates with less experienced surgeons
are much higher [12,13].

417
Postoperative evaluation — The early cure rate in patients with acromegaly is 80
to 90 percent for microadenomas and less than 50 percent for macroadenomas
(see 'Surgical cure rate' below). We measure insulin-like growth factor-1 (IGF-1)
levels and a random growth hormone (GH) approximately 12 weeks after surgery
as it may take this long for IGF-1 to normalize; a decision can then be made
whether adjuvant therapy should be initiated (algorithm 1). If a random GH is >1
mcg/L, we remeasure GH after a glucose load; a post-glucose serum GH less than
1 mcg/L is consistent with control of acromegaly [2].
The early cure rate in patients with acromegaly is 80 to 90 percent for
microadenomas and less than 50 percent for macroadenomas. (See 'Biochemical
outcomes' below and 'Surgical cure rate' below.)
We also suggest performing a pituitary magnetic resonance imaging (MRI) study
at least 12 weeks after surgery to look for residual tumor and assess adjacent
structures (algorithm 1). It is important to wait 12 weeks to allow for involution of
gel foam and fat packing [2].
Normal IGF-1 and no residual tumor on MRI — If transsphenoidal surgery
results in normalization of serum insulin-like growth factor-1 (IGF-1) concentration
and no evidence of residual tumor on magnetic resonance imaging (MRI), we
suggest no further therapy. Long-term biochemical monitoring and imaging
follow-up for these patients is described below. (See 'Monitoring' below.)
The risk of recurrence is reviewed below. (See 'Recurrence' below.)
Patients with residual disease — Patients with residual disease (biochemically or
on MRI) need additional treatment. This can include repeat surgery, medical
therapy, and/or radiation therapy (algorithm 1).
Additional therapy for residual disease
Repeat surgery — We suggest repeat transsphenoidal surgery for patients with
(algorithm 1):
●Residual intrasellar mass that compresses vital structures after initial
surgery
●Significant residual tumor in the sella that is resectable
Medical therapy — For patients with an abnormal serum IGF-1
and moderate symptoms of GH excess after transsphenoidal surgery, but who do
not need repeat surgery, we suggest medical therapy (algorithm 1).
For patients in whom transsphenoidal surgery does not result in normalization of
serum IGF-1 concentration, particularly if they have moderate symptoms of GH
excess, we suggest medical therapy with either a long-acting somatostatin analog
or pegvisomant. We often use a somatostatin analog first because it tends to
decrease the size of the adenoma, as well as its secretion of GH. Pegvisomant is
another option for medical therapy in this setting. If a somatostatin analog is

418
started first and treatment does not reduce IGF-1 levels to normal, we recommend
adding pegvisomant, which blocks the action of GH. (See 'Somatostatin
analogs' below and 'Pegvisomant' below.)
In patients with only modest biochemical abnormalities, eg, GH concentrations >1
mcg/L but <1.3 mcg/L and mild symptoms of GH excess, we suggest a trial
of cabergoline. (See 'Dopamine agonists' below.)
Stereotactic radiation therapy — If medical therapy is ineffective or not
tolerated, we suggest stereotactic radiation therapy (RT) (algorithm 1). Other
indications for RT include (see 'Radiation therapy' below):
●An adenoma increasing in size despite medical therapy (ie, somatostatin
analog plus pegvisomant)
●Aggressive or atypical adenomas
●Patient desire to avoid the cost and administration of long-term medical
therapy
The use of RT for the management of acromegaly is reviewed in detail below.
(See 'Radiation therapy' below.)
Role of primary medical therapy — Although we suggest transsphenoidal
surgery as the initial step for most patients, we suggest medical therapy with a
long-acting somatostatin analog as the initial step for patients who (algorithm 1)
[2]:
●Have an adenoma that does not appear to be fully resectable (eg, because of
extensive cavernous sinus invasion but have no chiasmal compression)
●Are poor surgical candidates or decline surgery
●Would benefit from preoperative medication to allow easier intubation by
reducing severe laryngeal swelling and macroglossia and to improve
obstructive apnea or cardiac dysfunction
Following initial treatment, patients should be evaluated every three to four
months by both clinical examination and measurement of serum IGF-1
concentration for at least the first year. Medication dose is titrated upwards as
needed; if IGF-1 is not normalized at the maximum dose of somatostatin analog,
alternative therapy should be considered. (See 'Efficacy' below.)
Specifics about somatostatin analog therapy (dosing, impact on symptoms and
adenoma size, and side effects) are reviewed below. (See 'Somatostatin
analogs' below.)
●Pegvisomant – Daily pegvisomant monotherapy may also be used as first-
line therapy; its efficacy is determined by measuring IGF-1 and not GH.
(See 'Pegvisomant' below.)
●Combination therapy – Pegvisomant may be administered in combination
with a somatostatin analog in patients in whom the IGF-1 response to the

419
 analog alone is suboptimal. If the combination is effective, it should be
continued and monitored every six months. (See 'Combination
therapy' below.)

If medical therapy is effective, it can be continued indefinitely.

Long-term management — Several steps are involved in the long-term

management of patients with acromegaly.
Monitoring
●Clinical and biochemical – Following initial treatment, patients should be
evaluated every three to four months by both clinical examination and
measurement of serum IGF-1 levels.
Following initial treatment of acromegaly, whether surgery or medication,
IGF-1 should be measured in two to three months. It should not be measured
sooner, because of the long half-life of IGF-1. An elevated level suggests that
the treatment has not been sufficient. If the IGF-1 level is normal after the
initial treatment, it should be measured again in six months and then
annually.
If IGF-1 levels are normal, measuring random GH or post-oral glucose
tolerance test (OGTT) nadir GH levels may not add helpful information.
Medical therapy dose adjustments should be made using the IGF-1 levels.
The Endocrine Society guidelines suggest that an age-normalized serum IGF-
1 and a random GH <1 mcg/L should both be therapeutic goals as they
correlate with control of acromegaly [2].
Patients who are being treated with a medication should have the dose
adjusted as needed [14]. If normal IGF-1 values are not achieved, alternative
therapy should be considered. In patients well controlled on medical therapy,
we suggest biochemical testing (serum GH, IGF-1) every six months.
●Imaging – MRI should be repeated 12 weeks after surgery and then yearly
for the first several years after initial treatment and less often thereafter.
Visual field assessment is indicated for patients whose adenomas threaten
the optic chiasm [2].
●Systemic evaluation – Acromegaly appears to be associated with an excess
risk of colonic polyps. Based upon these observations, we suggest that
colonoscopy be performed at baseline and then every five years thereafter in
patients in those found to have a polyp or those with persistently elevated
IGF-1 levels and every 10 years in those without polyps and with normal IGF-1
levels [2]. (See "Causes and clinical manifestations of acromegaly", section on
'Other tumors'.)

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 Comprehensive cardiovascular evaluation should be performed regularly,
and hypertension and heart failure should be treated [2]. (See "Causes and
clinical manifestations of acromegaly", section on 'Cardiovascular disease'.)
Biochemical outcomes — When transsphenoidal surgery is performed by
the most experienced pituitary neurosurgeons, GH secretion falls to normal in
approximately 80 to 90 percent of patients with microadenomas (less than 10 mm
in diameter) and pituitary secretion of other hormones is preserved [7,9,15]. The
success rate is lower in patients with macroadenomas and/or higher preoperative
serum GH concentrations [9,11,15,16].
●Time course – If surgery is successful, serum GH concentrations typically fall
to normal within one to two hours, depending upon the degree of elevation.
Serum IGF-1 concentrations fall more slowly, from 7 to 10 days to several
months [17]. There is a rapid diuresis, and soft-tissue swelling and
hyperglycemia can diminish remarkably in a few days. Vision, if impaired, and
headaches can also improve in days. Sleep apnea [18] and cartilaginous
overgrowth also improve but often persist [19].
Amelioration of symptoms — When effective control of GH hypersecretion is
achieved, serum GH and IGF-1 concentrations decline to normal [6], the
characteristic soft tissue overgrowth and related symptoms gradually recede, and
the metabolic abnormalities (such as diabetes mellitus) and quality-of-life
measures improve.
Sleep apnea, tissue swelling, headache, and arthralgias resolve or improve in
approximately 70 percent of patients controlled on medical therapy. Most patients
recover from obstructive sleep apnea after surgical of medical control of the
growth hormone excess [20]. Mortality outcomes appear to be more favorable
with rigorous biochemical control.
Skeletal, jaw, and joint changes are not reversible. This was illustrated in a study of
118 patients with acromegaly who were in long-term remission, as judged by
serum normal IGF-1 concentration; 77 percent reported joint symptoms [21].
(See "Causes and clinical manifestations of acromegaly", section on 'Bone and
joints'.)
Should GH deficiency be treated? — We do not suggest the routine use of
growth hormone (GH) therapy in patients with acromegaly who develop GH
deficiency, as available data are conflicting.
It is estimated that 50 to 70 percent of patients with acromegaly treated with
surgery alone or surgery combined with RT develop GH deficiency [10], a
complication that is associated with a decreased quality of life [22]. However, the
impact of GH therapy in those who develop GH deficiency is still unclear.

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In one trial, patients with cured acromegaly who developed GH deficiency had
improved body composition (decrease in total body fat mass and abdominal fat)
with GH therapy compared with placebo [23]. In contrast, a second trial reported
an increase in vascular events after two years of GH therapy in adults with GH
deficiency previously treated for acromegaly [24].
Pregnancy — Most women with untreated acromegaly have menstrual
dysfunction and infertility due to one or more of the following [25]:
●Decreased secretion of luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) due to compression of gonadotroph cells by a
macroadenoma
●Hyperprolactinemia due to pituitary stalk compression
●Hyperprolactinemia due to a mixed GH-prolactin secreting adenoma

We suggest the following approach to managing women planning pregnancy and

pregnant/postpartum women with acromegaly:

Preconception
●The serum GH and IGF-1 concentrations should be as tightly controlled as
possible in women with known acromegaly before attempting conception to
minimize the risk of gestational diabetes mellitus (GDM) and gestation
hypertension [2].
●Somatostatin analogs should be discontinued two months
and pegvisomant one month prior to trying to conceive.
Short-acting octreotide may be used as necessary to control signs and
symptoms of GH excess until conception [2].
During pregnancy/postpartum
●During pregnancy, medical therapy should be withheld. Short-
acting octreotide can be used, but only for control of headache and adenoma
size [2]. Most data suggest that somatostatin analog administration during
pregnancy has not been associated with adverse events [26-28].
●We suggest against routine measurement of either serum GH or IGF-1 in
pregnant patients. GH assays recognize both normal and placental variants
of GH in gravid women. GH stimulates production of IGF-1 and may raise IGF-
1 levels above the age-adjusted normal range [29,30].
●The majority of small pituitary adenomas do not grow during pregnancy
[31]. For women who have macroadenomas, we suggest monitoring visual
fields during each trimester of pregnancy. If visual fields show new defects,
MRI should be performed. If vision is newly impaired and growth of the
adenoma is the likely cause, surgery may be necessary.

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 ●Breastfeeding is a reasonable option for women who do not require
treatment hormone immediately after delivery.
Outcomes — When women with acromegaly do conceive, the majority appear to
have uncomplicated pregnancies, although data are limited [27]. In one
retrospective, multicenter study of 59 pregnancies in 46 women with GH-secreting
pituitary macroadenomas or less often microadenomas, 43 of the 46 women had
previously been treated with surgery or radiotherapy [31]. Prior to conception, GH
and IGF-1 hypersecretion was controlled in 23 (40 percent) and uncontrolled in 34
(60 percent) patients. Medical therapy was discontinued in early pregnancy in all
but four women. The following findings were noted:
●Pregnancy was uneventful for most women; the 59 pregnancies resulted in
64 healthy babies.
●No major neonatal malformations were encountered.
●Four women continued somatostatin analog therapy during pregnancy, all
gave birth to a small for gestational age infant.
●GDM and gestational hypertension, which developed in 7 and 14 percent of
pregnancies, respectively, was more common in women with active or
uncontrolled acromegaly. Among those who had postpartum MRI imaging
data available, only 2 of 22 (7 percent) showed an increase in pituitary tumor
size.
●Seventeen women breastfed with no complications.
In a second report of 13 pregnancies in women with acromegaly, similar findings
were seen; 10 of 13 received no medical therapy during the pregnancy. There were
no pregnancy complications and no congenital malformations, but one of the
three infants whose mother had received medical therapy (somatostatin analog)
had low birth weight [27].
REVIEW OF TREATMENT OPTIONS
Transsphenoidal surgery — Selective transsphenoidal surgical resection is the
treatment of choice for patients with somatotroph adenomas that are small, large
but still resectable, or large and cause visual impairment (algorithm 1)
[11,15,32,33]. Surgery may also be considered for large adenomas that are not
entirely accessible surgically (eg, those with cavernous sinus extension), with the
goal of removing a sufficient mass of tissue to increase the likelihood that
somatostatin analog treatment will be effective postoperatively. Some authorities
recommend somatostatin analog treatment preoperatively, although the studies
do not conclusively support this approach [34]. (See 'Role of primary medical
therapy' above.)
Transsphenoidal surgery has been widely employed to treat pituitary adenomas,
including somatotroph adenomas, since the 1970s. The approach during much of
423
this time has been sublabial and transseptal using an operating microscope.
During the past decade, an endoscopic approach has gained acceptance because it
provides superior visualization of the suprasellar compartment and cavernous
sinus walls. Studies describing patients treated for acromegaly by endoscopic
surgery suggest that although this approach is promising, outcomes for
acromegaly are not definitively superior to previously published microscopic series
[35,36]. (See "Transsphenoidal surgery for pituitary adenomas and other sellar
masses".)
Surgical cure rate — Accurate interpretation and comparison of studies reporting
surgical cure rates in patients with acromegaly is difficult since both the duration
of follow-up and the biochemical criteria for cure have varied. The current goal is a
serum insulin-like growth factor-1 (IGF-1) concentration normal for age and
gender and a serum growth hormone (GH) concentration less than 1 mcg/L or
lower by immunoradiometric or chemiluminescent assay.
The cure rate using these criteria is illustrated in a report of 57 patients followed
for at least 12 months postoperatively [37]. Surgical remission rates were 70, 67,
and 61 percent, as assessed by normal serum IGF-1, random serum GH
concentration <2.5 mcg/L, and glucose-suppressed GH concentration <1 mcg/L,
respectively [37].
Although summarizing surgical cure rates across studies is difficult for the reasons
noted above, the early cure rate in patients with acromegaly is 80 to 90 percent for
microadenomas and less than 50 percent for macroadenomas [3,7-
9,11,15,16,37,38].
Complications are reviewed above. (See 'Potential complications' above.)
Recurrence — Studies with several years of follow-up provide information on
recurrence rates. Approximately 3 to 10 percent of patients in whom the operation
is initially successful, as determined by normal basal and normal post-oral glucose
tolerance test (OGTT) serum GH concentrations, have a recurrence several years or
more after surgery, probably due to incomplete adenoma resection [7-9,11,37].
Higher rates of recurrence (eg, 19 percent) have been reported in series in which
initial surgical cure rates were lower than those cited above [38].
Even if the nadir of the serum GH concentrations after an OGTT is only slightly
above the target values, the risk of recurrence is greater, as illustrated by a study
of 77 patients with apparent biochemical remission after surgery (normal serum
IGF-1 concentrations) [39]. The patients were stratified according to the nadir
serum GH concentration after an OGTT. Fifty patients (group 1) were considered to
have a normal nadir GH (<0.14 mcg/L, based upon mean levels in normal, healthy
controls) and 26 had an abnormal nadir (>0.14 mcg/L, group 2). At a mean follow-

424
up of 3.2 years, the following results were seen in group 2 when compared with
group 1 patients:
●Higher mean hourly GH concentrations (based upon hourly GH sampling for
eight hours)
●Higher rate of recurrence, defined as an elevated serum IGF-1
concentration, in patients for whom data were available (5 of 19 versus 0 of
49)

Thus, patients with even subtle abnormalities in post-suppression GH levels may

have a greater risk of recurrence.

Medical therapy — Several medications are available for treating acromegaly,

including some that inhibit GH secretion and one that inhibits its action.
Pharmacologic treatment is used when surgery alone has not reduced serum GH
and IGF-1 to normal.
Patients for whom a medication can be considered as primary therapy include
those who have unacceptable surgical risk, refuse surgery, or have adenomas that
are unlikely to be cured surgically [1,40]. (See 'Role of primary medical
therapy' above.)
Somatostatin analogs — Octreotide and lanreotide are analogs of somatostatin
(GH-inhibitory hormone) that inhibit GH secretion more effectively than native
somatostatin because of their greater potency and longer plasma half-life (two
hours versus two minutes). Somatostatin analogs inhibit GH secretion by binding
to specific receptors for somatostatin and its analogs [41]. Their effect is greater
when the number of receptors is high [42,43]; repetitive administration does not
result in desensitization or loss of therapeutic efficacy [44].
Octreotide and lanreotide — Octreotide and lanreotide also cause pituitary
adenoma shrinkage in some patients. The mechanism of the shrinkage remains
unclear. In a study of tissue samples from 32 surgically resected somatotroph
macroadenomas, the mean growth fraction of adenomas exposed to octreotide
was 83 percent less than those not exposed [45]. However, in another report,
octreotide exhibited an antiproliferative effect but no effect on the apoptotic index
[46].
Dose and administration — Two somatostatin analogs, octreotide and lanreotide,
are widely available. The long-acting form of octreotide is given as an
intramuscular injection once a month. The initial dose is 20 mg once a month. If
the serum IGF-1 concentration does not decrease to normal within two months,
the dose can be increased to 30 mg and then to 40 mg a month.

425
Lanreotide is available in different forms in different countries. A deep
subcutaneous form (lanreotide autogel or depot) is given as 60 to 120 mg every
four to six weeks [47].
In a study of 30 patients with a partial response to a somatostatin analog, use
of high dose (180 mg/28 days) or high frequency (120 mg/21 days) both resulted
in normalization of IGF-1 in approximately 30 percent of subjects [48]. These
regimens were well tolerated, and adverse events were similar between the
groups. In a prior study, use of a high-dose, long-acting octreotide preparation (60
mg/28 days) resulted in normalization of IGF-1 in 36 percent of partial responders
[49]. Such regimen may be considered in such subjects.
Efficacy — Efficacy should be judged by normalization of the serum GH and IGF-1
concentrations, which should eventually be followed by regression of the soft
tissue manifestations of acromegaly and by shrinkage of adenoma size. The two
once-monthly preparations, octreotide long-acting release (LAR)
and lanreotide (autogel or depot) appear to be equivalent for control of
biochemical markers and symptoms [50].
●Predictors of response – Tumor subtypes may be a predictor of response to
somatostatin analog therapy. The densely granulated tumors are typically
smaller and more active (produce more GH) and respond well to
somatostatin analogs [51,52]. In contrast, the sparsely granulated subtype
tumors tend to be larger, more common in females and in younger patients,
more invasive, and are relatively less responsive to somatostatin analogs.
A hypointense T2 signal on magnetic resonance imaging (MRI) also appears
to be associated with a better response to somatostatin analog therapy when
given either pre- [53] or postoperatively [54].
●Biochemical improvement – Normalization of serum IGF-1 concentration
with somatostatin analogs occurs in 40 to 75 percent of patients. The success
rate varies markedly with study design, ranging in two reports from 38
percent in patients who were not preselected for responsiveness (figure 1)
[55] to a mean of 66 percent in a review of several studies, most of which
included patients who had been preselected for responsiveness to the short-
acting form [56]. Combined therapy with cabergoline and a somatostatin
analog may be effective when either alone is not [57].
●Improvement in symptoms – A somewhat greater percentage of patients
appear to experience improvement in symptoms with somatostatin analogs
than exhibit IGF-1 normalization, presumably because even a partial
decrease in GH results in some degree of symptomatic improvement [58].
(See 'Amelioration of symptoms' above.)

426
 Successful therapy is associated with an improvement in several signs and
symptoms during the year following a decrease in biochemical parameters
(see 'Amelioration of symptoms' above):
•Soft-tissue swelling, carpal tunnel syndrome, and snoring [56]
•Sleep apnea [59,60]
•Left ventricular mass and left ventricular function [61-63]
●Adenoma size – Somatostatin analog therapy leads to a reduction in
adenoma size of approximately 20 to 50 percent in 30 percent of patients
(figure 2 and image 1) [56]. In a 2005 systematic review of patients with
acromegaly receiving a somatostatin analog as primary medical therapy
(before or as an alternative to surgery and radiotherapy), approximately 37
percent experienced a significant reduction in adenoma size (mean 19
percent) [64]. In a subsequent study of 99 patients who received
somatostatin analogs as primary therapy, 45 percent had normalization of
serum IGF-1 concentration, and 44 percent had a >50 percent reduction of
adenoma size [65].
Side effects — Somatostatin analogs are usually well tolerated. Approximately
one-third of patients have nausea, abdominal discomfort, bloating, loose stools,
and fat malabsorption during the first several weeks of therapy, after which the
symptoms usually subside spontaneously with continued use [66].
Somatostatin analogs are associated with an increased risk of gallstone disease.
Up to 56 percent of patients develop asymptomatic cholesterol gallstones or
sludge during the first 18 months of therapy [56,67]. However, we do not suggest
routine abdominal ultrasound monitoring. We suggest ultrasound only if the
patient develops signs and symptoms suggestive of gallstone disease [2]. Less
common side effects include hair loss, constipation, and bradycardia.
Octreotide and lanreotide transiently inhibit insulin secretion, but their clinical
impact on glucose homeostasis is minimal. This was illustrated by a meta-analysis
of 18 trials in patients receiving these analogs for acromegaly. Fasting insulin
concentrations were significantly reduced and glucose levels were slightly higher
on an OGTT, but there were no significant changes in fasting glucose or glycated
hemoglobin (A1C) values [68].
Pasireotide — The somatostatin analog pasireotide is also effective in some
patients with acromegaly and is approved for its treatment, but it frequently
causes or worsens hyperglycemia.
In a 12-month trial of 358 patients with acromegaly (with no prior medical therapy)
receiving pasireotide LAR (40 mg once/month by intramuscular injection)
or octreotide LAR (20 mg/month intramuscular injection), biochemical control was
achieved in more patients receiving pasireotide when compared with octreotide

427
(31.3 versus 19.2 percent, respectively) [69]. Submaximal dosing of octreotide may
have contributed to its lower rate of biochemical control. Similar to what has been
observed in patients with Cushing's disease, hyperglycemia (often requiring insulin
treatment) was more common with pasireotide LAR than octreotide LAR (57.3
versus 21.7 percent). (See "Medical therapy of hypercortisolism (Cushing's
syndrome)", section on 'Pasireotide'.)
Oral octreotide — An oral formulation of octreotide (delayed-release capsules)
based on a transient permeability enhancer that enables bioactive gastrointestinal
absorption has been approved for use for the management of acromegaly [70].
This agent is indicated for long-term maintenance therapy in patients with
acromegaly who have responded to and tolerated treatment with either octreotide
or lanreotide.
It appears to be effective in some patients with acromegaly, but perhaps less so
than long-acting injectable preparations. In an open-label study of 155 patients
previously controlled on injectable somatostatin analogs, patients were switched
to oral octreotide capsules (40 mg/day in two divided doses, increased up to 80
mg/day as needed) [71]. Sixty-five percent (98 of 151) of the intent-to-treat
population achieved the primary endpoint of GH/IGF-1 control, compared with 91
percent (138 of 151) while taking long-acting injectable somatostatin analogs;
among the 91 patients who entered a subsequent fixed-dose phase (40 to 80 mg
daily), 85 percent (77 of 91) sustained control for up to a total of 13 months. The
adverse event profile was similar to that observed for injectable somatostatin
analogs.
Pegvisomant — Pegvisomant is a GH receptor antagonist that is a mutated GH
molecule to which polymers have been attached at several sites to prolong its half-
life [72]. The mutation results in increased affinity to site 1 on the GH receptor but
decreased binding to site 2. As a result, pegvisomant blocks native GH from
binding but does not activate the intracellular signaling that mediates its action.
Patients receiving pegvisomant should be monitored by measuring IGF-1 levels
(but not GH levels), as well as serial MRIs, to assure that there is no continued
tumor growth. In addition, liver function tests (LFTs) should be measured every six
months, and if more than threefold elevated, the drug should be discontinued.
Pegvisomant is administered as a daily, subcutaneous injection. The initial daily
dose is 10 mg. The serum IGF-1 concentration should be measured every four to
six weeks and the dose adjusted, in 5 mg increments, to a maximum of 30 mg/day,
to keep the serum IGF-1 within the normal range. Preliminary data suggest that
alternate-day dosing may be effective in some patients [73].
A number of factors affect the dose required to normalize serum IGF-1
concentrations [74]. Higher doses are needed the higher the baseline IGF-1

428
concentration and the greater the patient's weight, and women need higher doses
than men for the same weight. Lower doses are needed for patients who have had
radiation therapy (RT) for comparable IGF-1 values.
Serum GH cannot be used to monitor the effectiveness of treatment,
since pegvisomant inhibits the action of GH rather than its secretion.
Efficacy — Pegvisomant is an effective therapy for lowering serum IGF-1
concentrations. In a 12-week study of 112 patients, most of whom had received
other treatment, pegvisomant doses of 10, 15, or 20 mg daily resulted in dose-
dependent reductions in serum IGF-1 concentrations, as well as in fatigue, soft-
tissue swelling, perspiration, and ring size, compared with no changes in the
placebo group [75].
When the same patients and 48 others were treated with up to 40 mg/day for an
average of 425 days, 97 percent of those treated for 12 months or more achieved
normal IGF-1 concentrations (figure 3). This is a much higher response rate for IGF-
1 levels than achieved by any other therapy. At the same time, the serum GH
concentration increased by a mean 12.5 mcg/L [76].
The results in clinical practice may not be as good as in clinical trials. In an
international surveillance registry of 1288 patients with acromegaly
receiving pegvisomant for an average of 3.7 years [77], only 56.6 percent of
subjects had normal IGF-1 concentrations one year after beginning pegvisomant.
Because pegvisomant does not inhibit GH secretion and its use is associated with
an increase in the serum GH concentration, somatotroph adenoma size
presumably could continue to grow during its use. However, this appears to be
uncommon, as illustrated by the surveillance registry study cited above [77]. In 30
of 936 patients (3.2 percent) for whom MRI data were available, an increase in
adenoma size was noted in an average 2.1 years of follow-up. Based upon such
observations, patients receiving pegvisomant should have adenoma size assessed
by MRI at least once a year [78].
Safety — In the registry study noted above [77], 30 subjects (2.5 percent)
developed elevated liver enzymes greater than three times the upper limit of
normal. In the 23 subjects for whom follow-up data were available, liver enzymes
returned to normal after decrease or discontinuation of pegvisomant. There were
no reports of liver failure [77].
Pegvisomant should therefore not be prescribed to patients who have clearly
abnormal liver function, and patients who are treated should be monitored by
LFTs once a month during the first six months of treatment and every four to six
months thereafter. Pegvisomant has also been shown to be associated with
lipohypertrophy both at the injection site and at distant sites [79,80].

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Combination therapy — The combination of a long-acting somatostatin analog
and pegvisomant, in a few reports [81-83], decreased serum IGF-1 concentrations
to normal in a majority of patients, but the combination was not clearly better than
pegvisomant alone. For example, in 27 patients who were suboptimally controlled
while taking long-acting octreotide alone, randomization to either the combination
of the analog combined with pegvisomant or pegvisomant alone led to
normalization of IGF-1 in 62 and 56 percent, respectively [82]. The combination,
however, seems to be associated with a greater incidence of transaminase
elevations than either alone, as high as 38 percent [81-83].
Dopamine agonists — Dopamine agonists, especially cabergoline, may inhibit GH
secretion in some patients with acromegaly but do not work as well as
somatostatin analogs. However, their oral route of administration is an advantage
over the other treatments, which are administered parenterally. Cabergoline is the
most effective dopamine agonist for the adjuvant management of acromegaly and
is therefore the drug of choice in this category [84].
We currently suggest a trial of cabergoline, rather than somatostatin analogs
or pegvisomant, in patients with modest biochemical abnormalities, eg, GH
concentrations >1 mcg/L but <1.3 mcg/L and only mild symptoms of GH excess.
We also suggest cabergoline in combination with a somatostatin analog in
patients in whom somatostatin analog treatment alone has reduced serum IGF-1
concentrations almost to normal. This combination offers the possibility of
reducing the IGF-1 further to mid-normal with the addition of a relatively
inexpensive medication administered orally. (See 'Medical therapy' above.)
Cabergoline could also be tried as primary therapy in the occasional patient who
has only a mild elevation of IGF-1 and a small adenoma, is not a good candidate
for surgery, and refuses monthly injections of a somatostatin analog.
●Cabergoline dosing – The initial dose of cabergoline should be 0.5 mg once
a week or 0.25 mg twice a week. The dose should be increased, if necessary,
to 1 mg twice a week. Higher doses are not likely to decrease GH further [85].
The presence of hyperprolactinemia does not consistently predict GH and
IGF-1 response.
In a meta-analysis of 15 studies of cabergoline therapy in 227 patients with
acromegaly, cabergoline achieved normal serum IGF-1 levels in 51 of 149
patients (34 percent) [84]. In studies where cabergoline was added to a
somatostatin analog, 40 of 77 (52 percent) achieved normal IGF-1 levels.
However, these results should be interpreted with caution as some of the
studies included in the meta-analysis included poorly defined patient groups
and non-rigorous IGF-1 assays.

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 ●Side effects – The most common side effects of cabergoline are nausea,
light headedness, and mental fogginess. Less common are nasal stuffiness,
depression, and constipation. The high doses of cabergoline used in
Parkinson disease have been associated with valvular heart disease, but the
lower doses used for lactotroph adenomas have not. (See "Management of
hyperprolactinemia", section on 'Valvular heart disease' and "Initial
pharmacologic treatment of Parkinson disease", section on 'Limited role of
ergot dopamine agonists'.)
Radiation therapy — RT is effective in reducing the size of somatotroph
adenomas and decreasing GH and IGF-1 concentrations, often to normal, but
because the decreases in GH and IGF-1 usually take years to occur, we suggest its
use primarily for patients whose disease is not controlled by surgery or medical
therapy (algorithm 1) [86].
Types of radiation — The types of radiation therapy for pituitary adenomas,
radiation delivery systems, and their efficacy and side effects are reviewed in detail
separately. (See "Radiation therapy of pituitary adenomas".)
●Stereotactic radiosurgery (SRS) – Radiation can be administered as a single
dose (often called "stereotactic radiosurgery," or SRS, although there is no
surgery), by linear accelerator, gamma radiation, or protons. It has the
advantage of patient convenience and possibly faster control of hormonal
hypersecretion [86]. Gamma radiation has been available more widely than
the other forms of single-dose radiation (protons and x-radiation from a
linear accelerator), so more data are available about it. The most commonly
used stereotactic method used is the Gamma Knife.
A single dose of radiation cannot be used unless the adenoma is separated
by several millimeters from the optic chiasm and optic nerves (to limit the
exposure of the optic apparatus to less than 8 Gy), which would be severely
damaged by such a high dose, resulting in blindness. In this
situation, fractionated radiation must be used. (See "Radiation therapy of
pituitary adenomas".)
●Fractionated radiation therapy – Fractionated radiation therapy is the
delivery of radiation therapy in multiple, small, daily doses, usually five days
a week for five to six weeks. This is the way RT is delivered for most other
indications of radiation treatment.
●Delivery systems
•The linear accelerator is the most common device used for RT, ie, for
conventional radiation. Modifications have been made to deliver the
radiation to the desired location and dose. (See "Radiation therapy of
pituitary adenomas", section on 'Radiation delivery systems'.)

431
 •Gamma knife – Gamma Knife is an SRS treatment unit. Gamma radiation
can be administered from a cobalt source but only as a single, large dose.
Although this is called "Gamma Knife," there is no knife.
•Proton therapy – High-energy proton particles can be administered from
a cyclotron in either a single, large dose or multiple fractions.
•Use of somatostatin agonists during RT – It was suggested in an earlier
study that use of a somatostatin analog at the time of RT may limit its
effectiveness, but this consideration has been refuted by subsequent
studies [87-89]. However, most clinicians do hold somatostatin agonists
therapy while patients undergo RT.
Efficacy — Few patients who undergo fractionated radiation achieve the current
goal of therapy, ie, a basal serum GH concentration less than 1 mcg/L. Serum GH
and IGF-1 concentrations decline on average approximately 20 percent per year,
so that serum GH concentrations may not reach 5 to 10 mcg/L until 5 to 10 years
or more after treatment if the initial value is very high [90].
By 20 years after treatment, up to 90 percent of patients have serum GH
concentrations less than 5 mcg/L and 10 to 77 percent in different studies
eventually achieved serum GH concentrations <2.5 mcg/L (table 1) [90-94]. In one
series, as an example, only 5 of 30 patients (17 percent) followed for 10 or more
years reached this goal [95]. (See "Radiation therapy of pituitary adenomas",
section on 'Somatotroph adenomas (acromegaly)'.)
Normalization of the serum IGF-1 concentration occurs in approximately 55 to 70
percent of patients after 10 years, but the results vary among studies [91-94].
The efficacy of SRS appears to be similar to conventional RT. However, SRS may be
more appealing because the treatment duration is shorter. In three studies of 35
to 96 acromegalic patients followed after gamma radiation [96-98], cure rates
(defined as normal age- and gender-adjusted IGF-1 concentrations and basal GH of
<2.5 mcg/L or post-glucose load values of <1 mcg/L) were 46 to 60 percent in 5 to
10 years.

As with fractionated radiation, cure rates due to single-dose radiation are higher
the smaller the size of the adenoma and the lower the IGF-1 and GH.

Monitoring — Because the full therapeutic effect of the RT may take many years
and some patients may have limited response, it is important to perform annual
reassessment of radiation efficacy.

Once a normal serum IGF-1 level is achieved, medical therapy should be

withdrawn annually for one to three months (depending on the specific drug) for
reassessment of GH and IGF-1 levels.
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For patients who have undergone RT, we suggest annual pituitary hormone
testing to detect hypopituitarism, which is common post-RT. We also evaluate for
other delayed radiation effects such as cerebrovascular disease and cranial nerve
abnormalities.

Adverse effects
●Hypopituitarism – Within 10 years, approximately 40 percent of patients
treated with pituitary radiation develop deficiency of one or more pituitary
hormones [90,92], and the incidence continues to increase thereafter.
Gonadotropin deficiency is most common, followed by corticotropin (ACTH)
and then thyroid-stimulating hormone (TSH) deficiency. In the series of 884
patients, the percentage of patients with new hormone deficiencies 10 years
after irradiation were 18, 15, and 27 percent for luteinizing hormone
(LH)/follicle-stimulating hormone (FSH), ACTH, and TSH, respectively [90]. A
second study reported higher rates of hormone deficiencies, but patients had
more severe disease (higher baseline serum GH concentrations) and received
higher radiation doses (mean dose 52 Gy [92] versus 45 Gy [90]).
Hypopituitarism occurs after single-dose radiation, as it does with
fractionated, in approximately 40 percent of those treated by both gamma
and proton radiation [96,97,99].
●Other complications – Other complications are cranial-nerve palsies, loss of
vision, and memory deficits. All are rare and usually occur only when the dose
is high [92].
Second intracranial tumors have been reported in up to 1.7 percent of
patients within the first 10 years after pituitary radiation, a considerably
higher frequency (relative risk 16) than in normal subjects [100,101]. The
reported tumors include astrocytoma, glioblastoma, meningioma, and
sarcoma [14].
Some evidence points to RT as being a significant independent determinant
of overall mortality in acromegaly [102,103].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of acromegaly".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
433
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acromegaly (The Basics)")

●Beyond the Basics topics (see "Patient education: Acromegaly (Beyond the
Basics)")
Patients can also get information about pituitary adenomas and their
consequences from The Pituitary Society and The Endocrine Society.
SUMMARY AND RECOMMENDATIONSA summary of treatment effects is
provided in the table (table 1).
●For patients with a microadenoma, a macroadenoma that appears to be
fully resectable, or a macroadenoma threatening or impairing vision, we
recommend transsphenoidal surgery performed by a neurosurgeon with
considerable experience in pituitary surgery (algorithm 1) (Grade 1B).
(See 'Transsphenoidal surgery' above.)
●For patients with an adenoma that does not appear to be fully resectable
and for patients whose risk of surgery is great or who choose not to have
surgery, we suggest primary therapy with a long-acting somatostatin analog
(algorithm 1) (Grade 2B). (See 'Somatostatin analogs' above.)
●If transsphenoidal surgery results in normalization of serum insulin-like
growth factor-1 (IGF-1) concentration, we suggest no further therapy, but we
do suggest continued monitoring to detect a recurrence (Grade 2B).
(See 'Transsphenoidal surgery' above.)
●If transsphenoidal surgery does not normalize the serum IGF-1
concentration, we suggest medical therapy with a long-acting somatostatin
analog or growth hormone (GH) receptor antagonist. We suggest the
dopamine agonist cabergoline for mild disease (algorithm 1) (Grade 2B).
(See 'Additional therapy for residual disease' above.)
●If a somatostatin analog, with or without cabergoline, is ineffective, we
suggest pegvisomant alone or in combination with the somatostatin analog
(Grade 2B). (See 'Combination therapy' above.)
●If adenoma size increases or GH/IGF-1 hypersecretion persists despite
medical therapy (ie, somatostatin analog plus pegvisomant), we suggest

434
 radiation therapy (RT) or repeat surgery (algorithm 1) (Grade 2B).
(See 'Radiation therapy' above.)

For women who desire pregnancy:

●Pregnancy should be postponed, if possible, until GH and IGF-1 levels are

controlled and no residual tumor mass is seen. We suggest controlling the
serum GH and IGF-1 concentrations as tightly as possible before attempting
pregnancy to minimize the risk of gestational diabetes mellitus (GDM) and
gestational hypertension (Grade 2C). (See 'Pregnancy' above.)
●We suggest stopping medical therapy when pregnancy is confirmed (Grade
2C). The majority of adenomas do not grow during pregnancy. Short-
acting octreotide can be used during pregnancy, but only for control of
headache and adenoma size. (See 'Pregnancy' above.)
●Visual fields should be monitored during pregnancy in women with
macroadenomas starting at the end of the first trimester and every six weeks
thereafter. Magnetic resonance imaging (MRI), without contrast, should be
performed if visual field testing suggests a chiasmal lesion. If visual
impairment due to a chiasmal lesion is confirmed, surgery may be necessary.
(See 'Pregnancy' above.)

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Treatment of gonadotroph and other clinically
nonfunctioning adenomas
Author:
Peter J Snyder, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jul 30, 2021.
INTRODUCTIONGonadotroph adenomas are the most common pituitary
macroadenomas, comprising approximately 80 percent of clinically nonfunctioning
adenomas. These adenomas are difficult to identify because their secretory
products usually do not cause a recognizable clinical syndrome and because they
often secrete so inefficiently that serum concentrations of intact gonadotropins
and their subunits are often only minimally abnormal or not abnormal at all.
Consequently, they are typically not detected until they become sufficiently large
to cause neurologic symptoms, most often impaired vision due to pressure on the
optic chiasm. Clinically nonfunctioning or "silent" somatotroph and corticotroph
adenomas are also being identified with increasing frequency.
The treatment of gonadotroph and other clinically nonfunctioning adenomas will
be reviewed here. Their clinical manifestations and diagnosis are discussed
separately. (See "Clinical manifestations and diagnosis of gonadotroph and other
clinically nonfunctioning pituitary adenomas".)
INITIAL THERAPY: TRANSSPHENOIDAL SURGERY
Indications — Gonadotroph or other clinically nonfunctioning macroadenomas
are typically diagnosed when they become large enough to cause a neurologic
symptom (eg, visual loss, headache), a hormonal deficiency state, when an
imaging study is performed for an unrelated reason, or, less commonly, because
of hormonal hypersecretion.
For gonadotroph and other clinically nonfunctioning macroadenomas that are
impairing vision, we recommend transsphenoidal surgery because it is the only
treatment that can provide rapid relief of neurologic symptoms [1,2].
Transsphenoidal surgery reduces the size of the adenoma and its hormonal
hypersecretion in more than 90 percent of cases and improves vision in
approximately 80 percent [3].

436
For patients who have suprasellar extension but do not have neurologic
symptoms, we discuss the risks of surgery versus the risks of waiting. For example,
an adenoma that is markedly elevating the optic chiasm is very likely to begin to
cause visual abnormalities in the next few years, yet some patients will choose to
wait to undergo surgery until that occurs. Gonadotroph adenomas that are
asymptomatic and not an immediate threat to vision may not require immediate
surgery. (See 'Asymptomatic adenomas' below.)

Once identified, those with impaired vision should undergo transsphenoidal

surgery. Transsphenoidal surgery should be considered for those at high risk for
loss of vision (marked suprasellar extension).

The choice of transsphenoidal surgery procedure has evolved over time. The
microscopic technique was introduced first, but the endoscopic technique is now
considered the preferable approach because of better visualization. Transcranial
surgery is virtually never the preferred approach. This issue is discussed in more
detail separately. (See "Transsphenoidal surgery for pituitary adenomas and other
sellar masses", section on 'Surgical techniques'.)
Goals — The goals of treatment of a patient with a gonadotroph or clinically
nonfunctioning adenoma include:
●Relief of visual impairment or other neurologic symptoms.
●Removal of as much of the adenoma as possible to avoid recurrence.
●Replacement of hormonal deficiencies due to compression of
nonadenomatous pituitary cells by the macroadenoma. (See 'Postoperative
issues' below.)
Preoperative preparation — The most important aspects of the preoperative
preparation for pituitary surgery include:
●Confirming the sellar lesion is a gonadotroph or other clinically
nonfunctioning adenoma, which must be distinguished from a nonpituitary
lesion in or near the sella, which might best be approached differently.
Abnormalities that strongly suggest a gonadotroph adenoma include
elevated basal serum concentrations of intact follicle-stimulating hormone
(FSH) and alpha subunit and a response of either to exogenous thyrotropin-
releasing hormone (TRH), which is available only outside the United States.
Approximately 20 percent of gonadotroph adenomas will exhibit one or more
of these abnormalities. (See "Clinical manifestations and diagnosis of
gonadotroph and other clinically nonfunctioning pituitary adenomas",
section on 'Evaluation'.)
Clinically silent somatotroph adenomas can often be identified by elevated
serum levels of insulin-like growth factor 1 (IGF-1) [4] and clinically silent
437
 corticotroph adenomas by elevated levels of corticotropin (ACTH) [5].
(See "Clinical manifestations and diagnosis of gonadotroph and other
clinically nonfunctioning pituitary adenomas".)
●Identifying one of these biochemical markers can also be used to monitor
the response to surgery and subsequent therapy.
●Identifying a highly experienced pituitary surgeon.
(See 'Complications' below.)
●Identifying any pituitary hormone deficiencies that need to be treated
preoperatively, including hypothyroidism due to thyroid-stimulating
hormone (TSH) deficiency and hypocortisolism due to corticotropin (ACTH)
deficiency (algorithm 1). Hypothyroidism, which increases the risk of
respiratory insufficiency following postoperative administration of opiates or
barbiturates, should be corrected preoperatively, or pain medication should
be used in lower than usual doses. Hypocortisolism should be replaced
physiologically.
Glucocorticoid coverage — Because of the possibility that nonadenomatous
pituitary tissue could be removed inadvertently when attempting to remove the
large volume of adenoma, patients should be treated with 100 mg
of hydrocortisone beginning at the induction of anesthesia. The dose should be
gradually decreased during the next few days. We administer a replacement dose
(eg, 15 to 25 mg/day) following discharge until the initial postoperative evaluation
four to six weeks after discharge (algorithm 1).
Others recommend measuring serum cortisol on the third postoperative day, 24
hours after the previous dose of hydrocortisone, and if the value is low (less than 5
mcg/dL [138 nmol/L]) or borderline (5 to 15 mcg/dL [138 to 469 nmol/L]),
prescribing replacement hydrocortisone on discharge [6,7].
Exogenous hydrocortisone should be continued until a definitive determination of
adrenal status has been made.
Postoperative issues
Diabetes insipidus and SIADH — Both diabetes insipidus and the syndrome of
inappropriate antidiuretic hormone (SIADH) can occur shortly after
transsphenoidal surgery. Diabetes insipidus is most likely to occur within the first
two days after surgery and is usually transient but may be permanent. SIADH is
most likely to occur one week afterwards and is always transient. Rarely, a
"triphasic" response occurs, first diabetes insipidus, which then remits and is
followed by SIADH, which is followed by permanent diabetes insipidus [8,9].

The possibility of these abnormalities in vasopressin secretion dictate that any

patient who has transsphenoidal surgery be assessed frequently for these

438
conditions during the first week after surgery. In the first four days after surgery,
the patient should be asked about thirst, and fluid intake and output should be
recorded. If diabetes insipidus has not occurred by postoperative day 4, fluid
intake should then be restricted to 1 liter/day for the next three days, and the
serum sodium repeated on day 7. If the sodium is then normal, fluid restriction
can end.

Diabetes insipidus that occurs in the first day after surgery, when absorption
through the nasal mucosa is variable, should be treated
with desmopressin intravenously in doses from 0.25 to 1.0 mcg every 12 to 24
hours, titrated to keep urine volume and serum sodium normal. If diabetes
insipidus has not remitted by the time of discharge, the desmopressin can be
given as a nasal spray or orally.
Diabetes insipidus is more common than SIADH, occurring in 18.5 percent in one
series of 319 patients who underwent pituitary surgery at one institution [8] and
54.2 percent of 57 patients at another [10]. It usually occurs within the first 24
hours postoperatively and is usually transient but is sometimes permanent. In the
series of 319 patients, almost 50 percent had remitted in one week and
approximately 80 percent in three months [8].
SIADH occurred in 8.8 percent and 36.7 percent in the above two series [8,10]. In a
third series, in which sodium was measured routinely on postoperative day 7 in
241 patients, 23 percent had asymptomatic hyponatremia and 5 percent
symptomatic [9]. The mean serum sodium was 128 mmol/L in the asymptomatic
patients and 120 mmol/L in the symptomatic ones.
First evaluation post-discharge — Four to six weeks after discharge from the
hospital, the patient should be evaluated for the following:
●Amount of residual adenoma – A crude estimation of the amount of residual
adenoma can be determined by magnetic resonance imaging (MRI), but
artifacts of surgery may obscure the actual amount of residual adenoma
tissue for several months. A more accurate view is provided when the
artefacts of surgery have regressed three to six months later. Another
estimate of the amount of residual adenoma can be made by measuring the
serum concentration of any adenoma product that had been elevated before
surgery, such as FSH and alpha subunit for gonadotroph adenomas, IGF-1 for
clinically silent somatotroph adenomas, or ACTH for clinically silent
corticotroph adenomas.
●Visual function (by acuity and visual fields), performed by an
ophthalmologist.

439
 ●Hormonal function of the nonadenomatous pituitary, regardless of whether
it was normal or abnormal prior to surgery. This evaluation should include
measurements of:
Serum thyroxine (T4).
Early morning serum cortisol 24 hours after the previous dose
of hydrocortisone (algorithm 1).
•If the serum cortisol value is ≤5 mcg/dL (138 nmol/L), the patient has
secondary adrenal insufficiency (ACTH deficiency).
•If it is ≥15 mcg/dL (414 nmol/L), the patient has normal adrenal function,
and exogenous hydrocortisone can be discontinued.
•If it is between 5 and 15 mcg/dL (148 and 414 nmol/L) on a total of three
occasions, a test of ACTH reserve should be performed. Most clinicians
perform the cosyntropin stimulation test because of its ease of
administration. However, falsely normal results are sometimes seen in
patients with hypopituitarism in the first couple of weeks after pituitary
surgery [11]. The author of this topic prefers the metyrapone stimulation
test. (See "Diagnostic testing for hypopituitarism".)
●Serum estradiol in a premenopausal female.
●Serum testosterone in a male.

OUTCOMES OF SURGERY
Residual adenoma — Rates of complete adenoma removal are as low as 20
percent and as high as 65 to 75 percent, as surgical results vary widely by center
and surgeon. In a meta-analysis of 58 case series of patients with nonfunctioning
pituitary adenomas undergoing transsphenoidal surgery, complete removal of the
adenoma, as judged by the surgeon, was achieved in only 20 percent of cases [12].
More experienced surgeons and high-volume centers have higher rates of
complete removal (approximately 65 to 75 percent) [13,14].
If there is no or little discernible residual adenoma tissue by magnetic resonance
imaging (MRI) following surgery, the patient should be monitored by MRI and
hormonally, initially at six-month intervals. If there is considerable residual
adenomatous tissue, radiation should be administered. (See 'Adjuvant radiation
therapy' below.)
Long-term monitoring is necessary because the risk of adenoma regrowth is
significant, particularly after surgery alone. (See 'Long-term monitoring' below.)
Lifelong management of pituitary hormone deficiencies is required in many
patients. (See 'Adjuvant radiation therapy' below and 'Hormonal
abnormalities' below.)
Vision — Transsphenoidal surgery improves vision in approximately 80 percent of
patients [3]; improvement can be seen in the first few days after surgery [15,16]. If
440
vision was abnormal before surgery, it should be re-evaluated a month or two
afterward and less often until no further change occurs.
Hormonal abnormalities — Unlike the improvement in vision, improvement in
pituitary function is less likely. Preoperatively, the majority of patients have
pituitary hormone deficiencies, most commonly, growth hormone deficiency. In
the meta-analysis described above, in patients with preoperative pituitary
hormone abnormalities, 30 percent of patients experienced an improvement in
some hormone deficiency [12]. However, most patients are left with long-term
deficiencies that need replacement. In a systematic review of eight studies in over
1000 patients, the approximate frequencies of postoperative hormone deficiencies
were [3]:
●Growth hormone – 83 percent.
●Luteinizing hormone (LH)/follicle-stimulating hormone (FSH) – 60 percent.
Removal of the adenoma usually does not allow recovery of function of the
normal gonadotroph cells.
●Thyroid-stimulating hormone (TSH) – 30 percent.
●Corticotropin (ACTH) – 30 percent.
Although hormonal function four to six weeks after surgery usually indicates
function longer term, improvement may yet occur. In 109 patients who had
transsphenoidal surgery for pituitary adenomas and whose pituitary function was
tested before and periodically for a year after surgery, 15 had abnormal cortisol
response to cosyntropin six weeks afterwards, but five of those had a normal
cortisol response 12 months afterwards [17].
Complications — In the meta-analysis described above, the mortality rate in the
immediate postoperative period was 1 percent [12]. Serious complications
occurred in less than 5 percent of patients and included cerebrospinal fluid
leakage, fistula, meningitis, and new visual field defects.
The risk of complications is inversely proportional to the experience of the surgeon
in performing transsphenoidal surgery. In one study, 958 neurosurgeons reported
their own experiences in response to a questionnaire [1]. Both serious
complications (such as loss of vision and death) and less serious complications
(such as hormonal deficiencies) were higher among surgeons who had performed
fewer transsphenoidal procedures (table 1). For example, among neurosurgeons
who reported performing fewer than 200 transsphenoidal procedures, 1.2 percent
of procedures resulted in death, but among neurosurgeons who reported
performing more than 500 procedures, only 0.2 percent resulted in death.
A second study utilized a national database and found that among 825 surgeons
who performed 5497 operations, the complication rate was also less among
surgeons who performed more transsphenoidal procedures [18].

441
Recurrent adenoma — Approximately 20 percent of adenomas recur after
transsphenoidal surgery alone [12]; however, the risk of recurrence is much lower
if there is no MRI evidence of residual adenoma after surgery. Adjuvant radiation
therapy lowers the risk of recurrence. (See 'Adjuvant radiation therapy' below.)
ADJUVANT RADIATION THERAPY
Indications — Radiation therapy is useful in preventing regrowth of residual
adenoma tissue following transsphenoidal surgery. The decision whether to
recommend radiation is based on the amount and location of the residual tissue
by magnetic resonance imaging (MRI), the aggressiveness of the adenoma, and
the patient's age and general health. The MRI is performed three to six months
after surgery, when artefacts of surgery have regressed.
Radiation is also useful when there is evidence of adenoma regrowth in the
months or years after surgery. Radiation therapy is usually not employed as
primary therapy for gonadotroph and other clinically nonfunctioning pituitary
adenomas, because its effects occur too slowly for a patient with neurologic
symptoms. (See "Radiation therapy of pituitary adenomas", section on 'Clinically
nonfunctioning pituitary adenomas'.)
Types of radiation therapy — Radiation therapy can be administered from a
linear accelerator, which delivers photons; from a machine that delivers gamma
radiation from radioactive cobalt-60; or from a cyclotron or synchrotron that
delivers protons. Radiation can be delivered as a single high dose, which is
sometimes referred to a "stereotactic radiosurgery," or as multiple smaller
fractions, referred to as "fractionated." Each of these types of radiation can be
adjusted to the geometric shape of the lesion; terms used to describe these
adjustments are "stereotactic," "three-dimensional conformal," and "intensity
modulated."
Choice of radiation type — In deciding on the type of radiation for an individual
patient, the major choice is between single high-dose radiation and fractionated
radiation. The choice depends on the distance of the lesion from radiation-
sensitive tissues, such as the optic chiasm, and the size of the lesion. Lesions that
are only 3 to 5 mm from radiation-sensitive tissues, such as the optic chiasm, and
lesions that are 30 mm or more in diameter are more safely treated by
fractionated radiation.
Efficacy — Radiation appears generally effective in preventing regrowth of
clinically nonfunctioning pituitary adenomas following incomplete surgical
resection. No regrowth has been reported in 90 percent of patients after 5 to 10
years in patients treated by fractionated radiation from a linear accelerator [19-23]
or proton source [24] or by single high-dose radiation from a gamma source or
linear accelerator [25,26].
442
Adverse effects — All forms of radiation can cause delayed side effects.
Hypopituitarism is relatively common, and neurologic deficits are relatively
uncommon.
Pituitary hormonal deficiencies (hypoadrenalism, hypothyroidism, hypogonadism)
developed in approximately one-third of the subjects in three studies of
fractionated radiation during a median observation period of 40 or more months
[22-24]. In a multicenter study of single, high-dose gamma radiation, 86 of 410
patients with clinically nonfunctioning adenomas developed pituitary hormonal
deficiencies in a median follow-up time of 51 months [27]. The actuarial rates of
hypopituitarism were 7.8, 22.4, and 31.3 percent at 1, 5, and 10 years, respectively.
Neurologic deficits occur less commonly but are more serious. In a review of 35
studies that involved 1621 patients (452 with clinically nonfunctioning adenomas)
treated with single-dose radiation from a linear accelerator, gamma source, or
proton source, in which the median period of observation was <40 months in
approximately one-half and >40 months in approximately one-half, optic
neuropathy in approximately 1 percent, other cranial neuropathies occurred in
approximately 1.3 percent, and parenchymal brain damage (in the hypothalamus
and temporal lobe) occurred in approximately 0.8 percent [25].
LONG-TERM MONITORINGLong-term monitoring should include testing
every 6 to 12 months initially to detect growth of residual adenoma tissue and the
adequacy of hormonal replacement.
Adenoma regrowth — Evaluation for adenoma regrowth should include
measurement of whatever serum marker was elevated before surgery and
magnetic resonance imaging (MRI); if there is no regrowth after a year or two, the
interval between scans can be lengthened. Early detection permits appropriate use
of radiation therapy to minimize the need for repeat surgery. If MRI six months
after transsphenoidal surgery shows little adenoma tissue or the residual tissue is
not in a location of clinical significance, we recommend observation only by MRI,
initially yearly.
The frequency of regrowth of residual adenoma tissue varies but is more likely
when a patient does not have radiotherapy [12]. In one report of 91 patients with
nonfunctioning pituitary macroadenomas who underwent surgery but who did not
have radiotherapy afterwards, adenoma regrowth occurred in 10 percent of
patients; the mean time to adenoma regrowth was approximately six years [28]. In
two other series, of 491 and 159 patients, the recurrence rates were higher, 19 and
34 percent [13,29].
Not surprisingly, patients who have suprasellar extension of an adenoma are at
higher risk for recurrence following surgery [29,30]. Radiation therapy reduces this

443
risk but is associated with long-term morbidity and should not be used routinely.
(See 'Adjuvant radiation therapy' above.)
Quality of life — Quality of life has been reported to be reduced after long-term
cure of functioning pituitary adenomas [31,32]. Patients with nonfunctioning
pituitary macroadenomas treated successfully by transsphenoidal surgery alone or
combined with radiotherapy also have impaired quality of life when compared with
age-matched, healthy controls [33]. In addition, patients commonly experience
increased fatigue and daytime somnolence [34]. The impaired quality of life and
fatigue appear to be due to the underlying hypopituitarism [32], as well as
impaired sleep quality and abnormal distribution of sleep stages [35].
SPECIAL POPULATIONS
Aggressive tumors — Although most clinically nonfunctioning pituitary adenomas
causing symptoms are readily treated by surgery alone or surgery followed by
radiation, a very small number are unusually aggressive. These require
consultation with an oncologist for consideration of
chemotherapy. Temozolomide is the one chemotherapeutic agent that has been
shown to have some benefit in treating aggressive pituitary adenomas. A review
done in connection with development of clinical guidelines for management of
aggressive pituitary tumors by the European Society of Endocrinology reported
that in 11 studies, temozolomide reduced tumor volume in 47 percent of 106
patients [36].
Asymptomatic adenomas — Gonadotroph and other clinically nonfunctioning
adenomas that are asymptomatic and not an immediate threat to vision do not
require surgery, although hormonal deficiencies should be treated and re-
evaluation of adenoma size and pituitary function should be performed at yearly
intervals.
This situation is increasingly common because an increasing number of these
adenomas are detected as incidental findings when magnetic resonance imaging
(MRI) is performed for other reasons, such as head trauma. (See "Incidentally
discovered sellar masses (pituitary incidentalomas)".)
Only limited data are available on the natural history of nonfunctioning
macroadenomas because many patients who have them undergo surgery.
However, in studies that have monitored growth of these adenomas for more than
four to five years, approximately 50 percent of patients experienced adenoma
growth [3,37-39]. Thus, although watchful waiting may be appropriate in some
cases, long-term follow-up is necessary as adenoma growth can be anticipated in
50 percent.
In a small percent of cases, nonfunctioning adenomas may spontaneously regress.
In a review of 10 series, this occurred in 34 of 304 patients (11 percent) [3], while in
444
an individual series of 37 patients with five years of follow-up, four experienced
pituitary apoplexy [37].
THERAPIES NOT RECOMMENDEDThe extraordinary success of dopamine
agonists in reducing the size of, as well as secretion by, lactotroph adenomas has
prompted attempts to find a pharmacologic treatment for gonadotroph adenomas
(see "Management of hyperprolactinemia"). To date, however, no drug has been
found that consistently and substantially reduces the size of gonadotroph
adenomas.
Bromocriptine therapy for nonfunctioning adenomas has been disappointing
[3]; cabergoline may have some effect [40]. However, data are limited, and this
drug should not be considered an alternative to surgery. The cell membranes of
some clinically nonfunctioning pituitary adenomas have somatostatin receptors
[41,42], so two groups have administered octreotide (a somatostatin analog) to
such patients. One group found improvement in visual fields in three of four
patients, but no decrease in adenoma size [43]. The other group found decreases
in serum alpha subunit values in three of six patients and a reduction in adenoma
size and visual impairment in two each; there was, however, no correlation among
the three measurements [44].
Gonadotropin-releasing hormone (GnRH) agonists and antagonists have been
studied as potential therapies for gonadotroph-secreting adenomas; both are
ineffective. Administration of the GnRH antagonist, Nal-Glu GnRH, for six months
to men with gonadotroph adenomas normalized their high serum follicle-
stimulating hormone (FSH) concentrations but did not decrease the size of their
adenomas [45], suggesting that FSH secretion by gonadotroph adenomas, but not
adenoma size, is dependent upon endogenous GnRH. Administration of GnRH
agonist analogs to patients with gonadotroph adenomas usually has either an
agonist effect or no change in gonadotropin secretion and does not affect
adenoma size [46-48].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are

445
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pituitary adenoma (The Basics)")

SUMMARY AND RECOMMENDATIONS
●Transsphenoidal surgery – In patients with gonadotroph or other clinically
nonfunctioning pituitary adenomas that are large enough to cause
neurologic symptoms, such as visual field abnormalities, we recommend
transsphenoidal surgery as initial therapy (Grade 1B). The choice of surgical
procedure, microscopic or endoscopic, depends upon the neurosurgeon's
experience. (See 'Initial therapy: Transsphenoidal surgery' above.)
●Surgery versus waiting – For patients who have extrasellar extension but
do not have neurologic symptoms, we discuss the risks of surgery versus the
risks of waiting. For example, an adenoma that is markedly elevating the
optic chiasm is very likely to begin to cause visual abnormalities in the next
few years, yet some patients will choose to wait until that occurs. These
patients should be followed by magnetic resonance imaging (MRI) and visual
field examinations every 6 to 12 months. (See 'Indications' above.)
●Perioperative issues
•Preoperative hormonal deficiencies – Hormonal deficiencies due to
impaired function of the nonadenomatous pituitary should be replaced.
Whatever treatment is used, lifetime re-evaluation is needed.
(See 'Preoperative preparation' above.)
•Glucocorticoid coverage – Hydrocortisone should be administered in
high doses during surgery and doses gradually decreasing to replacement
within a few days. (See 'Glucocorticoid coverage' above.)
•SIADH and diabetes insipidus – For patients who undergo surgery, daily
postoperative monitoring for diabetes insipidus should be performed
until discharge and monitoring for syndrome of inappropriate antidiuretic
hormone (SIADH) at one week afterwards.
●Postoperative evaluation – Four to six weeks post-discharge, the patient
should again be evaluated for residual adenoma, hypocortisolism,
hypothyroidism, hypogonadism, and diabetes insipidus. In addition, the
patient should be evaluated for visual function and all other hormonal

446
functions of the nonadenomatous pituitary (algorithm 1). (See 'Postoperative
issues' above and 'First evaluation post-discharge' above.)
•Residual adenoma – If little or no residual adenoma tissue remains 6 to
12 months after surgery or if a larger amount remains but does not
threaten neurologic complications, we suggest monitoring the residual
tissue with MRI. (See 'Residual adenoma' above.)
•Adjuvant radiation therapy – If the residual tissue grows progressively,
we suggest adjuvant radiation therapy (Grade 2C). Administration of
radiation stereotactically should now be used exclusively. (See 'Adjuvant
radiation therapy' above.)
•Long-term monitoring – Long-term monitoring should include
assessment every 6 to 12 months initially to detect growth of residual
adenoma tissue and the adequacy of hormonal replacement. (See 'Long-
term monitoring' above.)
Evaluation for adenoma regrowth should include measurement of
whatever serum marker was elevated before surgery and an MRI; if there
is no regrowth after a year or two, the interval between scans can be
lengthened.
Hormonal hypersecretion by the adenoma preoperatively, when it occurs,
can be used to monitor the effects of treatment.
●Asymptomatic macroadenomas – For macroadenomas that are not
causing visual symptoms, we suggest yearly monitoring of pituitary function
and adenoma size (MRI). (See 'Asymptomatic adenomas' above.)
●Aggressive tumors – Although most clinically nonfunctioning pituitary
adenomas causing symptoms are readily treated by surgery alone or surgery
followed by radiation, a very small number are unusually aggressive. These
require consultation with an oncologist for consideration of chemotherapy.
(See 'Aggressive tumors' above.)

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Clinical features, diagnosis, and management of von
Hippel-Lindau disease
Authors:
Sharon E Plon, MD, PhD
Eric Jonasch, MD
Section Editors:
Michael B Atkins, MD
Helen V Firth, DM, FRCP, FMedSci
Ronald D Perrone, MD
Amar Gajjar, MD
Mitchell E Geffner, MD
Deputy Editor:
Sonali Shah, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 01, 2021.
What's New
Belzutifan for von Hippel-Lindau disease-associated tumors (October 2021,
Modified November 2021)
For patients with von Hippel-Lindau (VHL)-associated cancers, systemic treatment
options are limited. In a phase II trial of the hypoxia-inducible factor-2alpha
inhibitor belzutifan in 61 patients with VHL disease, objective response rates were 49
percent in systemic therapy-naïve renal cell carcinoma (RCC), 30 percent in central
nervous system (CNS) hemangioblastomas, and 91 percent in pancreatic
neuroendocrine tumors (pNET) [1,2]. Based on these data, the US Food and Drug
Administration approved belzutifan for adults with VHL disease who require therapy
for these tumors, but not immediate surgery. Our general approach is to use
belzutifan as an alternative to surveillance for rapidly growing tumors that could become
symptomatic if allowed to progress; for tumors not amenable to resection; and to delay
or defer local therapies such as surgery or radiation. (See "Clinical features, diagnosis,
and management of von Hippel-Lindau disease", section on
'Hemangioblastomas' and "Clinical features, diagnosis, and management of von Hippel-
Lindau disease", section on 'Pancreatic tumors' and "Clinical features, diagnosis, and
management of von Hippel-Lindau disease", section on 'Renal cell carcinomas'.)
Read more

INTRODUCTIONVon Hippel-Lindau (VHL) disease is an inherited, autosomal

dominant syndrome manifested by a variety of benign and malignant tumors. A
pathogenic variant in the VHL gene diagnostic for VHL disease is present in
approximately 1 in 36,000 individuals [1-3].
The initial manifestations of disease can occur in childhood, adolescence, or adulthood,
with a mean age at initial presentation of approximately 26 years [1]. The spectrum of
VHL-associated tumors includes:
●Hemangioblastomas of the brain (cerebellum) and spine
●Retinal capillary hemangioblastomas (retinal angiomas)
●Clear cell renal cell carcinomas (RCCs)

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 ●Pheochromocytomas
●Endolymphatic sac tumors of the middle ear
●Serous cystadenomas and neuroendocrine tumors of the pancreas
●Papillary cystadenomas of the epididymis and broad ligament
The different types of VHL disease, their clinical manifestations and management, the
genetic diagnosis of VHL, and appropriate surveillance protocols will be reviewed here.
The molecular biology and pathogenesis of VHL disease are discussed separately.
(See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
TYPES OF VHL DISEASEFamilies with VHL disease have been divided into
types 1 and 2, based upon the likelihood of developing pheochromocytoma [4]. Type 2
families are more likely to have a pathogenic variant encoding a missense change in
the VHL gene.
●Type 1 – Patients in kindreds with type 1 disease have a substantially lower risk
of developing pheochromocytomas (type 1A) and a lower risk of both
pheochromocytomas and renal cell carcinoma (RCC; type 1B), although they are
at high risk for the other VHL-associated lesions. Type 1B is due to a specific type
of deletion that includes the nearby BRK1 gene.
●Type 2 – Kindreds with type 2 disease are at high risk for developing
pheochromocytoma. Type 2 disease is subdivided based upon the risk of
developing RCC. Type 2A and 2B families have a low and high incidence of RCC,
respectively, while type 2C kindreds are characterized by the development of
pheochromocytomas only, without RCC or hemangioblastoma. These
subclassifications should be used as a guide and are not absolute. Continued
surveillance for other VHL-related lesions should continue, for example, in
individuals who present with type 2C characteristics.
The goal of improving survival and quality of life in patients with VHL disease has been
aided by a better understanding of the natural history of VHL-associated tumors [5]. As
a result, surveillance strategies have been developed and regularly updated for
individuals with VHL, which have led to the detection of small, asymptomatic tumors
prior to the development of metastases or other complications. In addition, therapeutic
advances (eg, renal-sparing surgery in RCC) have improved outcomes by decreasing
the incidence of renal failure when therapy is required. (See "Definitive surgical
management of renal cell carcinoma", section on 'Partial nephrectomy'.)
The molecular pathogenesis of VHL disease follows a "two-hit" model. Affected patients
have a germline loss of function variant that inactivates one copy of the VHL gene in all
cells. For disease to occur, there must be loss of expression of the second, normal
allele through somatic pathogenic variants or deletion of the second allele, or through
hypermethylation of its promoter. Further details on the molecular pathogenesis of VHL
disease is discussed separately. (See "Molecular biology and pathogenesis of von
Hippel-Lindau disease".)
OCCURRENCE AND AGE OF ONSET OF VHL-RELATED
LESIONSVHL-related lesions occur over a wide range of ages, as outlined in the
table (table 1) [6]. Age of onset of screening varies by lesion, with screening for retinal
lesions commencing in infancy and screening for other lesions starting slightly later.
(See 'Surveillance protocols' below.)
RENAL CELL CARCINOMAS
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Clinical presentation — Patients with VHL disease are at risk for developing multiple
renal cysts and renal cell carcinomas (RCC), which occur in approximately two-thirds of
patients [1]. Virtually all VHL-associated RCCs are clear cell tumors [2]. RCCs of
predominant papillary, chromophobe, or oncocytic histology are not associated with
VHL disease, but can be associated with other cancer susceptibility syndromes [7,8].
(See "Hereditary kidney cancer syndromes".)
Although the diagnosis of RCC is rare in VHL disease prior to age 20, there are teenage
cases of RCC, and thus, screening is now recommended to begin at age 15. RCC
occurs with increasing frequency thereafter [1,2,9]. The mean age at onset in one large
series was 44 years and it was estimated that 69 percent of patients surviving to age 60
would develop RCC [1]. The incidence of RCC is lower in patients who carry missense
changes in the VHL gene in which pheochromocytoma is prominent, although the same
surveillance recommendations apply independently of the type of pathogenic variant [4].
(See 'Types of VHL disease' above.)
RCCs are often multicentric and bilateral, and can arise either in conjunction with cysts
or de novo from noncystic renal parenchyma. Although renal cysts may be benign, they
are thought to represent a premalignant lesion; solid components within otherwise
benign-appearing renal cysts almost always contain RCC [10]. (See "Simple and
complex kidney cysts in adults".)
Histopathologic changes in the renal parenchyma are widespread and are not limited to
renal cysts [11]. Systematic microscopic analysis identified numerous clear cell
abnormalities, which are thought to be precursors for clear cell RCC. Similar clear cell
precursors were not seen in the renal parenchyma from patients with sporadic RCC or
from patients without RCC.
Growth kinetics of RCC in VHL patients were described in a series of 96 renal tumors in
64 VHL patients with analyzed germline pathogenic variants (54 out of 64 treated, 10
out of 64 active surveillance) over a mean follow-up of 55 months [12]. In this series, the
mean growth rate of 96 tumors was 4.4 mm/year (standard deviation [SD] 3.2, median
4.1 mm/year), and mean volume doubling time was 25.7 months (SD 20.2, median 22.2
months). Obviously, patients with larger lesions or faster growth rates need to have a
tailored approach to their follow-up.
The recommended surveillance strategy for early detection of suspicious renal cystic
lesions in patients with VHL disease is discussed below. (See 'Surveillance
protocols' below.)
Management — The management of patients with VHL disease and RCC is evolving.
Patients with VHL disease and renal masses should seek multidisciplinary care from
clinicians familiar with VHL management guidelines [13], including a nephrologist,
urologist, medical oncologist, and interventional radiologist. At the time of diagnosis, a
clinical geneticist should also be involved to ensure that the genetic diagnosis is secure
and appropriate strategies are in place to assess risk to other family members and offer
predictive genetic testing, where appropriate. Our approach to the management of
these patients is outlined below.
Locoregional tumors <3 cm
Surveillance — For patients with VHL disease and solid locoregional renal tumors <3
cm who are asymptomatic, we suggest initial surveillance rather than immediate surgery
or medical therapy (algorithm 1). These tumors can be monitored every three to six

450
months with magnetic resonance imaging (MRI) of the abdomen; once stability of the
lesions is confirmed over at least three consecutive scans, surveillance imaging can be
extended to every two years [13].
Solid renal tumors <3 cm in diameter that remain stable can be safely monitored as they
generally have very low metastatic potential. As an example, in one study, serial
imaging studies were performed in 96 patients with VHL disease and small renal tumors
[14]. Surgery was performed in 52 patients when a tumor reached a threshold size of 3
cm in diameter. At median follow-up of 60 months, only two patients required
nephrectomy, and none developed metastatic disease. In the remaining 44 patients, this
size threshold was not used as an indication for immediate surgery. In this group, at
median follow-up of 66 months, 12 patients required nephrectomy, and 11 developed
metastatic disease. (See "Diagnostic approach, differential diagnosis, and management
of a small renal mass".)
Belzutifan — For patients with VHL disease and solid locoregional renal tumors <3 cm
with accelerated tumor growth or for those who desire a more aggressive management
strategy, we offer belzutifan as an alternative to surveillance (algorithm 1). Although
there are no formal criteria, some experts define accelerated tumor growth as greater
than 5 millimeters per year. In these patients, belzutifan is effective, has durable
responses, and may be used to potentially postpone or avoid future surgical
interventions.
Belzutifan specifically inhibits hypoxia-inducible factor-2alpha (HIF-2alpha) , a key
protein regulated by the VHL pathway (figure 1). Belzutifan is administered orally at 120
mg daily until disease progression or unacceptable toxicity. Hypoxia and anemia are
common on-target toxicities associated with therapy and are managed as follows:
(See "Molecular biology and pathogenesis of von Hippel-Lindau disease", section on
'Molecular biology and pathogenesis'.)
●Management of anemia – Anemia can be managed by withholding belzutifan for
hemoglobin <9 g/dL, if a red blood cell transfusion is indicated, or in the event of
an urgent surgical intervention. Upon recovery of the hemoglobin to ≥9 g/dL,
belzutifan may be resumed at 120 mg daily. Belzutifan may be reduced to a dose
of 80 mg for anemia that is refractory to therapy or permanently discontinued,
depending upon the severity of the anemia. (See "Indications and hemoglobin
thresholds for red blood cell transfusion in the adult", section on 'Oncology
patient'.)
For patients who develop anemia on belzutifan, we also offer the use of
erythropoiesis-stimulating agents (ESAs), as these agents are highly effective in
treating anemia and can reduce the need for red blood cell transfusion in our
clinical experience. However, this approach diverges from the US Food and Drug
Administration label, which does not recommend the use of ESAs with this drug
due to limited safety data [15]. The indications for ESAs in the treatment of anemia
in patients with cancer are discussed separately. (See "Role of erythropoiesis-
stimulating agents in the treatment of anemia in patients with cancer".)
●Management of hypoxia – For patients with asymptomatic hypoxia, we
continue belzutifan and closely monitor oxygen saturation. For patients with
persistent or symptomatic hypoxia (pulse oximeter <88 percent or partial pressure
of oxygen [PaO2] <55 mmHg at rest or with exercise), we offer a dose reduction of

451
 belzutifan to 80 mg and oxygen therapy as indicated. (See "Long-term
supplemental oxygen therapy", section on 'Prescribing oxygen'.)
In an open-label phase II trial (Study 004) of 61 patients with VHL disease and systemic
therapy-naïve RCC, at median follow-up of 22 months, belzutifan demonstrated an
objective response rate of 49 percent, which were all partial responses [15,16], and two-
year progression-free survival of 97 percent. The median time to response was eight
months, and over half of patients (56 percent) experienced ongoing durable responses
lasting one year or longer. Grade ≥3 treatment-related toxicities included anemia and
hypertension (8 percent each), fatigue (5 percent), as well as dyspnea and myalgias (2
percent each) [16].
Based on these data, the FDA granted regulatory approval to belzutifan in adult patients
with VHL disease who require therapy for associated RCC and do not require
immediately surgery [15]. Belzutifan also has FDA approval for VHL-associated central
nervous system hemangioblastomas and pancreatic neuroendocrine tumors.
(See 'Hemangioblastomas' below and 'Pancreatic tumors' below.)
Locoregional tumors ≥3 cm
Nephron-sparing approaches — For patients with VHL and locoregional RCC greater
than or equal to 3 cm, we recommend a nephron-sparing approach rather than radical
nephrectomy (algorithm 1). We offer partial nephrectomy to patients who elect a
surgical approach. For those who elect nonsurgical therapy, options include cryotherapy
and radiofrequency ablation.
The therapeutic approach to locoregional RCC in patients with VHL disease has shifted
from radical nephrectomy to nephron-sparing approaches (eg, partial nephrectomy,
cryotherapy, and radiofrequency ablation) to preserve as much kidney parenchyma as
possible and reduce the risk of chronic kidney dysfunction [9,14,17,18]. Nephron-
sparing approaches are preferred for those with VHL disease, who are at risk for
bilateral and recurrent tumors, and are also extrapolated from data in those with
sporadic RCCs. (See "Definitive surgical management of renal cell carcinoma", section
on 'Partial nephrectomy' and "Definitive surgical management of renal cell carcinoma",
section on 'Partial versus radical nephrectomy'.)

Several factors have contributed to this change:

●Improved imaging modalities (eg, computed tomography [CT], MRI, and

ultrasound), combined with regular surveillance programs, have led to the
identification of more RCCs at an early stage.
●Partial nephrectomy appears to be as effective as total nephrectomy for early
stage RCC. Repeated partial nephrectomies may be feasible in carefully selected
patients to preserve kidney parenchyma and avoid dialysis [18]. The rationale and
results with partial nephrectomy for patients with RCC are discussed separately.
(See "Definitive surgical management of renal cell carcinoma", section on 'Partial
nephrectomy'.)
●Other nephron-sparing approaches, particularly cryoablation and radiofrequency
ablation, may permit the eradication of multiple small tumors while minimizing
damage to the normal kidney. (See "Radiofrequency ablation and cryoablation for
renal cell carcinoma".)

452
Continued close surveillance is required after treatment of RCC in VHL patients. New
kidney tumors are detected in approximately 30 percent of patients by five years and 85
percent by 10 years. The risk of metastatic disease appears to be low as long as the
patient is carefully monitored. However, in one report of 21 such patients, two
developed metastatic disease at a median follow-up of 29 months [9].
Indications for belzutifan — For patients who are not candidates for further surgery or
other nephron-sparing approaches, we alternatively offer systemic therapy
with belzutifan (algorithm 1). Candidates for this approach include patients with multiple
prior surgeries, or those with lesions in a solitary remaining kidney where further
locoregional interventions would render the patient anephric. The use of this agent is
discussed above. (See 'Belzutifan' above.)
Indications for kidney transplantation — Kidney transplantation has been used in
patients with VHL disease who required bilateral nephrectomy for RCC or developed
end-stage kidney disease. Experience is limited, because of concerns that
immunosuppressive therapy might enhance the risk of tumor recurrence. However, this
concern was not borne out in at least one study of 32 patients with VHL disease who
received kidney transplants and 32 matched transplant recipients without VHL disease
[19]. At an average follow-up of four years, no differences were observed between the
two groups in graft and patient survival or kidney function. (See "Kidney transplantation
in adults: Overview of care of the adult kidney transplant recipient".)
Metastatic disease — There are limited clinical trials evaluating systemic therapy in
patients with VHL disease and metastatic RCC, and the management of these patients
is extrapolated from the approach used for sporadic metastatic RCC. (See "Systemic
therapy of advanced clear cell renal carcinoma" and "Antiangiogenic and molecularly
targeted therapy for advanced or metastatic clear cell renal carcinoma".)
Data from early phase clinical trials suggest that antiangiogenic agents such
as sunitinib and pazopanib are effective in patients with VHL disease and metastatic
RCC [20,21]. With the advent of vascular endothelial growth factor (VEGF)-targeted
therapy that can decrease the size of RCC lesions, it may be possible to decrease the
frequency of surgical intervention through chronic or intermittent use of certain agents.
●Sunitinib – In a clinical trial of 15 patients with VHL disease treated
with sunitinib, partial responses were seen in 6 of 18 patients with RCC (33
percent) [21].
●Pazopanib – In a phase II trial of 31 patients with VHL disease treated
with pazopanib, the RCC lesional response rate was 52 percent [20].
●Is there a role for belzutifan? – Belzutifan, a HIF-2alpha inhibitor, does not
have regulatory approval in patients with metastatic RCC, and further data are
necessary in this patient population.
HEMANGIOBLASTOMAS
Clinical presentation — Hemangioblastomas are well-circumscribed, capillary vessel-
rich benign neoplasms, which do not invade locally or metastasize. However, they can
cause symptoms through pressure on adjacent structures and through hemorrhage, due
to either the hemangioblastoma itself or cyst formation around the lesion. The clinical
presentation and management of sporadic hemangioblastomas are discussed
elsewhere. (See "Hemangioblastoma".)

453
Hemangioblastomas are the most common lesions associated with VHL disease,
affecting 60 to 84 percent of patients, and typically occur in the cerebellum, spinal cord,
or retina [1,2,22]. Patients with VHL-associated hemangioblastomas tend to be younger
than those with sporadic hemangioblastomas with a mean age at diagnosis in one
series of 29 years, and a range of 9 to 78 years of age [1]. While sporadic
hemangioblastomas usually are solitary and generally do not recur after surgery, lesions
in patients with VHL disease tend to be infratentorial and multiple [23]. In a detailed
analysis of 160 patients with VHL disease and hemangioblastoma, 655 discrete tumors
were identified, of which 51 percent were in the spinal cord, 38 percent in the
cerebellum, 10 percent in the brainstem, and 2 percent supratentorial [22].
In a cohort of 188 consecutive patients presenting with a seemingly sporadic
hemangioblastoma, no family history of VHL, and no other evidence of the
disease, VHL germline pathogenic variants were present in 5 percent of cases [24]. Of
those who tested negative, 5 percent developed a VHL-related lesion in the ensuing
years, which may result from being mosaic for a VHL pathogenic variant. (See 'Patients
with somatic mosaicism' below.)
Thus, we recommend that all patients with either a retinal or central nervous system
(CNS) hemangioblastoma be tested for VHL germline pathogenic variants, even in the
case of a single lesion, given the high sensitivity and specificity of the testing. Where
access to genetic investigations is limited, it would be reasonable to focus testing on
patients with lesions presenting under the age of 50 years since the likelihood of
identifying a germline VHL pathogenic variant is inversely correlated with the age of the
patient.
Because CNS hemangioblastomas often initially develop in the second decade, routine
screening with magnetic resonance imaging (MRI) of the brain and spinal cord is
recommended in patients with VHL disease starting at age 11 years. (See 'Surveillance
protocols' below.)
Management
General approach — Patients with VHL are at risk for CNS hemangioblastomas in
deep and critical locations within the brainstem, cerebellum, and spinal cord. They are
at risk for slow, asymptomatic progression as well as for sudden deterioration due to
hemorrhage or cyst expansion. Some patients present with a symptomatic
hemangioblastoma as the first sign of VHL disease, while others are diagnosed later
through surveillance imaging or development of new neurologic symptoms.
(See "Hemangioblastoma", section on 'Treatment'.)
Because patients frequently develop multiple lesions, therapeutic efforts should focus
on avoiding treatment-related morbidity by minimizing the frequency of surgical
interventions. Although surgery can usually successfully remove lesions in the spinal
cord, brainstem, and cerebellum, intervention is reserved until lesions become
symptomatic or they display accelerated growth [22,23,25,26]. Patients who
demonstrate progression by CNS imaging should be followed at more frequent intervals
for evidence of clinical symptoms.
Surveillance and risk of progression — For patients with imaging evidence of one or
more hemangioblastomas who are asymptomatic and/or have indolent tumor growth,
we suggest surveillance with serial imaging rather than surgical or medical therapy.
Surveillance imaging with MRI can be obtained for these patients either annually or

454
more frequently as appropriate [13].Surveillance allows the deferral of therapy and its
associated toxicity until the development of more compelling disease progression, such
as tumor-related symptoms or accelerated growth.
Belzutifan, a hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitor, is a reasonable
alternative to surveillance for patients with tumors that could become symptomatic if
allowed to progress, or for those who wish to delay or defer future surgery. Small,
asymptomatic tumors should not be preemptively treated with radiation therapy (RT)
[27]. (See 'Symptomatic or progressive disease' below.)
CNS hemangioblastomas can remain dormant for unpredictable periods of time or can
present with accelerated growth [22,28]. There are no definitive clinical (eg, age, sex,
location), radiographic, or specific molecular markers (ie, underlying pathogenic
variants) that can predict the natural history of a given lesion. Therefore, regular follow-
up with imaging and observation of clinical signs and symptoms is necessary.
(See 'Surveillance protocols' below.)
A review of 225 patients with 1921 CNS hemangioblastomas demonstrated that 51
percent of lesions did not grow. In the remaining 49 percent of hemangioblastomas, 72
percent grew in a saltatory (stepwise), 6 percent in a linear, and 22 percent in an
exponential fashion [29]. Partial germline deletions and male sex were associated with
increased tumor burden. The unpredictable nature of hemangioblastoma growth
emphasizes the need for ongoing surveillance in these patients.
Symptomatic or progressive disease — For patients with VHL and symptomatic
and/or progressively enlarging CNS hemangioblastomas, options for therapy include
surgery, radiation therapy, and systemic agents (eg, belzutifan). VHL-associated
hemangioblastomas are best managed in a multidisciplinary fashion with input from
neurosurgeons, interventional neuroradiologists, radiation oncologists, and
neurooncologists with expertise in central nervous system malignancies.
(See "Hemangioblastoma", section on 'Treatment'.)
While surgery and radiation therapy have traditionally been first-line therapies for
progressive CNS disease, our approach is evolving with the development of effective
systemic therapies with CNS activity (eg, belzutifan).
Indications for surgery — Surgery is typically required for patients with
hemangioblastomas that are causing significant neurologic symptoms or are threatening
compromise due to mass effect or hemorrhage. Surgical management of
hemangioblastomas is discussed separately. (See "Hemangioblastoma", section on
'Surgery'.)
Patients with enlarging, operable tumors who do not have an immediate risk for decline
are good candidates for belzutifan in an effort to delay or avoid surgery.
(See 'Belzutifan' below.)
Belzutifan — For most patients with symptomatic or rapidly enlarging CNS
hemangioblastomas that are unresectable or pose a high risk of postoperative deficits,
we suggest a trial of systemic therapy with the HIF-2alpha inhibitor, belzutifan, rather
than initial RT or an attempt at high-risk surgical debulking. Belzutifan is also
appropriate in patients with recurrent/refractory tumors after surgery or RT.
The management of toxicities associated with belzutifan are discussed separately.
(See 'Belzutifan' above.)

455
Belzutifan has shown evidence of effective and durable responses in the CNS. A phase
II study (Study 004) of 61 patients with systemic therapy-naïve VHL-associated renal
cell carcinoma (RCC) included a subset of 50 patients with measurable CNS
hemangioblastoma [15,16]. At median follow-up of 22 months, among this subset,
objective responses were seen in 15 patients (30 percent), including three complete (six
percent) and 12 partial responses (24 percent) [16]. The median time to response was
three months, and approximately three-quarters of patients (73 percent) experienced
durable responses lasting one year or longer.
Based on these data, the US Food and Drug Administration (FDA) granted regulatory
approval to belzutifan in adult patients with VHL disease who require therapy for
associated CNS hemangioblastoma and do not require immediate surgery [15].
Belzutifan also has regulatory approval from the FDA for VHL-associated RCC and
pancreatic neuroendocrine tumors. (See 'Renal cell carcinomas' above and 'Pancreatic
tumors' below.)
Radiation therapy — Stereotactic radiosurgery (SRS) and conventional fractionated
RT play a selective role in treating recurrent/refractory lesions that are not readily
accessible by surgery and/or have failed belzutifan [30,31].
There are limited randomized prospective studies that compare the long-term efficacy
and safety of SRS with conventional RT for hemangioblastomas. In a prospective
observational study performed at the National Institutes of Health, diminishing tumor
control over time was observed in lesions treated with SRS [30].
Further details on the use of RT in patients with hemangioblastoma are discussed
separately. (See "Hemangioblastoma", section on 'Radiation therapy'.)
Antiangiogenic agents — Antiangiogenic agents such as pazopanib and sunitinib are
less preferred options, as they have limited efficacy in these neoplasms.
(See "Hemangioblastoma", section on 'Antiangiogenic therapy'.)
●Pazopanib – Pazopanib does provide clinical benefit in individuals with CNS
hemangioblastomas, but should be used with caution. Preclinical and
observational data suggested that pazopanib, which possesses modest inhibition
of fibroblast growth factor receptors (FGFRs), may provide some value in the
management of hemangioblastomas [32]. In a phase II trial of 31 patients with
VHL disease, pazopanib demonstrated a partial response in 4 percent of those
with hemangioblastomas and stabilization of disease in the majority of patients,
but resulted in CNS bleeding in two patients [20].
●Sunitinib – A prospective clinical trial with sunitinib, an antiangiogenic agent,
failed to demonstrate response in hemangioblastomas, although this class of
agents is active in RCCs [21].
RETINAL CAPILLARY HEMANGIOBLASTOMAS
Clinical presentation — Retinal capillary hemangioblastomas are typically found either
in the peripheral retina and/or the juxtapapillary region. Visual loss from retinal capillary
hemangioblastomas is generally caused by exudation from the tumor, causing retinal
edema or by tractional effects, in which glial proliferation on the surface of the tumor
induces retinal striae and distortion [33]. In addition, retinal capillary
hemangioblastomas can hemorrhage, leading to retinal detachment, glaucoma, and
loss of vision.

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Retinal capillary hemangioblastomas are found in up to 70 percent of VHL patients by
age 60 years; they are often multifocal and bilateral. Compared with patients with
sporadic retinal hemangioblastomas, patients with VHL are much younger and more
likely to have multiple lesions. In one series of 31 patients with VHL and 37 patients
without VHL disease, the VHL patients were younger (18 versus 36 years of age,
respectively), had an average of four tumors, and were more likely to develop new
tumors than those without the disease [34].
In a study of 890 patients with VHL disease, 335 patients had a retinal capillary
hemangioblastoma in at least one eye. Lesions were detected unilaterally in 42 percent
and bilaterally in 58 percent of affected patients. No correlation was detected between
the age, gender, or laterality of involvement. Of involved eyes, 87 percent had tumors
that could be individually visualized; of these, tumors were commonly found in the
peripheral retina (85 percent) only, and less commonly in the juxtapapillary area (15
percent). The tumor count in the periphery averaged 2.5+/-1.8 per eye, with 25 percent
of eyes having more than one quadrant of retinal involvement [35]. An assessment of
the genotype-phenotype relationship in retinal capillary hemangioblastoma suggested
that 15 percent of individuals with variants that result in complete loss of VHL protein
had hemangioblastoma development versus an overall prevalence in the patient
population of 37 percent. The risk of vision loss was found to increase with age although
tumor number did not increase significantly as a function of age.
As is the case with seemingly sporadic central nervous system (CNS)
hemangioblastomas, any patient presenting with a retinal capillary hemangioblastoma
(particularly if prior to age 40) should undergo germline genetic testing for pathogenic
variants in the VHL gene. (See 'Clinical presentation' above.)
Routine surveillance for retinal capillary hemangioblastoma is recommended for
patients with VHL disease because of its high frequency. The frequent onset of such
lesions during childhood makes it important to initiate ophthalmologic surveillance in the
pediatric population upon making the diagnosis, and it is one of the reasons that genetic
testing for VHL pathogenic variants in young children is recommended.
(See 'Surveillance protocols' below.)
Management — The treatment of retinal capillary hemangioblastoma requires that the
benefits of treatment be balanced against potential treatment-related complications.
Data are controversial for whether small lesions can be carefully observed without
specific treatment until there is any evidence of growth or symptoms [36]. Some groups
recommend that retinal capillary hemangioblastoma be treated immediately upon
detection (in order to prevent growth and complications) whereas others wait for some
change in size before initiating treatment. For those who initiate treatment, we suggest
laser photocoagulation rather than other therapies. Other alternative options include
photodynamic therapy or radiation therapy (RT; particularly for salvage therapy).
Systemic therapy with belzutifan is an acceptable option for patients who are ineligible
for local therapy due to tumor proximity to the optic nerve or multiple progressive
lesions. Clinical trials are encouraged, where available.
●Local therapies – Laser photocoagulation is effective in over 70 percent of
cases, generally with a single treatment, and is the preferred method of treatment
[36]. An exception is that hemangioblastomas of the optic nerve should not be
treated with these methods because of the deleterious side effects on the normal

457
 retina. Photodynamic therapy can also be considered as an option in the
treatment of retinal capillary hemangioblastoma, although limited data exist on its
efficacy. External beam RT may have a role for salvage therapy if other modalities
have failed [37].
●Belzutifan – Belzutifan, a hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitor,
is an option for patients with retinal capillary hemangioblastomas that are close to
the optic nerve or those with multiple progressive hemangioblastomas; such
patients are typically ineligible for local therapies. In a phase II study, belzutifan
improved disease in all 16 eyes (100 percent) in 12 patients with evaluable retinal
hemangioblastomas [16].
The management of toxicities associated with belzutifan is discussed separately.
(See 'Belzutifan' above.)
●Investigational therapies (antiangiogenic agents) – Further investigational
studies are needed to better understand the biology of the hemangioblastoma cell
of origin and its endothelium, as well as to develop active systemic therapies.
Several vascular endothelial growth factor (VEGF) receptor inhibitors which
interfere with angiogenesis, such as sunitinib, pazopanib, bevacizumab,
and ranibizumab, have demonstrated limited efficacy in retinal hemangioblastoma
[20,21,38,39]. (See "Hemangioblastoma", section on 'Antiangiogenic therapy'.)
PHEOCHROMOCYTOMAS
Clinical features — Pheochromocytomas are seen both sporadically and in association
with a number of genetic syndromes, including VHL disease, multiple endocrine
neoplasia type 2, pathogenic variants of the succinate dehydrogenase (SDH) subunits
A, B, D, and C, neurofibromatosis type 1, and other rare conditions. The different
familial syndromes manifesting pheochromocytomas are discussed in detail elsewhere.
(See "Pheochromocytoma in genetic disorders".)

All patients with pheochromocytoma should have a genetic evaluation to identify the
underlying syndrome so that proper surveillance can be initiated for other tumors for
which the patient is at risk. Given the increasing number of genes associated with these
tumors, genetic testing generally relies on a multigene next-generation sequencing
(NGS) panel for making the appropriate genetic diagnosis. The presence of
pheochromocytoma is used to define types 2A-C VHL disease.

In one evaluation of 271 patients with apparently sporadic pheochromocytoma (no other
tumors or family history of the disease) from population-based registries in Germany
and Poland, all were tested for germline pathogenic variants in VHL and three of the
other genes (RET, SDHB, SDHD) that have been implicated in familial
pheochromocytoma [40]. A germline VHL pathogenic variant was identified in 30
patients overall (11 percent) and in 42 percent of those who presented at age 18 or
younger. A positive family history had been established at last follow-up in 12 of the 30
patients and at least four others had a de novo germline VHL pathogenic variant since
both parents tested negative. (See "Clinical presentation and diagnosis of
pheochromocytoma".)
Pheochromocytomas in VHL disease tend to be seen in younger patients, are often
multiple, may be extra-adrenal, and are less likely to be associated with symptoms or
biochemical evidence of catecholamine production compared with those occurring in
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patients without VHL [41-45]. Pediatric cases of pheochromocytomas are not infrequent
[46,47].

Two large series illustrate the clinical characteristics of pheochromocytomas in patients

with VHL disease:

●In a report from the National Institutes of Health of 64 patients with VHL disease
and pheochromocytomas, a total of 106 tumors were identified [43]. Of these, 12
percent originated outside the adrenal gland and 35 percent of patients were
asymptomatic, without hypertension or evidence of increased catecholamine
production.
●Experience reported by the Mayo Clinic found that 20 of 109 patients with VHL
disease (18 percent) had a pheochromocytoma at a median age of 30 years,
including three originating outside the adrenal gland [42]. Detailed analysis of
these patients failed to reveal evidence of catecholamine production in one-third.
Tumors that produce catecholamines may be associated with the typical clinical signs
and symptoms of pheochromocytomas, including hypertension, diaphoresis,
tachycardia, and apparent mood changes. Patients with VHL disease and
catecholamine production due to pheochromocytoma almost exclusively produce
normetanephrines (indicating norepinephrine production) [48]. (See 'Diagnosis' below.)

The possibility of an occult pheochromocytoma needs to be considered whenever a

patient with VHL disease requires surgery because of the potential risk of anesthetic
complications, including sympathetic overactivity and severe hypertension.

Diagnosis — In addition to the surveillance described below, pheochromocytomas can

be detected with radiographic imaging via plasma metanephrine/normetanephrine
testing and, less commonly, urine metanephrine/normetanephrine testing.
(See 'Surveillance protocols' below.)

Conventional imaging may not be sufficient because of the potential for extra-adrenal
lesions, referred to as paragangliomas. Studies with 18-F-dihydroxy-phenyl-alanine
(18F-DOPA) positron emission tomography (PET) provide some context and suggest
that iobenguane (also known as metaiodobenzylguanidine [MIBG]) scanning is not
effective at detecting pheochromocytomas in patients with VHL:

●A pilot study of 18F-DOPA PET in seven patients with VHL indicated a high
detection rate (7 out of 7), as did computed tomography (CT) scan. On the other
hand [(123/131)I]-MIBG scintigraphy failed to detect 4 of the 7 lesions [49].
●These data were confirmed in an independent study of 48 patients with
hereditary and nonhereditary cases [50].
●In a prospective study assessing adrenal imaging of 52 patients with VHL
disease, 390 lesions were identified by CT (n = 139), magnetic resonance imaging
(MRI; n = 117), 18F-fluorodeoxyglucose (18F-FDG) PET (n = 94), and 18F-DOPA
PET (n = 40). 18F-DOPA PET identified 20 pancreatic and 20 extrapancreatic
tumors, including lesions in the adrenal gland (n = 11), kidney (n = 3), liver (n = 4),
lung (n = 1), and cervical paraganglioma (n = 1). These tumor sites were not seen

459
 by conventional imaging studies in 9.6 percent of patients and 4.4 percent of
lesions [51].
●In a prospective study of 197 patients with VHL-associated pancreatic lesions,
clinical and imaging characteristics were analyzed to study the associations
between 18F-FDG PET uptake, tumor growth, and the development of metastatic
disease [52]. PET imaging detected metastatic disease in three patients in whom
it was not detected by CT scan and suggested nonneoplastic disease in three
more patients.
Measurement of plasma metanephrines and normetanephrines provides important
diagnostic information. In a study of patients with VHL disease and multiple endocrine
neoplasia type 2 (MEN-2), measurements of plasma normetanephrines and
metanephrines provided a sensitivity of 97 percent and a specificity of 96 percent [48]. A
high normetanephrine-to-metanephrine ratio is expected because patients with VHL
disease almost exclusively produce normetanephrines (indicating norepinephrine
production).
Management — The treatment of choice for symptomatic pheochromocytomas is
surgical removal after appropriate alpha-adrenergic blockade and other supportive
measures, if needed [53].
It is critical to follow established protocols to suppress catecholamine production in the
preoperative period, and follow patients carefully perioperatively and postoperatively for
several weeks to ensure that endocrine and cardiovascular function has not been
compromised by prolonged overproduction of catecholamines. Additional information on
the pharmacologic management of patients with pheochromocytoma prior to surgery is
discussed elsewhere. (See "Treatment of pheochromocytoma in
adults" and "Pheochromocytoma and paraganglioma in children".)
ENDOLYMPHATIC SAC TUMORS OF THE MIDDLE EAR
Manifestations — Papillary cystadenomas of the endolymphatic sac are highly
vascular lesions arising within the posterior portion of the temporal bone [54]. Common
clinical manifestations include hearing loss, tinnitus, vertigo, and less often, facial
muscle weakness [54-57].
Three mechanisms have been described to account for the hearing loss and other
symptoms associated with endolymphatic sac tumors (ELSTs) [57].
●Tumors can invade the otic capsule, resulting in destruction of the membranous
labyrinth and disruption of endolymphatic flow.
●Sudden, irreversible hearing loss may be due to intralabyrinthine hemorrhage.
●Gradual onset of hearing loss, tinnitus, and vertigo can be caused by blockage of
endolymphatic sac resorption of fluid (hydrops).
Although these tumors also occur sporadically, they arise at a younger age in VHL
patients, in whom they are often bilateral. In one series, for example, bilateral tumors
were present in 28 percent of the patients with VHL versus 1 percent in the patients
without VHL disease [56]. In two other reports in VHL patients, 5 of 34 tumors (15
percent) were bilateral [54,55].
ELSTs are common in patients with VHL disease, within an incidence of approximately
15 percent on detailed evaluation [54-56,58-60].
Diagnosis — ELSTs may be difficult to detect with a single modality. Patients with VHL
disease should be questioned annually about any auditory or vestibular symptoms with
460
routine audiology performed for surveillance. Any patient with abnormalities in auditory
tests should be screened for the presence of these tumors by computed tomography
(CT) of the skull base or magnetic resonance imaging (MRI) with fine cuts of the
temporal bones (table 2) [54]. A one-time screening MRI of the internal auditory canal
can also be obtained in adolescence (table 2). These lesions can be very difficult to see
radiographically. Whether surgery is indicated for patients with an asymptomatic tumor
is controversial [57], and additional studies are required to assess the risk of acute
hearing loss in such patients.
Radiologic findings include retrolabyrinthine location, intratumoral calcification on CT
scan, hyperintense focal signals on T1-weighted (noncontrast-enhanced) MRI, and a
heterogeneous signal on T2-weighted MRI scan [61,62]. Visualization of these lesions
requires dedicated images, and ELSTs will often be missed on brain MRI scans ordered
for surveillance of cerebellar hemangioblastoma.
In a prospective 40-patient study, ELSTs were suspected based on audiovestibular
symptoms, audiometry, and MRI in 34, 30, and 12.5 percent of subjects, respectively.
More than 90 percent of radiologically diagnosed ELSTs were associated with abnormal
audiometric findings [63].
Management — Management of ELSTs needs to consider the presence and severity of
symptoms, their generally slow growth rate, and the potential complications associated
with surgery. Treatment of ELSTs is primarily surgical; if the lesions can be completely
excised, surgery is curative [64-66]. Stereotactic radiosurgery may have a role for
recurrent disease [67].
Cochlear implants may be an option for patients with hearing loss due to bilateral
ELSTs [68]. (See "Hearing amplification in adults", section on 'Cochlear implants'.)
PANCREATIC TUMORS
Clinical presentation — Pancreatic abnormalities are common in patients with VHL
disease. In a multi-institutional study of 158 consecutive patients from 94 affected
families, 77 percent had lesions in the pancreas, including cysts (70 percent), serous
cystadenomas (9 percent), and neuroendocrine neoplasms (9 percent) [69]. In another
series of 633 patients with VHL disease, neuroendocrine neoplasms were identified in
108 (17 percent) [70].
Simple pancreatic cysts and serous cystadenomas may be asymptomatic even when
the radiologic presentation is dramatic. However, such lesions can cause epigastric pain
and discomfort [71,72]. Pancreatitis and pancreatic failure are exceedingly rare
complications, although some degree of exocrine pancreatic dysfunction has been
reported. Asking about change in stool characteristics and digestive patterns should be
part of a comprehensive review of systems with patients with VHL disease and
pancreatic cysts. Mucinous cysts of the pancreas are not seen in association with VHL
disease, and patients with VHL disease do not have an increased risk of pancreatic
adenocarcinoma. (See "Classification of pancreatic cysts".)
Neuroendocrine neoplasms of the pancreas are often multifocal. While the majority are
well differentiated (grade 1 or 2) neuroendocrine tumors (G1 or G2 pancreatic
neuroendocrine tumors [pNETs]) [73,74], high-grade well-differentiated (ie, pNET, G3)
and high-grade poorly differentiated tumors (neuroendocrine carcinomas [NEC]) have
been described (table 3) [75,76].

461
pNETs may be benign or malignant (as indicated by the presence of metastases to local
nodes and/or liver). In one series of 108 patients with neuroendocrine tumors, nine (8
percent) had metastatic disease [70]. However, it is not possible to gauge clinical
behavior on the basis of histologic appearance. pNETs that are most likely to
metastasize are those that are >3 cm in diameter, have a rapid tumor doubling time
(<500 days), and those with VHL missense and/or exon 3 pathogenic or likely
pathogenic variants [70,73,74,77]. (See "Pathology, classification, and grading of
neuroendocrine neoplasms arising in the digestive system", section on 'Classification
and terminology'.)
Most of these neoplasms are nonfunctional and grow slowly for prolonged periods
without producing symptoms of peptide overproduction. In two combined series, none of
25 patients had symptoms related to peptide hormone secretion [69,78]. However, there
are reported cases of functional syndromes due to secreted peptides (eg, diarrhea from
vasoactive intestinal peptide and hypoglycemic episodes from insulin) [69].
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms".)
As a result of all of these issues, many of these lesions are diagnosed incidentally
during routine VHL surveillance for renal lesions [70]. (See 'Surveillance
protocols' below.)
Management
Role of surgery — Management of pNETs is primarily surgical, although the criteria for
surgical resection differ from those of patients with sporadic pNETs. (See "Surgical
resection of sporadic pancreatic neuroendocrine tumors".)
We suggest surgical resection rather than other interventions or systemic therapy for
patients with potentially resectable lesions greater than 3 cm in diameter in the body or
tail of the pancreas, or greater than 2 cm in diameter in the head of the pancreas. We
suggest belzutifan rather than other systemic therapies if surgery is not feasible or the
tumor is considered unresectable.
Nonoperative approaches (eg, surveillance, belzutifan) are appropriate for small primary
lesions (≤3 cm), incorporating other clinical factors such as VHL pathogenic or likely
pathogenic variant status and rate of tumor growth (algorithm 2) [70,73,77]. (See 'Role
of surveillance and belzutifan' below.)
Data support risk stratification of pNETs <2 to 3 cm according to both size [70,74] and
the results of VHL genotyping [73,79]. In one prospective observational study, 175
patients with VHL and solid pancreatic lesions consistent with a pNET (median of two
pNETs per patient) were managed according to the above surgical criteria. Among the
entire study population, 156 patients also underwent VHL gene sequencing. At median
follow-up of 53 months, the following results were noted:
●Patients with a greatest tumor diameter <1.2 cm (n = 83) had a 100 percent
negative predictive value for developing metastases and requiring surgical
intervention during follow-up.
●Patients with a tumor diameter >3 cm (n = 12) had a high risk of developing
metastatic disease (on multivariable analysis, hazard ratio [HR] 8.6, 95% CI 1.7-
43.2).
●Among the 80 patients with tumors ≥1.2 cm and ≤3 cm, only those with
a VHL missense pathogenic variant developed metastases over time (five versus

462
 zero for patients with other types of pathogenic variants). Surgical intervention
was required more frequently among patients with a missense VHL pathogenic
variant compared to other types of molecular alterations (40 versus 16 percent)
and those with an exon 3 (as compared with exon 1 or 2) pathogenic variant (on
multivariate analysis HR 8.8, 95% CI 1.2-66.3).
Earlier studies emphasized the prognostic influence of tumor growth rate [70,77].
Surgical principles are similar to those of sporadic pNET, although given tumor
multifocality and the potential for future pancreatic resections, pancreas-preserving
surgery is emphasized. Long-term outcomes of resected VHL-associated pNET appear
to be generally better than those of sporadic pNET [74,80]. (See "Surgical resection of
sporadic pancreatic neuroendocrine tumors", section on 'Extent of resection'.)
Role of surveillance and belzutifan — For patients with pNET ≤3 cm and indolent
tumor growth, we suggest surveillance with serial imaging rather than resection
(algorithm 2). Initial therapy with the hypoxia-inducible factor-2alpha (HIF-2alpha)
inhibitor belzutifan is an alternative to surveillance for patients with lesions that exhibit
rapid tumor growth (ie, accelerated doubling time <500 days) or those with a resectable
tumor who wish to delay or defer future surgical interventions, as this targeted therapy
has effective and durable responses in this patient population.
Despite limited data, we also suggest belzutifan over other systemic therapies for
localized tumors >3 cm if surgery is not feasible (ie, because of multiple primary
surgeries or multiple comorbidities) or if the tumor is otherwise unresectable.
Belzutifan has not been directly compared to other systemic therapies used for locally
advanced or metastatic well-differentiated pNETs, and its use in this population requires
further investigation. Further details on choices for systemic therapy for patients with
non-VHL-associated advanced pNETs are discussed separately. (See "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control
tumor growth and symptoms of hormone hypersecretion", section on 'General approach
to the patient'.)
A phase II study (Study 004) of 61 patients with systemic therapy-naïve VHL-associated
renal cell carcinoma (RCC) included a subset of 22 patients with measurable pNETs
[15,16]. At median follow-up of 22 months, among this subset, objective responses were
seen in 20 patients (91 percent), including 3 complete (14 percent) and 17 partial
responses (77 percent) [16]. The median time to response was approximately 8 months,
and no cases of progressive disease were reported. There were no data provided on
histologic differentiation or mitotic rate, VHL genotype, or prior therapies for those with
pNET.
Based on these data, the US Food and Drug Administration (FDA) granted regulatory
approval to belzutifan in adult patients with VHL disease who require therapy for VHL-
associated pNET and do not require immediate surgery [15]. Belzutifan also has
regulatory approval from the FDA for VHL-associated RCC and central nervous system
(CNS) hemangioblastomas. (See 'Renal cell carcinomas' above
and 'Hemangioblastomas' above.)
The management of toxicities associated with belzutifan are discussed separately.
(See 'Belzutifan' above.)
PAPILLARY CYSTADENOMAS OF THE EPIDIDYMIS AND BROAD
LIGAMENTPapillary cystadenomas occur in both the epididymis in men and the
463
broad ligament in women (also known as adnexal papillary tumors of probable
mesonephric origin) [81]. Bilateral papillary cystadenomas are almost pathognomonic of
VHL disease [2,82]. In contrast, single epididymal cysts are common in the general
population and should not raise suspicion for VHL disease in the absence of other VHL-
related findings.
In one series of 56 patients with VHL who were screened with both ultrasound and
physical examination, 30 had epididymal abnormalities, two-thirds of which were
bilateral. Papillary cystadenomas are benign and generally asymptomatic, and no
treatment is required [82]. (See "Nonacute scrotal conditions in adults".)
Papillary cystadenomas in the broad ligament in women are also asymptomatic in most
patients, and thus the true incidence of these lesions is unknown [83,84]. Symptoms
that have been reported include pain, dyspareunia, and menorrhagia; treatment is
symptomatic.
VHL SOMATIC PATHOGENIC VARIANTS IN SPORADIC
TUMORSSporadic renal cell carcinomas (RCCs), pheochromocytomas,
endolymphatic sac tumors (ELSTs), and hemangioblastomas frequently have acquired
somatic (as opposed to germline) abnormalities involving the VHL gene, supporting a
role for the VHL gene in tumorigenesis in sporadic cases [7,60,85-89]. As noted above,
two hits or loss of function events appear to be required in VHL disease in both the
hereditary and sporadic tumors. The hits can result from a combination of inherited or
somatic pathogenic variants followed by loss of heterozygosity, or loss of gene
expression caused by promoter hypermethylation. (See "Molecular biology and
pathogenesis of von Hippel-Lindau disease".)

The following observations illustrate the frequency with which this occurs:

●Somatic pathogenic variants of the VHL gene and/or allelic deletion may be

present in as many as 50 percent of sporadic hemangioblastomas.
(See "Hemangioblastoma", section on 'Molecular biology'.)
●Abnormalities of the VHL gene are also found in 50 to 60 percent of patients with
sporadic RCC, suggesting that the VHL gene has a role in pathogenesis in this
setting as well. (See "Epidemiology, pathology, and pathogenesis of renal cell
carcinoma", section on 'Von Hippel-Lindau gene'.)
●VHL gene abnormalities in apparently sporadic pheochromocytoma are observed
less commonly (in 4 percent of benign lesions and in 17 percent of malignant
tumors in a series of 72 patients) [87]. However, some of these patients actually
have germline pathogenic variants and, therefore, VHL disease [40].
(See 'Pheochromocytomas' above.)
DIAGNOSIS
Genetic testing — The diagnosis of VHL disease is typically established through
detection of a germline pathogenic (typically loss of function) variant in the VHL gene.
This is most commonly seen in patients who undergo genetic testing after being
diagnosed with a single manifestation of VHL disease, or those who are tested because
they have a close relative diagnosed with VHL disease [2,90]. The diagnosis of VHL
disease can also occur when genetic testing is performed for another reason and
unexpectedly reveals a secondary pathogenic variant in VHL. Rarely, in patients who do
464
not have access to genetic testing, the diagnosis of VHL disease can be based on
clinical criteria (eg, those with one VHL-associated lesion and a family history of VHL, or
those with multiple VHL-associated lesions).
Patients suspected of having VHL disease should be referred to specialized centers for
evaluation, genetic counseling, and definitive diagnosis through genetic testing, even if
there is no family history of VHL disease. Approved VHL Clinical Care Centers are listed
at the VHL Alliance website [13]. These centers have been approved for standards of
care that were developed by the VHL Alliance's medical advisory board. The VHL
Alliance also provides recommendations for ongoing surveillance of patients diagnosed
with VHL disease (table 2). (See 'Genetic counseling' below and 'Surveillance
protocols' below.)
How to perform and interpret genetic testing — Genetic testing is typically
performed on isolated DNA from a fresh blood sample, which is obtained primarily from
lymphocytes. Many laboratories can also perform this testing from DNA isolated from
saliva or buccal samples. Most DNA diagnostic laboratories rely on next-generation
sequencing (NGS) techniques, whether assessing a single gene or panel of hereditary
cancer genes. Deletions (either intragenic or whole gene) are assessed using read-
depth from NGS data [91] or confirmed directly using a targeted chromosomal
microarray and/or multiplex ligation-dependent probe amplification (MLPA) [92]. Many
patients now undergo genetic testing using larger multi-gene panels by NGS analysis
that include the VHL gene as one of the cancer susceptibility genes under study,
including those cancer patients undergoing paired tumor/normal sequencing [93].
A molecular diagnosis of VHL disease is based on the identification of a pathogenic or
likely pathogenic variant in the VHL gene based on the American College of Medical
Genetics and Genomics (ACMG) classification scheme [94]. Pathogenic variants in
the VHL gene can be inherited or arise de novo. The frequency of de novo pathogenic
variants has been reported to be as high as 20 percent of VHL patients in less
contemporary studies [95]. Rare patients may have the clinical features of VHL without
a detectable pathogenic variant from analysis of a blood sample due to mosaicism for
the VHL pathogenic variant. (See 'Patients with somatic mosaicism' below.)
It can be particularly challenging to have a patient with a single VHL-associated tumor
and a variant of uncertain significance (VUS) in the VHL gene. Many clinicians will use
their own judgment to decide whether to pursue VHL surveillance in that setting. The
Clinical Genome Resource (ClinGen) has launched a VHL Variant Classification Expert
Panel to try to further improve evaluation of germline variants in VHL and reduce the
number of VUS results [96,97].
Special populations
Patients with characteristic VHL lesions — Comprehensive genetic testing of the
VHL gene is recommended for individuals with the presence of one or more
characteristic lesions including hemangioblastomas of the brain, spine, or retina;
endolymphatic sac tumors; epididymal cystadenomas; pheochromocytoma (often as
part of a larger paraganglioma/pheochromocytoma hereditary panel); multiple
pancreatic cystadenomas; and clear cell RCC diagnosed at age 40 or younger. There is
also a large variety of hereditary cancer panels, many of which include the VHL gene.
Thus, individuals might be diagnosed with a pathogenic variant in VHL due to other

465
combinations of tumor diagnoses and family history (eg, those with a diagnosis of clear
cell RCC over the age of 40 and a family history of kidney cancer).
At-risk relatives — For at-risk relatives (eg, any individual with a family history of VHL
where prior genetic testing has been performed), testing should be obtained for the
pathogenic VHL variant identified in the affected relative. This approach is often called
"known familial pathogenic variant" testing. However, laboratories often use automated
sequencing platforms may re-evaluate the entire VHL gene for each family member.
Patients with secondary pathogenic variants — There is increasing clinical use of
whole exome sequencing for the diagnosis of Mendelian disorders [98,99]. As a result,
the ACMG published recommendations for the reporting of secondary (previously
referred to as "incidental") findings of pathogenic or likely pathogenic variants.
The VHL gene is included in this list that are thought to be medically actionable, even if
the original indication for testing was unrelated to a cancer diagnosis [100,101]. Data
suggest that a majority (over 90 percent) of patients undergoing this testing request to
have the results of secondary pathogenic variants reported to them [102]. Thus, certain
individuals (particularly young children) may be diagnosed with presymptomatic VHL
disease using such whole exome sequencing testing, prior to developing any features of
the disorder. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease",
section on 'Pathogenic variants and clinical manifestations of disease'.)
Patients with somatic mosaicism — In a patient with somatic mosaicism, a
pathogenic variant occurs during embryonic development after fertilization; in these
circumstances, some cells will be normal while others carry the pathogenic variant. In
contrast to detecting germline pathogenic variants, diagnostic difficulties are more likely
as the clinical presentation depends on the proportion of cells that carry this
mosaic VHL pathogenic variant [103,104]. Although an individual with somatic
mosaicism may present with classic VHL disease, the disease-associated variant may
not be detectable in the peripheral blood because the hematologic stem cells do not
carry the pathogenic variant. In this scenario, the individual carries three VHL alleles,
one "normal" allele inherited from each parent, and a third allele that contains the
pathogenic variant (which may occur on either parental chromosome (figure 2)).
Thus, the possibility of mosaicism should be considered in patients presenting with
VHL-associated tumors and a negative VHL genetic test using peripheral blood cells.
The disease manifestations in such patients are dependent upon when the de novo
pathogenic variant event occurred in embryogenesis. The earlier the new pathogenic
variant occurred, the more tissue types are likely to be affected. The use of NGS
technologies for VHL pathogenic variant analysis provides increased sensitivity to
detect VHL variants that exist at very low levels in the blood sample compared with
older Sanger sequencing methods [105]. Additional testing approaches for mosaicism
can include genetic analyses of skin fibroblasts or buccal mucosal cells. Testing of
multiple tumors from the same patient with mosaicism can sometimes provide
information on the causative pathogenic variant shared across tumors, but it should be
interpreted by an experienced geneticist or genetic counselor.
Genetic counseling — Patients should be referred for appropriate genetic advice in
conjunction with genetic testing for VHL pathogenic variants [90]. VHL disease is
inherited in an autosomal dominant fashion, and affected individuals have a 50 percent
probability of transmitting the disease-associated VHL variant to each offspring. Given

466
the variable age of tumor onset, most individuals with VHL live into adulthood and have
children, often before the diagnosis is made. Therefore, it is not unusual to see
multigenerational VHL pedigrees with many affected individuals, each having slightly
different patterns of tumor diagnoses and variable age of onset.

Among the rare patients with somatic mosaicism, the risk to offspring depends upon
whether or not the germline tissue carries the pathogenic variant, although that
generally is not determined clinically. Thus, patients with documented mosaicism should
be counseled that their risk of having an affected child may be as high as 50 percent
and that any affected child will inherit the pathogenic variant in 100 percent of their cells
and will potentially have more severe manifestations of the disease than the mosaic
parent.

The diagnosis of VHL in a child of unaffected parents can be very alarming, and the
concept of de novo pathogenic variants or variable expressivity (eg, where the parent
may not yet have been diagnosed with a VHL-associated tumor) should be carefully
explained. One should never assume that healthy parents are negative for
the VHL variant without direct genetic testing. Parents should be reassured and
potential guilt alleviated by explaining that a de novo pathogenic variant is unlikely to be
the result of any action that occurred immediately prior to or during the pregnancy.
There is increasing awareness of the concern of parents as to when to provide
information about the diagnosis to children with a positive VHL genetic test. In general,
it is best for this information to be conveyed in multiple settings as the child's maturity
increases, and parents may benefit from the support of a medical professional in
initiating these discussions [90]. The VHL Alliance provides resources that help explain
the disease to children, parents, and other health care professionals [13].
PREGNANCY AND VHL
Assessment of fetal VHL genetic status — Prospective parents planning or carrying
a pregnancy at risk for VHL disease have multiple options for learning
the VHL pathogenic variant status of the fetus.
Prenatal diagnosis — A couple may choose prenatal diagnosis after pregnancy is
initiated, utilizing a sample obtained by amniocentesis or chorionic villus sampling.
Some couples that choose prenatal diagnosis wish to know the VHL status prior to birth
in order to prepare, while others may elect to terminate a pregnancy if the fetus is
affected.
Prospective parents should also be provided with information about reproductive
technologies that greatly lower their risk of having a child with VHL disease, such as
sperm or oocyte donation (depending on which parent is affected), and preimplantation
genetic diagnosis. The latter involves testing embryos fertilized in vitro for the
familial VHL pathogenic variant, usually on a single cell of a blastocyst, and selecting
unaffected embryos for implantation [106]. In one study, 6.5 percent of couples with an
affected individual chose to pursue prenatal diagnosis [107]. The various reproductive
options available to prospective parents require thoughtful discussion and genetic
counseling. (See "Preimplantation genetic testing".)
Postnatal diagnosis — The couple may choose not to know their child's VHL genetic
status until after the child is born. If prenatal genetic testing is not performed, then all at-
risk children should be tested in infancy for the VHL pathogenic variant found in the
467
affected parent in order to determine whether or not the VHL disease surveillance
regimen is required. In such children diagnosed with VHL, surveillance should be
initiated promptly.
Surveillance prior to and during pregnancy — Women with VHL who are pregnant
should have close surveillance for associated lesions, due to the risk of VHL-related
pregnancy complications. Whether VHL-related lesions demonstrate new or accelerated
growth during pregnancy is controversial [108-110]. Nevertheless, for women known to
have VHL, it is recommended to have complete VHL surveillance performed to assess
for such lesions prior to attempted conception and on an as needed basis during
pregnancy (table 2). The VHL Alliance also provides recommendations for the care of
VHL patients prior to and during pregnancy [13]. (See 'Surveillance protocols' below.)
Pheochromocytoma — It is particularly important to evaluate for any evidence of
pheochromocytoma prior to conception. The growth or development of
pheochromocytomas can have catastrophic consequences during pregnancy and
delivery, such as the release of metanephrines due to pressure on the tumor during
labor and subsequent blood pressure instability [108,109]. All women with
pheochromocytomas, including those with VHL disease, need to have them surgically
removed before attempting to become pregnant. If preconception VHL screening is not
performed, then plasma metanephrines and normetanephrines are generally tested in
the first trimester and then early in the third trimester of pregnancy.
Further details on the management of pheochromocytoma in pregnancy and in adults
are discussed separately. (See "Clinical presentation and diagnosis of
pheochromocytoma", section on 'Pheochromocytoma in pregnancy' and "Treatment of
pheochromocytoma in adults".)
Other VHL lesions — Women with existing retinal, brain, and spinal cord lesions may
be at increased risk for tumor growth during pregnancy [109,111]. In such patients,
retinal exams should be performed regularly throughout the pregnancy. Additionally,
noncontrast magnetic resonance imaging (MRI) of the brain are performed in the fourth
month of pregnancy to follow up on central nervous system (CNS) lesions. Delivery via
cesarean section should be considered to lower the probability of developing increased
intracranial pressure.
A review of VHL progression during pregnancy at one VHL center in the Netherlands
demonstrated accelerated growth of cerebellar hemangioblastoma in the two years
around pregnancy [109], although this was not observed in a second series [111].
SURVEILLANCE PROTOCOLSMorbidity and mortality in patients with VHL
disease have decreased substantially due to an improved understanding of the natural
history of the serious clinical manifestations of the disorder, better imaging techniques,
and improvements in therapy. Surveillance is important not only to detect new lesions at
an early stage, but also to monitor small asymptomatic lesions for evidence of
progression.

Surveillance protocols focus on hemangioblastomas (including retinal capillary

hemangioblastomas), renal cell carcinomas (RCCs), pheochromocytomas and
audiology given the increased risk of endolymphatic sac tumors (ELST) in patients with
VHL. Surveillance recommendations may need to be adapted to the individual patient,
taking into account the patient’s current or prior tumor diagnoses. However, all

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individuals with VHL, even if currently asymptomatic, should understand that they may
develop manifestations of VHL disease and will benefit from following surveillance
guidelines.

Several organizations provide updated surveillance guidelines that account for

contemporary imaging and laboratory diagnostic methods. An international panel of
clinicians who care for children with VHL was convened in 2016 as part of the American
Association for Cancer Research (AACR) Childhood Cancer Predisposition Workshop.
The panel reviewed both the American and European VHL regimens and published
surveillance recommendations that incorporated increased intensity of and earlier
initiation of screening [112]. These guidelines were subsequently assessed by a
consensus panel formed by the VHL Alliance, consisting of clinicians covering all fields
of expertise involved in the management of VHL disease and representatives from the
AACR workshop. The following summarizes those recommendations from the VHL
Alliance consensus panel (table 2) [13].
Ages 0 to 4
●Every 6 to 12 months
•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist
skilled in diagnosis and management of retinal disease, especially for children
known to carry the VHL pathogenic variant from infancy
●Annually
•From age 1 year – History and physical examination by a clinician informed
about VHL disease
•From age 2 years – Blood pressure and pulse measurements
Ages 5 to 10
●Every 6 to 12 months
•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist
informed about VHL, using a dilated exam
●Annually
•History and physical examination by a clinician informed about VHL disease
•Blood pressure and pulse measurements
•Assessment of plasma metanephrines, or urinary metanephrines using 24-
hour urine testing
Age 11 and beyond
●Every 6 to 12 months
•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist
informed about VHL, using a dilated exam
●Annually
•History and physical examination by a clinician informed about VHL disease
•Assessment of plasma metanephrines or urinary metanephrines using 24-
hour urine testing
●Every 2 years
•Magnetic resonance imaging (MRI) with and without contrast of brain,
cervical, thoracic, and lumbar spine
•Audiogram performed by an audiologist
Ages 15 and beyond
469
 ●Every 6 to 12 months
•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist
informed about VHL, using a dilated exam
●Annually
•History and physical examination by a clinician informed about VHL disease
•Assessment of plasma metanephrines or urinary metanephrines using 24-
hour urine testing
●Every 2 years
•MRI with and without contrast of brain, cervical, thoracic, and lumbar spine
-A one-time MRI of the brain with thin cuts through inner ear/petrous
temporal bones (internal auditory canal) to rule out ELST of the middle ear
•MRI abdomen with and without contrast
•Audiogram performed by an audiologist
Beginning age 30
●Decrease frequency of eye exam to annually. All other testing remains the same.
Beginning age 65
●Annually
•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist
informed about VHL, using a dilated exam.
•History and physical examination by a clinician informed about VHL disease.
•Assessment of plasma metanephrines or urinary metanephrines using 24-
hour urine testing.
•Stop surveillance MRI imaging for areas that have not shown any disease
manifestations. For areas that have active disease, continue imaging at a
frequency that allows follow-up and management of lesions in question.
ADDITIONAL RESOURCESSummary information concerning VHL disease may
be useful for counseling patients and affected families. The following organization can
provide such information:

VHL Alliance

2001 Beacon Street, Suite 208

Boston, MA 02135

Telephone: 617-277-5667

Toll free number in the United States and Canada: 800-767-4VHL

FAX: 858-712-8712

www.vhl.org

470
The VHL Handbook is available in eight languages as a download on the
web info@vhl.org or through the VHL Alliance office. The handbook is a reference guide
for patients and their health care teams.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic
neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●Von Hippel-Lindau (VHL) disease – VHL disease is an inherited, autosomal
dominant syndrome manifested by a variety of benign and malignant tumors (table
1). (See 'Introduction' above.)
●VHL-associated tumors – For patients with VHL disease, the primary goal of
management is the early diagnosis and treatment of VHL-associated tumors that
otherwise might cause severe disability or death (table 2). The spectrum of such
tumors includes the following:
•Clear cell renal cell carcinomas (RCCs) (see 'Renal cell carcinomas' above)
•Hemangioblastomas (including retinal hemangioblastomas)
(see 'Hemangioblastomas' above and 'Retinal capillary
hemangioblastomas' above)
•Pheochromocytomas (see 'Pheochromocytomas' above)
•Endolymphatic sac tumors (ELSTs) of the middle ear (see 'Endolymphatic sac
tumors of the middle ear' above)
•Serous cystadenomas and neuroendocrine tumors of the pancreas
(see 'Pancreatic tumors' above)
•Papillary cystadenomas of the epididymis and broad ligament (see 'Papillary
cystadenomas of the epididymis and broad ligament' above)
●Clear cell RCCs – Clear cell RCCs occur in approximately 70 percent of VHL
patients who survive to 60 years of age. Surveillance imaging of the kidneys with
magnetic resonance imaging (MRI) should be initiated in early adolescence (table
2). (See 'Renal cell carcinomas' above.)
In patients with VHL disease, the management of locoregional RCC is as follows
(algorithm 1):
•Tumors <3 cm – For patients with solid renal tumors <3 cm who are
asymptomatic, we suggest initial surveillance rather than immediate surgery or
medical therapy (Grade 2C), due to the low metastatic potential of these
tumors. However, for such patients with accelerated tumor growth (>5
millimeters per year) or those who wish to potentially postpone or avoid future
surgical interventions, we offer belzutifan as an alternative to surveillance.
(See 'Locoregional tumors <3 cm' above and 'Belzutifan' above.)
•Tumors ≥3 cm – For patients with a diagnosis of RCC ≥3 cm, we recommend
a nephron-sparing approach rather than radical nephrectomy (Grade 1B),
based on data in patients with and without VHL disease. While data suggest
similar survival outcomes, nephron-sparing approaches preserve kidney
parenchyma and reduce the risk of chronic kidney dysfunction, which is
preferable for patients with VHL disease who are at risk for bilateral and
recurrent tumors. (See 'Locoregional tumors ≥3 cm' above and "Definitive
471
 surgical management of renal cell carcinoma", section on 'Partial
nephrectomy' and "Radiofrequency ablation and cryoablation for renal cell
carcinoma".)
●Central nervous system hemangioblastomas – Central nervous system (CNS)
hemangioblastomas are the most common lesions in patients with VHL disease
and tend to be multiple and infratentorial. Annual retinal examinations should be
initiated beginning in infancy to diagnose and treat retinal hemangioblastomas at
an early enough stage to preserve vision. Starting at the age of 11 years,
surveillance imaging of the brain and spinal cord with magnetic resonance
imaging (MRI) every other year is indicated to identify lesions as they develop and
minimize disease-related complications (table 2).
(See 'Hemangioblastomas' above and 'Surveillance protocols' above.)
In patients with VHL disease, the management of CNS hemangioblastomas is as
follows:
•For patients with imaging evidence of one or more hemangioblastomas who
are asymptomatic and/or have indolent tumor growth, we suggest surveillance
with serial imaging rather than surgery or medical therapy (Grade 2C).
However, belzutifan, a hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitor, is
a reasonable alternative to surveillance for patients with tumors that could
become symptomatic if allowed to progress or for those who wish to delay or
defer future surgery. (See 'Surveillance and risk of progression' above.)
•Surgery is typically required for patients with hemangioblastomas that are
causing significant neurologic symptoms or are threatening compromise due to
mass effect or hemorrhage. (See 'Indications for surgery' above.)
•For most patients with symptomatic or rapidly enlarging CNS
hemangioblastomas that are unresectable or pose a high risk of postoperative
deficits, we suggest a trial of systemic therapy with the HIF-2alpha
inhibitor, belzutifan, rather than initial radiation therapy (RT) or an attempt at
high-risk surgical debulking (Grade 2C). (See 'Belzutifan' above.)
•For patients with retinal hemangioblastoma who initiate treatment, we suggest
laser photocoagulation rather than other therapies (Grade 2C). Alternative
options include photodynamic therapy or RT (particularly for salvage
therapy). Belzutifan is an acceptable option for patients who are ineligible for
local therapy due to tumor proximity to the optic nerve or multiple progressive
lesions. (See 'Retinal capillary hemangioblastomas' above
and 'Management' above.)
●Pheochromocytomas – Pheochromocytomas tend to be seen in younger
patients, are often multiple or extra-adrenal, and although symptoms can be
present, are less likely to be associated with symptoms or biochemical evidence of
catecholamine production compared with those occurring in patients without VHL
disease who are primarily diagnosed based on the presence of symptoms. Annual
assessment of plasma metanephrines should begin with young children.
Surveillance imaging of the abdomen for pheochromocytomas should be initiated
in early adolescence (table 2). (See 'Pheochromocytomas' above.)
●Endolymphatic sac tumors of the middle ear – ELSTs are slowly growing
lesions that can cause significant hearing loss and may be bilateral. Baseline

472
audiometry should begin in early childhood, and appropriate imaging should be
carried out based on symptoms (table 2). Retesting and appropriate imaging are
indicated if there are symptoms of ringing, tinnitus, pain, or change in auditory
acuity. (See 'Endolymphatic sac tumors of the middle ear' above.)
●Pancreatic tumors – Patients with VHL may present with pancreatic
abnormalities such as simple cysts, serous cystadenomas and neuroendocrine
neoplasms (algorithm 2). Patients with VHL do not have an increased risk of
pancreatic adenocarcinoma. Surveillance imaging of the abdomen for pancreatic
tumors should be initiated in early adolescence (table 2) (See 'Pancreatic
tumors' above.)
•Tumors ≤3 cm (body or tail) or ≤2 cm (head) of pancreas – For patients
with primary lesions ≤3 cm in the body or tail of the pancreas, or ≤2 cm in the
head of the pancreas, we suggest surveillance with serial imaging rather than
resection (Grade 2C). Belzutifan is an alternative to surveillance for patients
with lesions that exhibit rapid tumor growth or those with resectable disease
who wish to delay or defer future surgical interventions. (See 'Role of
surveillance and belzutifan' above.)
•Tumors >3 cm (body or tail) or >2 cm (head) of the pancreas – For
patients with potentially resectable pancreatic neuroendocrine tumors (pNETs)
>3 cm in diameter in the body or tail of the pancreas, or >2 cm in diameter in
the head of the pancreas, we suggest surgical resection rather than other
interventions or systemic therapy (Grade 2C). For those with unresectable
disease, we suggest belzutifan over other systemic therapies (Grade 2C).
(See 'Role of surgery' above.)
●Diagnosis – The diagnosis of VHL disease is typically established through
detection of a germline pathogenic (typically loss of function) variant in
the VHL gene, most commonly in patients who undergo genetic testing after being
diagnosed with a single manifestation of VHL disease, or those who are tested
because they have a close relative diagnosed with VHL disease.
(See 'Diagnosis' above.)
With the increasing use of next-generation sequencing (NGS) test methods,
hereditary cancer panels, and tumor sequencing in the care of cancer patients,
there is an increase in the diagnosis of VHL disease in patients with the
apparently sporadic forms of VHL-associated tumors, as well as, more rarely, from
secondary findings in patients undergoing whole exome or genome sequencing
for other indications. Changes in ascertainment, for example as a secondary
finding, may result in a decrease in the estimate of VHL tumor risks since most
knowledge is based on individuals presenting with symptomatic disease and their
close relatives. (See 'Genetic testing' above.)
●Prospective parents – Prospective parents planning or carrying a pregnancy at
risk for VHL disease should be offered genetic counseling, provided with
information about reproductive technologies that lower their risk of having a child
with VHL, and be counseled on the multiple options for learning the VHL
pathogenic variant status of the fetus. (See 'Genetic counseling' above
and 'Assessment of fetal VHL genetic status' above.)

473
●Pregnancy and VHL – Women with VHL disease who plan to or who become
pregnant need a much higher level of surveillance than usual, with particular
attention to evaluating and treating pheochromocytomas prior to pregnancy.
(See 'Surveillance prior to and during pregnancy' above.)

474
Diagnostic dilemmas in hypoglycemia: Illustrative
cases
Author:
Adrian Vella, MD
Section Editor:
Irl B Hirsch, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jul 17, 2020.
INTRODUCTIONInsulinomas are rare tumors that may present a diagnostic
dilemma for the clinician. The classic diagnostic test for an insulinoma has been
the 72-hour fast. There are two reasons to perform a prolonged supervised fast:
●To confirm the presence of a hypoglycemic disorder (by demonstrating low
venous glucose concentrations at the time of symptoms and resolution of
these symptoms with reversal of hypoglycemia). In this setting, measurement
of serum insulin, C-peptide, and proinsulin helps establish the mechanism of
hypoglycemia [1,2].
●To determine the mechanism of hypoglycemia when the presence of a
hypoglycemic disorder has already been established.
This distinction is important because the criteria for ending a fast will differ. If the
presence of a hypoglycemic disorder is already established, a fast can be stopped
when glucose is ≤55 mg/dL (<3 mmol/L) even in the absence of hypoglycemic
symptoms. This is because at these concentrations, endogenous insulin secretion
should be suppressed [3].

If a patient has a spontaneous episode of symptomatic hypoglycemia that is

fortuitously observed and confirmed with laboratory testing, a 72-hour fast is not
needed. The 72-hour fast is also unnecessary in the rare patient with insulinoma
who has exclusively postprandial symptoms; in such cases, hypoglycemia is
evaluated during a mixed-meal test.

The presence of inappropriately high serum insulin, C-peptide, and proinsulin

concentrations at the time of symptomatic and confirmed hypoglycemia in a
patient who has a negative test for insulin secretagogues (sulfonylureas or
meglitinides) establishes the diagnosis of insulinoma.

475
We consider the following values (measured in highly sensitive assays) as
inappropriately high in a symptomatic patient with serum glucose concentration
≤55 mg/dL (≤3 mmol/L) (table 1). (See "Hypoglycemia in adults without diabetes
mellitus: Diagnostic approach".)
●Serum insulin – ≥3 microU/mL (immunochemiluminometric assay [ICMA])
●Serum C-peptide – ≥200 pmol/L
●Serum proinsulin – ≥5 pmol/L
When the serum insulin and C-peptide values are lower, determination of markers
of insulin action such as serum beta-hydroxybutyrate and the serum glucose
response to intravenous glucagon at the end of the fast may provide important
diagnostic information [1]. In normal subjects who fast for 72 hours, serum beta-
hydroxybutyrate concentrations rise, and liver glycogen stores are mobilized. In
contrast, in patients with an insulinoma who continue to secrete insulin, serum
beta-hydroxybutyrate concentrations remain low (2.7 mmol/L or less) and serum
glucose concentrations increase by more than 25 mg/dL (1.4 mmol/L) 30 minutes
after the intravenous administration of 1 mg glucagon. (See "Hypoglycemia in
adults without diabetes mellitus: Diagnostic approach".)

The cases described below highlight some of the problems that may be
encountered during the evaluation of patients suspected to have an insulinoma or
in the management of those with a biochemically confirmed insulinoma.

CASE 1A 41-year-old woman was referred for evaluation of repeated episodes of

sweating, slurred speech, tremulousness, and confusion during the last nine
months that could be aborted by eating. On one occasion, she was unresponsive
to questions and thrashing about in bed. Capillary glucose measured by
emergency personnel was 31 mg/dL (1.7 mmol/L), and she improved after
intravenous glucose administration.

After fasting for 24 hours, she became diaphoretic and confused. Serum values at
that time were as follows:

●Glucose – 32 mg/dL (1.8 mmol/L)

●Insulin – 19 microU/mL (114 pmol/L)
●C-peptide – 866 pmol/L
●Proinsulin – 160 pmol/L
●Beta-hydroxybutyrate – 0.1 mmol/L
●Glucose increase after glucagon – 64 mg/dL (3.6 mmol/L)
●Sulfonylurea – Negative

476
Ultrasonography and spiral computed tomography (CT) of the abdomen showed a
1.5 cm lesion in the head of the pancreas. The location of the tumor was confirmed
by intraoperative ultrasonography (see "Insulinoma"). The patient underwent
enucleation of the insulinoma; pathologic examination confirmed the preoperative
diagnosis of insulinoma.
Comment — This is a classic case of insulinoma. The patient was healthy but had
episodes of neuroglycopenia. Whipple's triad (symptoms of hypoglycemia, low
serum glucose concentrations at the same time, and relief of symptoms by glucose
administration) was satisfied. That the hypoglycemia was caused by endogenous
insulin was confirmed by the high serum insulin, C-peptide, and proinsulin
concentrations and supported by the low serum beta-hydroxybutyrate
concentration and the small rise in serum glucose after
intravenous glucagon administration.
The tumor was detected by our preferred techniques: ultrasonography and spiral
CT of the abdomen (see "Classification, epidemiology, clinical presentation,
localization, and staging of pancreatic neuroendocrine neoplasms"). Confirmation
of the location was established by intraoperative ultrasonography. In this instance,
enucleation was the surgical procedure of choice.
CASE 2A 29-year-old man with a past history of primary hyperparathyroidism
(single parathyroid adenoma) was referred for evaluation of hypoglycemia. During
the last year, he had repeated episodes of tremor, sweating, and confusion,
usually after physical exertion; the symptoms were relieved by eating. The
patient's father and three paternal aunts had primary hyperparathyroidism; in
addition, a distant cousin had hyperparathyroidism and a benign pancreatic
tumor.

During his initial evaluation, he had symptoms of hypoglycemia, at which time the
following serum values were obtained:

●Glucose – 25 mg/dL (1.4 mmol/L)

●Insulin – 100 microU/mL (600 pmol/L)
●C-peptide – 2800 pmol/L
●Proinsulin – 44 pmol/L
●Beta-hydroxybutyrate – 0.1 mmol/L
●Glucose increase after glucagon – 29 mg/dL (1.6 mmol/L)
●Sulfonylurea – Negative

Ultrasonography of the abdomen was uninterpretable. A spiral computed

tomography (CT) of the abdomen showed a 3 cm mass in the head of the pancreas
consistent with an insulinoma. Intraoperative ultrasonography confirmed the
477
presence of a mass in this location and revealed multiple small nodules in the body
and tail of the pancreas. He underwent enucleation of the dominant mass in the
head of the pancreas and distal subtotal pancreatectomy. Pathologic examination
of the resected pancreatic tissue revealed multiple islet cell adenomas.

Comment — This is a case of insulinoma in a patient with multiple endocrine

neoplasia type 1 (MEN1). Although the majority of patients with insulinoma have a
solitary adenoma, multicentric islet cell adenomas are the rule in patients with
MEN1 [4,5]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and
diagnosis".)
Because neither ultrasonography nor palpation at surgery may be sufficiently
sensitive to detect all small tumors, resection of most of the distal pancreas with
enucleation of any tumors elsewhere in the pancreas is often indicated [6]. Alcohol
ablation may be reasonable for small or unresectable tumors and can ameliorate
symptoms in selected cases [7]. (See "Insulinoma", section on 'Treatment'.)

MEN1 should be considered in all patients with a personal or family history of

hyperparathyroidism (or pituitary tumor) who have an insulinoma. These patients
are at risk for multiple insulinomas; as a result, they usually require extensive
pancreatic surgery to extirpate all the hyperfunctioning islet tissue.

CASE 3A 44-year-old woman was referred for evaluation of recurrent syncope for
five years. These episodes were characterized by premonitory symptoms of
headache and slurred speech followed by suddenly finding herself on the floor. A
"full-blown" episode could be aborted by eating. She had no family history of
diabetes, but her boyfriend was taking a sulfonylurea drug for type 2 diabetes
mellitus.
Three years ago, she had an 80 percent pancreatectomy, but no insulinoma was
found. She was asymptomatic for four months after the operation, but her
symptoms then recurred. She was treated with prednisone but became
hyperglycemic, at which time glipizide and metformin were added. The prednisone
(10 mg every other day) was discontinued three days and the glipizide (5 mg/day)
and metformin (500 mg twice daily) two days before she came to our institution
seeking another pancreatic operation. At that time, her serum glucose
concentration was 50 mg/dL (2.8 mmol/L) 12 hours after her last meal.

The results of an outpatient fasting study were:

●Glucose – 38 mg/dL (2.1 mmol/L)

●Insulin – 9 microU/mL (54 pmol/L)

478
 ●C-peptide – 490 pmol/L
●Proinsulin – 33 pmol/L
●Beta-hydroxybutyrate – 0.2 mmol/L
●Glucose increase after glucagon – 32 mg/dL (1.8 mmol/L)
When the fast was ended, she had no symptoms or signs of hypoglycemia.
Ultrasonography and spiral computed tomography (CT) of the abdomen were
normal. Serum samples sent for analysis of sulfonylurea revealed the presence
of glipizide, the concentrations being 473 and 853 ng/mL, respectively, when the
serum glucose concentrations were 50 and 38 mg/dL (2.8 and 2.1 mmol/L); no
other sulfonylureas were detected.
The patient did not acknowledge that she had continued to take glipizide. We
therefore considered it possible, though unlikely, that her hypoglycemia was not
due to glipizide. She then underwent an inpatient 72-hour supervised fast that was
completely normal. The serum values were:
●Glucose – 50 mg/dL (2.8 mmol/L)
●Insulin – Undetectable
●C-peptide – 159 pmol/L
●Proinsulin – 3 pmol/L
●Beta-hydroxybutyrate – 4.5 mmol/L
●Glucose increase after glucagon – 8 mg/dL (0.4 mmol/L)
●Sulfonylurea – Negative
Comment — The initial biochemical data in this patient were consistent with
endogenous hyperinsulinemia but were undoubtedly due
to glipizide (see "Factitious hypoglycemia"). It is unlikely that glipizide would be
measurable in high and increasing concentrations 48 hours or more after the last
dose. The serum insulin, C-peptide, proinsulin, and beta-hydroxybutyrate
concentrations in patients with hypoglycemia due to a sulfonylurea drug ingestion
may be very similar to those in patients with an insulinoma. It is therefore essential
to measure sulfonylureas in the same blood sample drawn for the other
measurements. Liquid chromatography tandem mass spectrometry can detect
both first- and second-generation agents and repaglinide at low dose.
Another noteworthy point in this case is that the initial fasting study was ended
despite the patient being asymptomatic. When a fast is ended on the basis of a low
serum glucose concentration in the absence of symptoms or signs of
hypoglycemia, the results should be interpreted with caution because, in some
normal young women, serum glucose concentrations may fall to 30 to 40 mg/dL
(1.7 to 2.2 mmol/L) with no symptoms [8,9]. Furthermore, some patients with an
insulinoma may appear normal when their serum glucose concentrations are low;
when the serum glucose is then raised, it may be apparent that the patient did not

479
have normal mental function when hypoglycemic. The decision to end the fast can,
therefore, be difficult. A Mini-Mental State Examination may help establish a
cognitive baseline to compare with repeat examination during a supervised fast
[10].
Although the patient continued to deny surreptitious administration of glipizide, a
diagnosis of sulfonylurea-induced hypoglycemia was suspected. The basis for this
diagnosis was the detection of glipizide in serum, a negative supervised 72-hour
fast when sulfonylurea was undetectable in serum, and the patient's access to a
sulfonylurea drug.
CASE 4A 27-year-old man was referred by his local clinician for evaluation of
hypoglycemia found incidentally during an assessment for peptic ulcer disease.
During the last four months, he had several episodes of weakness and feeling
"shaky inside" late in the evening. During the night, he would periodically drink
soda. When symptomatic, reflectance meter blood glucose values measured by the
patient using equipment purchased for his seven-year-old daughter (diagnosed
with type 1 diabetes one year earlier) had been in the range of 40 to 50 mg/dL (2.2
to 2.8 mmol/L). Serum values after an overnight fast were:
●Glucose – 36 mg/dL (2.0 mmol/L)
●Insulin – 140 microU/mL (840 pmol/L)
●C-peptide – <33 pmol/L
●Proinsulin – 0.9 pmol/L

The low serum C-peptide and proinsulin values indicate that the hyperinsulinemia
(140 microU/mL [840 pmol/L]) was due to exogenous insulin administration. The
patient's daughter was being treated with a split-mixed insulin program; her
mother administered the morning dose and her father the evening dose. When
confronted with the evidence for factitial hypoglycemia due to insulin self-
administration, the patient adamantly denied he was injecting himself.

Comment — This is a case of surreptitious insulin injection, which almost always

occurs in patients with ready access to insulin. The diagnosis of factitial
hypoglycemia due to insulin administration should be suspected if the serum
insulin concentration exceeds 100 microU/mL (600 pmol/L) when the patient is
hypoglycemic. It is confirmed if the serum C-peptide and proinsulin concentrations
are low. It is important to appreciate that insulin analogs may not always be
detected by a given insulin immunoassay, and exogenous insulin use should be
suspected when the patient has access to insulin and C-peptide is suppressed even
when insulin is not markedly elevated.
A serum insulin/C-peptide molar ratio of more than 1.0 has been suggested as
identifying factitial hypoglycemia due to insulin administration [11]. This is in
480
contrast to ratios of 0.2 at the end of a supervised fast in patients with an
insulinoma and in normal subjects [12]. In most patients with factitial
hypoglycemia due to insulin administration, the discrepancy between the serum
insulin and C-peptide concentrations is so great that determination of the molar
ratio is superfluous. (See "Factitious hypoglycemia".)
CASE 5A 75-year-old woman was referred for the evaluation of episodes of
weakness, tremor, and confusion that were relieved by eating. She was usually
weak in the morning and felt better after breakfast. On one occasion, she felt weak
and dizzy while walking and had to hold onto a tree to prevent herself from falling.
On another occasion, she became confused while driving and mistakenly parked
her car halfway across a sidewalk.
Her serum glucose, insulin, and C-peptide concentrations during an inpatient 72-
hour fast are shown in the table (table 2). The fast was continued for the full 72
hours despite hypoglycemia at 48 hours and later because the patient was
asymptomatic. At the end of the fast, her serum beta-hydroxybutyrate
concentration was 4.9 mmol/L and her serum glucose response to
intravenous glucagon was an increase of 12 mg/dL (0.7 mmol/L). On closer
questioning later, the patient acknowledged that she had blurred vision and
weakness during the last 24 hours of the fast. In retrospect, the fast was positive
and should have been terminated earlier. Ultrasonography of the abdomen
revealed a tumor in the head of the pancreas. The tumor was enucleated;
pathologic examination revealed an insulinoma.
Comment — This case illustrates the importance of carefully questioning and
examining patients for subtle symptoms and signs of hypoglycemia throughout
the duration of a prolonged fast. Despite the degree and duration of hypoglycemia
in this patient, the fast was not terminated, because she was judged to be
asymptomatic.

Should a fast be terminated solely on the basis of the serum glucose

concentration? This is problematic because there is no value that clearly
distinguishes a patient with an insulinoma from a normal subject. Thus, there is no
substitute for repeated assessment of cognitive function of any patient
undergoing a fast to help to decide when to end the fast. However, for the patient
who has already had Whipple's triad confirmed on another occasion, the purpose
of doing a 72-hour fast is to assess the role of beta cell polypeptides in the genesis
of hypoglycemia. In such a case, the fast can be terminated when the glucose is
<55 mg/dL (3.0 mmol/L) since beta cell polypeptides should be suppressed at that
glucose range.

481
The serum beta-hydroxybutyrate concentration and the serum glucose response
to intravenous glucagon at the end of the fast were not diagnostic for insulinoma.
It is possible that the counterregulatory forces operative during prolonged
hypoglycemia predominated over the effects of insulin. We chose to discount
these results because of the inappropriately high serum insulin, C-peptide, and
proinsulin concentrations. The presence of a pancreatic mass provided additional
evidence that the clinical assessment was correct. Markers of insulin action are
therefore most useful when serum insulin, C-peptide, and proinsulin values are
borderline.
CASE 6A 68-year-old woman had a six-year history of episodic confusion
associated with unsteadiness and slurred speech. These symptoms tended to
occur in the early morning hours and were relieved within five minutes after
eating. Shortly after admission to the hospital and 12 hours after her last meal, she
had the following serum values:
●Glucose – 31 mg/dL (1.7 mmol/L)
●Insulin – 43 microU/mL (258 pmol/L)
●C-peptide – 770 pmol/L
●Proinsulin – 240 pmol/L
●Beta-hydroxybutyrate – 0.4 mmol/L
●Glucose increase after glucagon – 45 mg/dL (2.5 mmol/L)
●Sulfonylurea – Negative
A diagnosis of insulinoma was made. Ultrasonography and spiral computed
tomography (CT) of the abdomen were negative. The patient underwent celiac axis
arteriography and a selective arterial calcium stimulation study in which calcium
gluconate is injected into the superior mesenteric, gastroduodenal, or splenic
arteries and blood is collected from the right hepatic vein for measurement of
insulin levels [13]. A positive result is defined as at least a tripling of the basal
hepatic venous serum insulin concentration. In one analysis, a fivefold or greater
rise in insulin is more specific for a diagnosis of insulinoma [14]. In this patient,
there was a more than twofold increase in serum insulin concentration after
calcium was injected into the superior mesenteric artery, a 1.4-fold increase after
calcium was injected into the splenic artery, and little increase after calcium was
injected into the gastroduodenal artery (table 3). (See "Insulinoma", section on
'Diagnosis and staging'.)

A small vascular mass was seen in the mid-body of the pancreas on angiography;
this is the typical appearance of an insulinoma on angiography. The blood supply
to this mass arose from both the superior mesenteric and splenic arteries, as

482
expected from the arterial stimulation test. The patient underwent successful
enucleation of an insulinoma from the mid-body of the pancreas.

Comment — This case illustrates the utility and potential pitfalls of selective

calcium stimulation for localization of a small insulinoma [15]. Ultrasonography
and spiral CT of the abdomen detect only approximately 60 percent of insulinomas
even in the most centers [16]. Accurate preoperative localization of an insulinoma
is desirable because 10 percent of tumors may not be palpable at the time of
surgery [17]. Intraoperative ultrasonography and palpation of the pancreas at
surgery have a sensitivity approaching 100 percent in centers with considerable
experience with this tumor [18].
Selective intra-arterial injection of calcium with sampling of hepatic venous insulin
for the regionalization of insulinoma has been reported from two centers. This test
is based upon the observation that calcium stimulates release of insulin from
insulinomas but not normal beta cells [13]. In this patient, the arteriographic
findings were subtle, and the presence of a positive calcium stimulation test in the
same arterial territory as the vascular abnormality helped to confirm the presence
of a tumor. The surgeon was therefore able to plan the operation in advance.
CASE 7A 76-year-old woman was referred for the evaluation of postprandial
adrenergic symptoms with occasional visual changes. There was one episode of
confusion while on a telephone call to her daughter. During an episode of
lightheadedness, sweating, weakness, and irritability two hours after breakfast
(which occurred while under observation), serum values were as follows:
●Glucose – 51 mg/dL (2.8 mmol/L)
●Insulin – 6.4 microU/mL (45.9 pmol/L)
●C-peptide – 858 pmol/L
●Proinsulin – 33 pmol/L
●Beta-hydroxybutyrate – 0.1 mmol/L
●Glucose increase after glucagon – 46 mg/dL (2.6 mmol/L)
●Sulfonylurea – Negative

A mixed-meal test was performed because of the presence of postprandial

symptoms accompanied by biochemical evidence of insulin-mediated
hypoglycemia. Biochemical testing 180 minutes after a mixed meal revealed the
following:

●Glucose – 43 mg/dL (2.4 mmol/L)

●Insulin – 22.0 microU/mL (157.8 pmol/L)
●C-peptide – 1551 pmol/L

483
The biochemical tests confirmed postprandial hypoglycemia. However, some
caution is needed as to the mechanism. In the postprandial period, there are no
clear normative values for beta-cell polypeptides, although in the absence of upper
gastrointestinal tract surgery, a diagnosis of endogenous hyperinsulinemic
hypoglycemia is likely. The differential diagnosis included noninsulinoma
pancreatogenous hypoglycemia (islet cell hypertrophy/nesidioblastosis), which is
associated with postprandial hypoglycemia, insulin autoimmune hypoglycemia
(postprandial or fasting hypoglycemia), or insulinoma, which more commonly, but
not always, presents as fasting hypoglycemia [5,19]. (See "Noninsulinoma
pancreatogenous hypoglycemia syndrome" and "Insulinoma".)
Insulin antibodies were negative, effectively ruling out insulin autoimmune
hypoglycemia. Imaging studies were performed to localize possible insulinoma.
However, ultrasound and computed tomography (CT) of the pancreas were
negative. Therefore, a selective arterial calcium stimulation test to distinguish
between a diffuse process (islet cell hypertrophy/nesidioblastosis) or a focal
abnormality (insulinoma) was performed. This test involves selective injection
of calcium gluconate into the gastroduodenal, splenic, and superior mesenteric
arteries with subsequent sampling of the hepatic venous effluent for insulin. A
positive result is a doubling or tripling of basal insulin concentrations.
In patients with insulinoma, the increase in insulin occurs in samples from the
artery supplying the tumor, which facilitates operative localization. In contrast,
patients with noninsulinoma pancreatogenous hypoglycemia have variable
responses. There may be a positive result after injection of the splenic artery alone,
splenic and gastroduodenal arteries, and occasionally after injection into all
arteries supplying the pancreas. (See "Insulinoma", section on 'Diagnosis and
staging'.)

The results were as follows:

Time (sec)    Gastroduodenal     Superior mesenteric    Splenic

0                            43                     283                     58
20                          33                     145                     57
40                          32                     249                     53
60                          44                     290                     56
The test was not positive, because it did not show a doubling or tripling of basal
insulin concentrations after calcium gluconate injection into any of the arteries
(see 'Case 6' above). However, the test results were unusual in that there was a
decrease in insulin concentration in the superior mesenteric artery (SMA) at 20
minutes and then an increase. Although a technical error in the performance of
the selective arterial calcium stimulation test or in the assay for insulin could not

484
be established, the test was considered uninterpretable and, therefore, was
repeated.

The repeat stimulation test was highly positive following the SMA injection and
negative for the other two arteries, consistent with a focal abnormality
(insulinoma) in the region of the SMA. The hepatic vein insulin concentrations after
SMA injection were as follows:

Time (sec)       Insulin values (microU/mL)/(pmol/L)

0                        41/294
20                      65/466
40                    333/2389
60                    441/3164

The focality (and magnitude) of the response to the repeat selective arterial
calcium stimulation test suggested a discrete lesion. Since the transabdominal
ultrasound and abdominal CT were negative, an endoscopic ultrasound was
performed for tumor localization. Endoscopic ultrasonography revealed a 1.3 cm
insulinoma in the uncinate process that was later enucleated at pancreatic
exploration.

Comment — This case illustrates the importance of distinguishing between a

negative test result and one that is uninterpretable. It is unclear why the initial
calcium stimulation test was uninterpretable, but the clinicians recognized that it
was unusual. Selective arterial calcium stimulation tests are performed at few
centers and are reserved for complex cases. They should be performed in centers
where clinicians regularly perform and interpret the results.

Another important feature of this case is that the patient presented with
postprandial hypoglycemia. Although insulinoma more commonly presents with
symptoms of fasting hypoglycemia, it can also cause exclusively postprandial
hypoglycemia.

CASE 8A 54-year-old woman presented for evaluation of postprandial

hypoglycemia. Ten years previously she was diagnosed with necrotizing fasciitis
and uncontrolled diabetes. After the fasciitis resolved, she was maintained on
insulin therapy for approximately four years. She discontinued insulin
approximately six years ago after losing weight. Hypoglycemia was documented in
the postprandial period on at least two prior occasions. She had blood drawn at
the endocrine testing center during a typical episode. Serum values were as
follows:
●Glucose – 51 mg/dL (2.8 mmol/L)
485
 ●Insulin– 2.2 microU/mL (13.2 pmol/L)
●C-peptide – 700 pmol/L
●Proinsulin – 10 pmol/L
●Beta-hydroxybutyrate – 0.1 mmol/L
●Glucose increase after glucagon – 60 mg/dL (3.3 mmol/L)
●Sulfonylurea – Negative

Due to clinical suspicion of exogenous insulin use, the laboratory used a mass
spectrometric analysis to demonstrate the presence of aspart insulin (442 pmol/L)
present at the time of hypoglycemia.

Comment — Many insulin immunoassays do not reliably detect insulin analogs.

Therefore, in situations where both C-peptide and insulin are suppressed, the use
of insulin analogs should be suspected. This is especially true in patients with a
prior history of insulin use or patients who have other access to insulin.
SUMMARYThe evaluation of patients suspected of having an insulinoma
traditionally involves a two-step approach that requires biochemical confirmation
of a low serum glucose in the presence of endogenous hyperinsulinemia (high
serum insulin and C-peptide concentrations) in the absence of any evidence of
hypoglycemic drug ingestion, followed by an attempt to localize the tumor
preoperatively.
The first of these objectives can be best achieved by studying the patient during a
spontaneous episode of hypoglycemia. Failing that, have the patient with food-
deprived symptoms fast for up to 72 hours and the rare patient with postprandial
symptoms undergo a mixed-meal test. The results are unequivocal in most
patients with insulinoma. Some patients, however, have serum insulin and C-
peptide concentrations that are borderline or normal and, therefore, indirect
assessment of hyperinsulinemia by measuring serum beta-hydroxybutyrate and
the serum glucose response to glucagon at the end of the fast may be helpful.
Ultrasonography and spiral computed tomography (CT) of the abdomen should be
performed once biochemical evidence of insulinoma is established. When these
imaging techniques do not disclose the site of the tumor, endoscopic
ultrasonography or arteriography and selective arterial calcium stimulation should
be considered.

486
Glucagonoma and the glucagonoma syndrome
Author:
Emily Bergsland, MD
Section Editors:
David M Nathan, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Mar 02, 2021.
INTRODUCTIONGlucagonomas are rare functioning neuroendocrine tumors
that secrete glucagon. This topic will review the clinical manifestations, diagnosis,
and management of glucagonomas. An overview of the clinical manifestations,
diagnosis, and management of pancreatic neuroendocrine tumors and other
functioning pancreatic neuroendocrine tumors are discussed in detail, separately.
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms" and "Surgical resection of sporadic
pancreatic neuroendocrine tumors" and "Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options to control tumor growth and
symptoms of hormone hypersecretion" and "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and symptoms of
hormone hypersecretion" and "Insulinoma" and "Somatostatinoma: Clinical
manifestations, diagnosis, and management" and "Zollinger-Ellison syndrome
(gastrinoma): Clinical manifestations and diagnosis" and "Management and
prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)
EPIDEMIOLOGYGlucagonomas are rare, with an annual incidence of 0.01 to 0.1
new cases per 1,000,000 [1]. Glucagonomas are usually solitary, and the majority
are located in the distal pancreas. Patients typically present in their fifth decade
[2]. While most glucagonomas are sporadic, up to 20 percent may be associated
with the multiple endocrine neoplasia syndrome type 1 (MEN1). However,
glucagonomas occur in only 3 percent of MEN1 patients [3]. Glucagonomas are
usually large (>3 cm), and approximately 50 to 80 percent are metastatic at
diagnosis. Unlike tumors complicated by carcinoid syndrome, however, liver
metastases are not typically a prerequisite for the clinical syndrome. (See "Clinical
features of carcinoid syndrome" and "Multiple endocrine neoplasia type 1: Clinical
manifestations and diagnosis".)

487
CLASSIFICATION, NOMENCLATURE, AND HISTOLOGYGlucagonomas
are neuroendocrine tumors (NETs) derived from multipotential stem cells of
endodermal origin. The World Health Organization classifies NETs arising within
the digestive system based upon the extent to which they resemble their normal
non-neoplastic counterparts (table 1). (See "Pathology, classification, and grading
of neuroendocrine neoplasms arising in the digestive system", section on '2010
and 2019 World Health Organization classification'.)
Nearly all reported cases of the glucagonoma syndrome have been associated
with tumors originating in the alpha cells of the pancreas [2,4]. Histologically, the
tumors consist of cords and nests of well-differentiated NETs with few mitoses and
a histologic appearance that is similar to that of other pancreatic NETs. The cells
are arranged in a solid, trabecular, gyriform, or glandular pattern, with fairly
uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm.
Glucagon is usually detectable within the tumor cells by immunoperoxidase
staining, and glucagon mRNA may be detected by in situ hybridization.
Characteristic alpha cell granules may be seen on electron microscopy.
PATHOPHYSIOLOGYGlucagonoma syndrome is thought to be directly related
to elevated glucagon levels. Glucagon, acting on the liver, increases both amino
acid oxidation and gluconeogenesis from amino acid substrates [5]. The weight
loss characteristic of glucagonoma may result from the catabolic action of
glucagon and through glucagon-like peptides such as GLP-1. Necrolytic migratory
erythema probably results from hyponutrition and amino acid deficiency [6].
Diarrhea may result from hyperglucagonemia and co-secretion of gastrin,
vasoactive intestinal peptide, serotonin, or calcitonin [2].
CLINICAL FEATURESAs the clinical features of glucagonoma syndrome are
non-specific, many patients are diagnosed late when the disease has metastasized
[7]. (See 'Epidemiology' above.)
Weight loss — Weight loss, often significant, is the most common presenting
feature, occurring in 60 to 80 percent of patients with glucagonoma syndrome
[2,7].
Necrolytic migratory erythema — Necrolytic migratory erythema (NME) is the
presenting feature of glucagonoma syndrome in approximately 70 to 80 percent
of patients [2,7,8]. Although the rash can occasionally be the only symptom, in
most cases patients have associated systemic symptoms. NME characteristically
begins as erythematous papules or plaques involving the face, perineum, and
extremities (picture 1) [9]. Over the ensuing 7 to 14 days, the lesions enlarge and
coalesce. Central clearing then occurs, leaving bronze-colored, indurated areas
centrally, with blistering, crusting, and scaling at the borders. The affected areas
are often pruritic and painful. The same process often affects the mucous
488
membranes, resulting in glossitis, angular cheilitis, stomatitis, and blepharitis.
Patients with NME often have associated hair loss and nail dystrophy.
The diagnosis of NME is made with skin biopsies obtained from the edge of the
lesions, which reveal superficial necrolysis with separation of the outer layers of
the epidermis and perivascular infiltration with lymphocytes and histiocytes.
However, multiple biopsies are often required to demonstrate these findings. NME
is not specific for glucagonoma syndrome and has been reported in association
with other disorders in the absence of elevated glucagon levels [10,11].
(See 'Differential diagnosis' below.)
Glucose intolerance/diabetes mellitus — Glucose intolerance occurs in 68 to 95
percent of patients with glucagonoma [2,7,12]. However, clinically significant
hyperglycemia with diabetes mellitus is only present at diagnosis in approximately
40 percent of patients. Hyperglycemia due to glucagonoma syndrome does not
usually result in diabetic ketoacidosis, since beta cell function is preserved and
insulin secretion is normal [2].
Other
●Chronic diarrhea is the most frequent gastrointestinal manifestation of
glucagonoma syndrome and is present in approximately 14 to 18 percent of
patients with glucagonoma syndrome [13].
●Venous thrombosis occurs in up to 50 percent of patients with glucagonoma
and usually manifests as deep vein thrombosis or pulmonary embolism
[12,14]. Unexplained thromboembolic disease in a patient with a
neuroendocrine tumor should alert one to the possibility of glucagonoma.
●Neuropsychiatric manifestations occur in 20 percent of patients with
glucagonoma. Manifestations include depression, insomnia, dementia,
psychosis, agitation, paranoid delusions, ataxia, hyperreflexia, optic atrophy,
and proximal muscle weakness [7,15].
●Dilated cardiomyopathy has been reported in patients with glucagonoma
syndrome [7,16,17].
●Glossitis, stomatitis, or cheilitis has been reported in 41 percent of patients
[7].
Laboratory abnormalities — In addition to elevated serum glucagon levels and
hyperglycemia, glucagonoma syndrome has been associated with other non-
specific laboratory abnormalities. A normocytic normochromic anemia is present
in up to 90 percent of patients [7]. Anemia may be due to anemia of chronic
disease or a direct effect of glucagon on erythropoiesis [4]. Amino acid levels are
markedly diminished. Patients with glucagonoma may also have minor elevations
of secondary hormones, including gastrin, somatostatin, vasoactive intestinal

489
peptide, serotonin, adrenocorticotrophic hormone, and pancreatic polypeptide [2].
(See 'Serum glucagon' below and 'Glucose intolerance/diabetes mellitus' above.)
DIAGNOSISGlucagonoma syndrome should be suspected in patients with
necrolytic migratory erythema with or without associated weight loss, glucose
intolerance, chronic diarrhea, or venous thrombosis. The diagnosis of
glucagonoma is established with an inappropriately elevated fasting plasma
glucagon level.
Serum glucagon — The diagnosis of a glucagonoma requires the demonstration
of increased plasma glucagon levels (>500 pg/mL) [2]. Plasma glucagon levels are
usually elevated 10- to 20-fold in patients with glucagonoma (normal <50 pg/mL).
Concentrations above 1000 pg/mL are virtually diagnostic of glucagonoma.
However, up to 70 percent of the immunoreactive glucagon may be biologically
inactive [18]. A blood glucose should be tested concurrently. Histologic diagnosis
by biopsy is not required to make the diagnosis.
Conditions other than glucagonoma that can induce moderate elevations in the
serum glucagon concentration (<500 pg/mL) include hypoglycemia, fasting,
trauma, sepsis, acute pancreatitis, abdominal surgery, Cushing's syndrome, and
renal and hepatic failure [2]. Idiopathic hyperglucagonemia syndrome, either
familial or sporadic, is associated with a large molecular weight form of the
peptide. In addition, other neuroendocrine tumors, such as carcinoid tumors,
insulinomas, and gastrinomas, can secrete glucagon, although rarely in high
enough levels to cause the classic clinical syndrome [19,20].
However, some glucagonomas are associated with serum levels of the peptide in
the "physiologically elevated" range, even in the presence of necrolytic migratory
erythema. Thus, in patients with the classic syndrome, a serum glucagon
concentration below 500 pg/mL does not exclude a glucagonoma [7,18].
GENETICSMost glucagonomas are sporadic, but up to 10 percent occur in the
setting of the Multiple Endocrine Neoplasia-Type I (MEN-1) hereditary cancer
syndrome [3]. Of note, a small subset of patients appearing to have MEN-1 do not
harbor mutations in the MEN-1  gene, but have a mutation in a cyclin dependent
kinase inhibitor (CDK) gene such as, CDK1B  [21].  In addition, data suggest that 17
percent of patients with seemingly sporadic panNETs harbor germline alterations
in any one of a variety of genes (including MUTYH, CHEK2, and BRCA2, as well
as MEN-1 and VHL), suggesting that all patients with glucagonoma should at least
be considered for testing for inherited genetic syndromes [22]. At a minimum,
patients should be evaluated for a personal or family history consistent with MEN-
1 or other inherited syndrome.
DIFFERENTIAL DIAGNOSISNecrolytic migratory erythema (NME) is not
specific for glucagonoma syndrome and has been reported in association with
490
hepatitis B and cirrhosis, jejunal and rectal adenocarcinoma, villous atrophy of the
small intestine, and myelodysplastic syndrome in the absence of elevated
glucagon levels. (See 'Necrolytic migratory erythema' above.)
NME-like lesions can be seen in a number of other disorders, including zinc
deficiency, pellagra, kwashiorkor, end-stage liver disease, toxic epidermal
necrolysis, pemphigus foliaceus, and pustular psoriasis. (See "Zinc deficiency and
supplementation in children", section on 'Acrodermatitis
enteropathica' and "Malnutrition in children in resource-limited countries: Clinical
assessment", section on 'Kwashiorkor (edematous malnutrition)' and "Stevens-
Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical
manifestations, and diagnosis", section on 'Cutaneous lesions' and "Pathogenesis,
clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus
foliaceus' and "Pustular psoriasis: Pathogenesis, clinical manifestations, and
diagnosis", section on 'Clinical manifestations'.)
TUMOR LOCALIZATION
Approach to imaging — Imaging studies are required to accurately localize the
tumor and stage the extent of disease [23]. Like other neuroendocrine tumors,
glucagonomas express somatostatin receptors, thus they are amenable to
localization using somatostatin analogs. We begin with helical (spiral) multiphasic
contrast-enhanced computed tomography (CT) or contrast-enhanced magnetic
resonance imaging (MRI) for evaluation of patients with a glucagonoma. As
appropriate, endoscopic ultrasound (EUS), somatostatin-receptor (SSTR)
scintigraphy (SRS) or SSTR-positron emission tomography (PET) imaging
(preferred) with 68-gallium-DOTA-D-Phe1-Tyr3-octreotate (Gallium Ga-68
DOTATATE), Ga-68 DOTATOC, or 64-Cu-DOTATATE PET/CT should be performed to
identify the tumor. Because of its greater sensitivity, SSTR-PET/CT is preferred over
conventional SRS with 111-In pentetreotide, where available [24-26]. In addition,
we perform Cu-64 DOTATATE, Ga-68 DOTATATE, or GA-68 DOTATOC PET imaging
to stage patients at risk for distant spread. (See "Metastatic well-differentiated
gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging,
and biochemical monitoring", section on 'Somatostatin receptor-based imaging
techniques'.)
●Computed tomography – CT scan is noninvasive and readily available.
Intravenous contrast enhances the detection of smaller lesions, especially
when images are obtained during the arterial phase. In addition, arterial
phase and portal venous phase sequences can be used to maximize the
conspicuity of liver metastases compared with the surrounding normal liver
parenchyma. CT scans are highly accurate for detecting primary pancreatic
neuroendocrine tumors (NETs), and, using multiphase imaging techniques,
491
sensitivity is >80 percent [27-29]. Since most pancreatic glucagonomas are
more than 3 cm in size at presentation, a pancreatic mass can usually be
identified by CT in the majority of cases [30]. The sensitivity of contrast-
enhanced CT for these tumors approaches 100 percent [31,32].
(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms", section on 'Computed
tomography'.)
●Magnetic resonance imaging – On MRI, pancreatic NETs are typically
characterized by low signal intensity on T1-weighted images and high signal
intensity on T2-weighted images (image 1 and image 2). MRI may have a
higher sensitivity for liver metastases as compared with CT [33].
(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms", section on 'Magnetic
resonance imaging'.)
●Somatostatin-receptor scintigraphy – SRS (OctreoScan) using radiolabeled
form of the somatostatin analog octreotide (Indium-111 [111-In]
pentetreotide) has the advantage of instantaneous whole body scanning,
which also allows detection of metastases outside of the abdominal region
[34]. While SRS can be used for localization and staging of well-differentiated
neuroendocrine tumors, it is rapidly being replaced by functional SSTR-PET
imaging with G8-Ga-DOTATATE, Ga-68 DOTATOC , or Cu-64 DOTATATE, which
have greater spatial resolution and quantification and thus a higher
specificity and sensitivity [26,35-37]. (See "Classification, epidemiology, clinical
presentation, localization, and staging of pancreatic neuroendocrine
neoplasms", section on 'Somatostatin-receptor-based imaging'.)
●Functional SSTR-PET imaging with Ga-68 DOTATATE, Cu-64 DOTATATE,
and Ga-68 DOTATOC – Several positron emission tomography (PET) tracers
for functional imaging have emerged (18-F-dihydroxy-phenyl-alanine [18F-
DOPA], 11-C-5-hydroxytryptophan [11-C-5-HTP], Ga-68-DOTA-D-Phe 1-Tyr3-
Octreotide [gallium Ga-68-DOTATOC], and Ga-68-DOTA-D-Phe 1-Tyr3-
Octreotate [galliumGa-68 DOTATATE]) that offer higher spatial resolution
than conventional SRS and are associated with improved sensitivity for
detection of small lesions [38]. Three of these are approved in the United
States for use with PET for localization of somatostatin receptor-positive
neuroendocrine tumors (NETs). Integrated PET/CT scanning using Ga-68
DOTATATE, Cu-64 DOTATATE, or Ga-68 DOTATOC is the functional imaging
modality of choice for staging and localization of most well differentiated
neuroendocrine tumors (where available) [26]. (See "Metastatic well-
differentiated gastroenteropancreatic neuroendocrine tumors: Presentation,

492
 prognosis, imaging, and biochemical monitoring", section on 'Somatostatin
receptor-based imaging techniques'.)
●Endoscopic ultrasound – EUS can detect pancreatic tumors as small as 2 to
3 mm, provide accurate information on the local extent of disease, and allow
for transmucosal needle biopsy of pancreatic lesions. However, EUS is rarely
used in the evaluation of glucagonomas, as these tumors are diagnosed by
hormonal assays and are usually detectable on CT/MRI at diagnosis.
(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms".)
●Other techniques – Invasive testing to localize the tumor with angiography,
laparotomy, or intraoperative ultrasound should be reserved for patients
who are strongly suspected of having a glucagonoma in whom imaging is
negative [39]. Advances in imaging have nearly eliminated the need for such
intervention. (See "Classification, epidemiology, clinical presentation,
localization, and staging of pancreatic neuroendocrine neoplasms", section
on 'Intraoperative localization techniques'.)
STAGINGPancreatic endocrine tumors such as glucagonomas are included in the
combined American Joint Committee on Cancer/ Union for International Cancer
Control (UICC) tumor-node-metastasis (TNM) staging system [40,41]. Five- and ten-
year survival rates for patients undergoing resection of pancreatic neuroendocrine
tumors (not just glucagonomas) stratified by stage at presentation are presented
in the following table (table 2) [42].
In the newest release of the TNM staging classification (8th edition, 2017), the
staging systems for endocrine pancreatic tumors (table 3) is separate from that
used for exocrine pancreatic tumors [43]. (See "Classification, epidemiology,
clinical presentation, localization, and staging of pancreatic neuroendocrine
neoplasms", section on 'Staging system'.)
TREATMENT
General measures
●Initial management of patients with glucagonoma syndrome consists of
supportive care and management of glucose intolerance/diabetes. Patients
with malnutrition may need nutritional support to reverse the catabolic
effects of elevated glucagon levels. Total parenteral nutrition may be
required preoperatively if resection is contemplated. (See "Overview of
general medical care in nonpregnant adults with diabetes mellitus" and "The
role of parenteral and enteral/oral nutritional support in patients with
cancer", section on 'The perioperative setting'.)
Intermittent infusions of amino and fatty acids have been associated with
long-term resolution of necrolytic migratory erythema (NME) [44]. However,
493
 the evidence to support their use is limited to observational studies. In
addition, amino acid infusions do not cause regression of tumor growth or
other symptoms.
●Somatostatin analogs (eg, octreotide, lanreotide) are the treatment of choice
to control symptoms related to glucagon hypersecretion [45]. Somatostatin
analogs inhibit hormone secretion, reducing serum glucagon concentrations,
and improving NME, diabetes, diarrhea, and neurologic symptoms [2,8,13,45-
49]. However, the improvement does not always correlate with the fall in
serum glucagon, suggesting a direct effect of octreotide on the peripheral
target or organ. The dosing and side effects of somatostatin analogues are
discussed in detail, separately. (See "Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options to control tumor growth
and symptoms of hormone hypersecretion", section on 'Somatostatin
analogs'.)
Pancreatic resection — For the minority of cases in which the tumor is localized at
the time of diagnosis, resection of the primary pancreatic tumor is indicated since
it offers the chance of complete cure. The type of pancreatic resection (eg, distal
pancreatectomy) is dictated by the site and extent of the tumor at the time of
laparotomy. Rapid resolution of hyperglucagonemia and NME usually result after
resection [50]. However, even in cases deemed to be localized preoperatively,
resection results in a cure rate of only about 30 percent [51]. (See "Surgical
resection of sporadic pancreatic neuroendocrine tumors" and "Surgical resection
of lesions of the body and tail of the pancreas".)
Management of advanced/metastatic disease
Liver-directed therapy
●Surgery – Hepatic resection is indicated for the treatment of metastatic liver
disease in the absence of diffuse bilobar involvement, compromised liver
function, or extensive extrahepatic metastases (eg, pulmonary, peritoneal).
Although the vast majority of cases will not be cured by surgery, resection
may increase survival and has the benefit of symptom palliation [52-54].
When feasible, surgical debulking leads to significant reductions in serum
glucagon concentration and in the severity of NME, which may resolve
completely in some patients [2,55,56]. (See "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control
tumor growth and symptoms of hormone hypersecretion", section on
'Surgical resection'.)
●Hepatic artery embolization – Hepatic arterial embolization with or
without selective hepatic artery infusion of chemotherapy is a palliative
technique in patients with symptomatic hepatic metastases who are not

494
 candidates for surgical resection. Embolization can be performed via the
infusion of Gelfoam powder into the hepatic artery through an angiography
catheter (bland embolization), or in conjunction with chemotherapy
(ie, doxorubicin, cisplatin, or streptozocin, or drug-eluting beads)
(chemoembolization). A third embolization technique uses radioactive
isotopes (eg, yttrium-90 [90-Y]) that are tagged to glass or resin microspheres
and delivered selectively to the tumor via the hepatic artery. Response rates
with embolization, as measured by a decrease in hormonal secretion or by
radiographic regression, are generally over 50 percent [57-73].
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Hepatic arterial embolization'.)
●Radiofrequency ablation and cryoablation – Ablation can be used as a
primary treatment modality for neuroendocrine liver metastases or as an
adjunct to surgical resection [53,54,74]. Ablation can be performed
percutaneously or laparoscopically and is less invasive than either hepatic
resection or hepatic artery embolization. However, ablation is applicable only
to smaller lesions (typically <3 cm), and its long-term efficacy is uncertain.
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Ablation'.)
●Liver transplantation – Liver transplantation is considered an
investigational approach for metastatic pancreatic neuroendocrine tumors,
including glucagonoma, as the number of patients with liver-isolated
metastatic disease in whom orthotopic liver transplantation has been
attempted is small, and follow-up data are insufficient to judge whether cure
has truly been achieved [75-77]. (See "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and
symptoms of hormone hypersecretion", section on 'Liver transplantation'.)
Somatostatin analogs — In addition to decreasing hormone secretion and
improving symptom control, somatostatin analogs likely have cytostatic activity in
this disease extrapolating from studies in other well differentiated neuroendocrine
tumors [78,79]. (See "Metastatic well-differentiated pancreatic neuroendocrine
tumors: Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion", section on 'Somatostatin analogs'.)
Molecularly targeted oral therapy — Molecularly targeted agents
(eg, everolimus, sunitinib) have a role in the management of patients with
progressive advanced glucagonomas and are discussed elsewhere [80,81]
(see "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic

495
therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Molecularly targeted therapy').
Peptide receptor radioligand therapy (PRRT) — A form of peptide receptor
radioligand therapy with a radiolabeled somatostatin analog (Lu177 dotatate) is
also approved for use in panNETs and has demonstrated efficacy in patients with
glucagonoma [82,83]. (See "Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options to control tumor growth and
symptoms of hormone hypersecretion", section on 'Peptide receptor radioligand
therapy'.)
Cytotoxic chemotherapy — For patients who are highly symptomatic due to
tumor bulk or who have rapidly enlarging metastases, chemotherapy has been
used as initial treatment together with a somatostatin analog. The options for
therapy typically include a streptozocin-based combination or a temozolomide-
containing regimen. However, experience with systemic chemotherapy in patients
with glucagonomas, specifically, is limited, and few patients have been included in
modern clinical series. The use of cytotoxic chemotherapy in patients with
pancreatic neuroendocrine tumors is discussed in detail elsewhere [84-86].
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic
therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Cytotoxic chemotherapy'.)
POST-TREATMENT SURVEILLANCEThere is limited evidence from which to
make recommendations for follow-up after resection of a glucagonoma.
Guidelines from the National Comprehensive Cancer Network, based upon expert
consensus, include the following recommendations for follow-up after treatment
of a pancreatic neuroendocrine tumor [87]:
●Three to 12 months post-resection: History and physical examination, serum
glucagon level, and abdominal multiphasic computed tomography (CT) or
magnetic resonance imaging (and chest CT scan +/-contrast as clinically
indicated).
●>1 year post-resection to a maximum of 10 years: History and physical
examination with serum glucagon level every 6 to 12 months. Abdominal
multiphasic computed tomography or magnetic resonance imaging (and
chest CT scan +/-contrast) as clinically indicated.
PROGNOSISGlucagonomas are generally slow-growing, but are usually
advanced by the time of diagnosis. The most common site of metastasis is the
liver, followed by regional lymph nodes, bone, adrenal gland, kidney, and lung.
Age, grade, and distant metastases are the most significant predictors of survival.
Once the tumor is metastatic, cure is rarely, if ever, achieved. However, case series
suggest that patients with metastatic disease have a prolonged survival [2,12].
496
Five- and 10-year survival rates for patients undergoing resection of
gastroenteropancreatic neuroendocrine tumors (both pancreatic neuroendocrine
and carcinoid tumors) stratified by stage at presentation are presented in the table
(table 2).
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●Glucagonomas are rare functioning neuroendocrine tumors that secrete
glucagon. They are usually solitary, and the majority are located in the distal
pancreas. Approximately 50 to 80 percent are metastatic at diagnosis.
(See 'Epidemiology' above.)
●Most glucagonomas are sporadic, but up to 10 percent occur in the setting
of the Multiple Endocrine Neoplasia-Type I (MEN-1) hereditary cancer
syndrome. At a minimum, patients should be evaluated for a personal or
family history consistent with MEN-1 or other inherited syndrome.
●Glucagonoma syndrome is thought to be directly related to elevated
glucagon levels. Glucagon, acting on the liver, increases both amino acid
oxidation and gluconeogenesis from amino acid substrates. Weight loss
results from the catabolic action of glucagon and through glucagon-like
peptides such as GLP-1. Necrolytic migratory erythema (NME) probably
results from hyponutrition and amino acid deficiency. Hyperglucagonemia
and co-secretion of gastrin, vasoactive intestinal peptide, serotonin, or
calcitonin lead to diarrhea. (See 'Pathophysiology' above.)
●Glucagonoma syndrome is characterized by NME, cheilitis, glucose
intolerance/diabetes mellitus, anemia, weight loss, chronic diarrhea, venous
thrombosis, and neuropsychiatric symptoms. Of these, weight loss and NME
are the most prevalent symptoms at diagnosis. However, NME is not specific
for glucagonoma syndrome and has been reported in association with other
disorders. (See 'Clinical features' above.)
●Glucagonoma syndrome should be suspected in patients with NME with or
without associated weight loss, glucose intolerance, chronic diarrhea, or
venous thrombosis. The diagnosis of glucagonoma is established with an
elevated fasting plasma glucagon level (>500 pg/mL). (See 'Diagnosis' above.)
●Imaging studies are required to accurately localize the tumor and stage the
extent of disease. We begin with helical (spiral) multiphasic contrast-
enhanced computed tomography (CT) or magnetic resonance imaging (MRI).
If cross-sectional imaging is inconclusive, endoscopic ultrasound or
497
functional imaging with somatostatin receptor positron emission
tomography (SSTR-PET) using Gallium-68-DOTA-0-Phe1-Tyr3-cctreotate
(Gallium Ga-68 DOTATATE), Ga-68 DOTA-0-Phe1Tyr3 octreotide (Ga-68
DOTATOC), or Cu-64 DOTATATE should be performed (or somatostatin
receptor scintigraphy if SSTR-PET is unavailable) to identify the tumor. In
addition, we perform SSTR-PET imaging to fully stage patients at risk for
metastatic disease. SSTR-PET imaging with Ga-68 DOTATATE, Ga-68
DOTATOC, or Cu-64 DOTATATE is preferred when available due to its higher
specificity and sensitivity (compared with somatostatin receptor
scintigraphy). (See 'Approach to imaging' above.)
●Initial management of patients with glucagonoma syndrome consists of
supportive care, management of glucose intolerance/diabetes and
somatostatin analogs (eg, octreotide) to control symptoms related to
glucagon hypersecretion. Patients with malnutrition may need nutritional
support to reverse the catabolic effects of elevated glucagon levels. For the
minority of cases in which the tumor is localized to the pancreas at the time
of diagnosis, resection of the primary pancreatic tumor is indicated.
In patients with metastatic disease, hepatic resection can be considered in
the absence of diffuse bilobar involvement, compromised liver function, or
extensive extrahepatic metastases. Hepatic arterial embolization with or
without selective hepatic artery infusion of chemotherapy may be used for
palliation in patients with symptomatic hepatic metastases who are not
candidates for surgical resection. Long-term efficacy of radiofrequency
ablation and cryoablation are unknown, and experience with orthotopic liver
transplantation is limited. Somatostatin analogs are used to delay
progression in patients with unresectable disease. In addition, cytotoxic
chemotherapy and molecularly targeted agents such
as sunitinib and everolimus have activity in well-differentiated panNET.
Peptide receptor radioligand therapy with Lu177 dotatate is also an approved
option for patients harboring locally advanced or metastatic somatostatin
receptor-positive panNETs by functional imaging. (See 'Treatment' above.)
●Glucagonomas are generally slow-growing, but are usually advanced by the
time of diagnosis. Once the tumor is metastatic, cure is rarely, if ever,
achieved. However, patients with metastatic disease have a prolonged
survival. Our approach for follow-up after treatment of a glucagonoma is
consistent with guidelines from the National Comprehensive Cancer Network
and consists of the following (see 'Prognosis' above):
•3 to 12 months post-resection: History and physical examination, serum
glucagon level, and abdominal multiphasic computed tomography or

498
magnetic resonance imaging (and chest CT scan +/-contrast as clinically
indicated).
•>1 year post-resection to a maximum of 10 years: History and physical
examination with serum glucagon level every 6 to 12 months. Consider
abdominal multiphasic computed tomography or magnetic resonance
imaging (and chest CT scan +/-contrast) as clinically indicated.

499
Insulinoma
Author:
Adrian Vella, MD
Section Editor:
David M Nathan, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 21, 2021.
INTRODUCTIONLow blood glucose concentrations were recognized as a
feature of several diseases in the 19th century. However, it was not until insulin
became available for the treatment of diabetes mellitus in the early 1920s that
clinical events similar to those arising from overtreatment with insulin were
identified in nondiabetic persons. This observation led to the postulation of a new
disease entity called hyperinsulinism [1].
Support for the existence of hyperinsulinism was provided by finding a malignant
pancreatic islet-cell tumor in a patient who had episodes of severe hypoglycemia in
1927 [2]. Extracts of the tumor caused marked hypoglycemia in rabbits. The first
cure of hyperinsulinism by removal of an insulinoma was reported in 1929 [3].
The clinical features, diagnosis, and treatment of insulinomas will be reviewed
here. The causes and evaluation of hypoglycemia, and the management of
metastatic neuroendocrine tumors are discussed separately. (See "Hypoglycemia
in adults without diabetes mellitus: Diagnostic approach" and "Hypoglycemia in
adults without diabetes mellitus: Clinical manifestations, diagnosis, and
causes" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion".)
CLINICAL FEATURESThe common clinical manifestation of an insulinoma is
fasting hypoglycemia, with discrete episodes of neuroglycopenic symptoms that
may or may not be preceded by sympathoadrenal (autonomic) symptoms.
However, postprandial hypoglycemia may be a feature or even the sole
manifestation of hypoglycemia in some patients [4]. The hypoglycemia in persons
with insulinoma is primarily due to reduced hepatic glucose output rather than
increased glucose utilization [5]. (See "Hypoglycemia in adults without diabetes
mellitus: Clinical manifestations, diagnosis, and causes" and "Physiologic response
to hypoglycemia in normal subjects and patients with diabetes mellitus".)
Evidence suggests that insulinomas arise from cells of the ductular/acinar system
of the pancreas rather than from neoplastic proliferation of islet cells [6]. The
500
mechanism by which insulinomas maintain high levels of insulin secretion in the
presence of hypoglycemia is unknown. However, one study reported that a variant
of insulin mRNA with increased translation efficiency is present in high amounts in
insulinomas when compared with normal islets [7]. (See "Pancreatic beta cell
function".)
Incidence — During a six-decade period of observation (1927 to 1986, during
which 224 patients had an insulinoma removed at their first pancreatic
exploration, which took place at the Mayo Clinic), there were eight cases of
insulinoma in residents of Olmsted County, Minnesota, indicating an incidence of
0.4 per 100,000 person-years (or four cases per million per year) [8]. The
distributions by age and sex in a subsequent (1987 to 2007) series from the same
institution were similar to those of the earlier cohort [4]. Insulinomas have been
observed in all ethnic groups.
Mayo Clinic series — Insulinomas are so rare that few institutions have accrued
enough experience to provide meaningful data regarding their demographic
characteristics. This discussion will highlight the demographic and incidence data
from the relatively large number of patients with insulinomas at the Mayo Clinic
and the comprehensive database for residents of Olmsted County (where the
Mayo Clinic is located) [4,8,9]. Patients with insulinoma and a prior history of
gastric bypass were excluded. The demographic features reported from other
centers have usually been similar [10,11].
Distribution of cases by age and sex — For the series observed from 1987 to
2007, there were 237 patients, the median age (and range) at the time of surgery
was 50 years (range 17 to 86 years), and 57 percent were women [4]. There were
no demographic differences between this series and that reported for the period
1927 to 1986 [8]. The demographic features of 40 Chinese patients with insulinoma
studied over a 15-year period match those of the Mayo series [12].
Symptoms — The neuroglycopenic symptoms of insulinoma included confusion,
visual change, and unusual behavior [9]. Sympathoadrenal symptoms may include
palpitations, diaphoresis, and tremulousness [13]. Amnesia for hypoglycemia is
common.
The median duration of symptoms before diagnosis was less than 1.5 years [8].
However, a few patients had probably been symptomatic for decades. As many as
20 percent of patients had been misdiagnosed with a neurologic or psychiatric
disorder before the insulinoma was recognized [9,14]. Seizure disorder is another
common misdiagnosis [8,13]. Weight gain was described in 18 percent of patients
[14].
Overall, symptoms of hypoglycemia occurred exclusively in the fasting state in 73
percent, whereas 21 percent reported both fasting and postprandial symptoms

501
and 6 percent reported only postprandial symptoms [4]. During the period of
study, there was an increase in the frequency of reporting only postprandial
symptoms (2 percent from 1987 to 1992 compared with 10 percent from 2003 to
2007).
MEN1 — Among the 237 patients in one cohort, 14 (6 percent) had multiple
endocrine neoplasia type 1 (MEN1), of whom 71 percent were men [4]. Thirteen (93
percent) had benign insulinomas. Twelve (86 percent) had multiple islet tumors, as
compared with only 3 percent in the rest of the cohort. (See "Multiple endocrine
neoplasia type 1: Clinical manifestations and diagnosis".)
Tumor distribution — Insulinomas can be single or multiple and benign or
malignant. Among the 224 patients in one cohort [8]:
●194 (87 percent) had single benign tumors (one being ectopic)
●16 (7 percent) had multiple benign tumors
●13 (6 percent) had malignant insulinomas, defined as the presence of
metastases
●1 had islet hyperplasia [15]

The median age (and range) of patients with malignant insulinoma was 48 years
(18 to 61 years), and 77 percent were men.

Patients who required additional surgical treatment because of failed initial

surgery or recurrence of insulinoma over the period 1927 to 1986 had an
increased prevalence of MEN1 with multiple tumors (25 percent) and malignant
insulinomas (13 percent) [8].
Among 103 patients, 90 with benign and 13 with malignant disease studied over a
30-year period, there were no differences in clinical characteristics nor diagnostic
criteria between the two groups [16].
Insulinomas have been reported in pregnant women, patients with type 2 diabetes
[17,18], in one patient with type 1 diabetes [15], and in one patient with renal
failure [19].
DIAGNOSIS AND STAGINGThe diagnosis of insulinoma is established by
demonstrating inappropriately high serum insulin concentrations during a
spontaneous or induced episode of hypoglycemia, eg, 72-hour fast for a patient
with fasting hypoglycemia, or in the case of the patient with solely postprandial
symptoms, the mixed-meal test. Virtually all insulinomas are islet-cell tumors;
there is one report of an insulin-secreting small cell carcinoma of the cervix [20].
Other tumors can produce hypoglycemia by different mechanisms, such as the
production of insulin-like growth factor-2. The diagnostic approach is reviewed in
detail separately. (See "Hypoglycemia in adults without diabetes mellitus:
Diagnostic approach".)
502
Staging system — In the newest release of the TNM staging classification
(8th edition, 2017), the staging systems for endocrine pancreatic tumors (table 1) is
separate from that used for exocrine pancreatic tumors [21]. (See "Classification,
epidemiology, clinical presentation, localization, and staging of pancreatic
neuroendocrine neoplasms", section on 'Staging system'.)
Malignant potential — Malignant insulinomas are rare, and therefore, there are
few data regarding their clinical presentation and long-term prognosis. They are
generally indolent tumors, and some patients have prolonged survival, even in the
presence of liver or lymph node metastases. (See 'Patient survival' below
and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring".)
The biologic behavior of pancreatic endocrine tumors does not always correspond
to their histologic characteristics; even malignant tumors show little or no cellular
pleomorphism, hyperchromasia, or increased mitotic activity. Thus, staging and
grading systems have been developed to better study and predict long-term
outcomes. As an example, the World Health Organization estimates the malignant
potential of gastroenteropancreatic neuroendocrine tumors using a classification
scheme that is based upon stage-related (ie, tumor size <2 versus >2 cm, and the
presence of metastases) and grade-related (mitotic rate, perineural and
lymphovascular invasion, Ki-67 proliferative index) criteria [22]. Another
classification scheme estimates malignant potential using similar staging criteria
but a simplified grading system (mitotic rate and presence of necrosis) [23].
Differential diagnosis — There are other disorders in which the biochemical
findings simulate those of an insulinoma because they are also associated with
hyperinsulinemia:
●Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), which is also
called familial hyperinsulinism, congenital hyperinsulinemia, and primary
islet cell hypertrophy (nesidioblastosis), is a genetic disorder that is usually
transmitted as an autosomal recessive trait, but autosomal dominant
inheritance has been described. (See "Pathogenesis, clinical presentation,
and diagnosis of congenital hyperinsulinism".)
●Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) presents
in adults and is also associated with islet hypertrophy and nesidioblastosis.
An unusual feature of this disorder is that hypoglycemia occurs
postprandially, two to four hours after a meal. Fasting hypoglycemia,
characteristic of insulinoma, is rare in this disorder. (See "Noninsulinoma
pancreatogenous hypoglycemia syndrome".)
●Pancreatic islet abnormalities have been described in patients with post-
gastric bypass hypoglycemia [24,25], although this finding has been

503
 questioned [26]. In very rare instances, an insulinoma may manifest in the
post-bariatric surgery setting. (See "Noninsulinoma pancreatogenous
hypoglycemia syndrome", section on 'Islet abnormalities after Roux-en-Y
gastric bypass surgery'.)
●Sulfonylurea-induced hypoglycemia should be considered in every patient
undergoing evaluation for a hypoglycemic disorder, especially when the
hypoglycemia has a chaotic occurrence, ie, no relation at all to meals or
fasting. In some cases, the clinical presentation can appear similar to that of
an insulinoma. The appropriate application and interpretation of available
tests will preclude surgical exploration in such patients. (See "Factitious
hypoglycemia", section on 'Ingestion of an oral insulin
secretagogue' and "Hypoglycemia in adults without diabetes mellitus:
Diagnostic approach", section on 'Approach to testing'.)
●Factitious hypoglycemia due to exogenous insulin administration does not
have the same biochemical findings as insulinoma. Insulin, C-peptide, and
proinsulin are elevated in insulinoma, whereas excessive exogenous insulin
typically is characterized by elevated insulin concentrations but suppressed C-
peptide and proinsulin concentrations. (See "Hypoglycemia in adults without
diabetes mellitus: Diagnostic approach", section on 'Interpretation of
data' and "Factitious hypoglycemia", section on 'Insulin measurements'.)
●Insulin autoimmune hypoglycemia occurs in patients who have antibodies
directed to endogenous insulin or to the insulin receptor. Symptoms can
occur postprandially, fasting, or in both states. In patients with insulin
autoantibodies, it has been postulated that insulin secreted in response to a
meal binds to the antibody and then disassociates in an unregulated fashion
causing hyperinsulinemia and hypoglycemia. In patients with antibodies to
the insulin receptor, hypoglycemia occurs as a result of antibody activation of
the receptor [27]. The presence of insulin or insulin receptor antibodies can
distinguish insulin autoimmune hypoglycemia from insulinoma. The
antibodies do not have to be measured during an episode of hypoglycemia.
(See "Hypoglycemia in adults without diabetes mellitus: Diagnostic
approach".)
TUMOR LOCALIZATION
Noninvasive tests — After diagnosis, imaging techniques are then used to
localize the tumor. Accurate preoperative localization of an insulinoma is desirable
because some tumors may not be palpable at the time of surgery, and patients
can be advised of the type of surgery planned [28]. The noninvasive procedures
available include spiral computed tomography (CT), magnetic resonance imaging
(MRI), transabdominal ultrasonography, 111-In-pentetreotide imaging, and
504
fluorine-18-L-dihydroxyphenylalanine positron emission tomography (18F-DOPA
PET) [29,30]. The choice of procedure depends upon which tests are available and
local radiologic skill. Transabdominal ultrasonography is our preferred initial test.
In a series of 237 patients with insulinoma who were evaluated at the Mayo Clinic,
the rate of detection by transabdominal ultrasound and triple-phase spiral CT of
the pancreas was approximately 70 percent [4].
Gallium Ga-68 DOTATATE PET/CT (a somatostatin-receptor-based imaging
modality) is an option when conventional imaging studies do not identify an
insulinoma. In a retrospective analysis of 31 patients with insulinoma, the
insulinomas were correctly localized in 9 of 10 patients by Ga-68 DOTATATE
PET/CT, and in one patient, it was only seen using this modality [31]. However,
insulinomas express relatively scant levels of subtype 2 somatostatin receptors
and may be less likely to be detected with somatostatin-receptor-based imaging.
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms", section on 'Somatostatin-receptor-based
imaging'.)
Many insulinomas have high concentrations of glucagon-like peptide-1 (GLP-1)
receptors. GLP-1 radioligands that bind to the GLP-1 receptor have been
developed. In a small series, GLP-1 receptor scintigraphy successfully localized
insulinoma in six patients [32]. This modality requires further investigation.
Invasive tests — In patients with endogenous hyperinsulinemic hypoglycemia
and negative noninvasive radiologic localization studies, endoscopic
ultrasonography or a selective arterial calcium stimulation test (SACST) with
hepatic venous sampling can be performed to localize the tumor [33,34]. Overall,
with appropriate preoperative localization studies plus intraoperative
ultrasonography and palpation, a tumor (or tumors) can be identified in 98 percent
of patients with insulinomas.
Endoscopic ultrasound — In small case series, the sensitivity of endoscopic
ultrasound for the detection of insulinoma confirmed by surgery but not detected
by transabdominal ultrasonography or CT ranged from 82 to 85 percent (image 1)
[33,35]. In the larger series (237 patients) from the Mayo Clinic, the sensitivity of
endoscopic ultrasound for localization of insulinoma was 75 percent [4].
Selective arterial calcium stimulation — The advantage of SACST is that it is also
a dynamic test. Arterial calcium stimulation with hepatic venous sampling involves
selective injection of calcium gluconate into the gastroduodenal, splenic, and
superior mesenteric arteries with subsequent sampling of the hepatic venous
effluent for insulin [34,36]. This test is based upon the observation that calcium
stimulates the release of insulin from hyperfunctional beta cells (insulinomas or
nesidioblastosis) but not normal beta cells. Calcium stimulates insulin release in

505
the same arterial territory as the abnormal beta cells, which facilitates operative
localization.
In the Mayo Clinic series of 237 patients with insulinoma, the sensitivity of SACST
for localization of insulinoma was 93 percent for those patients selected to
undergo this procedure [4]. When invasive testing (endoscopic ultrasound and/or
SACST) was performed in patients with negative noninvasive (ultrasound, CT
abdomen) testing, tumor localization was achieved in all cases from 1998 onward.
(See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach",
section on 'Selective arterial calcium stimulation'.)
SACST has been evaluated for its ability to differentiate insulinoma from
nesidioblastosis. In a retrospective review of 116 cases of endogenous
hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging
from the Mayo Clinic (1996 to 2014), 42 patients were subsequently shown at
surgery to have insulinoma and 74 nesidioblastosis [37]. Using maximum increase
in hepatic venous insulin concentration over baseline after calcium injection,
cutpoints of >91.5 microinternational units/mL and >263.5 microinternational
units/mL were 95 and 100 percent specific for insulinoma, respectively. In addition,
a 19-fold increase in hepatic venous insulin over baseline was 99 percent specific
for insulinoma. Whereas a robust response to injected calcium (especially in a
single artery) is suggestive of insulinoma and a modest response in more than one
artery is compatible with nesidioblastosis, the overlap in response characteristics is
such that there is not a criterion of response that will provide complete diagnostic
accuracy.
TREATMENT
Resection of primary tumor — Surgical removal of the insulinoma is the
treatment of choice. (See "Surgical resection of sporadic pancreatic
neuroendocrine tumors" and "Surgical resection of sporadic pancreatic
neuroendocrine tumors", section on 'Insulinoma'.)
The following procedures were performed in the Mayo Clinic cohort [8]:
●Enucleation of the insulinoma – 130 patients
●Partial distal pancreatectomy – 73 patients
●Enucleation of the insulinoma and partial pancreatectomy – 9 patients
●A Whipple procedure (removal of the head of the pancreas, gastrectomy,
duodenectomy, and splenectomy) – 1 patient
●Total pancreatectomy – 1 patient

The surgical procedure was chosen by the surgeon, and none of the operations in
the series (1927 to 1986) were done via the laparoscope. Since then, a few cases

506
have been managed laparoscopically. The rate of surgical complications was
approximately 10 percent.

In addition, eight patients with malignant insulinomas underwent biopsy of

metastatic lesions, and the tumor was found at autopsy after perioperative death
in one patient. Histologic examination of this tumor revealed a malignant islet cell
tumor that stained intensively for insulin (picture 1A-B).
Outcome — In the 1927 to 1986 series, the following results were noted after
surgery [8]:
●196 patients (87.5 percent) were cured, as defined by being totally free of
symptoms for at least six months after removal of the insulinoma
●19 patients (8.5 percent), 10 with benign insulinomas, eight with malignant
insulinomas, and one with islet-cell hyperplasia, had persistent hypoglycemia
●5 (2.2 percent) developed diabetes mellitus
●4 (1.8 percent) died perioperatively; all four were operated on before 1941

Among the 10 patients who had benign insulinomas and persistent hypoglycemia
after initial surgical treatment, six had multiple tumors (four due to multiple
endocrine neoplasia type 1 [MEN1]). Five of these six patients underwent
reoperation. Three of the five were found to have additional multiple tumors; one
was cured, and two developed diabetes mellitus after the second operation. Two
patients with single tumors at initial operation had persistent hypoglycemia after
the second operation because additional insulinomas were not identified.

For patients with insulinoma related to MEN1, some experienced surgeons

recommend local excision of any tumors found in the head of the pancreas plus a
distal subtotal pancreatectomy [38]. This approach differs from that in patients
with sporadic insulinomas, who typically have a solitary tumor and in whom
enucleation is usually successful.
Laparoscopic surgery — In some centers, laparoscopic pancreatic surgery is
sometimes performed for small, solitary insulinomas that have been localized
preoperatively [39-41]. Intraoperative laparoscopic ultrasound may help minimize
the need for conversion to open pancreatic surgery. (See "Surgical resection of
sporadic pancreatic neuroendocrine tumors", section on 'Minimally invasive
resection'.)
Chemical ablation — Ultrasound-guided fine-needle injection of ethanol into an
insulinoma in patients with prohibitively high surgical risk has been conducted
with successful resolution of hypoglycemia [42]. Seven patients with insulinoma
had resolution of hypoglycemia after injection with the sclerosing agent
lauromacrogol [43].
507
Evaluation for missed insulinoma — Reoperation for missed insulinoma presents
unique problems. First, the diagnosis must be confirmed. Second, one or more
localizing procedures should be done. (See 'Tumor localization' above.)
Reoperation for insulinoma should only be performed by a surgeon experienced
with this situation and accompanied by highly experienced endocrinologic and
radiologic support. Blind pancreatic resection should not be performed if a tumor
is not identified [44].
Risk of recurrence — As noted above, 196 patients in the 1927 to 1986 series
were in remission soon after surgery (defined as a six-month period free of
symptoms after initial removal of an insulinoma). Among these patients, 11 (6
percent) had recurrent hypoglycemia. Eight of these patients underwent repeat
exploration of the pancreas: six had pathologic confirmation of recurrent
insulinoma, one had persistent hypoglycemia despite total pancreatectomy, and
one died intraoperatively. Pancreatic re-exploration was not performed in the
other three patients, because of age and concerns about diabetes. Recurrence of
hypoglycemia within four years of the successful removal of an insulinoma
suggests regrowth of residual insulinoma tissue left behind as a result of
fracturing of the original tumor. In this case, the tumor is at the same site as the
original tumor [45].
The recurrences occurred from 4 to 18.5 years after the initial operation. The
cumulative incidence of recurrence was 6 percent at 10 years and 8 percent at 20
years. Recurrences were more common in the patients with MEN1; the cumulative
10- and 20-year recurrence rates were 21 percent at both times compared with 5
and 7 percent in those without MEN1 (p<0.001) (figure 1) [8]. Among four patients
with malignant insulinoma who were symptom free for six or more months after
the initial operation, two patients had recurrences at four and nine years.
Patient survival — The overall survival rate of patients with insulinoma did not
differ from that expected in the general population. Survival, however, was
significantly worse in the patients with malignant insulinomas (but better than in
patients with acinar pancreatic carcinoma), in older patients, and in those
diagnosed early in the period of observation (1927 through 1986) (figure 2) [8].
Some patients with malignant insulinoma appear to have a prolonged natural
history. In a series of 10 patients treated at the National Institutes of Health over a
20-year period for metastatic insulinoma, nine remained alive long term (up to 25
years), three with liver metastases [46]. Four had developed metastatic disease
from 4 to 12 years after initial diagnosis, while four had resected lymph node
metastases as the only site of disease. Various treatment modalities were used to
control hypoglycemia. In this series, short-term benefits were most often achieved

508
with embolization and diazoxide and less often with radiofrequency ablation,
radical debulking surgery, verapamil, octreotide, and chemotherapy.
Medical therapy to control symptomatic hypoglycemia — Medical therapy
should be considered in the patient whose insulinoma was missed during
pancreatic exploration, who is not a candidate for or refuses surgery, or who has
unresectable metastatic disease. The therapeutic choices to prevent symptomatic
hypoglycemia include:
●Diazoxide (which diminishes insulin secretion and is given in divided doses
of up to 1200 mg/day) is sometimes used for controlling hypoglycemia [46-
48]. However, it can cause marked edema (which may require high doses of
loop diuretics) and hirsutism.
●Octreotide, an analog of somatostatin (growth hormone-inhibitory
hormone), inhibits growth hormone secretion but, in large doses, also
inhibits the secretion of thyroid-stimulating hormone (TSH), insulin, and
glucagon. While octreotide is highly effective in controlling the symptoms
associated with glucagonomas, VIPomas, and carcinoid tumors, efficacy is
less predictable for symptomatic patients with insulinoma [46,49-52].
Nevertheless, it is a reasonable choice for patients with persistent
hypoglycemia that is refractory to diazoxide.
Lanreotide, another somatostatin analog that is available internationally and
in the United States for the treatment of acromegaly, appears to have similar
clinical efficacy as octreotide, and is also available in a long-acting depot form
(lanreotide SR). (See "Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options to control tumor growth
and symptoms of hormone hypersecretion", section on 'Benefits'.)
●Verapamil [46] and phenytoin [53] have also been used with some success.
However, none of these drugs is as effective as tumor resection.
●Although experience is limited, at least some data suggest that refractory
cases may respond to treatment with everolimus, an inhibitor of the
mammalian (mechanistic) target of rapamycin (mTOR). (See "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options
to control tumor growth and symptoms of hormone hypersecretion", section
on 'mTOR inhibitors'.)
Radiation therapy — Experience with external beam radiotherapy (EBRT) in the
management of islet cell tumors is limited. Although pancreatic neuroendocrine
carcinomas were previously considered to be radioresistant, data from published
case reports and small case series suggest that radiotherapy can produce high
rates of symptom palliation and freedom from local progression in patients who

509
are not candidates for surgical resection [54-57]. There are no data specifically on
the rate of symptom control in patients with symptomatic insulinomas.
Liver-directed therapy for metastatic disease — The liver and regional lymph
nodes are the most common sites of metastatic disease.
Resection — Hepatic resection is indicated for the treatment of metastatic liver
disease in the absence of diffuse bilobar involvement, compromised liver function,
or extensive extrahepatic metastases (eg, pulmonary, peritoneal). Although the
majority of cases will not be cured by surgery, prolonged survival is often possible,
given the slow-growing nature of these tumors. (See "Overview of hepatic
resection".)
In general, resection should be considered only for patients with a limited number
of hepatic metastases and is most successful when undertaken with curative
intent. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Surgical resection'.)
Hepatic artery embolization — Liver metastases derive most of their blood
supply from the hepatic artery, whereas healthy hepatocytes derive most of their
blood supply from the portal vein. This provides the rationale for therapeutic
embolization of the hepatic artery, with the goal of inducing necrosis of the
metastases with minimal damage to normal liver parenchyma.
Hepatic arterial embolization with or without selective hepatic artery infusion of
chemotherapy is frequently applied as a palliative technique in patients with
symptomatic hepatic metastases who are not candidates for surgical resection.
Response rates, as measured by a decrease in hormonal secretion or by
radiographic regression, are generally over 50 percent. (See "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control tumor
growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial
embolization'.)
RFA and cryoablation — Other approaches to the treatment of hepatic-
predominant disease include radiofrequency ablation (RFA) and cryoablation,
either alone or in conjunction with surgical debulking. These procedures, which
can be performed using percutaneous or laparoscopic approaches, appear to be
less morbid than either hepatic resection or hepatic artery embolization. However,
both techniques are applicable only to smaller lesions, and their long-term efficacy
is uncertain. (See "Metastatic gastroenteropancreatic neuroendocrine tumors:
Local options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Ablation'.)
Radioembolization — An alternative means of delivering focal radiotherapy uses
radioactive isotopes (eg, yttrium-90 [90-Y]) that are tagged to glass or resin

510
microspheres and delivered selectively to the tumor via the hepatic artery.
Evidence of benefit is limited. In one case report, radioembolization improved
refractory hypoglycemia for three months [58]. (See "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control tumor
growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial
embolization'.)
Liver transplantation — The number of patients with liver-isolated metastatic
disease in whom orthotopic liver transplantation (OLT) has been attempted is
small, and follow-up data are insufficient to judge whether complete cure has truly
been achieved. The limited availability of donor organs in many regions has
restricted investigation of this procedure. Until more data become available, most
clinicians consider that liver transplantation is an investigational approach for
metastatic islet cell tumors, including insulinoma.
Chemotherapy and novel treatment approaches — Experience with systemic
chemotherapy is limited. The traditional regimen of choice has
been streptozocin and doxorubicin. Although objective response rates as high as
69 percent were initially reported for metastatic islet cell tumors, the true
radiologic response rate is probably lower, between 10 and 40 percent.
Uncertainty as to efficacy, as well as the toxicity of this regimen (nausea,
prolonged myelosuppression, renal failure), has prevented its widespread
acceptance as a standard first-line therapy.
Antitumor activity has also been shown for regimens containing the orally active
alkylating agent temozolomide. In the absence of comparative trials, the choice of
first-line streptozocin/doxorubicin or a temozolomide-based regimen must be
individualized, taking into account the convenience of oral rather than intravenous
treatment, performance status, and the anticipated side-effect profile of both
combinations. (See "Metastatic well-differentiated pancreatic neuroendocrine
tumors: Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion", section on 'Cytotoxic chemotherapy'.)
The modest efficacy of conventional cytotoxic chemotherapy has prompted the
development of novel therapeutic approaches for patients with advanced islet cell
tumors. These include molecularly targeted therapy with small molecule tyrosine
kinase inhibitors and inhibitors of the mammalian (mechanistic) target of
rapamycin (mTOR), as well as peptide receptor radioligand therapy. These topics
are discussed in detail elsewhere. (See "Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options to control tumor growth and
symptoms of hormone hypersecretion", section on 'Molecularly targeted
therapy' and "Metastatic well-differentiated pancreatic neuroendocrine tumors:

511
Systemic therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Peptide receptor radioligand therapy'.)
POST-TREATMENT SURVEILLANCEThere are no evidence-based guidelines
for follow-up after resection of a malignant insulinoma. Consensus-derived
guidelines from the National Comprehensive Cancer Network following treatment
for an islet cell tumor include the following [59]:
●3 to 12 months postresection – History and physical examination, tumor
markers, and computed tomography (CT)/magnetic resonance imaging (MRI).
●Long term – History and physical examination with tumor markers (as
clinically indicated) every 6 to 12 months. Imaging studies are recommended
as clinically indicated.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basicstopic (see "Patient education: Low blood sugar in people without

diabetes (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Insulinomas are rare pancreatic islet cell tumors not limited to any ethnic
group (incidence of 1 case per 250,000 person-years); while most are
sporadic, some are associated with multiple endocrine neoplasia type 1
(MEN1) syndrome. The characteristic clinical manifestation of an insulinoma
is fasting hypoglycemia, (although some patients also have postprandial
hypoglycemia), with neuroglycopenic symptoms that may or may not be
512
preceded by sympathoadrenal (autonomic) symptoms. (See 'Clinical
features' above.)
Most insulinomas are solitary and benign. Multiple insulinomas are less
common and tend to be associated with MEN1. Malignant insulinomas are
also less common. (See 'Tumor distribution' above.)
●The diagnosis of insulinoma is established by demonstrating inappropriately
high serum insulin concentrations during a spontaneous or induced episode
of hypoglycemia (eg, 72-hour fast for fasting hypoglycemia or a mixed-meal
test for postprandial hypoglycemia). (See 'Diagnosis and staging' above
and "Hypoglycemia in adults without diabetes mellitus: Diagnostic
approach".)
Imaging techniques are then used to localize the tumor. Accurate
preoperative localization of an insulinoma is desirable. Transabdominal
ultrasonography and computed tomography (CT) are our preferred initial
test, followed by endoscopic ultrasonography or arterial stimulation with
hepatic venous sampling when an insulinoma has not been localized by
noninvasive techniques. (See 'Diagnosis and staging' above and 'Tumor
localization' above.)
●For initial therapy of patients with benign, solitary insulinomas, we
recommend surgical excision of the tumor (Grade 1A). The approach and
extent of surgery should be determined based upon tumor location.
(See 'Resection of primary tumor' above.)
●For patients with multiple insulinomas (typically in the setting of MEN1), we
suggest local excision of any tumors found in the head of the pancreas plus a
distal subtotal pancreatectomy (Grade 2B). (See 'Resection of primary
tumor' above.)
●For patients with persistent hypoglycemia after surgery in whom solitary or
multiple tumors are identified after additional localization procedures, we
recommend repeat operation (Grade 1A). (See 'Resection of primary
tumor' above.)
●For patients whose insulinoma cannot be located during pancreatic
exploration, who are not candidates for or refuse surgery, we
suggest diazoxide therapy for the medical management of hypoglycemia
(Grade 2C). (See 'Medical therapy to control symptomatic
hypoglycemia' above.)
●For patients with potentially resectable liver-isolated metastatic insulinoma,
we recommend surgical resection of the hepatic metastases along with the
primary tumor (Grade 1B). Although the majority of cases will not be cured

513
by surgery, given the slow-growing nature of the tumor, extended survival is
sometimes possible. (See 'Resection' above.)
●Other treatment options for patients with unresectable, hepatic-
predominant, symptomatic metastatic disease include embolization,
chemoembolization, radiofrequency ablation (RFA), and cryoablation.
(See 'Liver-directed therapy for metastatic disease' above.)
●The efficacy of somatostatin analogs for patients with diazoxide-refractory
symptomatic hypoglycemia is unpredictable, but some patients may
benefit. Octreotide, as well as other systemic therapy approaches (interferon,
chemotherapy, targeted radiotherapy), are discussed in detail elsewhere.
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors:
Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion".)

514
Management and prognosis of the Zollinger-
Ellison syndrome (gastrinoma)
Author:
Emily Bergsland, MD
Section Editor:
Mark Feldman, MD, MACP, AGAF, FACG
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: May 26, 2020.
INTRODUCTIONPatients with Zollinger-Ellison syndrome (ZES) have gastrin-
secreting tumors and the associated clinical consequences. This disorder can occur
sporadically, or as a manifestation of multiple endocrine neoplasia type 1 (MEN 1).
Medical therapy is the current standard of care for most patients with ZES as part
of the MEN 1 syndrome. By contrast, many patients with sporadic ZES are
candidates for surgical therapy. (See "Zollinger-Ellison syndrome (gastrinoma):
Clinical manifestations and diagnosis" and "Multiple endocrine neoplasia type 1:
Treatment" and 'Surgery' below.)
Prior to the development of effective acid suppression therapy, the major
morbidity and mortality of ZES were related to complications of fulminant peptic
ulcer disease; total gastrectomy was the only effective measure to protect patients
from these problems [1].
The development of H2 antagonists and the more powerful proton pump
inhibitors has resulted in a significant decrease in morbidity and mortality from
ulcer disease and has obviated the need for gastrectomy [2]. Of 212 patients with
ZES studied prospectively for a mean of 13.8 years, a ZES-related cause of death
could be identified in only one-half of the 31 percent who died. All of the ZES-
related deaths were due to tumor spread; none were due to hypersecretory
complications [3].
This topic review will discuss the two current goals of therapy in ZES [4]:
●Control of the complications resulting from autonomous release of gastrin
●Control of the tumor itself

MEDICAL MANAGEMENTThe goal of medical management in Zollinger-

Ellison syndrome (ZES) is to limit the clinical manifestations and complications of
peptic ulcer disease. Because peptic symptoms in patients with ZES are often a
poor marker of acid secretion, formal acid secretory studies have been advocated

515
to guide the dosage of acid suppressants, with the goal of reducing gastric acid
secretion to below 10 mEq/h prior to the next dose [5]. However, such studies are
often not available even in major medical centers, and it has become customary
among many gastroenterologists to initiate and maintain proton pump inhibitors
at high dosage, using symptoms alone as a signal to increase the dose. To the
author's knowledge, there have been few if any episodes of major peptic diathesis
associated with this approach.
Proton pump inhibitors — Proton pump inhibitors
(eg, omeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole,
and esomeprazole) effectively block acid secretion by irreversibly binding to and
inhibiting the hydrogen/potassium ATPase that resides on the luminal surface of
the parietal cell. (See "Proton pump inhibitors: Overview of use and adverse effects
in the treatment of acid related disorders".)
Their effects last for more than 24 hours; as a result, many patients can be treated
with a once a day regimen [5].
Patients with ZES should be started on a high dose of a PPI (eg, omeprazole 40 mg
twice daily, pantoprazole 80 mg twice daily) [4,6,7]. PPIs have been generally safe,
even when used in high doses. Some patients require an early upward titration of
these doses; however, once control of acid output has been achieved, a gradual
dose reduction is usually possible [8]. In a study of 37 patients who had received
high-dose omeprazole for almost two years, nearly 50 percent were able to titrate
the maintenance dose down to 20 mg daily [9]. Overall, 95 percent of patients
without MEN 1, severe gastroesophageal reflux, or previous partial gastrectomy
had safe reductions in their medication dose. PPIs are generally well tolerated and
can control hypergastrinemia in ZES for >10 years (although some patients
experience low vitamin B12 levels) [10]. (See "Proton pump inhibitors: Overview of
use and adverse effects in the treatment of acid related disorders", section on
'Adverse effects'.)
When PPIs are unable to control gastric acid secretion, somatostatin analogs such
as octreotide and lanreotide can inhibit secretion of gastrin [11,12]. However, due
to the unpredictability of the response and requirement for parenteral
administration, they are not first-line agents for symptomatic patients with
hypergastrinemia.
SURGERYPatients with a sporadic gastrinoma who do not have evidence of
metastatic spread of disease should be offered exploratory laparotomy and
resection with curative intent, even in the event of negative imaging studies in
approximately 17 percent of patients [1,4,13,14]. This recommendation stems from
the fact that 60 to 90 percent of gastrinomas are malignant and, in addition to
eliminating (or at least decreasing) the need for antisecretory medical therapy,
516
successful resection of sporadic gastrinomas protects against the possibility of
eventual morbidity and death from metastatic spread of the tumor (see below). In
the hands of an experienced surgeon, up to 50 percent of these patients will be
cured [13,15]. Lymphadenectomy exceeding more than 10 lymph nodes at the
time of surgery has been shown to achieve a higher biochemical cure as compared
with selective or no lymphadenectomy [16,17]. The number of positive lymph
nodes (or lymph node ratio) appears to have prognostic significance in gastrinoma
and other panNETs. Recognizing the potential for cure in patients undergoing
complete tumor removal (particularly with modern imaging tools and our ability to
control acid hypersecretion throughout the perioperative period), the merits (and
risks) of surgery need to be considered in the context of the life expectancy and co-
morbidities of each patient [10].
The likelihood for surgical cure is especially high for extrapancreatic gastrinomas
(eg, those in the duodenum or peripancreatic lymph nodes). In contrast,
laparotomy is not routinely recommended for patients with Zollinger-Ellison
syndrome (ZES) as part of MEN 1 since the multifocal nature of the tumors in this
disorder almost uniformly precludes cure of gastrin hypersecretion [4,15].
(See "Multiple endocrine neoplasia type 1: Treatment".) However, because a
minority of MEN-1 tumors can have aggressive growth patterns, some recommend
imaging techniques or even surgical exploration to identify those exceeding 2 cm
with the intent of resecting them. Of note, while not routine, some groups have
taken a more aggressive approach in MEN1 patients with gastrinomas, pursuing
surgical resection based on localization with the selective arterial secretagogue
injection test to achieve a biochemical cure [18].
Eighty percent of curable gastrinomas lie within the gastrinoma triangle
comprised of the head of the pancreas and the duodenal sweep. Sporadic
gastrinomas are often solitary and >2 cm and located in the pancreas; tumors
arising in the setting of MEN 1 most commonly arise in the duodenum and are
typically small (<2 cm) and multiple [19]. The combination of preoperative
localization techniques makes it possible for the experienced surgeon to identify
over 90 percent of sporadic gastrinomas [4,20]. Intraoperative transduodenal
illumination and duodenotomy are of particular value in detecting very small
gastrinomas arising in the wall of the duodenum [14,21]. Enucleation is preferred
when feasible, but local resection is often required for pancreatic head lesions and
a distal pancreatectomy may be necessary for large tail lesions [10]. Whipple
resections are not routine in ZES, but are reserved for pancreatic head or duodenal
lesions that cannot be removed by enucleation. In such cases, the potential
benefits, including improved lymph node retrieval, need to be weighed against the
risks of complications from the Whipple procedure. In the unlikely event that a

517
sporadic gastrinoma cannot be identified at surgery, we suggest deferring a
Whipple's procedure in favor of closure, with the intent of serial imaging every six
months to try to localize the neoplasm [22]. Laparoscopic surgery is controversial
in ZES compared with other panNETs, owing to the need for more extensive
exploration and lymphadenectomy in sporadic tumors. A minimally invasive
approach may be reasonable, however, in the setting of a pancreatic tail
gastrinoma occurring in the setting of MEN1 [10]. (See "Classification,
epidemiology, clinical presentation, localization, and staging of pancreatic
neuroendocrine neoplasms".)
Gastric secretion may not return to the normal range following gastrinoma
resection because of a residual excess of gastric parietal cells, a consequence of
the trophic effect of chronically elevated gastrin levels. Up to 40 percent of patients
will require prolonged antisecretory therapy to control hyperacidity following
curative resection, and such patients need continued monitoring for acid
hypersecretion [23,24]. Of 50 patients who underwent curative resection for ZES,
gastric hypersecretion was observed for a mean of eight years in 62 percent of
patients and was judged to be extreme in 28 percent despite normal blood gastrin
levels [25].
A parietal cell (proximal gastric) vagotomy performed at the time of tumor
resection has been advocated to reduce (and in some cases obviate) the need for
postoperative medical therapy, particularly when complete resection of the
gastrinoma tissue cannot be accomplished [23,26]. However, it is currently
uncommonly performed because of the efficacy of proton pump inhibitors.
Furthermore, relatively few surgeons currently perform this procedure.
The reduction in mortality associated with surgical therapy for patients without
metastatic disease was illustrated in a prospective study of 124 patients with
gastrinoma presumed to be free of metastasis by imaging studies [27]. Only 3
percent of the 98 patients who underwent resection developed liver metastases
during a mean follow-up period of 6.3 years [27]. By contrast, 23 percent of 26
patients treated medically developed metastatic disease over a slightly longer
follow-up period (8.7 years). Two deaths due to metastatic gastrinoma occurred in
the medically treated group compared with no disease-specific deaths in the
operative group.
Reoperation for recurrence — Although surgery decreases the incidence of
hepatic metastases and improves survival, long-term biochemical cure is achieved
in less than 30 percent. Reoperation may be of benefit in those with recurrent ZES
in whom the tumor can be identified and localized. In one study, for example, 17
patients with recurrent disease that was unequivocally imaged underwent 18
reoperations [28]. Five patients were disease free after operation, with a median

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follow-up of 28 months. There were no deaths in the cured group; two patients in
the group with persistent disease died during a median follow-up of 34 months
[29].
RADIATION THERAPY FOR NONSURGICAL CANDIDATESExperience
with external beam radiotherapy (RT) in the management of gastrinomas is
limited. Although pancreatic neuroendocrine tumors were previously considered
to represent a radioresistant neoplasm, data from published case reports and
small case series suggest that RT can produce high rates of symptomatic palliation
and freedom from local progression in patients who are not candidates for
surgical resection [30-36].
THERAPY OF METASTATIC DISEASEThe liver is the major metastatic site for
gastrinomas, as it is with other islet cell tumors. The second most common site is
bone (7 percent of patients in one series), almost all of which occur in patients who
also have liver metastases [37]. The axial skeleton (spine or sacrum) is the primary
site of bone metastasis, but other sites can be involved [37]. Historically,
somatostatin receptor scintigraphy and MRI have been thought to be the best
imaging modalities to detect these lesions; the former being preferred because
extra-axial lesions can occur. Because of its greater sensitivity, 68-Ga DOTATATE
PET/CT may be preferable to conventional somatostatin receptor scintigraphy, if
available [38,39].
Metastatic gastrinoma is now the most common cause of morbidity and mortality
in patients with Zollinger-Ellison syndrome (ZES). Unfortunately, current treatment
modalities are of limited benefit. A general algorithmic approach to therapy for
patients with metastatic disease is outlined in the figure (algorithm 1).
Somatostatin analogs — Somatostatin analogs like octreotide and lanreotide are
highly effective in controlling the symptoms associated with hormone
hypersecretion in other pancreatic islet cell tumors that express somatostatin
receptors such as glucagonomas and VIPomas, as well as carcinoid tumors; its
efficacy is less predictable for gastrinomas [40-42]. Octreotide can reduce gastrin
levels, and may slow tumor growth, but objective evidence of antitumor activity is
rare [42-45]. As an example, in a report of 15 patients treated with octreotide for
malignant gastrinoma and progressive hepatic metastases, seven had stabilization
of tumor growth, and one an objective decrease in tumor size [45]. The median
duration of benefit was 25 months. In the United States, octreotide is approved for
control of hormone-mediated symptoms in patients with neuroendocrine tumors.
Lanreotide appears to have similar clinical efficacy as octreotide, and is also
available in a long-acting depot form (Lanreotide-SR) [40,46]. It is approved for use
in the United States based on the results of the randomized phase III CLARINET
study showing a statistically significant improvement in progression-free survival
519
in patients with nonfunctional gastroenteropancreatic neuroendocrine tumors
treated with lanreotide compared to those treated with placebo [47].
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic
therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Benefits'.)
Liver-directed therapy
Resection — Hepatic resection is indicated for the treatment of metastatic liver
disease in the absence of diffuse bilobar involvement, compromised liver function,
or extensive extrahepatic metastases (eg, pulmonary, peritoneal). Although the
majority of cases will not be cured by surgery, prolonged survival is often possible,
given the slow-growing nature of these tumors [48,49].
In general, resection should be considered only for patients with a limited number
of hepatic metastases and is most successful when undertaken with curative
intent. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Surgical resection'.)
Hepatic artery embolization — Liver metastases derive most of their blood
supply from the hepatic artery, whereas healthy hepatocytes derive approximately
70 percent of their blood supply from the portal vein. This provides the rationale
for therapeutic embolization of the hepatic artery, with the goal of inducing
necrosis of the metastases with minimal damage to normal liver parenchyma.
Hepatic arterial embolization with or without selective hepatic artery infusion of
chemotherapy is frequently applied as a palliative technique in patients with
symptomatic hepatic metastases who are not candidates for surgical resection [50-
53]. Response rates, as measured by a decrease in hormonal secretion or by
radiographic regression, are generally over 50 percent. Randomized trials have not
yet been performed, thus it is not known with certainty if one type of embolization
is preferable to another. Radioembolization with selective internal radiation
therapy using Yttrium microspheres is also used, although prospective studies
comparing one type of embolization with another have not been completed [53].
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to
control tumor growth and symptoms of hormone hypersecretion", section on
'Hepatic arterial embolization'.)
RFA and cryoablation — Other approaches to the treatment of hepatic-
predominant disease include radiofrequency ablation (RFA) and cryoablation,
either alone or in conjunction with surgical debulking [54-56]. These procedures,
which can be performed using percutaneous or laparoscopic approaches, appear
to be less morbid than either hepatic resection or hepatic artery embolization.
However, both techniques are applicable only to smaller lesions, and their long-

520
term efficacy is uncertain. (See "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and symptoms of
hormone hypersecretion", section on 'Ablation'.)
Liver transplantation — The number of patients with liver-isolated metastatic
disease in whom orthotopic liver transplantation (OLT) has been attempted is
small, and follow-up data are insufficient to judge whether complete cure has truly
been achieved. The limited availability of donor organs in many regions has
restricted investigation of this procedure.
Until more data become available, most clinicians consider that liver
transplantation is an investigational approach for metastatic islet cell tumors,
including gastrinoma. (See "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Liver transplantation'.)
Chemotherapy and novel treatment approaches — Experience with systemic
chemotherapy for metastatic gastrinoma is limited. The traditional regimen of
choice has been streptozocin and doxorubicin. Although objective response rates
as high as 69 percent were initially reported for metastatic neuroendocrine
tumors, [57] with decreases in endocrine hyperfunction, the true radiologic
response rate is probably between 10 and 40 percent [58,59]. Uncertainty as to
efficacy, as well as the toxicity of this regimen, which can include nausea,
prolonged myelosuppression, and renal failure, has prevented its widespread
acceptance as a standard first-line therapy for patients with metastatic
neuroendocrine tumors, including gastrinoma.
Antitumor activity has also been shown for regimens containing the orally active
alkylating agent temozolomide. A retrospective review of 143 patients treated
with capecitabine plus temozolomide reported that 54 percent of patients
experienced a radiographic response to therapy [60]. Response to chemotherapy
was not influenced by O(6)-methylguanine DNA methyltransferase expression,
proliferative activity, or ALT pathway activation. More recently, the results from a
prospective randomized study (ECOG2211) of capecitabine plus temozolomide
compared with temozolomide alone in pancreatic neuroendocrine tumors
revealed similar response rates in both arms (approximately 30 percent), but the
median progression-free survival was longer in the combination arm (22.7 months
versus 14.4 months, HR 0.58, p=0.023) [61]. As a result of this study, use of
capecitabine plus temozolomide has become routine for advanced panNET.
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic
therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Cytotoxic chemotherapy'.)

521
The modest efficacy of conventional cytotoxic chemotherapy has prompted the
development of novel therapeutic approaches for patients with advanced
pancreatic neuroendocrine tumors. These include molecularly targeted therapy
with inhibitors of the mechanistic target of rapamycin (mTOR), small molecule
vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, and
lutetium Lu177 dotatate peptide receptor radioligand therapy [62-66].
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic
therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Molecularly targeted therapy' and "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options to
control tumor growth and symptoms of hormone hypersecretion", section on
'Peptide receptor radioligand therapy'.)
PROGNOSISMortality from gastrinomas largely depends upon whether the
tumor is benign or malignant, and the extent of disease involvement. In an
illustrative series, 185 patients with Zollinger-Ellison syndrome (ZES) were followed
prospectively for a mean of 12.5 years [67]. The following results were noted:
●Liver metastases were found in 24 percent of patients at the time of
diagnosis; the majority of these patients had a primary pancreatic neoplasm,
and 67 percent had primary tumors that were greater than 3 cm in size.
●Patients with liver metastases had a 10-year survival of only 30 percent
compared with a 15-year survival of 83 percent in those without liver
metastases.
●Patients with lymph node metastases had the same mortality as those who
were free of visceral metastases.
●Patients with MEN 1 had a significantly lower rate of metastasis at the time
of initial diagnosis (6 percent); their high overall survival rate (100 percent at
20 years) reflected this fact.
The level of fasting serum gastrin (FSG) at the time of initial diagnosis may provide
an indication of disease extent and estimated prognosis in patients with sporadic
ZES. In a follow-up report of 239 patients with ZES, the level of preoperative FSG
correlated with tumor size and presence of lymph nodes and liver metastases (as
found at exploration), as well as primary site (pancreas tumors associated with
highest levels of FSG) [68]. The five-year survival rates for patients with mild (0 to
499 pg/mL), moderate (500 to 1000 pg/mL), or severe elevations (>1000 pg/mL) of
FSG were 94, 92, and 86 percent, respectively. The corresponding 10-year survival
rates were 86, 87, and 73 percent.
POSTTREATMENT SURVEILLANCEThere is limited evidence from which to
make recommendations for follow-up after resection of a gastrinoma. Guidelines
from the National Comprehensive Cancer Network based upon expert consensus
522
include the following recommendations for follow-up after resection of pancreatic
neuroendocrine tumor [69]:
●3 to 12 months postresection – History and physical examination, serum
gastrin, and abdominal multiphasic computed tomography or magnetic
resonance imaging and chest CT (+/- contrast) as clinically indicated.
●Long-term – History and physical examination with tumor markers every 6
to 12 months for a maximum of ten years. Imaging studies with abdominal
multiphasic computed tomography or magnetic resonance imaging and
chest CT (+/- contrast) as clinically indicated.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●Medical therapy is the current standard of care for most patients with
Zollinger-Ellison syndrome (ZES) as part of the MEN 1 syndrome.
(See "Multiple endocrine neoplasia type 1: Treatment".) By contrast, we
recommend that (in addition to medical therapy) patients with a sporadic
gastrinoma and without evidence of metastatic spread of disease be treated
with exploratory laparotomy and resection with curative intent (Grade 1B). In
addition to eliminating or at least decreasing the need for antisecretory
medical therapy, successful resection of sporadic gastrinomas reduces the
risk of eventual morbidity and death from metastatic spread of the tumor.
(See 'Medical management' above.)
●The goal of medical management in ZES is to limit the clinical manifestations
and complications of peptic ulcer disease. We recommend that patients with
ZES should be started on a high dose proton pump inhibitor
(eg, omeprazole 40 mg twice daily) (Grade 1B). Subsequent lowering of
dosage without recurrence of symptoms is usually achievable. (See 'Medical
management' above.)
●Mortality from gastrinomas depends largely upon whether the tumor is
benign or malignant, and the extent of disease involvement. Metastatic
gastrinoma is the most common cause of morbidity and mortality in patients
with ZES. Unfortunately, the current modalities for treatment of metastatic
disease are not curative. (See 'Prognosis' above.)
●For patients with limited, resectable liver-isolated metastatic gastrinoma, we
recommend surgical resection of the hepatic metastases along with the
primary tumor (Grade 1B). Although the majority of cases will not be cured

523
by surgery, given the slow-growing nature of the tumor, extended survival is
sometimes possible. (See 'Resection' above.)
●Other treatment options for patients with unresectable hepatic-
predominant metastatic disease include bland embolization,
chemoembolization, selective internal radiation therapy (radioembolization),
RFA, and cryoablation. (See 'Liver-directed therapy' above.)
●The efficacy of somatostatin analogs for patients with symptomatic
metastatic gastrinoma is unpredictable, but some patients with somatostatin
receptor-positive tumors may benefit. (See 'Somatostatin analogs' above.)
●Other systemic therapy approaches (chemotherapy, molecularly targeted
agents, and peptide receptor radioligand therapy) to control symptoms and
tumor growth are discussed in detail elsewhere. (See "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options
to control tumor growth and symptoms of hormone hypersecretion".)

524
Somatostatinoma: Clinical manifestations,
diagnosis, and management
Author:
Emily Bergsland, MD
Section Editors:
David M Nathan, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Mar 16, 2020.
INTRODUCTIONSomatostatinomas are rare neuroendocrine tumors of D-cell
origin that contain and sometimes secrete excessive amounts of somatostatin
(figure 1) [1]. This topic will review the clinical manifestations, diagnosis, and
management of somatostatinomas. An overview of the clinical manifestations,
diagnosis, and management of pancreatic neuroendocrine tumors is discussed in
detail separately. (See "Classification, epidemiology, clinical presentation,
localization, and staging of pancreatic neuroendocrine neoplasms" and "Surgical
resection of sporadic pancreatic neuroendocrine tumors" and "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options to
control tumor growth and symptoms of hormone hypersecretion" and "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control tumor
growth and symptoms of hormone
hypersecretion" and "Insulinoma" and "Glucagonoma and the glucagonoma
syndrome" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations
and diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome
(gastrinoma)" and "VIPoma: Clinical manifestations, diagnosis, and management".)
EPIDEMIOLOGYSomatostatinomas are rare neuroendocrine tumors with an
annual incidence of 1 in 40 million [2]. The mean age at diagnosis of
somatostatinomas is 50 to 55 years (range 26 to 84), with a roughly equal gender
distribution [3]. Approximately 55 percent of somatostatinomas are in the
pancreas, and, of these, two-thirds arise within the head of the pancreas. The
remainder arises in the ampulla and periampullary region of the duodenum or
rarely in the jejunum [4]. Other rare primary sites include the liver, colon, and
rectum [3,5]. Approximately 75 percent of somatostatinomas are malignant, and
70 to 92 percent present with metastatic disease [6].

525
Although 35 to 45 percent of somatostatinomas occur in association with multiple
endocrine neoplasia (MEN)-1 syndrome or other familial syndrome,
somatostatinomas are among the least common functioning pancreatic
neuroendocrine tumors in patients with MEN-1 syndrome, occurring in less than 1
percent of patients [7]. Up to 10 percent of patients with neurofibromatosis I (NF-1;
von Recklinghausen disease) develop somatostatinomas. NF-1-associated
somatostatinomas are characteristically duodenal, are rarely associated with
somatostatinoma syndrome, and are less likely to metastasize as compared with
sporadic somatostatinomas [4,7,8].
PATHOPHYSIOLOGYSomatostatin is a tetradecapeptide that normally acts in
a paracrine manner to inhibit secretion of many hormones, including insulin,
glucagon, gastrin, and growth hormone. It also has direct effects on a number of
gastrointestinal functions [9]. In patients with somatostatinomas, cholelithiasis
may result from inhibition of cholecystokinin release, which reduces gallbladder
contractility [10]. Diarrhea and steatorrhea result from inhibition of pancreatic
enzyme and bicarbonate secretion and intestinal absorption of lipids. Many
patients with somatostatinomas also have gastric hypochlorhydria due to
decreased gastrin secretion. (See 'Clinical manifestations' below and "Physiology of
somatostatin and its analogues".)
Some somatostatinomas, particularly those arising in the ampullary and
periampullary area, contain immunoreactive granules but are not associated with
any functional syndrome [8,11]. In contrast, those arising in the pancreas may
secrete large amounts of somatostatin, resulting in a constellation of symptoms of
somatostatinoma syndrome. (See 'Clinical manifestations' below.)
CLINICAL MANIFESTATIONSWhile these tumors secrete somatostatin,
clinical symptoms related to high somatostatin levels are found in less than 10
percent of cases, depending on the location of the tumor (pancreas >duodenal),
and the likely intermittent nature of somatostatin secretion from the tumor [12].
When present, the most common symptoms in patients with somatostatinomas,
regardless of their location, are abdominal pain (50 percent) and weight loss (20 to
30 percent) [12].
Less often, patients present with somatostatinoma syndrome, characterized by the
triad of diabetes mellitus or glucose intolerance, cholelithiasis, and
diarrhea/steatorrhea. Somatostatinoma syndrome is more common in patients
with pancreatic somatostatinomas as compared with duodenal somatostatinomas
(19 versus 2 percent), due to differences in their secretion of somatostatin [4,13].
(See 'Pathophysiology' above.)
Duodenal somatostatinomas usually present with symptoms caused by local
complications [8,13]. These symptoms include abdominal pain, obstructive
526
jaundice, and gastrointestinal bleeding. Duodenal somatostatinomas can also be
associated with multiple paragangliomas, and polycythemia is due to somatic gain
of function of HIF2a, which activates the erythropoietin gene, causing
polycythemia [12,14,15].
DIAGNOSISSomatostatinoma syndrome should be suspected in patients with
the classical triad of diabetes/glucose intolerance, cholelithiasis, and
diarrhea/steatorrhea. Providers should look for elevated tissue concentrations of
somatostatin by immunohistochemistry and/or elevated plasma somatostatin
concentrations [12]. In patients with somatostatinoma syndrome, the diagnosis is
established by the presence of a fasting plasma somatostatin level exceeding 30
pg/mL. However, somatostatinoma syndrome is rare, and most somatostatinomas
are detected as pancreatic or duodenal masses during the course of evaluation of
abdominal pain, jaundice, or weight loss. In such patients, the diagnosis is often
established by histopathology of the surgical specimen that demonstrates well-
differentiated islet cells that stain positive for somatostatin on
immunohistochemistry. (See "Clinical manifestations, diagnosis, and staging of
exocrine pancreatic cancer", section on 'Biopsy and establishing the diagnosis'.)
TUMOR LOCALIZATION
Approach to imaging — Imaging can localize the tumor and stage the extent of
disease. Like other neuroendocrine tumors, glucagonomas express somatostatin
receptors, thus they are amenable to localization using somatostatin analogs. We
begin with helical (spiral) multiphasic contrast-enhanced computed tomography
(CT) or contrast-enhanced magnetic resonance imaging (MRI) for evaluation of
patients with a somatostatinoma. In patients with inconclusive cross-sectional
imaging, we perform endoscopic ultrasound (EUS). We perform somatostatin
receptor scintigraphy or integrated PET/CT using Gallium-68-DOTA-0-Phe 1-Tyr3-
Octreotate (Gallium Ga-68 DOTATATE) or Gallium-68-DOTA-0-Phe1-Tyr3-Octreotide
(Gallium Ga-68 DOTATOC) for indeterminate lesions, to work up occult primary
tumors, and to fully stage neuroendocrine tumors. Because of its greater
sensitivity, Ga-68 DOTATATE of Ga-68 DOTATOC PET/CT is preferred over
conventional somatostatin receptor scintigraphy, where available [16-21].
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms", section on 'Computed tomography'.)
●Computed tomography – Since the primary tumor is usually large (>3 cm
diameter) by the time of diagnosis, it is localizable by CT in the majority of
cases. Intravenous contrast enhances the detection of smaller lesions,
especially when images are obtained during the arterial phase. In addition,
arterial phase and portal venous phase sequences can be used to maximize

527
the conspicuity of liver metastases compared with the surrounding normal
liver parenchyma.
●Magnetic resonance imaging – On MRI, pancreatic neuroendocrine tumors
are typically characterized by low signal intensity on T1-weighted images and
high signal intensity on T2-weighted images (image 1 and image 2). MRI may
have a higher sensitivity for liver metastases as compared with CT.
(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms", section on 'Computed
tomography' and "Classification, epidemiology, clinical presentation,
localization, and staging of pancreatic neuroendocrine neoplasms", section
on 'Magnetic resonance imaging'.)
●Endoscopic ultrasound – EUS can detect pancreatic tumors as small as 2 to
3 mm, provides accurate information on the local extent of disease, and
allows transmucosal needle biopsy of pancreatic lesions in patients with
locally advanced tumors. (See "Classification, epidemiology, clinical
presentation, localization, and staging of pancreatic neuroendocrine
neoplasms", section on 'Endoscopic ultrasonography'.)
●Somatostatin receptor scintigraphy – Somatostatin receptor scintigraphy
(OctreoScan) using radiolabeled form of the somatostatin
analog octreotide (Indium-111 [111-In] pentetreotide) has the advantage of
instantaneous whole body scanning, which also allows detection of
metastases outside of the abdominal region [11,22]. While SRS can be used
for localization and staging of well-differentiated neuroendocrine tumors, it is
rapidly being replaced by functional PET imaging using Ga-68-DOTATATE or
Ga-68 DOTATOC, which have, thus, a higher specificity and sensitivity [18-21].
(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms", section on 'Somatostatin-
receptor-based imaging'.)
●Functional PET imaging with Ga-68 DOTATATE and Ga-68 DOTATOC –
Several positron emission tomography (PET) tracers for functional imaging
have emerged (18-F-dihydroxy-phenyl-alanine [18F-DOPA], 11-C-5-
hydroxytryptophan [11-C-5-HTP], Ga-68-DOTA-D-Phe1-Tyr3-Octreotide [gallium
Ga-68-DOTATOC], and Ga-68-DOTA-D-Phe1-Tyr3-Octreotate [gallium Ga-68
DOTATATE]) that offer higher spatial resolution than conventional SRS and
are associated with improved sensitivity for detection of small lesions [23].
Both Ga-68 DOTATATE and Ga-68 DOTATOC are approved in the United
States for use with PET for localization of somatostatin receptor positive
neuroendocrine tumors. Integrated PET/CT scanning using Ga-68 DOTATATE
or Ga-68 DOTATOC is the functional imaging modality of choice for staging

528
 and localization of most well differentiated neuroendocrine tumors (where
available). (See "Metastatic well-differentiated gastroenteropancreatic
neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical
monitoring", section on 'Somatostatin receptor-based imaging techniques'.)
STAGINGThe American Joint Committee on Cancer (AJCC)/Union for International
Cancer Control (UICC) and European Neuroendocrine Tumor Society (ENETS) have
proposed the staging systems for neuroendocrine tumors (table 1) [24]. The
AJCC/UICC tumor, node, metastasis (TNM) staging system covers both pancreatic
exocrine and neuroendocrine malignancies. Both staging systems are highly
prognostic for both relapse-free and overall survival [25-27]. The newest release of
the TNM staging classification (eight edition, 2017) has a staging system for
neuroendocrine tumors of the pancreas (table 2) that is separate from that used
for exocrine pancreatic tumors [28]. (See "Classification, epidemiology, clinical
presentation, localization, and staging of pancreatic neuroendocrine neoplasms",
section on 'Staging system'.)
DIFFERENTIAL DIAGNOSISThe differential diagnosis of somatostatinoma
varies based on the clinical presentation. Somatostatinoma can be differentiated
from other pancreatic and small intestine tumors by somatostatin levels and by
histology.
●The differential diagnosis of a pancreatic mass includes primary exocrine
pancreatic cancer, other pancreatic neuroendocrine tumors, lymphoma,
metastatic cancer, focal chronic pancreatitis, and autoimmune pancreatitis.
Evaluation of a patient with a pancreatic mass is presented in detail
separately. (See "Clinical manifestations, diagnosis, and staging of exocrine
pancreatic cancer", section on 'Pancreatic mass seen on an imaging study'.)
●The differential diagnosis of steatorrhea include cirrhosis, chronic
cholestasis, bacterial overgrowth, ileal resection, or ileal disease. The
evaluation of chronic diarrhea and steatorrhea are discussed in detail
separately. (See "Overview of nutrient absorption and etiopathogenesis of
malabsorption", section on 'Fat' and "Approach to the adult with chronic
diarrhea in resource-rich settings".)
TREATMENT
Pancreatic resection — Surgical resection is the treatment of choice [10]. Most
somatostatinomas are solitary and located in the head of the pancreas or
duodenum and can be managed with pancreaticoduodenectomy. However, as 70
to 92 percent of patients present with metastatic disease, curative surgery is often
not possible [6,29]. (See "Surgical resection of sporadic pancreatic neuroendocrine
tumors" and "Surgical resection of sporadic pancreatic neuroendocrine tumors",
section on 'Others'.)
529
Treatment of advanced/metastatic disease
Somatostatin analogue — Somatostatin and its analogues
(eg, octreotide, lanreotide) inhibit the secretion of somatostatin and are first-line
therapy for symptomatic disease in patients with unresectable tumors. Although
somatostatin analogues are highly effective at controlling the symptoms of
hormone hypersecretion, objective evidence of antitumor activity has not
specifically been demonstrated in somatostatinomas. Control of tumor growth is
expected, extrapolating from randomized controlled studies in metastatic midgut
neuroendocrine tumors (octreotide) and gastroenteropancreatic neuroendocrine
tumors without hormone-mediated symptoms (lanreotide) [12,30,31].
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic
therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Somatostatin analogs'.)
Liver-directed therapy for metastatic disease
●Surgery – Hepatic resection is indicated for the treatment of metastatic liver
disease in the absence of diffuse bilobar involvement, compromised liver
function, or extrahepatic metastases (eg, pulmonary, peritoneal). Although
cure is unlikely, resection may increase survival (eg, by "setting the clock
back" in a slow-growing disease) and has the benefit of symptom palliation)
[32,33]. (See "Surgical resection of sporadic pancreatic neuroendocrine
tumors" and "Overview of hepatic resection" and "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control
tumor growth and symptoms of hormone hypersecretion", section on
'Surgical resection'.)
Postoperative complications include rebound gastric acid hypersecretion and
intravascular fluid overload resulting from a shift of copious amounts of fluid
from the intestinal lumen. Proton pump inhibitor and somatostatin analog
therapy are recommended in the preoperative and perioperative period to
prevent these complications [34,35].
●Hepatic artery embolization and chemoembolization – Hepatic arterial
embolization, with or without selective hepatic artery infusion of
chemotherapy, is a palliative technique in patients with symptomatic hepatic
metastases who are not candidates for surgical resection. Embolization can
be performed via the infusion of Gelfoam powder into the hepatic artery
through an angiography catheter (bland embolization) or in conjunction with
chemotherapy (ie, doxorubicin, cisplatin, or streptozocin, or drug-eluting
beads) administered via the hepatic artery (chemoembolization). A third
embolization technique uses radioactive isotopes (eg, yttrium-90 [90-Y]) that
are tagged to glass or resin microspheres and delivered selectively to the

530
 tumor via the hepatic artery. Response rates, as measured by a decrease in
hormonal secretion or by radiographic regression, are generally over 50
percent [36-51]. (See "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Hepatic arterial embolization'.)
●Radiofrequency ablation and cryoablation – Ablation can be used as a
primary treatment modality for neuroendocrine liver metastases or as an
adjunct to surgical resection [52]. Ablation can be performed percutaneously
or laparoscopically and is less invasive than either hepatic resection or
hepatic artery embolization. However, ablation is applicable only to smaller
lesions (typically <3 cm), and its long-term efficacy is uncertain [52].
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Ablation'.)
●Liver transplantation – Liver transplantation is considered an
investigational approach for metastatic pancreatic neuroendocrine tumors,
as the number of patients with liver-isolated metastatic disease in whom
orthotopic liver transplantation has been attempted is small, and follow-up
data are insufficient to judge whether a complete cure has truly been
achieved [53,54]. (See "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Liver transplantation'.)
Molecularly targeted therapy — Molecularly targeted agents
(eg, everolimus, sunitinib) have a role in the management of patients with
progressive advanced somatostatinomas and have proven anti-tumor efficacy in
progressive pancreatic neuroendocrine tumors [55,56]. (See "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options to
control tumor growth and symptoms of hormone hypersecretion", section on
'Molecularly targeted therapy'.)
Peptide receptor radioligand therapy — A form of peptide receptor radioligand
therapy with a radiolabeled somatostatin analog (Lu177 dotatate) is now approved
for use in panNETs and is discussed in detail elsewhere. Activity has been noted in
patients with glucagonoma [57,58].
Cytotoxic chemotherapy — For patients who are highly symptomatic due to
tumor bulk or who have rapidly enlarging metastases, chemotherapy has been
used as initial treatment together with a somatostatin analogue. However,
experience with systemic chemotherapy in patients with somatostatinomas is
limited, and few patients have been included in chemotherapy series. The use of
cytotoxic chemotherapy in patients with pancreatic neuroendocrine tumors

531
typically includes streptozocin- or temozolomide-based chemotherapy and is
discussed in detail elsewhere [59-61]. (See "Metastatic well-differentiated
pancreatic neuroendocrine tumors: Systemic therapy options to control tumor
growth and symptoms of hormone hypersecretion", section on 'Cytotoxic
chemotherapy'.)
PROGNOSISThe prognosis of somatostatinomas with any therapy is poor when
metastatic disease is present [29]. There are not enough survival data for
somatostatinoma specifically to give accurate estimates of survival [4,62,63].
However, 5- and 10-year survival rates for patients undergoing resection for a
gastroenteropancreatic neuroendocrine tumor (both pancreatic neuroendocrine
and carcinoid tumors) stratified by stage at presentation are presented in the
Table (table 3) [64].
POST-TREATMENT SURVEILLANCEThere is limited evidence from which to
make recommendations for follow-up after resection of a somatostatinoma, and
guidelines are based on expert consensus [63]. Our approach for follow-up after
treatment of a somatostatinoma is consistent with guidelines from the National
Comprehensive Cancer Network and consists of the following [65]:
●3 to 12 months post-resection: History and physical examination, serum
somatostatin level, and abdominal multiphasic computed tomography (CT) or
magnetic resonance imaging (MRI) (and chest CT scan +/-contrast as clinically
indicated).
●>1 year post-resection to a maximum of 10 years: History and physical
examination with serum somatostatin level every 6 to 12 months. Consider
abdominal multiphasic CT or MRI (and chest CT scan +/-contrast) as clinically
indicated.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY
●Somatostatinomas are rare neuroendocrine tumors of D-cell origin that
contain and sometimes secrete excessive amounts of somatostatin (figure 1).
The mean age at diagnosis of somatostatinomas is 50 to 55 years.
Approximately 55 percent of somatostatinomas are in the pancreas, and, of
these, two-thirds arise within the head of the pancreas. The remainder arises
in the ampullary and periampullary area of the duodenum and rarely in the
jejunum. (See 'Epidemiology' above.)

532
●In patients with somatostatinomas, cholelithiasis may result from inhibition
of cholecystokinin release, which reduces gallbladder contractility.
Diminished insulin secretion leads to glucose intolerance/diabetes. Inhibition
of pancreatic enzyme and bicarbonate secretion and intestinal absorption of
lipids causes diarrhea and steatorrhea. (See 'Pathophysiology' above.)
●The most common symptoms in patients with somatostatinomas, regardless
of their location, are abdominal pain and weight loss. Less often, patients
present with somatostatinoma syndrome characterized by diabetes
mellitus/glucose intolerance, cholelithiasis, and diarrhea/steatorrhea.
Somatostatinoma syndrome is more common in patients with pancreatic
somatostatinomas as compared with duodenal somatostatinomas (19 versus
2 percent). Duodenal somatostatinomas usually present with obstructive
jaundice, weight loss, and gastrointestinal bleeding. (See 'Clinical
manifestations' above.)
●Somatostatinoma syndrome should be suspected in patients with the
classical triad of diabetes/glucose intolerance, cholelithiasis, and
diarrhea/steatorrhea. In patients with somatostatinoma syndrome, the
diagnosis is established by the presence of a fasting plasma somatostatin
level exceeding 30 pg/mL. However, somatostatinoma syndrome is rare, and
most somatostatinomas are detected as pancreatic or duodenal masses
during the course of evaluation of abdominal pain, jaundice, or weight loss.
In such patients, the diagnosis is often established by histopathology of the
surgical specimen that demonstrates well-differentiated islet cells that stain
positive for somatostatin on immunohistochemistry. (See 'Diagnosis' above.)
●Somatostatinomas can occur in the setting of the Multiple Endocrine
Neoplasia-Type I (MEN-1) or NF-1. At such, patients should be evaluated for a
personal or family history consistent with MEN-1 or other inherited
syndrome. Duodenal somatostatinomas can also be associated multiple
paragangliomas and polycythemia is due to somatic gain of function of HIF2a
which activates the erythropoietin gene causing polycythemia.
●Cross-sectional imaging with multiphasic computed tomography (CT) or
magnetic resonance imaging (MRI) of the abdomen can localize the tumor
and stage the extent of disease. If cross-sectional imaging is inconclusive,
endoscopic ultrasound or functional imaging with somatostatin-receptor
scintigraphy or integrated PET/CT using Gallium Ga-68 DOTATATE or Gallium
Ga-68 DOTATOC should be performed to identify the tumor. In addition, we
perform somatostatin-receptor scintigraphy/68-Ga DOTATATE PET/CT to fully
stage patients at risk for metastatic disease. (See 'Tumor localization' above.)

533
●As with other neuroendocrine tumors, surgical resection is the treatment of
choice. However, because 75 percent of patients have tumors that have
metastasized by the time the diagnosis is made, curative surgery is often not
possible. (See 'Pancreatic resection' above and "Surgical resection of sporadic
pancreatic neuroendocrine tumors", section on 'Others'.)
●Hepatic resection can be considered in patients with metastatic disease in
the absence of diffuse bilobar involvement, compromised liver function, or
extensive extrahepatic metastases. Hepatic arterial embolization, with or
without selective hepatic artery infusion of chemotherapy, may be used for
palliation in patients with symptomatic hepatic metastases who are not
candidates for surgical resection. Long-term efficacy of radiofrequency
ablation and cryoablation are unknown, and experience with orthotopic liver
transplantation is limited. Benefit has been shown for cytotoxic
chemotherapy and molecularly targeted agents such
as sunitinib and everolimus. (See 'Treatment of advanced/metastatic
disease' above and "Metastatic well-differentiated pancreatic neuroendocrine
tumors: Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion" and "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and
symptoms of hormone hypersecretion".)
●In the setting of unresectable disease, somatostatin analogs are used to
delay progression. In addition, benefit has been shown for cytotoxic
chemotherapy and molecularly targeted agents such
as sunitinib and everolimus. Peptide receptor radioligand therapy with Lu177
dotatate is also an approved option for patients harboring locally advanced
or metastatic somatostatin receptor-positive tumors by functional imaging.
(See 'Treatment of advanced/metastatic disease' above and "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options
to control tumor growth and symptoms of hormone
hypersecretion" and "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion".)
●Prognosis is generally poor when patients present with metastatic disease.
Our approach for follow-up after treatment of a somatostatinoma is
consistent with guidelines from the National Comprehensive Cancer Network
and consists of the following (see 'Prognosis' above and 'Post-treatment
surveillance' above):

534
 ●3 to 12 months post-resection: History and physical examination, serum
somatostatin level, and abdominal multiphasic CT or MRI (and chest CT scan
+/-contrast as clinically indicated).
●>1 year post-resection to a maximum of 10 years: History and physical
examination with serum glucagon level every 6 to 12 months. Consider
abdominal multiphasic computed tomography or magnetic resonance
imaging (and chest CT scan +/-contrast) as clinically indicated.
VIPoma: Clinical manifestations, diagnosis, and
management
Author:
Emily Bergsland, MD
Section Editors:
Kenneth K Tanabe, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Nov 02, 2021.
INTRODUCTIONVIPomas are rare functioning neuroendocrine tumors that
secrete vasoactive intestinal polypeptide (VIP) [1,2]. This topic will review the
clinical manifestations, diagnosis, and management of VIPomas. An overview of
the clinical manifestations, diagnosis, and management of pancreatic
neuroendocrine tumors and other functioning pancreatic neuroendocrine tumors
are discussed in detail, separately. (See "Classification, epidemiology, clinical
presentation, localization, and staging of pancreatic neuroendocrine
neoplasms" and "Surgical resection of sporadic pancreatic neuroendocrine
tumors" and "Metastatic well-differentiated pancreatic neuroendocrine tumors:
Systemic therapy options to control tumor growth and symptoms of hormone
hypersecretion" and "Metastatic gastroenteropancreatic neuroendocrine tumors:
Local options to control tumor growth and symptoms of hormone
hypersecretion" and "Insulinoma" and "Somatostatinoma: Clinical manifestations,
diagnosis, and management" and "Glucagonoma and the glucagonoma
syndrome" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations
and diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome
(gastrinoma)".)
EPIDEMIOLOGYVIPomas are detected in 1 in a million people per year [3]. The
majority of VIPomas arise within the pancreas, and are classified as functioning
pancreatic neuroendocrine (islet cell) tumors. In adults, VIPomas are
535
intrapancreatic in over 95 percent of cases. However, other VIP-secreting tumors
have been reported, including lung cancer, colorectal cancer,
ganglioneuroblastoma, pheochromocytoma, hepatoma, and adrenal tumors. In
children, VIPomas rarely arise in the pancreas [4]. Instead, VIP-secreting tumors
typically occur in the sympathetic ganglia (eg, ganglioneuroblastomas or
ganglioneuromas) and the adrenal glands [5-7]. (See "Classification, epidemiology,
clinical presentation, localization, and staging of pancreatic neuroendocrine
neoplasms", section on 'Classification and nomenclature'.)
VIPomas are usually diagnosed between 30 and 50 years of age in adults and
between two and four years of age in children. Symptomatic pancreatic VIPomas
are usually solitary, more than 3 cm in diameter, and occur in the tail of the
pancreas in 75 percent of patients. Approximately 60 to 80 percent of VIPomas
have metastasized by the time of diagnosis [8,9]. VIPomas usually occur as isolated
tumors, but in 5 percent of patients they are part of the multiple endocrine
neoplasia syndrome type 1 (MEN1) and occur in association with parathyroid and
pituitary tumors, gastrinoma, and other tumors [10,11]. (See "Multiple endocrine
neoplasia type 1: Clinical manifestations and diagnosis".)
PATHOPHYSIOLOGYThe VIPoma syndrome is caused by excessive,
unregulated secretion of vasoactive intestinal polypeptide (VIP) by the tumor.
However, other substances, such as prostaglandin E2, may occasionally be
secreted by the tumors [12]. VIP is a 28 amino acid polypeptide that binds to high
affinity receptors on intestinal epithelial cells, leading to activation of cellular
adenylate cyclase and cAMP production. This results in net fluid and electrolyte
secretion into the lumen, resulting in secretory diarrhea and hypokalemia [12,13].
Other biologic actions of VIP including vasodilation, inhibition of gastric acid
secretion, bone resorption, and enhanced glycogenolysis are responsible for
flushing as well as laboratory findings of hypochlorhydria, hypercalcemia, and
hyperglycemia in patients with VIPomas (table 1). (See "Vasoactive intestinal
polypeptide" and 'Clinical features' below and "Physiology of gastric acid
secretion".)
CLINICAL FEATURES
Clinical manifestations — The majority of patients with VIPoma have VIPoma
syndrome, which is also called the pancreatic cholera syndrome, Verner-Morrison
syndrome, and the watery diarrhea, hypokalemia, and hypochlorhydria or
achlorhydria (WDHA) syndrome. VIPoma syndrome is characterized by watery
diarrhea that persists with fasting. Stools are tea-colored and odorless with stool
volumes exceeding 700 mL/day. In 70 percent of patients, stool volume can exceed
3000 mL per day [14-16]. Abdominal pain is mild or absent. Associated symptoms
include flushing episodes in 20 percent of patients and symptoms related to
536
hypokalemia and dehydration, such as lethargy, nausea, vomiting, muscle
weakness, and muscle cramps (table 1). (See "Clinical manifestations and
treatment of hypokalemia in adults".)
Laboratory findings — Patients with VIPoma have secretory diarrhea with a low
osmotic gap (<50 mOsm/kg) (calculator 1) [17]. Hypochlorhydria occurs in 75
percent of patients and can result in iron and B12 deficiency. Other findings may
include hyperglycemia and hypercalcemia (table 1). Hypercalcemia may be due to
coexistent hyperparathyroidism as part of the MEN1 syndrome or to
hyperalbuminemia caused by dehydration. In patients with dehydration, the
serum total calcium concentration is increased, but the serum ionized (or free)
calcium concentration is normal. (See "Diagnostic approach to hypercalcemia",
section on 'Confirm hypercalcemia' and "Approach to the adult with chronic
diarrhea in resource-rich settings".)
DIAGNOSISThe diagnosis of a VIPoma is suspected in patients with unexplained
high-volume secretory diarrhea (>700 mL/day). The diagnosis is established by a
serum vasoactive intestinal polypeptide (VIP) concentration >75 pg/mL. However, a
single elevated VIP level should be confirmed by repeat testing.
Evaluation of the patient with secretory diarrhea to exclude other causes is
discussed in detail, separately. (See 'Differential diagnosis' below and "Approach to
the adult with chronic diarrhea in resource-rich settings".)
DIFFERENTIAL DIAGNOSISOther disorders that can cause secretory
diarrhea include surreptitious abuse of saline cathartics, enteritis caused by
enterotoxigenic Escherichia coli or Vibrio cholera, microscopic colitis, bile salt
malabsorption due to ileal resection, and the carcinoid syndrome (table 2).
(See "Approach to the adult with chronic diarrhea in resource-rich settings".)
TUMOR LOCALIZATION
Approach to imaging — After diagnosis, imaging studies are required to
accurately localize the tumor. Cross-sectional imaging with multiphasic computed
tomography (CT) or magnetic resonance imaging (MRI) of the abdomen can
localize the tumor and stage the extent of disease. We begin with helical (spiral)
multiphasic contrast-enhanced CT for evaluation of patients with a VIPoma. We
perform MRI when CT shows indeterminate lesions that need further
characterization. If cross-sectional imaging is inconclusive, endoscopic ultrasound
(EUS), somatostatin receptor scintigraphy, or integrated PET/CT using Gallium-68-
DOTA-0-Phe1-Tyr3-Octreotate (Gallium Ga-68 DOTATATE) or Ga-68-DOTA-0-Phe1-
Tyr3-Octreotide (Ga-68 DOTATOC), copper 64-Cu DOTATATE PET/CT, should be
performed to identify the tumor. Because of its greater sensitivity, 68-Ga
DOTATATE or Ga-68 DOTATOC PET/CT is preferred over conventional somatostatin
receptor scintigraphy, if available [18,19]. In addition, we perform Ga-68
537
DOTATATE (or Ga-68 DOTATOC) PET/CT in the evaluation of a patient with VIPoma
if the finding of extra-abdominal metastases would change treatment.
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms", section on 'Somatostatin-receptor-based
imaging'.)
●Computed tomography – CT scan is noninvasive and readily available.
Intravenous contrast enhances the detection of smaller lesions, especially
when images are obtained during the arterial phase. In addition, arterial
phase and portal venous phase sequences can be used to maximize the
conspicuity of liver metastases compared with the surrounding normal liver
parenchyma. CT scans are highly accurate for detecting primary pancreatic
neuroendocrine tumors (NETs), and, using multiphase imaging techniques,
sensitivity is >80 percent [20-22]. Since most pancreatic VIPomas are more
than 3 cm in size at presentation, a pancreatic mass can usually be identified
by CT in the majority of cases [23]. The sensitivity of contrast-enhanced CT for
these tumors approaches 100 percent [24,25]. (See "Classification,
epidemiology, clinical presentation, localization, and staging of pancreatic
neuroendocrine neoplasms", section on 'Computed tomography'.)
●Magnetic resonance imaging – On MRI, pancreatic NETs are typically
characterized by low signal intensity on T1-weighted images and high signal
intensity on T2-weighted images (image 1 and image 2). MRI may have a
higher sensitivity for liver metastases as compared with CT [26].
(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms", section on 'Magnetic
resonance imaging'.)
●Somatostatin receptor scintigraphy – Somatostatin receptor scintigraphy
(OctreoScan) using radiolabeled form of the somatostatin
analog octreotide (Indium-111 [111-In]) pentetreotide has the advantage of
instantaneous whole body scanning, which also allows detection of
metastases outside of the abdominal region [27]. However, somatostatin-
receptor scintigraphy (SRS) is less sensitive than PET-CT and has largely been
replaced by 68Ga/64Cu-DOTA-PET imaging. Guidelines from the European
Neuroendocrine Tumor Society, the European Society for Medical Oncology
(ESMO), and the National Comprehensive Cancer Network [28] suggest that
DOTA-PET-imaging is preferred over SRS [29-31]. (See "Classification,
epidemiology, clinical presentation, localization, and staging of pancreatic
neuroendocrine neoplasms", section on 'Somatostatin-receptor-based
imaging'.)

538
 ●Endoscopic ultrasound – EUS can detect pancreatic tumors as small as 2 to
3 mm, provide accurate information on the local extent of disease, and allow
for transmucosal needle biopsy of pancreatic lesions. However, EUS is rarely
used in the evaluation of VIPomas as these tumors are diagnosed by
hormonal assays and VIPomas are usually detectable on CT/MRI at diagnosis.
(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms".)
●Functional PET imaging with Ga-68 DOTATATE and Ga-68 DOTATOC –
Several positron emission tomography (PET) tracers for functional imaging
have emerged (18-F-dihydroxy-phenyl-alanine [18F-DOPA], 11-C-5-
hydroxytryptophan [11-C-5-HTP], Ga-68-DOTA-D-Phe1-Tyr3-Octreotide [gallium
Ga-68-DOTATOC], and Ga-68-DOTA-D-Phe1-Tyr3-Octreotate [galliumGa-68
DOTATATE]) that offer higher spatial resolution than conventional SRS and
are associated with improved sensitivity for detection of small lesions [32].
Like SRS, Ga-68 DOTATATE, Ga-68 DOTATOC, and Cu-64 DOTATATE detect
somatostatin receptor (SSTR) expression on NETs. These tracers are approved
in the United States for use with PET for localization of SSTR positive NETs.
Integrated DOTA-PET/CT or DOTA-PET/MRI scanning is the functional
imaging modality of choice for staging and localization of most well-
differentiated NETs (where available) [29-31]. (See "Metastatic well-
differentiated gastroenteropancreatic neuroendocrine tumors: Presentation,
prognosis, imaging, and biochemical monitoring" and "Metastatic well-
differentiated gastroenteropancreatic neuroendocrine tumors: Presentation,
prognosis, imaging, and biochemical monitoring", section on 'Somatostatin
receptor-based imaging techniques'.)
STAGINGPancreatic neuroendocrine tumors, including VIPomas, are staged
using the tumor, node, metastasis (TNM) classification from the joint American
Joint Committee on Cancer/Union for International Cancer Control adapted from
the ENETs staging system [33]. The staging system is highly prognostic for both
relapse-free and overall survival [34-36]. The newest release of the TNM staging
classification (8th edition, 2017) has a staging system for neuroendocrine tumors of
the pancreas that is separate from that used for exocrine pancreatic tumors [37].
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms", section on 'Staging system'.)
TREATMENT
Symptomatic treatment
Repletion of fluid and electrolytes — Treatment of a patient with a VIPoma
begins with replacement of fluid losses and correction of electrolyte abnormalities.
Many patients require more than 5 L of fluid and 350 mEq of potassium daily.
539
(See "Maintenance and replacement fluid therapy in adults", section on
'Replacement fluid therapy' and "Clinical manifestations and treatment of
hypokalemia in adults", section on 'Treatment' and "Treatment of hypovolemia
(dehydration) in children".)
Somatostatin analogs — Somatostatin and its analogs (eg, octreotide, lanreotide)
inhibit the secretion of vasoactive intestinal polypeptide (VIP) and are the
treatment of choice to control diarrhea in patients with VIPoma [3,38-40].
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic
therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Somatostatin analogs'.)
Symptomatic patients may be initiated on short-acting octreotide (50 to 100
micrograms subcutaneously every eight hours) with rapid transition to a long-
acting formulation and subsequent titration of dose to optimize symptom control
[41,42]. Sandostatin LAR, a depot preparation, is typically initiated at a dose of 20
mg IM monthly with gradual dose escalation as needed for optimal symptom
control [43]. Patients may use additional short-acting octreotide for breakthrough
symptoms while doses are being titrated; therapeutic levels of octreotide are not
reached until 10 to 14 days after the initiation of the LAR injection. Lanreotide,
another long-acting somatostatin analog (SSA), can be self-administered once
monthly using a deep subcutaneous injection and appears to have similar efficacy
to octreotide [44-46].
Somatostatin analogs are usually well tolerated, but there are some side effects,
including nausea, abdominal discomfort, bloating, loose stools, and fat
malabsorption [47,48]. Side effects are often worst during the first several weeks
of therapy, after which the symptoms subside. Mild glucose intolerance rarely
occurs, due to transient inhibition of insulin secretion. Somatostatin analogs
reduce postprandial gallbladder contractility and delay gallbladder emptying, and
up to 25 percent of patients develop asymptomatic cholesterol gallstones or
sludge during the first 18 months of therapy [48]. (See "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options to
control tumor growth and symptoms of hormone hypersecretion", section on 'Side
effects'.)
Other agents — The use of glucocorticoids (eg, prednisone 60 mg), clonidine,
and loperamide are generally reserved for patients with diarrhea that is refractory
to somatostatin analogs [3,39]. Emerging data suggest that cinacalcet may be
useful for treating cystic fibrosis transmembrane conductance regulator (CTFR)-
mediated secretory diarrhea as seen in VIPoma [49].
Pancreatic resection — Primary tumors can be managed with distal
pancreatectomy. However, up to 60 percent have metastasized to lymph nodes,

540
liver, kidneys, or bone at diagnosis [9,50]. Lack of symptomatic improvement after
resection of functional neuroendocrine tumors (NETs) is associated with worse
relapse-free survival [51]. (See "Surgical resection of lesions of the body and tail of
the pancreas" and "Surgical resection of sporadic pancreatic neuroendocrine
tumors", section on 'Others'.)
Management of advanced/metastatic disease
Liver-directed therapy for metastatic disease
●Surgery – Hepatic resection is indicated for the treatment of metastatic liver
disease in the absence of diffuse bilobar involvement, compromised liver
function, or extrahepatic metastases (eg, pulmonary, peritoneal). Although
eventual recurrence is the rule, palliation of symptoms stemming from
hormone hypersecretion can be achieved, and prolonged survival is often
possible given the slow-growing nature of these tumors [52,53].
Note that life-threatening fluid losses and electrolyte abnormalities should be
corrected before surgery with somatostatin analog treatment, plus
intravenous and electrolyte therapy [54]. Surgical resection for patients with
metastases from pancreatic NETs is discussed in detail, separately.
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Surgical resection'.)
●Hepatic artery embolization – Hepatic arterial embolization with or
without selective hepatic artery infusion of chemotherapy is a palliative
technique in patients with symptomatic hepatic metastases who are not
candidates for surgical resection. Embolization can be performed via the
infusion of gel foam powder into the hepatic artery through an angiography
catheter (bland embolization) or in conjunction with chemotherapy
(ie, doxorubicin, cisplatin, or streptozocin, or drug-eluting beads)
administered via the hepatic artery (chemoembolization). A third
embolization technique uses radioactive isotopes (eg, yttrium-90 [90-Y]) that
are tagged to glass or resin microspheres and delivered selectively to the
tumor via the hepatic artery. Response rates, as measured by a decrease in
hormonal secretion or by radiographic regression, are generally over 50
percent [55-69]. (See "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Hepatic arterial embolization'.)
●Radiofrequency ablation and cryoablation – Ablation can be used as a
primary treatment modality for neuroendocrine liver metastases or as an
adjunct to surgical resection [70]. Ablation can be performed percutaneously
or laparoscopically and is less invasive than either hepatic resection or

541
 hepatic artery embolization. However, ablation is applicable only to smaller
lesions (typically <3 cm), and its long-term efficacy is uncertain [71].
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Ablation'.)
●Liver transplantation – Liver transplantation is considered an
investigational approach for metastatic pancreatic NETs, including VIPoma,
as the number of patients with liver-isolated metastatic disease in whom
orthotopic liver transplantation has been attempted is small, and follow-up
data are insufficient to judge whether cure has been achieved [72-75].
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Liver transplantation'.)
Somatostatin analogs — In addition to decreasing hormone secretion and
improving symptom control, somatostatin analogs have cytostatic activity in well-
differentiated NETs [76,77]. Given their favorable safety profile, somatostatin
analogs are considered the treatment of choice in patients with slow-growing,
unresectable, metastatic well-differentiated NETs.
Molecularly targeted therapy and other novel agents — Molecularly targeted
agents (eg, everolimus, sunitinib) have a role in the management of patients with
progressive, advanced VIPomas and are discussed elsewhere [78,79]. These and
other novel therapies, such as peptide receptor radioligand therapy, are discussed
in detail elsewhere. (See "Metastatic well-differentiated pancreatic neuroendocrine
tumors: Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion", section on 'Molecularly targeted
therapy' and "Metastatic well-differentiated pancreatic neuroendocrine tumors:
Systemic therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Peptide receptor radioligand therapy'.)
Cytotoxic chemotherapy — For patients who are highly symptomatic due to
tumor bulk or who have rapidly enlarging metastases, chemotherapy has been
used as initial treatment together with a somatostatin analog. The options for
therapy typically include a streptozocin-based combination or a temozolomide-
containing regimen [80-82]. However, experience with systemic chemotherapy in
patients with VIPomas, specifically, is limited, and few patients have been included
in modern clinical series. The use of cytotoxic chemotherapy in patients with
pancreatic NETs is discussed in detail elsewhere. (See "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options to
control tumor growth and symptoms of hormone hypersecretion", section on
'Cytotoxic chemotherapy'.)

542
Peptide receptor radionuclide therapy — Peptide receptor radionuclide therapy
(PRRT) is another option for progressive SSTR positive pancreatic NETs and is
discussed elsewhere. Symptomatic and radiological responses have been noted in
the setting of treatment of functional pancreatic NETs, including VIPoma, with
Lu177-dotatate PRRT [83]. (See "Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options to control tumor growth and
symptoms of hormone hypersecretion", section on 'Peptide receptor radioligand
therapy'.)
POST-TREATMENT SURVEILLANCEThere is limited evidence from which to
make recommendations for follow-up after resection of a VIPoma, and guidelines
are based on expert consensus. Our approach for follow-up after treatment of a
VIPoma is consistent with guidelines from the National Comprehensive Cancer
Network and consists of the following [84]:
●3 to 12 months post-resection: History and physical examination, serum VIP
level, and abdominal multiphasic computed tomography (CT) or magnetic
resonance imaging (MRI); and chest CT scan +/- contrast as clinically
indicated.
●>1 year post-resection to a maximum of 10 years: History and physical
examination with serum VIP level every 6 to 12 months. Consider abdominal
multiphasic CT or MRI (and chest CT scan +/- contrast) as clinically indicated.
PROGNOSISThe median survival of patients with VIPomas is 96 months [85].
Prognosis is largely dependent on VIPoma tumor grade, staging, and surgical
resectability. Five- and ten-year survival rates for patients undergoing resection of
gastroenteropancreatic neuroendocrine tumors (both pancreatic neuroendocrine
and carcinoid tumors) stratified by stage at presentation are presented in the table
(table 3) [86].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●VIPomas are rare neuroendocrine tumors that secrete vasoactive intestinal
polypeptide (VIP). (See 'Introduction' above.)
●VIPomas are usually diagnosed between 30 and 50 years of age in adults
and between two and four years of age in children. Pancreatic VIPomas are
usually solitary, more than 3 cm in diameter, and occur in the tail of pancreas
in 75 percent of patients. Approximately 60 to 80 percent of VIPomas have
metastasized by the time of diagnosis.

543
●VIPomas usually occur as isolated tumors, but in 5 percent of patients they
are part of the multiple endocrine neoplasia syndrome type 1 (MEN1).
●VIPoma syndrome is characterized by watery diarrhea that persists even
during fasting. The stools are tea-colored, odorless with stool volumes
exceeding 700 mL/day. In 70 percent of patients, stool volume can exceed
3000 mL/day. Abdominal pain is mild or absent. Associated symptoms include
flushing, lethargy, nausea, vomiting, muscle weakness, and muscle cramps.
(See 'Clinical features' above.)
●Patients with VIPoma have secretory diarrhea with a low osmotic gap (<50
mOsm/kg) (calculator 1). Hypochlorhydria occurs in 75 percent of patients.
Other common laboratory findings include hyperglycemia and
hypercalcemia. (See 'Laboratory findings' above.)
●The diagnosis of a VIPoma is suspected in patients with unexplained high-
volume secretory diarrhea. The diagnosis is established by a serum
vasoactive intestinal polypeptide (VIP) concentration >75 pg/mL. However, a
single elevated VIP level should be confirmed by repeat testing.
(See 'Diagnosis' above.)
●Cross-sectional imaging with multiphasic computed tomography (CT) or
magnetic resonance imaging (MRI) of the abdomen can localize the tumor
and stage the extent of disease. If cross-sectional imaging is inconclusive,
endoscopic ultrasound, somatostatin receptor scintigraphy, or Gallium Ga-68
DOTATATE (or Gallium Ga-68 DOTATOC) PET/CT (preferred) should be
performed to identify the tumor. In addition, we perform somatostatin
receptor scintigraphy or Ga-68 DOTATATE (or Ga-68 DOTATOC) PET/CT
(preferred) in patients with VIPomas if the finding of extra-abdominal
metastases would change treatment. Because of its greater sensitivity, Ga-68
DOTATATE or Ga-68 DOTATOC PET/CT is preferred over conventional
somatostatin receptor scintigraphy, where available. (See 'Tumor
localization' above.)
●Treatment of hormone-mediated symptoms in a patient with a VIPoma
begins with replacement of fluid losses and correction of electrolyte
abnormalities. For treatment of the diarrhea, we suggest a somatostatin
analog (Grade 2B). Treatment is initiated with short-acting octreotide (50 to
100 micrograms subcutaneously every eight hours) with rapid transition to a
long-acting octreotide formulation and subsequent titration of dose to
optimize symptom control (lanreotide is also a reasonable consideration)
(see 'Somatostatin analogs' above). Furthermore, use of anti-cancer therapy,
particularly in the form of debulking surgery, liver-directed therapy,

544
 chemotherapy, or another systemic agent, may also lead to improved
symptom control.
●Primary tumors arising in the tail of the pancreas can be managed with
distal pancreatomy. However, up to 60 percent of VIPomas have
metastasized to lymph nodes, liver, kidneys, or bone at diagnosis.
(See "Surgical resection of sporadic pancreatic neuroendocrine
tumors" and 'Pancreatic resection' above.)
●Hepatic resection and/or ablation can be considered in patients with
metastatic disease in the absence of diffuse bilobar involvement,
compromised liver function, or extensive extrahepatic metastases. Hepatic
arterial embolization with or without selective hepatic artery infusion of
chemotherapy may be used for palliation in patients with symptomatic
hepatic metastases who are not candidates for surgical resection. Tumor
control can also be achieved with somatostatin analogs, cytotoxic
chemotherapy, and molecularly targeted agents such
as sunitinib and everolimus. Lu-177 dotatate peptide receptor radionuclide
therapy is also now approved for well-differentiated pancreatic
neuroendocrine tumors. (See 'Management of advanced/metastatic
disease' above and "Metastatic well-differentiated pancreatic neuroendocrine
tumors: Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion" and "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and
symptoms of hormone hypersecretion".)
●The median survival of patients with VIPomas is 96 months. Our approach
for follow-up after treatment of a VIPoma is consistent with guidelines from
the National Comprehensive Cancer Network and consists of the following
(see 'Post-treatment surveillance' above and 'Prognosis' above):
•3 to 12 months post-resection: History and physical examination, serum
VIP level, and abdominal multiphasic CT or MRI (and chest CT scan +/-
contrast as clinically indicated).
•>1 year post-resection to a maximum of 10 years: History and physical
examination with serum VIP level every 6 to 12 months. Consider
abdominal multiphasic CT or MRI (and chest CT scan +/- contrast) as
clinically indicated.
ACKNOWLEDGMENT

545
Zollinger-Ellison syndrome (gastrinoma): Clinical
manifestations and diagnosis
Author:
Emily Bergsland, MD
Section Editor:
Mark Feldman, MD, MACP, AGAF, FACG
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Nov 30, 2021.
What's New
Secretin stimulation testing in suspected Zollinger-Ellison syndrome
(November 2021)
In patients being evaluated for Zollinger-Ellison syndrome (ZES), discontinuation of
proton pump inhibitors (PPIs) is recommended before a secretin stimulation test
(SST). In a retrospective study of SSTs that compared test performance on
versus off PPIs, the sensitivity, specificity, and positive predictive value were
comparable with no false positive or negative results on PPI therapy [1]. However,
the majority of patients had a high pretest probability of ZES due to MEN1
syndrome. We continue to suggest PPI cessation for 1 week prior to SST for ZES
but administer high-dose H2 receptor antagonists until 12 to 30 hours prior to the
test and only perform testing once active ulcers have healed, as stopping a PPI in
patients with ZES can cause massive acid hypersecretion and lead to acute ulcer
complications. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical
manifestations and diagnosis", section on 'Secretin stimulation test'.)
Read more

INTRODUCTIONZollinger-Ellison (ZES) syndrome is characterized by gastric

acid hypersecretion resulting in severe acid-related peptic disease and diarrhea
[1,2]. The clinical manifestations and diagnosis of ZES will be reviewed here. The
management of ZES is discussed separately. (See "Management and prognosis of
the Zollinger-Ellison syndrome (gastrinoma)".)
EPIDEMIOLOGYZollinger-Ellison syndrome (ZES) is caused by secretion of
gastrin by duodenal or pancreatic neuroendocrine tumors (gastrinomas). The
annual incidence of gastrinomas is 0.5 to 2 per million population [3-5]. Most
patients are diagnosed between the ages of 20 and 50, with a higher incidence in
males as compared with females [6]. Approximately 80 percent of gastrinomas are
546
sporadic, but 20 to 30 percent occur in association with multiple endocrine
neoplasia type 1 (MEN1) [7,8]. (See "Multiple endocrine neoplasia type 1: Clinical
manifestations and diagnosis".)
Although gastrinomas are one of the most common functional pancreatic
neuroendocrine tumors, only 20 to 25 percent of gastrinomas arise in the
pancreas [6,9]. Approximately 50 to 88 percent of patients with sporadic ZES, and
70 to 100 percent of patients with ZES associated with MEN1, have duodenal
gastrinomas [8]. Duodenal gastrinomas are predominantly found in the first part
of the duodenum. As compared with pancreatic gastrinomas, duodenal
gastrinomas are usually small (<1 cm), are often multiple, and are less likely to
have metastasized to the liver at diagnosis (0 to 10 versus 22 to 35 percent)
[6,7,10,11]. In 5 to 15 percent of patients, gastrinomas arise in non-pancreatic,
non-duodenal abdominal (stomach, peripancreatic lymph nodes, liver, bile duct,
ovary), and extra-abdominal (heart, small cell lung cancer) locations [12-14].
CLASSIFICATION, NOMENCLATURE, AND HISTOLOGYThe World
Health Organization (WHO) classifies neuroendocrine tumors (NETs) arising within
the digestive system based upon the extent to which they resemble their normal
non-neoplastic counterparts (table 1). (See "Pathology, classification, and grading
of neuroendocrine neoplasms arising in the digestive system", section on '2010
and 2019 World Health Organization classification'.)
Histologically, most gastrinomas are well-differentiated NETs with few mitoses and
a histologic appearance that is similar to that of other pancreatic NETs. The cells
are arranged in a solid, trabecular, gyriform, or glandular pattern, with fairly
uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm. As with
other pancreatic NETs, the degree of malignancy cannot be predicted by
morphologic appearance alone. The cells produce abundant neurosecretory
granules, as reflected in the strong and diffuse immunohistochemical expression
of neuroendocrine markers such as synaptophysin and chromogranin. Gastrin is
the predominant peptide within the secretory granules of gastrinoma cells, but
other neuroendocrine peptides such as vasoactive intestinal peptide and glucagon
can sometimes be identified as well. The designation of the tumor as a gastrinoma
is based upon the presence of a clinical syndrome that results from tumor
production and secretion of gastrin, and not by its morphologic appearance or the
presence of gastrin in the secretory granules. Of note, not all patients with ectopic
gastrin secretion have the symptoms associated with Zollinger-Ellison syndrome,
as in many cases, the hormone is not processed to biologically active gastrin [15].
If a tumor stains for gastrin or secretes gastrin but does not produce symptoms of
Zollinger-Ellison syndrome, it should not be considered a gastrinoma.

547
(See "Pathology, classification, and grading of neuroendocrine neoplasms arising
in the digestive system", section on 'Functionality and nomenclature'.)
PATHOPHYSIOLOGYExcessive gastrin secretion from a gastrinoma results in
high gastric acid output (usually four- to sixfold, and up to over 10-fold) due to the
trophic action of gastrin on parietal cells and histamine-secreting
enterochromaffin-like (ECL) cells (picture 1) [15]. In addition, gastrin stimulates
parietal cells largely via the release of histamine. (See "Physiology of gastric acid
secretion".)
Chronic diarrhea in Zollinger-Ellison syndrome results from the following [6]:
●The high volume of gastric acid secretion that cannot be fully reabsorbed by
the small intestine and colon.
●The rate of gastric acid secretion exceeds the neutralizing capacity of
pancreatic bicarbonate secretion, resulting in an exceptionally low pH of
intestinal contents. The low pH inactivates pancreatic digestive enzymes,
interfering with the emulsification of fat by bile acids, and damaging
intestinal epithelial cells and villi. Maldigestion and malabsorption both result
in steatorrhea.
●Extremely high serum gastrin concentrations inhibit the absorption of
sodium and water by the small intestine, thereby adding a secretory
component to the diarrhea.
CLINICAL MANIFESTATIONS
Clinical presentation — Peptic ulcer disease (73 to 98 percent), heartburn (52 to
55 percent), diarrhea (60 to 75 percent), weight loss (7 to 53 percent), and
complications from acid hypersecretion (bleeding, stricture, fistulization,
perforation) are the most common symptoms in patients with Zollinger-Ellison
syndrome (ZES) (figure 1) [15,16]. Sixty to ninety percent of gastrinomas are
malignant [8]. The mean time to diagnosis is six years [16].
Approximately 1 to 10 percent of patients, especially with metastatic disease or
multiple endocrine neoplasia type 1 (MEN1), have symptoms due to a second
hormonal syndrome (eg, VIPoma, somatostatinoma, glucagonoma, ACTH) [17].
(See "Epidemiology and clinical manifestations of Cushing's syndrome", section on
'Clinical manifestations' and "Somatostatinoma: Clinical manifestations, diagnosis,
and management", section on 'Clinical manifestations' and "VIPoma: Clinical
manifestations, diagnosis, and management", section on 'Clinical
features' and "Glucagonoma and the glucagonoma syndrome", section on 'Clinical
features'.)
Endoscopic features — Over 90 percent of patients with ZES develop peptic ulcers
[18]. Patients with ZES, like those with sporadic peptic ulcer disease, often present
with solitary ulcers less than 1 cm in diameter. Approximately 75 percent of ulcers
548
are in the first portion of the duodenum, 14 percent in the distal duodenum, and
11 percent in the jejunum [19]. Ulcers are more likely to be refractory to proton
pump inhibitor therapy and to recur as compared with patients with sporadic ulcer
disease. Furthermore, in ZES, ulcers often occur in unusual locations (eg, beyond
the first or second fold of the duodenum). Over 90 percent of patients with ZES
often have prominent gastric folds. Patients may also have evidence of reflux
esophagitis. However, strictures of the esophagus, pylorus, or duodenum are
present in less than 10 percent of patients [16]. In the setting of MEN1, duodenal
gastrinomas are typically multifocal, small (<0.5 cm), and associated with lymph
node involvement in 40 to 60 percent [15].
DIAGNOSISZollinger-Ellison syndrome (ZES) should be suspected in patients
with multiple or refractory peptic ulcers; ulcers distal to the duodenum; peptic
ulcer disease and diarrhea, enlarged gastric folds, or multiple endocrine neoplasia
type 1 (MEN1) (table 2) [20]. ZES should also be suspected in patients with peptic
ulcer disease and a family history of peptic ulcer disease or MEN1, or in patients
with diarrhea that is responsive to proton pump inhibitors (PPIs). The diagnosis is
established by demonstrating an elevated basal or stimulated gastrin
concentration (in the setting of a low gastric pH).
Evaluation — Initial evaluation in a patient with suspected ZES is with
measurement of fasting serum gastrin concentration and measurement of gastric
pH. In patients with elevated gastrin levels/low gastric pH that are not diagnostic
for ZES, we perform a secretin stimulation test. The calcium infusion study
(intravenous infusion with calcium gluconate) is usually reserved for patients with
gastric acid hypersecretion in whom there is a strong clinical suspicion of
gastrinoma despite a negative secretin stimulation test [21]. Importantly, the
diagnosis of ZES can be difficult to make, as evidenced by the fact the average time
from onset of symptoms to diagnosis is >5 years. The symptoms can be
nonspecific and/or masked by PPI use [22]. Gastric antral/body biopsy for atrophic
gastritis combined with parietal cell and intrinsic factor antibodies can also be
useful for confirming situations of "appropriate" hypergastrinemia.
In patients in whom PPIs cannot safely be stopped, modern criteria for ZES have
been proposed [8]. An elevated gastrin level, combined with a history of current or
recent peptic ulcer disease, and improvement of diarrhea on a PPI supports a
diagnosis of ZES, particularly in the setting of a positive biopsy for a well
differentiated neuroendocrine tumor (in a patient with or without MEN1). The
diagnosis is less clear without a tissue diagnosis and with only a history of positive
somatostatin receptor imaging (with or without MEN1).

549
In patients with a positive imaging study and fasting hypergastrinemia without
peptic ulcer disease or diarrhea, a lack of atrophic gastritis and the absence of
parietal cell and intrinsic factor antibodies suggests gastrinoma. However, it is
important to note that atrophic gastritis can be missed with this approach as
detection depends on biopsy location and number, and parietal cell and intrinsic
factor antibodies are not always positive.

Furthermore, the use of somatostatin imaging (eg, 68Ga-DOTATATE positron

emission tomography [PET]/computed tomography [CT] or 111In-DTPA-octreotide
with single-photon emission CT [SPECT]/CT) for diagnosis is of limited value, as it
can detect any benign or malignant process overexpressing somatostatin
receptors, and there can be uptake in nonneoplastic conditions like arthritis,
infections, thyroid disease, granulomatous diseases [8].
Serum gastrin concentration — Fasting serum gastrin should be measured in
any patient suspected of having ZES [6]. A serum gastrin value greater than 10
times the upper limit of normal (1000 pg/mL) in the presence of a gastric pH below
2 is diagnostic of ZES. Higher levels are more likely with pancreatic (compared with
duodenal) tumors, larger tumor size, and with metastatic disease [6].
Measurement of gastric pH on a single specimen is important to exclude
secondary hypergastrinemia due to achlorhydria (eg, atrophic gastritis,
pangastritis-associated Helicobacter pylori infections, renal failure, vagotomy, and
ingestion of gastric acid antisecretory drugs [eg, PPIs]). In such cases the serum
gastrin level can exceed 1000 pg/mL, but the gastric pH is >2. Importantly, these
"appropriate" hypergastrinemic conditions are much more common and need to
be distinguished from inappropriate causes, such as ZES [8]. While assessment of
gastric pH is classically required for the diagnosis of ZES, case series suggest that
assessment of gastric acidity is underutilized. This is likely due to the inability to
stop PPIs or unfamiliarity with gastric pH testing).
Approximately two-thirds of patients with ZES have serum gastrin concentrations
less than 10 times the upper limit of normal (between 110 and 1000 pg/mL) [6].
This degree of hypergastrinemia is nonspecific and can also be present in patients
with increased gastric acid secretion (eg, antral G-cell hyperplasia, gastric outlet
obstruction, and retained gastric antrum). Patients receiving PPIs generally have
elevated serum gastrin levels. Fasting serum gastrin levels can fluctuate even
within the same patient, and elevated levels should be rechecked (see 'Differential
diagnosis' below). Importantly, no level of hypergastrinemia can distinguish
appropriate from inappropriate hypergastrinemia; high levels can be seen in the
setting of atrophic gastritis or PPI use [8]. However, persistently normal fasting
serum gastrin values are exceedingly uncommon in ZES [8].

550
Commercial immunoassay kits in current use vary in their accuracy [22,23]. In one
study that evaluated 12 different commercial assay kits, four of the kits returned
falsely low results in 20 to 80 percent of patients [23]. False negatives are most
likely to occur at relatively low gastrin concentrations, with most assays accurately
detecting patients with ZES whose serum gastrin concentrations are greater than
400 pmol/L (845 pg/mL).
Secretin stimulation test — The secretin stimulation test is used to differentiate
patients with gastrinomas from other causes of hypergastrinemia (eg, in the
setting of gastrin, <10-fold upper limit of normal and gastric pH ≤2). Although,
some have questioned the test’s utility since achlorhydria can lead to false
positives [8]. Secretin stimulates the release of gastrin by gastrinoma cells, and
patients with ZES tumors have a dramatic rise in serum gastrin. In contrast, normal
gastric G cells are inhibited by secretin.
The secretin test should not be performed in a patient on PPIs. False-negative
responses have been reported in 6 to 20 percent of patients [24]. However, other
studies suggest that false-negative results caused by PPIs may be low in
frequency, particularly in patients with a high pretest probability of ZES [25]. False-
positive results occurred in 15 to 39 percent of patients with achlorhydria induced
by PPIs or due to chronic atrophic gastritis [26]. However, if PPIs are discontinued
abruptly, patients with ZES are at high risk to develop complications (such as acute
bleeding and perforation) during the interim week [27]. As such, discontinuation of
a PPI in a patient suspected of having ZES should be done by an experienced
provider. Before this is attempted, an endoscopy should be performed to exclude
active ulcer disease. If ulceration is present, suppressive PPI therapy should be
used until active disease is healed before stopping PPI therapy [8]. One week prior
to the secretin study we substitute PPIs with high-dose H2 receptor antagonists
(eg, cimetidine 300 to 600 mg every six hours) until 12 to 30 hours prior to the test
[8]. Oral antacids are then taken as needed until midnight prior to the study.
Patients should be advised to seek immediate medical attention for nasogastric
aspiration if they develop significant exacerbation of ZES symptoms (eg, vomiting,
pain, diarrhea) during the taper period [28].
The secretin stimulation test is performed by administering 0.4 micrograms/kg by
rapid infusion intravenously over one minute; a baseline fasting serum gastrin is
measured twice before the secretin is administered and 2, 5, and 10 minutes later.
Several criteria have been proposed to define a positive test; an increase in gastrin
levels of greater than 120 pg/mL over basal fasting levels has a sensitivity and a
specificity of 94 and 100 percent, respectively (others use an absolute increase
greater than 110 or 200 pg/mL, or a 50 percent increase in gastrin levels)
[21,22,29]. Serum gastrin levels usually peak by 10 minutes (figure 2).

551
The secretin stimulation test should not be performed in patients with active
severe manifestations of ZES. This includes patients with severe abdominal pain,
vomiting and diarrhea to the point of dehydration, or endoscopic findings of
thickened gastric folds or multiple ulcers, as they are at particular risk for life-
threatening consequences of discontinuing acid suppression. In such patients,
tumor localization studies should be performed. (See 'Tumor localization' below.)
Other — Other tests that are supportive of the diagnosis of ZES but are less
commonly performed include the following [8]:
●Serum chromogranin A – Serum chromogranin A is elevated in most
patients with gastrinomas, and the level of elevation tends to correlate with
tumor volume [30]. In contrast to other neuroendocrine tumors, very high
levels of chromogranin A can be seen in gastrinomas without liver
metastases [31]. Chromogranin A levels are usually normal or near normal in
patients with high gastrin levels secondary to chronic atrophic gastritis.
(See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid)
tumors arising in the gastrointestinal and genitourinary tracts", section on
'Stomach'.)
However, serum chromogranin A is less sensitive for a gastrinoma as
compared with fasting serum gastrin levels. In addition, elevated
chromogranin A is not specific to gastrinomas and is a general marker for
well-differentiated neuroendocrine tumors [32]. Elevated chromogranin A
levels may be seen in a number of other conditions including PPI use [33,34].
●Gastric acid secretion studies – Gastric acid secretion studies to measure
basal acid output, which were once pivotal in establishing the diagnosis of
ZES, are no longer performed due to their technical difficulty [26]. Basal acid
output is measured by the passage of a nasogastric tube into the dependent
portion of the stomach with aspiration and quantification of gastric juice
production over a one-hour period. A basal acid output of >15 mEq/hour is
supportive of the diagnosis of ZES.
DIFFERENTIAL DIAGNOSIS
●Antral G-cell hyperplasia – Antral G-cell hyperplasia is a rare entity
associated with increase in the number of G cells and characterized by a
marked hypergastrinemia. Peptic ulcers can also be seen in patients with
antral G-cell hyperplasia. However, unlike Zollinger Ellison syndrome (ZES),
antral G-cell hyperplasia is characterized by a poor response
to secretin stimulation test, and absence of gastrinoma on imaging.
●Retained antrum syndrome – Retained antrum syndrome should be
suspected in patients with recurrent peptic ulceration after gastrectomy. In
such cases, peptic ulcer recurrence results from incomplete excision of the
552
 gastric antrum from the duodenum. Gastrin elevation in patients with
retained antrum syndrome is only modest as compared with patients with
ZES, and hypergastrinemia is reversible with excision of the retained antral
remnant.
TUMOR LOCALIZATIONAfter the diagnosis of Zollinger-Ellison syndrome
(ZES) is made, the gastrinoma must be located and staged. (See "Management and
prognosis of the Zollinger-Ellison syndrome (gastrinoma)" and "Multiple endocrine
neoplasia type 1: Treatment".)
●Tumor localization begins with an upper endoscopy if not already
performed, cross-sectional imaging with helical, contrast-enhanced, triple-
phase computed tomography (CT) or magnetic resonance imaging (MRI), and
somatostatin receptor-based imaging (somatostatin receptor scintigraphy
[SRS]) using 111-In pentetreotide, or integrated PET/CT using Gallium-68-
DOTA-0-Phe1-Tyr3-Octreotate (Gallium Ga-68 DOTATATE) or Gallium-68-DOTA-
0-Phe1-Tyr3-Octreotide (Gallium Ga-68 DOTATOC) [35,36]. Because of its
greater sensitivity, Ga-68 DOTATATE or Ga-68 DOTATOC PET imaging may be
preferable to conventional SRS with 111-In pentetreotide [37,38].
(See 'Endoscopic features' above and "Classification, epidemiology, clinical
presentation, localization, and staging of pancreatic neuroendocrine
neoplasms", section on 'Somatostatin-receptor-based imaging'.)
●If CT/MRI and somatostatin receptor-based imaging are negative, and
surgery is being considered, an endoscopic ultrasound (EUS) should be
performed because of its greater sensitivity in detecting small tumors. EUS
also permits fine-needle aspiration for histological identification.
(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms", section on 'Endoscopic
ultrasonography'.)
●We reserve invasive testing to localize the tumor with angiography or
selective arterial stimulation and venous sampling with secretin injection for
patients who are strongly suspected of having a gastrinoma in whom
imaging is negative [39]. The sensitivity for pancreas tumors is 75 to 100
percent, and the specificity is 95 percent; the sensitivity for duodenal tumors
is 38 to 63 percent [22].
●However, in some cases tumor localization can only be achieved at
laparotomy by direct palpation, duodenal transillumination, or intraoperative
ultrasound. (See "Classification, epidemiology, clinical presentation,
localization, and staging of pancreatic neuroendocrine neoplasms", section
on 'Intraoperative localization techniques' and 'Evaluation' above.)

553
STAGING SYSTEMTwo staging systems are available for pancreatic
neuroendocrine tumors such as gastrinomas, one from the combined American
Joint Committee on Cancer/Union for International Cancer Control (UICC) [40], and
another proposed by the European Neuroendocrine Tumor Society (table 3)
[40,41]. Both staging systems are highly prognostic for both relapse-free and
overall survival [42-44]. The newest update of the TNM staging classification
(8th edition, 2017) has a staging system for neuroendocrine tumors of the pancreas
(table 4) that is separate from that used for exocrine pancreatic tumors [45].
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms", section on 'Staging system'.)
ADDITIONAL EVALUATIONWe suggest biochemical studies to screen for
multiple endocrine neoplasia type 1 (MEN1) in patients with Zollinger-Ellison
syndrome (ZES), as 20 to 25 percent of patients have MEN1 and because up to 40
percent of MEN1/ZES patients have no family history [13].
●All patients with ZES should have serum parathormone levels, ionized
calcium levels, and prolactin levels at diagnosis and periodically thereafter
[13]. Screening for MEN1-associated tumors is discussed separately.
(See 'Epidemiology' above and "Multiple endocrine neoplasia type 1: Clinical
manifestations and diagnosis", section on 'Monitoring for MEN1-associated
tumors'.)
●Individuals with a family history of MEN1, suspicious clinical or laboratory
findings (eg, renal colic or nephrolithiases, history of hypercalcemia), or
multiple MEN1 tumor types (parathyroid gland, anterior pituitary, and
enteropancreatic) should undergo evaluation for MEN1 syndrome. The
management of patients with MEN1 is discussed separately. (See "Multiple
endocrine neoplasia type 1: Treatment".)
●All patients with gastrinoma should at least be considered for testing for an
inherited genetic syndrome. Data suggest that 17 percent of patients with
seemingly sporadic pancreatic neuroendocrine tumors harbor germline
alterations in any one of a variety of genes (including MUTYH, CHEK2,
and BRCA2, as well as MEN1 and VHL).
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●Zollinger-Ellison
syndrome (ZES) is caused by secretion of gastrin by
duodenal or pancreatic neuroendocrine tumors (gastrinomas). The annual

554
incidence of gastrinomas is 0.5 to 2 per million population. Most patients are
diagnosed between the ages of 20 and 50, with a higher incidence in males
as compared with females. While most gastrinomas are sporadic, 20 to 30
percent occur in association with multiple endocrine neoplasia type 1 (MEN1)
syndrome. Approximately 50 to 88 percent of sporadic ZES patients, and 70
to 100 percent of ZES and MEN1, have duodenal gastrinomas.
(See 'Epidemiology' above and 'Classification, nomenclature, and
histology' above.)
●Excessive gastrin secretion from a gastrinoma results in high gastric acid
output. Chronic diarrhea results from failure of resorption of the increased
gastric acid, inactivation of pancreatic enzymes, damage to intestinal
epithelium, and inhibition of the absorption of sodium and water.
(See 'Classification, nomenclature, and histology' above
and 'Pathophysiology' above.)
●Abdominal pain (75 percent) and diarrhea (73 percent) are the most
common symptoms in patients with ZES. Nearly half of patients have
heartburn due to gastroesophageal reflux (figure 1). Other symptoms include
weight loss (17 percent) and gastrointestinal bleeding (25 percent).
(See 'Clinical presentation' above.)
●Over 90 percent of patients with ZES develop peptic ulcers. Patients with ZES
often present with solitary ulcers less than 1 cm in diameter. Approximately
75 percent of ulcers are in the first portion of the duodenum, 14 percent in
the distal duodenum, and 11 percent in the jejunum. Ulcers in ZES may be
refractory to proton pump inhibitors and recur much more often as
compared with patients with sporadic ulcer disease. On upper endoscopy,
patients with ZES may have prominent gastric folds and evidence of reflux
esophagitis. However, strictures of the esophagus, pylorus, or duodenum are
present in less than 10 percent of patients. (See 'Endoscopic features' above.)
●ZES should be suspected in patients with multiple or refractory peptic ulcers;
ulcers distal to the duodenum; peptic ulcer disease and diarrhea, enlarged
gastric folds, an endocrinopathy or MEN1 (table 2). ZES should also be
suspected in patients with peptic ulcer disease and a family history of peptic
ulcer disease or MEN1. The diagnosis is established by demonstrating an
elevated basal or stimulated gastrin concentration, ideally assessed off a PPI
(if safe) and in the setting of a gastric pH <2. (See 'Diagnosis' above.)
●Tumor localization begins with an upper endoscopy if not already
performed, cross-sectional imaging with helical, contrast-enhanced, triple-
phase computed tomography (CT) or magnetic resonance imaging (MRI), and
somatostatin receptor-based imaging using somatostatin receptor

555
scintigraphy (SRS) with 111-In pentetreotide or integrated PET/CT
using Gallium Ga-68 DOTATATE or Ga-68 DOTATOC. Because of its greater
sensitivity, Ga-68 DOTATATE or Ga-68 DOTATOC PET/CT is preferred over
conventional SRS with 111-In pentetreotide, where available. If CT or MRI and
somatostatin receptor-based imaging are negative, and surgery is being
considered, endoscopic ultrasound should be performed to localize the
tumor. We reserve invasive testing to localize the tumor with angiography or
selective arterial stimulation and venous sampling with secretin injection for
patients who are strongly suspected of having a gastrinoma in whom
imaging is negative. However, in some cases, tumor localization can only be
achieved at laparotomy, by direct palpation, duodenal transillumination, or
intraoperative ultrasound. (See 'Tumor localization' above.)
●All patients with gastrinoma should at least be considered for testing for
inherited genetic syndromes. Approximately 20 to 30 percent of patients
develop ZES in the setting of MEN1 syndrome. As such, all patients with ZES
should be screened for MEN1 syndrome with serum parathormone levels,
ionized calcium levels, and prolactin levels at diagnosis, and periodically
thereafter. Individuals with a family history of MEN1, suspicious clinical or
laboratory findings (eg, renal colic or nephrolithiases, history of
hypercalcemia), or multiple MEN1 tumor types (parathyroid gland, anterior
pituitary, and enteropancreatic) should undergo evaluation for MEN1
syndrome. (See 'Additional evaluation' above and "Multiple endocrine
neoplasia type 1: Clinical manifestations and diagnosis", section on
'Diagnosis'.)

556
Diagnosis of primary aldosteronism
Author:
William F Young, Jr, MD, MSc
Section Editors:
Lynnette K Nieman, MD
George L Bakris, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 16, 2021.
INTRODUCTIONNonsuppressible (primary) hypersecretion of aldosterone is an
underdiagnosed cause of hypertension. The classic presenting signs of primary
aldosteronism are hypertension and hypokalemia, but potassium levels are frequently
normal in modern-day series of primary aldosteronism. The most common subtypes of
primary aldosteronism are:
●Aldosterone-producing adenomas (APAs)
●Bilateral idiopathic hyperaldosteronism (IHA; bilateral adrenal hyperplasia)

Less common forms include:

●Familial hyperaldosteronism (FH) types I to IV (see "Familial

hyperaldosteronism")
●Unilateral adrenal hyperplasia
●Pure aldosterone-producing adrenocortical carcinomas
●Ectopic aldosterone-producing tumors
The diagnosis of primary aldosteronism will be reviewed here. The clinical
manifestations and treatment of this disorder are discussed separately.
(See "Pathophysiology and clinical features of primary aldosteronism" and "Treatment
of primary aldosteronism".)
BACKGROUND
Prevalence of primary aldosteronism — Older studies suggested a prevalence of
primary aldosteronism of less than 1 percent of hypertensive patients. However, studies
published over the past 15 years document that the prevalence is considerably higher
[1-4]. In a retrospective, multicenter review, more widespread use of the plasma
aldosterone to renin ratio (plasma aldosterone concentration/plasma renin activity
[PAC/PRA] ratio) as a case-detection test in hypertensive patients resulted in marked
increases (1.3- to 6.3-fold) in the annual detection rate of primary aldosteronism and in
the proportion of hypertensive patients in whom primary aldosteronism was detected (1
to 2 percent before screening versus 5 to 10 percent after screening) [1,3,5].
Variable presentation — The presence of primary mineralocorticoid excess should be
suspected in any patient with the triad of hypertension, unexplained hypokalemia, and
metabolic alkalosis [6-8]. However, most patients with primary mineralocorticoid excess
are normokalemic and, rarely, some are hypokalemic but normotensive (primarily in
young adult females).

557
It is now estimated that only 9 to 37 percent of patients with primary aldosteronism are
hypokalemic [1,5]. This is likely related to earlier diagnosis as more patients with
hypertension are being screened with the PAC/PRA ratio as a case-detection test for
primary aldosteronism. (See "Pathophysiology and clinical features of primary
aldosteronism", section on 'Hypokalemia: An inconsistent finding'.)
A few patients with primary aldosteronism have hypokalemia but a normal systemic
blood pressure [9]. Surreptitious vomiting, diuretic therapy, and Bartter syndrome should
be excluded; each of these disorders is associated with secondary hyperaldosteronism
as the PRA and plasma renin concentration (PRC) are increased rather than
suppressed, as in primary aldosteronism. (See 'Secondary hyperaldosteronism' below.)
Normokalemia is the rule in patients with the rare genetic disorder glucocorticoid-
remediable aldosteronism (GRA). There are, however, important physiologic differences
between GRA and other forms of hyperaldosteronism that could account for the lesser
likelihood of potassium wasting. (See "Familial hyperaldosteronism".)
OVERVIEW OF APPROACHIdentifying primary aldosteronism is important
because of its prevalence and association with a higher rate of cardiovascular morbidity
and mortality when compared with age- and sex-matched patients with primary
hypertension and the same degree of blood pressure elevation [10]. In patients
diagnosed with primary aldosteronism, treatment of the mineralocorticoid excess results
in reversal or improvement of the hypertension and resolution of the increased
cardiovascular risk. (See "Treatment of primary aldosteronism".)

The diagnosis of primary aldosteronism includes:

●Case-detection testing – Testing should be performed in patient groups with a

relatively high prevalence of primary aldosteronism (see 'Who should be
tested?' below). Measurements of the plasma renin activity (PRA) (or plasma
renin concentration [PRC]) and plasma aldosterone concentration (PAC) are
obtained in the morning in a seated ambulatory patient. (See 'Case
detection' below.)
The initial evaluation should consist of documenting that the PRA or PRC is
suppressed (PRA <1 ng/mL/hour; PRC less than the lower limit of reference
range) and that the PAC is inappropriately high for the PRA (typically >15 ng/dL
[416 pmol/L], but as low as 10 ng/dL [277 pmol/L]) (algorithm 1).
(See 'Protocol' below.)
●Case confirmation – In most patients, an elevated PAC and a low renin does
not establish the diagnosis of primary aldosteronism, which must be confirmed by
demonstrating inappropriate aldosterone secretion with one of several tests.
The exception to the requirement for confirmatory testing is the patient with:
•Spontaneous hypokalemia
•Undetectable PRA or PRC
•PAC ≥20 ng/dL (555 pmol/L)
In this clinical setting, there is no other diagnosis except primary aldosteronism to
explain these findings. However, for all others, aldosterone suppression testing is
needed, and it can be performed with orally administered sodium chloride and

558
 measurement of urine aldosterone excretion or with intravenous sodium chloride
loading and measurement of PAC. (See 'Confirmation of the diagnosis' below.)
●Subtype classification – Once the diagnosis of primary aldosteronism has been
established, a unilateral aldosterone-producing adenoma (APA), or rarely,
carcinoma, must be distinguished from bilateral hyperplasia (idiopathic
hyperaldosteronism [IHA]). This is important since the treatment options are
different for the two disorders. We suggest the algorithm developed at the Mayo
Clinic that uses adrenal computed tomography (CT) and adrenal vein sampling
(AVS) (algorithm 2). (See 'Subtype classification' below.)
CASE DETECTIONCase-detection testing with measurement of plasma
aldosterone concentration (PAC) and renin (plasma renin activity [PRA] or plasma renin
concentration [PRC]) should be performed in patient groups with a relatively high
prevalence of primary aldosteronism. As noted, the prevalence of primary aldosteronism
in patients with hypertension is considerably higher than previously thought
(see 'Prevalence of primary aldosteronism' above). In addition, more widespread testing
has demonstrated that normokalemic, rather than hypokalemic, hypertension is the
most common presentation of primary aldosteronism [1,5,11,12]. (See 'Variable
presentation' above.)
Our approach outlined below is consistent with the Endocrine Society 2016 clinical
practice guidelines [5]. Recommendations for the treatment of primary aldosteronism
are reviewed separately. (See "Treatment of primary aldosteronism".)
Who should be tested? — We suggest case-detection testing for primary
aldosteronism in the following patients [5]:
●Hypertension and spontaneous or low-dose, diuretic-induced hypokalemia
The following patients should undergo testing even if they
are normokalemic (see "Pathophysiology and clinical features of primary
aldosteronism", section on 'Cardiovascular risk'):
●Severe hypertension (>150 mmHg systolic or >100 mmHg diastolic) or drug-
resistant hypertension (defined as suboptimally controlled hypertension on a
three-drug program that includes an adrenergic inhibitor, vasodilator, and diuretic)
●Hypertension with adrenal incidentaloma
●Hypertension with sleep apnea
●Hypertension and a family history of early-onset hypertension or cerebrovascular
accident at a young age (<40 years)
●All hypertensive first-degree relatives of patients with primary aldosteronism
●Hypertension and atrial fibrillation [10,13]
We do not recommend screening with PAC and renin (PRA or PRC) in older
normokalemic patients with mild hypertension or in patients in whom the diagnosis
would not change management (eg, the older patient where blood pressure is easily
controlled with a single antihypertensive agent). (See "Overview of hypertension in
adults", section on 'Definitions' and "Evaluation of secondary hypertension".)
Low rates of testing — In spite of clinical guidelines that recommend testing in patient
groups with a relatively high prevalence of primary aldosteronism (eg, treatment-
resistant hypertension and hypertension with hypokalemia), this disorder remains
underdiagnosed and untreated [5,14].

559
One example of low testing rates comes from a retrospective, multicenter cohort study
of 269,010 United States veterans with apparent treatment-resistant hypertension; only
4277 patients (1.6 percent) underwent the recommended testing for primary
aldosteronism [15] (see 'Initial testing' below). Low rates were observed at all centers,
and no improvements in testing were seen over the 17 years of the study (2000 to
2017). Among those who were tested, higher rates of mineralocorticoid receptor
antagonist use and better blood pressure control over time was observed. These
observations underscore the need for additional provider education about the
importance of testing, the increased renal and cardiovascular morbidity seen with
mineralocorticoid excess, and its reversal with appropriate treatment. (See "Treatment
of primary aldosteronism", section on 'Treatment goals'.)
Initial testing — The sequential evaluation of a patient with possible primary
aldosteronism begins with measurement of the PRA (or PRC) and aldosterone
concentration in a blood sample obtained in the morning in a seated ambulatory patient
(algorithm 1) [6-8]. Renin can be measured in terms of its enzymatic activity (PRA) or its
mass (active renin concentration) [16]. Details about PRA and PRC measurements are
reviewed separately. (See "Assays of the renin-angiotensin-aldosterone system in
adrenal disease", section on 'Renin'.)
Protocol — The test is performed by measuring a morning (preferably 8 AM),
ambulatory, paired, random PAC and PRA or PRC (algorithm 1).
●The PRA and PRC are typically very low (due in part to the associated mild
volume expansion) in patients with primary aldosteronism, usually less than 1
ng/mL per hour (0.2778 ng/L per sec) for PRA and usually undetectable or below
the lower limit of normal for PRC [17]. On the other hand, increased PRA or PRC
in a hypokalemic hypertensive patient is most often due to diuretic therapy,
renovascular or malignant hypertension, or, rarely, a renin-secreting tumor
(algorithm 1). (See 'Primary aldosteronism' below and 'Secondary
hyperaldosteronism' below.)
●The PAC is usually >15 ng/dL (416 pmol/L), but may be as low as 10 ng/dL (277
pmol/L).
Some clinicians calculate a PAC/PRA ratio as part of the case detection strategy, but
we prefer to use the paired random PAC and PRA (or PRC). The mean value for the
PAC/PRA ratio in normal subjects and patients with primary hypertension (formerly
called "essential" hypertension) is 4 to 10, compared with more than 30 to 50 in most
patients with primary aldosteronism [17,18]. PRA and PRC are low in a significant
number of patients with primary hypertension, but a high PAC (typically >15 ng/dL [416
pmol/L]) and a truly abnormal ratio are uncommon.
In general, a PAC/PRA ratio greater than 20 (depending upon the laboratory normals) is
considered suspicious for primary aldosteronism, although others use a cutoff criterion
of 30 (table 1) [18]. Cutoff values depend upon whether hormone concentrations are
expressed in conventional or SI units, and they vary with the PRA assay. The lower limit
of detection varies among the different PRA assays and can have a dramatic effect on
the PAC/PRA ratio [19]. As an example, a very different ratio is obtained if the lower
limit of detection for PRA is 0.6 ng/mL per hour compared with 0.1 ng/mL per hour; for a
PAC of 16 ng/dL (444 pmol/L), the PAC/PRA ratio would be 27 and 160, respectively. It
is for this reason that a PAC >10 ng/dL is part of the case-finding strategy and why we

560
do not favor the PAC/PRA for case detection (algorithm 1). Note that the conventional
units for aldosterone are "ng/dL" and SI units are "pmol/L." To convert ng/dL to SI units,
multiply by 27.74 (table 1).
The variability in threshold value for the PAC/PRA ratio is also illustrated by the range of
thresholds used in various studies. In one study, in which blood was drawn at 8 AM
after two hours of ambulation in 62 patients with primary aldosteronism (48 adrenal
adenoma, 14 adrenal hyperplasia), in 263 with presumed primary hypertension
(formerly called "essential" hypertension), and in 434 normotensive patients, the
combination of a PAC equal to or above 20 ng/dL (555 pmol/L) and a PAC/PRA ratio
above 30 had a sensitivity and specificity of 90 percent for the diagnosis of aldosterone-
producing adenoma (APA) [17]. Other studies have suggested that a ratio 50 or higher
or 40 or higher, rather than 30 [18,20,21], or a measurement of the ratio 60 to 90
minutes after a single dose of 25 to 50 mg of captopril [22] or 50 mg of losartan [21],
might give better diagnostic discrimination. The latter tests are not widely used.
As noted above, we do not favor the PAC/PRA for case detection. We prefer to use the
paired random PAC and PRA (or PRC) (algorithm 1).
Interfering drugs — Most antihypertensive medications can be continued, and posture
stimulation is not required [20,23-27]. For example, although beta-adrenergic
antagonists do lower PRA and PRC measurements and raise the PAC/PRA ratio [27],
the increased PAC/PRA ratio is not clinically important in this setting, because of the
low PAC (<10 ng/dL) in patients without primary aldosteronism [27]. In addition, one
should consider the risks of modifying antihypertensive medication programs (eg,
hypertensive crisis, severe hypokalemia, atrial fibrillation, heart failure) [28].

There are potentially clinically important issues with the following drugs:

●Mineralocorticoid receptor antagonists – It may be difficult to interpret data

obtained from patients treated with a mineralocorticoid receptor antagonist
(spironolactone and eplerenone). These drugs prevent aldosterone from
activating the receptor, resulting sequentially in sodium loss, a decrease in plasma
volume, and an elevation in PRA, which will reduce the utility of the PAC/PRA
ratio. For this reason, spironolactone and eplerenone should not be initiated until
the evaluation is completed and the final decisions about treatment are made.
However, there are exceptions to this rule. For example, if the patient is
hypokalemic despite treatment with spironolactone or eplerenone, then the
mineralocorticoid receptors are not fully blocked and PRA or PRC should be
suppressed in such a patient with primary aldosteronism. In addition, most
patients with primary aldosteronism who are treated with mineralocorticoid
receptor antagonists are given subtherapeutic doses. Thus, PAC and PRA should
be measured in patients treated with spironolactone or eplerenone, and if PRA is
suppressed, these medications are not interfering. Thus, if PRA is suppressed,
case-detection testing, confirmatory testing, and adrenal vein sampling (AVS) can
be performed without discontinuing the mineralocorticoid receptor antagonists.
However, if PRA is not suppressed, then the mineralocorticoid receptor antagonist
should be discontinued for four to six weeks before retesting. Other potassium-
sparing diuretics, such as amiloride and triamterene, usually do not interfere with
testing unless the patient is on high doses.
561
 ●ACE inhibitors, ARBs, direct renin inhibitors – Angiotensin-converting
enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin
inhibitors could potentially elevate PRC and have variable effects on PRA in
patients with primary aldosteronism. Thus, in a patient treated with one of these
drugs, a PRA >1 ng/mL/hour does not exclude the diagnosis of primary
aldosteronism. On the other hand, a strong predictor for primary aldosteronism is
a PRA <1 ng/mL/hour or low PRC in a patient taking one of these drugs.
Interpretation of results
Primary aldosteronism — Primary aldosteronism should be suspected when PRA is
suppressed to <1 ng/mL/hour (or PRC is below the lower limit of normal) and PAC is
≥10 ng/dL (277 pmol/L) (algorithm 1). The PAC/PRA ratio is usually >20 ng/dL per
ng/mL/hour (>555 pmol/L per ng/mL/hour) (table 1). Most patients require confirmatory
testing. (See 'Confirmation of the diagnosis' below.)
In one study, the combination of a PAC above 20 ng/dL (555 pmol/L) and a PAC/PRA
ratio above 30 had a sensitivity and specificity of 90 percent for the diagnosis of APA
[17].
Other causes of hypertension and hypokalemia
Secondary hyperaldosteronism — Secondary hyperaldosteronism (eg, renovascular
disease) should be considered when both the PRA (or PRC) and PAC are increased
and the PAC/PRA ratio is <10. In this setting, hypersecretion of renin leads sequentially
to increased angiotensin II and then increased aldosterone secretion.
An increased PRA or PRC in a hypokalemic hypertensive patient is most often due to
diuretic therapy (which may be surreptitious). Less common causes include
renovascular or malignant hypertension and rare renin-secreting tumors (algorithm 1).
(See "Assays of the renin-angiotensin-aldosterone system in adrenal disease".)
Cushing's syndrome may lead to hypokalemia, due in part to the overproduction of
corticotropin (ACTH)-dependent compounds such as deoxycorticosterone,
corticosterone, and cortisol. However, the diagnosis in this disorder is usually suspected
from the classic Cushingoid appearance, including rounded plethoric face,
supraclavicular fat pads, central obesity, thick purple-red abdominal striae, proximal
muscle weakness, and hirsutism. (See "Epidemiology and clinical manifestations of
Cushing's syndrome".)
The degree of ACTH and cortisol hypersecretion (and therefore the frequency of
hypokalemia) is much higher in the ectopic ACTH syndrome than with a pituitary
adenoma (50 versus 9 percent in one series) [29]. (See "Establishing the cause of
Cushing's syndrome".)
Patients with renin-secreting tumors are typically young (average age 22 years in one
report) and have severe hypertension and hypokalemia [30]. Contrast-enhanced
computed tomography (CT) appears to be the diagnostic procedure of choice since
false-negative results occur with arteriography or renal vein renin sampling. Surgical
removal of the tumor cures the disease.
Liddle's syndrome is a rare autosomal dominant condition in which there is a primary
increase in sodium reabsorption in the collecting tubules and, in most cases, potassium
secretion. The underlying defect is a gain-of-function mutation in the collecting tubule
sodium channel. (See "Genetic disorders of the collecting tubule sodium channel:

562
Liddle's syndrome and pseudohypoaldosteronism type 1", section on 'Liddle's
syndrome'.)
Non-aldosterone mineralocorticoid excess — The combination of suppressed PRA
or PRC and a low plasma or urinary aldosterone value in a patient with hypertension
and hypokalemia may indicate the presence of some non-aldosterone mineralocorticoid.
This can occur in the following settings (algorithm 1):
●Some types of congenital adrenal hyperplasia (deficiencies of 11-beta-
hydroxylase [CYP11B1, P450c11] or 17-alpha-hydroxylase [CYP17, P450c17])
cause hypertension and hypokalemia because of hypersecretion of the
mineralocorticoid deoxycorticosterone. Familial cortisol resistance has a similar
presentation. (See "Adrenal steroid biosynthesis".)
●Chronic licorice root ingestion, the rare genetic syndrome of apparent
mineralocorticoid excess, and severe cases of Cushing's syndrome, in which
cortisol acts as the primary mineralocorticoid. In the last setting, there may also be
hypersecretion of other mineralocorticoids such as deoxycorticosterone and
corticosterone. (See "Apparent mineralocorticoid excess syndromes (including
chronic licorice ingestion)".)
●A deoxycorticosterone-producing adrenal tumor, which can usually be detected
by CT or magnetic resonance imaging (MRI) [1].
●Similar findings in the absence of mineralocorticoid excess are seen in Liddle's
syndrome, which is caused by gain-of-function pathogenic variants in the beta or
gamma subunits of the amiloride-sensitive collecting tubule sodium channel,
resulting in increased sodium reabsorption, potassium wasting, hypertension, and
hypokalemia. Clinical genetic testing is available. Blocking the sodium channel
with amiloride or triamterene can treat both the hypertension and hypokalemia.
(See "Genetic disorders of the collecting tubule sodium channel: Liddle's
syndrome and pseudohypoaldosteronism type 1".)
24-hour urine collection — We do not order a 24-hour urine potassium collection
unless PRA is not suppressed, PAC is not elevated, or there is a clinical suspicion of
surreptitious vomiting or laxative abuse. The low serum potassium concentration
induced by mineralocorticoid excess is a result of increased urinary potassium
excretion. Thus, in the past, a 24-hour urine collection was typically obtained to
document the presence of inappropriate potassium wasting.

When a 24-hour collection is obtained, inappropriate potassium wasting is defined as

more than 30 mEq/day in a patient with hypokalemia. An appropriately low rate of
potassium excretion suggests either extrarenal losses (vomiting, diarrhea) or diuretic
treatment with the urine being collected after the diuretic effect has worn off.

Aldosterone excretion can also be measured with high values (>12 mcg/day [33
nmol/day]) on a high-sodium diet (urine sodium excretion >200 mEq/day) being
consistent with primary aldosteronism if the PRA is low. (See "Patient education:
Collection of a 24-hour urine specimen (Beyond the Basics)".)
Interpretation of the rate of potassium excretion requires attention to the patient's
volume status and rate of sodium excretion. The patient must not have a low sodium
intake or hypovolemia (as evidenced by less than 50 mEq of sodium being excreted per
day), since the associated decrease in sodium and water delivery to the distal
563
potassium secretory site can diminish potassium excretion even in patients with
hyperaldosteronism. On the other hand, the degree of potassium wasting and,
therefore, the diagnostic accuracy, can be increased by a high-sodium diet because the
combination of increased distal flow and hypersecretion of aldosterone will maximize
potassium losses [31].

A high-sodium diet can also be given as a provocative test in patients with an initial
serum potassium concentration in the normal or low-normal range. Sodium-induced
hypokalemia is strongly suggestive of nonsuppressible hyperaldosteronism. Normal
subjects do not waste potassium during sodium loading, because the increase in distal
flow is offset by reduced secretion of aldosterone.

CONFIRMATION OF THE DIAGNOSISAmong patients with hypertension and

an elevated plasma aldosterone concentration (PAC) ≥10 ng/dL (277 pmol/L) and low
renin (plasma renin activity [PRA] <1 ng/mL/hour or plasma renin concentration [PRC]
less than the lower limit of normal), the results may suggest either primary
aldosteronism (high PAC, low PRA or PRC), secondary hyperaldosteronism (high PAC
and nonsuppressed PRA or PRC), or non-aldosterone mineralocorticoid excess (low
PAC, low PRA or PRC). Each can be caused by a variety of disorders (algorithm 1).
In most patients, the diagnosis of primary aldosteronism must be confirmed by
demonstrating inappropriate aldosterone secretion with one of several tests. The
exceptions to the requirement for confirmatory testing are the patients with spontaneous
hypokalemia, low PRA or PRC, and a PAC ≥20 ng/dL, or those without spontaneous
hypokalemia but with low PRA or PRC and a PAC >30 ng/dL; in this clinical setting,
there is no other diagnosis except primary aldosteronism to explain these findings [32].
In a study of 252 patients with hypertension and suppressed renin, all 61 patients with
PAC >30 ng/dL were confirmed to have primary aldosteronism [32]. In addition, all 26
patients with spontaneous hypokalemia and PAC between 20 to 30 ng/dL were
confirmed to have primary aldosteronism [32].
However, aldosterone suppression testing is usually needed, and it can be performed
with orally administered sodium chloride and measurement of urine aldosterone
excretion or with intravenous sodium chloride loading and measurement of PAC [25,33].
Oral sodium loading — Many centers and experts, including the author of this topic,
use oral sodium loading over three days. After hypertension and hypokalemia are
controlled (hypokalemia suppresses aldosterone secretion), the patients should receive
a high-sodium diet for three days.
Patients should be given guidance on the sodium content of the types of food they need
to consume to achieve a 5000 mg sodium diet. In circumstances of high-sodium dietary
intolerance, patients can be given oral sodium chloride tablets (eg, two 1 g sodium
chloride tablets taken three times daily with food will provide approximately 90 mEq of
sodium). The risk of increasing dietary sodium in patients with severe hypertension
must be assessed in each case. In addition, since sodium loading typically increases
kaliuresis and hypokalemia, serum potassium should be measured daily and vigorous
replacement of potassium chloride should be prescribed as indicated.

On the third day of the high-sodium diet, serum electrolytes are measured and a 24-
hour urine specimen is collected for measurement of aldosterone, sodium, and
564
creatinine. The 24-hour urine sodium excretion should exceed 200 mEq (4600 mg) to
document adequate sodium loading. Urine aldosterone excretion >12 mcg/24 hours (33
nmol/day) in this setting is consistent with hyperaldosteronism.

Saline infusion test — An alternate method to suppress endogenous aldosterone

production is by the intravenous administration of 2 L of isotonic saline over four hours
(from 8 AM to 12 PM), ideally while the patient is seated [33,34]. The PAC will fall below
5 ng/dL (139 pmol/L) in normal subjects, whereas values above 10 ng/dL (277 pmol/L)
are consistent with primary aldosteronism [33]. False-negative rates may be as high as
30 percent, but they appear to be lower if the test is performed with the patient seated
rather than recumbent [34,35].
Other — Other available confirmation tests include the fludrocortisone suppression
and captopril challenge tests. As noted above, we suggest oral sodium loading.
(See 'Oral sodium loading' above.)
SUBTYPE CLASSIFICATIONOnce the diagnosis of primary aldosteronism has
been established, a unilateral aldosterone-producing adenoma (APA), or rarely,
carcinoma, must be distinguished from bilateral hyperplasia (idiopathic
hyperaldosteronism [IHA]). This is important since the treatment options are different for
the two disorders. We recommend using the algorithm developed at the Mayo Clinic
that uses adrenal computed tomography (CT) and adrenal vein sampling (AVS)
(algorithm 2) [25]. (See "Treatment of primary aldosteronism".)
●In general, APA patients have higher aldosterone secretion rates, resulting in
more severe hypertension, more profound hypokalemia (<3.2 mEq/L), and higher
plasma (>25 ng/dL) and urinary (>30 mcg/24 hour) levels of aldosterone; these
patients are also younger (<50 years) than those with IHA [25]. In one study, a
plasma aldosterone concentration/plasma renin activity (PAC/PRA) ratio of >32
had a sensitivity of 100 percent and specificity of 61 percent for an APA [20].
Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CTNNB1, and CACNA1D are
found in more than 80 percent of resected APAs [36-39]. In a study of 474
unselected patients with APAs, somatic heterozygous KCNJ5 mutations were
present in 38 percent, CACNA1D mutations in 9.3 percent, ATP1A1 mutations in
5.3 percent, and ATP2B3 mutations in 1.7 percent. Patients with KCNJ5 mutations
were more frequently female and diagnosed younger, compared
with CACNA1D mutation carriers or noncarriers [37]. However, the presence of
one of these somatic mutations does not affect diagnosis or treatment.
(See "Pathophysiology and clinical features of primary aldosteronism", section on
'Mutations in aldosterone-producing adenomas' and 'Familial
hyperaldosteronism' below.)
●Bilateral adrenal hyperplasia, which accounts for approximately 60 percent of
cases, is generally a milder disease with less hypersecretion of aldosterone and
less hypokalemia; it should be treated with a mineralocorticoid receptor
antagonist. The cause of primary aldosteronism due to bilateral adrenal
hyperplasia has not yet been determined. (See "Treatment of primary
aldosteronism".)
●The clear distinction between unilateral aldosteronoma and bilateral adrenal
hyperplasia has been challenged by the demonstration of the frequent presence of

565
 zona glomerulosa hyperplasia and aldosterone-producing cell clusters adjacent to
the dominant aldosteronoma. In addition, while ion channel mutations are
frequently found in the dominant aldosteronoma, they are not present in the
adjacent hyperplasia, suggesting that somatic development of a dominant
adenoma may occur in a background of bilateral mild hyperplasia [40,41].
Adrenal CT — Adrenal computed tomography (CT) should be the initial study to
determine subtype (adenoma versus hyperplasia) and exclude adrenal carcinoma [42].
When imaging adrenal glands, CT has superior spatial resolution compared with
magnetic resonance imaging (MRI). The CT scan may be done without intravenous
contrast; however, if an adrenal mass is detected, contrast administration provides
additional imaging information.
●An adrenal carcinoma should be suspected when a unilateral, large (>4 cm)
adrenal mass is found on CT in a patient with primary aldosteronism (image 1)
[43-47].
●Bilateral adrenal gland thickening or micronodular changes suggests adrenal
hyperplasia; however, patients with hyperplasia may also have normal-appearing
adrenal glands on CT [44].
●When a solitary, hypodense, unilateral macroadenoma (>1 cm) and normal
contralateral adrenal morphology (image 2) are found in a young patient (<35
years of age) with vigorous primary aldosteronism, unilateral adrenalectomy is a
reasonable therapeutic option [48]. However, because of the age-dependent risk
that a solitary unilateral adrenal macroadenoma may be a nonfunctioning cortical
adenoma, AVS should be considered in patients over 35 years of age who want to
pursue a surgical cure of hyperaldosteronism (algorithm 2).
Limitations — Some investigators suggest that the findings of hypokalemia,
nonsuppressible hyperaldosteronism, a PAC/PRA ratio exceeding 50, and a unilateral
mass on CT can be followed directly by surgery to remove a presumed adenoma [18].
However, CT findings are frequently misleading as many patients with biochemical
evidence of nonsuppressible hyperaldosteronism and a unilateral adrenal mass turn out
to have bilateral hyperplasia [45,47,49-51].
Another problem is that the absence of a mass does not exclude an adenoma (since
APAs can be very small [eg, <3 mm in diameter] and lesions less than 1 cm in diameter
may be missed on CT), and bilateral lesions are not diagnostic of hyperplasia (because
some patients with an aldosteronoma in one adrenal gland have a nonfunctioning
adrenal nodule in the other) [46,47].
The limitations of adrenal CT were illustrated in a study of 203 patients with primary
aldosteronism who were evaluated with both CT and AVS; CT was accurate in only 53
percent of patients [50]. Based upon CT, 42 patients (22 percent) would have been
incorrectly excluded as candidates for adrenalectomy and 48 (25 percent) might have
had unnecessary or inappropriate surgery. In another study, CT findings coincided with
the lateralization determined by AVS in 80 of 158 (51 percent) patients [52].
In a subsequent systematic review of 38 studies in a total of 950 patients with primary
aldosteronism (including the 203 patients described above), adrenal CT/MRI results did
not agree with AVS in 359 of 950 patients (37.8 percent) [51]. If CT/MRI alone had been
used to determine subtype, the following inappropriate treatment would have been
recommended:

566
 ●139 patients (14.6 percent) would have inappropriately undergone unilateral
adrenalectomy (unilateral mass on CT/MRI but bilateral findings on AVS), which
would not have been curative.
●181 patients (19.1 percent) would have been offered medical therapy instead of
curative adrenalectomy (bilateral findings on CT/MRI but unilateral secretion on
AVS).
●37 patients (3.9 percent) would have undergone adrenalectomy on the wrong
side (AVS showing unilateral secretion on the opposite side of CT/MRI
abnormalities).
These observations highlight the importance of performing AVS in most patients to
distinguish between unilateral and bilateral adrenal aldosterone hypersecretion.
(See 'Adrenal vein sampling' below.)
The role of CT and MRI in the evaluation of incidental adrenal masses is reviewed in
detail elsewhere. (See "Evaluation and management of the adrenal incidentaloma",
section on 'MRI'.)
Adrenal vein sampling — Measurement of aldosterone in samples of adrenal venous
blood, obtained by an experienced interventional radiologist, is the criterion standard
test to distinguish between unilateral adenoma and bilateral hyperplasia [53]. Unilateral
disease is associated with a marked (usually fourfold greater than contralateral adrenal)
increase in PAC on the side of the tumor, whereas there is little difference between the
two sides in patients with bilateral hyperplasia (figure 1 and figure 2) [50,54,55].
Indications — For patients who would like to pursue surgical management (unilateral
adrenalectomy) of their primary aldosteronism, we suggest AVS to confirm unilateral
disease if the CT scan is normal, shows bilateral abnormalities, or shows a unilateral
abnormality but the patient is over age 35 years [48].
We suggest that AVS may not be needed in patients under age 35 years who have a
unilateral adrenal macroadenoma (>1 cm and <2 cm), because they are unlikely to have
a nonfunctioning adrenal adenoma that could be confused with an APA (algorithm 2).
The development of adrenocortical nodularity is, in part, a function of age.
Other factors to consider before recommending AVS include the presence of comorbid
conditions that could increase surgical risk and the probability of finding an APA [56].
APA is more likely in patients who have spontaneous hypokalemia and marked
elevations in aldosterone in blood (eg, >30 ng/dL) or 24-hour urine collection (eg, >30
mcg).
Procedure — Some centers perform AVS without cosyntropin stimulation, but we
suggest continuous cosyntropin infusion (50 mcg per hour started 30 minutes before
sequential sampling of the adrenal veins and continued throughout the procedure) for
the following reasons:
●To minimize stress-induced fluctuations in aldosterone secretion during
nonsimultaneous AVS, which could potentially confound the interpretation of
lateralization data.
●To maximize the gradient in cortisol from adrenal vein to inferior vena cava (IVC)
and thus confirm successful sampling of the adrenal vein.
●To maximize the secretion of aldosterone from an APA [50,54].
Some investigators have suggested that when given as a bolus injection and when the
adrenal veins are sampled simultaneously, cosyntropin administration does not improve

567
the diagnostic accuracy of AVS and may misclassify some patients [55,57,58].
However, as noted above, we suggest continuous cosyntropin infusion for optimal
results [50,54]. Confidence in successful cannulation of both adrenal veins is critical to
patient care. If the clinician cannot be confident that both adrenal veins were
successfully sampled, the AVS data are not clinically useful.
Aldosterone and cortisol concentrations are measured in the blood from all three sites
(right adrenal vein, left adrenal vein, and IVC). All of the blood samples should be
assayed at 1:1, 1:10, and 1:50 dilutions; absolute values and accurate laboratory
assays for cortisol and aldosterone are essential for successful interpretation of the AVS
data. An AVS-specific report should be developed by the laboratory to prevent any
confusion on data interpretation (figure 2) [25,50,59].
Confirming successful catheterization — The cortisol concentrations from the
adrenal veins and IVC are used to confirm successful cannulation of both adrenal veins.
With cosyntropin infusion, the adrenal vein to IVC cortisol ratio is typically more than
10:1 [50]; a ratio of at least 5:1 is required to be confident that the adrenal veins were
successfully catheterized (figure 2).
However, when cosyntropin infusion is not used, an adrenal vein to IVC cortisol gradient
of more than 3:1 is recommended [60]. Some centers require only a 10 percent gradient
between an adrenal vein and the IVC [55,57], a change that can be seen in minute-to-
minute adrenal cortisol secretion and that is within the coefficient of variation of some
cortisol assays. Thus, as noted, we suggest cosyntropin infusion during AVS.
Cortisol-corrected ratios — Dividing the right and left adrenal vein PAC by their
respective cortisol concentrations corrects for the dilutional effect of the inferior phrenic
vein flow into the left adrenal vein; these are termed "cortisol-corrected ratios."
●At Mayo Clinic, where AVS is performed with cosyntropin infusion, the mean
cortisol-corrected aldosterone ratio (APA-side PAC/cortisol to normal adrenal
PAC/cortisol) in patients with confirmed APA is 18:1 [50]. We use a cutoff for the
cortisol-corrected aldosterone ratio from high-side to low-side of more than 4:1 to
indicate unilateral aldosterone excess [50].
●In patients with presumed IHA, the mean cortisol-corrected aldosterone ratio is
1.8:1 (high-side to low-side); a ratio less than 3:1 is suggestive of bilateral
aldosterone hypersecretion [50].
Thus, most patients with a unilateral source of aldosterone will have cortisol-corrected
aldosterone lateralization ratios greater than 4; ratios greater than 3, but less than 4,
represent a zone of overlap. A ratio less than 3 is consistent with bilateral aldosterone
hypersecretion [50].
In addition, the contralateral aldosterone to cortisol ratio is less than the IVC
aldosterone to cortisol ratio in 93 percent of patients with surgically confirmed APA [50],
indicative of suppression of aldosterone secretion by the noninvolved adrenal gland.
Centers that perform AVS without cosyntropin infusion use lower lateralization cutoff
values [55,57]. However, using the diagnostic cutoffs described above for cosyntropin-
stimulated AVS, the sensitivity and specificity for detecting unilateral aldosterone
hypersecretion are 95 and 98.6 percent, respectively [48]. These test characteristics
deteriorate when lower cutoffs are used to determine successful catheterization and
lateralization.

568
Results — AVS may be most useful when there is no adrenal abnormality on CT or
when both adrenal glands are abnormal but asymmetric. In one report, for example, 24
of 58 patients (41 percent) with normal adrenal CT and 16 of 33 (49 percent) with
bilateral micronodules on CT had a unilateral source of aldosterone by AVS [50].
There are isolated cases of primary aldosteronism due to an ectopic adrenal adenoma
(as in the kidney) [61]. These patients have low serum aldosterone concentrations in
AVS, and CT or MRI may identify the site of the tumor.
One limitation to AVS is an inability to obtain good samples as the right adrenal vein is
small and sometimes difficult to locate. Success rates vary in part with local expertise.
In two series, catheterization was successful in 43 of 49 patients (88 percent) and 194
of 203 patients (96 percent), respectively (figure 2) [49,50].
The complication rate in published studies is 2.5 percent or less [50,57,59,60,62]. The
most common complication is groin hematoma; adrenal hemorrhage and adrenal vein
dissection are rare [63].
Tests not recommended — Other tests that have been used in the past to distinguish
unilateral APAs from bilateral disease before the development of the adrenal CT and
AVS approach have limited clinical utility. These tests include:
●Posture stimulation test – The posture stimulation test was based upon the
observation that patients with bilateral idiopathic hyperplasia have a characteristic
rise in PAC when going from the supine to standing position (thought to be due to
an enhanced sensitivity of the adrenal zona glomerulosa to the small changes in
angiotensin II that occur with standing) [64]. In contrast, no such changes would
be expected in patients with an APA, because their hypersecretion of aldosterone
is autonomous and diurnal.
However, this test does not discriminate well between unilateral adenoma and
bilateral hyperplasia [6,43,65,66]. As an example, in a study of 20 patients with
primary aldosteronism (15 with a unilateral APA) undergoing a postural stimulation
test, PAC increased after four hours of standing in all patients with hyperplasia
and in 8 of 15 patients with adenomas (based upon a 30 percent rise) [43].
●18-hydroxycorticosterone – Patients with an APA typically have elevated
supine plasma 18-hydroxycorticosterone levels at 8 AM (>100 ng/dL), while
patients with bilateral IHA do not [42]. However, the accuracy of the test is low,
and it does not help with localization [42,66].
●Iodocholesterol scintigraphy – Radionuclide scintigraphy with 131-I-
iodocholesterol or an analog (NP-59) is no longer used in most centers. While it
has the potential advantage of correlating function with anatomic findings, it is not
useful for evaluating small adrenal nodules, as tracer uptake is poor in APAs <1.5
cm in diameter [67]. In addition, this imaging modality is no longer available in the
United States.
Familial hyperaldosteronism — There are four rare forms of familial
hyperaldosteronism (FH) associated with adrenal hyperplasia (see "Familial
hyperaldosteronism"):
●FH type I or glucocorticoid-remediable aldosteronism (GRA) due to a
CYP11B1/CYP11B2 chimeric gene
●FH type II, caused by germline pathogenic variants in the chloride channel
CLCN2 [68]

569
 ●FH type III, caused by germline pathogenic variants in the potassium channel
subunit KCNJ5
●FH type IV, caused by germline pathogenic variants in the CACNA1H gene,
which encodes the alpha subunit of an L-type voltage-gated calcium channel
(Cav3.2)
CORTISOL COSECRETIONClinically important aldosterone-producing adenoma
(APA) cortisol cosecretion may occur in patients with larger APAs (eg, ≥1.5 cm in
diameter). It is reasonable to screen for this possibility in patients with apparent APAs
≥1.5 cm in diameter by measuring a baseline serum dehydroepiandrosterone sulfate
(DHEAS) and performing a 1 mg overnight dexamethasone suppression test. When
autonomous cortisol cosecretion is documented, it is important to cover the patient
perioperatively with stress doses of glucocorticoids and a planned postoperative taper.
PREGNANCYPrimary aldosteronism is uncommon in pregnancy, with fewer than 60
patients reported in the medical literature; most patients have had aldosterone-
producing adenomas (APAs) [69-73]. Primary aldosteronism can lead to intrauterine
growth retardation, preterm delivery, intrauterine fetal demise, and placental abruption
[73,74].
Case-detection testing for primary aldosteronism in the pregnant woman is the same as
for nonpregnant patients: morning blood sample for the measurement of aldosterone
and plasma renin activity or renin concentration (see 'Who should be tested?' above).
Suppressed renin and an aldosterone level >10 ng/dL is a positive case-detection test
for primary aldosteronism. If spontaneous hypokalemia is present in the woman with
high aldosterone (≥20 ng/dL) and suppressed renin, confirmatory testing is not needed.
In the normokalemic woman with a positive case-detection test, confirmatory testing
should be pursued. However, the captopril stimulation test is contraindicated in
pregnancy, and the saline infusion test may not be well tolerated. One option is
measurement of sodium and aldosterone in a 24-hour urine collection on an ambient
sodium diet. (See 'Confirmation of the diagnosis' above.)
Subtype testing with abdominal magnetic resonance imaging (MRI) without gadolinium
is the test of choice. Adrenal imaging with computed tomography (CT), iodocholesterol
scintigraphy, and adrenal vein sampling (AVS) should be avoided in pregnancy. As
highlighted in the revised Endocrine Society guidelines on primary aldosteronism [5],
AVS may not be needed in patients with vigorous primary aldosteronism who are less
than 35 years old and have a clear-cut, unilateral adrenal adenoma on cross-sectional
imaging [48]. (See 'Subtype classification' above and "Treatment of primary
aldosteronism", section on 'Pregnancy'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Primary aldosteronism".)
SUMMARY AND RECOMMENDATIONS
●Nonsuppressible (primary) hypersecretion of aldosterone is an underdiagnosed
cause of hypertension. The classic presenting signs of primary aldosteronism are
hypertension and hypokalemia. However, normokalemia may be more common
than hypokalemia in patients diagnosed with primary aldosteronism.
(See 'Variable presentation' above.)

570
●Excessive secretion of aldosterone is associated with an increased risk of
cardiovascular disease and morbidity, including left ventricular hypertrophy, atrial
fibrillation, myocardial infarction, and stroke. (See 'Overview of approach' above.)
●The most common causes of primary aldosteronism are aldosterone-producing
adenomas (APAs) and bilateral adrenal hyperplasia, and in rare cases, familial
hyperaldosteronism (FH) type I (glucocorticoid-remediable aldosteronism [GRA]),
type II, type III, or type IV. (See 'Subtype classification' above and "Familial
hyperaldosteronism".)
●Consistent with the 2016 Endocrine Society guidelines, we recommend case-
detection testing for primary aldosteronism in patients with (see 'Who should be
tested?' above):
•Hypertension and spontaneous or low-dose, diuretic-induced hypokalemia
•Severe hypertension (>150 mmHg systolic or >100 mmHg diastolic) or drug-
resistant hypertension (defined as suboptimally controlled hypertension on a
three-drug program that includes an adrenergic inhibitor, vasodilator, and
diuretic)
•Hypertension with an adrenal incidentaloma
•Hypertension with sleep apnea
•Hypertension and a family history of early-onset hypertension or
cerebrovascular accident at a young age (<40 years)
•All hypertensive first-degree relatives of patients with primary aldosteronism
(see 'Case detection' above)
•Hypertension and atrial fibrillation
●The initial evaluation should consist of documenting that the plasma renin activity
(PRA) or plasma renin concentration (PRC) is reduced (typically undetectable)
and that the plasma aldosterone concentration (PAC) is inappropriately high for
the PRA (typically >10 ng/dL [>277 pmol/L]); the net effect is a PAC/PRA ratio
greater than 20 (depending upon the laboratory normals). As noted above, we
prefer to use the paired random PAC and PRA (or PRC) for case detection rather
than the PAC/PRA ratio (table 1 and algorithm 1). (See 'Case detection' above
and 'Initial testing' above.)
●We recommend confirming the diagnosis by demonstrating inappropriate
aldosterone secretion. For aldosterone suppression testing, we use oral sodium
loading and measurement of urine aldosterone excretion. Some experts prefer
intravenous sodium chloride loading and measurement of the PAC.
The exceptions to the requirement for confirmatory testing are the patients with
spontaneous hypokalemia, low PRA or PRC, and a PAC ≥20 ng/dL, or those
patients without spontaneous hypokalemia but with low PRA or PRC and a PAC
>30 ng/dL; in these clinical settings, there is no other diagnosis except primary
aldosteronism to explain the findings. (See 'Confirmation of the diagnosis' above.)
●We suggest adrenal computed tomography (CT) as the initial test to distinguish
between APA and bilateral hyperplasia. Adrenal CT will also exclude
adrenocortical carcinoma (algorithm 2). (See 'Adrenal CT' above.)
●When the CT scan is normal, shows bilateral abnormalities, or shows a unilateral
abnormality, but the patient is over age 35 years, we recommend adrenal vein
sampling (AVS) to confirm unilateral disease if the patient would like to pursue
571
surgical management of their primary aldosteronism (figure 2 and algorithm 2).
(See 'Adrenal vein sampling' above.)
●AVS should only be performed by an experienced radiologist. (See 'Adrenal vein
sampling' above.)

572
Epidemiology and clinical manifestations of
Cushing's syndrome
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 05, 2021.
INTRODUCTIONThe symptoms and signs of Cushing's syndrome result directly
from chronic exposure to excess glucocorticoid. Establishing the diagnosis is often
difficult because few of the symptoms or signs are pathognomonic of the
syndrome in isolation. There is a large spectrum of manifestations from subclinical
to overt syndrome, depending on duration and intensity of excess steroid
production. Furthermore, some of them (such as obesity, hypertension, and
glucose intolerance) are common in individuals who do not have adrenal
hyperfunction. An important clinical clue to the presence of glucocorticoid excess
is the simultaneous development and increasing severity of several of these
symptoms.
The major manifestations of Cushing's syndrome will be reviewed here. The
diagnosis and treatment of this disorder and Cushing's syndrome during
pregnancy are discussed separately. (See "Establishing the diagnosis of Cushing's
syndrome" and "Establishing the cause of Cushing's syndrome" and "Overview of
the treatment of Cushing's syndrome" and "Diagnosis and management of
Cushing's syndrome during pregnancy".)
EPIDEMIOLOGYEstimates of the incidence of Cushing's syndrome are
imprecise and likely underestimate the incidence of iatrogenic Cushing's
syndrome, undiagnosed mild hypercortisolism, and the ectopic corticotropin
(ACTH) syndrome.
●Iatrogenic Cushing's syndrome – More than 10 million Americans receive
pharmacologic doses of glucocorticoids each year. Therefore, iatrogenic
Cushing's syndrome must be more common than any other cause but is
seldom reported. (See "Major side effects of systemic glucocorticoids",
section on 'Dermatologic effects and appearance'.)

573
 ●Cushing's disease – Pituitary ACTH-dependent Cushing's causes 65 to 70
percent of Cushing's syndrome [1]. The reported incidence was 1.2 to 2.4 per
million per year in European population-based studies [2,3] and 6.2 to 7.6 per
million person-years in the United States [4]. (See "Causes and
pathophysiology of Cushing's syndrome", section on 'Cushing's disease'.)
●Ectopic ACTH syndrome – Recognized ectopic ACTH syndrome causes 10 to
15 percent of cases. However, its true incidence is probably more common
because a number of these patients do not present with catabolic features
and are not diagnosed. For example, small cell lung cancer is diagnosed in
approximately 8 of 100,000 persons annually, in whom the ectopic ACTH
syndrome is diagnosed in approximately 1 percent, approximately 1 per
million [5,6]. As ectopic ACTH secretion accounts for only approximately 15
percent of Cushing's syndrome, it is clear that it is underdiagnosed. Other
causes of ectopic ACTH syndrome, such as pulmonary neuroendocrine
tumors, are reviewed separately. (See "Causes and pathophysiology of
Cushing's syndrome", section on 'Ectopic ACTH syndrome'.)
●Adrenal tumors – Adrenal carcinoma and adenoma cause a similar number
of cases of Cushing's syndrome in most series, together comprising
approximately 20 percent of all cases. However, a preponderance of
Cushing's syndrome caused by adrenal adenomas has been described in
Hokkaido, Japan and in Italy [7,8]. Based on the United States Surveillance,
Epidemiology, and End Result (SEER) database, the incidence of adrenal
carcinoma from 2000 to 2012 was estimated to be 1.26 per million per year
[9]. A population-based study in Denmark reported the incidence of adrenal
adenoma and adrenal carcinoma as 0.6 and 0.2 per million per year,
respectively [2]. (See "Clinical presentation and evaluation of adrenocortical
tumors".)
●All other causes of Cushing's syndrome are extremely rare, including
Cushing's syndrome due to either bilateral macronodular adrenal hyperplasia
or primary pigmented nodular adrenocortical disease, which are discussed
elsewhere. Ectopic production of corticotropin-releasing hormone (CRH) is
perhaps the most uncommon cause of the syndrome. (See "Cushing's
syndrome due to primary bilateral macronodular adrenal
hyperplasia" and "Cushing's syndrome due to primary pigmented nodular
adrenocortical disease".)
The incidence of Cushing's syndrome varies by both sex and age. The sex-
related distribution of Cushing's syndrome varies with the cause:
●Males had a three times greater incidence of the ectopic ACTH syndrome 30
years ago, but the increasing incidence of lung cancer in cigarette-smoking

574
 females has narrowed that margin. (See "Pathobiology and staging of small
cell carcinoma of the lung", section on 'Epidemiology'.)
●Females are three to eight times more likely than males to develop
Cushing's disease [1], approximately three times more likely to have either
benign or malignant adrenal tumors, and approximately four to five times
more likely to have Cushing's syndrome associated with an adrenal tumor
[1,10-12]. The reasons for this preponderance in females are unknown.
The age at presentation varies depending upon the cause of hypercortisolism:
●The age at which the ectopic ACTH syndrome develops parallels the
development of lung carcinoma, increasing rapidly after age 50 years. Ectopic
ACTH secretion due to more benign neuroendocrine tumors (previously
termed carcinoids) can occur at earlier ages but is rare in children.
(See "Pathobiology and staging of small cell carcinoma of the lung", section
on 'Epidemiology'.)
●Cushing's disease occurs mainly in women aged 25 to 45 years. It is unusual
in children but still accounts for up to 46 percent of cases of childhood
Cushing's syndrome, occurring mostly after puberty [13,14]. In two small
studies reporting on approximately 20 prepubertal children, boys were
affected more often than girls (18:2), while 36 of 53 adolescents with
Cushing's disease were female [13,15-17]. (See "Causes and pathophysiology
of Cushing's syndrome", section on 'Cushing's disease'.)
●Adrenal tumors have a bimodal age distribution, with small peaks in the first
decade of life for both adenomas and carcinomas and major peaks at
approximately 50 years for adenomas and 40 years for carcinomas [11,18].
One literature review found that adrenal tumors (benign and malignant)
cause 41 percent of all cases of childhood Cushing's syndrome, with primary
pigmented nodular dysplasia accounting for approximately 6 percent [14].
Girls are affected slightly more often than boys. (See "Clinical presentation
and evaluation of adrenocortical tumors".)
CLINICAL MANIFESTATIONSThe major symptoms and signs of Cushing's
syndrome are listed in the table (table 1) and reviewed in detail in this section [19-
21].
In adults, signs and symptoms most suggestive of the presence of
hypercortisolism include proximal muscle weakness, facial plethora, wasting of the
extremities with increased fat in the abdomen and face, wide purplish striae,
bruising with no obvious trauma, and supraclavicular fat pads [22-24]. An
important clinical clue to the presence of glucocorticoid excess is the simultaneous
development or accumulation of new features over time and increasing severity of
several of these symptoms.
575
The clinical manifestations of Cushing's syndrome can be categorized as
reproductive, dermatologic, metabolic, cardiovascular, musculoskeletal,
neuropsychiatric, and infectious. In addition to the considerable morbidity caused
by hypercortisolism, there is also an increase in mortality rates.
(See 'Mortality' below.)
Severity of symptoms — When hypercortisolism is severe, its signs and
symptoms are unmistakable. However, many of the signs and symptoms of
Cushing's syndrome can occur in individuals without hypercortisolism, and not all
patients with Cushing's syndrome present with obvious features.

The presence and relative severity of symptoms varies, being determined by the
following factors:

●The degree and duration of hypercortisolism.

●The presence or absence of androgen excess (because hypercortisolism
alone causes neither hirsutism nor pustular acne).
●The cause of the hypercortisolism (because hyperpigmentation is caused by
increased secretion of corticotropin [ACTH]) and androgen excess occurs only
in females with adrenal cancer or ACTH-stimulated hyperandrogenism (the
adrenal gland being a major source of androgen production in females but
not males). Adrenal adenomas generally secrete only glucocorticoids.
●Adrenal carcinoma or the ectopic ACTH syndrome can cause tumor-related
symptoms that may overshadow the effects of hypercortisolism (such as
weight loss instead of weight gain).
●In patients with adrenal adenomas, both the degree of hypercortisolemia
and many of the clinical manifestations of Cushing's syndrome tend to be
less severe in patients >50 years of age [20]. Many patients with incidentally
discovered adrenal adenomas have subclinical Cushing's syndrome (mild
hypercortisolism without clinical manifestations of Cushing's syndrome, now
often referred to as "autonomous cortisol secretion"), but glucose intolerance
and hypertension are common [21]. (See "Evaluation and management of the
adrenal incidentaloma", section on 'Subclinical Cushing's syndrome'.)
Reproductive
Menstrual irregularities — Menstrual irregularities are common in women with
Cushing's syndrome. In one series of 45 women with newly diagnosed Cushing's
disease, 80 percent had abnormal menstrual cycles, 31 percent had
oligomenorrhea, 33 percent had amenorrhea, and the remainder had excess or
variable menses [25]. The menstrual abnormalities correlated with increased
serum cortisol and decreased serum estradiol concentrations but not with serum
androgen concentrations. Because both luteinizing hormone and follicle-
576
stimulating hormone levels are low, the menstrual irregularities appear to be due
to suppression of secretion of gonadotropin-releasing hormone by
hypercortisolemia [26].
Signs of adrenal androgen excess — Females with some types of Cushing's
syndrome (most commonly adrenal carcinoma) have signs of androgen excess
[27]. The adrenal glands are the major source of androgens in females [28]. In
contrast, the testes are the major source of androgens in males [29]. Thus, males
with Cushing's syndrome do not have signs of androgen excess, because cortisol
has no androgenic activity [30].
Signs of androgen excess in Cushing's syndrome are most common in women with
adrenal carcinomas [10,18]. These tumors usually secrete large amounts of
androgenic precursors because they are inefficient at converting cholesterol to
cortisol [31,32]. In comparison, signs of androgen excess are usually mild in
women with ACTH-dependent Cushing's syndrome and do not occur in women
with adrenal adenomas [18].

Androgen excess in affected women can cause the following symptoms:

●Hirsutism, which is usually mild and limited to the face but can be
generalized. Downy sideburns and increased hair on the upper lip and under
the chin are most common (picture 1). The scalp hair often becomes thin, but
temporal balding is rare.
●Oily facial skin and acne on the face, neck, or shoulders.
●Increased libido (however, decreased libido is more common, occurring in
70 percent of patients in one series [33]).
●Virilization, including temporal balding, deepening voice, male body habitus,
male escutcheon, and clitoral hypertrophy, occurs only in girls or women with
extremely high serum concentrations of androgens due to an adrenal
carcinoma. Prepubertal males may develop premature puberty (picture 2).
Dermatologic — Many changes in the skin and subcutaneous tissue occur in
patients with Cushing's syndrome. Unlike most other symptoms and signs
associated with Cushing's syndrome, which can occur alone or in combination in
normal subjects and patients with pseudo-Cushing's states, the dermatologic
changes characteristic of Cushing's syndrome seldom occur in other subjects
[22,34].
●Easy bruisability – Loss of subcutaneous connective tissue due to the
catabolic effects of glucocorticoid results in easy bruising after minimal, often
unremembered, injury (picture 3). Extensive ecchymoses at venipuncture
sites are also common, and it is often difficult to maintain intravenous lines
without fluid infiltration into the surrounding tissues. As a result, patients
577
with Cushing's syndrome are sometimes thought to have senile purpura or a
bleeding diathesis [35].
●Striae – Purple striae occur as the fragile skin stretches due to the enlarging
trunk, breasts, and abdomen (picture 4). The striae appear as wide, reddish-
purple streaks because the increasingly thin skin does not hide the color of
venous blood in the underlying dermis. Striae occur most often in younger
patients, can be numerous, and are most common on the abdomen and
lower flanks; however, they can also occur on the breasts, hips, buttocks,
shoulders, upper thighs, upper arms, and axillae [36].
●Skin atrophy – The skin usually atrophies, the stratum corneum is thinned,
and there is loss of subcutaneous fat to a sufficient degree that
subcutaneous blood vessels may be seen [37]. The skin eventually becomes
fragile due to these changes and, in extreme cases, peels off after being
covered with adhesive tape. Minor wounds heal slowly, and surgical wounds
may dehisce. Such changes should be considered in the context of sex and
age differences in skin thickness, with healthy men and younger individuals
having greater skin thickness.
●Fungal infections – Cutaneous fungal infections, especially tinea versicolor,
are often found on the trunk. Some patients have fungal infections of the
nails, but oral candidiasis is rare.
●Hyperpigmentation – Hyperpigmentation is induced by increased ACTH,
not cortisol, secretion. ACTH is the principal pigmentary hormone in humans.
It acts via binding to melanocyte-stimulating hormone receptors [38]. The
degree of hyperpigmentation is dependent upon both the duration and the
degree of increase in ACTH secretion.
Hyperpigmentation occurs most often in patients with the ectopic ACTH
syndrome, less often in those with pituitary overproduction of ACTH, and not
at all in patients with adrenal tumors in whom ACTH secretion is suppressed.
Hyperpigmentation may be generalized but is most conspicuous in areas
exposed to light (such as the face, neck, and back of the hands) or to chronic
mild trauma, friction, or pressure (such as the elbows, knees, spine, knuckles,
waist [belt], midriff [girdle], and shoulders [brassiere straps]) (picture 5A-B).
Patchy pigmentation may occur on the inner surface of lips and the buccal
mucosa along the line of dental occlusion (picture 6). The hyperpigmentation
is less pronounced than in patients with chronic primary adrenal
insufficiency.
Acanthosis nigricans also can be present in the axillae and around the neck.
Surgical or traumatic scars that form when plasma ACTH concentrations are
markedly elevated are permanently pigmented. In comparison, scars

578
 incurred before ACTH hypersecretion or after it is reduced are not
pigmented.
Metabolic
Glucose intolerance — Glucose intolerance is common in Cushing's syndrome. It
is primarily due to stimulation of gluconeogenesis by cortisol and peripheral
insulin resistance caused by obesity, but direct suppression of insulin release also
may contribute. (See "Major side effects of systemic glucocorticoids".)
Overt hyperglycemia occurs in only 10 to 15 percent of patients, usually those with
a family history of type 2 diabetes mellitus [39]. Diabetic ketoacidosis is rare and, if
present, usually indicates unsuspected type 1 diabetes exacerbated by
hypercortisolemia.
Poorly controlled hyperglycemia in a person with obesity may be a clue to the
presence of Cushing's syndrome. One report, for example, found that 3 percent of
such patients had Cushing's syndrome [40]. In a prospective study of 200
individuals with obesity, type 2 diabetes, and no symptoms of Cushing's syndrome,
four patients (2 percent) were identified as having occult Cushing's syndrome
(three with Cushing's disease and one with an adrenal adenoma) [41]. However, a
subsequent study of 201 patients did not identify any with Cushing's syndrome
[42]. Thus, it is not recommended to screen diabetic patients unless they have
other features of the disorder [23].
Patients with Cushing's syndrome who have hyperglycemia should be treated like
any other patient with type 2 diabetes (see "Overview of general medical care in
nonpregnant adults with diabetes mellitus"). The hyperglycemia becomes much
easier to control and may completely remit if the hypercortisolism is reversed [43].
Increased urinary albumin excretion appears to be common in Cushing's
syndrome, and it is reversible. In a study of 13 patients, 80 percent had increased
urinary albumin excretion, but neither the presence nor the degree of albuminuria
was correlated with blood pressure or fasting plasma glucose concentrations [44].
Kidney biopsies in three patients with microalbuminuria showed normal glomeruli
with no evidence of diabetic or hypertensive nephropathy.
Progressive obesity — The most common feature of patients with Cushing's
syndrome is progressive, central (centripetal) obesity (picture 7), usually involving
the face, neck, trunk, abdomen (picture 8), and, internally, spinal canal and
mediastinum [45,46]. The extremities are often spared and may be wasted. Some
authors report generalized obesity in a majority of adults with Cushing's syndrome
[22].
Children with Cushing's syndrome almost invariably have generalized obesity and
growth retardation; the latter may be the first indication of glucocorticoid excess.
As a result, any child whose weight rises and height falls in percentile rank as

579
compared with age-matched normal children should be considered to have
Cushing's syndrome until proven otherwise (figure 1). These abnormalities both
improve after successful treatment of patients whose bones have not yet fused
[47].

Fat can also accumulate in the following areas in patients with Cushing's
syndrome:

●Fat accumulation in the cheeks and the temporal fossae results in a "moon"
face that sometimes obscures the ears when a patient is examined from the
front (picture 1).
●A "buffalo hump" or dorsocervical fat pad is common and is usually
consistent with the general degree of obesity (picture 9).
●Enlarged fat pads that fill the supraclavicular fossae and obscure the
clavicles are one of the most specific signs of Cushing's syndrome [22],
although they occasionally occur in exogenous obesity. The bulging,
supraclavicular fat pads make the neck appear thick and shortened (picture
1). Retroorbital fat deposition may result in exophthalmos, which is present in
up to 5 percent of patients [48,49].
●Rarely, fat accumulation in the epidural space leads to neurologic
abnormalities, usually in patients with ectopic ACTH secretion or exogenous
steroid administration [50].
The degree of fat accumulation in Cushing's syndrome is variable. Patients who
diet and exercise rigorously may have little or no weight gain, facial rounding, or
central weight redistribution. Other patients with no weight gain still have central
weight redistribution. The cause of abdominal fat may be caused by cortisol-
induced downregulation of adenosine monophosphate-activated protein kinase
(AMPK), which regulates lipid and carbohydrate metabolism [51].
The conversion of cortisone to cortisol also contributes to fat deposition, as shown
by a report of the absence of abnormal fat accumulation in a patient with a
mutation that prevented this conversion [52].
Patients with Cushing's syndrome have higher serum leptin concentrations than
obese subjects with a similar body mass index (BMI) [53]. Leptin secretion does not
respond to changes in plasma ACTH or serum cortisol concentrations, but it does
appear to vary according to changes in fat mass and peripheral insulin resistance
(and therefore serum insulin concentrations), as it does in other obese subjects
[54].
Sleep apnea — In one study, sleep apnea was diagnosed in 10 of 22 patients with
Cushing's disease or adrenal adenoma [55]. In the same study, patients without
sleep apnea showed abnormal sleep architecture and fragmented sleep with
580
shortened rapid eye movement latency, similar to that seen in depression [55].
These abnormalities may contribute to the fatigue that is common in these
patients [33].
It is likely that central obesity and possibly myopathy of the muscles that maintain
airway patency both contribute to the development of sleep apnea [56]. There are
no data regarding reversal after cure of Cushing's syndrome.
Cardiovascular — Patients with endogenous Cushing's syndrome are at increased
risk of death from cardiovascular disease, including myocardial infarction, stroke,
and thromboembolism [2,3,57]. (See 'Thromboembolic events' below.)
Other common cardiovascular problems in patients with Cushing's syndrome
include hypertension and dyslipidemia. In addition, a study of 15 patients with
ACTH-dependent Cushing's syndrome reported an increase in markers of
subclinical atherosclerosis (coronary calcifications and noncalcified plaque
volumes) when compared with controls [57].
Cardiovascular risk — One study estimated cardiovascular risk in 49 patients with
active Cushing's syndrome according to World Health Organization
(WHO)/International Society of Hypertension (ISH) criteria. Eighty percent of
patients had a high or very high risk: 85 percent were hypertensive, 47 percent
were diabetic, and 41 percent were obese [58]. Thus, aggressive treatment of
these factors is warranted.
Although markers of cardiovascular risk, including lipid profiles, waist-to-hip ratios,
and carotid artery intima medial thickness, improve in patients cured of their
Cushing's disease, they may not normalize, suggesting that cured patients
continue to have excess cardiovascular risk (possibly due to residual abdominal
obesity and/or insulin resistance) [59,60].
Patients with subclinical Cushing's syndrome due to an adrenal incidentaloma may
also have excess cardiovascular risk [61-63]. (See "Evaluation and management of
the adrenal incidentaloma", section on 'Subclinical Cushing's syndrome'.)
Hypertension — The pathogenesis of hypertension in Cushing's syndrome is
multifactorial and not fully understood; however, the following factors may be
important [64,65]:
●Increased peripheral vascular sensitivity to adrenergic agonists [66].
●Increased hepatic production of renin substrate (angiotensinogen); based
on this observation, one consensus paper suggests that angiotensin-
converting enzyme (ACE) inhibitors should be considered the first-line
treatment of hypertension in Cushing's syndrome patients [67].
●Activation of renal tubular type 1 (mineralocorticoid) receptors by cortisol
(this mechanism applies mainly to patients with severe hypercortisolism,
which is usually due to ectopic ACTH secretion) [68,69].

581
 ●It is also possible that cortisol has a direct cardiotoxic effect [70].
Treatment of hypertension in patients with Cushing's syndrome does not differ
from that of patients with primary hypertension (formerly called "essential"
hypertension). However, blocking mineralocorticoid activity
with spironolactone may be particularly effective in patients with very high serum
cortisol concentrations, especially those with hypokalemia. The hypertension
usually becomes easier to control and may entirely disappear when the Cushing's
syndrome is treated [71].
Severe hypertension and hypokalemia are more prevalent in patients with ectopic
ACTH [72]. The high serum cortisol concentrations overwhelm the ability of the
kidneys to convert cortisol to cortisone, resulting in activation of mineralocorticoid
receptors as described above. Hypokalemia may also result from adrenal
hypersecretion of mineralocorticoids, such as deoxycorticosterone and
corticosterone [73]. (See "Apparent mineralocorticoid excess syndromes (including
chronic licorice ingestion)", section on 'Ectopic ACTH syndrome'.)
Thromboembolic events — An increase in venous thromboembolism (VTE) risk
has been reported in most studies of patients with Cushing's syndrome [22,74-77].
In a systematic review of 15 studies, the risk of postoperative VTE ranged from 0 to
5.6 percent (with one outlier of 20 percent) [78]. In two of the studies, the risk of
VTE not related to surgery was reported to be 1.9 and 2.5 percent. Based upon the
6 to 9.7 years of follow-up in these studies, this corresponded to an incidence of
2.5 to 3.1 per 1000 person-years [78], much higher than the estimated incidence in
an age- and sex-matched population (VTE incidence for 40-year-old women = 0.3
per 1000 person-years) [79].
In a multicenter cohort study of patients with Cushing's syndrome published after
the systematic review (n = 473; 360 with ACTH-dependent pituitary Cushing's
syndrome, 113 with ACTH-independent adrenal disease), VTE rates not related to
surgery were higher than reported in the systematic review, while postoperative
rates were in a similar range [80]:
●Prior to treatment, 17 patients with Cushing's syndrome (4 percent) had a
VTE, for an incidence rate of 12.9 per 1000 person-years.
●The frequency of postoperative VTE (within three months after
transsphenoidal surgery for ACTH dependent or adrenalectomy for ACTH
independent) was 3.4 and 0 percent, respectively [80]. The 3.4 percent
postoperative risk in those with ACTH-dependent disease (12 events in 350
patients) translates to an incidence of 141 per 1000 person-years. No
episodes of postoperative VTE were seen in a control group of 185 patients
undergoing pituitary surgery for nonfunctioning adenomas.

582
The risk is possibly due to glucocorticoid-induced increases in plasma
concentrations of clotting factors, especially factor VIII and von Willebrand factor
complex, and decreases in fibrinolytic activity [74-76]. Elevated serum
homocysteine concentrations, which appear to be associated with an increased
risk of cardiovascular disease and venous thrombosis, have been reported in
patients with Cushing's syndrome [81]. (See "Overview of homocysteine".)
Clinical features that appear to contribute to the excess risk of thromboembolism
include obesity and surgery [78]. Another study that examined factors in 20 of 176
patients who developed venous thromboembolism found risk factors of age ≥69
years, reduced mobility, acute severe infections, previous cardiovascular events,
midnight plasma cortisol level more than 3.15 times the reference range, and
shortened activated partial thromboplastin time (aPTT) [82].
Prophylactic postoperative anticoagulation may reduce the risk of thromboembolic
complications. This was illustrated in a retrospective study of 307 patients with
Cushing's syndrome; postoperative prophylactic anticoagulation with heparin
and/or warfarin appeared to reduce the risk of thromboembolic complications (14
of 232 patients [6 percent]) compared with a historical control group that was not
anticoagulated (15 of 75 patients [20 percent]) [75]. Although further studies are
needed to confirm its benefit, postoperative anticoagulation prophylaxis seems
warranted at present for nonambulatory patients. In the absence of further
studies, we would not recommend postoperative anticoagulation in patients who
are ambulatory.

We also encourage our hospitalized patients to get out of bed during the day and
to walk for 15 to 20 minutes two or three times a day, if possible.

Other — Hypercortisolism may also be associated with heart failure and dilated

cardiomyopathy:
●One series reported heart failure in almost one-half of patients older than 40
years [83], but in our experience, it is rare. Dependent edema can also occur,
although the mechanism is not well understood. It should not be caused by
excess mineralocorticoid activity, due to the phenomenon of aldosterone
escape [84].
●Dilated cardiomyopathy occurs rarely in Cushing's syndrome but it is
generally reversible [85]. In one literature review, it was associated with
Cushing's disease in approximately one-quarter of the patients and with
adrenal adenomas in the remainder [85], but it has also been reported in a
single patient with ectopic ACTH secretion [86]. It is characterized by cell
hypertrophy and myocardial fibrosis [87].
Bone health/musculoskeletal
583
Proximal muscle wasting and weakness — Weakness and proximal muscle
wasting are common in Cushing's syndrome, being induced by the catabolic
effects of excess glucocorticoid on skeletal muscle (picture 10). As a result, many
patients cannot rise from a squatting position without assistance; patients with
more severe disease may be unable to climb stairs or get up from a deep chair.
The catabolic effects of cortisol are amplified by physical inactivity [88]
(see "Glucocorticoid-induced myopathy"). In a number of studies, muscle wasting
and weakness were uncommon in patients with pseudo-Cushing's syndrome
[34,48,49,89]. However, in one study of 23 patients with pseudo-Cushing's
syndrome and 32 with Cushing's syndrome, the incidence of weakness was similar
in the two groups (approximately 30 percent) [90].
Hypokalemia, due to decreased renal conversion of cortisol to cortisone by 11-beta
hydroxysteroid dehydrogenase type II, allowing for cortisol to exert
mineralocorticoid effects, can accentuate the weakness in patients with severe
hypercortisolism [69]. On the other hand, a high-protein diet and exercise may
improve or mitigate muscle wasting and increase strength.
Bone loss — Osteoporosis is common in patients with Cushing's syndrome. It is
caused by decreased intestinal calcium absorption, decreased bone formation,
increased bone resorption, and decreased renal calcium reabsorption [91,92]. It
can be demonstrated by densitometry of the lumbar vertebrae, even in young
patients. Pathologic fractures may occur, often resulting in severe skeletal pain.
(See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

The following skeletal abnormalities may be seen:

●A study of 80 patients with Cushing's syndrome showed a 76 percent

prevalence of osteoporosis [93]. Multiple fractures were more common in
patients with ectopic ACTH secretion.
●Pathologic rib and long-bone fractures [94].
●Osteonecrosis (aseptic necrosis) of the femoral heads and rarely the
humeral heads, usually only with chronic, high-dose glucocorticoid therapy
[95]. Osteonecrosis of the femoral head has been described in few patients
with Cushing's syndrome [96] and, rarely, it may be the presenting
manifestation of Cushing's syndrome [97]. (See "Treatment of nontraumatic
hip osteonecrosis (avascular necrosis of the femoral head) in adults".)
●Low back pain is very common and is attributed to osteoporosis, vertebral
compression, muscle wasting, and the lordotic posture resulting from weight
gain.
●Lower-extremity insufficiency fractures, particularly of the feet, were
reported in 10 women, five of whom had mild disease [98].
584
Increased bone resorption can also lead to hypercalciuria and renal calculi [99].
Hypercalcemia is very rare.
Bone mineral density improves in adults and children after successful treatment of
Cushing's syndrome [21,100]. One study of 17 adults found normal bone mineral
density in the spine and hip when measured on average at 8.6 years after cure of
Cushing's syndrome [101]; others have reported normalization within five years in
children [102].
Subclinical hypercortisolism — Even patients with mild chronic hypercortisolism,
such as women who have adrenal incidentalomas causing slightly increased
cortisol secretion but no other clinical manifestations of Cushing's syndrome (ie,
subclinical Cushing's syndrome), may have increased bone turnover, decreased
bone mineral density, and vertebral fractures [103]. (See "Evaluation and
management of the adrenal incidentaloma", section on 'Subclinical Cushing's
syndrome'.)
Neuropsychologic changes and cognition — A number of neuropsychologic
symptoms may occur, including insomnia, depression, and memory loss.
Symptoms of psychiatric disease occur in over one-half of patients with Cushing's
syndrome of any etiology and are, therefore, presumably caused by excess cortisol
[48,104,105]. Some patients have psychiatric illness as the presenting symptom
[105]. (See "Glucocorticoid effects on the nervous system and behavior", section on
'Behavior'.)
Depression occurs in up to 86 percent of patients with Cushing's syndrome
[33,106,107]. Most have the increased appetite and weight gain that is usually
associated with atypical depression [106]. Rarely, however, anorexia and weight
loss predominate as is common in melancholic depression [108]. Severely
depressed patients may also be suicidal [48,104].
On the other hand, some patients appear euphoric or manic, particularly early in
the course of the illness. Children tend to be overachievers, often ranking near the
top of their class [109].
The most common psychologic symptoms are [33,48,104-106]:
●Emotional lability
●Depression (37 to 86 percent of patients)
●Irritability (86 percent)
●Anxiety (up to 80 percent)
●Panic attacks (up to 30 percent)
●Mild paranoia and mania are less common [33]
After correction of the hypercortisolism, resolution of the psychiatric symptoms is
variable [110-112] (see "Glucocorticoid effects on the nervous system and
behavior", section on 'Correction of hypercortisolism'):

585
 ●In one study of 33 patients with Cushing's syndrome, important
psychopathology (predominantly atypical depression) was present in 55
percent before treatment compared with 24 percent one year after
successful treatment [110]. There was also a significant improvement in
overall mood score. However, important psychopathology developed after
treatment in 4 of 17 patients who had no prior psychiatric symptoms, and
one of the four became suicidal.
●Other data suggest that Cushing's disease has adverse effects on mood and
social functioning that persist after surgical cure [112,113]. This was
illustrated in a follow-up report of 114 patients with pituitary tumors who had
undergone successful pituitary surgery. The 15 patients with treated
Cushing's disease had significantly worse scores on measures of psychosocial
well-being and psychosocial functioning compared with patients with other
tumors (nonfunctioning adenomas, macroprolactinomas, acromegaly) in
whom the scores were similar [112].
In adults, learning, cognition, and memory (especially short-term memory) are
impaired by hypercortisolism [114,115]. Bedside assessment of these attributes
may be useful in assessing the presence of hypercortisolism [116].
Hypercortisolism is also associated with a decrease in hippocampal volume and a
general reduction in brain volume [114,117]. In one study, the degree of impaired
memory was associated with a decrease in hippocampal volume [118]. Brain
volume increases but does not always return to normal after cure of the
hypercortisolism [117]. (See "Glucocorticoid effects on the nervous system and
behavior", section on 'Loss of brain volume'.)
In patients with Cushing's disease in remission, cognitive function may improve
but not return to baseline [119,120]. In a study of 24 patients studied before and
after treatment, some, but not all, had an improvement in cognitive and memory
function [119]. Improvements in the ability to remember a list of unrelated words
was associated with an increase in hippocampal volume.
One study of 11 children found a decline in intelligence quotient (IQ) and cognitive
performance at one year after curative surgery, in the absence of
psychopathology, despite reversal of cerebral atrophy [121].
Infection and immune function — Glucocorticoids inhibit immune function,
thereby contributing to an increased frequency of infections [122]. In parallel with
this, there may be thymic atrophy [123]. Infection accounted for 21.6 percent of
deaths in one study of 311 patients with Cushing's disease [124]. Nevertheless,
opportunistic infections with organisms of low pathogenicity occur only in patients
with severe hypercortisolemia, such as those with ectopic ACTH syndrome [125]. In
one study, patients with serum cortisol concentrations above 40 mcg/dL (1100

586
nmol/L), urinary cortisol excretion greater than 2000 mcg/day (5500 nmol/L), or
urinary 17-hydroxycorticosteroid (17-OHCS) excretion greater than 35 mg/g
creatinine (96 micromol/g creatinine) were likely to have severe infections [126].
Bacterial infections were most common (74 percent), but opportunistic pathogens
or both (42.1 and 13.8 percent, respectively) were frequent and should be
considered when giving empiric antibiotic coverage to such patients [126].
The mechanism by which glucocorticoid excess predisposes to infection is poorly
understood. One mechanism may be a fall in circulating CD4 cells and decline in
natural killer cell activity [127]. Perhaps the major effect is that glucocorticoids
inhibit the synthesis of almost all cytokines, apparently by inducing the synthesis
of I kappa B alpha, a protein that traps and thereby inactivates nuclear factor
kappa B [128,129]. The latter protein is an activator of cytokine genes and
mediator of the inflammatory action of tumor necrosis factor.

Inhibition of cytokine release has another clinically important effect with regard to
infection; the associated reduction in inflammatory and febrile responses to
bacterial infection may make these infections difficult to detect.

The increased susceptibility to infection occurs despite a glucocorticoid-induced

rise in the circulating neutrophil count. The granulocytosis is partly due to
decreased margination and partly to increased circulating granulocyte colony-
stimulating factor [130].
Ophthalmologic findings — Increased intraocular pressure, cataracts, and central
serous chorioretinopathy occur rarely as a result of endogenous Cushing's
syndrome and are more common with exogenous glucocorticoid administration,
in particular, topical steroids [96,131-133].
Mortality — Cushing's syndrome is associated with considerable morbidity and
increased mortality [2,134].
●In a meta-analysis of seven studies, patients with Cushing's disease in whom
initial surgical cure was not obtained had excess mortality compared with the
general population, while patients with initial remission did not [135].
●In contrast, mortality was twice as high (hazard ratio [HR]
2.3) before treatment in a mixed group of 343 patients with benign Cushing's
syndrome of adrenal or pituitary origin compared with controls; the mortality
rate in 186 patients remained elevated, despite cure, during long-term
follow-up (HR 2.31) [122]. Mortality risk was the same in adrenal Cushing's
and pituitary Cushing's. Increases in potential causes of mortality were seen,
including VTE (HR 2.03), stroke (HR 1.91), and myocardial infarction (HR 4.38).
●In a retrospective cohort study of patients who had been cured of
hypercortisolism for at least 10 years at study entry, an increased risk of
587
 overall mortality was observed compared with the general population,
particularly from cardiovascular disease [134]. However, median survival
from cure was still excellent (approximately 40 years).
Side effects of exogenous glucocorticoids — Although endogenous cortisol
hypersecretion is relatively rare, many clinicians care for patients receiving
prolonged, often high-dose, glucocorticoid therapy for autoimmune disorders,
such as vasculitis, systemic lupus erythematosus, and rheumatoid arthritis; for
allergic disorders, such as asthma; and to prevent transplant rejection. These
patients have a relatively high frequency of serious glucocorticoid-induced side
effects, which are reviewed separately. (See "Major side effects of systemic
glucocorticoids".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basicstopics (see "Patient education: Cushing's syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Cushing's syndrome
(Beyond the Basics)")
SUMMARY
●Iatrogenic (exogenous) Cushing's due to pharmacologic doses of
glucocorticoids is likely the most common cause of Cushing's syndrome,
followed by pituitary corticotropin (ACTH)-dependent Cushing's syndrome.
(See 'Epidemiology' above.)
●Cushing's syndrome caused by benign and malignant adrenal tumors is
accounts for approximately 20 percent of endogenous Cushing's syndrome
cases. (See 'Epidemiology' above.)
●Ectopic ACTH secretion causes up to 15 percent of endogenous Cushing's
syndrome. Approximately 1 percent of patients with small cell lung cancer

588
have ectopic ACTH syndrome. Hypercortisolism may not be recognized in
these patients, because of weight loss and paraneoplastic syndromes.
(See 'Epidemiology' above.)
●The presence and relative severity of symptoms varies, being determined by
the following factors (see 'Severity of symptoms' above):
•The degree and duration of hypercortisolism.
•The presence or absence of androgen excess (because hypercortisolism
alone causes neither hirsutism nor pustular acne).
•The cause of the hypercortisolism (because hyperpigmentation is caused
by increased secretion of ACTH) and androgen excess occurs only in
females with adrenal cancer or ACTH-stimulated hyperandrogenism (the
adrenal gland being a major source of androgen production in females
but not males). Adrenal adenomas generally secrete only glucocorticoid.
•Adrenal carcinoma or the ectopic ACTH syndrome can cause tumor-
related symptoms that may overshadow the effects of hypercortisolism
(such as weight loss instead of weight gain).
●In adults, signs and symptoms most suggestive of the presence of
hypercortisolism include proximal muscle weakness, facial plethora, wasting
of the extremities with increased fat in the abdomen and face, wide purplish
striae, bruising with no obvious trauma, and supraclavicular fat pads. Other
symptoms are described above (table 1). (See 'Clinical manifestations' above.)
●An important clinical clue to the presence of glucocorticoid excess is the
simultaneous development or accumulation of new features and severity of
multiple symptoms consistent with Cushing's syndrome. (See 'Clinical
manifestations' above.)
●Some of the most common manifestations of Cushing's syndrome, such as
obesity, hypertension, and glucose intolerance, are less suggestive of the
presence of hypercortisolism as they are also common in individuals who do
not have adrenal hyperfunction. (See 'Clinical manifestations' above.)
●In addition to the considerable morbidity caused by hypercortisolism, there
is also an increase in mortality rates. (See 'Mortality' above.)

589
Establishing the cause of Cushing's syndrome
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 30, 2021.
INTRODUCTIONAfter the diagnosis of hypercortisolism is established, its
cause must be determined (table 1). All of the biochemical tests for the differential
diagnosis of Cushing's syndrome take advantage of the physiologic principle that
chronic excessive exposure to glucocorticoids (eg, cortisol) suppresses
hypothalamic corticotropin-releasing hormone (CRH) and corticotropin (ACTH)
secretion. As a result, ACTH and cortisol responses to testing reflect tumoral
contributions and not those of normal corticotrophs.
In order to ensure that normal corticotroph secretion of ACTH is suppressed, we
suggest that urine free cortisol (UFC) or late-night salivary cortisol be measured for
four to six weeks before initiating differential diagnostic testing and to proceed
with testing only if consistent hypercortisolism is confirmed (UFC >2-fold normal
and bedtime salivary cortisol 1.5-fold normal). When hypercortisolism does not
reach this threshold, physiologic, non-neoplastic entities should be excluded.
(See "Establishing the diagnosis of Cushing's syndrome".)
The approach to establishing the cause of Cushing's syndrome will be reviewed
here. The causes, pathophysiology, and diagnosis of Cushing's syndrome are
discussed separately. (See "Causes and pathophysiology of Cushing's
syndrome" and "Establishing the diagnosis of Cushing's syndrome".)
IS HYPERCORTISOLISM ACTH-DEPENDENT OR INDEPENDENT?
Cushing's syndrome may be caused by excessive corticotropin (ACTH) secretion
from a pituitary or nonpituitary ACTH-secreting tumor, which drives adrenal
cortisol production (termed ACTH-dependent), or by autonomous adrenal
secretion of excessive amounts of cortisol, which is not stimulated by ACTH
(termed ACTH-independent) (table 1 and figure 1) [1,2].
Measure plasma ACTH — The first step to distinguish between these is to
measure plasma corticotropin (ACTH) on two occasions (algorithm 1). This test
should be performed using a two-site immunoradiometric assay (IRMA) [3] and
may be performed in the morning in patients with sustained hypercortisolism.
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(See "Measurement of ACTH, CRH, and other hypothalamic and pituitary
peptides".)
ACTH secretion is episodic in patients with Cushing's syndrome of any cause [4].
Because of this, measurement on at least two separate days is recommended.
●ACTH <5 pg/mL (1.1 pmol/L) – A low plasma ACTH concentration (<5 pg/mL
[1.1 pmol/L]) in a hypercortisolemic patient is evidence of ACTH-independent
disease. (See 'Primary adrenal CS (suppressed ACTH)' below.)
●ACTH >20 pg/mL (4.4 pmol/L) – If the plasma ACTH concentration is above
20 pg/mL (4.4 pmol/L) in a patient with sustained hypercortisolism, one can
assume that cortisol secretion is ACTH-dependent (ie, due to pituitary disease
or ectopic ACTH or corticotropin-releasing hormone [CRH] secretion).
(See 'ACTH-dependent CS (ACTH >20 pg/mL)' below.)
However, patients with ACTH-independent causes of Cushing's syndrome
who have cyclic or mild hypercortisolism (and consequently lack suppression
of normal corticotrophs) may have normal ACTH values, falsely indicating an
ACTH-dependent condition.
Equivocal results
●ACTH between 5 and 20 pg/mL (1.1 to 4.4 pmol/L) – Plasma ACTH values
between 5 and 20 pg/mL (1.1 to 4.4 pmol/L) are less definitive but usually
indicate that cortisol secretion is ACTH dependent. For these patients we
suggest the following:
•If not already done, urinary free cortisol (UFC) or late-night salivary
cortisol should be collected for four to six weeks. ACTH levels should be
repeated after four to six weeks of significant hypercortisolism (ie, UFC
twice normal and salivary cortisol >50 percent increased above normal).
•Measurement of serum dehydroepiandrosterone sulfate (DHEAS) is
useful as it is generally decreased in adrenal causes of Cushing's
syndrome and normal or increased in ACTH-dependent causes [5].
•If three ACTH values remain in the intermediate range of 5 to 20 pg/mL,
lack of a response to the CRH stimulation test suggests an ACTH-
independent etiology. Hypercortisolemic patients with adrenal tumors
and most with ectopic ACTH-secreting tumors do not respond, because
pituitary ACTH secretion is suppressed. CRH is currently unavailable in the
United States. (See 'CRH stimulation test' below and "Corticotropin-
releasing hormone stimulation test" and "Desmopressin (DDAVP)
stimulation test", section on 'ACTH-dependent Cushing's syndrome'.)
PRIMARY ADRENAL CS (SUPPRESSED ACTH)A low plasma corticotropin
(ACTH) concentration (<5 pg/mL [1.1 pmol/L]) in a hypercortisolemic patient is
evidence of ACTH-independent disease; ie, primary adrenal disease, which could
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include a unilateral adenoma, micro- or macronodular hyperplasia, or
adrenocortical carcinoma (table 1) [6].
Imaging — If the patient has ACTH-independent Cushing's syndrome (ACTH <5
pg/mL [1.1 pmol/L]), thin-section computed tomography (CT) imaging of the
adrenal glands is the next step in the evaluation, looking for an adrenal mass
(image 1A-B). Magnetic resonance imaging (MRI) is not recommended as the initial
procedure, as it does not provide Hounsfield unit information.
●Adrenal adenomas are typically smaller than carcinomas and have a lower
unenhanced CT attenuation value (Hounsfield unit <10) [7]. The presence of
necrosis, hemorrhage, and calcification favors a diagnosis of carcinoma [7].
(See "Clinical presentation and evaluation of adrenocortical
tumors" and "Evaluation and management of the adrenal incidentaloma".)
●When the unenhanced CT attenuation values are >10 Hounsfield units, MRI
or positron emission tomography (PET) scanning with fluorodeoxyglucose
may provide additional information about the benign or malignant nature of
a unilateral adrenal tumor [8]. Blood levels of adrenal androgens also may be
elevated in patients with adrenal carcinoma. (See "Clinical presentation and
evaluation of adrenocortical tumors", section on 'Imaging'.)
●Bilateral adrenal hyperplasia may be seen on imaging with both primary
bilateral macronodular adrenal hyperplasia (PBMAH) and longstanding ACTH-
dependent disease (image 2A-B), although patients with PBMAH tend to have
nodularity superimposed on the hyperplasia. (See "Cushing's syndrome due
to primary bilateral macronodular adrenal hyperplasia".)
●Bilateral micronodular adrenal glands containing nodules <1 cm in diameter
characterize primary pigmented nodular adrenal hyperplasia (PPNAD),
although older patients may also have nodules >1 cm. Adjacent tissue may be
either atrophic, in which case the nodules look like beads on a string [9], or
the adjacent tissue may be somewhat hyperplastic. (See "Cushing's syndrome
due to primary pigmented nodular adrenocortical disease".)
Additional evaluation — If imaging suggests a unilateral adrenal adenoma, no
further testing is needed. Management is reviewed separately. (See "Overview of
the treatment of Cushing's syndrome", section on 'Adrenal adenomas'.)

If bilateral disease or a possible carcinoma is seen, additional testing may be

indicated to:

●Stage the possible adrenal cancer. (See "Clinical presentation and evaluation

of adrenocortical tumors", section on 'Staging'.)

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 ●Distinguish whether bilateral masses are both functional, or whether one is
a nonfunctioning incidentaloma. (See "Evaluation and management of the
adrenal incidentaloma".)
●Identify forms of PBMAH that may be amenable to medical treatment.
(See "Cushing's syndrome due to primary bilateral macronodular adrenal
hyperplasia".)
●Determine whether patients with possible PPNAD have components of the
Carney Complex. (See "Cushing's syndrome due to primary pigmented
nodular adrenocortical disease".)
ACTH-DEPENDENT CS (ACTH >20 PG/ML)Patients with a plasma
corticotropin (ACTH) >20 pg/mL (4.4 pmol/L) have ACTH-dependent Cushing's
syndrome. The great majority of these patients have a pituitary corticotroph
adenoma (Cushing's disease) (table 1 and image 3) rather than ectopic ACTH
secretion. Rarely, ectopic corticotropin-releasing hormone (CRH) secretion may
cause Cushing's syndrome.
Source of excess ACTH: Pituitary or ectopic? — The next step is to determine the
source of excess ACTH secretion (pituitary versus ectopic) that is causing the
hypercortisolism (algorithm 1).
Test strategy — Various tests, alone or in combination, have been used to
distinguish between pituitary and ectopic sources of ACTH. The choice of tests for
an individual patient will vary depending on availability, diagnostic accuracy,
technical expertise, and risk. Ideally, this decision is made by an endocrinologist
with experience in managing Cushing's syndrome patients.

There are three approaches that have been advocated for distinguishing between
pituitary and ectopic sources of ACTH:

●Perform noninvasive biochemical testing with CRH

and/or desmopressin (DDAVP) and dexamethasone suppression. When at
least one of these tests suggests Cushing's disease, perform pituitary
magnetic resonance imaging (MRI) and possible petrosal sinus sampling.
●Perform biochemical tests and pituitary MRI, and if Cushing's disease is not
diagnosed, perform imaging to identify an ectopic source of ACTH. If such a
source is not found, proceed to petrosal sinus sampling [10].
●Perform pituitary MRI and then petrosal sinus sampling if no mass >6 mm is
identified.
Noninvasive biochemical testing — No noninvasive test has a high diagnostic
accuracy in ACTH-dependent Cushing's syndrome, but some are performed to help
distinguish Cushing's disease and ectopic ACTH.

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CRH stimulation test — Corticotroph tumors, like normal corticotrophs, generally
respond with ACTH, and cortisol increases within 45 minutes after the intravenous
administration of corticotropin-releasing hormone (CRH) [11-17].

Hypercortisolemic patients with adrenal tumors and most with ectopic ACTH-
secreting tumors do not respond, because pituitary ACTH secretion is suppressed.
However, patients with adrenal tumors would be identified by plasma ACTH
measurement and usually would not receive CRH.

Thus, a response to CRH should differentiate Cushing's disease from all other
causes of Cushing's syndrome (algorithm 1). However, the criteria for
interpretation have varied at different centers. Overall, up to 15 percent of patients
with Cushing's disease and those with ectopic ACTH secretion may be
misdiagnosed by the test. (See "Corticotropin-releasing hormone stimulation
test".)
High-dose dexamethasone suppression tests — Corticotroph tumors are only
relatively resistant to negative feedback regulation by glucocorticoids [18]. In
contrast, most nonpituitary tumors associated with the ectopic ACTH syndrome
are completely resistant to feedback inhibition [19], with the exception of some
carcinoid tumors, usually bronchial carcinoids [20,21] (see "Causes and
pathophysiology of Cushing's syndrome" and "Dexamethasone suppression tests",
section on 'High-dose DSTs'). As a result, patients with Cushing's disease tend to
decrease serum and urine cortisol values after 8 mg of dexamethasone. However,
up to 50 percent of patients with Cushing's disease may fail to respond, and the
specificity of this test is less than 100 percent [22], particularly if less stringent
criteria (eg, 50 percent suppression) are used to judge the result. (See "Establishing
the diagnosis of Cushing's syndrome" and "Dexamethasone suppression tests".)
Although the "high-dose" dexamethasone test always uses an 8 mg dose, the
schedule of administration, endpoints, and route of administration vary. Most
endocrinologists use the overnight high-dose dexamethasone suppression test (8
mg dexamethasone given orally at 11 PM to midnight) with serum cortisol
endpoints because it is shorter than the standard two-day test and avoids urine
collection [18,23]. (See "Establishing the diagnosis of Cushing's
syndrome" and "Dexamethasone suppression tests".)
Desmopressin stimulation test — Desmopressin (DDAVP), like
endogenous vasopressin, also stimulates ACTH release in most patients with
Cushing's disease and usually induces a response similar to that of CRH [24].
Patients with ectopic ACTH secretion rarely respond, but up to 20 percent of those
with Cushing's disease do not respond [25]. The test is mostly used in countries in
which CRH is not available, depending on the criteria used to judge a response. We
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do not recommend its use if CRH is available, because the diagnostic accuracy of
the CRH test has been better characterized. (See "Desmopressin (DDAVP)
stimulation test" and "Corticotropin-releasing hormone stimulation test".)
Combination testing with CRH (or desmopressin) and dexamethasone — As
noted, no noninvasive test has a high diagnostic accuracy in ACTH-dependent
Cushing's syndrome. Therefore, we recommend using either the corticotropin-
releasing hormone (CRH) test or the desmopressin test in addition to
the dexamethasone suppression test, even in patients who meet current criteria
for suppression. Another, but more costly, option is to give both desmopressin and
CRH together, which may improve sensitivity in Cushing's disease [24].
If the two tests (CRH and/or desmopressin, and dexamethasone) both indicate
Cushing's disease, rare patients with ectopic ACTH secretion are falsely diagnosed,
but a number with Cushing's disease are missed. Any other combination of results
does not discriminate between the forms of ACTH-dependent Cushing's syndrome
[12,26].
As a result, many patients require inferior petrosal sinus sampling (IPSS), and
some have advocated for initial use of this procedure in all patients [27].
(See "Corticotropin-releasing hormone stimulation test" and 'Petrosal venous sinus
catheterization' below.)
Not recommended — The metyrapone stimulation test was recommended in the
past. The test is rarely used now because it does not discriminate well between
Cushing's disease and ectopic ACTH secretion, the compound is difficult to obtain,
access to the necessary assays is limited, and the possible need for inpatient
admission is inconvenient [28]. (See "Metyrapone stimulation tests".)
Petrosal venous sinus catheterization
Indications — Patients with noninvasive testing and imaging consistent with
Cushing's disease do not need further confirmation with petrosal sinus sampling.
(See 'Test strategy' above.)
Some investigators recommend that all patients with ACTH-dependent Cushing's
syndrome undergo bilateral catheterization of the inferior petrosal venous sinuses
[29-33]. However, while petrosal sinus sampling has the best overall diagnostic
accuracy (approximately 95 percent), it is more expensive, less safe, and less
available than noninvasive tests.

That said, a significant proportion of patients have one or more negative

responses on biochemical testing. These patients are still statistically more likely to
have Cushing's disease than ectopic ACTH secretion. The choice of additional
diagnostic tests will be influenced not only by their availability and cost, but also by
other features such as extremely elevated urinary free cortisol (UFC) and plasma

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ACTH concentrations, hypokalemia, and rapid onset of hypercortisolism, all of
which favor the diagnosis of ectopic ACTH secretion.

Petrosal sinus is indicated to distinguish between a pituitary and ectopic tumoral

cause in patients with ACTH-dependent Cushing's syndrome in the following
situations:

●Patients without a pituitary lesion on MRI, or with a lesion less than 6 mm in

diameter.
●Patients with a biochemical result(s) consistent with Cushing's disease who
have undergone subtotal or total hypophysectomy without clinical
improvement or any effect on ACTH secretion.
●Patients with the above indications and previous petrosal sinus sampling
that was technically unsuccessful due to lack of experience, improper sample
handling, or lack of prolactin measurements for normalization, or which was
done when the patient was not hypercortisolemic [34].
(See 'Procedure' below.)

Routine petrosal sinus sampling is not indicated in the following situations:

●Patients with responses to CRH and dexamethasone that suggest Cushing's

disease and:
•A pituitary tumor >6 mm on MRI – In our opinion, the risk of petrosal
venous sampling is rarely justified in a patient with a clear-cut pituitary
tumor larger than 6 mm on MRI if the patient has responses to CRH
and dexamethasone that support the diagnosis of Cushing's disease.
•A normal pituitary MRI – In patients with a normal pituitary MRI and
positive responses to both CRH and dexamethasone are nearly certain to
have Cushing's disease [12,26]. In this setting, IPSS is not needed to
establish the diagnosis. However, there are varying opinions on this
approach.
•Recurrent Cushing's disease if the diagnosis was confirmed by an ACTH-
staining corticotroph tumor or clear remission without a history of cyclic
hypercortisolism.
●Petrosal venous sinus catheterization should not be performed just to
determine the location of the pituitary tumor (there is a 50 percent chance of
correctly predicting the location without the aid of any anatomical data).
Procedure — The most direct way to demonstrate pituitary ACTH hypersecretion
is to document a central-to-peripheral ACTH gradient in the blood draining the

596
tumor. The petrosal venous sinus drains the pituitary via the cavernous sinus [35-
37].

To perform this procedure, catheters are inserted via the jugular or femoral veins
into both inferior petrosal veins. It is important that each catheter be in the proper
location, not in the jugular bulb or vein, because of the large dilution factor
produced by blood returning from other areas of the cranium.

ACTH is measured in petrosal and peripheral venous plasma before and within 10
to 12 minutes after intravenous administration of CRH, 1 mcg/kg up to 100 mcg.
CRH is given to overcome the pulsatility of ACTH secretion (figure 2).
Desmopressin has been used in place of CRH to perform petrosal sinus sampling
in areas where CRH is unavailable or too expensive [38,39]. In a retrospective
series of 56 patients with ACTH-dependent Cushing's syndrome, desmopressin
alone was found to amplify the central-to-peripheral ACTH gradient and to provide
sensitivity and specificities similar to reported series using CRH [40].
(See "Desmopressin (DDAVP) stimulation test".)
We continue to recommend the use of CRH during the procedure, if it is available,
and if not, desmopressin. The procedure has a poor diagnostic accuracy if only
sampling is done and no stimulating factor is used [37].
Both inferior petrosal sinuses can be catheterized successfully in up to 90 percent
of patients, but only when attempted by clinicians who perform the procedure
often [41]. Cavernous-inferior petrosal sinus venography should be performed at
the end of the procedure to document adequate catheter placement and normal
venous anatomy.
Interpretation
Pituitary source of ACTH — A central-to-peripheral plasma corticotropin (ACTH)
gradient of ≥2 before CRH administration, or ≥3 after CRH, is diagnostic of a
pituitary source of ACTH in patients with consistent hypercortisolism; the gradient
is usually much greater, especially after CRH injection [42]. In 14 studies, 759 of a
total of 800 patients with proven Cushing's disease were correctly identified (95
percent sensitivity), while 115 of 124 with presumed or proven ectopic ACTH
secretion were correctly identified (93 percent specificity) [6,41-52].
Patients with a central-to-peripheral plasma ACTH gradient are then referred for
transsphenoidal surgery. Some experts also propose transsphenoidal exploration
for patients without a gradient. This strategy is most likely to succeed if other
testing suggests a pituitary source of ACTH (eg, no ectopic source identified on
body imaging, peripheral ACTH levels during petrosal sampling increase
significantly with CRH stimulation, and the dexamethasone suppression test
supports a pituitary etiology) [53].
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Tumor localization within the sella — Some studies have shown that a gradient
of ≥1.4 between the ACTH concentrations in the two sinuses predicted the side of
the tumor with up to 71 percent accuracy if catheters were appropriately placed
[42]. However, others have not found such strong predictive values [30,48,54]. In
the largest series, the location of the tumor was correctly predicted by a gradient
of ≥1.4 in 69 percent of 396 patients with a lateral tumor. Left-sided and consistent
lateralization improved the positive predictive values to 76 and 72 percent,
respectively [55].
False negatives — False-negative results likely result from poor catheter
placement or anomalous or asymmetric venous drainage. A false-negative result
was found in 0.8 percent in one series of 501 patients but in 11 percent of another
series of 78 patients with Cushing's disease [44,53]. Thus, lack of a central-to-
peripheral gradient on IPSS is useful only if cavernous-inferior petrosal sinus
venography demonstrates normal and symmetrical venous drainage [29-31]. In
one study, a peak petrosal sinus ACTH concentration (before or after CRH) of <400
pg/mL (88 pmol/L) was found in all 10 of 501 patients with a false-negative result.
Thus, low IPSS ACTH values in the setting of a negative response should prompt
reconsideration of results [55].
Prolactin measurement of inferior petrosal sinus samples may help to validate
IPSS results in the absence of a central-to-peripheral gradient. In one study of 33
patients with Cushing's disease and 5 with ectopic ACTH secretion, petrosal-to-
peripheral ratios for ACTH were normalized to petrosal sinus-to-peripheral ratios
for prolactin. Three patients without a central ACTH gradient had ACTH-to-
prolactin ratios within the range of patients with Cushing's disease and were cured
after pituitary surgery [56]. Another three studies endorse the approach [57-59],
including one that used desmopressin stimulation instead of CRH [9]. However,
while this is a promising approach, the specific criteria for interpretation vary
among centers. Because repeat petrosal sinus sampling is costly and increases
risk, we recommend drawing the samples for prolactin and sending them for assay
only if the ACTH results do not show a gradient. This minimizes the overall cost of
the procedure. Additionally, if there is a central-to-peripheral gradient consistent
with Cushing's disease, there is no need to measure prolactin, even if the anatomy
is abnormal or the catheters were incorrectly positioned [58].
False positives — False-positive results are rare in patients with ectopic ACTH
syndrome or an adrenal tumor. When a false-positive result does occur, it is
presumably due to incomplete suppression of pituitary ACTH secretion [27,60].
Because of this concern, we recommend documentation of consistent
hypercortisolism four to six weeks before IPSS to ensure that the normal
corticotrophs are suppressed. (See 'Measure plasma ACTH' above.)

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Complications — When the procedure is performed by an experienced
radiologist, the incidence of serious complications, such as a cerebrovascular
accident, is 0.2 percent [61]. In one series of 166 patients, transient cranial nerve
palsy occurred in one patient [45]. In another series of 44 patients, one developed
hemiparesis and gaze palsy after the study [62].
Pulmonary embolism and deep venous thrombosis have been reported, but their
frequency in large series is not known [63,64]. In view of the risk of
thromboembolic events, some groups give heparin for anticoagulation before the
procedure and protamine afterward to avoid the possibility of inferior petrosal
and/or cavernous sinus venous thrombosis, but most do not believe that this is
necessary. We recommend its use.

The frequency of less serious complications, such as inguinal or jugular

hematomas, is more common.

Other venous sampling tests

●Bilateral internal jugular venous sampling – Bilateral internal jugular
venous sampling has been proposed as a useful alternative test, with the
advantages of simplicity, safety, and no requirement for specialized
expertise. However, the sensitivity of this test (83 to 87.5 percent) is relatively
close to the pretest probability of Cushing's disease and is inferior to that of
petrosal sinus sampling [50-53,65]. Its utility may be restricted to those
patients who would benefit from venous sampling, such as those with
conflicting results on noninvasive tests, who do not have access to petrosal
sinus sampling.
●Cavernous sinus sampling – Cavernous sinus sampling has been evaluated
for its ability to localize a tumor. In two large series, the sensitivity and
specificity of a cavernous sinus-to-peripheral venous plasma ACTH gradient
were similar to those of petrosal sinus sampling. Localization of the
adenoma, based on a lateralization ratio of ≥1.4, was correct in 62 to 83
percent in whom tumors were found at surgery [66,67]. However,
hemihypophysectomy was curative in only approximately 50 percent of
patients when it was based on the location of tumor predicted by cavernous
sinus sampling [67]. Thus, this technically more demanding procedure does
not appear to have superior diagnostic accuracy or lateralization ability
compared with petrosal sinus sampling.
Pituitary MRI — Unenhanced and gadolinium-enhanced high-resolution magnetic
resonance images (MRI) of the sella turcica should be obtained for two reasons:
●Before petrosal sinus sampling to exclude a tumor more than 6 mm in size,
which might obviate the need for the petrosal sampling. If such a lesion is
599
 seen, the diagnosis of Cushing's syndrome can be further confirmed with a
noninvasive test. This 6 mm cutoff is based upon the observation that
approximately 10 percent of healthy individuals have a pituitary lesion on
MRI <6 mm [68].
●Before transsphenoidal exploration to document the anatomy of the sella
turcica.
●Pituitary imaging is not necessary in patients in whom endocrine testing
suggests ectopic ACTH secretion if petrosal sinus sampling will not be done.
Although MRI is more sensitive than computed tomography (CT) for detecting
corticotroph adenomas, it detects only approximately 50 percent of these tumors
[68]. In a report from one center, the presence of a lesion on preoperative MRI
correlated with adenoma location in 171 of 201 patients (85 percent) with
surgically proven Cushing's disease [55] but falsely suggested tumor in up to 18
percent of patients with ectopic ACTH secretion [49].
Dynamic MRI (ie, obtaining images very rapidly after gadolinium administration) or
spoiled gradient recalled acquisition MRI techniques may provide slightly greater
sensitivity than conventional MRI but yield more false-positive scans [69,70].
If a microadenoma or no lesion is seen, either IPSS and/or biochemical tests (a
high-dose dexamethasone suppression test and a CRH stimulation
and/or desmopressin test) should be performed. The choice of testing strategy
should take into account the local technical experience with IPSS. If this is lacking,
the CRH/desmopressin and dexamethasone test approach is preferred, or,
alternatively, referral to a center with IPSS experience is an option.
ECTOPIC ACTH-SECRETING TUMORSThe optimal strategy for detecting
corticotropin (ACTH)-secreting tumors has not been defined. The available
modalities (computed tomography [CT], magnetic resonance imaging [MRI],
positron emission tomography [PET], and octreotide scintigraphy) are
complementary. Imaging of the lungs or abdomen is unnecessary in patients who
have a positive inferior petrosal sinus sampling (IPSS) test [71]. However, if the
diagnostic strategy of noninvasive tests followed by pituitary and whole-body
imaging is used, a thin-slice whole-body CT is performed to identify a possible
ectopic ACTH-producing tumor [10]. If imaging is performed after petrosal sinus
sampling suggests an ectopic tumor, the type and sequence of studies are
outlined below.
Anatomic imaging
●Chest imaging – It is cost effective to obtain images of the chest first since
most ACTH-secreting tumors are located there. CT and MRI scans can identify
and localize anatomically some tumors. In one prospective study, the
sensitivity of CT was higher (53 percent) than that of MRI (37 percent),
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 although confidence intervals overlapped [72]. Thus, when resources are
constrained, we recommend initial CT imaging of the thorax using thin cuts (1
to 2 mm).
Small bronchial carcinoids can be confused with pulmonary vasculature on
CT or MRI [73]. Small thymic masses are seen on MRI in approximately one-
third of patients with Cushing's disease; these are usually not thymic
carcinoids but represent residual normal thymic tissue, particularly in
patients under the age of 40 years [74].
●Abdominal imaging – Anatomic abdominal imaging (CT, MRI) rarely detects
occult ectopic ACTH-secreting tumors but may reveal hepatic metastases.
●Neck and pelvic imaging – Anatomic imaging (CT, MRI) can detect ectopic
ACTH sources such as medullary thyroid cancer and paraganglioma in the
neck and neuroendocrine tumors of the gut, ovary, or prostate. Often these
are deferred until a potential target is identified by functional images, as
these locations are less likely to harbor a tumor than the thorax.
(See 'Functional imaging' below.)
Functional imaging — These are nuclear medicine techniques that take
advantage of functional characteristics of neuroendocrine ACTH-secreting tumors,
which take up 18-F-dihydroxy-phenyl-alanine (18F-DOPA), and have somatostatin
cell surface receptors. These studies are useful adjunctive means to both validate
anatomic findings, or when negative, to evaluate potential false-positive anatomic
results.
●Somatostatin analogs – Some ectopic ACTH-secreting tumors can be
detected by scintigraphy with 111-In-octreotide or an analog
of octreotide ([111-In-diethylene triamine penta-acetic acid-D-Phe-1]-
octreotide, or pentetreotide) because, like other neuroendocrine tumors,
their cells have cell-surface receptors for somatostatin (image 1A-B) [75-77].
●111-In-pentetreotide scintigraphy – Pentetreotide is not specific for ACTH-
secreting tumors; it is also taken up by non-neuroendocrine tumors, such as
breast carcinomas, brain tumors, and malignant lymphomas [78], and by
white blood cells in active autoimmune or infectious inflammatory lesions
and active and chronic granulomatous lesions [79].
●Octreotide scintigraphy – The sensitivity of octreotide scintigraphy for
detecting occult tumors that secrete ACTH ranges from 30 to 53 percent
[72,80-82]. Failure to detect these tumors may be related to their small size or
inadequate expression of somatostatin receptors. In three studies, 6 of 30
patients had false-positive results (radiation fibrosis, inflammation, follicular
thyroid adenoma, accessory spleen). In a few patients, however, scintigraphy,

601
 but not CT or MRI, identified the tumor, and in five patients, negative
scintigraphy correctly refuted false-positive CT or MRI scans [80-82].
Because of the high false-positive rate, the presence of the tumor ideally
should be confirmed by CT or MRI [83,84]. The role of repeat scintigraphy
after a negative scan is not known.
●68-Ga DOTATATE PET/CT – Gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3
octreotate-PET integrated with CT is an alternative imaging ligand that also
binds to somatostatin receptors. It is useful in detecting non-ACTH-secreting
medullary thyroid cancer; gastrointestinal, pancreatic, and bronchial
neuroendocrine tumors; as well as pheochromocytoma, paraganglioma,
meningioma, and oncogenic osteomalacia [85,86]. In one study, Ga-68
DOTATATE identified the suspected tumor in 11 of 17 patients (65 percent)
undergoing initial evaluation. Nine of these patients underwent surgery,
which confirmed tumor in eight; a false-positive adrenal gland was found in
the other patient. Changes in management occurred after scans of 11
patients with a known diagnosis of ectopic ACTH secretion who underwent
Ga-68 DOTATATE evaluation during follow-up [87-89].
●Not recommended – In one study (18)F-fluorodeoxyglucose PET did not
identify any tumor not shown by CT and/or MRI and, thus, is not
recommended for routine use [72].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of Cushing's
syndrome".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

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 ●Basicstopics (see "Patient education: Cushing's syndrome (The Basics)")
●Beyond the Basics topics (see "Patient education: Cushing's syndrome
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONSA series of steps in patients with
proven endogenous Cushing's syndrome can usually establish the cause of
hypercortisolism. We suggest the following approach (algorithm 1):
●Determine whether the hypercortisolism is corticotropin (ACTH) dependent
(ie, due to a pituitary or nonpituitary ACTH-secreting tumor) or ACTH
independent (ie, due to an adrenal source) by measuring plasma ACTH.
(See 'Is hypercortisolism ACTH-dependent or independent?' above.)
●A low plasma ACTH concentration (<5 pg/mL [1.1 pmol/L]) in a
hypercortisolemic patient is evidence of ACTH-independent disease; thin-
section computed tomography (CT) imaging of the adrenal glands is usually
the next diagnostic procedure in these patients. (See 'Imaging' above.)
●Patients with ACTH-independent disease and bilateral adrenal micronodular
or macronodular hyperplasia on imaging require additional testing.
(See 'Additional evaluation' above.)
●Patients with an intermediate plasma ACTH concentration, 5 to 20 pg/mL
(1.1 to 4.4 pmol/L), should undergo repeat testing of ACTH concentrations
after four to six weekly urine free cortisol (UFC) or late-night salivary cortisol
values are elevated. If the value remains in the intermediate range,
corticotropin-releasing hormone (CRH) testing is helpful. The presence of an
ACTH response suggests Cushing's disease, while the absence of a response
suggests adrenal disease or ectopic ACTH secretion. (See 'Noninvasive
biochemical testing' above.)
●Patients with ACTH-dependent disease (ACTH >20 pg/mL [>4.4 pmol/L])
should undergo a pituitary magnetic resonance imaging (MRI). If a clear
pituitary lesion >6 mm is identified and high-dose dexamethasone and CRH
tests are consistent with Cushing's disease, no further diagnostic tests are
required. (See 'Pituitary MRI' above.)
●The remaining majority of patients with ACTH-dependent disease (ACTH >20
pg/mL [>4.4 pmol/L]) should undergo noninvasive tests (a high-
dose dexamethasone suppression test and CRH stimulation test) and/or
inferior petrosal sinus sampling (IPSS). (See 'ACTH-dependent CS (ACTH >20
pg/mL)' above.)
●Suppression of cortisol during dexamethasone administration, as well as
increases in ACTH and cortisol after CRH administration, are consistent with
the diagnosis of a pituitary adenoma (Cushing's disease). (See 'Noninvasive
biochemical testing' above.)
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●Petrosal sinus sampling with CRH stimulation is recommended for patients
with unclear MRI (lesions <6 mm) or nonconcordant noninvasive tests to
distinguish between Cushing's disease and ectopic ACTH secretion.
(See 'Petrosal venous sinus catheterization' above.)

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Establishing the diagnosis of Cushing's syndrome
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: May 29, 2020.
INTRODUCTIONThe possible presence of Cushing's syndrome (CS) is
suggested by certain symptoms and signs. Unfortunately, none of these are
pathognomonic, and many are nonspecific (eg, obesity, hypertension, menstrual
irregularity, and glucose intolerance). As a result, the diagnosis must be confirmed
by biochemical tests.
The laboratory diagnostic evaluation to determine if the patient has
hypercortisolism (CS) will be reviewed here. The approach to the differential
diagnosis of established hypercortisolism is discussed separately.
(See "Establishing the cause of Cushing's syndrome".)
OVERVIEW OF DIAGNOSTIC APPROACH
Who should be tested? — We suggest testing for hypercortisolism in patients in
whom a diagnosis is most likely, including the following (table 1) [1,2]:
●Unusual findings for their age (osteoporosis or hypertension in young
adults)
●Multiple progressive features of Cushing's syndrome (CS), particularly those
that are predictive of CS such as facial plethora, proximal myopathy, striae
(>1 cm wide and red/purple), and easy bruising
●Unexplained severe features (resistant hypertension, osteoporosis) at any
age
●Adrenal incidentalomas
Exclude exogenous glucocorticoids — Before evaluation for possible CS, it is
essential that a careful history has excluded exogenous glucocorticoid intake, as
these patients should not be evaluated for CS:
●The most common cause of hypercortisolism is ingestion of prescribed
glucocorticoid, usually for nonendocrine disease. However, CS can also be
caused by other oral, injected, topical, and glucocorticoids [3-5] and by high
doses of megestrol acetate or other progestins with some intrinsic
glucocorticoid activity [6].
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 The clearance of some inhaled or injected steroids may be delayed
by ritonavir, which inhibits CYP3A4 metabolism of many glucocorticoids,
leading to CS [7,8]. CS may also be caused by the use of glucocorticoid-
containing creams or herbal preparations [9,10].
●All glucocorticoids, including potent inhaled and topical glucocorticoids such
as beclomethasone and fluocinolone, and especially inhaled fluticasone,
inhibit corticotropin (ACTH) secretion if given in sufficient doses (see "Major
side effects of inhaled glucocorticoids", section on 'Adrenal suppression').
Thus, plasma ACTH and serum cortisol concentrations and urinary cortisol
excretion (unless cortisol or cortisone is the steroid administered) may all be
low [11].
In contrast, urinary cortisol excretion may be falsely elevated with
vulvovaginal application of hydrocortisone [12].
●Surreptitious intake of glucocorticoids is known as factitious Cushing's
syndrome, a rare disorder that may be seen in individuals who are close to
the health professions [11,13]. Factitious CS is responsible for less than 1
percent of patients with CS, but even a careful history may fail to detect this
disorder and it may be difficult to exclude with laboratory tests [13-15].
Important clues to the diagnosis are low or erratic values for urinary cortisol,
suggesting ingestion of a synthetic glucocorticoid or intermittent ingestion of
cortisol or cortisone [13], or excessive urinary cortisol values relative to
serum cortisol concentrations, suggesting the addition of hydrocortisone to
urine specimens [15]. The most valuable laboratory test is the detection of
synthetic glucocorticoids in the urine by high-pressure liquid
chromatography or by gas chromatography/mass spectometry (GCMS)
[11,13,14].
Initial testing — The initial diagnostic tests for hypercortisolism should be highly
sensitive, even though the diagnosis may be excluded later by more specific tests
[16,17]. The diagnosis of CS is established when at least two different first-line
tests are unequivocally abnormal.
Once the diagnosis is established, additional evaluation is done to identify the
cause of the hypercortisolism. (See "Establishing the cause of Cushing's
syndrome".)
We agree with the diagnostic approach outlined by the evidence-based 2008
Endocrine Society clinical guidelines [1]:
●For patients with a low index of suspicion, we suggest initial testing with one
of the following first-line tests: late-night salivary cortisol (two
measurements), 24-hour urinary free cortisol (UFC) excretion (two
measurements), or the overnight 1 mg dexamethasone suppression test

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 (DST). For example, a woman with oligomenorrhea and hirsutism might be
tested for CS; however, the pre-test probability of the syndrome is low if there
are no other associated signs or symptoms.
●For patients with a high index of suspicion, such as those with features
suggestive of CS, we do two or three first-line tests (with repeated
measurement for UFC or salivary cortisol)
●To optimize sensitivity, we suggest using the upper limit of the reference
range for UFC and salivary cortisol and a serum cortisol concentration <1.8
mcg/dL (50 nmol/L) after dexamethasone as the cutoffs for a normal
response.
●If UFC is chosen as the initial screening test, the result should be
unequivocally increased (threefold above the upper limit of normal for the
assay) or the diagnosis of CS is uncertain and other tests should be
performed.
●Some centers use the longer low-dose DST (2 mg/day for 48 hours) as an
initial test [1].
●UFC and late-night salivary cortisol measurements are each obtained at least
twice because the hypercortisolism in CS may be variable. Two
measurements must be abnormal for the test to be considered abnormal; for
patients with mild or fluctuating disease, this may require collecting a
number of salivary cortisols or UFCs over weeks.
Normal results — If initial testing is normal in an individual with a low index of
suspicion for CS, it is unlikely that the patient has CS unless it is extremely mild or
cyclic. We do not suggest additional evaluation unless symptoms progress or cyclic
CS is suspected. In this case, we suggest referral to an endocrinologist for repeat
testing and further evaluation.

On the other hand, if initial testing is normal in someone with a high index of
suspicion for CS (clinical features suggestive of CS), we suggest referral to an
endocrinologist for additional evaluation to confirm or exclude the diagnosis of CS.

Any abnormal result — In patients with at least one abnormal test result (which
could represent true CS or a false positive result), we suggest additional
evaluation. This includes excluding physiologic hypercortisolism and referral to an
endocrinologist. Additional evaluation may include repeating the initial test or
other first-line tests.
Exclude physiologic hypercortisolism — Hypercortisolism can occur in several
disorders other than CS [2]. When such patients present with clinical features
consistent with CS, they may also be referred to as having physiologic
hypercortisolism or pseudo-CS. Clinically, patients with these physiologic forms of
607
hypercortisolism seldom have the cutaneous (ie, easy bruising, thinning, and
friability) or muscle (ie, proximal muscle atrophy and weakness) signs of CS [16].
However, these conditions/disorders should be excluded when evaluating patients
for CS.

Examples of conditions associated with physiologic hypercortisolism that may have

some clinical features of CS include:

●Pregnancy
●Patients with severe obesity, especially those with visceral obesity or PCOS
●Patients with psychological stress, especially patients with a severe major
depressive disorder and melancholic symptoms
●Poorly controlled diabetes mellitus
●Rarely, chronic alcoholism
●Physical stress (illness, hospitalization/surgery, pain)
●Obstructive sleep apnea
Examples of conditions associated with physiologic hypercortisolism that
are unlikely to have clinical features of CS include:
●Malnutrition, anorexia nervosa
●Intense chronic exercise
●Hypothalamic amenorrhea
●High corticosteroid-binding globulin (CBG) (increased serum cortisol but not
UFC)
●Glucocorticoid resistance

We suggest against routine testing for CS in these patients unless they develop
features predictive of CS such as wide purplish stria, proximal myopathy, or easy
bruising.

The distinction between physiologic hypercortisolism and CS is not always simple

because patients with CS can have serious infections, are frequently depressed
(although it is often an atypical, agitated depression) [18,19], and presumably have
a prevalence of chronic alcoholism similar to that of the general population.
The psychiatric literature suggests that as many as 80 percent of patients with
major depressive disorders have increased cortisol secretion [20-22]. However,
cortisol hypersecretion, when present, is usually minimal. Furthermore, even
severely depressed patients with substantial cortisol hypersecretion rarely develop
clinical CS. However, some depressed patients may be difficult to distinguish
clinically or biochemically from those with Cushing's disease. Their abnormal
cortisol secretion presumably results from hypothalamic-pituitary-adrenal (HPA)

608
axis hyperactivity [21], and disappears after remission of depression [23].
(See "Unipolar depression in adults: Epidemiology", section on 'Prevalence in
general medical disorders'.)
About three dozen patients with chronic alcoholism and clinical or biochemical
manifestations of CS have been reported [24,25]. Most had liver dysfunction,
although the hormonal changes did not correlate closely with the degree of
abnormality in liver function. In addition to liver dysfunction, these patients
probably have transiently increased secretion of corticotropin-releasing hormone
(CRH) or impaired hypothalamic or pituitary responsiveness to cortisol. However,
their peripheral and petrosal sinus plasma CRH concentrations are normal,
although these tests are not clinically indicated [26]. The hormonal abnormalities
disappear rapidly during abstinence from alcohol.
Women with hypothalamic amenorrhea due to stress or weight loss also may have
elevated UFC [27], and male obligate exercisers have increased evening cortisol
and ACTH levels [28]. (See "Functional hypothalamic amenorrhea: Pathophysiology
and clinical manifestations".)
UFC and cortisol values normalize in patients with anorexia nervosa who gain
weight and normalize body mass index (BMI) [29] (see "Anorexia nervosa:
Endocrine complications and their management", section on 'Adrenal'). This
suggests that treatment of other physiologic causes of hypercortisolism may result
in normalization of UFC and assist in the discrimination between these physiologic
states and CS.
CRH after dexamethasone test — The CRH (corticorelin)
after dexamethasone test exploits the greater sensitivity of ACTH secretion to
dexamethasone suppression in depressed patients [30] and their blunted serum
cortisol response to exogenous CRH as compared with patients with CS [22].
However, neither of these responses alone provides a reliable method for
distinguishing depressed patients from those with CS [31].
In one report, for example, the serum cortisol concentration was <1.4 mcg/dL (38
nmol/L) 15 minutes after CRH (given two hours after the last 0.5
mg dexamethasone dose in the standard two-day low-dose dexamethasone test)
in all 19 patients with pseudo-CS versus none of 35 with Cushing's disease, none of
two with ectopic ACTH secretion, and none of two with primary adrenal disease
(100 percent sensitivity and 100 percent specificity for CS) [31]. However, only the
15-minute sample was accurate, and a serum cortisol concentration <1.4 mcg/dL
(38 nmol/L) two hours after the last dexamethasone dose had 90 percent
sensitivity and 100 percent specificity without the administration of CRH.
Other studies of patients being evaluated for CS did not confirm the improved
diagnostic accuracy of the CRH after dexamethasone test when compared with the

609
low-dose dexamethasone test alone [32-35]. It is not clear whether these
differences reflect differences in dexamethasone metabolism, as dexamethasone
levels were not evaluated, or differences in the cortisol assays. In a larger study,
101 patients were divided into two groups according to whether they were taking
medications that might alter dexamethasone metabolism [36,37]. In general, the
CRH-dexamethasone test is more cumbersome than dexamethasone alone and
probably does not add further information.
Refer to endocrinologist for additional testing — As noted, in patients with at
least one abnormal test result, we suggest referral to an endocrinologist for
additional evaluation. Additional evaluation may include repeating the abnormal
study or other first-line tests.
Normal (CS unlikely) — We suggest no further testing for Cushing's syndrome in
patients with negative results on two different tests (unless cyclical disease is
suspected, which is rare).
Abnormal (CS confirmed) — The diagnosis of CS is established when at least two
different first-line tests are unequivocally abnormal [1], and physiologic
hypercortisolism has been excluded. Once the diagnosis is established, additional
evaluation is done to identify the cause of the hypercortisolism. (See "Establishing
the cause of Cushing's syndrome".)

For the occasional patient with a high pretest probability of CS but negative or
discordant results on initial and repeat testing, we suggest follow-up with
additional testing.

Delays in diagnosis — Early diagnosis is important to avoid the complications and

excess mortality associated with CS. However, for most patients, it takes years to
be diagnosed. In some patients, this may be due to clinical features that are
nonspecific and seen in individuals without hypercortisolism (hypertension,
obesity, and glucose intolerance) (see "Epidemiology and clinical manifestations of
Cushing's syndrome"). In a meta-analysis of 44 studies (including 5367 patients),
the mean time to diagnosis was 38 months (95% CI 33-43) for patients with
pituitary CS, and 30 months (95% CI 24-36) for adrenal CS [38]. The duration was
shorter for those with ectopic CS, likely due to the severity of their
hypercortisolism (14 months [95% CI 11-17]).
AVAILABLE TESTSNone of the initial tests have ideal sensitivity or specificity.
For example, in one study of 369 overweight and obese patients with two
additional features of Cushing's syndrome (CS), the specificity of these tests
ranged from 84 percent to 96 percent [39]. As a result, the choice of test should be
individualized to minimize false positive results.

610
For example, a late-night salivary cortisol test is likely to be abnormal in a shift
worker, and a dexamethasone suppression test (DST) response may be abnormal
in a woman taking oral estrogen, because of increased corticosteroid-binding
globulin (CBG) (and hence total cortisol). These tests would not be ideal and other
tests would be chosen based on the individual's history and lifestyle.
24-hour urinary cortisol excretion — Twenty-four-hour urinary cortisol excretion
provides a direct and reliable practical index of cortisol secretion [40,41].
Corticotropin (ACTH) and cortisol are secreted in discrete bursts, not only in
normal subjects but also in most patients with Cushing's disease [42-44]; in
addition, cortisol is secreted episodically by some adrenal tumors (figure 1) [43].
(See "Measurement of urinary excretion of endogenous and exogenous
glucocorticoids".)
Twenty-four hour urinary cortisol excretion is an integrated measure of the serum
free cortisol concentration (ie, cortisol that is not bound to CBG [transcortin] or
other serum proteins). The two most important factors in obtaining a valid result
are collection of a complete 24-hour specimen and a reliable reference laboratory.
The former can usually be obtained by carefully explaining to the patient how to
collect the specimen and by measuring urinary creatinine excretion (see "Patient
education: Collection of a 24-hour urine specimen (Beyond the Basics)"). Urinary
cortisol assays are reviewed in detail separately. (See "Measurement of urinary
excretion of endogenous and exogenous glucocorticoids", section on 'Types of
assays'.)
The best evidence for the utility of urinary free cortisol (UFC) as a screening test
comes from a systematic review and meta-analysis of studies of diagnostic tests
for CS performed in conjunction with the 2008 Endocrine Society guidelines [45].
Tests with a high likelihood ratio for a positive (abnormal) result indicate tests that
help rule in CS, while those with a very low likelihood ratio for a negative (normal)
result indicate tests that help rule it out. Salivary cortisol, UFC, and the overnight
DST had similar accuracy. For urinary cortisol, 14 studies were included of 646
patients with CS and 5226 patients who did not have CS. The likelihood ratio of
10.6 (95% CI 5.5-20.5) for an abnormal result and a likelihood ratio for CS of 0.16
(95% CI 0.08-0.33) for a normal result. However, other studies suggest that in cases
of mild CS, UFC has less diagnostic sensitivity than dose salivary cortisol [46,47].
Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods
are more analytically specific than immunoassays, their use for measuring UFC has
been questioned, as they give a lower, and potentially falsely negative, result [48].
Some experts argue that UFC determinations are unnecessary, because late-
evening serum or salivary cortisol values have similar diagnostic utility and are
more convenient (see 'Late-night salivary cortisol' below). If it is not convenient to

611
collect urine as a second test, then the DST should be used in combination with a
late-night cortisol test.
Interpretation and limitations — The patient can be assumed to have CS if basal
urinary cortisol excretion is more than three times the upper limit of normal (which
may vary somewhat in different assays) and one other test is abnormal. The
patient should then be evaluated for the cause of the hypercortisolism.
(See "Establishing the cause of Cushing's syndrome".)
●Subclinical hypercortisolism – UFC is of limited utility in patients with
subclinical hypercortisolism, eg, patients with mild CS caused by an adrenal
incidentaloma. These patients may have normal urine cortisol values but an
elevated late-night salivary cortisol concentration [1]. The overnight DST is
suggested for patients with adrenal incidentalomas. (See "Evaluation and
management of the adrenal incidentaloma", section on 'Subclinical Cushing's
syndrome'.)
●False positive results
•Physiologic hypercortisolism – Patients with equivocally raised values
(above normal but less than three times the upper reference value) may
have physiologic hypercortisolism (pseudo-Cushing's). For example, up to
40 percent of patients with severe depression or polycystic ovary
syndrome (PCOS) have slightly high 24-hour urinary cortisol excretion
[13,49]. In this setting, patients should either be reevaluated after several
weeks or undergo one or more of the other first line tests, depending
upon the level of clinical suspicion.
•High fluid intake – People who drink very large volumes of liquid also
excrete more cortisol (64 percent more cortisol excreted with an intake of
5 liters per day), while excretion of creatinine and 17-
hydroxycorticosteroids remains unaltered [50]. Therefore, modest
increases of urinary cortisol excretion in patients with urine volumes of
more than 3 liters should be interpreted with caution.
●False negative results – If urinary cortisol excretion is indeterminate (above
the upper limit of the reference range but less than threefold above the
upper limit), and the late-evening serum or salivary cortisol concentrations
are normal, the patient does not have CS unless it is cyclic or mild [46,51].
Emerging literature reports that some Cushing's disease patients may have
normal UFC (measured by tandem mass spectrometry) but are more likely to
have abnormal late-night salivary cortisol [46,52]. In a study of 426 patients
with CS, for example, 47 percent of 288 patients with Cushing's disease, 31
percent of 80 patients with adrenal adenoma, 21 percent of 25 patients with
ectopic ACTH or corticotropin-releasing hormone (CRH) secretion, and 5

612
 percent of 24 patients with adrenal carcinoma had at least one 24-hour
urinary cortisol value in this equivocal range [53].
These examples illustrate the need for complementary tests, careful
consideration of the tests that are chosen, and correlation of the test results.
Late-night salivary cortisol — A late-evening salivary cortisol concentration can
be used to establish the diagnosis of CS [54-61]. Saliva is easily collected, and
cortisol is stable in saliva even at room temperature for several days. Saliva
collection has the distinct advantage of being noninvasive and can be performed
by the patient at home. It is especially useful for patients suspected of having
cyclical or intermittent CS, who can collect many samples over an extended period
of time and return the accumulated samples to the clinician at one time. As with
other cortisol assays, it is useful to evaluate at least three samples from different
days.
Measurement of serum or salivary cortisol in the late evening before bedtime is
based upon the fact that the normal evening nadir in serum cortisol is preserved in
obese and depressed patients but not in those with CS (see "Measurement of
cortisol in serum and saliva"). Because cortisol levels appear to be entrained to the
initiation of sleep, late-night salivary cortisol measurement is not a good test for
patients with erratic sleep schedules or shift work.
The criteria used to interpret salivary cortisol results differ among studies, perhaps
because of assay or collection differences. As a result, published reference ranges
are not appropriate for all commercial assays (table 2) [62]. (See "Measurement of
cortisol in serum and saliva".)
In addition, a study of older men (mean age 61 years), some with co-morbidities of
diabetes and/or hypertension, showed poor specificity. Twenty percent of the
participants had false positive results (eg, a late-night salivary cortisol value above
the upper limit of normal [1.6 ng/mL, 4.3 nmol/L] when measured by enzyme
immunoassay) [63]. None had CS.
In the meta-analysis described above, late-night salivary cortisol was an accurate
diagnostic test based upon pooled analysis of six studies in 136 patients with CS
[45]. It found a likelihood ratio of 9.5 (CI 1.7-54.1) for an abnormal result and a
likelihood ratio of 0.09 (CI 0.03-0.28) for a normal result. (See '24-hour urinary
cortisol excretion' above.)

Thus, while a late-evening salivary cortisol measurement is a useful test for the
diagnosis of CS, appropriate assay-specific and perhaps age-specific normative
values must be used for its interpretation.

613
In some situations, other second-line tests may be used. These tests may be
chosen because of site-specific constraints, lack of access to salivary cortisol
assays, or preferences based on experience.

Late-night serum cortisol — As noted for late-night salivary cortisol,

measurement of serum cortisol in the late evening, usually at midnight, is also
based upon the fact that the normal evening nadir in serum cortisol is preserved in
obese and depressed patients but not in those with CS. This test is less convenient
than the late-night salivary cortisol and is therefore not used routinely in clinical
practice. However, it is sometimes used at specialized centers.
A late-night serum cortisol >7.5 mcg/dL (207 nmol/L) is used to identify CS. This is
based upon a study of 198 patients with Cushing's disease, 27 patients with ectopic
ACTH syndrome, 15 patients with primary adrenal CS, and 23 patients with
pseudo-CS. A single late-night serum cortisol concentration >7.5 mcg/dL (207
nmol/L) correctly identified 225 of 234 patients with CS; normal values were seen
in all 23 patients with pseudo-CS (96 percent sensitivity, 100 percent specificity)
[64].
This test has usually been performed in the hospital, and one group obtains the
blood after the patient appears to be asleep [65]. However, sleeping versus awake
results have not been evaluated systematically, and our experience is that the test
can reliably be performed on an ambulatory basis. This can be done by inserting a
heparin-lock earlier in the day to avoid stress-induced cortisol release caused by
the anticipation of or pain caused by venipuncture, and asking the patient to
return between 11 PM and midnight for blood drawing. We try to obtain samples
on at least two evenings. Patients with intermediate values should be reevaluated
after several weeks. (See "Measurement of cortisol in serum and saliva".)
Low-dose dexamethasone suppression tests — The low-dose DSTs are
standard screening tests to differentiate patients with CS of any cause from
patients who do not have CS. The high-dose DSTs are not used to make the
diagnosis of CS. They are used after the diagnosis of CS is made to distinguish
patients with Cushing's disease (CS caused by pituitary hypersecretion of ACTH)
from patients with ectopic ACTH syndrome (CS caused by nonpituitary ACTH-
secreting tumors). (See "Dexamethasone suppression tests" and "Establishing the
cause of Cushing's syndrome".)
There are two forms of low-dose DST: the 1 mg "overnight" and the two-day 2 mg
test [18]. These tests are discussed in detail elsewhere. (See "Dexamethasone
suppression tests".)
The DSTs are not a good choice for patients in whom CBG levels may be abnormal
or in those taking medications that may alter the metabolism of the drug [66].

614
Estrogen-containing drugs, such as oral contraceptives, raise CBG and may result
in a false-positive DST. Oral contraceptives should be stopped for six weeks before
performing a DST, or an alternate test should be used. Overnight DSTs are also not
a reliable test in pregnancy. (See 'Pregnancy' below and "Diagnosis and
management of Cushing's syndrome during pregnancy".)
●Overnight 1 mg test – The overnight test consists of administration of 1 mg
of dexamethasone at 11 PM to 12 AM (midnight), and measurement of serum
cortisol at 8 AM the next morning. (See "Measurement of cortisol in serum
and saliva".)
The 2008 Endocrine Society guidelines suggest a diagnostic cortisol criterion
of 1.8 mcg/dL (50 nmol/L), recognizing that this choice will optimize
sensitivity but decrease specificity. Despite use of this stringent criterion for
sensitivity, in one study, 8 percent (6 of 80) patients with Cushing's disease
showed suppression to less than 2 mcg/dL (55 nmol/L) [67].
The low-dose dexamethasone tests should not be used as the sole criterion
for the diagnosis of CS. At least one additional test should be done to
establish or exclude the diagnosis.
●Standard two-day 2 mg test – The two-day 2 mg test, which is done
commonly in some countries but not others, consists of administering 0.5 mg
of dexamethasone every six hours for eight doses, and measurement of
serum (not urinary) cortisol either two or six hours after the last dose. The
same criteria for normal suppression (<1.8 mcg/dL [<50 nmol/L]) used for the
1 mg dexamethasone test are used for the two-day 2 mg test. The two-day 2
mg dexamethasone test is described in greater detail separately.
(See "Dexamethasone suppression tests".)
●Diagnostic accuracy – In the meta-analysis described above, the 1
mg dexamethasone test and the two-day 2 mg test were both accurate
diagnostic tests [45] (see '24-hour urinary cortisol excretion' above):
•For the 1 mg test, in 14 studies including 249 patients with CS out of 5305
undergoing testing (using various diagnostic criteria), there was a
likelihood ratio of 16.4 (CI 9.3-28.8) for an abnormal result and 0.06 (CI
0.03-0.14) for a normal result.
•For the two-day 2 mg test, eight studies were identified, including 136
patients with CS out of 323 who were tested. It found a likelihood ratio of
7.3 (CI 3.6-15.2) for an abnormal result and 0.18 (CI 0.06-0.52) for a normal
result.
Serum collected at the time of cortisol measurement should be retained for
measurement of dexamethasone (available in commercial laboratories), to clarify
otherwise confusing results caused by noncompliance and individual variability in,

615
and drug effects on, dexamethasone metabolism [68,69]. (See "Dexamethasone
suppression tests".)
SPECIAL POPULATIONS
Pregnancy — We suggest a 24-hour urinary free cortisol (UFC) test or late-night
salivary cortisol test in pregnant women with suspected Cushing's syndrome (CS)
rather than the low-dose dexamethasone suppression test (DST) [70].
(See "Diagnosis and management of Cushing's syndrome during pregnancy",
section on 'Diagnosis during pregnancy'.)
Adrenal incidentaloma — Subtle dysregulation of the hypothalamic-pituitary-
adrenal (HPA) axis, manifest by abnormal response to DST, is the most frequent
hormonal abnormality detected. Therefore, we suggest the 1 mg DST as the first-
line test to screen for hypercortisolism in these patients (see "Evaluation and
management of the adrenal incidentaloma" and 'Interpretation and
limitations' above). Some adrenal incidentalomas secrete sufficient cortisol to
suppress corticotropin (ACTH), at least partially. Although these patients lack many
of the usual stigmata of overt CS, they may have one or more of the effects of
endogenous cortisol over-secretion such as obesity, hypertension, glucose
intolerance or diabetes, dyslipidemia, osteoporosis.
Depending on the importance of cortisol secretion by primary adrenal tumors, the
spectrum of biochemical abnormalities will vary. Milder cases will present normal
24-hour urinary cortisol levels with slightly elevated late-night salivary cortisol,
incompletely suppressed morning serum cortisol following 1 mg DST, and partially
suppressed plasma ACTH levels. In more severe cases, UFC, late-night salivary
cortisol, and serum cortisol following 1 mg DST will be clearly elevated and plasma
ACTH may be undetectable [71]. Testing with 1 mg DST is most likely to be
abnormal in this population and should be undertaken only if there are metabolic
and other features compatible with CS, as patients without any clinical features
would not undergo treatment. This topic is reviewed in detail separately.
(See "Evaluation and management of the adrenal incidentaloma".)
Cyclic Cushing's — Some patients have cyclic CS, which is characterized by
episodes of cortisol excess alternating with periods of normal cortisol secretion.
The episodes of hypercortisolism can occur regularly or irregularly, with intercyclic
phases ranging from days to months [51]. For patients with suspected cyclic CS, we
suggest UFC or late-night salivary cortisol over the DST. If initial testing is normal
but clinical suspicion is high, we suggest follow-up with repeat testing. True cyclic
CS is relatively rare, but variability in UFC excretion is common in all etiologies of
CS [72,73].

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Other — For patients with renal failure, we suggest the 1 mg overnight DST
instead of UFC. For those with epilepsy, UFC or late-night cortisols rather than the
DST are suggested because antiseizure drugs increase dexamethasone clearance.

The overnight DST is unreliable (false positive results) in women taking oral
contraceptives because of the increase in corticosteroid-binding globulin (CBG).
Ideally, oral contraceptives or other forms of estrogen should be held for four to
six weeks before initiating testing.

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of Cushing's
syndrome".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basicstopics (see "Patient education: Cushing's syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Cushing's syndrome
(Beyond the Basics)" and "Patient education: Cushing's syndrome treatment
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●We suggest testing for hypercortisolism in patients in whom a diagnosis is
most likely, including those with (see 'Who should be tested?' above):
•Unusual findings for their age (osteoporosis or hypertension in young
adults)
•Multiple progressive features of Cushing's syndrome (CS), particularly
those that are predictive of CS such as facial plethora, proximal myopathy,
striae (>1 cm wide and red/purple), and easy bruising
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 •Unexplained severe features (resistant hypertension, osteoporosis) at any
age
•Adrenal incidentalomas
●Before evaluation for possible CS, it is essential that a careful history has
excluded exogenous glucocorticoid intake, as these patients should not be
evaluated for CS. (See 'Exclude exogenous glucocorticoids' above.)
●For patients with a low index of suspicion, we suggest initial testing
with one of the following first-line tests: late-night salivary cortisol (two
measurements), 24-hour urinary free cortisol (UFC) excretion (two
measurements), or the overnight 1 mg dexamethasone suppression test
(DST). (See 'Initial testing' above.)
●For patients with a high index of suspicion, we suggest initial testing
with two or three of the first-line tests: late-night salivary cortisol (two
measurements), 24-hour UFC excretion (two measurements), or the
overnight 1 mg DST. (See 'Initial testing' above.)
●If UFC is chosen as the initial screening test, the result should be
unequivocally increased (threefold above the upper limit of normal for the
assay), or the diagnosis of CS is uncertain and other tests should be
performed. (See 'Initial testing' above.)
●We suggest using the upper limit of the reference range for UFC and salivary
cortisol and a serum cortisol concentration <1.8 mcg/dL (50 nmol/L)
after dexamethasone as the cutoffs for a normal response. (See 'Initial
testing' above.)
●Our choice of initial tests in special situations (pregnancy, adrenal
incidentalomas, cyclic Cushing's) are reviewed above. (See 'Special
populations' above.)
●In patients with at least one abnormal test result (which could represent
true CS or a false positive result), we suggest additional evaluation. This
includes excluding physiologic hypercortisolism and referral to an
endocrinologist. Additional evaluation may include repeating the initial test
or other first-line tests. (See 'Any abnormal result' above.)
●The diagnosis of CS is established when at least two different first-line tests
are unequivocally abnormal and cannot be explained by other conditions that
cause physiologic hypercortisolism. The patient should undergo additional
evaluation if only one test is abnormal or only slightly abnormal.
(See 'Abnormal (CS confirmed)' above.)
●If test results are normal, the patient does not have CS unless it is extremely
mild or cyclic. We do not suggest additional evaluation unless symptoms
progress or cyclic CS is suspected. (See 'Normal (CS unlikely)' above.)

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●Once the diagnosis is established, additional evaluation is done to identify
the cause of the hypercortisolism. (See "Establishing the cause of Cushing's
syndrome".)

619
Evaluation and management of the adrenal
incidentaloma
Authors:
William F Young, Jr, MD, MSc
Electron Kebebew, MD, FACS
Section Editors:
Lynnette K Nieman, MD
Sally E Carty, MD, FACS
Deputy Editors:
Kathryn A Martin, MD
Wenliang Chen, MD, PhD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 01, 2020.
INTRODUCTIONAn adrenal incidentaloma is a mass lesion greater than 1 cm
in diameter, serendipitously discovered by radiologic examination [1]. This entity is
the result of technological advances in imaging such as computed tomography
(CT) and magnetic resonance imaging (MRI) and their widespread use in clinical
practice. Discovery of an adrenal mass raises two questions that determine the
degree of evaluation and the need for therapy [2]:
●Is it malignant?
●Is it functioning?
The approach to the evaluation and management of adrenal incidentalomas is
reviewed here. Detailed discussions of adrenal carcinoma and functioning adrenal
tumors such as pheochromocytomas and aldosteronomas are found elsewhere.
(See "Clinical presentation and evaluation of adrenocortical tumors" and "Clinical
presentation and diagnosis of pheochromocytoma" and "Pathophysiology and
clinical features of primary aldosteronism".)
PREVALENCE
Unilateral masses — Adrenal masses may be found incidentally when computed
tomography (CT) scans or magnetic resonance imaging (MRI) is done for other
reasons. In a study of 61,054 abdominal CT scans performed from 1985 to 1990, an
incidental adrenal tumor (incidentaloma >1 cm) was detected in 259 patients (0.4
percent of all CT scans) [3]. A subsequent study, utilizing higher resolution
scanners, reported a prevalence of adrenal incidentaloma on abdominal CT of 4.4
percent [4]. The prevalence of adrenal incidentaloma is higher in older patients (10
percent) [5].

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In autopsy studies, the prevalence of incidentalomas is 2 percent, and it ranges
from 1 to 9 percent. The prevalence is higher in obese, diabetic, and hypertensive
patients [5]. As an example, in a series of 739 autopsies, adrenal masses between 2
mm and 4 cm in size were present in 9 percent of normotensive patients and in 12
percent of patients who had hypertension [6].
Bilateral masses — Analyses from two large adrenal incidentaloma studies with
887 and 202 patients showed that bilateral masses were found in 10 to 15 percent
of cases [7,8]. Bilateral adrenal masses can be seen with metastatic disease,
congenital adrenal hyperplasia, cortical adenomas, lymphoma, infection (eg,
tuberculosis, fungal), hemorrhage, corticotropin (ACTH)-dependent Cushing's,
pheochromocytoma, primary aldosteronism, amyloidosis, infiltrative disease of the
adrenal glands, and bilateral macronodular adrenal hyperplasia (BMAH). In one
study of 208 adrenal incidentaloma patients, 19 (9 percent) proved to have adrenal
metastases; 10 of the 19 patients (53 percent) had bilateral disease [9].
In some patients with bilateral disease, one adrenal mass proves to be a
nonfunctioning cortical adenoma, while the contralateral adrenal mass is hormone
secreting [8]. In addition, adrenocortical hypofunction may occur in patients with
bilateral adrenal masses. Therefore, all patients with bilateral adrenal masses
should be screened for adrenocortical hyper- and hypofunction.
EVALUATION FOR MALIGNANCYMalignancy is an uncommon cause of
adrenal incidentaloma in patients without a known diagnosis of cancer. Although
estimates have varied widely, the actual frequency of primary adrenal carcinoma in
patients with adrenal incidentaloma is approximately 2 to 5 percent; another 0.7 to
2.5 percent have non-adrenal metastases to the adrenal gland [1,5,10-12]. The size
and imaging characteristics ("imaging phenotype") of the mass may help
determine whether the tumor is benign or malignant [1,11,13].
Size — The maximum diameter of the adrenal mass is predictive of malignancy.
This was illustrated in a study of 887 patients with adrenal incidentalomas from the
National Italian Study Group on Adrenal Tumors [7]. Adrenocortical carcinomas
were significantly associated with mass size, with 90 percent being more than 4 cm
in diameter when discovered.
Adrenal mass size is also important because the smaller the adrenocortical
carcinoma is at the time of diagnosis, the better the overall prognosis. In a
retrospective review of 62 patients with adrenocortical carcinoma, five-year
survival was approximately 16 percent overall, but much higher (42 percent) in
patients with smaller tumors (stages I and II, confined to the adrenal gland) who
were more likely to undergo curative resection [14]. (See "Clinical presentation and
evaluation of adrenocortical tumors" and "Treatment of adrenocortical
carcinoma".)
621
In the report from the National Italian Study Group, a 4 cm cutoff had a 93 percent
sensitivity of detecting adrenocortical carcinoma, even though specificity was
limited (76 percent of masses larger than 4 cm in diameter were benign) [7,11]. In
the Mayo Clinic study cited above, all 20 adrenal carcinomas were between 4 and 6
cm in diameter [3]. Therefore, surgical removal of unilateral adrenal masses larger
than 4 cm should be considered to avoid missing adrenal carcinomas, particularly
in younger patients. (See 'Management' below.)
However, adrenal mass size should not be used as the only parameter to guide
treatment. In a retrospective, single-center cohort of 4085 patients with adrenal
tumors, 705 (17 percent) had adrenal masses measuring 4 cm or more in
diameter; 216 (31 percent) were adrenocortical adenomas, 158 (22 percent) were
pheochromocytomas, 116 (16 percent) were other benign adrenal tumors, 88 (13
percent) were adrenocortical carcinomas, and 127 (18 percent) were other
malignant tumors [15]. On multivariate analysis, older age at diagnosis, male sex,
nonincidental mode of discovery, larger tumor size, and higher unenhanced
computed tomography (CT) attenuation were all found to be statistically significant
predictors of malignancy [15]. (See 'Imaging phenotype' below and 'Monitoring
when surgery not performed' below.)
Imaging phenotype — CT or magnetic resonance imaging (MRI) with 2 to 3 mm
cuts may allow prediction of the histologic type of the adrenal tumor [1,7]. As an
example, the lipid-rich nature of a cortical adenoma is helpful in distinguishing this
benign tumor from carcinoma (image 1).
CT scan
Unenhanced attenuation — On computed tomography (CT) scanning, the density
of the image (black is less dense) is attributed to radiograph attenuation. The
intracytoplasmic fat in adenomas results in low attenuation on unenhanced CT;
non-adenomas have higher attenuation in unenhanced CT. The Hounsfield scale is
a semiquantitative method of measuring radiograph attenuation. Typical
precontrast Hounsfield unit (HU) values are for adipose tissue (-20 to -150 HU) and
kidney (20 to 150 HU). If an adrenal mass measures <10 HU on unenhanced CT (ie,
has the density of fat), the likelihood that it is a benign adenoma is nearly 100
percent. However, up to 30 percent of adenomas do not contain large amounts of
lipid and may be indistinguishable from non-adenomas on nonenhanced CT scans
and are termed lipid-poor adenomas.
●HU<10 – A consensus panel noted that a homogeneous adrenal mass with a
smooth border and an attenuation value <10 HU on unenhanced CT is very
likely to be a benign adenoma [2]. This appears to be a reasonable CT HU
cutoff based upon a retrospective analysis of 151 patients with adrenal
masses who underwent both a noncontrast CT scan and adrenalectomy [16].

622
 The mean HU (± standard deviation [SD]) for adrenal adenomas/hyperplasia
was significantly lower than for adrenal carcinomas, metastases, and
pheochromocytomas (16.2±13.6 versus 36.9±4.1, 39.2±15.2, and 38.6±8.2,
respectively). The only patients in the nonadenoma groups with a
noncontrast CT HU <10 were those with myelolipomas (which were all less
than -40 and therefore easily distinguishable). In this series, an unenhanced
CT attenuation ≤10 HU or a combination of tumor size ≤4 cm and HU ≤20
excluded non-adenomas in 100 percent of cases.
●HU>10 – In a retrospective cohort study of 353 patients with adrenal
nodules who underwent adrenal biopsy and/or adrenalectomy, 80 percent of
patients presented with known or suspected extra-adrenal malignancy [17].
Adrenal masses with unenhanced CT attenuation >10 HU diagnosed
malignancy with a sensitivity of 100 percent, specificity of 33 percent, positive
predictive value (PPV) of 72 percent, and negative predictive value (NPV) of
100 percent. Unenhanced CT attenuation of ≤10 HU excluded malignancy
even in this high-risk population.
Delayed contrast-enhanced CT — On delayed contrast-enhanced CT, adenomas
typically exhibit rapid contrast medium washout, whereas non-adenomas have
delayed contrast material washout [16]. Ten minutes after administration of
contrast, an absolute contrast medium washout of more than 50 percent was
reported to be 100 percent sensitive and specific for adenoma when patients with
adenomas were compared with carcinomas, pheochromocytomas, and metastases
[16,18,19]. Although imaging phenotype does not predict hormonal function, it
does predict underlying pathology, and surgical resection should be considered in
patients with adrenal incidentalomas that have a suspicious imaging phenotype
[1].
MRI — Although CT is the recommended primary adrenal imaging procedure in
most cases, magnetic resonance imaging (MRI) has advantages in certain clinical
situations. For example, follow-up imaging with MRI avoids the radiation exposure
of repeated CT imaging.
●Conventional spin-echo MRI is the most frequently used technique. Using
low or mid-field-strength magnets, T1- and T2-weighted imaging can
distinguish benign adenomas from malignancy and pheochromocytoma.
●On gadolinium-diethylene triamine pentaacetic acid (DTPA)-enhanced MRI,
adenomas demonstrate mild enhancement and a rapid washout of contrast,
while malignant lesions show rapid and marked enhancement and a slower
washout pattern.
●MR with chemical shift imaging (CSI) accurately distinguishes adrenal
adenomas from non-adenomas based on their elevated amounts of

623
 intracytoplasmic fat [20]. In a meta-analysis of 1280 lesions (859 adenomas),
CSI demonstrated a sensitivity of 94 percent (95% CI 88-97 percent) and a
specificity of 95 percent (95% CI 89-97 percent). No difference in diagnostic
performance was seen when quantitative versus qualitative image analysis
was compared.
Other — Positron emission tomography (PET) with either fludeoxyglucose F 18
(FDG) [21,22] or 11C-metomidate (MTO) [23] can be helpful in selected patients (eg,
those with a prior history of malignancy or those in which unenhanced CT
attenuation or washout analysis is inconclusive or suspicious for malignancy [5])
because of their high sensitivity for detecting malignancy [1]. (See "Clinical
presentation and evaluation of adrenocortical tumors", section on 'Radiographic
studies'.)
Typical imaging features — The imaging characteristics of adrenal masses are
summarized here.
Benign adenomas
●Round and homogeneous density, smooth contour, and sharp margination
[24]
●Diameter less than 4 cm, unilateral location
●Low unenhanced CT attenuation values (≤10 HU) (image 1)
●Rapid contrast medium washout (10 minutes after administration of
contrast, an absolute contrast medium washout of more than 50 percent)
●Isointensity with liver on both T1- and T2-weighted MRI sequences
●Chemical shift evidence of lipid on MRI
Pheochromocytomas
●Increased attenuation on unenhanced CT (>20 HU) [25]
●Increased mass vascularity (image 2)
●Delay in contrast medium washout (10 minutes after administration of
contrast, an absolute contrast medium washout of less than 50 percent)
●High signal intensity on T2-weighted MRI (image 3)
●Cystic and hemorrhagic changes
●Variable size and may be bilateral
Adrenocortical carcinoma
●Irregular shape
●Inhomogeneous density because of central areas of low attenuation due to
tumor necrosis (image 4)
●Tumor calcification
●Diameter usually >4 cm
●Unilateral location
●High unenhanced CT attenuation values (>20 HU)

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 ●Inhomogeneous enhancement on CT with intravenous contrast
●Delay in contrast medium washout (10 minutes after administration of
contrast, an absolute contrast medium washout of less than 50 percent)
●Hypointensity compared with liver on T1-weighted MRI and high to
intermediate signal intensity on T2-weighted MRI
●High standardized uptake value (SUV) on FDG-PET-CT study
●Evidence of local invasion or metastases (see "Clinical presentation and
evaluation of adrenocortical tumors", section on 'Radiographic studies')
Adrenal metastases
●Irregular shape and inhomogeneous nature (image 5)
●Tendency to be bilateral
●High unenhanced CT attenuation values (>20 HU) and enhancement with
intravenous contrast on CT
●Delay in contrast medium washout (10 minutes after administration of
contrast, an absolute contrast medium washout of less than 50 percent)
●Isointensity or slightly less intense than the liver on T1-weighted MRI and
high to intermediate signal intensity on T2-weighted MRI (representing an
increased water content)
●Elevated SUV on FDG-PET scan
Other — Adrenal cysts, adrenal hemorrhage, and myelolipoma (image 6) are
usually easily characterized because of their distinctive imaging characteristics.
Fine-needle aspiration biopsy — Cytology from a specimen obtained by fine-
needle aspiration (FNA) biopsy cannot distinguish a benign cortical adrenal mass
from the less common adrenal carcinoma. It can, however, distinguish between an
adrenal tumor and a metastatic tumor [26]. In a patient with a known primary
malignancy elsewhere who has a newly discovered adrenal mass that has an
imaging phenotype consistent with metastatic disease, performing a diagnostic
CT-guided FNA biopsy may be indicated, but only after excluding
pheochromocytoma with biochemical testing. Adrenal biopsy would not be needed
if the patient was already known to have widespread metastatic disease [27,28].
One report, as an example, evaluated patients with known lung cancer and an
adrenal mass; FNA biopsy revealed a benign adrenal lesion in two-thirds of cases
[24]. When the non-adrenal cancer is occult, most adrenal masses are
incidentaloma cortical adenomas (91 of 95 in one study [29]). Thus, FNA biopsy is
not useful in the routine evaluation of incidentalomas in patients suspected to
have small non-adrenal cancers.
Image-guided FNA biopsy is relatively safe; the complication rate was 2.8 percent
in one series of 277 biopsies [30]. The risks of this procedure include adrenal and
liver hematoma, abdominal pain, hematuria, pancreatitis, pneumothorax,

625
formation of an adrenal abscess, and tumor recurrence along the needle track
[30,31]. The FNA biopsy of a pheochromocytoma may result in hemorrhage and
hypertensive crisis [32]. Therefore, the possibility of pheochromocytoma should
always be ruled out by biochemical testing before FNA biopsy is undertaken [32-
34].
EVALUATION FOR HORMONAL SECRETIONWhile most adrenal
incidentalomas are nonfunctional, 10 to 15 percent secrete excess amounts of
hormones [11,12]. The most complete analysis of this issue comes from a review of
all 828 published articles on adrenal incidentalomas from 1980 to 2008 [12]. Only
20 of the 828 articles were selected as having met the strict criteria for a "true"
adrenal incidentaloma; of these, only nine had adequate data on both diagnosis
and follow-up. Patients who were suspected as having cancer were excluded.
Among the 1800 patients in these nine series, these overall mean percentages of
diagnoses were reported:
●Malignant – Primary adrenal carcinoma 1.9 percent, metastases 0.7 percent
●Benign – Nonfunctioning 89.7 percent, subclinical Cushing's syndrome 6.4
percent, pheochromocytoma 3.1 percent, primary aldosteronism 0.6 percent
Three forms of adrenal hyperfunction should be considered in all patients who are
diagnosed with an adrenal incidentaloma (algorithm 1):
●Subclinical glucocorticoid secretory autonomy (subclinical Cushing's
syndrome), assuming that another diagnosis (eg, pheochromocytoma)
is not present
●Pheochromocytoma if the unenhanced computed tomography (CT)
attenuation is >10 HU
●Primary aldosteronism if the patient is hypertensive or has hypokalemia
Subclinical Cushing's syndrome — Subclinical Cushing's syndrome (or
autonomous cortisol secretion [ACS]; cortisol secretion without clinical
manifestations of Cushing's syndrome) is the most frequent hormonal abnormality
detected in patients with adrenal incidentalomas. Some adrenal incidentalomas
secrete cortisol independently of corticotropin (ACTH) [35], which may have
clinically important consequences. Cortisol secretion can be under the control of
one or more aberrant hormone receptors in patients with unilateral adenomas or
incidental bilateral macronodular adrenal hyperplasia (BMAH) [36,37].
(See "Cushing's syndrome due to primary bilateral macronodular adrenal
hyperplasia", section on 'Aberrant hormone receptors'.)
Clinical manifestations — Although these patients lack many of the usual
stigmata of overt Cushing's syndrome, they may have one or more of the effects of
continuous ACTH-independent cortisol secretion, including hypertension,

626
dyslipidemia, diabetes, weight gain, osteoporosis, and evidence of atherosclerosis
[38-40].
In a two-year longitudinal study of 103 consecutive patients with adrenal
incidentaloma, the incidence of new vertebral fractures was higher in the group
with subclinical Cushing's syndrome (48 percent) than the adrenal incidentaloma
group without subclinical Cushing's (13 percent) [41].
Atrial fibrillation (AF) is more common in patients with ACS when compared with
those with nonsecreting adenomas. In a retrospective study of patients with ACS
or nonsecreting adenomas (n = 632), the prevalence of AF was higher at baseline in
the ACS patients (8.5 percent, 18 of 212) compared with the nonsecreting group
(3.1 percent, 13 of 420) [42]. At the completion of the study (median follow-up of
7.7 years), the AF rate remained higher in the ACS group: 20 percent (22 of 108)
versus the nonsecreting group, 12 percent (30 of 249). Given these rates, patients
with ACS should be monitored for AF.
Diagnosis — Subclinical Cushing's syndrome should be ruled out by obtaining a
baseline serum dehydroepiandrosterone sulfate (DHEAS) and performing the 1 mg
overnight dexamethasone suppression test (DST) (algorithm 1) [43]. Of note, the
overnight DST should not be performed if the patient is thought to have a
pheochromocytoma based upon the initial imaging study (unenhanced CT
attenuation >10 HU). Reports of catecholaminergic crisis (some fatal) during DSTs
have been described in patients with pheochromocytoma. Although most have
been with high-dose DST, cases with low-dose DST have also been described
[44,45].
A low DHEAS reflects chronic suppression of ACTH secretion. In a study of 185
patients with adrenal incidentaloma, 29 patients (16 percent) were diagnosed with
subclinical Cushing's syndrome [46]. An age- and sex-specific DHEAS ratio (derived
by dividing the DHEAS by the lower limit of the respective reference range for age
and sex) of <1.12 was sensitive (>99 percent) and specific (91.9 percent) for the
diagnosis of subclinical Cushing's syndrome [46].
An abnormal 1 mg overnight DST (cortisol >1.8 mcg/dL [>50 nmol/L]) is consistent
with ACTH-independent autonomous cortisol production, a finding that should be
further evaluated with 24-hour urinary free cortisol, serum ACTH concentration,
and a high-dose (8 mg) overnight DST. Clinically significant glucocorticoid
secretory autonomy is confirmed by a post-overnight 8 mg DST 8 AM serum
cortisol concentration >1.8 mcg/dL (>50 nmol/L). (See "Establishing the diagnosis
of Cushing's syndrome".)
Because of a lack of sensitivity of most ACTH assays at the lower part of the
reference range, most centers rely on an alternate measure of autonomous
cortisol secretion: baseline DHEAS and the overnight 1 mg DST. Some centers use

627
a higher dose of dexamethasone (eg, 3 mg rather than the standard 1 mg) to
reduce false-positive results [47].
A study of the two-day, low-dose DST [48] showed a gradation between subnormal
and complete suppression of serum cortisol concentrations in 57 patients with
adrenal incidentalomas (21 percent had undetectable serum levels of cortisol, 67
percent had values between 1 and 5 mcg/dL, and 12 percent had values between
5.0 and 7.8 mcg/dL). Thus, the question for the clinician when glucocorticoid
secretory activity is found is whether the cortical adenoma has clinically
significant glucocorticoid secretory activity.
Bilateral adrenal masses and subclinical Cushing's syndrome — This clinical
scenario is being increasingly recognized. When the bilateral adrenal masses are
consistent with solitary bilateral adenomas on cross-sectional computed imaging,
consideration should be given to adrenal venous sampling [49,50] (see "Diagnosis
of primary aldosteronism", section on 'Adrenal vein sampling'). In this setting,
adrenal venous sampling is performed without cosyntropin administration and
successful adrenal vein catheterization is confirmed with either catecholamine or
metanephrine gradients between the adrenal veins and the inferior vena cava.
In a study of 14 patients with bilateral adrenal nodules and ACTH-independent
subclinical or clinical Cushing's syndrome 10 had bilateral and 4 had unilateral
cortisol overproduction [50]. In patients where the computed images of the
adrenal glands are consistent with BMAH (image 7), adrenal vein sampling
is not needed, because this is a bilateral adrenal disorder. (See "Cushing's
syndrome due to primary bilateral macronodular adrenal hyperplasia".)
Pheochromocytoma — Approximately 3 percent of adrenal incidentalomas prove
to be pheochromocytomas [12]. In the past, it was thought that all patients with
pheochromocytoma are symptomatic. However, with widespread use of computed
imaging, pheochromocytomas are being discovered in the presymptomatic stage
[51,52]. In a study of 271 consecutive patients with pheochromocytoma treated
from 2005 to 2016, 61 percent were discovered as an incidental finding on cross-
section imaging, 27 percent due to pheochromocytoma-related symptoms, and 12
percent due to mutation-based testing [53]. (See "Clinical presentation and
diagnosis of pheochromocytoma", section on 'Approach to initial evaluation'.)
Biochemical testing for pheochromocytoma should be performed if the
unenhanced CT attenuation is ≥10 HU, but not if it is <10 HU (algorithm 1) [25].
(See "Clinical presentation and diagnosis of pheochromocytoma", section on
'Imaging'.)
Small pheochromocytomas (eg, <1.5 cm) may have normal biochemical testing
(image 8). Pheochromocytomas need a critical mass before they can become

628
biochemically detectable. Surgical resection of apparent nonfunctioning lipid-poor
and vascular adrenal masses should be considered (algorithm 1).
Aldosteronomas — Aldosteronomas are rare (less than 1 percent) causes of an
adrenal incidentaloma. However, because the majority of patients with primary
aldosteronism are not hypokalemic, all patients with hypertension and an adrenal
incidentaloma should be evaluated by measurements of plasma aldosterone
concentration and plasma renin activity [1,2]. In addition, patients who are
normotensive but have spontaneous hypokalemia should also be tested for
primary aldosteronism (algorithm 1). (See "Diagnosis of primary
aldosteronism" and "Pathophysiology and clinical features of primary
aldosteronism".)
Confirmatory testing — The diagnosis and confirmation of clinically important
subclinical Cushing's syndrome is described above (see 'Subclinical Cushing's
syndrome' above). If there is biochemical evidence of either a pheochromocytoma
or aldosterone-secreting adenoma on initial testing, confirmatory testing is
required before treatment is considered. Confirmatory testing for these disorders
is described elsewhere. (See "Clinical presentation and diagnosis of
pheochromocytoma", section on 'Indeterminate case-detection
test' and "Diagnosis of primary aldosteronism", section on 'Confirmation of the
diagnosis'.)
MANAGEMENT
Unilateral adrenal masses
●Pheochromocytoma and adrenal cancer – All patients with documented
pheochromocytoma and adrenocortical cancer should undergo prompt
surgical intervention because untreated pheochromocytoma may result in
significant cardiovascular complications. Alpha-adrenergic blockade should
be given before patients undergo adrenalectomy. (See "Treatment of
pheochromocytoma in adults".)
Patients with adrenocortical cancer or lesions suspicious for adrenocortical
cancer should also undergo prompt adrenalectomy as their disease may
progress rapidly. (See "Treatment of adrenocortical carcinoma".)
●Aldosterone-producing adenomas – Patients with aldosterone-producing
adenomas should be offered surgery to cure aldosterone excess.
(See "Treatment of primary aldosteronism".)
●Subclinical Cushing's syndrome – Should all patients with this diagnosis
undergo unilateral adrenalectomy? In the absence of a prospective,
randomized study, it is reasonable to consider that younger patients and
those who have disorders potentially attributable to autonomous
glucocorticoid secretion (eg, recent onset of hypertension, diabetes, obesity,
629
 and low bone mass) and have well-documented glucocorticoid secretory
autonomy (ie, suppressed dehydroepiandrosterone sulfate [DHEAS], failure
to suppress cortisol normally on 1 mg overnight dexamethasone test [DST],
low serum corticotropin [ACTH] concentration, lack of suppression to high-
dose overnight DST [8 AM serum cortisol >1.8 mcg/dL]) are candidates for
adrenalectomy.
If adrenalectomy is performed, perioperative glucocorticoid coverage should
be administered because of the risk of adrenal insufficiency, hemodynamic
crisis, and death. Patients should be sent home from the hospital on
glucocorticoid replacement and monitored for recovery of the hypothalamic-
pituitary-adrenal axis [54]. Weight loss, improvement in hypertension and/or
glycemic control, and normalization of markers of bone turnover are
frequently found following unilateral adrenalectomy in patients with
subclinical Cushing's syndrome [55-57].
●Lipid-poor adrenal masses – Adrenal masses with either suspicious
imaging phenotype or size larger than 4 cm should be considered for
resection because a substantial fraction will be adrenocortical carcinomas
[2,14]. The clinical scenario and patient age frequently guide the
management decisions in patients who have adrenal incidentalomas that fall
on either side of the 4 cm diameter cutoff. As an example, most clinicians
would advise resecting a lipid-poor (29 HU) 3.2 cm adrenal incidentaloma in a
23-year-old woman; whereas, most clinicians would choose serial imaging
follow-up in an 83-year-old woman with a lipid-rich (9 HU) 4.7 cm adrenal
incidentaloma. Before surgery, all patients should undergo appropriate
testing for functional tumors. (See 'Evaluation for hormonal secretion' above.)
●Adrenal myelolipoma – This is a benign tumor composed of mature fat and
interspersed hematopoietic elements that resemble bone marrow. On
computed imaging, the presence of large amounts of macroscopic fat in an
adrenal mass is diagnostic of a myelolipoma (image 6) [58]. Although adrenal
myelolipomas may grow over time, they can usually be followed without
surgical excision. However, when larger than 6 cm in diameter or when
causing local mass-effect symptoms, surgical removal should be considered.
When adrenal myelolipomas are bilateral, the clinician should consider the
diagnosis of congenital adrenal hyperplasia [59].
Bilateral adrenal masses — The management of bilateral adrenal masses is
different from that for unilateral masses. As an example, in cases of bilateral
macronodular adrenal hyperplasia (BMAH) (image 7), size is not an indication for
surgery, whereas the degree of cortisol secretory autonomy should guide surgical
decision-making. Patients with BMAH and clinical Cushing's syndrome usually are

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best treated with bilateral adrenalectomy, whereas patients with BMAH and
subclinical Cushing's syndrome may be managed by resecting the larger adrenal
gland.
Surgical management should be guided by the findings on adrenal venous
sampling in patients with ACTH-independent Cushing's syndrome or subclinical
Cushing's syndrome in the setting of solitary bilateral adrenal adenomas [49,50].
Adrenalectomy — Adrenalectomy for patients with aldosteronomas,
pheochromocytoma, cortisol-secreting tumors, and adrenal incidentalomas is safe
and effective [60]. An adrenalectomy may be done laparoscopically, endoscopically
via the posterior approach, or as an open procedure. Laparoscopic adrenalectomy,
compared with open adrenalectomy, is associated with less pain, shorter
hospitalization time, less blood loss, and faster recovery [61]. The laparoscopic
approach is used for most adrenal masses.
In patients with known or suspected adrenal carcinoma, the laparoscopic
approach should only be considered if the adrenal mass is <10 cm and does not
appear to be locally invasive [62,63]. An open adrenalectomy is recommended for
all large (>10 cm) adrenal masses, including those benign imaging features, as the
adrenal mass may be diagnosed as malignant on a definitive histologic review
[62,64-67]. (See 'Imaging phenotype' above and "Adrenalectomy techniques",
section on 'Approach by indication'.)
Monitoring when surgery not performed — For incidentalomas with a benign
appearance on imaging, repeat imaging after 12 months should be performed to
reconfirm the initial diagnosis of a benign adrenal mass [5]. The decision to obtain
additional images (eg, at 3, 6, 12, and 24 months after the initial image) and the
type of image obtained (eg, computed tomography [CT] or magnetic resonance
imaging [MRI]) should be guided by the individual clinical circumstance, imaging
phenotype, and clinical judgment (algorithm 1).
As an example, a single repeat image is reasonable in patients who have no history
of malignancy and who have small (less than 2 cm), uniform, low unenhanced CT
attenuation cortical nodules (ie, benign imaging phenotype). There are no
prospective studies of the optimal frequency and duration of follow-up for adrenal
incidentalomas. In addition, the radiation exposure related to CT should be
considered [12]. (See "Radiation-related risks of imaging", section on 'Clinical
decision-making and informing patients'.)
Most experts would consider resecting any tumor that enlarges by more than 1 cm
in diameter during the follow-up period (algorithm 1). However, most adrenal
masses that grow are not malignant. However, surgical removal should be
considered for masses ≥4 cm to avoid missing adrenal carcinomas, particularly in
younger patients. (See 'Size' above.)

631
The observation that autonomous function (glucocorticoid) not present at baseline
may be detected at follow-up testing [68-70] has led to the recommendation for
repeating the baseline DHEAS and the overnight DST annually for four years in
cases where initial evaluation is negative [1,69,70]; however, the yield and cost
effectiveness of such testing is also unknown [5,12].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of Cushing's
syndrome" and "Society guideline links: Adrenal incidentaloma".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topic (see "Patient education: Adrenal cancer (The Basics)")

SUMMARY AND RECOMMENDATIONSAn adrenal incidentaloma is a mass
lesion greater than 1 cm in diameter, serendipitously discovered by radiologic
examination. This entity is the result of technological advances in imaging such as
computed tomography (CT) and magnetic resonance imaging (MRI).

All patients with adrenal incidentalomas should be evaluated for the possibility of
malignancy and subclinical hormonal hyperfunction:

●A homogeneous adrenal mass <4 cm in diameter, with a smooth border,

and an attenuation value <10 Hounsfield unit (HU) on unenhanced CT, and
rapid contrast medium washout (eg, >50 percent at 10 minutes) is very likely
to be a benign cortical adenoma. (See 'CT scan' above.)
●The imaging characteristics that suggest adrenal carcinoma or metastases
include: irregular shape, inhomogeneous density, high unenhanced CT
attenuation values (>20 HU), delayed contrast medium washout (eg, <50
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percent at 10 minutes), diameter >4 cm, and tumor calcification. Other
characteristics are described above. (See 'Adrenocortical carcinoma' above.)
●Pheochromocytoma should be excluded in all patients with adrenal
incidentalomas with unenhanced CT attenuation >10 HU by measuring 24-
hour urinary fractionated metanephrines and catecholamines or plasma
fractionated metanephrines. (See 'Pheochromocytoma' above.)
●Subclinical Cushing's syndrome should be ruled out by measuring baseline
dehydroepiandrosterone sulfate (DHEAS) and performing the 1 mg
overnight dexamethasone suppression test (DST). To detect clinically
significant glucocorticoid secretory autonomy, the post-overnight 1 mg DST
8 AM serum cortisol concentration cutoff is >1.8 mcg/dL (>50 nmol/L). An
abnormal 1 mg overnight DST is consistent with corticotropin (ACTH)-
independent cortisol production, a finding that should be confirmed with 24-
hour urinary free cortisol, serum ACTH concentration, and a high-dose (8 mg)
overnight DST. (See 'Subclinical Cushing's syndrome' above.)
●If the adrenal incidentaloma patient is hypertensive or is hypokalemic, a
plasma aldosterone and plasma renin activity should be obtained to screen
for primary aldosteronism. (See 'Aldosteronomas' above.)
●We recommend surgery for all patients with biochemical documentation of
pheochromocytoma. The preoperative management and surgical approach
of patients with pheochromocytoma is reviewed elsewhere. (See "Treatment
of pheochromocytoma in adults".)
●We suggest a surgical resection for patients with subclinical Cushing's
syndrome who are good surgical candidates and who have disorders
potentially attributable to excess glucocorticoid secretion (eg, recent onset of
hypertension, diabetes, obesity, and low bone mass) (Grade 2C).
(See 'Unilateral adrenal masses' above.)
●In a patient with a known primary malignancy elsewhere who has a newly
discovered adrenal mass that has an imaging phenotype consistent with
metastatic disease, performing a diagnostic CT-guided fine-needle aspiration
(FNA) biopsy may be indicated, but only after excluding pheochromocytoma
with biochemical testing. Adrenal biopsy is not needed if the patient is
already known to have widespread metastatic disease. (See 'Fine-needle
aspiration biopsy' above.)
●We suggest excision of a tumor if the initial imaging phenotype is suspicious
(Grade 2C). (See 'Unilateral adrenal masses' above.)
●For all adrenal masses larger than 10 cm, including those masses with
benign imaging phenotypes, we suggest an open adrenalectomy rather than
a laparoscopic procedure (Grade 2C). (See 'Adrenalectomy' above.)

633
●In patients with adrenal masses greater than 4 cm in diameter, we consider
surgical resection. However, the clinical scenario, imaging characteristics, and
patient age frequently guide the management decisions in patients who have
adrenal incidentalomas that fall on either side of the 4 cm diameter cutoff.
(See 'Size' above and 'Unilateral adrenal masses' above.)
●For incidentalomas with a benign appearance on imaging, we suggest a
repeat imaging study at 12 months after initial discovery. The rationale is that
many malignant lesions will grow in this interval, leading to earlier
intervention. Whether to obtain additional images (eg, at 6, 12, and 24
months after initial discovery) and the type of image obtained (eg, CT, MRI, or
ultrasound) should be guided by clinical judgment and imaging phenotype.
The yield and cost-effectiveness of such a strategy are not known.
(See 'Monitoring when surgery not performed' above.)
●We suggest removal of any tumor that enlarges by more than 1 cm in
diameter during the follow-up period (Grade 2C). (See 'Monitoring when
surgery not performed' above.)
●We suggest that baseline DHEAS and an overnight DST be repeated annually
for four years in cases where initial evaluation is negative, although the yield
and cost effectiveness of such testing is also unknown. Autonomous function
(glucocorticoid) not present at baseline may be detected at follow-up testing.
(See 'Monitoring when surgery not performed' above.)

634
Medical therapy of hypercortisolism (Cushing's
syndrome)
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 06, 2021.
INTRODUCTIONThe hypercortisolism of Cushing's syndrome is primarily
treated surgically, regardless of its cause (ie, due to corticotropin [ACTH]-
producing pituitary tumor [Cushing's disease], ectopic ACTH secretion by a
nonpituitary tumor, or cortisol secretion by an adrenal adenoma or carcinoma).
However, when surgery is delayed, contraindicated, or unsuccessful, medical
therapy is often required. Adrenal enzyme inhibitors are the most commonly used
drugs, but adrenolytic agents, drugs that target a pituitary or ectopic tumor, and
glucocorticoid-receptor antagonists are also available.
The pharmacologic management of hypercortisolemia in Cushing's syndrome will
be reviewed here. An overview of the treatment options for Cushing's syndrome
and additional details about drugs that inhibit cortisol synthesis are discussed
separately. (See "Overview of the treatment of Cushing's
syndrome" and "Pharmacology and toxicity of adrenal enzyme inhibitors and
adrenolytic agents" and "Persistent or recurrent Cushing's disease: Surgical
adrenalectomy".)
INDICATIONSThe main indications for medical therapy of Cushing's syndrome
include (see "Overview of the treatment of Cushing's syndrome"):
●Control of hypercortisolism in preparation for surgery – Although the
hypercortisolism of Cushing's disease is optimally treated surgically, medical
therapy is often required when surgery is delayed. (See "Overview of the
treatment of Cushing's syndrome", section on 'Transsphenoidal surgery'.)
●Management of hypercortisolism if surgery is contraindicated.
(See "Overview of the treatment of Cushing's syndrome", section on 'Medical
therapy'.)

635
 ●Management of persistent or recurrent hypercortisolism after initial
surgery. (See "Primary therapy of Cushing's disease: Transsphenoidal surgery
and pituitary irradiation".)
●Patients who have undergone radiation therapy – Control of
hypercortisolism while waiting for the effect of pituitary radiation in patients
with corticotropin (ACTH)-secreting pituitary tumors (Cushing's disease).
●Patients with ectopic ACTH syndrome – Treatment of occult or metastatic
ectopic ACTH syndrome.
Our approach is largely consistent with the Endocrine Society Clinical Practice
Guideline [1].
CHOOSING THERAPIESMedical treatment of Cushing's syndrome can be
divided into two broad categories: medications that decrease cortisol production
and those that antagonize the action of cortisol at the glucocorticoid receptor.
●Drugs that decrease cortisol production – Drugs that decrease cortisol
production include steroidogenesis inhibitors, which act directly on the
adrenal gland to inhibit enzymes involved in cortisol synthesis and may also
be adrenolytic, and agents that reduce corticotropin (ACTH) secretion by
pituitary corticotroph tumors or ectopic tumors, and hence reduce the
adrenal stimulation for cortisol production. (See 'Adrenal enzyme
inhibitors' below.)
●Glucocorticoid receptor antagonists – An example of a glucocorticoid
receptor antagonist is mifepristone. (See 'Glucocorticoid-receptor
antagonists' below.)
Issues for all patients
●Patients' goals and preferences – These should be explored together
before choosing medical therapy. For example, a young woman's desire for
pregnancy in the near future may influence a choice of adrenalectomy over
medical treatment. Other potential issues include a preference for oral versus
injectable route of administration; daily versus multiple daily doses; impaired
memory (ie, possible reduced adherence); a desire to "get on with life," which
may favor surgery or agents with a faster onset of action; insurance,
availability, and affordability.
●The variability in day-to-day cortisol production – In patients with highly
variable cortisol production, fixed dosing regimens may result in adrenal
insufficiency alternating with normal or increased cortisol production.
Instead, a "block and replace" strategy is used in which the medication dose
is titrated to completely block cortisol secretion, with the addition of a
physiologic exogenous glucocorticoid dose to "replace" cortisol.

636
 Thus, before deciding on a specific medication, 24-hour urine cortisol
secretion should be measured to determine the degree of variability of
cortisol production. While no studies have identified criteria for "high"
variability, one approach is to look at the percentage or fold changes in at
least three pretreatment urinary free cortisol (UFC) values. If the
pretreatment values differ by threefold, ideal dosing would achieve values of
20 to 60 mcg/day (within and slightly above the normal range of
approximately 5 to 50 mcg/day). However, a result of 20 mcg/day implies
threefold results of 0 to 60, risking adrenal insufficiency, and a value of 50
would imply possible results of 17 to 150 mcg/day, risking undertreatment.
Thus, a variability criterion of no more than twofold is probably best to use
when choosing a fixed-dose regimen.
Considerations for individual medications — These issues are discussed below:
●The cause of Cushing's syndrome – Some agents are used only for pituitary
Cushing's or ectopic ACTH-producing tumors.
●Likelihood of long-term normalization of signs and symptoms – Some
agents are more effective when hypercortisolism is mild. Others may
effectively mitigate hypercortisolism but have an adverse side-effect profile
that prevents their use or limits long-term use.
●The likelihood of adrenal insufficiency.
●Drug-drug interactions.

INITIAL THERAPY
Adrenal enzyme inhibitors — Ketoconazole, metyrapone, and mitotane are orally
active medications that inhibit one or more steps in cortisol synthesis (figure 1).
They are most often used to control corticotropin (ACTH)-dependent cortisol
excess [2-6]. These drugs are not available in all countries. The most commonly
used agent is ketoconazole in the United States and metyrapone in the United
Kingdom. Other drugs that inhibit adrenal enzymes but are either no longer
available (aminoglutethimide and trilostane), or rarely used (fluconazole), will not
be considered further.
In addition to inhibiting adrenal enzymes, mitotane is adrenolytic and is used for
the treatment of adrenocortical carcinoma (see "Treatment of adrenocortical
carcinoma"). The steroidogenesis inhibitor etomidate is the only agent for
intravenous use.
Ketoconazole — Ketoconazole inhibits the first step in cortisol biosynthesis (side-
chain cleavage) and, to a lesser extent, the conversion of 11-deoxycortisol to
cortisol; it is an even more potent inhibitor of C17-20 desmolase, decreasing
androstenedione, testosterone, and estradiol production (figure 1). At therapeutic
doses, it also impairs corticotroph adenylate cyclase activation and ACTH secretion
637
in vitro [7]. However, the contribution of this effect to its action in patients with
Cushing's disease has not been demonstrated.
In a series of 200 patients with Cushing's disease, 75 percent achieved either
normal free cortisol (UFC) levels (49 percent) or at least a 50 percent decrease, at a
median final dose of 600 mg/day. However, 20 percent stopped the treatment due
to poor tolerance [8].
Ketoconazole may cause reversible hepatotoxicity [8,9]. In the study described
above [8], mild (<5-fold normal values) and major (>5-fold normal values) increases
in liver enzymes were observed in 13.5 and 2.5 percent of patients, respectively. In
2013, the US Food and Drug Administration (FDA) issued a warning about the risk
of potentially fatal liver toxicity, even in patients without pre-existing hepatic
disease [10], which was followed by a temporary withdrawal in European
countries. The regulatory warnings were revised to discourage use of
ketoconazole for management of fungal infections, and the drug is now widely
available [11]. In the United States, it is an off-label use for the treatment of
Cushing's syndrome.
●Liver function tests should be performed before initiation of ketoconazole.
The drug is contraindicated in patients with liver disease whose alanine
aminotransferase (ALT) values are ≥3 times the upper normal range. Patients
with elevated values <3 times the upper normal range often have cortisol-
induced nonalcoholic hepatosteatosis that improves with ketoconazole
treatment.
●ALT should be monitored weekly for the first month, monthly for three
months, and less frequently thereafter.
●If ALT values increase to ≥3 times the upper normal range, we suggest
stopping the ketoconazole or reducing it to a previously well-tolerated dose.
Ketoconazole-induced decreases in estradiol and testosterone production may
lead to gynecomastia, decreased libido, and impotence in men but usually are not
clinically apparent in women because of the oligomenorrhea or amenorrhea
associated with Cushing's syndrome [12].
Ketoconazole is teratogenic and toxic to animal embryos but has been used
successfully and without harm to fetuses from as early as the seventh week of
pregnancy [13,14]. However, ketoconazole is not the treatment of choice during
pregnancy. (See "Diagnosis and management of Cushing's syndrome during
pregnancy", section on 'Management'.)
Ketoconazole requires an acidic environment for maximal absorption; its
bioavailability may be reduced as much as 50 percent if it is given with a proton
pump inhibitor [15]. Such agents should be discontinued, if at all possible, if
ketoconazole is used.

638
Ketoconazole is a strong inhibitor of CYP3A4. Coadministration of CYP3A4
substrates should be avoided if possible and may result in increased plasma
concentrations of these drugs, with increased or prolonged therapeutic or adverse
effects. For example, coadministration of certain ergot derivatives, lovastatin,
and alprazolam may result in dangerous elevations of those agents and is
contraindicated [16].
Ketoconazole can prolong the QT interval; thus concomitant administration of
other agents that also prolong the QT interval (such
as cisapride, methadone, quinidine) is contraindicated as they may synergize to
cause life-threatening ventricular arrhythmia [16].
Metyrapone — We do not suggest metyrapone as the first-line drug for women
with Cushing's disease requiring long-term control of hypercortisolism. However,
its use is not precluded in women for projected short-term use (for example, for
treatment before surgery), or when ketoconazole is not a good alternative.
Metyrapone inhibits CYP11B1, leading to increases in 11-deoxycortisol, the
immediate precursor of cortisol. It also inhibits CYP11B2, leading to increases in
deoxycorticosterone, the immediate precursor of aldosterone (figure 2), which
may cause salt retention and hypertension. As a consequence of decreasing
cortisol levels, ACTH secretion from a pituitary tumor may increase, stimulating
increases in adrenal androgen production, which can cause hirsutism in women.
When given in a dose of approximately 4 g/day, metyrapone decreases cortisol
secretion, but usually not to normal, in patients with Cushing's disease [17]. Thus,
like the other adrenal enzyme inhibitors, metyrapone is most useful as adjunctive
therapy in patients with mild disease or after pituitary irradiation, which prevents a
further increase in ACTH secretion [2,18-21]. A dose of 500 to 750 mg three or four
times a day is usually required in these patients. Metyrapone has been used in
pregnancy with mixed results efficacy [22-24]. (See "Diagnosis and management of
Cushing's syndrome during pregnancy", section on 'Management'.)
In the largest retrospective, multicenter series, 195 patients with Cushing's
syndrome (all causes) were treated with metyrapone (as monotherapy in 84
percent) [25]. Complete normalization of cortisol secretion was achieved in
approximately 50 percent of patients treated both short and long term. Among 38
patients treated long term (mean 18 months), 77 percent achieved complete
normalization of cortisol secretion. The drug was generally well tolerated:
gastrointestinal upset (23 percent) and hypoadrenalism (7 percent) were the most
frequent side effects; hypokalemia, hypertension, and hirsutism were very seldom
found.
Metyrapone is currently available in North America through its distributor HRA
Pharma (Paris, France) via its specialty pharmacy Direct Success Inc with order

639
forms available on the web (www.metopirone.us) or by phone at 1-855-674-7663.
Like ketoconazole, its use for treatment of Cushing's syndrome is an off-label use.
Osilodrostat — Osilodrostat is an oral agent that has been approved for adults
with Cushing's disease who are not candidates for pituitary surgery or who have
undergone transsphenoidal surgery but have persistent disease [26-28].
Like metyrapone, it blocks the 11-beta-hydroxylase enzymes (CYP11B1 and
CYP11B2), thereby reducing the synthesis of aldosterone and cortisol [26].
Osilodrostat's safety and effectiveness for treating adults with Cushing's disease
was evaluated in a six-month, single-arm, open-label study of 137 adult patients
with Cushing's disease, who were either not surgical candidates or who had
undergone transsphenoidal surgery but were not cured. The starting dose for all
was 2 mg twice daily that could be increased by 1 to 2 mg every two weeks up to
30 mg twice/day. At the end of 24 weeks, approximately one-half of patients had
24-hour UFC levels less than or equal to the upper limit of normal (ULN) [29].
In this same trial, subjects who achieved a 24-hour UFC less than or equal to ULN
at week 24, without up-titration after week 12, entered into an 8-week randomized
trial of continued osilodrostat or placebo [30]. Of the 137 patients initially enrolled,
72 were eligible for the randomized trial. More patients maintained a complete
response with osilodrostat than placebo (86 versus 29 percent, respectively).
Side effects of the drug include hypocortisolism, prolongation of the QT interval,
nausea, headache, and adrenal insufficiency [27,30,31]. There are limited data on a
faster dose escalation strategy or use of the agent in patients without Cushing's
disease. In one report of three patients with ectopic ACTH secretion, the dose was
increased by 1 mg every two to five days, based on morning plasma cortisol levels
[32].
Mitotane — Mitotane is an adrenolytic drug that acts on adrenocortical cell
mitochondria to inhibit CYP11B1 (11-beta-hydroxylase) and cholesterol side-chain
cleavage (CYP11A1) enzymes. A metabolite binds to important macromolecules in
the mitochondria, causing mitochondrial destruction and necrosis of
adrenocortical cells [33]. Because of its adrenolytic action, it is used primarily for
the treatment of adrenal carcinoma, which will not be considered further here.
(See "Treatment of adrenocortical carcinoma", section on 'Adjuvant mitotane'.)
Mitotane also can be used to achieve medical adrenalectomy with or without
pituitary irradiation in patients with Cushing's disease or as an adjunctive
medication in patients with ectopic ACTH secretion [34-36]. Mitotane treatment of
Cushing's syndrome not caused by adrenocortical cancer should be started with
0.5 g given at bedtime, adding single 0.5 g doses at a mealtime every week or so,
as the patient's tolerance permits, to reach a maximal dose of 2 to 3 g/day, one-
half of which is taken at bedtime to reduce nausea. Thereafter, the concentrations

640
are maintained by doses of 1 to 2 g daily. At these doses, mitotane tends to spare
the zona glomerulosa [37] so that mineralocorticoid replacement is not needed.
The major side effects are nausea, vomiting, and anorexia. Additional side effects
that occur with the higher doses used for adrenal carcinoma are discussed
separately. (See "Treatment of adrenocortical carcinoma", section on 'Adjuvant
mitotane'.)
When given as adjunctive therapy after radiotherapy for Cushing's
disease, mitotane is stopped when cortisol levels normalize, on average after six to
nine months. A sustained cure rate was reported in approximately 60 percent of
cases at 5 to 15 years [34]. Similar findings were reported in a study of 46 patients
treated with higher doses of mitotane but no pituitary irradiation [35]. Four of 92
patients developed Nelson syndrome.
Mitotane is taken up by adipose tissues and persists in plasma long after the drug
is discontinued [38]. Mitotane is teratogenic and should not be given to pregnant
women; women anticipating pregnancy should have levels measured after its
discontinuation to ensure that it is safe to proceed [39].
Dose adjustments and monitoring — Unless mitotane is given in adrenolytic
doses, these medications do not permanently cure the hypercortisolism, leading to
recurrence when the drug is discontinued. As a result, they must be continued
indefinitely until bilateral adrenalectomy is performed, or a tumor is found and
excised or pituitary radiotherapy is effective.
●Ketoconazole/metyrapone/osilodrostat – Doses of ketoconazole and
metyrapone can be increased every three to seven days based on serum
cortisol and/or urine cortisol excretion. In clinical trials, the osilodrostat dose
was adjusted every two weeks; this dose adjustment period is recommended
in the FDA label. At the outset of treatment with these steroidogenesis
inhibitors, we recommend measurement of a morning serum cortisol level on
the day that urine is returned for cortisol measurement. This allows the two
to be correlated, allowing later use of the morning cortisol only, as most
patients find a blood draw to be more convenient than urine collection.
●For patients with relatively invariant cortisol production, a fixed dose
schedule can be used with the goal of "normalization" of cortisol. A serum
cortisol target of 7 to 12 mcg/dL (193 to 331 nmol/L) can be used while
awaiting the urine result, with a goal urine value in the middle to slightly
above the upper limit of the reference range. While this approach minimizes
the chance of adrenal insufficiency, patients nevertheless should receive
education about adrenal insufficiency signs and symptoms and how to
administer emergency doses of glucocorticoid. (See "Treatment of adrenal
insufficiency in adults".)

641
 ●For patients requiring a "block and replace" strategy, the dose of drug(s) is
increased at intervals until serum or urine cortisol is in the normal range, at
which time a glucocorticoid is added. The dose is increased further until
serum or urine cortisol values are very low or undetectable.
(See 'Replacement glucocorticoid therapy' below.)
●Once the dose appears to be optimal, monitoring may occur less often,
perhaps monthly or less frequently.
●Metyrapone administration increases 11-deoxycortisol, which may cross-
react with the antibodies in some cortisol immunoassays, while tandem mass
spectrometry results are not affected [40]. If urine or serum cortisol
measurement by tandem mass spectrometry is not available, a cortisol
immunoassay that does not cross-react with 11-deoxycortisol should be used.
●Mitotane – Doses of mitotane are increased more slowly, due to its long half-
life. Urinary cortisol excretion is the optimal measure of the efficacy of
mitotane therapy. Mitotane increases cortisol-binding globulin (CBG) levels,
so that serum cortisol levels increase and do not reliably reflect biologically
active free levels [41]. If serum cortisol levels are used to monitor treatment,
they should be correlated with urinary cortisol excretion, at least initially and
after dose changes.
Replacement glucocorticoid therapy — In a block and replace strategy, patients
must receive replacement glucocorticoid therapy when the serum or urine cortisol
is in the normal range.
●When ketoconazole, osilodrostat, and/or metyrapone are used to decrease
cortisol levels, any glucocorticoid replacement can be used in the usual way
(see "Treatment of adrenal insufficiency in adults"). If hydrocortisone is used,
urine collections to assess efficacy must be done after switching
to dexamethasone, which does not cross-react in cortisol assays.
Alternatively, a pre-hydrocortisone serum cortisol level can be used to
monitor therapeutic effectiveness, with a goal of very low or undetectable
level of urine or serum cortisol.
●When mitotane is used, one cannot predict when a patient will become
hypocortisolemic. As a result, replacement glucocorticoid, usually 5 mg
of prednisone or 0.5 mg of dexamethasone each day, should be started when
cortisol in urine or saliva begin to decrease. Mitotane increases the
metabolism of dexamethasone [42], fludrocortisone, and cortisol and induces
an increase in CBG levels [5]. Thus, replacement dose hydrocortisone usually
requires a two- to threefold increase in the usual dose after long-term
therapy with mitotane. (See "Treatment of adrenocortical carcinoma", section
on 'Adjuvant mitotane'.)

642
 If dexamethasone is used for replacement therapy
during mitotane administration, it may be necessary to increase its dose (and
that of fludrocortisone, if it is required) to three to seven times the usual
dose; in these cases, amelioration of symptoms of hypocortisolism or
normalization of UFC values must be used to guide glucocorticoid
replacement, while symptoms and signs of volume depletion or excess
(postural hypotension, systemic hypertension, or edema), serum electrolytes,
and plasma renin activity are used to guide mineralocorticoid replacement.
(See "Treatment of adrenal insufficiency in adults".)
Because mitotane levels may remain measurable for months after its
discontinuation due to release from adipose tissue, cortisol levels may
remain suppressed so that replacement glucocorticoid may have to be
tapered over a period of several weeks to months.
Combination therapy — Combinations of these drugs often have additive or
synergistic therapeutic effects at lower individual doses, thereby minimizing side
effects.
●If ketoconazole does not control cortisol secretion, it should be maintained
at a total dose of 1200 mg/day and metyrapone and/or mitotane should be
added.
●We suggest adding metyrapone at a dose of 250 mg two or three times a
day and increasing rapidly, to a maximum dose of approximately 4.5 g/day
[15]. Most patients show near-maximal responses at a daily dose of 2 g
(see 'Metyrapone' above). Particularly in patients with severe
hypercortisolism, it is important to control cortisol synthesis quickly. In these
patients, the doses should be increased every two or three days if laboratory
results are available.
●An alternative approach is to begin treatment with metyrapone and
add ketoconazole if cortisol is not adequately controlled.
●In one study of 11 cases of severe hypercortisolism in whom adrenalectomy
was not feasible, triple drug therapy with mitotane, metyrapone,
and ketoconazole normalized UFC [43].
Intravenous etomidate — Etomidate is a substituted imidazole anesthetic drug
that blocks CYP11B1 synthesis of cortisol and is the only available agent for
hospitalized patients unable to take medication by mouth (figure 3). Etomidate is
infused intravenously, initially with a low, nonhypnotic dose of 0.04 to 0.05 mg/kg
per hour (approximately 2.5 to 3 mg/hour), with dose titration based upon serum
cortisol (up to 0.1 to 0.3 mg/kg/hour). This approach has been effective in
approximately 30 adults and children who were acutely ill [44]. It lowers serum
cortisol to normal (ie, 10 mcg/dL [28 nmol/L]) within approximately 10 hours [5].

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Monitoring in an intensive care unit is suggested when using etomidate.
Intravenous hydrocortisone is added if complete block rather than cortisol
normalization is the goal. Sedation, a theoretical side effect of this drug, was not
observed in the few patients studied to date.
OTHER AGENTS
Drugs that target a pituitary tumor — Only the somatostatin
analogue, pasireotide, and the dopamine agonist, cabergoline, have shown
benefit; other agents that are not effective include bromocriptine, cyproheptadine,
and valproate.
Cabergoline — Cabergoline is useful when Cushing's disease is associated with
urinary free cortisol (UFC) values up to twice normal. In two studies, chronic
cabergoline therapy (1 mg once weekly to 1 mg orally every day) decreased 24-
hour UFC to ≤125 percent of normal in 12 of 42 patients with Cushing's disease
[45,46]. Normalization of UFC was achieved in 30 percent of patients with up to five
years of follow-up [46]. A meta-analysis found that patients with milder
hypercortisolism were more likely to respond [47]. Gastrointestinal side effects,
particularly nausea (14 percent) and dizziness were most common; severe adverse
effects included adrenal insufficiency and hypotension. The agent has been used in
a small number of pregnant women with good outcomes [48].
Pasireotide — The somatostatin analog pasireotide binds to somatostatin
receptors and blocks the release of corticotropin (ACTH) from the corticotrophs via
its high affinity for somatostatin receptor subtype 5 [49]. Pasireotide injection has
been approved in the United States, Europe, Canada, and parts of Asia and South
America and is recommended for the treatment of patients with Cushing's disease
for whom surgery has been unsuccessful or who are not surgical candidates [1,50].
It is available as a short-acting subcutaneous preparation for twice-daily use and
as a once-monthly intramuscular (IM) injection. In a study of 162 patients with
Cushing's disease receiving subcutaneous pasireotide (0.6 or 0.9 mg twice daily for
six months), 24-hour UFC decreased by a mean of 48 percent in the whole group
and normalized it in 21 of 80 (26 percent) and 12 of 82 (15 percent) of those in the
0.9 or 0.6 mg group, respectively [51]. Patients who achieved UFC control also
experienced other clinical improvements, including a decrease in total and low-
density lipoprotein cholesterol [52]. Reductions in blood pressure and body mass
index occurred even without normalization of UFC. Hyperglycemia was common,
occurring in 118 of 162 patients (73 percent); 74 of 162 patients (63 percent)
required initiation of a glucose-lowering medication. Pasireotide-associated
hyperglycemia is related to decreases in insulin secretion and incretin hormone
responses (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic
polypeptide [GIP]), but not to changes in hepatic/peripheral insulin sensitivity [53].
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Other side effects were similar to other somatostatin analogs (gastrointestinal
symptoms and gallstones). (See "Treatment of acromegaly".)
The recommended initial dose of the short-acting formulation is 0.6 mg
subcutaneously twice daily, which may be increased to 0.9 mg twice daily if UFC
does not normalize after one to two months of therapy. If there is no clinical
response to 0.9 mg, treatment should either be stopped or combined therapy
should be considered. A sustained response for up to five years has been reported
in three individuals [54,55]; two had initially developed glucose intolerance
with pasireotide, but with clinical and biochemical reversal of their
hypercortisolism, they were eventually able to discontinue all diabetes
pharmacotherapy [55].
A long-term study of 53 patients showed a tumor volume reduction of at least 20
percent at 6 and 12 months that was more common in those taking the 0.9 mg
dose than the 0.6 mg dose (75 and 89 percent versus 44 and 50 percent) [56].
In a trial of 150 patients receiving either 10 or 30 mg once-monthly
IM pasireotide for 12 months, approximately 40 percent in each group reached the
primary endpoint (UFC concentration less than or equal to upper limit of normal by
seven months) [57]. Adverse events include hyperglycemia (47 to 49 percent),
diarrhea (35 to 43 percent), gallstones (20 to 45 percent), and type 2 diabetes (19
to 24 percent). In an open-label extension study that enrolled 81 of the 150
patients, the safety profile was similar to that reported in the first 12 months [58].
The recommended starting dose for pasireotide is 10 mg.

The monthly preparation may be useful for patients who have difficulty
remembering to take medications, but is not a first-line choice for patients with
diabetes.

The pasireotide warning and precaution for hyperglycemia and diabetes has been

updated to include ketoacidosis [59].
Drugs that target an ectopic ACTH-secreting tumor — Chemotherapy or
immunotherapy may reduce corticotropin (ACTH) and cortisol levels in patients
with ectopic ACTH secretion [60-62]. A few patients have been successfully treated
with octreotide and/or cabergoline [63-65]. However, these are case reports or
small series, and the overall efficacy of these approaches is not known.
Combination therapy — In a report of 17 patients with Cushing's disease, the
somatostatin analog pasireotide, followed by cabergoline, and, if
necessary, ketoconazole, achieved normalization in UFC in five (29 percent for
pasireotide alone), four (53 percent for pasireotide and cabergoline), and six
patients (88 percent for three drugs), respectively [66].

645
In another report, for patients in whom cabergoline therapy (3 mg/week) provided
a suboptimal response, addition of ketoconazole (200 to 400 mg daily) achieved a
normal UFC in six of nine patients [45].
In another study, cabergoline (n = 6, dose up to 3 mg weekly) or ketoconazole (n =
8, daily dose of 200 to 600 mg) was the first agent for four to six months [67]. UFC
remained abnormal with the initial treatment but normalized in 13 patients on
combination therapy.
The combination of mitotane (3 to 5 g/24 hours), metyrapone (3 to 4.5 g/24 hours),
and ketoconazole (400 to 1200 mg/24 hours) was able to rapidly correct severe
hypercortisolism in a series of 11 cases of Cushing's syndrome in acute care
situations [43].
Glucocorticoid-receptor antagonists — Mifepristone (RU-486) is an anti-
progestational drug that is best known as an abortifacient. At much higher doses,
it acts as a glucocorticoid receptor antagonist. Currently, mifepristone is the only
available glucocorticoid antagonist, although other agents are in clinical trials.
Mifepristone is approved in the United States as a once-daily oral medication to
control hyperglycemia secondary to hypercortisolism in adults with endogenous
Cushing's syndrome and type 2 diabetes or glucose intolerance who have failed
surgery or are not candidates for surgery [68]. Because patients were not
categorized as clinically normal during treatment, the role of mifepristone apart
from treatment of hyperglycemia is not clear [69].
Mifepristone may be a reasonable short-term intervention for patients with
Cushing's syndrome who have an acute crisis, such as cortisol-induced psychosis,
as symptoms improve rapidly in response to the glucocorticoid receptor blockade
[70,71].
Mifepristone also blocks the action of exogenous glucocorticoids, making it
difficult to treat symptoms of adrenal insufficiency. Should symptoms of adrenal
insufficiency occur, we suggest giving dexamethasone 4 mg to overcome the
blockade.
Because mifepristone blocks cortisol action, the levels of ACTH and cortisol
increase in patients with Cushing's disease [72] and are variable in patients with
ectopic ACTH secretion [73], so that hormonal measurement cannot be used to
judge either therapeutic efficacy or adrenal insufficiency. Instead, the goal is
normalization of clinical and biochemical manifestations of hypercortisolism in
each individual. For example, if hypertension, weight gain, and diabetes are
signs/symptoms for a specific patient, monitoring should ensure that these
improve and then resolve. It may be helpful to develop a list of each patient's signs
and symptoms of Cushing's syndrome and then monitor these regularly,
increasing the dose of the medication if they do not improve.

646
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of Cushing's
syndrome".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basicstopics (see "Patient education: Cushing's syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Cushing's syndrome
(Beyond the Basics)" and "Patient education: Cushing's syndrome treatment
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The hypercortisolism in Cushing's syndrome is primarily treated surgically,
regardless of its cause. However, when surgery is delayed, contraindicated,
or unsuccessful, medical therapy is often required. (See 'Indications' above.)
●The main indications for pharmacologic control of hypercortisolism include:
in preparation for surgery, persistence or recurrence of hypercortisolism
after surgery, while waiting for the effect of pituitary radiation, occult ectopic
corticotropin (ACTH) syndrome, severe or malignancy-related
hypercortisolism, and when surgery is contraindicated.
(See 'Indications' above.)
●Among patients with hypercortisolism in whom medical therapy is indicated,
we suggest ketoconazole as initial therapy (Grade 2C). Liver function tests
must be carefully monitored because of rare occurrences of hepatotoxicity
(see 'Ketoconazole' above). If ketoconazole does not control cortisol
secretion, we suggest adding metyrapone (Grade 2C). (See 'Initial
therapy' above.)

647
●An alternative approach is to start with metyrapone and add ketoconazole if
cortisol secretion is not controlled. (See 'Issues for all patients' above.)
●Mitotane is an adrenocorticolytic drug that is used primarily for the
treatment of adrenal carcinoma. (See 'Mitotane' above.)
●Mitotane also can be used to as adjunctive therapy during or after pituitary
irradiation in patients with Cushing's disease. The usual duration of mitotane
therapy in patients with Cushing's disease is six to nine months.
(See 'Mitotane' above.)
●Mitotane has significant side effects. However, important advantages over
surgical adrenalectomy include a possible decreased risk of developing
Nelson syndrome and the possibility of not requiring mineralocorticoid
replacement. (See 'Mitotane' above.)
●Drugs directed at reducing ACTH levels in Cushing's disease include the
dopamine agonist, cabergoline (off-label use), and the parenteral
somatostatin analog pasireotide (approved for therapy of Cushing's disease).
(See 'Cabergoline' above and 'Pasireotide' above.)
●Mifepristone, a glucocorticoid-receptor antagonist, is approved in the United
States for treatment of hyperglycemia in Cushing's syndrome patients who
cannot undergo surgery. (See 'Other agents' above.)

648
Overview of the treatment of Cushing's syndrome
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Nov 30, 2021.
INTRODUCTIONThe hypercortisolemia in Cushing's syndrome is usually due to
a corticotropin (ACTH)-producing pituitary tumor (Cushing's disease), ectopic ACTH
secretion by a nonpituitary tumor, or cortisol secretion by an adrenal adenoma or
carcinoma. There are also very rare tumors that secrete corticotropin-releasing
hormone (CRH) ectopically, and occasional cases are caused by cortisol secretion
by ACTH-independent macronodular or micronodular hyperplasia of the adrenal
cortex.

Treatment should be directed, whenever possible, at the primary cause of the

syndrome. This topic provides an overview of the various therapeutic options
available in the treatment of Cushing's syndrome. A detailed review of therapy for
Cushing's disease and some of the primary adrenal causes of hypercortisolism is
presented separately.

●(See "Primary therapy of Cushing's disease: Transsphenoidal surgery and

pituitary irradiation".)
●(See "Medical therapy of hypercortisolism (Cushing's syndrome)".)
●(See "Persistent or recurrent Cushing's disease: Surgical adrenalectomy".)
●(See "Cushing's syndrome due to primary bilateral macronodular adrenal
hyperplasia".)
●(See "Cushing's syndrome due to primary pigmented nodular adrenocortical
disease".)
●(See "Diagnosis and management of Cushing's syndrome during
pregnancy".)
GENERAL PRINCIPLES
Goals — Ideal therapy of Cushing's syndrome would achieve the following goals
[1,2]:
●Reverse the clinical manifestations by reducing cortisol secretion to normal
●Eradicate any tumor threatening the health of the patient
649
 ●Avoid permanent dependence upon medications
●Avoid permanent hormone deficiency

In individual patients, however, one or more of the last three goals may have to be
sacrificed to achieve the essential first goal. The therapeutic protocols described
below proceed from permanently curing the disorder by resecting or ablating its
cause to merely controlling the hypercortisolism in patients in whom a cure cannot
be achieved. Each stage in the treatment should provide maximum probability of
cure with the least chance of permanent endocrine deficiency or other undesirable
side effects.

Specific treatment may be delayed during diagnostic testing or while drug

adjustments are made to achieve eucortisolism. During this time, treatment of
comorbidities such as hypertension, osteoporosis, and diabetes should be
instituted [3]. The use of medications to prevent thrombosis or bone loss should
be considered. Treatment should be continued after remission and discontinued
only if these comorbidities reverse. Our approach is largely consistent with the
Endocrine Society Clinical Practice Guideline [4].
Exogenous Cushing's syndrome — The treatment of Cushing's syndrome due to
exogenous therapy is to stop the glucocorticoid. Most patients who have taken
enough glucocorticoid for a long enough time to cause Cushing's syndrome will
have a period of hypothalamic-pituitary adrenal insufficiency when therapy is
discontinued. Thus, gradual withdrawal is necessary. (See "Pharmacologic use of
glucocorticoids", section on 'HPA axis suppression'.)
CUSHING'S DISEASEThe approach to the treatment of Cushing's disease as
outlined here is consistent with a 2015 consensus statement on the treatment of
corticotropin (ACTH)-dependent Cushing's syndrome [4].
Transsphenoidal surgery — The treatment of choice for Cushing's disease (ACTH-
producing pituitary tumor) is transsphenoidal microadenomectomy when a clearly
circumscribed microadenoma can be identified at surgery (algorithm 1). In the
remaining patients, subtotal (85 to 90 percent) resection of the anterior pituitary
may be indicated if future fertility is not desired.
It is difficult to predict residual pituitary function after partial hypophysectomy;
some patients have normal pituitary function even after subtotal hypophysectomy.
However, the more extensive the resection, the greater the risk of loss of pituitary
function. (See "Primary therapy of Cushing's disease: Transsphenoidal surgery and
pituitary irradiation".)

A practical approach to the uncertainty of surgical localization is to make a

contract among the endocrinologist, the patient, and the neurosurgeon before
650
surgery. If the neurosurgeon finds a microadenoma, he removes it. If he does not
and fertility is not a concern of the patient, he performs a more extensive
resection, proceeding to a subtotal hypophysectomy if no adenoma is found.
Among expert pituitary neurosurgeons, the cure rate approximates 70 to 80
percent, but late recurrences reduce the permanent cure rate to approximately 60
to 70 percent.

Medical therapy — Although the hypercortisolism of Cushing’s disease is

optimally treated surgically, medical therapy is often required when surgery is
delayed, contraindicated, or unsuccessful. Adrenal enzyme inhibitors are the most
commonly used drugs, but adrenolytic agents, drugs that target the pituitary, and
glucocorticoid-receptor antagonists also have been used. Medical therapy
targeting the corticotroph tumor such as cabergoline or pasireotide can result in
normalization of 24-hour urinary free cortisol in 20 to 40 percent of them,
especially if they have only mild hypercortisolism. The glucocorticoid (as well as
progestin) antagonist mifepristone is approved in the United States for treatment
of glucose intolerance in patients with Cushing’s syndrome who are not surgical
candidates [5]. This topic is reviewed in detail separately. (See "Medical therapy of
hypercortisolism (Cushing's syndrome)".)
Aggressive corticotroph tumors — While up to one-third of pituitary tumors,
mostly macroadenomas, are locally invasive, a few are more aggressive and 0.1 to
0.2 percent are carcinomas that metastasize in the central nervous system or
systemically. These aggressive tumors are resistant to treatment and result in
death, usually within several months, or occasionally after several years [6].
Chemotherapy may offer temporary remission in a minority of patients. In a
review of 20 patients with aggressive tumors refractory to conventional treatment,
the alkylating agent temozolomide resulted in a partial response in approximately
two-thirds of patients [7]. The use of immunohistochemical demonstration of low
expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase
(MGMT) appeared to predict responsiveness to the agent. While preliminary, these
reports offer a new approach to patients with aggressive or metastatic tumors.
Pituitary irradiation — For patients in whom fertility is an important concern and
in whom a tumor is not found or who are not cured by transsphenoidal resection
of a tumor, pituitary irradiation is one of the next treatment options; it may also be
considered as primary therapy for children under age 18 years. Conventional
megavoltage linear accelerator after transsphenoidal surgery will correct the
hypercortisolism in up to 85 percent of adults when used after debulking surgery
and in 85 percent of children when used as monotherapy [4,8,9].

651
Maximum benefit is usually achieved within 6 to 12 months, but may require two
to three years, and during this time period hypercortisolism should be controlled
with one or several adrenal enzyme inhibitors. Pituitary irradiation may also
decrease the occurrence of Nelson's syndrome in patients not cured by irradiation
for whom adrenalectomy becomes necessary, but this has not been tested in a
prospective randomized trial.

Stereotactic radiosurgery (SRS) is the delivery of a single high dose of radiation

therapy using a high-precision localization system to treat a small target. SRS is
more convenient (a single treatment) than fractionated radiation therapy (many
treatments) and provides less irradiation to neuronal tissues It may also provide
more rapid biochemical control of cortisol excess than conventional radiation, but
this is not well established.

However, adenomas that are too close, 3 to 5 mm, to radiation-sensitive tissues,

such as the optic chiasm or other parts of the optic pathway, are more safely
treated with fractionated radiation therapy since a large, single dose of radiation
to these tissues can cause blindness. In addition, large adenomas should be
treated with conventional radiotherapy.

In a retrospective study of 278 patients who underwent SRS for Cushing’s disease,
with a mean follow-up of 5.6 years, cumulative control of hypercortisolism at 10
years was 80 percent (mean time to normalization 14.5 months) [10]. However, 18
percent of patients experienced a recurrence after cortisol normalized. This study
suggests that the a similar percent of patients undergoing SRS or conventional RT
eventually have normal cortisols. However, SRS is more convenient, and time to
cure may be faster.
Adrenalectomy — Bilateral total adrenalectomy with lifelong daily glucocorticoid
and mineralocorticoid replacement therapy is the final definitive cure, and may be
preferred by some patients instead of radiation therapy. In one series,
laparoscopic adrenalectomy was successful in 42 patients with Cushing's disease
who had not been cured by previous pituitary surgery, radiotherapy and/or
medical therapy [11]. (See "Persistent or recurrent Cushing's disease: Surgical
adrenalectomy".)
ECTOPIC ACTH AND CRH SYNDROMES
Ectopic ACTH — The optimal therapy of the ectopic corticotropin (ACTH) syndrome
(secretion of ACTH by a nonpituitary tumor) is surgical excision of the tumor,
thereby removing the source of ACTH and curing the metabolic disorder. In

652
several reports, remission occurred after removal of 28 of 34, 10 of 12, and 10 of
26 pulmonary carcinoid tumors and eight of nine localized neuroendocrine or
other carcinoid tumors [12-14]. Metastatic tumors cannot be treated by surgical
excision.
In patients with metastases limited to the liver, after resection of the primary
tumor, resection or cryoablation of the metastases or even liver transplantation
may result in cure [15]. In a study of 103 patients with neuroendocrine carcinomas
metastatic to the liver, 60 percent of patients were alive two years after liver
transplantation and 47 percent, half of whom were disease-free, were alive after
five years [16]. Patients who were less than 50 years old, had primary lung or
bowel tumors, and had pretransplant somatostatin treatment had the best
prognosis. Depending on the tumor type, chemotherapy and/or radiotherapy may
be helpful. (See "Diagnosis of carcinoid syndrome and tumor localization".)
Nonresectable tumors — For those patients with nonresectable tumors, the
hypercortisolism can be controlled with adrenal enzyme inhibitors, such
as ketoconazole, metyrapone, and etomidate. (See "Medical therapy of
hypercortisolism (Cushing's syndrome)", section on 'Initial therapy'.)
●Therapy with an adrenal enzyme inhibitor can be continued for a prolonged
period in patients in whom a tumor cannot be identified. Such patients
should be reexamined periodically with 111-In-pentetreotide, computed
tomography (CT), or magnetic resonance imaging (MRI) for several years, if
necessary, until the tumor can be located and treated [13,14].
●Some patients have indolent tumors and a long life expectancy but cannot
be cured surgically. These patients can be treated with mitotane to achieve a
medical adrenalectomy. (See "Medical therapy of hypercortisolism (Cushing's
syndrome)".)
Bilateral surgical adrenalectomy or long-term treatment with steroidogenesis
inhibitors may be used as an alternative to mitotane (figure 1) [12-14].
Patients whose hypercortisolism is controlled by any means may occasionally
develop rebound thymic hyperplasia. Recognition of this condition is important
because it may be confused radiologically with tumor recurrence or metastasis in
the anterior mediastinum [17].
Other potential treatment options that have been tried
include mifepristone and octreotide:
●The glucocorticoid (as well as progestin) antagonist mifepristone has been
used to control hyperglycemia secondary to hypercortisolism in adults with
endogenous Cushing’s syndrome and type 2 diabetes or glucose intolerance
who have failed surgery or are not candidates for surgery (See "Medical

653
 therapy of hypercortisolism (Cushing's syndrome)", section on
'Glucocorticoid-receptor antagonists'.)
●Octreotide, a long-acting analogue of somatostatin, rapidly reduces ectopic
ACTH secretion by some nonpituitary tumors, but does not usually reduce
tumor size [18,19]. Uptake of 111-In-pentetreotide by the tumor also predicts
a positive response to the drug [20]. The agent may be given either as a
twice-daily or monthly injection and is expensive [21]. It therefore has limited
value in treating patients with the ectopic ACTH syndrome.
Ectopic CRH secretion — Ectopic corticotropin-releasing hormone (CRH) secretion
is a very rare disorder, having been proved in only a small number of cases, mostly
with fairly well-differentiated pulmonary carcinoid tumors [22]. The treatment and
prognosis of this condition is the same as for ectopic ACTH secretion. The
Cushing's syndrome can easily be controlled, but the ultimate prognosis depends
upon the malignancy of the tumor and whether it can be completely resected.
PRIMARY ADRENAL DISEASESSeveral different adrenal diseases can cause
Cushing's syndrome; the approach to such patients is generally directed at
removal of the adrenal gland(s). Adrenal tumors should be removed with unilateral
adrenalectomy while bilateral adrenalectomy is required for bilateral micronodular
and most patients with macronodular adrenal hyperplasia. The management of
adrenal carcinoma is reviewed separately. (See "Treatment of adrenocortical
carcinoma".)
Adrenal adenomas — Some functional adenomas hypersecrete cortisol and cause
Cushing's syndrome. Approximately 10 percent of cases of overt Cushing's
syndrome are due to adrenal adenomas.
Unilateral adrenalectomy — Adenomas are always cured with unilateral
adrenalectomy.
●Because of the reduction in postoperative morbidity, hospital stay, and
expense compared with open laparotomy, laparoscopic adrenalectomy by an
experienced endocrine surgeon is the preferred approach for adrenal
adenomas. The laparoscopic approach, which can be done via either the
anterior or posterior approaches, has become standard (at least for patients
with adenomas <6 cm in diameter). Hospital stays appear to be shorter with
this approach (usually one to five days) and complications fewer, as
compared with open surgery. Surgical adrenalectomy and details on the
anterior and posterior laparoscopic approach are reviewed separately.
(See "Adrenalectomy techniques", section on 'Selection of operative
approach'.)
●Cushing’s syndrome creates a hypercoagulable state due to an activated
coagulation cascade and impaired fibrinolysis and patients have more than a
654
 10-fold greater risk of developing venous thromboembolic disease,
particularly if undergoing surgery [23,24]. (See "Epidemiology and clinical
manifestations of Cushing's syndrome", section on 'Thromboembolic events'.)
We therefore suggest thromboprophylaxis be used in patients with Cushing’s
syndrome undergoing surgery [4]. The approach to prevention of venous
thromboembolism in the surgical patient is reviewed separately.
(See "Prevention of venous thromboembolic disease in adult nonorthopedic
surgical patients".)
●There may be cardiovascular and metabolic benefits to surgery for patients
with subclinical Cushing’s syndrome, who often present with adrenal
incidentalomas [25]. (See "Evaluation and management of the adrenal
incidentaloma", section on 'Subclinical Cushing's syndrome'.)
Outcome — Virtually all patients with adrenocortical adenomas are cured by
surgery [26-28]. Postoperative glucocorticoid therapy is needed because excess
cortisol secretion has suppressed corticotropin-releasing hormone (CRH) and
corticotropin (ACTH).

In patients with Cushing's syndrome due to adrenal adenomas, the recovery of

normal ACTH secretion from pituitary corticotropes after prolonged inhibition may
be delayed. There will be secondary atrophy of nontumorous adrenal zonae
fasciculata and reticularis cells in the contralateral adrenal gland. As a result, the
patient often requires glucocorticoid replacement therapy for several months to a
year and sometimes even longer after resection of the tumor. The principles of
glucocorticoid replacement are similar to those for patients with Cushing's disease
who are cured by resection of a pituitary adenoma.

Generally, patients are given higher than normal glucocorticoid replacement

intraoperatively and postoperatively to avoid symptoms and signs of acute steroid
withdrawal. A dose of 150 to 200 mg
of hydrocortisone (or dexamethasone equivalent if bilateral adrenalectomy is not
done) may be administered by constant infusion or in divided doses intravenously
over the first 24 hours after induction of anesthesia. A rapid taper follows over a
few days until hydrocortisone can be given by mouth. A taper may be achieved by
decreasing each successive daily dose to 50 percent of the previous day’s dose.
The patient with subclinical Cushing's syndrome with partial suppression of
hypothalamic-pituitary-adrenal axis should also be treated with perioperative
glucocorticoid coverage because of the risk of adrenal insufficiency; recovery will
usually be faster than for patients with severe Cushing’s syndrome.
(See "Evaluation and management of the adrenal incidentaloma", section on
'Subclinical Cushing's syndrome'.)
655
ACTH-independent bilateral adrenal hyperplasia — There are two forms of
ACTH-independent bilateral adrenal hyperplasia: primary pigmented nodular
adrenocortical disease (PPNAD, also called micronodular adrenal hyperplasia); and
bilateral macronodular adrenal hyperplasia (BMAH). (See "Cushing's syndrome due
to primary pigmented nodular adrenocortical disease" and "Cushing's syndrome
due to primary bilateral macronodular adrenal hyperplasia".)
●Surgical bilateral adrenalectomy is uniformly effective in PPNAD; subtotal or
unilateral adrenalectomy should not be performed since recurrence can
occur. Bilateral adrenalectomy is also indicated in most patients with
macronodular adrenal hyperplasia.
●Bilateral adrenalectomy is now usually performed by laparoscopy and
causes permanent adrenal insufficiency, but not Nelson's syndrome. In
selected cases with macronodular adrenal hyperplasia and aberrant
hormone receptors, pharmacologic blockade on the aberrant receptor can
result in long-term normalization of cortisol secretion.
●Medical management of patients after bilateral adrenalectomy is reviewed
separately. (See "Persistent or recurrent Cushing's disease: Surgical
adrenalectomy", section on 'Postoperative management'.)
●Although medical treatment does not cure ACTH-independent micronodular
or macronodular adrenal hyperplasia, the adrenal enzyme inhibitors
(metyrapone or ketoconazole) can be given to reduce cortisol secretion in an
attempt to improve the patient's physical condition before surgery. As with
adrenocortical tumors, ACTH secretion will not increase and override the
pharmacologic blockade. (See "Medical therapy of hypercortisolism
(Cushing's syndrome)".)
COURSE AFTER EFFECTIVE THERAPYPhysical symptoms and signs of
Cushing's syndrome disappear gradually over a period of 2 to 12 months.
Overweight, hypertension, and glucose intolerance improve but may not
disappear.
The osteoporosis of Cushing's syndrome begins to improve about six months after
the hypercortisolemia is cured, improves rapidly during the ensuing two years, and
more gradually thereafter, but may not normalize [29-31]. For patients with
marked bone loss, oral bisphosphonate therapy is recommended; calcium
supplementation, vitamin D, and gonadal steroid replacement may also be useful
[32]. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Cushing's syndrome also impairs health-related quality of life (HRQL), which
partially, but not completely resolves after transsphenoidal surgery. This was
illustrated in a study of 23 patients with Cushing's disease who completed a SF
(short-form) 36 survey (which evaluates HRQL) before and after transsphenoidal
656
surgery, and in a group of 343 Cushing's patients who were in remission for up to
25 years after surgery (mostly pituitary, but some had adrenal or ectopic
Cushing’s) [33]. Active Cushing's disease was associated with low physical and
mental summary scores on the HRQL survey; after transsphenoidal surgery, all
HRQL parameters improved, but did not normalize in these patients.
Similar results were observed in a meta-analysis of 47 studies in 2643 patients
treated for Cushing’s syndrome [34]. The majority of patients had Cushing's
disease, but patients with ectopic ACTH secretion and adrenal Cushing's were also
included. When compared with a healthy control population (n = 2335), all quality-
of-life domains improved, but did not normalize. One domain of cognitive
functioning normalized after treatment (intelligence), while attention and
executive functioning did not. Similar results were seen in a subgroup analysis of
patients with Cushing's disease. Additional strategies are needed to improve
outcomes for patients with persistent impairment of quality of life and/or cognitive
functioning after treatment.
In adults, psychiatric symptoms improve, but underlying psychopathology may
persist, and one study found an increase in the frequency of suicidal ideation and
panic [35]. Cognitive deficits persist despite improvement, but not normalization,
of apparent brain volume [36,37]. One study of 11 children found a decline in
intelligence quotient (IQ) and cognitive performance at one year after curative
surgery, in the absence of psychopathology, despite reversal of cerebral atrophy
[38].
In children, bone density and growth rate both increase after treatment, although
neither returns to normal [39].
PROGNOSISUntreated Cushing's syndrome is often fatal, with most deaths
being due to cardiovascular, thromboembolic, or hypertensive complications or
bacterial or fungal infections. Years ago there was a 50 percent mortality five years
after the development of symptoms [40], but the prognosis is much better now.
No patient with Cushing's syndrome of any cause should die from persistent
hypercortisolism, since cortisol production can always be controlled by adrenal
enzyme inhibitors, mitotane, or adrenalectomy.
Cushing's disease is virtually always curable, although rarely patients may die of
perioperative or other complications [41].
Patients with ectopic corticotropin (ACTH) secretion or adrenocortical carcinoma
may have a poor prognosis associated with the underlying tumor. The prognosis is
dictated by the nature of the tumor and the severity of the hypercortisolism. Most
patients with overt metastases at the time of presentation die of the cancer within
one year, although patients with indolent tumors may survive for many years.
Patients with small-cell lung cancer, medullary thyroid cancer, and gastrinoma
657
have a particularly poor prognosis [13,14]. Regardless of the prognosis, no patient
should suffer from the effects of persistent hypercortisolism, because it can readily
be controlled.
Patients with severe Cushing's syndrome may die from opportunistic infections
before completion of diagnostic studies [42-44]. Increased coagulability is also
associated with deep vein thrombosis, pulmonary edema, and myocardial
infarction [23].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of Cushing's
syndrome".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, “The Basics” and “Beyond the Basics.” The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on “patient info”
and the keyword(s) of interest.)

●Basicstopics (see "Patient education: Cushing's syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Cushing's syndrome
(Beyond the Basics)" and "Patient education: Cushing's syndrome treatment
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONSThe goal of treatment of all
patients with Cushing's syndrome is to achieve normalization of hypothalamic-
pituitary-adrenal function and subsequent reversal of Cushingoid signs/symptoms
and comorbidities.
●Optimal treatment involves localization and complete removal of a
corticotropin (ACTH)-secreting pituitary or ectopic tumor or cortisol-secreting
adrenal tumor(s). (See 'General principles' above.)
●In patients with Cushing’s disease who were not cured by pituitary surgery,
medical therapy targeting the corticotroph tumor such

658
as cabergoline or pasireotide can result in normalization of 24-hour urinary
free cortisol in 20 to 40 percent of them, especially if they have only mild
hypercortisolism. (See 'Medical therapy' above.)
●Pituitary irradiation is another second-line treatment for persistent or
recurrent Cushing's disease. Adrenal enzyme inhibitors must be used to
control hypercortisolism until RT is effective. Conventional RT will correct the
hypercortisolism in up to 85 percent of adults when used after debulking
surgery. (See 'Pituitary irradiation' above.)
●Bilateral adrenalectomy is a definitive treatment for ACTH-secreting pituitary
or ectopic tumors. (See 'Adrenalectomy' above.)
●Metastatic or occult ectopic ACTH-secreting tumors may respond to
somatostatin analog treatment, adrenal enzyme inhibitors or mitotane.
(See 'Ectopic ACTH and CRH syndromes' above.)
●The physical symptoms and signs of Cushing's syndrome resolve gradually
over a period of two to 12 months after effective cure of Cushing syndrome.
Hypertension, osteoporosis and glucose intolerance improve but may not
disappear. (See 'Course after effective therapy' above.)
●Patients may have impaired quality of life for many years despite remission
of hypercortisolism. However the long-term prognosis of cured patients who
had benign disease is excellent. The prognosis of patients with malignancy is
variable and relates to the ability to control hypercortisolism and treat the
cancer. (See 'Prognosis' above and 'Ectopic ACTH and CRH
syndromes' above.)

659
Pathophysiology and clinical features of primary
aldosteronism
Author:
William F Young, Jr, MD, MSc
Section Editor:
Lynnette K Nieman, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Mar 19, 2021.
INTRODUCTIONNonsuppressible (primary) hypersecretion of aldosterone is an
underdiagnosed cause of hypertension. The classic presenting signs of primary
aldosteronism are hypertension and hypokalemia, but potassium levels are often
normal in modern-day series of aldosteronomas.
The pathophysiology and clinical features of primary aldosteronism will be
reviewed here. The treatment of this disorder and an approach to the diagnosis of
hypertension and hypokalemia are discussed separately. (See "Treatment of
primary aldosteronism" and "Diagnosis of primary aldosteronism".)
TYPES OF PRIMARY ALDOSTERONISMRenin-independent, incompletely
suppressible (primary) hypersecretion of aldosterone is an increasingly recognized
but still underdiagnosed cause of hypertension [1-3]; it is estimated to be
responsible for 5 to 13 percent of hypertension in humans [4,5]. Many subtypes of
primary aldosteronism have been described since Conn's original report of the
aldosterone-producing adenoma (APA) in 1954 [6-9].

The most frequent causes of primary aldosteronism include:

●Bilateralidiopathic hyperaldosteronism (or idiopathic hyperplasia [IHA], 60

to 70 percent)
●Unilateral APAs (30 to 40 percent)

Less common forms include:

●Unilateral hyperplasia or primary adrenal hyperplasia (caused by

micronodular or macronodular hyperplasia of the zona glomerulosa of one
adrenal gland). The clinical presentation and outcome of these patients is
similar to those with APAs [10,11]. (See "Treatment of primary
aldosteronism", section on 'Patients with unilateral adenoma or hyperplasia'.)
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 ●Familial hyperaldosteronism (FH) type I (glucocorticoid-remediable
aldosteronism [GRA]) due to a CYP11B1/CYP11B2 chimeric gene, type II (the
familial occurrence of APA or bilateral IHA or both) caused by
germline CLCN2 pathogenic variants), type III caused by
germline KCNJ5  pathogenic variants, type IV caused by
germline CACNA1H pathogenic variants, and primary aldosteronism with
seizures and neurologic abnormalities (PASNA) caused by
germline CACNA1D pathogenic variants. (See "Familial hyperaldosteronism".)
●Pure aldosterone-producing adrenocortical carcinomas and ectopic
aldosterone-secreting tumors (eg, neoplasms in the ovary or kidney).
(See "Clinical presentation and evaluation of adrenocortical tumors", section
on 'Adrenocortical carcinoma'.)
PATHOPHYSIOLOGY
Renal actions of aldosterone — The clinical features of primary aldosteronism
are, in part, determined by the renal actions of aldosterone. The primary effect of
aldosterone is to increase the number of open sodium channels in the luminal
membrane of the principal cells in the cortical collecting tubule, leading to
increased sodium reabsorption [12]. The ensuing loss of cationic sodium makes
the lumen electronegative, thereby creating an electrical gradient that favors the
secretion of cellular potassium into the lumen through potassium channels in the
luminal membrane (figure 1) [13].
Although aldosterone initially induces sodium and water retention, this is followed
within a few days by a spontaneous diuresis (called aldosterone escape) that
returns excretion to the level of intake and partially lowers the extracellular fluid
volume toward normal (figure 2) [14-16]. This response is induced by the volume
expansion as escape typically occurs in humans after a weight gain of
approximately 3 kg [14]. The mechanisms responsible for the escape phenomenon
are incompletely understood, but at least three factors may be important:
increased secretion of atrial natriuretic peptide (ANP) induced by the
hypervolemia [17], decreased abundance of the thiazide-sensitive sodium-chloride
co-transporter that mediates sodium reabsorption in the distal tubule [18],
and pressure natriuresis [16,19]. In contrast, there appears to be no change in
the abundance of the aldosterone-sensitive collecting tubule sodium channel [18].
Similar considerations apply to hypokalemia. The potassium-wasting effect of
excess aldosterone is counterbalanced by the potassium-retaining effect of
hypokalemia itself. As a result, the plasma potassium concentration stabilizes at a
lower level, but progressive hypokalemia does not occur unless some other factor
is added, such as increased aldosterone production or the use of diuretic therapy.
The mechanisms by which hypokalemia limits further potassium wasting are
661
discussed elsewhere. (See "Causes of hypokalemia in adults", section on 'Increased
urinary losses'.)
With both sodium and potassium handling, a new steady state is established in
which the extracellular fluid volume and plasma potassium concentration are
stable, although respectively increased and decreased because of the initial effects
of aldosterone. In the steady state, both urinary sodium and potassium excretion
are roughly equal to dietary intake, similar to that in normal subjects. Similar
principles apply to the administration of diuretics as a new steady state is achieved
within two to three weeks. (See "General principles of disorders of water balance
(hyponatremia and hypernatremia) and sodium balance (hypovolemia and
edema)", section on 'The steady state' and "Time course of loop and thiazide
diuretic-induced electrolyte complications".)
Mutations in aldosterone-producing adenomas — Somatic mutations appear to
be the cause of aldosterone hypersecretion in approximately 90 percent of
patients with aldosterone-producing adenomas (APAs) [20]. Some of these
mutations are associated with specific clinical features. Of note, identification of a
mutation in an APA does not currently affect management.
Ion channel mutations
KCNJ5 mutations — Somatic mutations in KCNJ5  appear to be present in
approximately 40 percent of patients with APAs [20-27]. Point mutations in and
near the selectivity filter of the potassium channel KCNJ5 produce increased
sodium conductance and cell depolarization, triggering calcium entry into
glomerulosa cells, the signal for aldosterone production and cell proliferation.
In a multicenter study of 351 aldosterone-producing lesions from patients with
primary aldosteronism and 130 other adrenocortical lesions, two somatic
mutations in KCNJ5 (G151R or L168R) were identified in 47 percent of APAs [21].
Somatic KCNJ5 mutations were absent in patients with primary aldosteronism due
to unilateral hyperplasia and in 130 non-aldosterone-secreting adrenal
lesions. KCNJ5 mutations were overrepresented in APAs from women compared
with men (63 versus 24 percent), and APAs with KCNJ5 mutations were larger than
those without (27.1 versus 17.1 mm) [21].
In a separate multicenter study, KCNJ5 sequencing was performed on somatic
(APA, n = 380) and peripheral (APA, n = 344; bilateral adrenal hyperplasia, n = 174)
DNA of patients with primary aldosteronism [22]. Somatic KCNJ5 mutations (G151R
or L168R) were found in 34 percent (129 of 380) of APAs. They were significantly
more prevalent in women (49 percent) than men (19 percent, p<0.001) and were
associated with higher preoperative aldosterone levels but not with therapeutic
outcome after surgery [22]. Germline KCNJ5 mutations were not found in patients
with bilateral adrenal hyperplasia [22].

662
Other — Other less common somatic mutations in ATP1A1, ATP2B3,
CACNA1D,  and CTNNB1 genes have also been identified. In APAs that did not
have KCNJ5 mutations, somatic mutations of ATP1A1 (encoding an Na+/K+ ATPase
alpha subunit) were found in 16 (5.2 percent) and of ATP2B3 (encoding a Ca2+
ATPase) in five (1.6 percent) [28]. Similar results were noted in a second study [29].
Mutation-positive cases showed male dominance, increased plasma aldosterone
concentrations, and lower potassium concentrations compared with mutation-
negative cases [28].
Additional somatic APA mutations have been identified in CACNA1D, encoding a
voltage-gated calcium channel [30]. In one study, CACNA1D mutations were
identified in 11 percent of aldosteronomas and were exclusive of KCNJ5 mutations
[31]; patients carrying these mutations had smaller tumors and were older than
those with KCNJ5 mutations. In two cases with early onset of primary
aldosteronism, de novo germline mutations of CACNA1D were identified and
associated with complex, severe neurologic and neuromuscular abnormalities
(cerebral palsy, seizures, athetosis, spastic quadriplegia). The distribution of
somatic mutations may vary by racial background. In a study of 75 patients with
APAs, 66 (88 percent) of whom were White, the most frequently mutated genes
were KCNJ5 (28 patients; 43 percent), CACNA1D (14; 21 percent), ATP1A1 (11; 17
percent), ATP2B3 (3; 4 percent), and CTNNB1 (2; 3 percent) [20]. In contrast, among
73 African American patients with APAs, somatic driver mutations were found in 65
(89 percent): CACNA1D (27 patients; 42 percent), KCNJ5 (22; 34 percent), ATP1A1 (5; 8
percent), and ATP2B3 mutations (3; 4 percent) [27].
Activating mutations of CTNNB1 (beta-catenin) — Activating mutations of exon
3 of the CTNNB1 gene (beta-catenin) in the Wnt signaling pathway have been
identified in benign adrenocortical tumors (typically in larger and nonsecreting
adenomas), in APAs, and in adrenocortical carcinomas. (See "Clinical presentation
and evaluation of adrenocortical tumors", section on 'Beta-catenin mutations
(CTNNB1)'.)
In primary aldosteronism, aldosterone secretion is relatively independent from the
suppressed renin-angiotensin system but can be regulated by several hormones
activating variable levels of eutopic or aberrant hormone receptors, including
those for luteinizing hormone (LH)/human chorionic gonadotropin (hCG) or
gonadotropin-releasing hormone (GnRH) [32-35]. The role of aberrant hormone
receptors in adrenal disease is reviewed separately. (See "Cushing's syndrome due
to primary bilateral macronodular adrenal hyperplasia", section on 'Aberrant
hormone receptors' and "Clinical presentation and evaluation of adrenocortical
tumors", section on 'Aberrant receptors'.)

663
Activating somatic CTNNB1 mutations have been identified in tumors of three
women with APAs, two of whom presented during pregnancy and one after
menopause [36]. All three had heterozygous activating mutations of CTNNB1 and
large overexpression of aberrant LH/hCG and GnRH receptors (100-fold higher
than in other APAs). This suggests that CTNNB1  mutations stimulate Wnt activation
and cause adrenocortical cells to de-differentiate toward their common adrenal-
gonadal precursor cell type. It is thought that the high levels of endogenous hCG
during pregnancy and of GnRH and LH after menopause led to the identification of
APAs in these patients.
Idiopathic hyperplasia — The underlying pathophysiology of increased secretion
of aldosterone by the zona glomerulosa in patients with bilateral idiopathic
hyperaldosteronism (or idiopathic hyperplasia [IHA], occasionally unilateral [37]) is
still incompletely understood. An aldosterone secretory factor has not been
identified. Although angiotensin II adrenal hypersensitivity in patients with IHA has
been recognized for many years [38], the hyperaldosteronism in patients with IHA
is not reversed with angiotensin II inhibitors. Thus, the driving factor for
aldosterone hypersecretion in IHA remains unexplained. Genetic studies may
provide clues to understanding the genetic susceptibility to bilateral idiopathic
adrenal hyperplasia [39].
CLINICAL FEATURESPrimary and nonsuppressible hypersecretion of
aldosterone is an increasingly recognized but still underdiagnosed cause of
hypertension. The classic presenting signs of primary aldosteronism are
hypertension and hypokalemia, but potassium levels are frequently normal in
modern-day series of primary aldosteronism. In general, when compared with
patients with idiopathic hyperplasia (IHA), patients with an aldosterone-producing
adenoma (APA) tend to have more severe hypertension and are more frequently
recognized to be hypokalemic. However, these clinical findings do not reliably
distinguish between APA and IHA.
Hyperaldosteronism exerts deleterious cardiovascular effects independent of the
plasma potassium concentration. The overall treatment goal in patients with
primary aldosteronism is to prevent the adverse outcomes associated with excess
aldosterone, including hypertension, hypokalemia, renal toxicity, and
cardiovascular damage. (See 'Renal effects' below and 'Cardiovascular risk' below.)
Hypertension — Hypertension is the major clinical finding in primary
aldosteronism [6-9]. The elevation in blood pressure is dependent upon the mild
volume expansion that occurs, being prevented in animals and effectively treated
in humans by dietary sodium restriction [40,41]. Persistent hypervolemia also
leads to an increase in systemic vascular resistance that helps to perpetuate the
hypertension [40].
664
In addition to promoting the development of hypertension, hypervolemia is
responsible for another characteristic finding in primary aldosteronism: marked
suppression of renin release, leading to a very low plasma renin activity and
plasma renin concentration [7-9]. The finding of suppressed renin measurements
is of diagnostic importance in distinguishing primary from secondary
hyperreninemic forms of hyperaldosteronism, as occur with renovascular
hypertension, coarctation of the aorta, renin-secreting neoplasms, or diuretic
therapy. (See "Diagnosis of primary aldosteronism".)
The blood pressure in primary aldosteronism is often substantially elevated. In one
series, as an example, the mean blood pressure was 184/112 and 161/105 mmHg
in patients with an adrenal adenoma and hyperplasia, respectively [42]. Despite
these high blood pressure levels, malignant hypertension is a rare occurrence [43].
Primary aldosteronism may be associated with resistant hypertension, which is
defined as failure to achieve goal blood pressure despite adherence to an
appropriate, three-drug regimen including a diuretic. In a review of 1616 patients
with resistant hypertension, 11 percent fulfilled criteria for primary aldosteronism;
hypokalemia was seen in only 45 percent [44]. (See "Definition, risk factors, and
evaluation of resistant hypertension", section on 'Primary aldosteronism'.)
Rarely, hypertension is absent in patients with primary aldosteronism [45,46]. In
this setting, the blood pressure may become very low with relief of the aldosterone
excess, suggesting that aldosterone excess produced the expected significant
increase in blood pressure over baseline.
Even serum aldosterone levels in the high-normal range may be associated with
increased blood pressure. This was illustrated in a report from the Framingham
Offspring study in which baseline serum aldosterone levels were obtained among
1688 initially nonhypertensive participants (mean blood pressures of 121/75 and
117/71 mmHg for men and women, respectively) [47]. At follow-up at four years,
an increase in blood pressure category or the development of hypertension had
occurred in 34 and 15 percent of individuals, respectively. Compared with the
lowest quartile of serum aldosterone (range of 2 to 7 ng/dL), the highest quartile
(range of 14 to 60 and 72 ng/dL) was associated with an increased risk of elevated
blood pressure (odds ratio [OR] 1.60, 95% CI 1.19-2.14) and hypertension (OR 1.61,
95% CI 1.05-2.46). Although these results are intriguing, interpretation of serum
aldosterone levels requires knowledge of the exact level of salt and potassium
intake and plasma renin values. These parameters were not available in enrolled
individuals.
Hypokalemia: An inconsistent finding — Although hypokalemia has historically
been considered to be one of the major clinical features of primary aldosteronism,
it is now estimated that only 9 to 37 percent of patients with primary

665
aldosteronism are hypokalemic [1,48]. This is likely related to earlier diagnosis as
more patients with hypertension are being screened with the plasma aldosterone
to plasma renin activity ratio as a case-detection test for primary aldosteronism
[8,9,44,48-50].
In a retrospective, international report combining data from five centers (Italy,
United States, Singapore, Chile, and Australia), less than 50 percent of patients
diagnosed with primary aldosteronism were hypokalemic at presentation [48]. In a
second series, hypokalemia was found in 50 percent of patients with APAs and 17
percent of patients with bilateral hyperplasia [51]. (See "Diagnosis of primary
aldosteronism".)
Hypokalemia is more often present in patients with primary aldosteronism who
are on an adequate sodium intake [8,9,42]. Two factors contribute to the urinary
potassium wasting in this setting: the hypersecretion of aldosterone, which directly
promotes potassium secretion in the cortical collecting tubule, and adequate
delivery of sodium and water to the distal secretory site [52]. As an example,
increasing sodium intake and therefore distal delivery will exacerbate the
hypokalemia in this setting since aldosterone secretion will not be appropriately
suppressed by the volume expansion [53].
The fall in the plasma potassium concentration in primary aldosteronism is
accompanied by metabolic alkalosis. This disorder is largely due to increased
urinary hydrogen excretion mediated both by hypokalemia and by the direct
stimulatory effect of aldosterone on distal acidification. (See "Pathogenesis of
metabolic alkalosis".)
For patients who do have hypokalemia, the plasma potassium tends to be
relatively stable, at least over the short term, since the potassium-wasting effect of
excess aldosterone is counterbalanced by the potassium-retaining effect of
hypokalemia itself. Progressive hypokalemia does not occur unless some other
factor is added, such as increased aldosterone production or the use of diuretic
therapy (see 'Renal actions of aldosterone' above). The mechanisms by which
hypokalemia limits further potassium wasting are discussed elsewhere.
(See "Causes of hypokalemia in adults", section on 'Increased urinary losses'.)
Cardiovascular risk — Patients with primary aldosteronism have a higher rate of
cardiovascular morbidity and mortality than age- and sex-matched patients with
primary hypertension and the same degree of blood pressure elevation [54-58].
The cardiovascular effects of hyperaldosteronism are independent of the plasma
potassium concentration.
Patients with primary aldosteronism have greater left ventricular (LV) mass
measurements and decreased LV function when compared with age-, sex-, and

666
blood pressure-matched patients with other types of hypertension [56,58]. Other
cardiovascular risks include stroke, myocardial infarction, and atrial fibrillation:
●A retrospective study compared 124 patients with primary aldosteronism
with 465 patients with apparent primary hypertension who were matched for
age, gender, and blood pressure (mean 175/107 mmHg) [57]. The patients
with primary aldosteronism had significantly higher rates of prior stroke (12.9
versus 3.4 percent in those with primary hypertension), nonfatal myocardial
infarction (4 versus 0.6 percent), and atrial fibrillation (7.3 versus 0.6 percent).
The rate of cardiovascular complications appeared to be similar in those with
an adrenal adenoma and adrenal hyperplasia, but a rigorous distinction
between these two subtypes was not pursued.
●Similar findings were noted in a prospective study that compared 54
patients with primary hyperaldosteronism, who were treated with either
surgical resection of an adrenal adenoma or the mineralocorticoid receptor
antagonist spironolactone, with a control group with primary hypertension,
matched for age, gender, body mass index (BMI), and duration of
hypertension [59]. Prior to treatment, the prevalence of cardiovascular events
was greater in patients with primary hyperaldosteronism than in patients
with primary hypertension (OR 4.6, 95% CI 2.4-9.0).
The excess cardiovascular risk was no longer present after appropriate
treatment of the mineralocorticoid excess. During a mean follow-up of 7.4
years after treatment, a similar proportion of patients in each group (18.5
and 17.6 percent, respectively) reached the primary outcome, which was a
composite cardiovascular endpoint of myocardial infarction, stroke,
revascularization procedure, or sustained arrhythmia.
●In a meta-analysis of 31 studies, including 3838 patients with primary
aldosteronism and 9284 patients with essential hypertension, patients with
APA and IHA had an increased risk of stroke (OR 2.58), coronary artery
disease (OR 1.77), atrial fibrillation (OR 3.52), and heart failure (OR 2.05) [60].
In addition, the diagnosis of primary aldosteronism increased the risk of
diabetes (OR 1.33), metabolic syndrome (OR 1.53), and left ventricular
hypertrophy (OR 2.29) [13].
Dietary salt may affect the impact of primary aldosteronism on cardiac damage. In
a case-control study of 21 patients with primary aldosteronism and 21 control
patients with primary hypertension, 24-hour urinary sodium excretion was an
independent predictor for LV wall thickness and mass in patients with primary
aldosteronism but not primary hypertension [61]. Although data are limited,
dietary salt restriction may help reduce cardiovascular risk in these patients.

667
Additional evidence for the adverse cardiovascular effects of excess aldosterone
comes from randomized, controlled trials that have demonstrated improved
survival with the mineralocorticoid receptor antagonists spironolactone (in
patients with advanced heart failure) and eplerenone (in patients with LV
dysfunction after a myocardial infarction) [62,63]. (See "Secondary pharmacologic
therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on
'Evidence on MRAs'.)
These observations are consistent with animal and human studies showing that
hyperaldosteronism exerts deleterious cardiovascular effects independent of the
plasma potassium concentration. These effects may be mediated at least in part by
mineralocorticoid receptors in the heart and blood vessels (including coronary
artery and aorta) [64-66]. Activation of the mineralocorticoid receptor may act in
part by impairing endothelial function, an effect that may be mediated by reduced
glucose 6-phosphate dehydrogenase activity [67]. These effects can be largely or
completely abolished by the administration of a mineralocorticoid receptor
antagonist or by reducing plasma aldosterone concentrations by adrenalectomy
[65,67].
Metabolic syndrome — Type 2 diabetes and metabolic syndrome are more
prevalent in patients with primary aldosteronism than in controls matched for sex,
age, BMI, and blood pressure [68]. This may explain, at least in part, the increased
cardiovascular disease morbidity and mortality in primary aldosteronism patients.
Renal effects — Aldosterone may raise the glomerular filtration rate (GFR) and
renal perfusion pressure independent of systemic hypertension. In addition,
increased urinary albumin excretion is common. These changes appear to be
largely reversible with treatment, as illustrated by the following findings:
●In a report of 25 patients with primary aldosteronism, the GFR and effective
renal plasma flow decreased six months after surgery for removal of adrenal
adenoma but did not change after blood pressure control in the comparison
group with primary hypertension (formerly called "essential" hypertension)
[69]. In addition, hyperaldosteronism was associated with tubular
dysfunction, as assessed with urinary beta-2 microglobulin excretion, which
improved six months after surgery. These changes cannot be explained by
reductions in blood pressure alone, since the patients with adrenal adenoma
and primary hypertension had similar blood pressure at baseline and blood
pressure control at six months.
●Similar findings were seen in a second series of 50 patients with primary
aldosteronism treated with adrenalectomy or spironolactone and 100
patients with primary hypertension started on antihypertensive therapy [70].
At baseline, the GFR and albumin excretion were higher in the patients with

668
 primary aldosteronism. In the first six months of follow-up, the reductions in
GFR and albuminuria were significantly greater in the patients with primary
aldosteronism, who also were more likely to have restoration of normal
albumin excretion. Blood pressure control was similar in the two groups.
●In a third report of 408 patients with primary aldosteronism and a control
group of 408 patients with primary hypertension, more patients in the
primary aldosteronism group had a serum creatinine concentration above
1.25 mg/dL than controls (29 versus 10 percent in the primary aldosteronism
and control groups, respectively) [71]. Age, male sex, low potassium, and
high serum aldosterone concentrations were independent predictors of a
lower GFR. In the primary aldosteronism group, adrenalectomy increased the
serum creatinine and decreased the mean GFR from 71 to 64 mL/min.
Treatment with spironolactone resulted in a similar decline in GFR. Thus,
surgical cure or mineralocorticoid receptor blockage reverses the
hyperfiltration state and unmasks the underlying renal insufficiency.
Quality of life — Several studies have demonstrated the negative impact of
primary aldosteronism on quality of life [72-74]. In a systematic review of 15
studies, untreated patients with primary aldosteronism (APA and IHA) showed an
impaired physical and mental quality of life compared with the general population
[73]. Symptoms of anxiety, demoralization, stress, depression, and nervousness
were more frequently reported in untreated patients with primary aldosteronism
than in the general population and in patients with hypertension [73]. Surgical
management often normalizes quality of life measures. Medical therapy improves
quality of life, but not to the same extent as surgery [74].
Other
Mild hypernatremia — The persistent mild volume expansion resets the osmostat
regulating antidiuretic hormone release and thirst upward by several mEq/L [75].
As a result, patients with primary aldosteronism usually have a stable plasma
sodium concentration between 143 and 147 mEq/L.
Hypomagnesemia — Mild hypomagnesemia due to urinary magnesium wasting
also may occur in patients with persistent mineralocorticoid excess. How this
occurs is incompletely understood. The ascending limb of the loop of Henle, as an
example, is the primary site of tubular magnesium reabsorption [76]; inhibition of
sodium transport in this segment during aldosterone escape [15] may be
associated with a parallel decline in magnesium reabsorption. (See "Regulation of
magnesium balance".)
Muscle weakness — Muscle weakness can occur in patients with primary
aldosteronism. It is primarily due to hypokalemia and is not typically prominent
unless the plasma potassium concentration is below 2.5 mEq/L. (See "Clinical

669
manifestations and treatment of hypokalemia in adults", section on 'Severe muscle
weakness or rhabdomyolysis'.)
Genotype-phenotype correlation — As noted above, somatic mutations are the
cause of aldosterone hypersecretion in approximately 90 percent of patients with
APAs. Some mutations have been associated with specific clinical features, but
their identification does not currently affect management. Genotype-phenotype
correlations include the following (see 'Mutations in aldosterone-producing
adenomas' above):
●APAs with KCNJ5 mutations are more common in women than men and
appear to be larger than APAs without mutations [21,22].
●APAs with ATP1A1 or  ATP2B3 mutations appear to be more common in men
and associated with higher plasma aldosterone concentrations and lower
potassium concentrations compared with mutation-negative cases [28].
●Patients with CACNA1D mutations appear to have smaller tumors and are
older than patients with KCNJ5 mutations [31].
SUMMARY
●Nonsuppressible (primary) hypersecretion of aldosterone is an
underdiagnosed cause of hypertension. The classic presenting signs of
primary aldosteronism are hypertension and hypokalemia. The most
common subtypes are aldosterone-producing adenoma (APA) and bilateral
idiopathic hyperaldosteronism. (See 'Types of primary aldosteronism' above.)
●Somatic mutations appear to be the cause of aldosterone hypersecretion in
approximately 90 percent of patients with APAs. (See 'Mutations in
aldosterone-producing adenomas' above.)
●Primary aldosteronism may be associated with resistant hypertension, which
is defined as failure to achieve goal blood pressure despite adherence to an
appropriate, three-drug regimen including a diuretic.
(See 'Hypertension' above.)
●Although hypokalemia is considered to be a "classic" sign of primary
aldosteronism, many patients with primary aldosteronism due to an adrenal
adenoma and, more commonly, those with adrenal hyperplasia, are not
hypokalemic. With increasing measurement of plasma aldosterone and
plasma renin activity to screen hypertensive patients for primary
aldosteronism, more nonhypokalemic patients are being identified.
(See 'Hypokalemia: An inconsistent finding' above.)
●Aldosterone may raise the glomerular filtration rate (GFR) and renal
perfusion pressure independent of systemic hypertension. In addition,
increased urinary albumin excretion is common. These changes appear to be
largely reversible with treatment. (See 'Renal effects' above.)
670
●Patientswith primary aldosteronism, when matched for age, blood
pressure, and the duration of hypertension, have a greater risk of
cardiovascular disease when compared with patients with other types of
hypertension, including primary hypertension (formerly called "essential"
hypertension), pheochromocytoma, and Cushing's syndrome. The excess
cardiovascular risk resolves after appropriate treatment of the
mineralocorticoid excess. (See 'Cardiovascular risk' above.)

671
Primary therapy of Cushing's disease:
Transsphenoidal surgery and pituitary irradiation
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 06, 2019.
INTRODUCTIONCushing's disease is caused by pituitary corticotropin (ACTH)-
secreting tumors. These tumors are almost always benign and are usually
microadenomas (ie, <10 mm in diameter). In 30 to 40 percent, the microadenoma
is so small that it is not detectable by magnetic resonance imaging (MRI), while in
10 to 15 percent a macroadenoma is present. Treatment is aimed first at the
anterior pituitary gland.
The progressive stages of treatment that may be required to cure a patient of
Cushing's disease are shown in the figure (algorithm 1). Primary therapy consists
of transsphenoidal surgery or pituitary irradiation. Patients who fail this first
approach can be treated either by repeat transsphenoidal surgery, medical
therapy, radiotherapy, or, as a final resort, surgical or medical adrenalectomy. An
overview of transsphenoidal surgery and pituitary irradiation for the primary
therapy of Cushing's disease will be reviewed here. An overview of the
management of Cushing's syndrome, as well as medical therapy and surgical
adrenalectomy for Cushing's are reviewed separately. (See "Overview of the
treatment of Cushing's syndrome" and "Medical therapy of hypercortisolism
(Cushing's syndrome)" and "Persistent or recurrent Cushing's disease: Surgical
adrenalectomy".)
TRANSSPHENOIDAL SURGERYTranssphenoidal microadenomectomy is
currently the treatment of choice for Cushing's disease. When successful, the
patient is cured and is eventually left with normal hypothalamic-pituitary-adrenal
function [1]. Surgical techniques and results of transsphenoidal surgery for
pituitary adenomas are also reviewed in a separate topic. (See "Transsphenoidal
surgery for pituitary adenomas and other sellar masses", section on 'Corticotroph
adenomas'.)

672
Magnetic resonance imaging (MRI) is performed preoperatively to try to locate the
pituitary tumor. However, surgery should be performed even if a tumor is not
visualized.

Approach — The operative approach varies. Traditionally, the procedure involved

transsphenoidal exploration through either a sublabial or endonasal approach,
followed by use of a high-powered microscope that allowed for binocular vision.
More recently, use of an endoscope, which does not provide binocular vision, has
been advocated but has not been definitively shown to be superior [2].
(See "Transsphenoidal surgery for pituitary adenomas and other sellar masses",
section on 'Comparison of microscopic versus endoscopic techniques'.)
Extent of surgery — The extent of surgery varies. Ideally, the entire tumor is
removed while normal pituitary tissue is left behind. However, in adult patients in
whom a microadenoma cannot be identified at the time of surgery and for whom
fertility is not an issue, 80 to 90 percent of the pituitary should be resected, leaving
a small island attached to the stalk. (See "Transsphenoidal surgery for pituitary
adenomas and other sellar masses", section on 'Determination of the extent of
resection'.)
Preoperative localization — In general, tumors are localized by the preoperative
MRI scan or by intraoperative exploration and observation by the surgeon.
MRI — The decision to operate should not depend upon radiographic
demonstration of the tumor. High-resolution, contrast-enhanced, thin-section
computed tomography (CT) scans detect only approximately one-third of the
microadenomas, which appear hypodense after contrast injection (image 1) [3-5].
Because CT scans define bony structures better, the neurosurgeon may, on
occasion, request them.
Coronal projections of high-resolution MRI at 1.5 T with gadolinium enhancement
reveal microadenomas in approximately 60 percent of patients and have replaced
CT for localization (image 2 and image 3) [5,6]. In one report, a modified technique
known as "spoiled gradient recalled acquisition technique" had superior sensitivity
compared with conventional, post-contrast, spin-echo technique (80 versus 49
percent, respectively) but a higher false positive rate (4 versus 2 percent) [7]. False-
positive MRI scans can be obtained in 10 percent of subjects with no endocrine
disorders [8], who may or may not have "nonfunctioning" microadenomas [9].
False negative scans can occur in patients with an empty sella [10]. Some
microadenomas that cannot be visualized with preoperative MRI can be identified
using intraoperative ultrasonography [11].

673
The preoperative radiographic demonstration of tumor improved the likelihood of
cure in some but not all centers; other possible confounding factors such as
technical experience might account for the differences:

●In one retrospective analysis of 54 patients with Cushing's disease (26 with
pituitary microadenoma on preoperative MRI and 28 with a normal MRI but
confirmed pituitary origin of corticotropin [ACTH] secretion on bilateral
petrosal sinus sampling), clinical outcome of transsphenoidal surgery was
similar regardless of the preoperative MRI findings [12]. Early surgical
success rates were 78 and 88 percent in the normal and abnormal MRI
groups, respectively: a difference that was not statistically significant.
●In a second study of 167 patients with clear-cut microadenoma on MRI, 148
of 167 (88 percent) achieved remission, suggesting that imaging localization
may improve outcome [13].
●In a third study, 183 of 185 (99 percent) with microadenomas on MRI had
initial remission [14].
Inferior petrosal sinus sampling — Measurement of ACTH gradients between
the two sinuses during inferior petrosal venous sinus catheterization predicts the
correct side of the pituitary tumor in 69 to 80 percent of patients with lateral
tumors [15-17]. In the absence of a lesion on MRI, the gradient may be used to
choose the side for initial exploration, but if no tumor is found, the other side must
be explored. The role of inferior petrosal sinus sampling for localization is
reviewed in detail separately. (See "Establishing the cause of Cushing's syndrome",
section on 'Petrosal venous sinus catheterization'.)
Perioperative glucocorticoids
●Before surgery – Preoperative glucocorticoid replacement is not necessary
unless cortisol production has been blocked completely by adrenal enzyme
inhibitors. In this instance, the patient should be treated like a patient with
adrenal insufficiency. (See "Treatment of adrenal insufficiency in adults".)
Practice patterns are variable. Some surgeons do not administer
glucocorticoids [18], while others give higher than normal glucocorticoid
replacement intraoperatively and for one to three days postoperatively to
avoid symptoms and signs of acute steroid withdrawal [19]. There have been
no comparisons of the benefits of one or the other approach. One typical
regimen is dexamethasone 0.5 mg every six hours for four doses only, eg,
only 24 hours of glucocorticoid therapy.
Perioperative glucocorticoid therapy entails virtually no risk for the patient.
●After surgery – Glucocorticoids must be stopped for 24 hours before serum
cortisol can be measured to assess cure. Glucocorticoid replacement can be

674
 held for a few days, with careful observation for the development of adrenal
insufficiency.
Patients who meet the criterial for successful surgery are hypocortisolemic
for up to 12 months after microadenomectomy and require glucocorticoid
replacement therapy, which must be supplemented during stress.
(See "Treatment of adrenal insufficiency in adults".)
Occasional patients become anorectic and have generalized malaise and
postural hypotension three or four days after surgery. These problems often
respond to higher doses of glucocorticoid for several days.
Other rare patients with longstanding, severe Cushing's disease have such
severe symptoms of glucocorticoid withdrawal that replacement doses of
glucocorticoid are inadequate, and they temporarily require higher doses, up
to twofold higher. Both clinician and patient must recognize that
administration of such doses constitutes iatrogenic hypercortisolism. Every
effort should be made to taper to a replacement dose, ideally within a few
weeks.
Surgical complications
Diabetes insipidus — Transient, central diabetes insipidus is common and was
reported at a rate of 22 percent in a single institution with a high volume of
pituitary surgery [20]. In contrast, permanent diabetes insipidus occurs in only a
few percent of patients, even among those who have subtotal resection of the
gland, although more extensive resection may increase the incidence of
permanent diabetes insipidus to as much as 25 percent. (See "Evaluation of
patients with polyuria" and "Treatment of central diabetes insipidus".)
Permanent diabetes insipidus is typically accompanied by impaired secretion of
other anterior pituitary hormones, particularly thyroid-stimulating hormone (TSH)
[21]. In a survey answered by 958 neurosurgeons, anterior pituitary insufficiency
was cited as a complication of transsphenoidal hypophysectomy in 19 percent of
cases [22].
Hyponatremia occurs in 8 to 24 percent of patients, presenting from postoperative
day 1 to 10, with maximal antidiuresis at day 7 [19,23]. In one study of 52 patients
without postoperative diabetes insipidus, 7 percent had symptomatic
hyponatremia (plasma sodium <125 mmol/L) with nausea, headache, and/or
emesis [19].
Other — Other complications, apart from surgically related morbidity, include
venous thrombosis and infection, which occurred in four and one patients,
respectively, of 105 studied retrospectively [24]. Since the risk of thromboembolic
complications is increased in Cushing's syndrome, perioperative prophylaxis
seems warranted in patients who are not ambulatory within a few days of surgery

675
[25]. (See "Epidemiology and clinical manifestations of Cushing's syndrome",
section on 'Thromboembolic events'.)
Cure rates — A neurosurgeon experienced with transsphenoidal surgery for
Cushing's patients can achieve an initial cure rate of 80 to 90 percent with
microadenomas [26-33], but less than 60 percent with macroadenomas [32,34],
although initial cure of 11 of 12 patients (92 percent) was reported from one center
[35]. A meta-analysis of 18 reports since 1995 showed an overall initial cure rate for
micro- and macroadenomas combined of 79 percent [36]. It is important to
recognize that patients who are initially "cured" should be considered to be in
remission rather than cured, as some will recur. (See "Transsphenoidal surgery for
pituitary adenomas and other sellar masses", section on 'Corticotroph adenomas'.)
●It is likely that the approach to tumor resection influences the cure rate. In
one study of 483 patients, 261 (54 percent) were considered intraoperatively
to have an encapsulated adenoma confined to the anterior lobe of the
pituitary gland; 166 (34 percent) had tumors invading the dura surrounding
the pituitary; 11 (2 percent) had tumors within the posterior lobe; and in 45 (9
percent), no tumor could be identified at surgery. Remission occurred in 147
(89 percent) of the 166 patients with invasive tumors following resection that
included the tumor and dural wall, all 11 patients with posterior lobe tumors
following exploration of the posterior pituitary, and 34 (76 percent) of the 45
patients in whom no tumor could be found at surgery and a portion of the
anterior lobe (30 to 100 percent) was removed. All 261 patients with an
encapsulated adenoma had remission, following use of the histological
tumor pseudocapsule so that the tumor is removed in a single specimen [14].
Increased use of the pseudocapsule approach may improve cure rates at
other centers.
●Less experienced neurosurgeons may have a cure rate as low as zero [37].
The cure rates with microadenomas depend upon pathologic confirmation of
an adenoma or unequivocal demonstration of cure after resection, since
approximately one-half of these tumors cannot be imaged in advance of
surgery [38]. (See "Transsphenoidal surgery for pituitary adenomas and other
sellar masses", section on 'Experience of the surgeon'.)

Other than inexperience, the reasons for failure include the following:

●Allof the contents of the sella cannot be seen at surgery, so that some
adenoma tissue may be missed. Diligent exploration of the entire gland is
optimal if tumor is not recognized initially.
●Diffuse corticotroph hyperplasia may be present. However, this is extremely
rare.
676
 ●The adenoma may arise in the pituitary stalk, which is not readily accessible
to the surgeon. This occurred in 10 of 516 patients in one series, although all
were successfully removed, with preservation of pituitary function in nine
[39].
●Adenomas that arise on the surface of the gland tend to be locally invasive;
tumor cells in the interstices of the dura mater or in the cavernous sinus
cannot be surgically excised [40].
●Rarely, adenomas arising in ectopic sites may be the cause [41,42]. In one
series of 626 patients with Cushing's disease, five patients (0.8 percent) had
parasellar tumors; a sixth patient appeared to have two distinct ACTH-
secreting corticotroph adenomas, one in the periphery of the pituitary gland
and the other in the cavernous sinus [43].
●ACTH-secreting adenomas may rarely be located within the posterior lobe of
the pituitary gland [44].
Adults — There is no consensus on the criteria for "cure" after transsphenoidal
surgery for Cushing's disease. When judged in the immediate postoperative
period, patients with persistent elevations in urine cortisol are not in remission.
However, the remaining patients show a spectrum of biochemical features ranging
from hypoadrenalism, with undetectable serum cortisol and plasma ACTH
concentrations, to apparently normal ACTH and cortisol levels.
When judged by long-term outcome, patients with a postoperative serum cortisol
less than 50 nmol/L (1.8 mcg/dL) have the highest long-term remission rates, 85 to
100 percent [45-47]. As noted, initial cure rates of up to 80 to 90 percent after
transsphenoidal microadenectomy, based on postoperative serum cortisol
concentrations <5 mcg/dL (138 nmol/L) within 14 days of surgery, have been
reported [26,28,37,48,49]. In two studies, long-term remission rates were 65 and
80 percent in patients judged by this less stringent postoperative criterion [49,50].
Factors affecting postoperative cortisol — A variety of factors influence the
immediate postoperative cortisol value:
●The normal corticotropes of patients with mild or intermittent
hypercortisolism may not be suppressed sufficiently to cause hypocortisolism
after complete tumor resection. Normal cortisol dynamics in these patients
reflect normal function and not residual tumor. This can be inferred by
documentation of a normal diurnal cortisol pattern as opposed to relatively
invariant pattern in patients with persistent Cushing's disease.
●Plasma ACTH concentration and, therefore, the serum cortisol
concentration, depends upon the number of adenomatous corticotrophs
remaining immediately after surgery. The number may be too low to
stimulate detectable cortisol secretion, either basally or in response to

677
 stimulation, but may be sufficient to survive, slowly multiply, and eventually
reconstitute a large enough adenoma to cause recurrent Cushing's
syndrome. In addition, rare patients have diffuse or multicentric disease [12].
●Postoperative glucocorticoid administration has been postulated to inhibit
ACTH secretion from remaining tumor cells and thus possibly lead to a falsely
reassuring suppressed cortisol [46].
Late remission — Some patients appear to have a late remission, and early
postoperative assessment of serum cortisol concentration is not sufficient to
predict outcome, as illustrated by the following observations:
●Some patients show a gradual decline in cortisol during the first three
months after surgery, possibly indicating progressive necrosis of remaining
tumor cells. This was illustrated in a study of 17 patients whose serum
cortisol remained higher than 50 nmol/L (1.8 mcg/dL) within the first 14 days
after surgery. However, serum cortisols had decreased to <50 nmol/L (1.8
mcg/dL) by three months after surgery, and all remained in remission during
one to eight years of follow-up [51].
●In a second study, 5.6 percent of 620 patients had late remission occurring
at 38±50 days, suggesting that decisions about additional therapy should
await additional testing in patients with persistent hypercortisolism after
transsphenoidal surgery [52].
Children — Similar surgical cure rates have been observed in children [31,53,54].
●In one series of 42 children, remission occurred in 35 (83 percent), 26 of
whom were carefully followed for a mean of 7.2 years. Seven subsequently
relapsed after an average of 4.2 years [54]. Overall, pituitary surgery
performed once or twice resulted in a long-term remission in approximately
80 percent of children.
●In another series of 72 children, 70 achieved initial and 66 of 72 (92 percent)
achieved long-term remission during follow-up of 24 to 120 months [55].
Macroadenomas — In general, patients with macroadenomas have lower cure
rates.
●As an example, of 137 patients with microadenomas operated on at a single
center, 123 (90 percent) were cured initially. Of those, seven (6 percent) had a
recurrence during a mean follow-up period of six years (range 1 to 11 years)
[32]. Seventeen patients had macroadenomas, of whom 11 (65 percent) were
cured initially; 3 of the 11 (27 percent) later had a recurrence.
●In another study, initial remission was reported in five of eight patients with
macroadenomas extending beyond the sella (63 percent) and in 43 of 52 with
intrasellar macroadenomas (83 percent) [56]. Both of these studies defined
surgical cure as a postoperative serum cortisol <5 mcg/dL (138 nmol/L).

678
 ●In contrast, the cure rate (after surgery alone) in a series of 18
macroadenomas was only 12.5 percent when the more stringent criterion
described above was used (serum cortisol <1.8 mcg/dL [50 nmol/L]) [57].
Biochemical criteria — A variety of criteria have been used to assess cure after
transsphenoidal surgery [58]. The recommendations below apply only to those
patients with active hypercortisolism at the time of surgery. The normal
corticotropes in eucortisolemic patients on medical therapy (or those with
symptom remission on glucocorticoid receptor blockers) or with mild or cyclic
hypercortisolism may have recovered from previous inhibition, leading to normal
cortisol levels after total tumor resection. In these patients, tests for the initial
diagnosis of Cushing's syndrome must be used to infer remission.
(See "Establishing the diagnosis of Cushing's syndrome".)

We currently suggest the following approach to assessing patient outcome in

patients with active hypercortisolism:

Serum cortisol should be measured at 8 AM at least 24 hours after the last

physiologic dose of glucocorticoid, beginning three to seven days after surgery, to
assess cure [59]. Ideally, measurements are obtained for three consecutive days
without glucocorticoid therapy.

The best criteria of cure are:

●An undetectable serum cortisol concentration

●An undetectable plasma ACTH concentration
Although an extremely low serum cortisol concentration (<1.8 mcg/dL, 50 nmol/L)
is the best predictor of cure, some patients with low but detectable serum cortisol
concentrations (2 to 4 mcg/dL [55 to 110 nmol/L]) that suppress with low-
dose dexamethasone may remain in remission [59], as may those with cortisol
values <5 mcg/dL (138 nmol/L) [49,50].
However, a persistently detectable serum cortisol concentration, even though it
represents a major decrease from the preoperative concentration and is well
within the normal range, may represent incomplete resection and an increased
risk of recurrence. In these patients, measurement of cortisol every one to two
weeks for up to three months may reveal a decline to less than 50 nmol/L (1.8
mcg/dL) [51]. Patients without a fully suppressed postoperative cortisol
concentration may require some glucocorticoid replacement; ideally, this is 10 mg
or less of hydrocortisone daily in the morning to avoid suppression of
corticotropes. The blood sample is obtained before the morning hydrocortisone

679
dose is taken. If the serum cortisol concentration becomes undetectable, the
patient is considered cured.
Measurement of 24-hour urinary cortisol excretion may be useful since it confirms
the serum cortisol concentration. The urine collection should begin at least 24
hours after the last small dose (10 mg or less) of hydrocortisone; a small
maintenance dose (0.25 to 0.5 mg) of dexamethasone may be substituted before
and during the collection. Excretion of less than <10 mcg/day (28 nmol/day) is
consistent with cure.
Management of patients with intermediate postoperative values of serum or
plasma cortisol should be individualized. If there is a reason to suspect that tumor
tissue was left behind and that the normal values reflect tumor ACTH secretion,
measurement of salivary cortisol at midnight can be helpful as it is likely to be
abnormal with persistent disease. Lack of cortisol suppression to the overnight 1
mg dexamethasone suppression test may help confirm the suspicion of persistent
disease. In these cases, additional therapy may be recommended. Patients with
normal cortisol dynamics, in whom the normal corticotropes may not be
suppressed, may be followed.
ACTH, CRH, or metyrapone stimulation tests are not helpful in these patients,
because it is not clear how to interpret the results in this setting. A persistent
response of cortisol and ACTH to the administration of
intravenous desmopressin (10 mcg) may suggest a higher risk of recurrence [60-
62]. (See "Desmopressin (DDAVP) stimulation test", section on 'Evaluating for
remission of Cushing's disease'.)
Recurrence — The true long-term cure rate is not known with certainty, in part
because of differing criteria for cure and also because of inadequate follow-up
[46,47,49-51,53,63-66].
The average reported interval to recurrence is approximately 40 months. However,
this figure is in part an artifact of the relatively short duration of follow-up of many
patients. One study prospectively analyzed the recurrence rate in 79 cured patients
by survival analysis; 19 percent had recurrences by five years, and the cumulative
recurrence rate was 26 percent at 10 years [66]. Others have reported a similar
recurrence rate of 22 percent in 45 patients at a mean follow-up of nine years [67].
There is a similar time-to-recurrence in children; the average interval in seven
children was 4.2 years (nine months to 6.2 years) [54].
The likelihood of recurrence can be predicted only in part by postoperative serum
cortisol measurements. As an example, a recurrence rate as high as 12 percent
was reported in patients with undetectable postoperative cortisol levels [47].
Complete normalization of adrenocortical function may be a better predictor of
outcome. As an example, in one study of patients after transsphenoidal surgery,

680
those who had low postsurgery serum cortisol concentrations and subsequent
recovery of normal circadian rhythm and responsiveness to insulin-induced
hypoglycemia had much lower recurrence rates (3.4 percent) than those who did
not recover normal hypothalamic-pituitary-adrenal function (50 to 65 percent) [45].
Other hormone tests also provide prognostic information. In one report, for
example, the recurrence rate increased from 11 percent in patients who had
postoperative urinary cortisol values of 20 mcg/day (56 nmol/day) or less to 36
percent when the value was above 35 mcg/day (96 nmol/day; normal range 20 to
48 mcg/day [55 to 331 nmol/day]). Similarly, the recurrence rate increased from 8
percent in patients with a plasma ACTH concentration of 20 pg/mL (4.4 pmol/L) or
less to 53 percent in those with a plasma ACTH concentration of 35 pg/mL (7.7
pmol/L) or more (normal range up 100 pg/mL [22 pmol/L]) [66].
Long-term monitoring — All patients should be reevaluated annually for several
years and less frequently thereafter. This is particularly true in those who had
initial intermittent hypersecretion of cortisol; these patients may seem to be cured
after surgery but continue to secrete excess cortisol intermittently [68].
Reevaluation should include measurements of late-night salivary cortisol, a 24-
hour urinary cortisol, and/or the 1 mg dexamethasone suppression test [64], using
the same criteria as for diagnosis (see "Establishing the diagnosis of Cushing's
syndrome"). Patients should be encouraged to consider reevaluation at any time if
they experience a return of their initial symptoms.
Treatment if surgery fails — For patients with clear, persistent disease after
surgery (elevated urine cortisol excretion), one must first review the pathology
results. If a tumor is not present on pathology, it is prudent to review the results of
the tests for the differential diagnosis. In one study, 5 of 52 patients who failed
surgery were found to have ectopic ACTH secretion [30]. In patients with equivocal
results, additional testing may be needed.

Five therapeutic options remain in patients who are not cured in whom the
diagnosis of Cushing's disease appears to be correct:

●Repeat resection of residual corticotroph adenoma, particularly if residual

tumor is visible on MRI. Reoperation has a lower success rate than initial
surgery. In three studies, 57 to 71 percent of patients who underwent early
reoperation had evidence of biochemical cure [48,69,70]. However, many of
them developed other pituitary hormone deficiencies as a result of the
second procedure. In one study, immediate reoperation was most successful
when the pathology indicated incomplete resection.
●Irradiation of the pituitary gland. (See 'Pituitary irradiation' below.)

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 ●Medical therapy. (See "Medical therapy of hypercortisolism (Cushing's
syndrome)".)
●Adrenalectomy – Medical or surgical.
•Medical adrenalectomy with mitotane, for example, may be used in
conjunction with pituitary irradiation (algorithm 1). (See "Medical therapy
of hypercortisolism (Cushing's syndrome)", section on 'Mitotane'.)
•Surgical adrenalectomy. (See "Persistent or recurrent Cushing's disease:
Surgical adrenalectomy", section on 'Surgical adrenalectomy'.)
The choice for therapy is individualized. For example, a young woman desiring
fertility might choose to have adrenalectomy or repeat transsphenoidal
exploration to avoid hypogonadism associated with radiotherapy and the
teratogenicity of mitotane. A patient with extreme hypercortisolism might choose
adrenalectomy to achieve rapid control.
PITUITARY IRRADIATIONPituitary irradiation is the rational choice when
pituitary surgery is either not the initial therapy or has failed. In addition, it may be
considered as the initial therapy in children because it is as successful as
transsphenoidal surgery [54,71,72]. (See "Radiation therapy of pituitary
adenomas", section on 'Corticotroph adenomas (Cushing's disease)'.)
Patients with hypercortisolism should receive adrenal enzyme inhibitors (such
as mitotane, metyrapone, or ketoconazole) to achieve eucortisolism until the
radiation therapy is successful [1]. The ability of these agents to achieve
eucortisolism should be evaluated prior to radiation therapy. If they are not
effective, a different treatment should be considered. (See "Medical therapy of
hypercortisolism (Cushing's syndrome)".)

Radiation treatment is considered for corticotroph adenomas causing Cushing's

disease when surgery has been unsuccessful. The principal goal is to lower
corticotropin (ACTH) secretion and thereby lower cortisol secretion to normal.

●Type of radiation – Stereotactic radiosurgery (20 Gy) is considered the first

choice if the adenoma is not close to the optic pathway; fractionated
radiation (42 to 45 Gy) is used for those that are [73-78]. Stereotactic
radiosurgery may be targeted when a pathologically confirmed lesion was
partially resected; when the location of the tumor is not known, the entire
sella must be radiated.
●Efficacy – Reduction of cortisol to normal occurs in 50 to 80 percent of
subjects. Addition of pharmacologic therapy increases the remission rates to
85 to 100 percent. Normalization of cortisol may occur somewhat faster after
stereotactic radiosurgery than fractionated therapy, a median of 7.5 to 33
months versus 18 to 42 months [79]. Efficacy appears similar among all forms
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 of stereotactic radiosurgery: Gamma Knife [73], linear accelerator [77], and
proton [78].
A second goal of radiation therapy is control of adenoma growth, especially in
corticotroph macroadenomas. All modalities of radiation therapy control adenoma
growth in 90 to 100 percent of patients [73,75-77], similar to nonfunctioning
adenomas.
Corticotroph adenomas associated with Nelson syndrome may be less responsive
to radiation than other corticotroph adenomas, but the data are limited [76].

To judge the effectiveness of radiation therapy, steroidogenesis inhibitor(s) can be

stopped for a few days and 24-hour urine cortisol measured. Patients should
receive teaching about adrenal insufficiency symptoms and should be instructed
to return to the clinician if they experience such symptoms.

Fractionated radiation — A total of 42 to 45 Gy (4200 to 4500 rad) of conventional

megavoltage radiation is delivered to the pituitary gland at a rate of 1.8 to 2
Gy/day (180 to 200 rad/day), usually via multiple collimated ports using a linear
accelerator.
Primary therapy — The results of fractionated pituitary radiation as primary
treatment can be summarized as follows:
●Approximately 80 percent of children are cured [71].
●The cure rate in adults is 15 to 53 percent [1,80].
●Another 25 to 30 percent of adults are sufficiently improved that they
require no additional therapy or only small doses of an adrenal enzyme
inhibitor [1].
In contrast to the almost immediate reduction in ACTH and cortisol secretion after
successful pituitary surgery, the maximal benefits of pituitary radiation do not
occur for at least 9 to 12 months and occasionally as long as 18 to 24 months.
Occasional "improved" patients may be cured several years after treatment.
Children usually respond more rapidly, often within three months [71].
Secondary therapy — The percent of patients responding to fractionated
radiation therapy may be somewhat higher after failed transsphenoidal surgery
[74,81].
●As an example, one study evaluated the efficacy of somewhat higher doses
of radiation (48 to 54 Gy, mean 50 Gy) in 30 adults with persistent or
recurrent Cushing's disease after unsuccessful transsphenoidal surgery [74].
The remission rate increased progressively with time from 20 percent at six
months to 43 percent at 12 months to 83 percent at 60 months. None of the
25 patients who were cured had a relapse of Cushing's disease after
remission was achieved.
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 ●In another study of 40 patients, 32 achieved remission at a follow-up interval
of nine years [75].
Side effects — Serious side effects are rare in either adults or children with the
treatment schedule described above given as primary therapy [1,82].
●Less than 5 percent of the patients developed clinical growth hormone or
thyroid-stimulating hormone (TSH) deficiency, sometimes years after
radiation.
●With provocative testing, some degree of pituitary deficiency has been
detected in a majority of patients who receive two to three times the
currently recommended fractional dose [83].
●Hypopituitarism was more frequent in the reports described above in
patients with failed transsphenoidal surgery [74,75]. In these studies, 43 to 57
percent of the patients had growth hormone deficiency and approximately 33
percent had deficiencies of one or more other pituitary hormones. In one
study of children, five of six who received both transsphenoidal surgery and
radiation developed growth hormone deficiency, which was transient in two
[84].

There is a longstanding controversy regarding a possible increased risk of death

from cerebrovascular disease after radiation therapy:

●A long-term, follow-up study of 342 patients with pituitary tumors (mostly

nonsecreting tumors) treated by surgery and radiation suggested that
radiation per se is not responsible for these deaths. The characteristics of
radiation were not different in the cerebrovascular deaths (31 patients),
compared with a control group that received radiation but did not have a
cerebrovascular event [85]. Patients with Cushing's disease (and acromegaly)
were excluded from this study because of the increased incidence of
cerebrovascular complications in these patients irrespective of the mode of
therapy.
●In a second study, 33 of 334 patients with pituitary adenoma died of
cerebrovascular disease after radiation therapy, representing an increased
relative risk of 4.11 compared with national age, sex, and interval mortality
rates [86].
Higher cure rates can be attained by delivering up to 110 Gy (11,000 rad) of alpha-
particle or proton beam external radiation over a few days [87,88] or 198Au or 90Y
interstitial radiation [89,90]. These regimens, however, are associated with a
higher incidence of side effects, especially hypopituitarism.
Stereotactic radiosurgery — Stereotactic radiosurgery with the 60Co Gamma
Knife or the linear accelerator photon knife is another treatment option [91,92].
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These instruments can deliver over 100 Gy (10,000 rad) of radiation with great
precision in one treatment session (image 4A-B). (See "Stereotactic cranial
radiosurgery".)
Results of primary therapy — In one series, 89 patients aged 5 to 67 with ACTH-
producing tumors were treated with stereotactic radiosurgery, and 18 were
followed for 12 to 22 years [93]. Of the 89 patients, 64 received one, and 25 had
two or more courses of treatment. There were no treatment-related deaths, and
vision and visual fields were not affected. Urinary cortisol levels gradually
normalized in 83 percent, and no tumor recurrences were noted.
Results of secondary therapy — In a study of Gamma Knife after failed
transsphenoidal surgery, 49 of 90 patients (54 percent) were cured, as indicated by
normal urine cortisol excretion, on average approximately one year after
treatment [73]. Ten patients (20 percent) had subsequent recurrence of
hypercortisolism within five years.
Side effects of stereotactic radiotherapy — As with conventional fractionated
radiotherapy, hypopituitarism is the most common side effect of radiosurgery.
●In the series of 89 patients mentioned above, two-thirds developed
radiation-induced endocrine deficiencies, some as late as 10 years after
treatment [93].
●In the series of 90 patients mentioned above, 20 (22 percent) developed new
hormonal deficiencies. Five patients developed new visual deficits or third,
fourth, or sixth cranial nerve deficits; two of these patients had undergone
prior conventional fractionated radiation therapy, and four of them had
received previous Gamma Knife therapy.
●Other studies have shown that when side effects do arise with stereotactic
radiation, they may occur within two years of treatment [94], although the
median time is five years [95].

Stereotactic radiosurgery is more convenient for patients as it requires only one or

two treatments, but it is generally more expensive than conventional radiation
therapy (in the United States). There are not sufficient data to know if the side-
effect profile differs between the two.

RESOLUTION OF CUSHING'S STIGMATAIn patients who are cured of

Cushing's disease or whose hypercortisolism is controlled, signs and symptoms of
hypercortisolism improve rapidly and disappear over a period of 2 to 12 months.
Thinning of the skin improves within weeks; muscle strength improves more
slowly. Central obesity is usually lost, whereas patients with generalized obesity,
especially if sustained for years rather than months, usually have difficulty losing

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the additional weight. Hypertension and glucose intolerance improve but may not
be cured.
Unlike other forms of osteoporosis, the osteoporosis of Cushing's syndrome
improves rapidly during the first two years after cure and more gradually
thereafter [96]. Unfortunately, vertebral compression fractures and aseptic
necrosis of the proximal humerus and femur cause permanent deformity and are
a major incentive for early cure of Cushing's syndrome.
Five years after cure, 15 patients in one study had a higher prevalence of
atherosclerosis and increased cardiovascular risk factors, probably due to residual
abdominal obesity and insulin resistance [81]. Similar findings were reported in a
study of 41 patients who had a higher prevalence of obesity and dyslipidemia than
case controls at a mean follow-up duration of 11 years [97].
Resolution of neuropsychiatric symptoms after surgery is variable.
(See "Glucocorticoid effects on the nervous system and
behavior" and "Epidemiology and clinical manifestations of Cushing's syndrome",
section on 'Neuropsychologic changes and cognition'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Diagnosis and treatment of Cushing's
syndrome".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basicstopics (see "Patient education: Cushing's syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Cushing's syndrome
(Beyond the Basics)" and "Patient education: Cushing's syndrome treatment
(Beyond the Basics)")

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SUMMARY AND RECOMMENDATIONSCushing's disease is caused by
pituitary corticotropin (ACTH)-secreting tumors. These tumors are almost always
benign and are usually microadenomas (ie, <10 mm in diameter); in 30 to 40
percent, the microadenoma is so small that it is not detectable by magnetic
resonance imaging (MRI), while in 10 to 15 percent, a macroadenoma is present.
Treatment is aimed first at the anterior pituitary gland.
●For most adult patients with Cushing's disease, we suggest transsphenoidal
surgery with an experienced surgeon as primary therapy (Grade 1B).
(See 'Transsphenoidal surgery' above.)
●MRI is performed preoperatively to try to locate the pituitary tumor.
However, surgery should be performed even if a tumor is not visualized.
The operative approach varies. Traditionally, the procedure involved
transsphenoidal exploration through either a sublabial or endonasal
approach, followed by use of a high-powered microscope that allowed for
binocular vision. More recently, use of an endoscope, which does not provide
binocular vision, has been advocated.
The extent of surgery varies. Ideally, the entire tumor is removed, while
normal pituitary tissue is left behind. However, in adult patients in whom a
microadenoma cannot be identified at the time of surgery and for whom
fertility is not an issue, 80 to 90 percent of the pituitary should be resected,
leaving a small island attached to the stalk.
●Surgical complications – The main surgical complication is diabetes
insipidus, which occurs transiently in up to approximately 20 percent of
patients but is rarely permanent. (See 'Diabetes insipidus' above.)
●Biochemical assessment for cure – Serum cortisol should be measured at 8
AM at least 24 hours after the last physiologic dose of glucocorticoid,
beginning two to seven days after surgery, to assess cure. Ideally,
measurements are obtained for three consecutive days without
glucocorticoid therapy. Although an extremely low serum cortisol
concentration (<1.8 mcg/dL [50 nmol/L]) is the best predictor of cure, there
are exceptions to this as described above. (See 'Biochemical criteria' above.)
●Long-term monitoring – All patients should be reevaluated annually for
several years and less frequently thereafter. This is particularly true for those
who had intermittent hypersecretion of cortisol initially; these patients may
seem to be cured after surgery but continue to secrete excess cortisol
intermittently. (See 'Long-term monitoring' above.)
●Management if surgery fails – First, the presence of tumor on pathology and
the previous testing should be examined to ensure that the diagnosis is

687
correct. If only a part of the tumor has been resected, immediate repeat
surgery is an option. (See 'Treatment if surgery fails' above.)
●For patients with a secure diagnosis in whom surgery has failed and with
little or no radiologically detectable residual tumor, we suggest radiation
therapy as the next step (Grade 2C). In patients with mild disease in whom
the possibility of an additional two to four months of hypercortisolism is not
deemed too risky, medical therapy with cabergoline or pasireotide is an
alternative, recognizing that it is successful in only a minority of individuals.
Radiation with adjunctive medical therapy may be best in those with dural
invasion or who have unresectable remaining tumor. Adrenalectomy may be
favored in those with severe hypercortisolism who need immediate cure or in
women desiring pregnancy in whom steroidogenesis inhibitors are
contraindicated.

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Treatment of adrenocortical carcinoma
Authors:
André Lacroix, MD
Gary D Hammer, MD, PhD
Section Editors:
Lynnette K Nieman, MD
Alberto S Pappo, MD
Deputy Editors:
Kathryn A Martin, MD
Sonali Shah, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 28, 2021.
What's New
Long-term survival in patients with pediatric adrenocortical carcinoma
(November 2021)
For pediatric patients with adrenocortical carcinoma (ACC), there are limited
data for the long-term prognosis of this rare disease. A prospective, single-arm
study of approximately 80 pediatric patients with ACC described the outcomes of
stage I patients treated with adrenalectomy; stage II patients treated with
adrenalectomy and retroperitoneal lymph node dissection; and stage III or IV
patients treated with mitotane and chemotherapy, followed by surgery as clinically
indicated [1]. Five-year overall survival rates, according to stage, were 95 percent
for stage I; 79 percent for stage II; 95 percent for stage III; and 16 percent for
stage IV disease. Although patients with stage III disease had better outcomes
relative to those with stage II disease, potentially due to receipt of mitotane and
chemotherapy, we consider multiple factors (eg, grade, extent of vascular
invasion) in decisions regarding systemic therapy. (See "Treatment of
adrenocortical carcinoma", section on 'Management'.)
Read more

INTRODUCTIONAdrenocortical carcinomas (ACCs) are rare and frequently

aggressive tumors that may be functional (hormone-secreting) and cause
Cushing's syndrome and/or virilization, or nonfunctional and present as an
abdominal mass or as an incidental finding.
The management of ACC will be discussed here. The clinical presentation and
diagnostic evaluation of patients with adrenal masses, the staging workup for ACC,
and the management of benign adrenal adenomas are reviewed separately.

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(See "Clinical presentation and evaluation of adrenocortical
tumors" and "Evaluation and management of the adrenal incidentaloma".)
A modification has been proposed for the ENSAT staging system that incorporates
histologic grade of differentiation (table 1) [1]. In one report, incorporating patient
age (>55 years) into available staging systems appeared to better predict overall
survival in patients with stage I and II ACC [2].
PRIMARY TREATMENTOur approach to management is largely consistent
with the clinical practice guidelines on the management of adrenocortical cancer
published by the European Society of Endocrinology in collaboration with the
European Network for the Study of Adrenal Tumors (ENSAT) [3].
Initial surgery — Complete surgical resection is the only potentially curative
treatment for adrenocortical carcinoma (ACC) [3,4]. For patients with potentially
resectable stage I to III disease who are surgical candidates, we recommend
complete surgical resection as initial therapy.
Before proceeding to a surgical excision, all patients must undergo a complete
hormonal assessment to determine the secretory activity of the tumor. It is
particularly important to identify those with cortisol-producing tumors. These
patients, even those with mild hypercortisolism, have some degree of
hypothalamic-pituitary-adrenal (HPA) axis suppression and require glucocorticoid
coverage to prevent postoperative adrenal insufficiency [3,5]. (See "Clinical
presentation and evaluation of adrenocortical tumors", section on 'Hormonal
evaluation'.)
The surgery should be performed in a specialized referral center by teams of
surgeons with specific expertise to avoid tumor spillage and incomplete resection,
which is associated with a poor prognosis [3,6,7]. (See 'Stage and margin
status' below.)
The preoperative preparation for and techniques of surgical adrenalectomy are
discussed elsewhere. (See "Adrenalectomy techniques".)
For potentially resectable tumors invading adjacent organs, surgery often needs to
be extensive, with en bloc resection of involved organs such as kidney, liver,
spleen, pancreas, stomach, and colon [8]. Intracaval extension or tumor thrombus
is not a contraindication to surgery; resection may be facilitated by
cardiopulmonary bypass [9].
Suspicious lymph nodes should be resected, but the benefit of routine
lymphadenectomy has not yet been established. ACCs often spread via lymphatic
drainage. A benefit for routine lymphadenectomy during adrenalectomy was
suggested in a report from the German ACC Study Group of 283 patients with
completely resected ACC [10]. There was a significantly reduced risk for tumor
recurrence and disease-related death (hazard ratio [HR] 0.54, 95% CI 0.29-0.99) in
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patients who underwent lymphadenectomy versus those who did not. In a second
study, peritumoral lymph node resection was associated with improved overall
survival [11].
Metastatic lymphatic spread may be more extensive than previously thought. In a
study of 56 patients with ACC, lymphatic recurrence was detected in a number of
areas [12].

Left-sided ACC (n=36):

●Left renal hilum (50 percent)

●Perirenal fat tissue cranial to the renal hilum (47 to 55 percent in ventral and
dorsal areas)
●Para-aortic (47 percent)
●Interaortocaval (22 percent)
●In the perirenal fat tissue caudal to the renal hilum (17 to 20 percent)

Right-sided ACC (n = 20):

●Perirenal fat tissue cranial to the renal hilum (45 to 55 percent in ventral and
dorsal areas)
●Interaortocaval (35 percent)
●In the area of the right renal artery (10 percent)
●Paracaval (15 percent)
●Left para-aortic lymph node (10 percent)
Although resection is technically possible for most patients with stage I to III
disease (table 2), it is not curative for many, presumably because occult
micrometastases are present at the time of initial presentation, even with stage I
disease [13-17]. As an example, in a single center report of 202 consecutive cases
of ACC, 40 percent of patients with stage I to III disease (table 2) had developed
distant metastasis two years after diagnosis (27, 46, and 63 percent of patients
with stage I, II, and III disease, respectively) [18].
However, there is some evidence that outcomes are improving over time.
(See 'Prognosis' below.)
Even if the tumor cannot be removed entirely, some clinicians advocate maximal
debulking as a means of improving survival [13,19-22], although others disagree
as to the survival benefit of this strategy [23,24]. Data to support routine debulking
of nonresectable tumors are lacking, and decision making must be individualized,
taking into account the underlying tumor biology, rate of progression, and the
histologic grade [3,6]. For patients with advanced functioning tumors, debulking
may help to control hormone hypersecretion and increase the efficacy of further

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therapies [4,7,25]. Overall, however, patients with unresectable disease have a
poor prognosis, particularly with high-grade disease, often surviving only three to
nine months, and they are often better palliated with medical management
[20,26]. (See 'Recurrent or advanced adrenocortical cancer' below.)
The role of neoadjuvant systemic therapy prior to surgery for patients with locally
advanced disease is not defined, and this is not considered a standard approach.
The value of neoadjuvant cisplatin-based chemotherapy is being addressed in a
clinical trial from the Children's Oncology Group that is enrolling individuals up to
age 21 years with ACC [27]. In adults, one retrospective study suggested that
patients with locoregionally advanced tumors might benefit from cisplatin-based
neoadjuvant chemotherapy [28]. However, definitive evidence is still lacking, and
therapeutic decisions should be individualized.
Laparoscopic versus open resection — We suggest open rather than
laparoscopic adrenalectomy for patients with ACC. Laparoscopic surgery has
largely replaced the open technique for management of benign adrenal
pathology, and laparoscopic removal of even large adrenal tumors can be
performed safely by experienced surgeons [29-31]. (See "Adrenalectomy
techniques".)
However, the role of laparoscopic resection for ACCs is controversial, and open
surgery remains the standard approach at least in our centers, despite the
European clinical practice guideline on adrenal incidentaloma, which recommends
laparoscopic resection for tumors less than 6 cm even when ACC is suspected in
the absence of local tumor invasion [32]. Clinical practice guidelines recommend
surgery for all tumors with radiologic findings suspicious of malignancy and
evidence for local invasion [3]. However, for tumors <6 cm without any evidence of
local invasion (unknown if benign or malignant), laparoscopic adrenalectomy is
reasonable if the surgeon has sufficient experience. Several retrospective studies
have shown more frequent or earlier recurrences and a shorter disease-free
survival when this technique is used for management of ACC [6,33-35]. This is not a
universal finding, however, and others have shown comparable outcomes from
laparoscopic and open adrenalectomy, particularly for tumors up to 10 cm in size
in specialized centers [36-40]. Nonetheless, this is not a widely accepted approach,
and we and others [36] suggest open rather than laparoscopic resection for
known or highly suspected ACC, regardless of size [6,33,41,42].
Prognostic factors
Stage and margin status — The most important clinical factors that determine
prognosis of ACC are disease stage and completeness of
resection [3,14,18,19,26,43-46] (see "Clinical presentation and evaluation of
adrenocortical tumors", section on 'Staging'). In the previously cited series of 253

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patients from the French Association of Endocrine Surgeons Study Group, five-year
overall survival was 66, 58, 24, and 0 percent for stage I, II, III, and IV (metastatic)
disease, respectively [43].
However, survival differs widely for any given tumor stage, and many other factors
influence outcomes. Regardless of stage, incomplete resection is associated with a
poor prognosis (median survival generally less than one year) [6,7]. The influence
of margin status on prognosis was shown in a report from the National Cancer
Database, in which five-year overall survival rates for patients with ACC and
uninvolved, microscopically involved, and macroscopically involved margins were
46, 21, and 10 percent, respectively [47].
Histology — In addition to stage and completeness of resection, the biologic
behavior of ACCs is also influenced by pathologic/morphologic factors.
Histologically, the appearance of ACCs ranges from mild atypia to wildly anaplastic
tumors composed of monstrous giant cells. The widely applied multifactorial
scoring system of Weiss is based upon nine histopathologic features (nuclear
grade, mitotic rate, atypical mitoses, clear cell component, diffuse architecture,
tumor necrosis, invasion of venous or sinus structures, or tumor capsule); tumors
with less than three features are usually considered as benign [48]. (See "Clinical
presentation and evaluation of adrenocortical tumors", section on 'Fine-needle
aspiration biopsy'.)
These criteria have been validated as prognostic factors in more contemporary
series both in adults and children [14,45,46]. As an example, in one study of 124
patients with ACC, significant predictors of disease progression included distant
metastasis at presentation; tumor invasion of vessels, tumor capsule, or adjacent
organs; tumor necrosis; a high mitotic rate; the presence of atypical mitosis; and
overexpression of mdm-2 [14]. Five-year disease-free survival was significantly
different for patients with one or two, three or four, or more than four adverse
features (84, 37, and 9 percent, respectively).
Several studies confirm the prognostic value of markers of proliferation, including
mitotic rate, and Ki67 expression (as detected by a monoclonal antibody against
Ki67, MIB1) [14,49-53]. The importance of proliferative rate in prognostication was
shown in an analysis of 124 patients with ACC, in whom the five-year disease-
specific survival rates for individuals with tumor mitotic rates of ≤5, 6 to 10, 21 to
50, and >50 per 50 high-power fields [HPF] were 63, 50, 25, and 0 percent,
respectively [14].
The combined utility of tumor stage and mitotic rate to assess prognosis was
addressed in a study of 92 patients with malignant ACC [50]. Three risk groups
were identified (low [stage I/II, mitoses ≤9/50 HPF], intermediate [stage I/II plus >9
mitoses/50 HPF or stage III/IV plus mitotic rate ≤9/50 HPF], and high [stage III/IV

693
and mitotic rate >9/50 HPF]) that had significantly different rates of mean disease-
free survival (62, 17, and 12 months, respectively) and overall survival (not
attained, 66, and 26 months, respectively).
The Ki67 labeling index (LI) has been used to select patients for adjuvant
chemotherapy in addition to mitotane. While the absolute value of Ki67 LI that
permits the differentiation of a "high-risk" from low- or intermediate-risk ACC is
not established [5,54], a high-grade ACC, which is defined in part by a high mitotic
rate (and/or Ki67 score >20 percent), is at a higher risk of recurrence than a low-
grade ACC. (See 'Adjuvant chemotherapy with or without mitotane' below.)
Other factors — Other clinical factors, immunohistochemistry, and molecular
markers are associated with poor survival. Among clinical factors, older age at
diagnosis and hypersecretion of cortisol have been recognized as adverse factors
[18].
Molecular predictors of malignant potential and survival are emerging, but none
are ready for clinical use [55-60].
Some reports suggest the value of mutated TP53, mutated b-
catenin, ERCC1 (excision-repair, complementing defective in Chinese Hamster 1
gene), IGF2, SF1 (splicing factor-1), the glucose transporter GLUT1, low expression
of the SGK1  (serum/glucocorticoid-regulated kinase 1) gene, and G0S2  (G0/G1
Switch 2 gene) hypermethylation are predictors of poor prognosis [14,61-68].
Studies with global gene expression profiling suggest that specific patterns of
gene expression are strongly associated with poor outcomes, independently of
traditional histologic predictors such as tumor stage and Weiss score
[55,56,58,60,69].
Adjuvant mitotane — We agree with the European Society of Endocrinology
clinical guidelines on ACC and suggest adjuvant mitotane use (alone, without
chemotherapy) for patients at the highest risk of recurrence, eg, those who have
histologically high-grade disease (Ki67 staining of >10 percent of tumor cells, >20
mitotic figures per 50 HPF regardless of tumor size [1,70]), intraoperative tumor
spillage or fracture, and some large tumors that are low grade but have vascular
or capsular invasion. (See 'Indications' below.)
Mitotane (o,p'-DDD, a congener of the pesticide dichlorodiphenyltrichloroethane
[DDT]) is an adrenocorticolytic drug that has efficacy in patients with ACC [13,71-
73]. It has been used in the adjuvant setting for primary therapy of unresectable
disease and for the treatment of disease recurrence, either alone or in
combination with other cytotoxic agents. (See "Pharmacology and toxicity of
adrenal enzyme inhibitors and adrenolytic agents" and 'Mitotane
monotherapy' below.)

694
Efficacy — Data demonstrating the benefit of routine postoperative (adjuvant)
administration of mitotane have been mixed, in large part due to the rarity of ACC
and the lack of prospective, randomized clinical trials. While a number of
uncontrolled reports suggest that adjuvant mitotane may delay or prevent
recurrence in patients undergoing complete primary resection for nonmetastatic
disease [6,16,74-82], others have failed to show any benefit in terms of disease-
free or overall survival [7,19,24,43,49,83-89]. Among the potential reasons for
these disparate results are insufficient dosing in some studies and variability in an
individual tumor's ability to metabolize mitotane (which is required for therapeutic
action).
The best available evidence that adjuvant mitotane improves outcomes for
patients with resected stage I to III ACC comes from a retrospective analysis of 177
patients who had undergone macroscopically complete radical surgery at eight
Italian and 47 German centers between 1985 and 2005 [76]. In the Italian cohort,
47 received adjuvant mitotane while 55 patients did not (Italian control group).
None of the 75 patients in the German cohort received adjuvant mitotane (German
control group).

The groups were well matched, with the exception that the German control
patients were more likely to have stage I or II disease (84 versus 67 percent of both
Italian groups). With a median follow-up that ranged from 43 to 68 months in the
three groups, the following results were seen:

●In the mitotane group, 27 patients received 1 to 3 grams daily, and the

remainder received 3 to 5 grams daily. Serum levels were not routinely
measured. The median duration of treatment was 29 months for both doses.
●Mitotane treatment was associated with a significantly longer recurrence-
free survival as compared with either control group (median recurrence-free
survival 42 versus 10 and 25 months in the Italian and German control
groups, respectively).
●There were also fewer deaths from ACC in the mitotane group than in either
control group (25 versus 55 and 41 percent, respectively). Median overall
survival durations in the three groups were 110 months in the mitotane
group compared with 52 months in the Italian controls and 67 months in the
German control group.
●Mitotane was reasonably well-tolerated. Grade 3 gastrointestinal (nausea,
vomiting, or elevated serum gamma-glutamyl transpeptidase [GGT]) or
neurologic events (confusion, ataxia, vertigo) were observed in 15 and 20
percent of the patients who received the higher dose mitotane regimen;
neither of these problems occurred with lower doses.
695
These data support the view that adjuvant mitotane therapy, even at relatively low
doses, improves recurrence-free and overall survival after macroscopically
complete radical resection for stage I, II, or III ACC. The strengths of this
retrospective series include its large size, involvement of multiple institutions, well-
matched control cohort, long duration, systematic nature of follow-up, and
carefully conducted statistical analysis [81]. A report of this cohort after nine
additional years of follow-up suggests that the benefit of adjuvant mitotane on
disease-free survival is maintained [90].
Benefit was also supported by three other studies [82,91,92]. In one report of 149
German ACC registry patients with stage II ACC, the subgroup of 35 patients who
received adjuvant mitotane displayed a significantly better five-year survival than
the 114 patients not receiving adjuvant mitotane (87 versus 53 percent,
respectively). In a retrospective study of 100 patients treated with adjuvant
mitotane and 52 who did not receive mitotane, adjuvant therapy lowered the risk
of recurrence but did not improve overall survival [92]. However, a survival benefit
was seen in a subset of mitotane-treated patients (those with stage III ACC or an
elevated Ki67 index).
Indications — In the past, adjuvant therapy has been recommended for most
patients with ACC because, even after radical resection, recurrence rates up to 60
to 80 percent were reported [14,86]. However, newer reports have suggested that
the survival rate in localized ACC is probably much better than that of most
published retrospective series [82], and this has led to an ongoing debate as to
which patients are in need of adjuvant therapy.
Increasingly, decisions about adjuvant mitotane are being made on the basis of
tumor stage, completeness of resection, and proliferation rate, the three major
prognostic factors [50,51,93]. Studies, including data on prognostic factors from
the original Weiss criteria [48] (see 'Histology' above) and data from the European
Network for the Study of Adrenal Tumors (ENSAT) ACC registry [51,54], have shown
that a high proliferation rate (as determined by the mitotic rate, MIB1 staining, or
Ki67 expression) is associated with a poor prognosis. (See 'Prognostic
factors' above.)
As noted, we consider that patients who have the highest risk for recurrence are
those who have histologically high-grade disease (Ki67 staining of >10 percent of
tumor cells, >20 mitotic figures per 50 HPF regardless of tumor size [1,70]),
intraoperative tumor spillage or fracture, and some large tumors that are low
grade but have vascular or capsular invasion. We suggest adjuvant mitotane use
for all patients who meet these criteria.
These recommendations differ from those of an international consensus panel on
the treatment of ACC, which concluded that adjuvant mitotane was indicated for

696
patients with a potentially incomplete resection and for all patients with a high
proliferative rate (as assessed by Ki67 staining of >10 percent of cells) [51].
However, they also concluded that adjuvant mitotane was not mandatory for stage
I or II disease, histologically proven complete (R0) resection, and Ki67 staining of
≤10 percent of cells.
The role of adjuvant mitotane therapy for patients with low-grade ACC who have
an open resection and no tumor fracture or spillage at the time of surgery is
unclear. Based upon data from the German ACC registry, some suggest that
observation alone is only appropriate if, in addition to the above criteria (stage I or
II disease, histologically proven complete [R0] resection, and Ki67 staining of ≤10
percent of cells), patients also have tumor size <8 cm and no microscopic evidence
of invasion of blood vessels or the tumor capsule [94]. National Comprehensive
Cancer Network (NCCN) guidelines suggest that mitotane be "considered"
(category 3 recommendation, with major disagreement that the intervention is
appropriate) for all patients with resected low- or high-grade localized ACC
regardless of stage or tumor size [95].

We treat some of these patients (eg, those with stage III low-grade disease, or a
large [>20 cm] stage II tumor with a borderline mitotic rate or Ki67 score), but in
this setting, we are more likely to treat for a shorter duration and discontinue the
drug if side effects are difficult to manage.

A large, international, randomized trial (mitotane versus observation) in patients

with presumably low- to intermediate-risk resected disease (stage I to III,
microscopically complete [R0] resection, Ki67 <10 percent) is currently ongoing
(the ADIUVO trial), and if available, eligible patients should be referred for
enrollment.
In the future, molecular markers might help to better define individual risk for
recurrence to tailor decisions about therapy [55,60], but no test is ready for clinical
use yet. (See 'Other factors' above.)
Duration — We aim to continue adjuvant mitotane treatment for five years in
patients with high-risk ACC independent of stage on the assumption that it is very
atypical for a patient with ACC to recur after four to five years. For patients with
low-risk ACC, we aim for a minimum of two to three years and will, at times,
continue for five years if the drug is well tolerated. However, the optimal duration
of adjuvant mitotane is not known, particularly for patients with low-risk disease.
In the adjuvant study reported above, the median duration of treatment was 29
months [76]. (See 'Efficacy' above.)
Most guidelines suggest a minimum of two years of therapy [3,93], and this is the
duration being tested in the adjuvant ADIUVO trial described above for
697
intermediate- to low-risk disease. International guidelines suggest to aim for two
years but treat longer if the patient is doing well [6].
Suggested regimen — While benefit of mitotane in the adjuvant setting has been
reported using relatively low doses (1 to 3 grams daily) [76], current treatment
protocols are based upon achieving therapeutic mitotane serum levels. We
suggest that all patients receiving mitotane (including those being treated for
advanced disease) undergo therapeutic monitoring with plasma mitotane levels
every four to six weeks.
The following represents our approach to managing therapy with mitotane:
●We initiate adjuvant treatment as soon as possible after surgery (within
three months).
●Mitotane is initiated at 0.5 g twice per day and increased to 6 g/day over 4 to
12 weeks as tolerated, with monitoring of mitotane level every two to three
weeks.
●Because of the long serum half-life and accumulation in adipose tissue,
several weeks may be necessary to raise serum mitotane concentrations to
the target level of 14 to 20 mcg/mL [88,96].
●When serum mitotane monitoring is not available, we suggest trying to push
dosing to toxicity (up to 6 to 8 g per day) for patients with high-risk disease
and adjust according to tolerability. Some patients may not tolerate more
than 2 g per day.
●At some centers, mitotane is administered to all patients using rapid
escalation of high doses (4 g/day rapidly escalating to therapeutic doses
within two weeks) [97]. This regimen may shorten the time needed to reach
therapeutic levels of mitotane, but it requires closer follow-up and combined
clinical and mitotane level monitoring and may be more frequently
associated with side effects.
●Nausea should be treated using metoclopramide or a serotonin (5-HT3)
receptor antagonist such as ondansetron. (See "Prevention and treatment of
chemotherapy-induced nausea and vomiting in adults".)
Our approach of measuring serum mitotane levels, targeting a range of 14 to 20
mcg/mL, has been validated in several studies as correlating with therapeutic
response while minimizing toxicity [8,84,88,96,98-101]. As examples:
●A retrospective series included 91 patients receiving mitotane for
unresectable or metastatic ACC who underwent assay of serum mitotane
levels within three months of attaining the best response to mitotane with or
without chemotherapy [99]. A significantly higher number of responders (11
of 17 responders) had serum mitotane levels >14 mcg/mL, and of the six
responders who had lower levels, all were receiving concurrent

698
 chemotherapy. Survival was also significantly longer among patients with
levels >14 mcg/mL (median survival 24 versus 18 months, hazard ratio [HR]
for death 0.52, 95% CI 0.28-0.97).
●In a prospective study, therapeutic monitoring achieved better tolerance of
adjuvant mitotane therapy with fewer side effects [98].
●Furthermore, in the adjuvant setting, improved outcomes for patients with
therapeutic mitotane levels were shown in a report of 43 consecutive patients
undergoing surgical treatment for ACC followed by monitored mitotane; 29
(67 percent) had stage III or IV tumors, and 33 underwent potentially curative
surgery [8]. Four patients treated prior to 1990 (when mitotane monitoring
was not available) received a low dose of the drug (1 g twice daily), while 13
others did not tolerate the drug and were kept at lower levels; 24 patients (75
percent of whom had stage III or IV tumors) were maintained at mitotane
levels exceeding 14 mcg/mL. Despite the preponderance of stage III and IV
tumors, the five-year disease-specific survival rate was high (64 percent).
When the HR for death from ACC was compared over time between the
patients with high mitotane levels versus the patients with lower doses or
without mitotane treatment, there was a positive survival effect that
persisted up to four years after surgery.
Every patient metabolizes mitotane to different degrees and, hence, requires
unique dosing to achieve therapeutic blood levels. Therapeutic serum levels can at
times be achieved with low doses of mitotane. As an example, in one series of
eight patients receiving 3 g daily (of the non-micronized formulation), therapeutic
concentrations (14 to 20 mcg/mL) were reached in three to five months (after a
cumulative dose of approximately 360 g), and five patients maintained clinical
benefit (stable disease or disease free) with minimal toxicity for 8 to 40 months
with as little as 1 to 2 g daily [102].
Inherited polymorphisms in drug-metabolizing enzymes have been described that
may predict the individual response to adjuvant mitotane [103-105]. However, at
present, there is no defined clinical role for genotyping prior to the initiation of
mitotane therapy in this or any other setting.
In the United States and Canada, plasma levels of mitotane can be measured in
commercial laboratories and some academic centers; in Europe, they are available
through HRA Pharma, which distributes mitotane as an orphan drug. We
recommend monitoring plasma mitotane levels in all patients if possible, as
outlined below.
Monitoring response
Imaging — The efficacy of adjuvant mitotane can be assessed periodically during
therapy by the following techniques:

699
 ●Surveillance for recurrence of disease should include contrast-enhanced
computed tomography (CT) scans (or magnetic resonance imaging [MRI]) of
the chest, abdomen, and pelvis every three months for two to three years,
then every four to six months for five years. (See "Radiation-related risks of
imaging".)
●Although the role of fluorodeoxyglucose (FDG)-positron emission
tomography (PET) in post-treatment monitoring is not yet established, some
centers add integrated FDG-PET/CT at six-month intervals in the post-
treatment follow-up strategy [36]. Limited studies comparing the usefulness
of integrated PET/CT scans (which are typically done without intravenous [IV]
contrast) versus diagnostic (ie, contrast-enhanced) CT performed at the same
time have shown that integrated PET/CT detects more lesions than does PET
or CT alone, and that PET should be considered a complementary
examination to contrast-enhanced CT or MRI [106-108]. In one study, PET was
more sensitive than CT in detecting local recurrence, while CT was more
sensitive in detecting small lung or peritoneal metastases [108].
Nevertheless, the utility of PET in the setting of primary treatment remains
controversial. At the University of Michigan, PET is not performed routinely,
either prior to primary surgery for a suspected ACC or as a component of the
post-treatment surveillance strategy. However, other centers (including that
of one of the authors [AL]) routinely perform PET prior to surgery for a
suspected ACC and add integrated FDG-PET/CT at six-month intervals in the
post-treatment follow-up strategy for patients with high-risk disease who
have been shown to have FDG-avid disease preoperatively (see 'Local
therapy' below). In more advanced disease, PET/CT may be preferred for
assessment of chemotherapeutic response; in a small proportion of patients
in one report, PET/CT predicted response before anatomic changes were
detected on CT [109].
Biochemical — For patients with a completely resected, steroid-producing ACC,
some groups monitor for recurrent hormone excess every three months for two
years with steroid tumor markers such as cortisol (measured in the morning
before hydrocortisone dose), dehydroepiandrosterone sulfate (DHEAS),
androstenedione, testosterone, estradiol, or mineralocorticoid based upon the
steroid profile in the initial tumor. Other groups do not routinely screen for
recurrent hormone excess unless or until there is evidence of recurrent disease.
Mitotane, which increases serum concentrations of corticosteroid-binding globulin
(CBG), may result in serum cortisol values that are artifactually elevated [110]
without significant changes in corticotropin (ACTH). Despite alterations in cortisol
metabolism induced by mitotane, 24-hour urinary free cortisol excretion remains

700
the best index of cortisol production currently available (table 3) [110].
(See 'Adrenal insufficiency' below.)
Use of liquid chromatography-mass spectroscopy assays for urine cortisol and its
metabolites should eventually offer better tools to assess steroid hormone
production and requirements in ACC patients receiving mitotane [111].
Toxicities
Side effects — The toxicity profile of mitotane limits tolerability, particularly at
doses above 6 grams per day. The most common side effects are fatigue, nausea,
vomiting, and anorexia, but skin rash, diarrhea, lethargy, sedation, confusion,
dizziness, ataxia, gynecomastia, arthralgias, leukopenia, prolonged bleeding time,
hematuria, and reversible growth arrest in children also occur [17,112].
Other adverse effects include hypercholesterolemia (elevated low-density
lipoprotein [LDL] cholesterol), hypouricemia, and hepatotoxicity (table 3). If statins
are used for the dyslipidemia, pravastatin and rosuvastatin should be considered
as they have less drug interaction with mitotane.
While increased concentrations of serum GGT and alkaline phosphatase are almost
invariably observed, a significant rise in transaminases or bilirubin is infrequent.
(See "Pharmacology and toxicity of adrenal enzyme inhibitors and adrenolytic
agents".)
Adrenal insufficiency — Use of mitotane routinely induces atrophy and/or
steroidogenic inhibition of the normal adrenal glands, thereby causing cortisol
deficiency. The zona glomerulosa is more resistant to the adrenolytic effect of
mitotane, and aldosterone deficiency may not occur until after several months of
therapy. (See "Pharmacology and toxicity of adrenal enzyme inhibitors and
adrenolytic agents" and "Medical therapy of hypercortisolism (Cushing's
syndrome)".)
Glucocorticoid replacement therapy is necessary for patients treated
with mitotane (unless the ACC is an advanced, glucocorticoid-producing tumor
presenting as Cushing's syndrome). Independent of the pharmacologic effects of
mitotane, for patients with cortisol-secreting ACC, suppression of ACTH-adrenal
axis will require replacement with glucocorticoids following complete tumor
resection. (See 'Initial surgery' above.)

Our approach to managing adrenal insufficiency includes the following:

●Close monitoring of blood sodium, potassium, creatinine, ACTH, and 24-

hour urine free urinary cortisol levels is necessary to avoid adrenal
insufficiency and acute hyperkalemia in patients treated with mitotane,
whether in the adjuvant setting or for advanced disease (table 3).

701
●We suggest starting replacement glucocorticoid therapy
when mitotane treatment is initiated because one cannot predict when a
patient will become hypocortisolemic.
●For all patients who are receiving mitotane, we initiate replacement
with hydrocortisone (30 to 40 mg daily in divided doses, two to three times
per day). Of note, most patients eventually require a two- to threefold
increase in hydrocortisone. Patients undergoing mitotane treatment should
wear a medical alert bracelet and be instructed to increase their doses of
hydrocortisone during stress.
●In patients with residual ACC and persistent hypercortisolemia,
glucocorticoid replacement should not be initiated until hypercortisolism is
controlled with mitotane and steroid enzyme inhibitors. (See 'Medical
treatment of hormone excess' below.)
●Several times the usual maintenance doses of glucocorticoids are
sometimes needed as the induction of hepatic cytochrome P450 enzymes
by mitotane increases the rate of metabolism of
cortisol, dexamethasone [113,114], and fludrocortisone. Inadequately treated
adrenal insufficiency enhances mitotane-induced side effects and reduces
drug tolerance [17,80,98]. A brief trial of a higher glucocorticoid dose may
mitigate some side effects that could be attributable to inadequate cortisol
replacement and allow continuation of mitotane at the same dose.
Measurement of serum mitotane levels together with 24-hour urine free
cortisol with an assessment of side effects should guide mitotane
and hydrocortisone dosing. If side effects do not abate with glucocorticoid
therapy, temporary discontinuation of mitotane is indicated, followed by
reinstitution at a lower dose. Measuring cortisol levels in hair may eventually
become useful to assess chronic hydrocortisone replacement in ACC [115].
●Mitotane can also eventually cause aldosterone deficiency. Unlike
glucocorticoid replacement, we do not start mineralocorticoid replacement
right away. Instead, we suggest monitoring blood pressure at each visit,
serum potassium at every three months, and plasma renin every six months
(table 3). Mineralocorticoid deficiency should be suspected if the patient
develops postural hypotension, hyponatremia, or hyperkalemia and has an
elevation in plasma renin activity.
When clinical and biochemical signs of aldosterone deficiency become
present, we suggest starting fludrocortisone (0.1 to 0.3 mg daily) to restore
normal clinical and biochemical parameters (table 3). As noted, the
metabolism of fludrocortisone is increased by mitotane.

702
 ●After stopping mitotane therapy, hydrocortisone therapy should be
continued until the patient has no clinical or biochemical evidence of adrenal
insufficiency. Depending upon the duration of mitotane therapy, adrenal
insufficiency may be permanent.
Reproductive issues — In men receiving mitotane therapy, hypogonadism is
common, often requiring replacement testosterone therapy. In addition to its
effect on CBG, mitotane increases serum concentrations of other binding
globulins, including sex hormone-binding globulin (SHBG) [17,98]. In addition to
potential decreases in free testosterone levels, mitotane induces a strong
inhibition of systemic 5-alpha-reductase activity, which may explain the relative
inefficiency of testosterone replacement in mitotane-treated men [114]. Serum
testosterone should be measured routinely in men receiving mitotane (table 3).
(See "Clinical features and diagnosis of male hypogonadism" and "Testosterone
treatment of male hypogonadism".)
The impact of mitotane on reproductive function in women is less clear. Increased
levels of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) have
been observed, which in some premenopausal women has resulted in the
development of large ovarian cysts [116]. These cysts may be associated with
lower abdomen discomfort and pain; cases of ovarian torsion requiring surgery
have also been observed. (See "Ovarian and fallopian tube torsion".)
There are concerns that pregnancy could lead to an increased likelihood of
relapse, although data are minimal [42]. In addition, the safety of mitotane during
pregnancy is unknown. Therefore, for women of reproductive age scheduled to
receive adjuvant mitotane therapy after ACC resection, we suggest contraception
during and for at least one year after mitotane as the drug has a long half-life and
is deposited in adipose tissues. We suggest barrier methods of contraception as
mitotane accelerates steroid metabolism and may decrease the contraceptive
efficacy of hormonal contraception. (See "Contraception: Counseling and
selection".)
Hypothyroidism — In addition to its effect on CBG, mitotane increases serum
concentrations of other binding globulins, including thyroid hormone-binding
globulin (TBG). Therefore, serum concentrations of free thyroxine (T4) may be
decreased [17,98]. In addition, newer studies indicate a direct inhibitory effect of
mitotane on secretion of thyroid-stimulating hormone (TSH) [98]. As patients on
mitotane therapy often present with fatigue, thyroid function tests should be
monitored periodically (table 3). Hypothyroidism with low TSH is frequent, and free
T4 should be monitored. Thyroid hormone replacement is suggested in patients
with clinical symptoms of hypothyroidism and low free T4 values.

703
Drug interactions — Mitotane is a potent inducer of CYP3A4 metabolism. Limited
data suggest that this can result in important drug-drug interactions [117]. In a
report of two patients with ACC who were receiving mitotane in combination
with sunitinib (a drug metabolized by CYP3A4), serum sunitinib concentrations
were decreased by approximately 80 percent of expected values [118]. Although
clinical data are currently unavailable, mitotane administration could reduce the
efficacy of other drugs relevant to the management of patients with ACC, such as
steroid hormone replacement, benzodiazepines, macrolide antibiotics, some
opioids and statins, and dihydropyridine type calcium channel antagonists [117].
Specific interactions of mitotane with other medications may be determined
using Lexicomp drug interactions.
Adjuvant chemotherapy with or without mitotane — It is not known if cytotoxic
chemotherapy alone or in combination with mitotane is more effective than
adjuvant mitotane alone. Although there are no high-quality data to support this
practice, a cisplatin-based adjuvant regimen might be considered in conjunction
with mitotane in patients who are thought to be at high risk for an early
recurrence, eg, very high Ki67 staining (>20 percent) and extensive vascular
invasion/vena cava thrombus [5].

Few data are available on the efficacy of cytotoxic chemotherapy in the adjuvant
setting:

●The combination of cisplatin and etoposide was explored in the adjuvant

setting in a small series of five individuals aged 1.2 to 21 years [119]. All
received etoposide 165 mg/m2 and cisplatin 90 mg/m2 every three to four
weeks for at least six cycles, beginning shortly after surgical resection, and all
remained in remission 29 to 109 months later. However, ACC in children has
a different natural history than that arising in adults. There are no data
addressing the benefit of adjuvant cisplatin plus etoposide in adults with ACC.
(See 'Pediatric patients' below.)
●The combination of mitotane plus streptozotocin as adjuvant therapy was
evaluated in a nonrandomized phase II trial of 17 patients who had
undergone complete tumor resection. Disease-free survival was significantly
better in patients who then received combination mitotane-streptozotocin
adjuvant therapy compared with a separate cohort of 11 patients who
received no adjuvant therapy after complete resection (49 versus 12 months)
[120]. However, in the absence of a comparator group receiving mitotane
alone, it cannot be concluded that combined therapy is superior. This
approach should not be considered for adjuvant treatment after a complete
resection of ACC outside of the context of a clinical trial.
704
 ●The use of Ki67 LI to select patients for adjuvant chemotherapy in addition
to mitotane has been suggested [93,94]. A potential prognostic role for Ki67
LI following complete resection of ACC was shown in an analysis of 319
patients with resected ENSAT stage I to III ACC [54]. On multivariate analysis,
age, tumor size, venous tumor thrombus, and Ki67 LI were all significantly
correlated with recurrence-free and overall survival; however, Ki67 LI was the
most important prognostic factor. The median recurrence-free survival
durations in patients with a Ki67 LI <10, 10 to 19, and ≥20 percent were 53,
32, and 9 months, respectively; the corresponding values for median overall
survival were 181, 114, and 42 months, respectively. Importantly, the
predictive value of Ki67 LI (ie, its ability to predict benefit from cytotoxic
chemotherapy) was not addressed.
While the absolute value of Ki67 LI that permits the differentiation of a "high-
risk" from low- or intermediate-risk ACC is not established [5], a high-grade
ACC, which is defined in part by a high mitotic rate (and/or Ki67 score >20
percent), is at a higher risk of recurrence than low-grade ACC.
Adjuvant radiation therapy — Data on the usefulness of adjuvant radiation
therapy following surgical resection has been limited by the retrospective nature
of studies with small number of patients. The European Society of Endocrinology
clinical practice guidelines panel suggest against the routine use of radiation
therapy in patients with stage I to II and R0 resection. However, they suggest
considering radiation in addition to mitotane therapy in patients with R1 or Rx
resection or in stage III [3].

We suggest the addition of postoperative radiation therapy (RT) for all patients
with incompletely resected ACC, stage III disease, those who have tumor spillage
at the time of resection, and for all patients with high-grade ACC (>20 mitotic
figures per 50 HPF). The benefit of adjuvant RT is limited to improved local control;
no clear survival benefit has been shown except in one study. We suggest starting
RT as soon as possible following surgery (ideally within 12 weeks).

In the past, ACC was thought to be a relatively radioresistant tumor. However, this
is likely not true with modern RT techniques [121]. While there are no randomized
trials testing the efficacy of adjuvant RT in patients with resected ACC, some, but
not all, studies support a benefit in certain patients who are at high risk for a local
recurrence [121-126].
●One retrospective report addressing the benefit of adjuvant RT is from the
German ACC registry [122]. Outcomes of 14 patients (stage I, II, and III (table
2) in seven, three, and three patients, respectively) without macroscopic
residual disease who received postoperative RT were compared with 14
705
 others who did not receive RT and who were matched for resection status,
use of adjuvant mitotane, stage, and tumor size. Local recurrence developed
in 2 of 14 irradiated patients compared with 11 of 14 who did not receive RT.
However, despite this apparent benefit, neither disease-free nor overall
survival were significantly better in irradiated patients.
A later analysis of patterns of failure in these patients suggested that many of
the recurrences developed in the inter-aortocaval region [121]. This
observation emphasizes the importance of covering this area in the radiation
portal, as well as the ipsilateral lymphatic drainage bed, if adjuvant RT is
planned.
●A retrospective study from the University of Michigan compared outcomes
of 20 patients with localized ACC undergoing an R0/R1 resection followed by
postoperative RT (median dose 55 Gy) with those of 20 patients treated
contemporaneously with surgery alone, matched for stage, surgical margin
status, tumor grade, and use of adjuvant mitotane [124]. At a median follow-
up of 34 months, local recurrence was significantly more frequent in those
not receiving RT, with local recurrence in 12 patients versus one (60 versus 5
percent, HR 12.59, 95% CI 1.62-97.88). As was seen in the German ACC
registry analysis, this benefit did not translate into an improvement in
recurrence-free or overall survival.
●In contrast, in a retrospective study of 16 patients with ACC who had
undergone either surgery followed by adjuvant RT (n = 16) or surgery only (n
= 32), the rate of local recurrence was not significantly reduced by adjuvant
RT (7 of 16 [44 percent] and 10 of 32 [31.3 percent] in the RT and control
groups, respectively) [127].
●In the largest single institution study (including 39 patients), gross surgical
resection of ACC improved local recurrence-free survival, all recurrence-free
survival, and overall survival in a propensity-matched analysis. Therefore, we
suggest that adjuvant RT should be considered a part of multidisciplinary
management for patients with ACC [128].

Larger, prospective, randomized studies are needed to better define the role of
adjuvant RT after resection of ACC, in particular to confirm if the decrease in local
recurrence rate provides any overall survival benefit.

Our approach is similar to that of the investigators from the German ACC registry,
who recommended adjuvant RT for all patients with microscopically incomplete
(R1 or R2) or uncertain (Rx) margin status and for those with stage III disease
(according to ENSAT criteria (table 4)) even if resection has been complete [4,121].
They suggest that adjuvant RT be considered for patients who have had a
706
complete (R0) resection of a tumor >8 cm in size with tumor invasion of the blood
vessels (but not large tumor thrombus in the vena cava) and a Ki67 proliferative
index of >10 percent, and for patients who have intraoperative violation of the
tumor capsule, tumor spillage, or dissemination of "necrotic" fluid. Because the
risk of a local recurrence is highest in the first two years, they recommend starting
RT no later than three months after surgery.

There is disagreement as to the role of adjuvant RT in patients who have

undergone laparoscopic rather than open resection, and there are no published
data to help in resolving this point. There are different opinions regarding the
safety and efficacy of laparoscopic resection of primary ACC. Thus, it is
understandable that there are different opinions regarding the use of adjuvant RT
in the setting of laparoscopic resection for a resected ACC that does not otherwise
meet the criteria described above for adjuvant RT (tumor spillage at the time of
resection, incompletely resected, high-grade lesion). The German ACC group does
not recommend adjuvant RT in this situation.

The Adrenal Cancer Program at the University of Michigan, as reflected in the

opinion of one of the authors (GH), does not recommend laparoscopic
adrenalectomy for ACC and hence is more aggressive in recommending adjuvant
RT following a laparoscopic resection of ACC if there is any concern that a sufficient
oncologic resection was not performed. The other author (AL) does not pursue
adjuvant RT after a laparoscopic resection (ACC at pathology, low ACC risk by
preoperative investigation and German ACC criteria described above) as long as
the laparoscopic surgery was performed by an expert surgeon (ie, one who
specializes in and is trained in minimally invasive endocrine or oncology surgery,
who practices in a large academic referral center, and who does adrenal surgery
weekly).

RECURRENT OR ADVANCED ADRENOCORTICAL CANCERThere is no

curative therapy for metastatic or recurrent adrenocortical carcinoma (ACC).
However, the symptoms of steroid excess can be controlled by medical therapy. In
most cases, metastatic disease is fatal within one year, although there are rare
long-term responses ascribed to chemotherapy with or
without mitotane [3,112,129,130].
Local therapy
Surgery — For patients with isolated, locally recurrent ACC that is surgically
accessible, we suggest complete surgical resection followed by mitotane therapy.

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Where complete removal is feasible, aggressive surgical resection of locally
recurrent disease, with the aim of achieving negative surgical margins, should be
undertaken [75,76,131-133]. The best candidates are those who have potentially
resectable disease with a disease-free interval of at least one year after initial
treatment.
Resection may also be considered in the rare patient who presents with
synchronous limited, potentially resectable hepatic or pulmonary metastases
[134]. Resection of locally recurrent disease may also be indicated for patients in
whom surgery will be able to remove a majority of tumor burden or decrease
severe hypercortisolism that is otherwise difficult to control; however, recovery
from surgery may be slow, delaying administration of systemic therapy [6]. Thus,
this approach should be limited to selected patients with uncontrollable
symptomatic hormone excess or who are in imminent danger from organ invasion
or compression.
Aggressive resection of locally recurrent or distant disease may prolong survival in
some patients [6,7,131-133,135,136], and at least some reports suggest that long-
term survival rates are higher among patients who undergo resection compared
with those who do not [86,131,134,137,138]:
●In a series of 47 patients with ACC undergoing resection for locally recurrent
or distant metastatic disease at Memorial Sloan-Kettering Cancer Center
(MSKCC), five-year survival rates for patients with completely and
incompletely resected locally recurrent disease were 57 and 0 percent,
respectively [131].
●Similar outcomes were reported in a series of 57 patients undergoing 116
procedures (23 for liver metastases, 48 for pulmonary metastases, 13 for
metastases at other sites, 22 for abdominal disease including local
recurrences) for recurrent or metastatic ACC [138]. Five-year survival was 41
percent, and median survival was significantly longer for those with a
disease-free interval >12 months (6.6 versus 1.7 years). The use of
chemotherapy and mitotane had no effect on survival.
●In another report of 28 patients undergoing resection for liver metastases
from ACC (25 isolated, three with extrahepatic metastases), the five-year
survival rate was 39 percent [136].
Response to neoadjuvant chemotherapy may be useful in defining which patients
may benefit from surgical intervention. Radiofrequency ablation (RFA) is an
alternative approach for these patients. (See 'Radiofrequency ablation' below.)
Radiation therapy — For palliation of symptoms from locally advanced or distant
metastatic disease (eg, a bone metastasis), we use palliative radiation therapy (RT).
The available data support the palliative benefit of RT for unresectable local tumor

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that is causing local symptoms or for distant symptomatic metastases, such as in
bone [6,75,121,139-141]. In a survey of published reports totaling 91 patients
receiving palliative RT for advanced ACC from the German ACC registry, benefit (ie,
pain relief, reduction in paresthesia or paralysis) was observed in 57 percent [121].
(See "Radiation therapy for the management of painful bone metastases".)
Stereotactic radiosurgery may be beneficial for patients who have a good
performance status and limited metastases to the brain, lung, or liver.
(See "Stereotactic cranial radiosurgery" and "Radiation therapy techniques in
cancer treatment", section on 'Stereotactic radiation therapy techniques'.)
Radiofrequency ablation — Percutaneous RFA may provide short-term local
control of an unresectable primary tumor, particularly for those <5 cm in diameter
[6,142,143]. The long-term impact on survival is unknown. RFA has also been used
to treat small liver metastases [142,144,145].
Systemic therapy
Mitotane monotherapy — Primary treatment with mitotane may be indicated for
patients who have histologically proven ACC in whom surgery is incomplete, not
feasible, or contraindicated.
The quality of the available literature on mitotane monotherapy is poor, and the
results are highly variable. Most studies were conducted in early years without
monitoring of tumor response with adequate imaging. Moreover, mitotane has
often been given in a suboptimal way; much of the variability in outcomes may be
attributable to subtherapeutic serum concentrations (see 'Suggested
regimen' above). No data are available on survival or drug tolerance among
patients with unresectable disease who are treated with an approach that includes
monitoring of plasma mitotane concentrations (see 'Suggested regimen' above
and 'Toxicities' above). Determinants of mitotane efficacy are unknown;
CYP2W1, which is highly expressed in ACC, may represent a new predictive marker
for the response to mitotane treatment [103].
Treatment benefits are generally short lived [19,20], and survival is not consistently
prolonged. While there are isolated case reports of long-term disease control and
rare cases of prolonged complete remission in patients with inoperable or
metastatic disease [112,146-148], these are almost always patients with low-grade
disease. In several studies of primary mitotane therapy, the median survival was
only 6.5 months [72,149], no different from that expected in untreated patients
[20,85,150].
The main benefit of mitotane for patients with unresectable advanced disease is
usually reduction in symptoms of hypercortisolism (weakness, myopathy, diabetes,
immunosuppression, insomnia). While a decrease in excess hormone production is
reported in up to 75 percent of patients and tumor size is reduced in as many as

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one-third of cases [72,83,84,149], mitotane therapy alone is usually not sufficient
to significantly decrease cortisol levels or have long-lasting effects on tumor
growth. In a review of nine prospective series totaling 246 patients with advanced
ACC (not restricted to primary therapy), the estimated mean objective regression
rate with mitotane was only 26 percent [17]. Furthermore, some patients who have
an objective response with mitotane are incapacitated by the side effects of the
drug [151]. (See 'Toxicities' above.)
We reserve mitotane monotherapy for the few patients who have a minimal
burden (low number of tumor-involved organs) of low-grade (ie, low mitotic rate)
disease and have recurred relatively late (two to three years) after surgery. These
are the patients who are likely to have a prolonged survival [53]. In the setting of
extensive (multiple tumor-involved organs), rapidly progressive, high-grade
disease, mitotane is almost always administered in combination with cytotoxic
chemotherapy because of a generally accepted view that response rates are
higher. (See 'Chemotherapy plus mitotane' below.)
For patients with active disease and visible lesions, mitotane is typically continued
lifelong or until disease progression. However, several protocols for new targeted
agents for ACC specifically require discontinuation of mitotane because of
potentially detrimental drug interactions. Specific issues related to dosing,
monitoring of serum levels during therapy, side effects, and drug interactions are
addressed above. (See 'Suggested regimen' above and 'Drug interactions' above
and 'Toxicities' above.)
For patients whose disease progresses while receiving adjuvant mitotane, or
whose disease is high grade or rapidly progressing (on or off mitotane), our usual
practice is to initiate cytotoxic chemotherapy, oftentimes while continuing
mitotane, given the higher response rates.
Cytotoxic chemotherapy — Many cytotoxic drugs have been studied in patients
with advanced ACC, either alone or in combination with mitotane. Few non-
mitotane-containing chemotherapy regimens have been tested in ACC, largely due
to the rarity of the disease. Progress in therapy of advanced ACC has been limited
by the rarity of the disease and the relatively small number of patients in each
study.
●Although they are frequently used, single agents such
as cisplatin or doxorubicin are associated with response rates that are
generally less than 30 percent and of short duration [152-154].
●Results are disappointing for chemotherapy combinations when not
combined with mitotane [155-160].
Chemotherapy plus mitotane — It is generally accepted, though not proven, that
chemotherapy plus mitotane produces better outcomes than does mitotane alone.

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Therefore, in the setting of extensive (multiple tumor-involved organs), rapidly
progressive, high-grade disease, mitotane is almost always administered in
combination with cytotoxic chemotherapy. For patients receiving combined
therapy, we suggest mitotane in combination with etoposide, doxorubicin,
and cisplatin (EDP) as front-line therapy.
Mitotane increases the cytotoxic activity of other chemotherapeutic drugs on
human adrenal carcinoma cells in vitro, possibly by acting as an antagonist of the
multidrug resistance (MDR) protein, which is found in high concentrations in ACC,
and functions as a drug efflux pump [161,162]. These data provide a rationale for
combination therapy.
A few prospective trials have explored combination regimens that
contain mitotane. Although no chemotherapy regimen has been shown to improve
overall survival in patients with advanced ACC, some of the more encouraging
results have been with the combination of EDP plus mitotane:
●An early study of EDP plus mitotane in 72 ACC patients described an overall
response rate of 49 percent [163].
●The largest trial of advanced ACC to date, the First International Randomized
trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment
(FIRM-ACT), randomly assigned 304 patients with advanced ACC not
amenable to radical surgery to mitotane plus either EDP or streptozotocin
[164]. Rates of objective tumor response (23 versus 9 percent) and median
progression-free survival (5 versus 2.1 months) were both significantly better
in the EDP-mitotane (EDP-M) group, although these benefits did not translate
into a significantly prolonged survival (median 14.8 versus 12 months). This
lack of significant difference in overall survival, despite better progression-
free survival for EDP-M, is possibly due to the crossover design of the study
since EDP-M was superior as a second-line treatment as well. Rates of serious
adverse events did not differ significantly between treatments. The efficacy of
both regimens as second-line therapy was similar to their efficacy as first-line
therapy.
●Results with other chemotherapy drugs combined with mitotane seem to be
less promising [120,165-168].
Newer and investigational approaches — Several novel approaches are under
study for treatment of advanced ACC, many of which represent molecularly
targeted therapies. These therapies have only been evaluated in the context of
clinical trials, often after progression of disease on standard therapies
(eg, mitotane or EDP-mitotane).
Immunotherapy — Programmed cell death ligand (PD-L1) is expressed in some
adrenocortical carcinomas (ACCs) and their associated tumor infiltrating

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lymphocytes, leading to interest in the use of checkpoint inhibitor immunotherapy
in these patients. Further studies are needed to determine predictors of
immunotherapy response in those with ACC as treatment appears effective
regardless of microsatellite instability-high (MSI-H) status [169].
Pembrolizumab has shown a good safety profile and response rates ranging from
14 to 50 percent in phase II studies conducted in both adult and pediatric
populations [169-171]:
●In an open-label, single-arm phase II study, 39 adult patients with advanced
ACC were treated with pembrolizumab [169]. A majority had received prior
systemic therapy (either mitotane or platinum-based chemotherapy). At a
median follow-up of approximately 18 months, the objective response rate
was 23 percent (9 patients); median progression-free and overall survival
were 2 and 24 months respectively. Additionally, responses were seen in two
of six patients with microsatellite instability high/mismatch repair deficient
(MSI-H/MMR-D) tumors. Rates of grade ≥3 toxicity were low (13 percent).
●Similar results were seen in another open-label, single-arm phase II trial. In
this study, 16 adult patients with ACC refractory to previous therapies
(approximately one-half with cortisol-producing tumors) were treated with
the programmed death 1 (PD-1) inhibitor pembrolizumab [170]. At
approximately seven-month follow-up, objective responses were seen in two
patients (14 percent) and stable disease in seven patients (50 percent). Rates
of grade ≥3 toxicities were low (13 percent), with only one patient
discontinuing therapy due to pulmonary toxicity.
●In a phase I-II open label trial of pembrolizumab (KEYNOTE-051), which
enrolled 154 pediatric patients with various relapsed solid tumors, two of
four patients with adrenocortical carcinoma achieved a partial response
[171].
Other approaches
●IGF1R inhibitors – Approximately 80 percent of ACCs overexpress insulin-
like growth factor (IGF) type 2 (IGF-2), which is known to signal predominantly
through the IGF-1 receptor (IGF1R).
While preclinical and early phase studies of monoclonal antibodies or small
molecules inhibiting IFG1R were initially promising [172-175], a subsequent
phase I-II trial of the anti-IGF1R antibody cixutumumab demonstrated only
limited overall efficacy [176]. Additionally, a placebo-controlled phase III trial
of linsitinib, an oral small molecule of both the IGF1R and insulin receptor,
did not demonstrate an improvement in disease-free or overall survival in
patients with advanced ACC [177]. However, partial responses and disease
stabilization in a subset of patients were observed with these drugs as single

712
 agents [176-178] and in combination with other drugs (such as temsirolimus)
[179].
Although we do not offer IGF1R inhibitors in patient with advanced ACC,
further studies may determine molecular markers that can predict which
patients may benefit from this approach.
●VEGF inhibitors – Vascular endothelial growth factor (VEGF) is upregulated
in ACC tumor tissue, and some studies have found that circulating VEGF
levels are significantly greater in patients with ACC as compared with those
with adrenal adenomas.
While case reports suggested activity of the antiangiogenic
agents thalidomide [180,181], sorafenib, and sunitinib [180-183], subsequent
phase II trials have demonstrated limited efficacy of VEGF inhibitors both as
single agents (eg, axitinib [184], sunitinib [185]), or in combination with
chemotherapy (eg, bevacizumab plus capecitabine [186]; sorafenib plus
weekly paclitaxel [187]).
●EGFR inhibitors – The finding that over 80 percent of ACCs express the
epidermal growth factor receptor (EGFR) [188,189] provides a rationale for
the study of agents that target the EGFR. Unfortunately, salvage therapy with
the small molecular EGFR inhibitor erlotinib in combination
with gemcitabine was of little benefit in a trial of 10 assessable patients with
advanced ACC who had failed at least two other systemic chemotherapy
regimens [190]. Only one patient experienced a minor response, while eight
patients experienced disease progression.
●Radionuclide therapy – ACC can also be targeted with therapeutic
radionuclides. In a study testing the efficacy of iodine-131-metomidate in 11
patients with refractory/advanced ACC, there was only a single partial
response; however, long-term disease stabilization was achieved in five
patients [191].
Medical treatment of hormone excess
Hypercortisolism — Adrenal function should be closely monitored in patients with
ACC because they can have either adrenal insufficiency (caused by surgery
or mitotane) or excess cortisol secretion (caused by persistent or recurrent tumor).
In patients with hypercortisolism (either those who are not taking mitotane or
those whose hypercortisolism is not controlled by mitotane), addition of a more
specific adrenal enzyme inhibitor is often required. Control of hypercortisolism is
important as patients can die prematurely of infections related to
immunosuppression induced by their hypercortisolism and chemotherapy rather
than by tumor burden.

713
While there have been no published large series to determine which available
steroidogenic enzyme inhibitors result in better control, we
consider metyrapone as the first drug of choice in patients with ACC and
hypercortisolism. While ketoconazole is effective in benign adrenal disease, it is
our experience at the University of Michigan that it is rarely able to control the
hypercortisolism in ACC.
Metyrapone, which is now more easily available in North America (new distributor
HRA Pharma, Paris, France, via its specialty pharmacy Direct Success Inc. with
order form available on the web [192] or by phone at 1-855-674-7663), can be very
effective in ACC, achieving eucortisolemia within three to seven days. If
eucortisolism is not achieved with metyrapone, combination therapy
with ketoconazole and mitotane can be utilized. The choice of therapy has been
influenced by different drug availability in various countries.
Medical therapy of hypercortisolism is reviewed in detail separately, but
summarized briefly below (see "Medical therapy of hypercortisolism (Cushing's
syndrome)"):
●For patients with ACC, we suggest metyrapone starting at 250 mg four times
daily and increasing up to 6 g per day.
●If metyrapone alone is insufficient or not tolerated, ketoconazole is started
at 200 mg three times/day, increasing daily as needed to 400 mg three
times/day. Higher doses are seldom more effective.
●Their effect can be assessed within a few days by measuring 24-hour urine
cortisol on a frequent basis initially. Combination of both drugs
and mitotane may be necessary to achieve adequate control.
●In severe uncontrolled cases, addition of mifepristone, a glucocorticoid
receptor antagonist, can be beneficial [193].
●In acute situations with patients who are unable to take drugs orally,
intravenous etomidate (which blocks 11-beta-hydroxylase) can be used in a
low, nonhypnotic dose of 0.3 mg/kg per hour. However, this drug is difficult
to use and requires inpatient monitoring. (See "Medical therapy of
hypercortisolism (Cushing's syndrome)" and "Pharmacology and toxicity of
adrenal enzyme inhibitors and adrenolytic agents".)
Adrenal insufficiency is managed as described above using replacement mainly
with hydrocortisone. Aldosterone deficiency is replaced with addition
of fludrocortisone (0.1 to 0.3 mg daily) and adjusted to restore normal blood
pressure and serum levels of potassium and renin. (See 'Adrenal
insufficiency' above.)
For patients who have increased hypercortisolism and are being treated
with metyrapone, salt retention and hypertension can occur because of increased

714
production of the mineralocorticoid deoxycorticosterone. We routinely use a
mineralocorticoid receptor inhibitor (spironolactone or eplerenone) or amiloride in
this situation, adding diuretics and additional antihypertensive drugs if necessary.

When potassium-sparing diuretics are used in association with potassium

supplements, frequent serum potassium monitoring is necessary as acute
hyperkalemia can occur when hypercortisolism becomes controlled or when renal
function is impaired. Adequate control of diabetes and high blood pressure are
also important.

Other — A small percentage of adult ACC and a high percentage of pediatric ACC
often presents with virilization with/without hypercortisolism. Virilization is best
treated with specific androgen blockage with androgen receptor inhibitors
(bicalutamide at 50 mg per day) or 5-alpha-reductase inhibition (finasteride at 5
mg per day).
While spironolactone is often used to control androgen effects in women with
androgen excess in the setting of benign disease, it is often ineffective in the
setting of ACC with very high serum androgen concentrations.
Rare estrogen-producing ACCs are treated with any of the antiestrogen therapies
(such as tamoxifen). (See "Management of gynecomastia", section on
'Pharmacologic therapy'.)
PROGNOSISOverall, survival is poor for adrenocortical carcinoma (ACC)
[18,19,43,47,49,75-77,131,194,195]. Five-year survival is approximately 45 to 60
percent for early stage disease and 10 to 25 percent for advanced stage disease
[3].
Past results suggested a poor prognosis even for patients with early stage disease
[13,19,26]. However, some contemporary series suggest that outcomes are
improving and that patients with these tumors are living longer [43,49,77,131], as
illustrated by the following data:
●Among 139 adults treated for ACC over a 20-year period at MD Anderson
Cancer Center, the five-year survival rate was 60 percent, despite the fact that
47 (34 percent) had distant metastases at diagnosis [49].
●In a second series of 113 patients treated at Memorial Sloan-Kettering
Cancer Center (MSKCC), those who underwent complete resection of primary
(not recurrent) disease (n = 68) had a five-year survival of 55 percent (median
74 months) [131].
●Patients followed closely after surgery for stage II ACC in specialized centers
and who received adjuvant mitotane had a much better prognosis than
previously reported for this stage [82]. (See 'Adjuvant mitotane' above.)

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 ●The improved prognosis of treated patients in contemporary series can be
illustrated by the previously described French Association of Endocrine
Surgery series of 253 patients (age range 5 to 81 years, mean 47 years) with
ACC treated between 1978 and 1997 [43]. The distribution by stage was as
follows: stage I, 16; stage II, 126; stage III (locoregionally advanced disease),
57; stage IV (distant metastases only), 54 patients. Potentially curative
surgery was performed in 182 (72 percent), and postoperative mitotane was
administered to 135 (54 percent) patients.
Five-year survival rates were 38 percent overall and 50 percent in the
curatively treated group. Stratified by disease stage, five-year survival rates
were 66, 58, 24, and 0 percent for stage I, II, III, and IV (metastatic) disease,
respectively. Despite no significant difference in the numbers of patients
undergoing potentially curative surgery, outcomes were significantly better
among those treated after 1988.
The reasons for the improved outcomes from treatment of ACC over time are not
clear. Although the use of mitotane increased over the 20-year time period, this
had a significant impact on prognosis in multivariate analysis only for those
patients who did not undergo potentially curative resection.
SPECIAL POPULATIONS
Pediatric patients — Pediatric patients with adrenocortical carcinoma (ACC) differ
from adults in clinicopathologic characteristics, prognosis, and management.
Clinicopathologic characteristics
●Familial cancer syndromes – Most children with adrenocortical tumors
have associated familial cancer syndromes (mainly Beckwith-Wiedemann
syndrome and Li-Fraumeni syndrome) [196]. (See "Clinical presentation and
evaluation of adrenocortical tumors", section on 'Hereditary cancer
syndromes' and "Li-Fraumeni syndrome" and "Beckwith-Wiedemann
syndrome".)
●Histopathology – Unlike adults, severe histopathologic features in children,
such as high Weiss score, are not reliable predictors of poor prognosis [61].
(See "Clinical presentation and evaluation of adrenocortical tumors", section
on 'Fine-needle aspiration biopsy'.)
●Germline mutations in TP53 – Approximately 50 percent or more of
pediatric patients with ACCs in North America have germline mutations in
the TP53  gene (which encodes the p53 tumor protein) [197-199]. In contrast,
approximately 8 percent of adults have these mutations [200]. Loss of
heterozygosity for 17p13 (the cytogenetic location of the TP53 gene) occurs in
25 to 70 percent of sporadic ACCs [200-203].

716
Prognosis — The prognosis in children who have ACC appears to be better than
that of adults, especially those for those with early-stage disease [44,195,204-207].
●In an observational series of 228 children and adolescents under age 20 with
ACC, the estimated five-year event-free survival (EFS) rate was 54 percent
overall; and for those with stage I or II disease, 91 and 53 percent,
respectively [44]. Stage I disease (completely excised nonmetastatic tumors
≤200 g), presenting signs of virilization alone, and age less than three years
were all associated with significantly better survival. In contrast, the
prognosis was poor for patients with metastatic or residual disease or larger
resected tumors (weighing more than 200 grams).
●Similar results were seen in an analysis of 85 patients with ACC under age 20
years reported to the National Cancer Institute (NCI) Surveillance,
Epidemiology, and End Results (SEER) database between 1973 and 2008
[208]. Younger patients (≤4 years old) were more likely to have favorable
features than older patients (4 to 19 years), including local disease (76 versus
31 percent), tumor size <10 cm (69 versus 31 percent), and better five-year
survival (91 versus 30 percent). In multivariate analysis, the most significant
independent predictors of disease-specific death were age greater than four
years and distant disease. After accounting for tumor size, the only significant
predictor of cancer-specific death was age 5 to 19 years.
Management — Because the clinicopathologic features and prognosis of ACC in
pediatric patients differs from that of adults, they should be managed at a center
with multidisciplinary expertise in pediatric ACC when possible [198]. An
International Pediatric Adrenocortical Tumor Registry has been established to
facilitate data collection, study, and treatment of these rare pediatric tumors [205].

There are limited prospective studies evaluating management strategies for

pediatric patients with ACC.

A prospective, single-arm study from the Children's Oncology Group (ARAR0332)

reported the survival outcomes of 78 pediatric patients with ACC who received
different treatment strategies based on disease stage as follows [199]:
●Stage I disease – Adrenalectomy alone
●Stage II disease – Adrenalectomy and retroperitoneal lymph node
dissection
●Stage III or IV (metastatic) disease – Mitotane plus chemotherapy
(etoposide, doxorubicin, and cisplatin [EDP]), followed by surgery of the
primary tumor and metastases as clinically indicated

717
At median follow-up of 60 months, the five-year EFS and overall survival (OS)
results were:

●All patients – 63 and 77 percent

●Stage I – 86 and 95 percent
●Stage II – 53 and 79 percent
●Stage III – 81 and 95 percent
●Stage IV – 7 and 16 percent
Approximately one-third (32 percent) of patients receiving mitotane plus
chemotherapy experienced significant treatment-related toxicity and could not
complete scheduled therapy. Thus, although patients without metastatic disease
who received chemotherapy (stage III disease) demonstrated improved survival
compared with those treated with adrenalectomy and lymph node dissection
alone (stage II disease), further treatment modifications may be necessary to
improve chemotherapy tolerance. This difference in survival also suggests that
lymph node dissection may not have been adequate to remove all
micrometastases. Other possible explanations include increased efficacy of
chemotherapy for treating micrometastases in stage III tumors, or more
aggressive biology in stage II tumors.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Adrenal cancer" and "Society guideline
links: Adrenal incidentaloma".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topic (see "Patient education: Adrenal cancer (The Basics)")

718
SUMMARY AND RECOMMENDATIONS
●Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy that can
cause Cushing's syndrome, virilization, hyperaldosteronism, feminization, an
abdominal mass, or no symptoms and be discovered incidentally.
(See "Clinical presentation and evaluation of adrenocortical tumors".)
●Past results suggest a poor prognosis even for patients with early stage
adrenal cancer. However, some contemporary series suggest that patients
with ACC are living longer. The reasons for the possible improvement in
prognosis are unclear, but adjuvant mitotane therapy appears to be
beneficial. (See 'Prognosis' above.)
●Progress in treating advanced ACC has been severely limited by the rarity of
the disease. However, multicenter clinical trials for recurrent and advanced
disease, several of which are studying molecularly targeted therapy, are in
progress. (See 'Newer and investigational approaches' above.)
Initial treatment, potentially resectable disease:
●The only potentially curative treatment for ACC is surgical resection.
Although resection is technically possible in most patients with stage I to III
disease, it is not curative for many, presumably because occult
micrometastases are present at the time of initial presentation. (See 'Initial
surgery' above.)
●For patients with potentially resectable stage I to III adrenocortical cancer
who are surgical candidates, we recommend complete surgical resection as
initial therapy (Grade 1B). We suggest open rather than laparoscopic
resection regardless of tumor size (Grade 2C). Suspicious lymph nodes
should be resected, but the benefit of routine lymphadenectomy has not
been fully established yet. (See 'Initial surgery' above.)
●We suggest adjuvant mitotane therapy for all patients who have a high risk
of disease recurrence after complete resection, including all those with high-
grade disease (Ki67 >10 percent or mitotic rate greater than 20 per 50 high-
power fields [HPF]), incompletely resected disease, intraoperative tumor
spillage or fracture, and some large tumors that are low grade but have
vascular or capsular invasion (Grade 2C). (See 'Adjuvant mitotane' above.)
The role of adjuvant mitotane for all patients with resected low-grade ACC is
unclear, but this approach is being studied in the ADIUVO trial, and eligible
patients should be encouraged to enroll. (See 'Indications' above.)
It is not known if cytotoxic chemotherapy alone or in combination
with mitotane is more effective than adjuvant mitotane alone. Although there
are no high-quality data to support this practice, a cisplatin-based adjuvant
regimen might be considered in conjunction with mitotane in patients who
719
are thought to be at high risk for an early recurrence, eg, very high Ki67
staining (>20 percent) and extensive vascular invasion/vena cava thrombus.
(See 'Adjuvant chemotherapy with or without mitotane' above.)
●The optimal duration of adjuvant mitotane therapy is not established. We
treat high-risk patients for five years. For those with a lower risk of
recurrence, we prefer five years of therapy but aim for at least two to three
years, as tolerated. (See 'Duration' above.)
●If available, serum monitoring during mitotane therapy should be used to
achieve therapeutic levels and avoid toxicity. Mitotane levels should be
maintained between 14 and 20 mcg/mL. (See 'Suggested regimen' above.)
●Glucocorticoid replacement is necessary following resection of cortisol-
secreting ACC. It should also be started in patients with non-cortisol-secreting
tumors when adjuvant mitotane therapy is initiated because the drug's
adrenolytic activity will result in adrenal insufficiency in most patients. We
use hydrocortisone rather than dexamethasone for glucocorticoid coverage.
Supraphysiologic doses become indicated because mitotane progressively
accelerates cortisol metabolism by induction of the P450 system.
(See 'Adrenal insufficiency' above.)
●Mitotane can also eventually cause aldosterone deficiency. We suggest
monitoring blood pressure at each visit, serum potassium at every three
months, and plasma renin every six months (table 3). When clinical and
biochemical signs of aldosterone deficiency become present, addition
of fludrocortisone (0.1 to 0.3 mg daily) is initiated and adjusted to restore
normal clinical and biochemical parameters. (See 'Adrenal
insufficiency' above.)
●We suggest the addition of postoperative radiation therapy (RT) for all
patients with incompletely resected ACC, stage III disease, those who have
tumor spillage at the time of resection, and for all patients with high-grade
ACC (>20 mitotic figures per 50 HPF) (Grade 2C). (See 'Adjuvant radiation
therapy' above.)
There is disagreement as to the role of adjuvant RT in patients who have
undergone laparoscopic resection for an ACC that otherwise does not meet
criteria for postoperative RT. (See 'Radiation therapy' above.)
Post-treatment surveillance includes computed tomography (CT) scans of the
chest and abdomen every three months for two years, then every six months
for five years. The benefit of fluorodeoxyglucose (FDG)-positron emission
tomography (PET) in the post-treatment surveillance strategy is controversial,
and practice is variable. (See 'Imaging' above.)

720
 For patients with a completely resected, steroid-producing ACC, some groups
monitor patients every three months for two years with steroid tumor
markers such as cortisol (measured in the morning
before hydrocortisone dose), dehydroepiandrosterone sulfate (DHEAS),
androstenedione, testosterone, estradiol, or mineralocorticoid based on the
steroid profile in the initial tumor. Other groups do not routinely screen for
recurrent hormone excess unless or until there is evidence of recurrent
disease. (See 'Biochemical' above.)
Unresectable, recurrent, or advanced disease:
●For patients with isolated, locally recurrent ACC that is surgically accessible,
we suggest complete surgical resection followed by mitotane therapy (Grade
2C) (see 'Local therapy' above). Resection may also be considered in the rare
patient who presents with limited, potentially resectable hepatic or
pulmonary metastases and for selected patients with uncontrollable
symptomatic hormone excess. (See 'Local therapy' above.)
●For patients with unresectable disease, mitotane monotherapy is a
reasonable option for patients with a limited burden of low-grade, slowly
progressive disease (see 'Mitotane monotherapy' above). However, for most
patients, we suggest combined mitotane plus chemotherapy rather than
mitotane or chemotherapy alone (Grade 2C).
For patients receiving combined therapy, we suggest mitotane in
combination with etoposide, doxorubicin, and cisplatin (EDP) rather than
streptozotocin (Grade 2C). If possible, patients should be referred to centers
conducting randomized clinical trials. (See 'Chemotherapy plus
mitotane' above.)
●Percutaneous radiofrequency ablation (RFA) may provide short-term local
control of an unresectable primary tumor, particularly for those <5 cm in
diameter. (See 'Radiofrequency ablation' above.)
●In patients with hypercortisolism (who are either not taking mitotane or
whose hypercortisolism is not controlled by mitotane), we
suggest metyrapone or, if necessary, its combined use with ketoconazole and
mitotane to achieve control of hypercortisolism. Appropriate control of
glucose, potassium levels, blood pressure, and infections are also important.
(See 'Medical treatment of hormone excess' above.)
●For palliation of symptoms from locally advanced or distant metastatic
disease (eg, a bone metastasis), we use palliative RT. (See 'Radiation
therapy' above.)

721
Treatment of primary aldosteronism
Author:
William F Young, Jr, MD, MSc
Section Editor:
Lynnette K Nieman, MD
Deputy Editor:
Kathryn A Martin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 20, 2021.
INTRODUCTIONPrimary and nonsuppressible hypersecretion of aldosterone is
an increasingly recognized, but still underdiagnosed, cause of hypertension. The
classic presenting signs of primary aldosteronism are hypertension and
hypokalemia, but potassium levels are frequently normal in current series of
primary aldosteronism.
The overall treatment goal in patients with primary aldosteronism is to prevent the
adverse outcomes associated with excess aldosterone, including hypertension,
hypokalemia, renal toxicity, and cardiovascular damage. The subtype-directed
treatment of primary aldosteronism will be reviewed here and in this algorithm
(algorithm 1). The pathophysiology, clinical manifestations, and diagnosis of this
disorder and other less common causes of mineralocorticoid excess are discussed
separately. (See "Pathophysiology and clinical features of primary
aldosteronism" and "Diagnosis of primary aldosteronism" and "Familial
hyperaldosteronism".)
OVERVIEW
Subtypes of primary aldosteronism — Renin-independent, incompletely
suppressible (primary) hypersecretion of aldosterone is an increasingly
recognized, but still underdiagnosed, cause of hypertension [1,2]; it is estimated to
be responsible up to 10 percent of hypertension in humans [3]. Many subtypes of
primary aldosteronism have been described since Conn's original report of the
aldosterone-producing adenoma (APA) in 1954 [4-7].

The subtypes of primary aldosteronism include:

●Bilateral idiopathic hyperaldosteronism (or idiopathic adrenal hyperplasia

[IHA], 60 to 70 percent). The underlying pathophysiology of the zona
glomerulosa autonomy in patients with IHA is unknown. (See 'Idiopathic
adrenal hyperplasia' below.)

722
 ●Unilateral APAs (30 to 40 percent). Somatic mutations in KCNJ5  or other ion
channels  appear to be present in most patients with APAs.
(See "Pathophysiology and clinical features of primary aldosteronism",
section on 'Mutations in aldosterone-producing adenomas'.)
●Unilateral hyperplasia or primary adrenal hyperplasia (PAH), caused by
micronodular or macronodular hyperplasia of the zona glomerulosa of
predominantly one adrenal gland (approximately 3 percent) [7]. While less
common, the clinical presentation and outcome of these patients is similar to
those with APAs [8]. (See 'Patients with unilateral adenoma or
hyperplasia' below.)

This topic reviews only the treatment of the above subtypes of primary
aldosteronism. Other causes are reviewed elsewhere:

●Familial hyperaldosteronism type I (glucocorticoid-remediable

aldosteronism [GRA]), type II (the familial occurrence of APA or bilateral IHA
or both), type III (germline mutations in the KCNJ5 potassium channel), and
type IV (mutations in the CACNA1H gene, which encodes the alpha subunit of
an L-type, voltage-gated calcium channel, Cav3.2). The four types of familial
hyperaldosteronism and their treatment are reviewed in detail separately.
(See "Familial hyperaldosteronism".)
●Pure aldosterone-producing adrenocortical carcinomas and ectopic
aldosterone-secreting tumors (eg, neoplasms in the ovary or kidney). Patients
with these disorders are reviewed separately. (See "Clinical presentation and
evaluation of adrenocortical tumors", section on 'Adrenocortical carcinoma'.)
Treatment goals — The overall treatment goal in patients with primary
aldosteronism is to prevent the morbidity and mortality associated with
hypertension, hypokalemia, renal toxicity, and cardiovascular damage. Excessive
secretion of aldosterone is associated with an increased risk of cardiovascular
events (which are independent of hypokalemia), including an increase in left
ventricular (LV) mass measurements, stroke, myocardial infarction, heart failure,
and atrial fibrillation [6,7,9-12]. The excess cardiovascular risk resolves after
appropriate treatment of the mineralocorticoid excess.
Therefore, the goals of therapy for primary aldosteronism due to either unilateral
or bilateral adrenal disease are the same and include:
●Reversal of the adverse cardiovascular effects of hyperaldosteronism
●Normalization of the serum potassium in patients with hypokalemia
●Normalization of the blood pressure

723
Determination of the correct subtype diagnosis is essential since the treatment of
primary aldosteronism is based upon the cause (algorithm 1). (See "Diagnosis of
primary aldosteronism", section on 'Subtype classification'.)

Once the correct subtype diagnosis is confirmed, the approach to management

includes the following:

●For patients with unilateral disease (APAs or unilateral hyperplasia), we

suggest laparoscopic adrenalectomy. Surgery is curative only in patients with
unilateral disease. Although surgery is the preferred approach,
mineralocorticoid receptor antagonists (MRAs), when given at an appropriate
dosage, are an alternative in patients who are not candidates for or who
decline surgery. (See 'Patients with unilateral adenoma or
hyperplasia' below.)
●For patients with bilateral idiopathic hyperaldosteronism, we suggest MRA
therapy. (See 'First line: Mineralocorticoid receptor antagonists' below.)
•Amiloride, a potassium-sparing diuretic, is an alternative for patients
intolerant of both spironolactone and eplerenone. (See 'Second line:
Potassium-sparing diuretics' below.)
•We suggest not performing subtotal adrenalectomy in these patients.
(See 'Role of subtotal adrenalectomy' below.)
Our approach follows that of the 2016 Endocrine Society clinical practice guidelines
for the diagnosis and treatment of primary aldosteronism [13]. (See "Diagnosis of
primary aldosteronism", section on 'Case detection'.)
PATIENTS WITH UNILATERAL ADENOMA OR HYPERPLASIA
Laparoscopic adrenalectomy — Surgery is the preferred treatment for patients
with unilateral disease (aldosterone-producing adenomas [APAs] or unilateral
hyperplasia). Unilateral adrenalectomy in these patients induces a marked
reduction in aldosterone secretion and correction of the hypokalemia in almost all
patients [7,14,15]. Hypertension is improved in all and is cured in approximately 35
to 60 percent of patients [7,14-18].
We suggest laparoscopic adrenalectomy (by an experienced endocrine surgeon)
over open adrenalectomy because it is associated with shorter hospital stays and
fewer complications [19-21].
We also suggest resection of the entire affected adrenal gland rather than a
laparoscopic partial adrenalectomy (removal of an adenoma, leaving the
remaining gland intact). Partial adrenalectomy has been tried as a strategy to
further reduce surgical morbidity, but it is an inadequate procedure in many cases.
This was illustrated in a series of 92 patients with primary aldosteronism
undergoing laparoscopic adrenalectomy [22]. Postoperatively, all 63 patients with
724
total adrenalectomy had improved blood pressure and normal plasma
aldosterone, while 2 of 29 with partial adrenalectomy had persistent hypertension
and high plasma aldosterone. Of the 63 removed adrenal glands, 17 (27 percent)
contained multiple nodules along with what was thought to be the hypersecretory
adenoma. Using sensitive pathologic methods, zona glomerulosa hyperplasia and
nodules were observed adjacent to the resected aldosteronoma in 17 of 25 (68
percent) of cases studied [23].
These findings were further confirmed in a study of 55 patients with primary
aldosteronism who underwent adrenalectomy; three (5.5 percent) had persistent
hyperaldosteronism postoperatively [24]. All three patients had undergone partial
adrenalectomy to remove a computed tomography (CT)-detected nodule present
on the same side with adrenal vein sampling (AVS) lateralization. However, in the
two cases with available data, immunohistochemistry showed a CYP11B2-negative
nodule [24]. Thus, CT-detected adrenal nodules are not always a source of
aldosterone excess, even when ipsilateral with AVS lateralization.
Preoperative management — Preoperatively, hypertension should be controlled,
and hypokalemia should be corrected with potassium supplementation or a
mineralocorticoid receptor antagonist (MRA) (eg, spironolactone or eplerenone)
[2]. The blood pressure response to spironolactone preoperatively often predicts
the blood pressure response to unilateral adrenalectomy in patients with APAs.
(See 'First line: Mineralocorticoid receptor antagonists' below.)
Postoperative management — Postoperative management after unilateral
adrenalectomy should include the following [1,6]:
●Plasma aldosterone should be measured the day after surgery to assess for
cure. This should be a morning venipuncture, just as is done for the initial
evaluation. An undetectable plasma aldosterone concentration confirms
correct preoperative subtype assignment and long-term cure (analogous to a
low serum cortisol the day after pituitary surgery for Cushing's syndrome,
which predicts a long-term cure). However, if the postoperative plasma
aldosterone concentration is >5 ng/dL, the patient should be followed closely
by monitoring daily home blood pressure measurements and weekly serum
potassium concentrations. Re-evaluation for persistent hyperaldosteronism is
indicated in those patients with either persistent hypokalemia or lack of
blood pressure improvement postoperatively.
●Potassium supplements and MRA (eg, spironolactone or eplerenone) should
be discontinued in all patients, and, if possible, antihypertensive therapy
should be decreased. When patients are treated with multiple
antihypertensive agents prior to surgery, postoperatively we either
discontinue or decrease the doses of those drugs that may predispose to

725
hyperkalemia (eg, angiotensin-converting enzyme [ACE] inhibitors and
angiotensin II receptor blockers [ARBs]) and, if needed for blood pressure
control, continue those that are potassium neutral (eg, calcium channel
blockers).
●Patients should be monitored closely for hyperkalemia, which may result
from transient hypoaldosteronism due to chronic suppression of renal renin
release and contralateral adrenal gland aldosterone secretion.
Serum potassium should be measured during the hospitalization and,
subsequently as an outpatient, once weekly for four weeks. In a
retrospective study of 192 patients with surgically treated primary
aldosteronism, 12 (6.3 percent) developed hyperkalemia (median serum
potassium 5.5 mmol/L), with a median time to onset of 13.5 days (range 7 to
55 days) [25]. Four patients received mineralocorticoid replacement therapy
with fludrocortisone. On univariate analysis, hyperkalemic patients had
slightly greater preoperative serum creatinine levels (1.2 versus 1 mg/dL),
higher postoperative creatinine (1.3 versus 1 mg/dL), lesser median
contralateral suppression index (0.14 versus 0.27), and larger adenomas (1.9
versus 1.4 cm). On multivariable logistic regression, the contralateral
aldosterone suppression index remained the only significant predictor of
postoperative hyperkalemia with an optimal cutoff of <0.47 [25].
In another retrospective study of 110 patients with APA who were treated
with unilateral adrenalectomy, 12 (11 percent) developed transient
postoperative hyperkalemia [26]. Prolonged hyperkalemia was observed in
six patients (5 percent), and these patients required mineralocorticoid
replacement therapy for 11 to 46 months. Preoperative decreased
glomerular filtration rate and increased serum creatinine, as well as
increased postoperative creatinine and microalbuminuria, were significant
predictors of hyperkalemia.
●Serum creatinine should be followed serially in patients who had renal
insufficiency preoperatively. Primary aldosteronism has been associated with
renal toxicity [27-30], and improvement of hypertension corrects renal
hyperfiltration and may unmask the preexisting renal damage. In a long-term
study that included 50 patients with primary aldosteronism and 100 patients
with primary hypertension (formerly called "essential" hypertension), during
30 to 90 days after surgical or medical intervention, the mean glomerular
filtration rate decreased in patients with primary aldosteronism by 13.6
mL/min but only by 2.1 mL/min in patients with primary hypertension despite
similar blood pressure values [27].

726
 ●The preferred intravenous fluid after surgery is isotonic saline without
potassium (unless the patient is still hypokalemic), and a sodium-rich diet
should be considered before and after discharge [6].
Outcomes
Hypertension — Although hypertension is cured in some patients, a lesser degree
of hypertension persists in as many as 40 to 65 percent of cases [14-18,31,32]. A
number of clinical features help to identify patients who are more likely to
experience complete resolution of their hypertension after adrenalectomy,
including [14]:
●Lack of family history of hypertension
●Shorter duration of hypertension
●Preoperative use of two or fewer antihypertensive agents
●Younger age
●Higher preoperative ratio of plasma aldosterone concentration to plasma
renin activity
●Higher urine aldosterone level
Persistent hypertension may be related to underlying primary hypertension and/or
the development of nephrosclerosis after a prolonged period of uncontrolled
hypertension [17,33]. It is also possible that an error in subtype assignment has
been made and that the patient has bilateral adrenal hyperplasia, a disorder that
usually should be treated medically, not with unilateral adrenalectomy. If the
patient has persistent primary aldosteronism after surgery, it should be treated
with an MRA (eg, spironolactone or eplerenone). As many as one-third of patients
thought to have a unilateral lesion on imaging studies have bilateral adrenal
hyperplasia on AVS. (See "Diagnosis of primary aldosteronism", section on 'Adrenal
vein sampling'.)
Biochemical outcomes — As indicated, if the preoperative subtype assignment
was correct (ie, unilateral hyperaldosteronism), the immediate postoperative
plasma aldosterone concentration should be low. In most patients, aldosterone
secretion from the remaining adrenal gland recovers over a couple of weeks as
renal renin release recovers from chronic suppression. If preoperative
hypokalemia was present, it should resolve in a matter of days. The concern in the
first several weeks after surgery is for hyporeninemic hypoaldosteronism and
resultant hyperkalemia (see 'Postoperative management' above). Patients who
have recurrent hypokalemia at any point following surgery should undergo formal
reevaluation with case detection testing for recurrent primary aldosteronism.
Left ventricular mass — Although it has been suggested that adrenalectomy is
more effective than MRA therapy for reduction of left ventricular (LV) mass [34], a
meta-analysis of four studies including 355 patients reported that while

727
adrenalectomy was more effective than medical therapy for blood pressure
reduction, both treatments had a similar effect on LV mass change [35,36].
Quality of life — Quality of life is low in patients with unilateral disease (APAs or
unilateral hyperplasia) when compared with healthy individuals but improves to
normal within 3 to 12 months of unilateral adrenalectomy [37,38]. The
improvement appears to be maintained at six months. Quality of life is also
improved by medical therapy, but not to the level found in the general population
[38,39]. (See 'Efficacy' below.)
Nonsurgical candidates — The goals of medical therapy in patients with
unilateral disease who refuse or are not candidates for surgery are the same as
those with bilateral disease receiving MRAs: correction of hypokalemia, restoration
of normal blood pressure, and reversal of the effects of hyperaldosteronism on the
heart. (See 'Medical therapy' below.)
Pharmacologic therapy — Although laparoscopic adrenalectomy is more cost
effective over time [40], the administration of an MRA is a reasonable alternative in
patients who refuse or are not candidates for surgery [41-44]. The efficacy of this
approach was illustrated in a study of 24 patients with adenomas who were
treated medically for at least five years [42]. The following results were reported:
●Systolic and diastolic blood pressures decreased from 175/106 to 129/79
mmHg
●The serum potassium concentration increased from 3.0 to 4.3 mEq/L
●Five tumors had increased in size by at least 0.5 cm (as determined by CT
scan), but there was no evidence of malignant transformation in any patient
However, one study suggests that patients with primary aldosteronism treated
with MRAs (if renin activity remains suppressed) have a higher rate of
cardiovascular events than patients with essential hypertension, independent of
blood pressure control. However, patients on higher doses of MRAs with
unsuppressed renin have no excess cardiovascular risk [45]. This was illustrated in
a cohort study of 602 patients with primary aldosteronism treated with MRAs and
41,853 age-matched patients with essential hypertension. The incidence of
cardiovascular events was higher in patients with primary aldosteronism on MRAs
than in patients with essential hypertension (56.3 versus 26.6 events per 1000
person-years, adjusted hazard ratio [HR] 1.91, 95% CI 1.63-2.25). Patients with
primary aldosteronism also had higher adjusted risks for incident mortality (HR
1.34, 95% CI 1.06-1.71), diabetes (HR 1.26, 95% CI 1.01-1.57), and atrial fibrillation
(HR 1.93, 95% CI 1.54-2.42).
The excess risks of cardiovascular events were independent of blood pressure
control and were limited to patients with primary aldosteronism whose renin
activity remained suppressed on MRAs (<1 microgram/L per hour) (adjusted HRs

728
2.83, 95% CI 2.11-3.80), whereas patients who were treated with higher MRA doses
and had unsuppressed renin (≥1 microgram/L per hour) had no significant excess
risk [45].
Not recommended: Ablative procedures — Although published data are limited,
some centers have advocated percutaneous ablative therapy for unilateral adrenal
adenomas, including percutaneous acetic acid injection and radiofrequency
ablation [46-48].

Percutaneous ablative therapy requires overnight hospitalization. It is also

associated with a variety of adverse effects, including hypertensive crisis,
abdominal pain, hematuria, pancreatitis, pneumothorax, bleeding, adrenal
abscess formation, risk of tumor seeding, and incomplete ablation.

Given the limited experience, uncertain success rate, and potential complications,
we cannot recommend adrenal percutaneous ablative therapy.

PATIENTS WITH BILATERAL DISEASEThere are four forms of primary

aldosteronism due to bilateral adrenal zona glomerulosa hyperplasia: idiopathic
adrenal hyperplasia (IHA); the rare glucocorticoid-remediable aldosteronism (GRA),
which responds to the administration of exogenous glucocorticoid; type III familial
hyperaldosteronism due to germline KCNJ5 potassium channel mutations; and
type IV due to mutations in the CACNA1H gene. As noted above, GRA and type III
and IV familial hyperaldosteronism are reviewed in detail separately. (See "Familial
hyperaldosteronism", section on 'Familial hyperaldosteronism type I (FH type I) or
glucocorticoid-remediable aldosteronism (GRA)' and "Familial
hyperaldosteronism", section on 'Familial hyperaldosteronism type III (FH type
III)'.)
Idiopathic adrenal hyperplasia — IHA is generally a milder disease than adrenal
adenoma, with less hypersecretion of aldosterone and less hypokalemia. Such
patients should be treated with a mineralocorticoid receptor antagonist (MRA).
However, in patients with severe primary aldosteronism (spontaneous
hypokalemia and serum aldosterone concentration >30 ng/dL) and who have
marked asymmetry on adrenal venous sampling (AVS) (aldosterone lateralization
ratio between 3 and 4), unilateral laparoscopic adrenalectomy can be considered
(algorithm 1) [49].
Medical therapy — We recommend that patients with bilateral adrenal
hyperplasia be treated with medical therapy and not adrenalectomy because:
●Blood pressure control is often inadequate with subtotal adrenalectomy

729
 ●The risks associated with bilateral adrenalectomy (including the need for
lifelong glucocorticoid and mineralocorticoid replacement) outweigh the
potential benefits
First line: Mineralocorticoid receptor antagonists — Optimal treatment of IHA
consists of mineralocorticoid receptor blockade
with spironolactone or eplerenone. Spironolactone has long been the drug of
choice; eplerenone, although shorter-acting, is more specific for the aldosterone
receptor and is associated with fewer side effects.
The goals of therapy are: raising serum potassium into the high-normal range,
normalization of the blood pressure, and reversal of the effects of
hyperaldosteronism on the heart and kidneys. (See 'Treatment goals' above.)
Choice of MRA — Our current approach is to start with the mineralocorticoid
receptor antagonist (MRA) spironolactone and, if endocrine side effects are
limiting, switch to eplerenone. Eplerenone is now available as a generic, but it
remains substantially more expensive than spironolactone.
Efficacy — One open-label study suggested
that spironolactone and eplerenone have a similar effect on blood pressure in
patients with primary aldosteronism [50]. However, a randomized, clinical trial in
patients with primary aldosteronism reported that spironolactone was more
effective for hypertension than eplerenone [51].
Dietary sodium restriction (<100 mEq/day), maintenance of ideal body weight,
avoidance of alcohol, and regular aerobic exercise contribute to the success of
pharmacologic therapy in almost any patient with hypertension [7].
In patients with bilateral adrenal hyperplasia, quality of life, as measured by the
validated Medical Outcomes Study Short Form 36 General Health Survey (SF-36),
improves during treatment with MRAs [39]. However, the improvement appears to
be more modest and occurs more slowly when compared with historical control
patients undergoing unilateral adrenalectomy for unilateral adrenal adenoma
[38,39].
Dosing and monitoring — When using spironolactone or, if not
tolerated, eplerenone, we suggest the following regimen, which is consistent with
the 2016 Endocrine Society guidelines [13].
●Spironolactone (or eplerenone) is titrated upward to a mid- to high-normal
serum potassium concentration without the aid of potassium supplements.
The spironolactone starting dose is 12.5 to 25 mg daily with food, which
increases drug absorption [1]. The dose can be increased every two weeks
until the target serum potassium of 4.5 mEq/L is reached. The typical
maximum dose is between 100 to 400 mg daily.

730
 The starting dose of eplerenone, which has 50 percent less mg per mg
potency than spironolactone, is 25 mg twice daily (total of 50 mg/day). The
maximum eplerenone dose approved by the US Food and Drug
Administration (FDA) for hypertension is 100 mg daily. However, to effectively
treat primary aldosteronism, higher doses are frequently required [51].
The target of a mid- to high-normal serum potassium concentration without
the aid of potassium supplements reflects the goal of blocking the
mineralocorticoid receptor from excess aldosterone effect. Another approach
is to monitor plasma renin activity with the goal level higher than 1
ng/mL/hour [45].
●The blood pressure goal is often difficult to achieve with monotherapy
because of concomitant essential hypertension [14-16].
(See 'Outcomes' above and 'Patients with persistent hypertension' below.)
●With each medication change, it is important to monitor the effect on both
blood pressure and serum potassium. Serum potassium, creatinine, and
blood pressure should be monitored frequently during the first four to six
weeks of medical therapy (especially in patients with renal insufficiency or
diabetes mellitus). Clinical course and circumstances dictate the frequency of
monitoring thereafter.
Precautions and side effects
●Spironolactone – There are some precautions with the use of
spironolactone:
•Serum potassium and creatinine should be monitored frequently during
the first four to six weeks of therapy, especially in patients with renal
insufficiency or diabetes mellitus. The clinical course and circumstances
dictate the frequency of subsequent monitoring.
•Concomitant therapy with salicylates or nonsteroidal antiinflammatory
drugs (NSAIDs) may interfere with the antihypertensive efficacy
of spironolactone (and other antihypertensive medications).
Spironolactone is also a progesterone receptor agonist and androgen
receptor antagonist, resulting in side effects such as breast tenderness and
menstrual irregularities in women and impotence, decreased libido, and
gynecomastia in men [42,43]. In a review of 699 patients with primary
aldosteronism treated with spironolactone, the incidence of gynecomastia
was dose dependent: 6.9 percent at doses below 50 mg/day and 52 percent
at doses above 150 mg/day [42]. Spironolactone may also be associated with
minor gastrointestinal symptoms. (See "Clinical features, diagnosis, and
evaluation of gynecomastia in adults".)

731
 ●Eplerenone – As noted, eplerenone may be less effective
than spironolactone for hypertension, but it has fewer side effects.
Eplerenone is a highly selective MRA.
In a multicenter trial, 141 patients were randomized to treatment
with spironolactone (75 to 225 mg once daily) or eplerenone (100 to 300 mg
once daily) [51]. Changes from baseline in diastolic blood pressure were less
on eplerenone (-5.6±1.3 SEM mmHg) than spironolactone (-12.5±1.3 SEM
mmHg).
Compared with spironolactone, eplerenone has 0.1 percent of the binding
affinity to androgen receptors and less than 1 percent of the binding affinity
to progesterone receptors, properties that are favorable for minimizing side
effects. In the multicenter trial above, eplerenone was associated with a
lower incidence of endocrine side effects when compared with
spironolactone. The overall incidence of side effects was similar, but more
patients receiving spironolactone developed gynecomastia or, in women,
mastodynia (21.1 versus 0 percent).
Because of its short half-life, eplerenone is more effective if given twice daily.
Thus, until more data become available, it is reasonable to start
with spironolactone and, if endocrine side effects are limiting, switch to
eplerenone.
Patients with persistent hypertension — If hypertension persists, we add
another antihypertensive drug (eg, 12.5 to 25 mg
of hydrochlorothiazide or chlorthalidone daily) or an angiotensin-converting
enzyme (ACE) inhibitor (eg, lisinopril 5 to 10 mg daily). The efficacy of an ACE
inhibitor in the low plasma renin state may, in part, reflect the role of low
concentrations of angiotensin II as an aldosterone secretagogue in adrenal
hyperplasia.
Second line: Potassium-sparing diuretics — Potassium-sparing diuretics are an
alternative for patients intolerant of both spironolactone and eplerenone [52].
These drugs (amiloride, triamterene) block the aldosterone-sensitive sodium
channel in the collecting tubules, lowering the blood pressure and raising the
serum potassium concentration [52,53]. However, these drugs
are not recommended for first-line therapy, because of persistence of the effect of
the hyperaldosteronism at the mineralocorticoid receptor, with its possible
deleterious cardiovascular effects. (See "Mechanism of action of diuretics", section
on 'Potassium-sparing diuretics'.)
Amiloride dosing may be started at 5 mg twice daily and increased to the dose
needed to correct the hypokalemia. If the hypertension persists, a second-step
drug should be added. Low doses of a thiazide diuretic (eg, 12.5 to 25 mg

732
of hydrochlorothiazide or chlorthalidone daily) are preferred because
hypervolemia is a major reason for resistance to amiloride [42,43].
Role of subtotal adrenalectomy — Subtotal adrenalectomy has been tried in
patients with IHA, but only a minority of patients have a clinically significant
hypotensive response [54]. However, unilateral adrenalectomy in patients with
bilateral adrenal hyperplasia does have the potential to effectively "debulk" the
amount of adrenal tissue responsible for aldosterone hypersecretion and may, in
selected patients, provide improved blood pressure control (algorithm 1) [49].
However, the risk of long-term morbidity from mild hyperaldosteronism from the
remaining gland has not been defined.
PREGNANCYPrimary aldosteronism is uncommon in pregnancy, with fewer
than 40 patients reported in the medical literature; most patients have had
aldosterone-producing adenomas (APA) [55-58]. Primary aldosteronism can lead to
intrauterine growth retardation, preterm delivery, intrauterine fetal demise,
preeclampsia, and placental abruption [59,60].
An unusual feature of primary aldosteronism during pregnancy is that the degree
of disease may be either improved or aggravated. In some women with primary
aldosteronism, the high blood levels of pregnancy-related progesterone are
antagonistic at the mineralocorticoid receptor and partially block the action of
aldosterone; these patients have an improvement in the manifestations of primary
aldosteronism during pregnancy [61,62]. In other pregnant women, increased
expression of luteinizing hormone choriogonadotropin receptor (LHCGR) has been
documented in APAs harboring beta-catenin mutations, and the degree of
hyperaldosteronism is aggravated by the increased pregnancy-related blood levels
of human chorionic gonadotropin [63,64].
The type of treatment for primary aldosteronism in pregnancy depends on how
difficult it is to manage the hypertension and hypokalemia. If the patient is in the
subset of patients who have a remission in the degree of primary aldosteronism,
then surgery or treatment with a mineralocorticoid receptor antagonist (MRA) can
be avoided until after delivery. However, if hypertension and hypokalemia are
marked, then surgical and/or medical intervention is indicated. Unilateral
laparoscopic adrenalectomy during the second trimester can be considered in
those women with confirmed primary aldosteronism and a clear-cut unilateral
adrenal macroadenoma (>10 mm). (See 'Laparoscopic adrenalectomy' above.)
There are concerns about spironolactone use during pregnancy because it crosses
the placenta and has been associated with feminization of newborn male rats.
However, there is only one human case in the medical literature where treatment
with spironolactone in pregnancy led to ambiguous genitalia in a male infant; this
occurred in a woman treated with spironolactone for polycystic ovary syndrome
733
(PCOS) prepregnancy and through the fifth week of gestation [65]. There are some
concerns about eplerenone as well. Therefore, for pregnant women who will be
managed medically, the hypertension should be treated with standard
antihypertensive drugs approved for use during pregnancy rather than
mineralocorticoid receptor antagonists (MRAs). Hypokalemia, if present, should be
treated with oral potassium supplements (see "Treatment of hypertension in
pregnant and postpartum patients", section on 'Overview of antihypertensive
drugs used in pregnancy'). For those patients with refractory hypertension and/or
hypokalemia, the addition of eplerenone may be cautiously considered [55,66].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Primary aldosteronism".)
SUMMARY AND RECOMMENDATIONS
●From a treatment perspective, the two major forms of primary
aldosteronism are unilateral adrenal aldosterone hypersecretion (eg,
adenoma, unilateral hyperplasia, or carcinoma) and bilateral aldosterone
hypersecretion (eg, idiopathic adrenal hyperplasia [IHA]). (See 'Patients with
unilateral adenoma or hyperplasia' above and 'Patients with bilateral
disease' above.)
●The goals of therapy for primary aldosteronism due to either unilateral or
bilateral adrenal disease are the same and include: normalization of the
serum potassium in hypokalemic patients; normalization of the blood
pressure, which often may persist after correction of the hyperaldosteronism;
and reversal of the adverse cardiovascular effects of hyperaldosteronism.
(See 'Treatment goals' above.)
●For most patients with confirmed unilateral aldosterone hypersecretion (eg,
adrenal adenoma or unilateral adrenal hyperplasia), we suggest unilateral
adrenalectomy over medical therapy (Grade 2B). (See 'Laparoscopic
adrenalectomy' above.)
●For patients with adrenal adenomas, we suggest laparoscopic
adrenalectomy rather than open laparotomy because of the reduction in
postoperative morbidity, hospital stay, and expense (Grade 2C). In addition,
the surgery should be performed by an experienced endocrine surgeon.
Hypokalemia should be corrected with potassium supplementation
or spironolactone preoperatively. (See 'Laparoscopic adrenalectomy' above.)
●Plasma aldosterone should be measured the day after adrenal surgery to
assess for cure. Potassium supplements and spironolactone should be
discontinued, and, if possible, antihypertensive therapy should be decreased.
Serum potassium should be measured during the hospitalization and, as an
734
outpatient, once weekly for four weeks (to monitor for hyperkalemia, which
may result from transient hypoaldosteronism due to chronic suppression of
renal renin release and contralateral adrenal gland aldosterone secretion).
(See 'Postoperative management' above.)
●We recommend that patients with bilateral adrenal hyperplasia be treated
with medical therapy, not adrenalectomy (Grade 1B). Blood pressure control
is often inadequate with subtotal adrenalectomy, and the risks associated
with bilateral adrenalectomy (including the need for lifelong glucocorticoid
and mineralocorticoid replacement) outweigh the potential benefits.
(See 'Patients with bilateral disease' above.)
●For patients with either bilateral adrenal hyperplasia or confirmed unilateral
adrenal aldosterone hypersecretion (who refuse or are not candidates for
surgery), we suggest a mineralocorticoid receptor antagonist (MRA)
(eg, spironolactone or eplerenone) over other potassium-sparing diuretics
(eg, amiloride, triamterene) as our first choice for pharmacologic therapy
(Grade 2B). (See 'First line: Mineralocorticoid receptor antagonists' above.)
●Of the MRAs, we suggest spironolactone as the first-line drug (Grade 2C)
and switch to eplerenone if side effects are limiting. Eplerenone is a more
selective MRA than spironolactone and is associated with fewer side effects;
however, when administered once daily and compared with spironolactone,
eplerenone is a less effective antihypertensive agent. (See 'Choice of
MRA' above.)
●For patients who do not tolerate spironolactone or eplerenone, we switch to
a potassium-sparing diuretic such as amiloride. (See 'Second line: Potassium-
sparing diuretics' above.)
●Serum potassium, creatinine, and blood pressure should be monitored
frequently during the first four to six weeks of medical therapy (especially in
patients with renal insufficiency or diabetes mellitus). Clinical course and
circumstances dictate the frequency of monitoring thereafter. (See 'Dosing
and monitoring' above.)
●The type of treatment for primary aldosteronism in pregnancy depends on
how difficult it is to manage the hypertension and hypokalemia. If the patient
is in the subset of patients who have a remission in the degree of primary
aldosteronism, then surgery or treatment with an MRA can be avoided until
after delivery. However, if hypertension and hypokalemia are marked, then
surgical and/or medical intervention is indicated. (See 'Pregnancy' above.)

735
Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and
symptoms of hormone hypersecretion
Authors:
Jennifer Ang Chan, MD, MPH
Matthew Kulke, MD
Thomas E Clancy, MD
Section Editor:
Richard M Goldberg, MD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 02, 2021.
INTRODUCTIONNeuroendocrine tumors (NETs) are a heterogeneous group of
neoplasms that are thought to arise from neuroendocrine cells and their precursors
located throughout the body. These tumors are characterized by variable but most often
indolent biologic behavior. They are also classically characterized by their ability to
secrete peptides resulting in distinctive hormonal syndromes.
Classification and nomenclature — NETs can arise at different sites within the body
and are classified according to their histologic features. While there are differences in
terminology and grading depending on site of origin, all commonly used classification
systems reflect a basic separation between more indolent, well-differentiated NETs
(which in the digestive system were previously referred to as carcinoid tumors and
pancreatic neuroendocrine [islet cell] tumors) and far more aggressive, poorly
differentiated neuroendocrine carcinomas (which behave clinically more like small cell
carcinoma of the lung). (See "Metastatic well-differentiated gastroenteropancreatic
neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring",
section on 'Classification and nomenclature'.)

This topic review will cover local treatment options for patients with well-differentiated
metastatic gastroenteropancreatic NETs. Systemic treatment options to control tumor
growth and/or symptoms of hormone hypersecretion from gastroenteropancreatic NETs
and the treatment of poorly differentiated neuroendocrine carcinomas are discussed
elsewhere, as are the clinical presentation, imaging, and biochemical monitoring for
patients with advanced gastroenteropancreatic NETs; pathology and classification of
gastroenteropancreatic NETs; clinical features of NETs; diagnosis of carcinoid
syndrome and tumor localization; treatment of early stage NETs; lung NETs; localization
and treatment of pancreatic NETs; evaluation and management of NETs of unknown
primary site; management of symptoms of the carcinoid syndrome; carcinoid heart
disease; and functioning pancreatic NETs:

●(See "Metastaticwell-differentiated gastrointestinal neuroendocrine (carcinoid)

tumors: Systemic therapy options to control tumor growth".)

736
 ●(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic
therapy options to control tumor growth and symptoms of hormone
hypersecretion".)
●(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring".)
●(See "Pathology, classification, and grading of neuroendocrine neoplasms arising
in the digestive system".)
●(See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid)
tumors arising in the gastrointestinal and genitourinary tracts".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors,
classification, histology, diagnosis, and staging".)
●(See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-
differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)
●(See "Treatment of the carcinoid syndrome".)
●(See "Carcinoid heart disease".)
●(See "Classification, epidemiology, clinical presentation, localization, and staging
of pancreatic neuroendocrine neoplasms".)
●(See "Neuroendocrine neoplasms of unknown primary site".)
●(See "Insulinoma".)
●(See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and
diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome
(gastrinoma)".)
●(See "Glucagonoma and the glucagonoma syndrome".)
●(See "Somatostatinoma: Clinical manifestations, diagnosis, and management".)
●(See "VIPoma: Clinical manifestations, diagnosis, and management".)
NATURAL HISTORY AND TREATMENT OPTIONSNETs are a
heterogeneous group of malignancies characterized by variable but most often indolent
biologic behavior. Clinical behavior and prognosis correlate closely with histologic
differentiation and grade. The World Health Organization (WHO) classifies well-
differentiated gastroenteropancreatic NETs into low-grade (G1), intermediate-grade
(G2), and high-grade (G3) categories based on histologic appearance and proliferative
rate (as assessed by mitotic count and/or Ki-67 labeling index) (table 1) [1]. With rare
exceptions, the vast majority of poorly differentiated neuroendocrine neoplasms are G3
neuroendocrine carcinomas. (See "Pathology, classification, and grading of
neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019
World Health Organization classification'.)
Among patients with G1 or G2 histology and distant disease, survival is highly variable
and can depend on other factors, including primary tumor location. As an example,
among patients with advanced NETs, outcome is worst for patients with lung and colon
(other than cecum) primaries (median survival 17 and 7 months, respectively) and is
most favorable for tumors arising in the jejunum, ileum, and cecum (median survival 55
to 65 months) [2]. This wide difference in natural history complicates the comparative
assessment of benefit from individual therapies.
Patients with metastases from a gastroenteropancreatic NET may become symptomatic
from hormone hypersecretion rather than from tumor bulk. Approximately 10 to 30
737
percent of pancreatic NETs secrete hormones resulting in clinical syndromes;
additionally, patients with midgut (small bowel or appendiceal) NETs may develop
carcinoid syndrome, typically after development of hepatic metastases and entry of
vasoactive substances, such as serotonin, into the systemic circulation. (See "Clinical
features of carcinoid syndrome" and "Classification, epidemiology, clinical presentation,
localization, and staging of pancreatic neuroendocrine neoplasms".)
Symptoms of hormonal excess from functional NETs can often be well controlled with
somatostatin analogs, such as octreotide or lanreotide. Similarly, somatostatin analogs,
molecularly "targeted" therapies, and cytotoxic chemotherapy may be beneficial in
controlling tumor growth. (See "Metastatic well-differentiated gastrointestinal
neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)
In patients with limited metastases, however, local options can also be considered. The
following sections will discuss local treatment options to control symptoms and tumor
growth. Systemic options are discussed in detail elsewhere. (See "Metastatic well-
differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy
options to control tumor growth".)
OVERVIEW OF THE APPROACH TO LOCAL TREATMENT For initial
management of patients with hepatic metastases from gastrointestinal or pancreatic
NETs in whom complete resection is possible, surgery is appropriate in the absence of
extrahepatic metastases, diffuse bilobar involvement, or compromised liver function,
particularly for low-volume or symptomatic disease and low-grade tumors. The benefit
of surgical debulking in patients with incompletely resectable metastatic NETs is
controversial and not universally accepted. (See 'Surgical resection' below.)
Another point of controversy is whether the primary site should be resected in patients
with metastatic disease. For most malignancies, there is little rationale to resect the
primary site when widespread, unresectable metastases are present. In patients with
NETs, however, resection of the primary may be beneficial if the primary site is causing
symptoms, even in the setting of metastatic disease, given the sometimes prolonged
survival of such patients. Additionally, if the primary and liver metastases are both
amenable to potentially curative resection, surgery should be performed. On the other
hand, the benefit of resecting asymptomatic small bowel primary sites in patients with
unresectable metastatic disease has not been clearly established. (See 'Management of
the primary tumor in patients with metastatic disease' below.)
The role of ablation (radiofrequency ablation [RFA], cryoablation, microwave ablation) in
the therapeutic management of small (<3 cm) neuroendocrine liver metastases,
particularly in patients who are eligible for resection, is undefined. Because the majority
of patients present with multifocal and bilateral disease, ablation is most often used as
an adjunct to surgical resection to allow local treatment of all disease when major
hepatectomy alone might compromise residual liver function. (See 'Ablation' below.)
For symptomatic patients with hepatic-predominant, unresectable gastrointestinal or
pancreatic NETs, transarterial therapy with hepatic arterial embolization,
chemoembolization, or radioembolization is a potential alternative to medical therapy
alone for symptom palliation. While many studies demonstrate successful control of
symptoms related to hormone secretion or tumor bulk, survival benefits from
transarterial therapy are less clear. (See 'Hepatic arterial embolization' below.)

738
Orthotopic liver transplantation is not currently a standard option for unresectable
neuroendocrine liver metastases, and further investigation is needed to evaluate its
benefits for patients with metastatic gastrointestinal and pancreatic NETs. (See 'Liver
transplantation' below.)
HEPATIC-PREDOMINANT METASTATIC DISEASEThe majority of patients
with advanced gastroenteropancreatic NETs have liver metastases. How to best
manage patients with liver metastases from NETs is a complex issue requiring a
multidisciplinary team approach, taking into account factors such as the extent and
biology of disease, presence of tumor-related symptoms, and patient-related factors
(such as age and performance status). The role of primary tumor resection in patients
with metastatic disease is also discussed below. (See 'Management of the primary
tumor in patients with metastatic disease' below.)
Surgical resection — For patients with liver metastases from a well-differentiated
gastroenteropancreatic NET, surgical resection is an option in the absence of diffuse
bilobar involvement, compromised liver function, or extrahepatic metastases. The
presence of poorly differentiated neuroendocrine carcinoma is also usually a
contraindication to resection. (See "High-grade gastroenteropancreatic neuroendocrine
neoplasms", section on 'Poorly differentiated NEC'.)

Resection of neuroendocrine liver metastases via anatomic hepatectomy or multiple

nonanatomic "wedge" resections can be performed even with bilobar involvement,
provided sufficient functional hepatic reserve is preserved, typically over 20 percent of
total liver volume and the presence of two contiguous preserved liver segments. The
ability of the liver to undergo compensatory hypertrophy is decreased by cirrhosis,
hepatitis, or steatosis related to obesity.

A surgical approach to hepatic-predominant disease has traditionally been advised

given the limited availability of systemic therapy and the relatively indolent nature of
disease. Historical recommendations have supported resection if at least 90 percent of
the tumor can be feasibly removed [3]. However, the precise method of measuring 90
percent debulking is not defined, and the precise amount of tumor burden that must be
treated for benefit remains unclear. Furthermore, randomized studies comparing hepatic
resection versus a nonsurgical approach have not been performed. Finally, the indolent
nature of the disease and the potential for selection bias have complicated the
assessment of the efficacy of a surgical approach to hepatic-predominant disease.
Nonetheless, the long-term survival and symptomatic improvement reported in select
populations of patients undergoing hepatic resection of neuroendocrine liver metastases
compare favorably with outcomes with other management approaches for advanced
NETs (table 2). A few of the largest series are described in detail:
●A large, early, single-institution series included 170 patients undergoing liver
resection over a 20-year period [4]. Metastases were bilateral in the majority of
patients, and most had hormonal symptoms. Symptom control was achieved in 96
percent of patients who presented with symptoms related to a functioning tumor;
five-year symptom recurrence was 59 percent. Overall survival in the group was
61 and 35 percent at 5 and 10 years, respectively, with a median survival of 81
months. These outcomes compare favorably with historical controls [5,6]. Of note,
recurrence rates were 84 and 95 percent at 5 and 10 years, respectively. Although
739
 nearly all patients developed a disease recurrence, surgery appeared to offer
significant improvements in expected survival.
●Others report a lower rate of disease recurrence after hepatic resection, at least
at five years [7-10]. As examples:
•A second series of 144 patients undergoing resection with or without ablation
for neuroendocrine liver metastases over a 30-year period at a single
institution described a median overall survival of 9.6 years, with 5- and 10-year
survivals of 77 and 50 percent, respectively [8]. While nearly 50 percent of all
patients developed a recurrence of liver disease, most were able to have
further local treatment with repeat resection or ablation. The authors
acknowledge the selected nature of the patients undergoing surgical resection,
as this number represented only 25 percent of the patients with stage IV NETs
seen at that institution in the same time frame.
•The largest published multi-institutional series of patients undergoing surgery
for neuroendocrine liver metastases included 376 patients treated over a 24-
year period across 10 hepatobiliary referral centers [7]. Most presented with
bilobar disease, extrahepatic disease was present in 9 percent, and 22 percent
of procedures included ablation as a component of the intervention. In the
entire cohort, the disease-free survival rate at five years was 46 percent;
overall survival was not reported. However, there was a tail to the disease-free
survival curve beyond 10 years, suggesting that approximately 35 to 40
percent did not recur during this time frame. In multivariate analysis, the type of
NET (pancreatic nonfunctional versus other), grade of tumor differentiation
(moderately/poorly versus well), and extent of liver involvement were the only
independent predictors of inferior disease-free survival.
Despite the apparent benefit of surgical resection in terms of symptom palliation and
potentially increased survival, most series share a high recurrence rate, even with
complete resection and microscopically negative margins. The high rate of intrahepatic
recurrence is likely related to an underestimation of the true extent of disease burden
with preoperative cross-sectional imaging. In a study comparing preoperative radiology
findings with the pathologic review of resected neuroendocrine liver metastases, the
extent of disease was underestimated by up to 50 percent, with many additional
metastases <2 mm identified in the pathologic specimen that had not been visualized
on preoperative imaging [9].
While surgical resection may benefit highly selected patients, the potential for selection
bias in these series and the lack of randomized data have made it difficult to assess the
long-term benefits of this approach as compared with less invasive treatment strategies.
One report of a large prospective database of 649 patients with neuroendocrine liver
metastases who were followed for a median follow-up of 44 months suggested that
hepatic resection was associated with a highly favorable overall survival (90 percent at
five years) compared with other local modalities, such as radiofrequency ablation (RFA;
84 percent) and chemoembolization (55 percent), but the potential for selection bias (ie,
that surgery was only offered to those patients who had an inherently better tumor
biology) complicates interpretation of the results [10].

740
Some authors have attempted to address confounding factors by using propensity index
modeling to identify patients with common characteristics for comparative analyses
[11,12]:
●As an example, one report compared outcomes in a series of 339 patients with
neuroendocrine liver metastases undergoing surgical therapy versus 414 patients
with neuroendocrine liver metastases undergoing intra-arterial therapy (IAT) [11].
Patients undergoing IAT had more hormonally functioning tumors, a greater
proportion of tumors with synchronous presentation of liver metastases, more
extrahepatic metastases, more bilateral disease, and a greater extent of hepatic
involvement, and they less frequently had their primary tumor resected. In the
unadjusted analysis, median and five-year survival were, not surprisingly,
significantly better for patients undergoing surgery as compared with IAT.
Propensity score matching was used to identify a group of patients with balanced
clinicopathologic characteristics who were most likely to have been considered for
either treatment. While survival was significantly better in the surgical group in the
unadjusted analysis, the propensity-adjusted analysis suggested that surgery was
associated with superior outcomes in patients with a low (<25 percent) hepatic
disease burden and in those who were symptomatic and had >25 percent hepatic
tumor involvement. There was no treatment-related difference in long-term
outcome in asymptomatic patients with >25 percent hepatic tumor involvement.
●A similar statistical approach was applied to an analysis of 376 patients with
neuroendocrine liver metastases from small intestinal NETs [12]. In this series,
103 patients undergoing hepatectomy or ablation were compared with 273
patients treated nonsurgically. Patients selected for surgery were less likely to
have symptomatic disease, were less likely to have residual or unresected
extrahepatic disease or nodal metastases, and had lower overall disease burden
and lower grade tumors. In an unadjusted comparison, five-year overall survival
was 78 percent after surgery or ablation versus 56 percent in controls. To account
for selection bias, propensity score matching identified two groups, each with 72
patients, without significant differences in baseline features. The five-year overall
survival was 74 percent in both the matched surgery/ablation and nonsurgically
treated groups, suggesting that surgery may not be clearly superior to
nonoperative therapy for many patients.
Taken together, these data support the view that although intrahepatic disease
progression and recurrence rates are high, resection of neuroendocrine liver
metastases can provide symptom control and has been associated with favorable long-
term survival, with 10-year survival rates approaching 50 to 60 percent in some series
[10]. Consensus-based guidelines from the National Comprehensive Cancer Network
(NCCN) recommend consideration of cytoreductive surgery or ablative therapy if near-
complete treatment of tumor burden can be achieved [13].
For patients with carcinoid syndrome, octreotide should be readily available during any
surgical procedure. (See 'Prevention and management of carcinoid crisis' below.)
Appropriate preoperative assessment and complications of hepatic resection are
discussed in detail elsewhere. (See "Overview of hepatic resection".)
Nonsurgical liver-directed therapy

741
Ablation — Ablation can be used as a primary treatment modality for neuroendocrine
liver metastases or as an adjunct to surgical resection. The most commonly used
ablation technique is RFA, but other modalities, including cryoablation and microwave
ablation, can be utilized. These procedures, which can be performed percutaneously,
laparoscopically, or at the time of laparotomy, are less morbid than either hepatic
resection or hepatic arterial embolization. However, because the zone of ablation is
limited, ablative techniques may be applicable only to smaller lesions (typically ≤3 cm).
Many published reports of tumor ablation are small case studies of fewer than 40
patients [14-19]. The largest published series examining ablation for neuroendocrine
liver metastases included 89 patients undergoing laparoscopic RFA [20]. The mean
number of lesions treated per patient was six (range 1 to 16), with a mean lesion size of
3.6 cm (range 1 to 10 cm). There was one postoperative death and a 6 percent
perioperative morbidity rate, most frequently related to hemorrhage. Among patients
with hormonal symptoms (44 percent), significant or complete symptom relief occurred
in 73 percent of patients when assessed one week postprocedure, and relief was
sustained for a median of 14 months. At a median follow-up of 30 months, the median
disease-free survival after the first RFA treatment was 16 months, with an overall
survival of six years. Twenty-two percent of patients developed a local liver recurrence,
and 59 percent developed extrahepatic disease. Multimodality treatment subsequently
was used to control disease, including octreotide (30 percent), repeat RFA (27 percent),
chemoembolization (7 percent), and chemotherapy (18 percent).
The role of ablation in the therapeutic management of small neuroendocrine liver
metastases, particularly in patients who are eligible for resection, is undefined. Because
the majority of patients present with multifocal and bilateral disease, a primary role for
ablation may be as an adjunct to surgical resection to allow local treatment of all
disease when major hepatectomy alone might compromise residual liver function.
Ablation may also be particularly useful for patients with an intrahepatic disease
recurrence in whom surgical options are limited due to prior hepatectomy. The
combination of resection and ablation is a well-described strategy for a variety of
malignancies. In the series reported by Mayo et al, 66 of 339 patients (19 percent)
undergoing liver-directed therapy underwent a combination of resection and ablation at
the initial surgical attempt. A smaller number of patients underwent a second liver-
directed procedure (n = 46), with increasing use of ablation alone (7 of 46; 15.2 percent)
or resection plus ablation (17 of 46; 37 percent) during the second procedure [21].
Hepatic arterial embolization — We suggest hepatic arterial embolization,
chemoembolization, or radioembolization as an alternative to medical therapy alone as
a palliative technique for symptomatic patients with hepatic-predominant unresectable
gastrointestinal or pancreatic NETs.

Hepatic arterial embolization is frequently applied as a palliative technique in patients

with a hepatic-predominant metastatic NET who are not candidates for surgical
resection. It is based on the principle that tumors in the liver derive most of their blood
supply from the hepatic artery, whereas healthy hepatocytes derive most of their blood
supply from the portal vein.

Embolization can be performed via the infusion of gel foam powder into the hepatic
artery through an angiography catheter (bland embolization) or in conjunction with
742
chemotherapy (ie, doxorubicin, cisplatin, or streptozocin, or drug-eluting beads)
administered via the hepatic artery (chemoembolization). A third embolization technique
uses radioactive isotopes (eg, yttrium-90 [90-Y]) that are tagged to glass or resin
microspheres and delivered selectively to the tumor via the hepatic artery.
Technique and outcomes — In the absence of randomized trials, we consider any of
the three techniques (bland embolization, chemoembolization, or radioembolization) to
be a reasonable approach for the palliation of patients with NETs and hepatic-
predominant disease who are not candidates for surgical resection.

In uncontrolled studies, efficacy appears to be similar for the three techniques:

●The response rates associated with all of these techniques, as measured by

either decreased hormone secretion, symptomatic benefit, or radiographic
regression, are generally over 50 percent, even among patients with massive
hepatic tumor burden [22-38]. While many studies demonstrate symptom control,
survival benefits from transarterial therapy are less clear [25,27,39-43].
Comparisons between studies and between methods of transarterial therapy are
frustrated by the heterogeneity of inclusion criteria and the wide range of
techniques used.
●A year 2015 systematic review of 18 studies conducted by a multidisciplinary
panel of experts examined the clinical efficacy and safety of hepatic arterial
chemoembolization, bland embolization, and radioembolization for patients with
neuroendocrine liver metastases [44]:
•Although patient heterogeneity and differences in embolic technique make
comparisons between studies and modalities difficult, similar tumor response
rates, survival, and symptom palliation were observed with all techniques.
•In 11 studies examining bland embolization or chemoembolization, objective
radiologic response rates ranged from 11 to 100 percent. Median survival
durations ranged between 18 and 80 months.
•In seven studies of radioembolization, objective radiologic response rates
ranged from 22 to 71 percent. Reported median survival durations ranged
between 22 and 70 months.
●In one of the largest reports of 81 patients undergoing bland embolization or
chemoembolization for a gastrointestinal NET, the median response duration was
17 months, and progression-free survival (PFS) rates at one, two, and three years
were 75, 35, and 11 percent [37].
A second series of 69 patients with a gastrointestinal NET and 54 with a
pancreatic NET suggested better results for gastrointestinal NETs (response rate
67 versus 35 percent, median PFS 23 versus 16 months, and median overall
survival 34 versus 23 months) [34]. The addition of chemotherapy to hepatic
arterial embolization seemed to benefit pancreatic but not gastrointestinal NETs.
●Experience with 90-Y radioembolization in metastatic NETs has been growing
[29-31,35,36,45]. In the largest series, reported by Kennedy et al, of 148 patients
with unresectable liver metastases, 64 percent had an objective response [29].
Fatigue (7 percent) was the most common side effect.
As with other techniques, radioembolization has been reported to reduce
symptoms in approximately one-half of patients with functioning tumors [31,35]. A
743
 single case report describes control of refractory hypoglycemia for three months
following radioembolization of a metastatic malignant insulinoma [46].
Several publications have evaluated the incidence of hepatic toxicity with 90-Y
radioembolization in patients with neuroendocrine liver metastases. Cases of
radiation-induced hepatic fibrosis and cirrhosis developing over the course of
several years have been reported [47-49].
Retrospective comparative studies of 90-Y radioembolization versus transarterial
chemoembolization have come to variable conclusions as to whether either
approach is superior, at least in part due to heterogeneous patient populations
[50-53]. Randomized trials are needed.
●Concern has been raised as to the high incidence of biliary injury with
transarterial chemoembolization using drug-eluting beads [54].
●Information is expected from the RETNET (Randomized Embolization Trial for
NeuroEndocrine Tumor metastases to the liver) trial, a prospective, multicenter,
randomized, controlled trial designed to determine the optimal embolotherapy
technique for NET liver metastases (NCT02724540). In this trial, patients with
progressive or symptomatic unresectable neuroendocrine liver metastases will be
randomized to bland embolization or transarterial chemoembolization. An arm of
this trial evaluating transarterial chemoembolization using drug-eluting beads has
closed due to concerns regarding hepatic toxicity.
Regardless of the approach that is chosen, appropriate patient selection is important to
minimize treatment- and disease-related adverse effects, which can include pain,
nausea, fever, fatigue, and biochemical abnormalities (elevated liver enzymes) [55].
Importantly, the toxicity and safety of 90-Y radioembolization for patients who have
undergone or may be candidates for future peptide receptor radionuclide therapy
(PRRT) have not been established. (See "Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options to control tumor growth and
symptoms of hormone hypersecretion", section on 'Lutetium-177
dotatate' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid)
tumors: Systemic therapy options to control tumor growth", section on 'Lutetium Lu-177
dotatate'.)
Contraindications and complications of transarterial therapies, which are similar whether
the approach is being used for NETs or for hepatocellular cancer, are presented
elsewhere. However, in contrast to hepatocellular cancer, the presence of extrahepatic
disease is not a contraindication to transarterial embolization for NETs, particularly for
highly symptomatic patients [33]. (See "Localized hepatocellular carcinoma: Liver-
directed therapies for nonsurgical candidates not eligible for local thermal ablation",
section on 'Radioembolization'.)
Prophylaxis for carcinoid crisis should also be considered prior to embolization in
patients with carcinoid syndrome [56]. (See 'Prevention and management of carcinoid
crisis' below.)
Liver transplantation — Orthotopic liver transplantation (OLT) is not currently a
standard option for unresectable neuroendocrine liver metastases, and further
investigation is needed to evaluate its benefits.
The number of patients with liver-isolated metastatic disease in whom OLT has been
attempted is relatively small, and the role of OLT in patients with metastatic NETs is not

744
yet established and remains controversial [57-62]. One of the largest reported series
included 213 patients who underwent OLT for NETs in 35 centers in 11 European
countries between 1982 and 2009 [63]. Perioperative mortality within three months of
transplantation was 10 percent. At a median follow-up of 56 months, the one-, three-,
and five-year overall survival rates were 81, 65, and 52 percent, respectively, while the
corresponding disease-free survival rates were 65, 40, and 30 percent.
In a report from the United Network for Organ Sharing (UNOS) database, 150
transplants were performed for metastatic NETs between 1988 and 2008 [62], including
51 for gastrointestinal NETs, 29 for pancreatic NETs, and 70 for unspecified NETs. The
one-, three-, and five-year survival rates for the 137 patients undergoing isolated OLT
were 81, 65, and 49 percent, respectively, and there were no differences based on site
of tumor origin.
While long-term recurrence-free survival may be obtained in a minority of patients, the
majority of those undergoing OLT for metastatic NETs ultimately develop recurrent
disease [57,64-66]. Strict selection of patients for transplantation is therefore critical. In
a systematic literature review of liver transplantation for hepatic metastases from NETs
(64 studies, 57 of which were single-center reports), recurrence rates ranged from 33 to
57 percent [66].
The limited availability of donor organs in many regions has also limited the widespread
use of this procedure. In the United States, where allocation of donor organs for
transplantation is based on the Model for End-Stage Liver Disease (MELD) as
proscribed by the Organ Procurement Transplantation Network (OPTN)/UNOS, there
are no MELD exception points for NETs like there are for hepatocellular cancer.
(See "Liver transplantation for hepatocellular carcinoma", section on 'Requirements for
listing and management while on the wait list'.)
However, guidance on MELD exception review is available from OPTN for patients with
liver metastases from NETs, which is intended to be used by regional review boards to
evaluate case requests for liver transplantation in these patients in order to promote
consistent review of these patients throughout the country.
MANAGEMENT OF THE PRIMARY TUMOR IN PATIENTS WITH
METASTATIC DISEASE
Small bowel primaries — We suggest resection for symptomatic small bowel primary
sites and for asymptomatic primaries if both the primary site and liver metastases are
amenable to potentially curative resection. The benefit of resecting asymptomatic small
bowel primary sites in patients with unresectable metastatic disease has not been
clearly established, and we suggest not pursuing this approach.
For most malignancies, there is little rationale to resect the primary site when
widespread, unresectable metastases are present. In patients with small bowel NETs,
however, resection of the primary may be beneficial if the primary site is causing
symptoms, even in the setting of metastatic disease, given the sometimes prolonged
survival of such patients. Additionally, if the primary and liver metastases are both
amenable to potentially curative resection, surgery should be performed [4,67,68].
Small bowel NETs are often associated with desmoplasia and fibrosis, which can result
in intermittent small bowel obstruction and, in some cases, bowel ischemia [69,70].
Surgical resection of the primary should therefore be considered in patients
experiencing intermittent obstruction or abdominal discomfort thought to be related to
745
the primary tumor, even in the presence of metastatic disease [71]. Mesenteric
angioplasty or stenting could be an option in selected patients, although experience with
this approach is limited [69]. (See "Chronic mesenteric ischemia", section on
'Revascularization'.)

While some have also advocated the routine resection of asymptomatic small bowel
primary tumors in patients with unresectable metastatic disease, this practice remains
controversial. Guidelines on the surgical management of small bowel NETs are
available from the North American Neuroendocrine Tumor Society (NANETS), the
European Neuroendocrine Tumor Society (ENETS), the National Comprehensive
Cancer Network (NCCN), and the European Society for Medical Oncology (ESMO):

●The NANETS guidelines recommend that resection of the primary tumor be

considered, when feasible, to relieve symptoms, to avoid future symptoms, and for
a potential survival advantage [72]. However, they also point out that the benefits
of removing an asymptomatic primary tumor are controversial, that clinical factors,
including the extent of metastatic disease, need to be considered, and that the
risks of resection need to be weighed against the potential benefits [72,73].
●The ENETS guidelines do not provide specific recommendations regarding
resection of an asymptomatic primary small intestinal NET in the presence of
unresectable liver metastases, but they do state that there may be a role for
resection to prevent later complications and acknowledge that the lack of
prospective trials does not allow firm conclusions on any potential survival benefit
[74,75].
●The NCCN recommends that both the primary and metastases be resected if
both are resectable and that resection also be considered for symptomatic primary
tumors in the setting of metastatic disease, but provides no recommendation for
patients with asymptomatic primary tumors and categorically unresectable
metastatic disease [76].
●ESMO guidelines also endorse palliative resection of primary small intestinal
NETs in advanced disease to prevent complications related to bowel obstruction
or intestinal ischemia, also noting that there are contradictory data on the survival
benefit of this approach [77].

The available data on the survival benefits of resecting an asymptomatic primary are
conflicting:

●A systematic review of six studies in which there was a comparison between

patients who had and patients who had not undergone resection of a primary
midgut tumor in the setting of unresectable liver metastases concluded that there
was a trend toward longer survival in patients who underwent surgical resection
[78]. However, the retrospective nature of these studies makes the data difficult to
interpret given the high potential for selection bias in patients taken to surgery
compared with those who were not.
●A large retrospective cohort of 4076 patients with metastatic midgut NETs
derived from the National Cancer Database also concluded that there was a

746
 survival benefit for resection of the primary tumor (hazard ratio for death for those
with primary tumor resection versus without 0.63, 95% CI 0.51-0.78) [79].
●On the other hand, a survival benefit for primary tumor resection could not be
shown in a cohort study from Sweden, which examined outcomes among 161
patients with metastatic small bowel NETs without abdominal symptoms who had
prophylactic surgery within six months of diagnosis combined with oncologic
treatment, compared with 202 similar patients who underwent nonsurgical
treatment or delayed surgery as needed in combination with oncologic treatment
[80]. Prophylactic primary tumor resection conferred no survival benefit compared
with delayed surgery as needed, and patients undergoing prophylactic surgery
needed more reoperations for intestinal obstruction compared with delayed
surgery as needed (14 versus 3 percent).
Pancreatic neuroendocrine tumors — The benefit of resecting the primary tumor in
patients with metastatic nonfunctioning pancreatic NETs is also controversial. In
contrast to small bowel primaries, in most series, removal of the primary tumor has
been associated with longer survival, even in the setting of unresectable metastatic
disease. However, all of the experience comes from retrospective analyses, and it
remains possible that the perceived survival benefit is the result of selection bias. The
issue of resection of the primary tumor in patients with nonfunctioning pancreatic NETs
is discussed in detail elsewhere. (See "Surgical resection of sporadic pancreatic
neuroendocrine tumors", section on 'Candidates for resection' and "Surgical resection of
sporadic pancreatic neuroendocrine tumors", section on 'Nonfunctional'.)
PREVENTION AND MANAGEMENT OF CARCINOID CRISIS Carcinoid
crisis is a life-threatening form of carcinoid syndrome that may be triggered by tumor
manipulation (biopsy, palpation at the bedside or during surgery) or by anesthesia. It is
less commonly reported after chemotherapy, hepatic arterial embolization, or
radionuclide therapy, mostly in patients with extensive tumor bulk.
Carcinoid crisis results from the release of an overwhelming amount of biologically
active compounds from the tumor (table 3). In addition to hemodynamic instability,
symptoms include flushing, diarrhea, tachycardia, arrhythmias, bronchospasm, and
altered mental status.
Octreotide should be readily available during any surgical procedure. Preoperative
administration of octreotide (300 mcg intravenously or subcutaneously) can reduce the
incidence of carcinoid crisis and is recommended for patients with a history of carcinoid
syndrome who require procedures including surgery and hepatic arterial embolization.
(See 'Surgical resection' above.)
Treatment for carcinoid crisis differs from that for other causes of acute intraoperative
hypotension. Symptoms are generally refractory to fluid resuscitation alone. Calcium
and catecholamines may provoke the release of mediators from the tumor and worsen,
rather than ameliorate, the syndrome. During a carcinoid crisis, blood pressure should
be supported by infusion of plasma and octreotide (300 mcg intravenously) given
immediately. A continuous intravenous drip of octreotide may be needed. In patients
with a high risk of carcinoid crisis, an intravenous octreotide drip may be initiated
preoperatively. Carcinoid crisis is discussed in more detail elsewhere. (See "Treatment
of the carcinoid syndrome", section on 'Prevention and management of carcinoid crisis'.)

747
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic
neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●For initial management of patients with hepatic metastases from well-
differentiated gastrointestinal or pancreatic neuroendocrine tumors (NETs) that
can be completely resected, we suggest resection rather than medical therapy
(Grade 2B). Resection is an appropriate treatment for liver metastases in the
absence of extrahepatic metastases, diffuse bilobar involvement, or compromised
liver function, particularly for low-volume or symptomatic disease and low-grade
tumors. The benefits of surgical debulking in patients with incompletely resectable
metastatic gastrointestinal or pancreatic NETs remain controversial, and this
should be considered an investigational approach. (See 'Surgical
resection' above.)
●We suggest resection for symptomatic small bowel primary sites and for
asymptomatic primaries if both the primary site and liver metastases are
amenable to potentially curative resection (Grade 2C). The benefit of resecting
asymptomatic small bowel primary sites in patients with unresectable metastatic
disease has not been clearly established, and we suggest not pursuing this
approach (Grade 2C). (See 'Management of the primary tumor in patients with
metastatic disease' above.)
●For patients undergoing surgery for metastatic NETs who have a history of
carcinoid syndrome, we recommend prophylactic administration of octreotide prior
to the procedure to reduce the incidence of carcinoid crisis (Grade 1B).
(See 'Prevention and management of carcinoid crisis' above and "Treatment of the
carcinoid syndrome", section on 'Prevention and management of carcinoid crisis'.)
●Orthotopic liver transplantation (OLT) is not currently a standard option for
unresectable neuroendocrine liver metastases, and further investigation is needed
to evaluate its benefits for patients with metastatic gastrointestinal and pancreatic
NETs. (See 'Liver transplantation' above.)
●We suggest hepatic arterial embolization, chemoembolization, or
radioembolization as an alternative to medical therapy alone as a palliative
technique for symptomatic patients with hepatic-predominant unresectable
gastrointestinal or pancreatic NETs (Grade 2C). The toxicity and safety of yttrium-
90 (90-Y) radioembolization for patients who have undergone or may be
candidates for future peptide receptor radionuclide therapy (PRRT) have not been
established. (See 'Hepatic arterial embolization' above.)

748
Metastatic well-differentiated
gastroenteropancreatic neuroendocrine tumors:
Presentation, prognosis, imaging, and
biochemical monitoring
Authors:
Jennifer Ang Chan, MD, MPH
Matthew Kulke, MD
Section Editor:
Richard M Goldberg, MD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 13, 2021.
INTRODUCTIONNeuroendocrine cells are distributed widely throughout the
body, and neuroendocrine neoplasms can arise at many sites. While there are
differences in terminology and grading for tumors arising at different sites, all
commonly used classification systems reflect a basic separation between more
indolent, well-differentiated neuroendocrine tumors (NETs; which in the past, were
referred to as carcinoid tumors when arising in the digestive system [now termed
gastrointestinal NETs], or pancreatic islet cell tumors [pancreatic NETs]) and far
more aggressive, poorly differentiated neoplasms that behave clinically more like
small cell carcinoma of the lung (termed neuroendocrine carcinomas). (See "High-
grade gastroenteropancreatic neuroendocrine neoplasms" and "Pathobiology and
staging of small cell carcinoma of the lung".)

The clinical presentation, prognosis, radiographic imaging, and tumor marker

evaluation of patients with well-differentiated NETs arising in the digestive system
are discussed in this topic review. Pathology and nomenclature of
gastroenteropancreatic NETs, treatment options for advanced or metastatic NETs,
as well as issues relating to the presentation, localization, and treatment of early
stage gastrointestinal NETs and pancreatic NETs are presented elsewhere, as are
small cell lung cancer, high-grade gastroenteropancreatic neuroendocrine
carcinoma, and neuroendocrine carcinoma of unknown primary site.

●(See "Pathology, classification, and grading of neuroendocrine neoplasms

arising in the digestive system".)

749
 ●(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone
hypersecretion".)
●(See "Clinical characteristics of well-differentiated neuroendocrine
(carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Staging, treatment, and post-treatment surveillance of non-metastatic,
well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)
●(See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors,
classification, histology, diagnosis, and staging".)
●(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms".)
●(See "Insulinoma".)
●(See "Glucagonoma and the glucagonoma syndrome".)
●(See "Somatostatinoma: Clinical manifestations, diagnosis, and
management".)
●(See "VIPoma: Clinical manifestations, diagnosis, and management".)
●(See "Neuroendocrine neoplasms of unknown primary site".)
●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
●(See "Pathobiology and staging of small cell carcinoma of the lung".)

CLASSIFICATION AND NOMENCLATUREThe World Health Organization

(WHO) classification of neuroendocrine neoplasms arising in the digestive system
separates these tumors into two broad categories (table 1) [1] (see "Pathology,
classification, and grading of neuroendocrine neoplasms arising in the digestive
system", section on 'Pathology, tumor classification, and nomenclature'):
●Well-differentiated NETs, which show a solid, trabecular, gyriform, or
glandular pattern, with fairly uniform nuclei, salt-and-pepper chromatin, and
finely granular cytoplasm. They are divided into low-grade (G1), intermediate-
grade (G2), and high-grade (G3) subtypes based on proliferative rate.
●Poorly differentiated neuroendocrine carcinomas, which are G3 carcinomas
that resemble small cell or large cell neuroendocrine carcinoma of the lung
(picture 1) [2]. (See "High-grade gastroenteropancreatic neuroendocrine
neoplasms" and "Pathology of lung malignancies", section on
'Neuroendocrine tumors'.)
Poorly differentiated neuroendocrine carcinomas are often associated with a rapid
clinical course; as such, their clinical behavior is similar to that of small cell
carcinoma of the lung, and they are treated similarly with platinum-based
chemotherapy. (See "High-grade gastroenteropancreatic neuroendocrine
neoplasms".)
750
By contrast, most well-differentiated gastroenteropancreatic NETs generally have a
much better prognosis. Even in the presence of liver metastases, some patients
may survive for many years. However, these tumors are not a homogeneous
group, but instead display a spectrum of aggressiveness. Within the subgroup of
well-differentiated NETs, morphology alone cannot predict tumor behavior.
Proliferative rate, as assessed by mitotic count and/or Ki-67 labeling index, is of
prognostic significance, independent of tumor stage [3,4].
There is a small subset of patients with NETs that appear histologically well
differentiated, with fewer than 20 mitoses per 10 high-power fields (G2 by mitotic
count), but are associated with high Ki-67 proliferation indices (>20 percent) that
fall into the G3 range. The clinical behavior of these grade-discordant tumors is
somewhat worse than grade-concordant well-differentiated G2 NETs but is better
than that of bona fide poorly differentiated neuroendocrine carcinomas.
(See "Pathology, classification, and grading of neuroendocrine neoplasms arising
in the digestive system", section on 'High-grade, well-differentiated neoplasms'.)
Digestive tract NETs can also be defined by their functional, or hormone-secreting,
status. Functioning NETs are characterized by the presence of clinical symptoms
due to excess hormone secretion by the tumor. Functioning (hormone-secreting)
pancreatic NETs are classified according to the predominant hormone they secrete
and the resulting clinical syndrome (eg, insulinoma, gastrinoma, glucagonoma,
VIPoma, somatostatinoma). Functioning gastrointestinal NETs (ie, those associated
with the carcinoid syndrome) are not classified differently than nonfunctioning
tumors. Although functionality may impact prognosis (eg, insulinomas are
generally indolent tumors), the biologic behavior of most functioning NETs is
defined by the grade and stage of the tumor, just as it is in nonfunctioning tumors.
The vast majority of functioning tumors are well differentiated.
(See "Insulinoma" and "Zollinger-Ellison syndrome (gastrinoma): Clinical
manifestations and diagnosis" and "Glucagonoma and the glucagonoma
syndrome" and "VIPoma: Clinical manifestations, diagnosis, and
management" and "Somatostatinoma: Clinical manifestations, diagnosis, and
management" and "Clinical features of carcinoid syndrome" and "Diagnosis of
carcinoid syndrome and tumor localization" and "Pathology, classification, and
grading of neuroendocrine neoplasms arising in the digestive system", section on
'Functionality and nomenclature'.)
CLINICAL PRESENTATIONThe clinical course of patients with metastatic well-
differentiated gastroenteropancreatic NET is highly variable. Some untreated
patients with indolent tumors remain symptom free for years, while others have
symptomatic disease, either from tumor bulk or peptide hormone hypersecretion.
Patients with functioning pancreatic NETs typically have symptoms caused by the
751
specific type of hormone being produced by the tumor. (See "Glucagonoma and
the glucagonoma syndrome", section on 'Clinical features' and "Insulinoma",
section on 'Symptoms' and "Somatostatinoma: Clinical manifestations, diagnosis,
and management", section on 'Clinical manifestations' and "VIPoma: Clinical
manifestations, diagnosis, and management", section on 'Clinical features'.)
For patients with metastatic gastrointestinal NETs, the secretion of serotonin and
other vasoactive substances causes carcinoid syndrome, which is manifested by
episodic flushing, wheezing, diarrhea, and eventual right-sided valvular heart
disease [5]. The carcinoid syndrome is most commonly seen with midgut NETs
(small intestine, appendix, proximal large bowel), almost exclusively in the setting
of metastatic (usually liver) disease. It is rare with foregut (gastric, bronchial) and
hindgut (distal colon, rectum, genitourinary) NETs. In addition, foregut NETs can
be associated with an atypical variant of carcinoid syndrome. Patients with
extraintestinal (eg, ovarian and bronchial) NETs can develop carcinoid syndrome in
the absence of liver metastases (table 2). (See "Clinical features of carcinoid
syndrome" and "Clinical characteristics of well-differentiated neuroendocrine
(carcinoid) tumors arising in the gastrointestinal and genitourinary
tracts" and "Diagnosis of carcinoid syndrome and tumor localization".)
PROGNOSISEven when advanced, survival times for patients with well-
differentiated gastroenteropancreatic NETs are generally better than those for
patients with other malignancies, although prognosis can be highly variable. A
major factor impacting overall survival is primary tumor site. In an analysis of
cases in the National Cancer Institute (NCI) Surveillance, Epidemiology, and End
Results (SEER) database of NETs diagnosed between 2000 and 2012, the median
survival for patients with distant metastases from grade 1 to 2 pancreatic NETs
was 50 months. For patients with distant metastases from grade 1 to 2 small
intestinal NETs, median survival was 103 months; by contrast, it was only 14
months for patients with colonic primary tumors [6].
Another major prognostic factor is histologic grade, which is assigned based on
the mitotic rate or Ki-67 labeling index [6,7]. As an example, in the SEER database
analysis, patients with a grade 1 or 2 appendiceal NET, or a grade 1 rectal NET had
a median survival >30 years. By contrast, patients with grade 3 neuroendocrine
carcinoma had poor overall survival irrespective of primary tumor site, ranging
from 30 to 33 months for small intestine and appendix, respectively, to 8 months
for cecum and colon [6]. (See "Pathology, classification, and grading of
neuroendocrine neoplasms arising in the digestive system", section on 'Staging
system'.)
Other prognostic factors in patients with metastatic disease include disease
burden, the presence of distant extrahepatic metastases, race, and older age [6,8].
752
IMAGINGThe predominant site of metastatic spread well-differentiated NETs is
the liver (picture 2). Liver function tests are an unreliable indicator of tumor
involvement; the serum total bilirubin and/or alkaline phosphatase are frequently
normal despite extensive liver involvement. Imaging is therefore an important
aspect of monitoring patients with advanced gastroenteropancreatic NETs for
evidence of disease progression or treatment response.
Well-differentiated neuroendocrine tumors
Cross-sectional imaging — For patients with advanced gastroenteropancreatic
NETs, cross-sectional anatomic imaging is the standard approach to monitoring
patients and is generally performed with either multiphasic computed tomography
(CT) or magnetic resonance imaging (MRI). Triphasic helical CT of the abdomen
and pelvis is recommended to image metastatic gastrointestinal and pancreatic
NETs [9,10]. These tumors are highly vascular and may appear isodense with the
liver during certain contrast phases (image 1). They generally enhance most
intensely with intravenous contrast during the early arterial phases of imaging,
with washout during the delayed portal venous phase.
MRI is a reasonable alternative, as lesions can be visualized without contrast in T1
and T2-weighted sequences, reducing the variability sometimes seen with CT-
based imaging results (image 2 and image 3). In one study, MRI detected
significantly more metastases than either planar somatostatin receptor
scintigraphy (SRS) using indium-111 (111-In) pentetreotide (OctreoScan) or CT
(sensitivity rates for MRI, planar SRS, and CT were 95, 79, and 49 percent,
respectively) [11]. As a result of this greater sensitivity for liver metastases, some
clinicians prefer MRI over CT. Consensus-based guidelines from the European
Neuroendocrine Tumor Society (ENETS) state that MRI should be considered
superior to CT for the detection and follow-up of liver metastases from NETs
[12,13].
Somatostatin receptor-based imaging techniques — Over 90 percent of
gastroenteropancreatic NETs, including nonfunctioning NETs (with the exception
of insulinomas), have high concentrations of somatostatin receptors and can be
imaged using a radiolabeled form of the somatostatin analog octreotide (111-In
pentetreotide). More recently, a number of positron emission tomography (PET)-
based, somatostatin receptor-based imaging techniques have also been evaluated.
One of these radionuclides, gallium Ga-68 DOTATATE (Ga-68 DOTATATE), was
approved by the US Food and Drug Administration (FDA) for routine use in patients
with NETs in June 2016 [14]. The higher sensitivity of Ga-68 DOTATATE suggests
that this is the preferred option for most clinical scenarios, particularly in patients
with smaller tumor volume or an occult primary tumor [15]. Two other

753
radionuclides, gallium Ga-68 DOTATOC (Ga-68 DOTATOC) and copper Cu-64
DOTATATE (Cu-64 DOTATATE), were subsequently approved.
Clinical use — Baseline imaging using one of the somatostatin receptor-based
imaging techniques is generally recommended in patients with advanced NETs,
both as an adjunct to routine cross-sectional imaging and because evidence of
somatostatin receptor expression (based on a positive scan) can be predictive of a
clinical response to therapy with somatostatin analogs, such
as octreotide and lanreotide [16], as well as peptide receptor radioligand therapy.
(See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid)
tumors: Systemic therapy options to control tumor growth", section on
'Somatostatin analogs' and "Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options to control tumor growth and
symptoms of hormone hypersecretion", section on 'Somatostatin
analogs' and "Metastatic well-differentiated pancreatic neuroendocrine tumors:
Systemic therapy options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Peptide receptor radioligand therapy' and "Metastatic
well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic
therapy options to control tumor growth", section on 'Peptide receptor radioligand
therapy'.)
Whether either of these techniques should be used to assess tumor response or
progression in patients with advanced disease is unclear, and this has not yet been
formally studied [15]. These imaging techniques rely in part on the assessment of
somatostatin receptor density, rather than direct measurements of tumor volume.
Using somatostatin receptor-based techniques may, in theory, not always
correlate with disease progression or response to therapy, and further studies are
needed to assess the utility of these technologies (including Ga-68 DOTATATE, Ga-
68 DOTATOC, and Cu-64 DOTATATE) in this setting.
For patients treated with somatostatin analogs, it has generally been
recommended that therapy with short-acting analogs be discontinued for 24 hours
before somatostatin receptor-based imaging, with treatment resumed the day
after, when clinically feasible [17]. For patients receiving long-acting preparations
(Sandostatin LAR, lanreotide) the recommendation has been to allow a wash-out
period of four weeks before imaging or to image just prior to dosing with long-
acting somatostatin analogs. However, these recommendations preceded the
availability of more sensitive imaging techniques using PET. Several studies have
found that treatment with long-acting somatostatin analogs
(lanreotide, octreotide) did not alter Ga-68 DOTATATE uptake into tumors or affect
imaging results, suggesting that the recommended dose separation of these

754
agents may not be needed in this setting [18-20]. We no longer recommend
holding the somatostatin analog for a period of time prior to PET imaging.
Clinical studies — Scanning using 111-In pentetreotide has been widely available
and has been commonly used to perform whole-body somatostatin receptor-
based imaging in patients with NETs [21-23].
However, several PET tracers for functional imaging have emerged (Ga-68
DOTATATE, Ga-68 DOTATOC, Cu-64 DOTATATE, 18-F-dihydroxy-phenyl-alanine
[18F-DOPA], and 11-C-5-hydroxytryptophan [11-C-5-HTP]), which in combination
with high-resolution PET and integrated CT, improve the detection and staging of
NETs. Novel PET modalities such as Ga-68 DOTATATE, Ga-68 DOTATOC and Cu-64
DOTATATE PET offer higher spatial resolution than conventional 111-In
pentetreotide imaging and are more sensitive for detection of small lesions (image
4) [24-33].
Ga-68 DOTATATE is a positron-emitting analog of somatostatin that works by
binding to these receptors; its highest affinity is for subtype 2 receptors (sstr2). The
higher sensitivity of Ga-68 DOTATATE PET for the detection of
gastroenteropancreatic NETs was best shown in a prospective study in which 131
patients with a known or suspected gastroenteropancreatic NET underwent
conventional anatomic imaging with CT and/or MRI, 111-In pentetreotide
SPECT/CT imaging, and Ga-68 DOTATATE PET/CT [24]. The following findings were
noted:
●When all of the lesions demonstrated by any of the imaging studies were
used as the imaging denominator, Ga-68-DOTATATE PET/CT imaging
detected significantly more (95 percent, 95% CI 92.4-96.8) than did anatomic
imaging (45 percent, 95% CI 37.9-52.9 percent) or 111-In pentetreotide
SPECT/CT (30.9 percent, 95% CI 25.0-37.5 percent). Overall, 422 of the total
891 lesions were detected by 68-Ga-DOTATATE PET/CT and missed both by
111-In pentetreotide SPECT/CT and anatomic imaging.
●Of the 14 patients with an unknown primary tumor, four were identified
using Ga-68 DOTATATE (none of which were seen with 111-In pentetreotide
and two of which were not seen on cross sectional imaging).
(See "Neuroendocrine neoplasms of unknown primary site".)
●The 25 patients who underwent surgery had 113 lesions that were
histologically proven to be gastroenteropancreatic NETs (37 primary tumors,
69 lymph nodes, and 7 distant metastases). On a per-lesion analysis, Ga-68
DOTATATE had the highest true positive rate (72 of 113 [64 percent] versus 25
of 113 [22 percent] for 111-In pentetreotide and 44 of 113 [39 percent] for
anatomic imaging). All 38 lesions that were not detected by any imaging
study represented lymph node metastases.

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 ●The addition of Ga-68-DOTATATE scanning to cross-sectional imaging and
111-In pentetreotide resulted in a clinically significant change in
management in 43 of 131 patients (33 percent).
A newer PET radiotracer, Ga-68 DOTATOC, appears to have comparable diagnostic
accuracy to Ga-68 DOTATATE for the detection of neuroendocrine neoplasms that
express somatostatin receptors [34]. Although FDA approved in the United States
in 2019 [35], it is not yet commercially available.
A third PET radiotracer, Cu-64 DOTATATE, appears also to have comparable
diagnostic accuracy to Ga-68 DOTATATE [36] and was approved in the United
States in September 2020.
Whole-body imaging using radiolabeled somatostatin analogs such as Ga-68
DOTATATE and DOTATOC, or Cu-64 DOTATATE may unexpectedly reveal other
somatostatin receptor-expressing tumor types, including meningiomas [37]. The
differential diagnosis includes a wide range of neoplastic and nonneoplastic
entities, including metastatic NET (table 3). (See "Epidemiology, pathology, clinical
features, and diagnosis of meningioma", section on 'Diagnostic
evaluation' and "Management of known or presumed benign (WHO grade 1)
meningioma", section on 'Small, asymptomatic tumors'.)
Poorly differentiated neuroendocrine tumors — Imaging for high-grade poorly
differentiated neuroendocrine carcinomas arising in the gastrointestinal tract is
discussed elsewhere. (See "High-grade gastroenteropancreatic neuroendocrine
neoplasms", section on 'Diagnosis and staging'.)
BIOCHEMICAL MONITORING
Hormonal biomarkers
Urinary 5-HIAA — Elevated urinary levels of 5-hydroxyindoleacetic acid (5-HIAA)
are highly specific for serotonin-producing NETs (ie, those arising in the midgut),
but they are not particularly sensitive. In one study, only 73 percent of patients
with metastatic NETs had elevated levels [38]. Furthermore, 5-HIAA levels are
generally most useful in patients with primary midgut NETs. Foregut and hindgut
NETs only rarely secrete serotonin; they lack the enzyme DOPA decarboxylase and
cannot convert 5-hydroxytryptophan to serotonin and, therefore, to 5-HIAA (figure
1).
Clinical utility can also be limited by false positives. The normal rate of 5-HIAA
excretion ranges from 2 to 8 mg (10 to 42 micromol) per day. Values of up to 30
mg (157 micromol) per day may be found in patients with malabsorption
syndromes (eg, celiac disease), and following ingestion of large amounts of
tryptophan/serotonin-rich foods; use of certain drugs also interferes with assay of
urinary 5-HIAA (table 4). Although many patients with advanced well-differentiated
midgut NETs have values above 100 mg (523 micromol) per day, some have more
756
modest elevations. In one study, urinary 5-HIAA excretion in patients with
carcinoid syndrome ranged from 99 to 2070 mg (518 to 10826 micromol) per day
[39]. Lower but still elevated values were seen in patients with metastatic NETs
without carcinoid syndrome (50 to 260 mg [262 to 1360 micromol] per day).
Urinary 5-HIAA is the most sensitive test for establishing the diagnosis of carcinoid
syndrome. (See "Diagnosis of carcinoid syndrome and tumor localization", section
on 'Biochemical testing for carcinoid syndrome'.)
For patients with advanced disease, serial measurements of 24-hour urine 5-HIAA
do not correlate with symptomatic benefit from various treatments [40].
Functioning pancreatic neuroendocrine tumors — While they are specific for
the individual hormonal syndrome, the hormones produced by functioning
pancreatic NETs (ie, insulin, glucagon, somatostatin, VIP) may not be easily
measurable. Assessment of specific hormone levels should be performed based on
patient symptoms and suspicion for a functional NET. (See "Insulinoma", section
on 'Diagnosis and staging' and "Glucagonoma and the glucagonoma syndrome",
section on 'Serum glucagon' and "Zollinger-Ellison syndrome (gastrinoma): Clinical
manifestations and diagnosis", section on 'Serum gastrin
concentration' and "VIPoma: Clinical manifestations, diagnosis, and management",
section on 'Diagnosis' and "Somatostatinoma: Clinical manifestations, diagnosis,
and management", section on 'Diagnosis'.)
Nonhormonal biomarkers
Chromogranin A — Chromogranin A (CgA) is a 49-kD protein that is contained in
the neurosecretory vesicles of NET cells and is detectable in the plasma of patients
with a range of neuroendocrine neoplasms, including nonfunctioning pancreatic
NETs. Because it does not rely on serotonin secretion, serum CgA is a more
sensitive and broadly applicable tumor marker for NETs than is urinary 5HIAA, but
it is less specific (table 5). (See "Overview of tumor biomarkers in
gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A
(CgA)'.)
Among the clinical scenarios where CgA may be used includes patients with
foregut and rectal NETs (in whom urinary 5HIAA levels are less likely to be
elevated), as well as in patients with pancreatic NETs, in whom CgA is more often
elevated than it is with gastrointestinal tract NETs [41-51]. Levels are higher in
patients with diffuse metastases than with localized disease or isolated hepatic
involvement [45,51]. (See "Clinical characteristics of well-differentiated
neuroendocrine (carcinoid) tumors arising in the gastrointestinal and
genitourinary tracts", section on 'Foregut tumors' and "Clinical characteristics of
well-differentiated neuroendocrine (carcinoid) tumors arising in the
gastrointestinal and genitourinary tracts", section on 'Hindgut tumors'.)

757
Plasma CgA levels have been shown to correlate with treatment response and may
also have prognostic value. Elevated CgA levels have been associated with shorter
overall survival times in several studies [3,52-55]. However, the utility of CgA as a
marker of prognosis has been limited by wide variability in CgA ranges in the
setting of metastatic disease, as well as variability in CgA assays in the United
States and Europe. Caution is also needed when using serum CgA as a marker of
disease activity in patients treated with somatostatin analogs. These agents
significantly reduce plasma CgA levels, a change that may be more reflective of
changes in hormonal synthesis and release from tumor cells than an actual
reduction in tumor mass [44]. Finally, CgA is not recommended as a diagnostic
marker for NETs, as it can be elevated in a number of unrelated conditions. These
conditions include use of proton pump inhibitors, renal insufficiency, and hepatic
insufficiency. For patients who are receiving treatment with a proton pump
inhibitor, the drug should be stopped or replaced with an H2 receptor blocker if
possible in order to obtain reliable CgA values [56]. The utility of measuring CgA
levels in patients undergoing radiographic surveillance for detection of recurrence
following surgery is debatable, as is its role in the routine follow-up of patients
with advanced disease [57]. (See "Overview of tumor biomarkers in
gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A
(CgA)'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY
●Neuroendocrine neoplasms arising at different sites within the body are
classified according to their histologic features. All commonly used
classification systems reflect a basic separation between more indolent, well-
differentiated tumors and far more aggressive, high-grade, poorly
differentiated neoplasms (neuroendocrine carcinomas) that behave clinically
more like small cell lung cancer (table 1). (See 'Classification and
nomenclature' above.)
●The clinical course of patients with metastatic well-differentiated
gastroenteropancreatic neuroendocrine tumors (NETs) is highly variable.
Some patients with indolent tumors may remain symptom free for years,
even without treatment. Others have symptomatic metastatic disease, either
from tumor bulk or peptide hormone hypersecretion, and require therapy.
(See 'Clinical presentation' above.)

758
●Even when advanced, survival times for patients with well-differentiated
gastroenteropancreatic NETs are generally better than those for patients
with other malignancies, although highly variable. The main prognostic
factors are differentiation and grade (table 1), tumor site (table 6), disease
burden, and the presence of extrahepatic metastases.
(See 'Prognosis' above.)
●The predominant site of metastatic spread is the liver. Patients in whom
metastatic disease is suspected should be evaluated with a triple-phase
contrast-enhanced helical computed tomography (CT) or magnetic resonance
imaging (MRI) scan to rule out liver metastases. Some clinicians prefer MRI
because of its greater sensitivity for liver metastases. (See 'Cross-sectional
imaging' above.)
●Uptake of radiolabeled somatostatin analogs is predictive of a clinical
response to therapy with somatostatin analogs and to peptide receptor
radionuclide therapy, and it can assist in identifying an otherwise occult
primary site. The greater sensitivity of gallium Ga-68 DOTATATE, Ga-68
DOTATOC, or copper Cu-64 DOTATATE positron emission tomography
(PET)/CT makes these methods for somatostatin receptor-based imaging
preferred over indium-111 (111-In) pentetreotide (OctreoScan) where
available. (See 'Somatostatin receptor-based imaging techniques' above.)
●Changes in biochemical markers may be associated with disease
progression and/or response to treatment. Elevated urinary levels of 5-
hydroxyindoleacetic acid (5-HIAA) are highly specific for serotonin-producing
NETs (ie, those arising in the midgut), although they are not sensitive.
(See 'Urinary 5-HIAA' above.)
●For non-serotonin-producing NETs, serum chromogranin A (CgA) may be
more useful than 5-HIAA. However, serum CgA is not specific to NETs and can
also be elevated in non-neuroendocrine-related conditions. The utility of
measuring CgA levels in patients undergoing radiographic surveillance for
detection of recurrence following surgery, and the role of CgA in the follow-
up of patients with advanced disease are debatable. (See 'Chromogranin
A' above.)

759
Metastatic well-differentiated gastrointestinal
neuroendocrine (carcinoid) tumors: Systemic
therapy options to control tumor growth
Authors:
Jennifer Ang Chan, MD, MPH
Matthew Kulke, MD
Section Editor:
Richard M Goldberg, MD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Nov 17, 2021.
INTRODUCTIONNeuroendocrine cells are distributed widely throughout the
body, and neoplasms of these cells, which are termed neuroendocrine tumors
(NETs), can arise at many sites.
NETs are a heterogeneous group of malignancies characterized by variable but
most often indolent biologic behavior. Clinical behavior and prognosis correlate
closely with histologic differentiation and grade, as assessed by mitotic count
and/or Ki-67 labeling index (table 1) [1]. (See "Pathology, classification, and grading
of neuroendocrine neoplasms arising in the digestive system", section on
'Classification and terminology'.)

Systemic treatment options to control tumor growth in patients with advanced or

metastatic well-differentiated NETs arising in the gastrointestinal tract
(gastrointestinal NETs [GINETs]) will be discussed in this topic review. Management
of symptoms related to hormone hypersecretion, and systemic therapy options for
pancreatic NETs and for poorly differentiated neuroendocrine carcinomas arising
in the digestive tract are discussed elsewhere, as are local management options
for well-differentiated metastatic gastroenteropancreatic NETs; the clinical
presentation, imaging, biochemical monitoring, pathology, and classification of
gastroenteropancreatic NETs; the clinical features of primary NETs; the diagnosis
of carcinoid syndrome and tumor localization; the treatment of early stage NETs;
bronchial NETs; thymic NETs; and the evaluation and management of NETs of
unknown primary site:

●(See "Treatment of the carcinoid syndrome".)

760
 ●(See "Metastatic well-differentiated pancreatic neuroendocrine tumors:
Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion".)
●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
●(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone
hypersecretion".)
●(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring".)
●(See "Pathology, classification, and grading of neuroendocrine neoplasms
arising in the digestive system".)
●(See "Clinical characteristics of well-differentiated neuroendocrine
(carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Staging, treatment, and post-treatment surveillance of non-metastatic,
well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)
●(See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis".)
●(See "Thymic neuroendocrine (carcinoid) tumors".)
●(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms".)
●(See "Neuroendocrine neoplasms of unknown primary site".)

CLASSIFICATION, BIOLOGIC BEHAVIOR, AND IMPLICATIONS FOR

TREATMENTThe World Health Organization (WHO) classifies all
gastroenteropancreatic NETs based on differentiation status and grade. Well-
differentiated gastroenteropancreatic NETs are divided into low-grade (G1),
intermediate-grade (G2), and high-grade (G3) categories based on mitotic count
and proliferative index (Ki-67) (table 1) [1]. Poorly differentiated NETs are G3
neuroendocrine carcinomas. (See "Pathology, classification, and grading of
neuroendocrine neoplasms arising in the digestive system", section on '2010 and
2019 World Health Organization classification'.)
●Well-differentiated NETs arising within the digestive system have been
traditionally referred to as carcinoids when they arise within the tubular
gastrointestinal tract and pancreatic NETs (islet cell tumors) when they arise
in the pancreas or, in the case of gastrinoma, the proximal duodenum.
GINETs and pancreatic NETs may have similar characteristics on routine
histologic evaluation, but they have a different pathogenesis and biology [2].
Pancreatic NETs have a worse prognosis than GINETs [3,4] and respond
differently to anticancer agents, with most agents demonstrating higher
response rates among patients with pancreatic NETs than those with GINETs.
761
 (See "Metastatic well-differentiated pancreatic neuroendocrine tumors:
Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion".)
●G2 gastroenteropancreatic NETs have a worse prognosis than G1 tumors
[4,5]. Although they are treated similarly at present, as new treatment
modalities become available, it is likely that the histologic grade of a well-
differentiated NET will affect the selection of appropriate treatment.
●There is a subset of well-differentiated tumors with a proliferative rate that
places them in the high-grade category (G3 NET). These tumors have a clinical
behavior that is between G2 NET and poorly differentiated neuroendocrine
carcinoma. Management is discussed in detail elsewhere. (See "High-grade
gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade,
well-differentiated tumors (NET G3)'.)
●By contrast, poorly differentiated neuroendocrine carcinomas have a rapidly
progressive clinical course and a poor prognosis. They are generally treated
with platinum-based chemotherapy regimens according to small cell lung
carcinoma guidelines. (See "High-grade gastroenteropancreatic
neuroendocrine neoplasms", section on 'Poorly differentiated
NEC' and "Extensive-stage small cell lung cancer: Initial management".)
Among well-differentiated GINETs, site may also impact clinical behavior. As an
example, among patients with metastatic well-differentiated NETs, survival,
according to the Surveillance, Epidemiology, and End Results (SEER) registry data,
varies according to primary site; it is worst for patients with lung and colon
primaries (median survival for distant G1 or G2 disease 24 and 14 months,
respectively) and is most favorable for tumors arising in the small intestine
(median survival 103 months) [4]. This heterogeneity in clinical behavior
complicates the comparative assessment of benefit from individual therapies.
(See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-
differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on
'Stage and site of origin'.)
GENERAL APPROACH TO THE PATIENTThe majority of patients with
advanced metastatic GINETs have liver metastases [6]. An approach to
management is outlined in the algorithm (algorithm 1) and summarized below:
●Potentially resectable disease – For patients who have potentially
resectable disease, resection may provide prolonged control of symptoms
and tumor growth. Although the majority of patients recur, even after a
complete resection, metastasectomy is generally preferred over medical
therapy for patients with potentially resectable liver metastases.
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
762
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Surgical resection'.)
●Unresectable, symptomatic disease – For patients with unresectable
symptomatic disease, initial therapy with a somatostatin analog is highly
effective for controlling symptoms of the carcinoid syndrome and for control
of tumor growth. (See "Treatment of the carcinoid syndrome".)
●Unresectable, asymptomatic disease – Initial therapy for asymptomatic
patients with unresectable disease must be individualized. Therapeutic
options in this situation include observation, particularly if tumor burden is
limited, or initial therapy with a somatostatin analog, particularly if tumor
burden is high. If an initial approach of observation is chosen, initiation of a
somatostatin analog should be considered at time of progression.
(See 'Somatostatin analogs' below.)
●Therapy for progression of hormone-related symptoms – Patients who
have worsening symptoms of hormone secretion may benefit from escalation
of somatostatin analog. Refractory diarrhea may benefit from the addition of
the oral serotonin inhibitor telotristat. (See "Treatment of the carcinoid
syndrome", section on 'Telotristat'.)
●Therapy at progression – For patients with radiologic disease progression
despite use of a somatostatin analog, therapeutic options for patients with
hepatic predominant disease include systemic therapy, noncurative
debulking surgery (in highly selected patients), or nonsurgical liver-directed
therapy (eg, transarterial bland embolization, chemoembolization, or
radioembolization). (See "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Hepatic-predominant metastatic
disease' and "Metastatic gastroenteropancreatic neuroendocrine tumors:
Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Nonsurgical liver-directed therapy'.)
For patients with more widespread disease that is not eligible for liver-
directed therapy, systemic therapy options include everolimus (which was
approved in the United States in February 2016 for the treatment of adults
with progressive, well-differentiated, nonfunctional NETs of gastrointestinal
origin with unresectable, locally advanced or metastatic disease) [7] and, for
patients with somatostatin-receptor-positive tumors, peptide receptor
radioligand therapy (eg, lutetium Lu-177 dotatate [177Lu-Dotatate] [8]), where
available. Studies evaluating the optimal sequencing of therapy have not
been conducted. Furthermore, interpretation of an attempted network meta-
analysis to rank the relative efficacy and toxicity of a variety of systemic

763
 therapies for GINETs is limited due to variability in patient populations,
variability in eligibility and response criteria, a lack of trials directly comparing
active treatments, as well as unclear efficacy of the comparator arm in some
cases (especially interferon) [9,10]. Randomized trials comparing different
systemic therapy options are desperately needed, and eligible patients
should be encouraged to enroll in available trials, such as the COMPETE trial
evaluating lutetium Lu-177 edotreotide with everolimus (NCT03049189). If
trial participation is not available or desired, for patients with midgut NETs
whose disease is highly avid on somatostatin receptor imaging, 177Lu-Dotatate
could be considered prior to everolimus, depending on availability, and
patient preference.
The value of cytotoxic chemotherapy for GINETs continues to be debated,
and no specific regimen can be recommended. (See 'Molecularly targeted
therapy' below and 'Peptide receptor radioligand therapy' below
and 'Cytotoxic chemotherapy' below.)
The benefit of continuing therapy with a long-acting somatostatin analog in
patients who progress while receiving such therapy is not well defined. For
patients with functional tumors, we continue the somatostatin analog to
minimize hormone secretion. For patients with nonfunctional tumors who
experience unequivocal radiographic progression on a somatostatin analog
and for whom treatment with everolimus or cytotoxic chemotherapy is
planned, we would consider discontinuing the somatostatin analog.
(See 'Should the somatostatin analog be continued?' below.)
The following sections will discuss the various systemic treatment options to
control symptoms and tumor growth. Local treatment options are discussed in
detail elsewhere. (See "Metastatic gastroenteropancreatic neuroendocrine tumors:
Local options to control tumor growth and symptoms of hormone
hypersecretion".)
SOMATOSTATIN ANALOGSSomatostatin analogs,
including octreotide and lanreotide, are highly effective in controlling the
symptoms associated with carcinoid syndrome. In addition to controlling
symptoms associated with hormone hypersecretion, somatostatin analogs have
also been shown to control tumor growth. However, the optimal time to initiate
treatment with a somatostatin analog in asymptomatic patients remains
uncertain, given the varied natural history. We suggest initiation of a somatostatin
analog in patients with unresectable, asymptomatic, well-differentiated GINETs
and a high tumor burden, an approach that is consistent with guidelines from the
European Neuroendocrine Tumor Society (ENETS) [11], the North American
Neuroendocrine Tumor Society (NANETS) [12], and the National Comprehensive
764
Cancer Network (NCCN) [13]. For patients with asymptomatic, advanced,
unresectable GINETs and small-volume disease, we suggest observation alone
rather than early administration of a somatostatin analog. In such patients, we
initiate somatostatin analog therapy if there is evidence of clinically meaningful
tumor progression.
Somatostatin is a 14-amino acid peptide that inhibits the secretion of a broad
range of hormones in vivo. Somatostatin and analogs of somatostatin (such
as octreotide and lanreotide) act by binding to somatostatin receptors (SSTRs),
which are expressed on the majority of NETs [14]. The ability of octreotide and
lanreotide to inhibit the secretion of peptides from NET cells is mediated mainly
through SSTR-2 and SSTR-5.
The presence of SSTRs can be determined by diagnostic imaging using a
radiolabeled somatostatin analog (indium-111 [111-In] pentetreotide [OctreoScan]
or PET using gallium Ga-68 DOTATATE [Ga-68 DOTATATE] or gallium Ga-68
DOTATOC [Ga-68 DOTATOC]). While either traditional imaging with 111-In
pentetreotide or Ga-68 DOTATATE/Ga-68 DOTATOC can be used to assess SSTR
status in patients with NETs, the higher sensitivity of Ga-68 DOTATATE and Ga-68
DOTATOC PET suggests that they may be the preferred option in certain clinical
scenarios, particularly in patients with smaller tumor volume. In general, uptake of
radiotracer by the tumor is predictive of a response to therapy with somatostatin
analogs. However, in some cases (eg, miliary disease), diagnostic imaging may be
negative even if SSTRs are present on the tumor. In such cases, a trial of
somatostatin analog therapy can be considered even in the presence of a negative
scan. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring", section
on 'Somatostatin receptor-based imaging techniques'.)
Somatostatin analogs, including octreotide and lanreotide, are highly effective in
controlling the symptoms associated with carcinoid syndrome. (See "Treatment of
the carcinoid syndrome", section on 'Somatostatin-analog therapy'.)
In addition to controlling symptoms associated with hormone hypersecretion,
somatostatin analogs have also been shown to control tumor growth. Although
past studies indicated that <10 percent of patients with advanced GINETs have
objective tumor shrinkage with somatostatin analogs [15-26], more recent reports
suggest that, in addition to an improvement in symptoms, treatment with
somatostatin analogs can significantly delay progression [19,27,28]. Whether
somatostatin analogs also increase overall survival is not yet known, although a
correlation between progression-free survival (PFS) and overall survival in patients
with advanced NET treated with single-agent somatostatin analog therapy has
been shown [29].

765
Median duration of PFS and overall survival depend on several factors, including
primary tumor location, Ki-67 percent, extent of liver metastases, presence of bone
and/or peritoneal metastases, and the presence of symptoms when initiating
treatment. A nomogram has been developed to estimate PFS in patients with well-
differentiated gastroenteropancreatic NET based upon these and other factors
[30].

At least two placebo-controlled trials have addressed the PFS and overall survival
benefits of long-acting somatostatin analogs:

●In the PROMID trial, 85 patients with locally inoperable or metastatic small
bowel GINETs were randomly assigned to receive treatment with either long-
acting octreotide (Sandostatin LAR 30 mg monthly) or placebo [19]. The
median time to tumor progression was significantly longer with octreotide
compared with placebo (14.3 versus 6 months), confirming an antitumor
effect in this population. Patients with functionally active and inactive tumors
appeared to have a similar benefit. In a later report, while a trend toward
improved overall survival was observed in the patients randomized to receive
octreotide, the number of patients in this study was relatively small, and the
difference was not statistically significant [31].
●Further support for the antiproliferative effect of somatostatin analogs in
patients with gastroenteropancreatic NETs was provided by the CLARINET
trial, a randomized, placebo-controlled, phase III trial evaluating the
antiproliferative effects of lanreotide in 204 patients with advanced well- or
moderately differentiated, nonfunctioning, gastroenteropancreatic NETs,
including both GINETs and pancreatic NETs [27]. Patients were randomly
assigned to either 120 mg lanreotide depot (n = 101) or placebo (n = 103)
every four weeks for 96 weeks or until progressive disease or death. The
primary endpoint for the trial was PFS as determined by Response Evaluation
Criteria in Solid Tumors (RECIST) criteria (table 2). Most patients (96 percent)
had no tumor progression per RECIST criteria in the three to six months
before randomization. Compared with placebo, there was a highly significant
advantage in PFS with the use of lanreotide. At a time-point of two years
following initiation of treatment, median PFS was not reached with
lanreotide, compared with 18 months with placebo (hazard ratio for
progression or death 0.47, 95% CI 0.30-0.73). Estimated rates of PFS at 24
months were 65 versus 33 percent, and there were no differences in quality
of life or overall survival. The most common treatment related adverse effect
was diarrhea (26 versus 9 percent with lanreotide and placebo, respectively).
Based on these data, lanreotide has been approved in the United States for
766
 the treatment of patients with unresectable, well- or moderately
differentiated, locally advanced, or metastatic gastroenteropancreatic NETs.
As with symptomatic patients, we typically initiate therapy with 20 or 30 mg of
long-acting octreotide, or lanreotide depot 120 mg every four weeks. Whether
higher or escalating doses of a somatostatin analog provide higher rates of
disease control is unclear. Three retrospective studies using either octreotide LAR
(160 mg intramuscularly every 14 days for two months, then monthly) or
lanreotide (750 to 15,000 mcg per day) demonstrated disease stabilization in 37 to
75 percent of patients [32-34]. However, the number of patients included in these
studies was small (12 to 30), follow-up was short (≤12 months), and the number of
objective responses was not higher than reported with conventional doses (3 to 5
percent).
Dose-escalated therapy — Dose escalation is an option at the time of initial
disease progression on a long-acting somatostatin analog, but it is not our
preferred option. The benefits of escalating the dose and/or frequency of a
somatostatin analog for disease control are not well established, and clinical
practice is variable. At least some data suggest the potential for prolonged periods
of stable disease when the dose intensity (higher doses or reduced dosing interval)
is increased after an initial period of long-acting somatostatin analog use [35,36].
However, whether this reflects indolent biology rather than an intrinsic dose-
response relationship is not clear. Furthermore, how this strategy compares with
other systemic treatments for disease control after progression on a long-acting
somatostatin analog (eg, peptide receptor radioligand therapy) is not known.
(See 'Peptide receptor radioligand therapy' below.)
Continuation after progression — The benefits of continuing somatostatin
analog therapy following disease progression when a different antitumor therapy
is being considered are not well defined. For patients with functional NETs,
somatostatin analogs are typically continued to control hormone secretion and
symptoms related to hormone hypersecretion. It is reasonable to discontinue
somatostatin analog therapy in patients with nonfunctional NETs whose disease
has unequivocally progressed on somatostatin analog therapy.
MOLECULARLY TARGETED THERAPYMolecularly targeted therapy for
NETs, including GINETs, includes agents that target the vascular endothelial
growth factor (VEGF) and everolimus, an inhibitor of the mechanistic (previously
called mammalian) target of rapamycin (mTOR).
NETs are among the most highly vascular of solid tumors and frequently express
the VEGF and its receptor (VEGFR), which are key drivers of angiogenesis. In
preclinical models, disruption of these and other signaling pathways inhibits
neuroendocrine cell growth. VEGF-targeting agents can be generally divided into
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two categories: antiangiogenic small molecular tyrosine kinase (TK) inhibitors and
circulating VEGF inhibitors, of which the most commonly used is the anti-VEGF
monoclonal antibody bevacizumab.
mTOR is a threonine kinase that mediates downstream signaling in a number of
pathways that are implicated in NET growth, including the VEGF and insulin-like
growth factor (IGF) signaling pathways [37,38]. In addition, mTOR regulates
angiogenesis by controlling the production of hypoxia inducible factor.
Among patients with gastroenteropancreatic NETs, studies have demonstrated
antitumor activity associated with bevacizumab and several TK inhibitors that
inhibit VEGFR (including sunitinib), as well as the mTOR inhibitor everolimus. A
progression-free survival (PFS) benefit has been shown for everolimus and
sunitinib as single agents in patients with pancreatic NETs, leading to the approval
of both compounds in the United States for treatment of advanced pancreatic
NETs. Everolimus has demonstrated PFS benefit in GINET, but the benefit of VEGF
pathway inhibitors in GINET is less well established. (See "Metastatic well-
differentiated pancreatic neuroendocrine tumors: Systemic therapy options to
control tumor growth and symptoms of hormone hypersecretion", section on
'Molecularly targeted therapy'.)
Everolimus — For patients with GINETs and progressive disease despite a
somatostatin analog who are not eligible for liver-directed therapy, everolimus is
an option.
The benefit of everolimus for GINET has been evaluated in the following studies
(table 3):
●In a phase II study of everolimus in conjunction with octreotide in 30
patients with advanced GINETs, partial responses were observed in 5 of 30
(17 percent) patients, but the median time to tumor progression was
relatively short, under eight months [39].
Further support for antitumor activity of everolimus comes from a phase II
trial in which 34 patients with radiologically progressing, locally advanced,
recurrent, or metastatic but nonfunctioning NETs at a variety of sites,
including the intestinal tract (n = 22), received everolimus 10 mg daily [40].
The best response was a partial response in three patients and stable disease
in 28, for an overall disease control rate of 94 percent. The median PFS was
15.3 months, and the four-month PFS rate was 78 percent. The major grade 3
or 4 adverse events were thrombocytopenia (15 percent), hyperglycemia,
stomatitis, and anemia (6 percent each).
●Two phase III trials have been conducted, both of which suggest benefit
compared with long-acting octreotide alone or placebo:

768
•The RADIANT 2 trial randomly assigned 429 patients with advanced
GINETs, a history of carcinoid syndrome, and radiologic disease
progression in the preceding 12 months to octreotide LAR (30 mg
intramuscularly every 28 days) with or without everolimus (10 mg daily)
[41,42]. As assessed by central radiographic review, combined therapy
was associated with a potentially clinically meaningful prolongation in
median PFS, but it was only of borderline statistical significance (16.4
versus 11.3 months; hazard ratio [HR] for tumor progression 0.77, 95% CI
0.59-1.0). Imbalances between study groups were noted in important
prognostic variables, including disease site and performance status, all of
which favored the control group and could have affected the primary
outcome results. A later analysis, presented at the 2012 American Society
of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, found a
significant PFS benefit for everolimus after adjusting for randomization
imbalances (HR for progression 0.62, 95% CI 0.51-0.87, p = 0.003) [42].
In the final analysis, there was no significant difference in overall survival
between the two groups (HR for death 1.17, 95% CI 0.92-1.49) [43];
however, patients who were randomly assigned to the placebo group
were permitted to cross over to the active treatment group, potentially
obscuring any meaningful survival benefit.
•The most definitive demonstration of benefit from everolimus comes
from the RADIANT-4 trial, a phase III study in which 302 patients with
advanced, nonfunctional lung or GINETs (most common sites: lung [30
percent], ileum [24 percent], and rectum [13 percent]) were randomly
assigned to everolimus or placebo [7]. Everolimus was associated with a
significant improvement in median PFS, the primary endpoint (11.0 versus
3.9 months; HR for progression 0.48, 95% CI 0.35-0.67). There was an
overall objective response rate of 2 percent for everolimus compared with
1 percent for placebo, but the disease control rate was 81 percent for
patients assigned to everolimus compared with 64 percent for placebo.
Adverse events were mainly grade 1 or 2 and included stomatitis,
diarrhea, peripheral edema, fatigue, and rash. Most frequent severe
(grade 3 or 4) adverse events, which were more common with everolimus,
were diarrhea (7 versus 2 percent), stomatitis (9 versus 0 percent), and
anemia (5 versus 2 percent). In the most recent update presented at the
2016 annual ASCO meeting, at a median follow-up of 33 months,
everolimus was associated with a 27 percent reduction in the risk of
death, but the difference was not statistically significant (HR 0.73, 95% CI

769
 0.48-1.11, two-year survival 77 versus 62 percent) [44]. The benefits of
everolimus were achieved while preserving overall quality of life [45].
Largely based upon these results, everolimus was approved in February
2016 by the US Food and Drug Administration for the treatment of adults
with progressive, well-differentiated, nonfunctional NET of
gastrointestinal tract origin with unresectable, locally advanced or
metastatic disease. (See 'General approach to the patient' above.)
Treatments targeting tumor angiogenesis
Several small-molecule tyrosine kinase inhibitors (TKIs) that target angiogenesis,
including sunitinib, sorafenib, pazopanib, lenvatinib, and cabozantinib, have been
evaluated in advanced GINETs in phase II trials (table 3). Response rates have been
low, although all studies report a high rate of disease stabilization and potentially
encouraging PFS durations. As examples:
●Pazopanib – Alliance A021202, a randomized phase II trial including 171
patients with progressive advanced nonpancreatic NET, demonstrated
improvement in PFS with pazopanib versus placebo. The majority of patients
(66 percent) had primary tumors originating in the small intestine. Median
PFS in patients receiving pazopanib (n = 97) was 11.6 months compared with
8.5 months in those receiving placebo (n = 74, HR 0.53, p = 0.0005). There was
no improvement in overall survival in patients randomized to receive placebo;
however, crossover from placebo to pazopanib at the time of disease
progression confounds interpretation of the overall survival endpoint. This is
the first randomized study suggesting that the VEGF pathway is a valid target
for treatment of well-differentiated nonpancreatic NET.
●Nintedanib – Nintedanib is a potent inhibitor of VEGFR 1, 2, and 3 as well as
fibroblast growth factor (FGF) 1, 2, and 3. Efficacy in nonpancreatic NETs was
suggested in a phase II trial of 32 patients with grade 1 or 2 NETs on a stable
dose of a somatostatin analog (although progressive disease was not
required) [46]. At 16 weeks, 83 percent remained progression free (the
primary endpoint). Although only one patient had a partial response, 23 of
the 26 evaluable patients with stable disease had had progressive disease in
the most immediate prior therapy. Nintedanib was well tolerated and delayed
deterioration in quality of life.
●Others – The phase II TALENT trial demonstrated modest antitumor activity
(16 percent objective response rate, median PFS 15.9 months)
for lenvatinib after progression on a somatostatin analog [47]. An
ongoing randomized phase III study being conducted by the Alliance for
Clinical Trials in Oncology Group (A021602) is evaluating the efficacy
of cabozantinib compared with placebo for patients with advanced NETs.

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 ●Bevacizumab – Activity for the anti-VEGF monoclonal antibody bevacizumab
was suggested in a phase II trial, in which 44 patients with advanced or
metastatic GINETs on a stable dose of octreotide were randomly assigned to
18 weeks of bevacizumab or pegylated interferon alfa (IFNa)-2b (table 3) [48].
At disease progression or at the completion of 18 weeks of therapy
(whichever came first), all patients received bevacizumab plus interferon.
During the first 18 weeks of therapy, four (18 percent) of the bevacizumab-
treated patients experienced radiographic partial responses, while 17 (77
percent) had stable disease. Furthermore, after 18 weeks, 95 percent of
patients treated with octreotide plus bevacizumab remained progression-free
compared with only 68 percent of those receiving octreotide plus IFNa-2b.
These results led to a large randomized study of octreotide plus bevacizumab
versus octreotide plus interferon in 427 patients with advanced (unresectable
or metastatic) NETs of the gastrointestinal tract and lung with progressive
disease or other indicators of poor prognosis (table 3) [49]. Radiologic
responses were more frequent among patients treated with bevacizumab (12
versus 4 percent), but median PFS (the primary endpoint as determined by
central review) was not significantly different (16.6 versus 15.4 months).
A role for bevacizumab in combination with octreotide in the treatment of
GINETs is not yet established. Results with bevacizumab in combination
with capecitabine are discussed below. (See 'Capecitabine plus
bevacizumab' below.)
PEPTIDE RECEPTOR RADIOLIGAND THERAPY
Radiolabeled somatostatin analogs — For patients with somatostatin-receptor-
positive GINETs that are progressive despite standard-dose long-acting
somatostatin analog therapy or despite somatostatin analog therapy
and everolimus, peptide receptor radioligand therapy (PRRT) using a radiolabeled
somatostatin analog is a reasonable option, either following progression on the
somatostatin analog or following progression on everolimus. There are no data
specifically comparing PRRT with everolimus in patients progressing on long-
acting somatostatin analog therapy, and the choice of therapy in this situation
should be based upon the availability of lutetium Lu-177 dotatate (177Lu-Dotatate)
and patient preference. Somatostatin receptor (SSTR) expression is determined by
use of diagnostic imaging using radiolabeled somatostatin analogs.
(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring", section
on 'Somatostatin receptor-based imaging techniques'.)
There has been substantial interest in targeted radiation therapy using
radiolabeled somatostatin analogs [50-60]. The most frequently used radionuclides
771
for targeted radiation therapy include yttrium-90 (90Y) and lutetium-177 (177Lu),
which differ from one another in terms of emitted particles, particle energy, and
tissue penetration. In general, objective tumor response rates are up to 30
percent, and approximately one-third have symptomatic improvement. Long-term
side effects include loss of renal function, pancytopenia, and myelodysplastic
syndrome (MDS). (See "Metastatic well-differentiated pancreatic neuroendocrine
tumors: Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion", section on 'Radiolabeled somatostatin analogs'.)
Most of the series reporting efficacy and toxicity with radiolabeled somatostatin
analogs have included both pancreatic NETs and GINETs [56,61-63].
Yttrium-90 Dotatoc — The most extensive experience with 90Y-DOTA-TOC (90Y-
Dotatoc) comes from a large single-institution series of 1109 patients with
metastatic gastroenteropancreatic NETs and disease progression within 12
months of study entry, with visible tumor uptake on pretreatment SSTR
scintigraphy [63]. After the initial dose, additional treatment cycles were withheld if
there was tumor progression or permanent toxicity; otherwise, patients were
offered retreatment; the specific interval was not specified. The median number of
courses administered was two, range 1 to 10.
Overall, 378 patients (34 percent) had a "morphologic" response (defined as
any measurable decrease in the sum of the longest diameters of all
pretherapeutically detected tumor lesions by computed tomography [CT],
magnetic resonance imaging [MRI], or ultrasound), 172 (15 percent) had a
biochemical response (defined as any post-treatment decrease in a tumor
marker that had demonstrated progression prior to enrollment), and 329
(29.7 percent) improved symptomatically. The median survival from diagnosis
was 94.6 months. Longer survival correlated with responses by any of the
above criteria. Transient grade 3 or 4 hematologic toxicities developed in 142
(12 percent), and loss of renal function was the main dose-limiting toxicity. In
all, 103 patients (9 percent) had permanent grade 4 or 5 (fatal, n = 35) renal
toxicity. Older age, low baseline glomerular filtration rate, and high kidney
uptake score were associated with severe nephrotoxicity.
Lutetium Lu-177 dotatate — Increasing data suggest that 177Lu-Dotatate
outperforms 90Y-Dotatoc, although randomized trials have not been undertaken
[8,56,64,65]:
●The most compelling demonstration of benefit for 177Lu-Dotatate in midgut
GINETs was shown in the phase III international NETTER-1 trial, in which 230
patients with inoperable, somatostatin-receptor-positive midgut NETs who
experienced progressive disease on standard doses (20 to 30 mg every three
to four weeks) of octreotide LAR were randomly assigned to four doses

772
 of 177Lu-Dotatate every eight weeks or octreotide LAR 60 mg every 28 days [8].
The estimated rate of progression-free survival (PFS) at month 20 was
significantly higher with 177Lu-Dotatate (65.2 versus 10.8 percent); median PFS
for octreotide LAR alone was 8.4 months, while it had not been reached in
the 177Lu-Dotatate group (with approximately 30 months of follow-up since
initiation of treatment). An interim analysis also suggested longer overall
survival with 177Lu-Dotatate (14 versus 26 deaths, hazard ratio [HR] for death
0.40, p = 0.0004). The HR for disease progression or death favored 177Lu-
Dotatate (HR 0.21, 95% CI 0.13-0.33). Among patients evaluable for
radiographic response, 177Lu-Dotatate was also associated with a significantly
higher objective response rate (18 versus 3 percent). Radiopharmaceutical
therapy was well tolerated overall; serious adverse events that were
considered related to treatment were more common with 177Lu-Dotatate (9
versus 1 percent). The most common adverse event in the 177Lu-Dotatate
group was nausea (all grade, 59 percent; grade 3 or 4, four percent), thought
to be due to the amino acid infusions administered during therapy to protect
the kidneys. Hematologic toxicities (caused by irradiation of the bone
marrow) included mostly mild degrees of thrombocytopenia (25 percent),
lymphopenia (18 percent, grade 3 or 4 in 9 percent), anemia (14 percent), and
leukopenia (10 percent). Nadir counts commonly occur four to six weeks after
each infusion and resolve within eight weeks [66].
A later report assessing the impact of treatment on quality of life concluded
that time to deterioration in quality of life was significantly longer with 177Lu-
Dotatate compared with higher dose octreotide in several domains, including
global health status, physical functioning, role functioning, fatigue, pain,
diarrhea, disease-related worries, and body image [67]. The differences were
clinically significant in global health status (median time to deterioration in
quality of life 28.8 versus 6.1 months) and physical functioning (25.2 versus
11.5 months).
Largely based on data from the NETTER-1 trial, in January 2018, the US Food and
Drug Administration approved 177Lu-Dotatate for the treatment of somatostatin-
receptor-positive gastroenteropancreatic NETs in adults [68]. The recommended
dose is 7.4 GBq (200 millicuries) as an intravenous infusion over 30 minutes every
eight weeks for a total of four doses [69]. The limitations of 177Lu-Dotatate at
present include the complexity of administration; the lack of trials comparing this
agent with other systemic therapies, such as everolimus; and the lack of
widespread availability.
The optimal selection of candidates for 177Lu-Dotatate is not established. Guidelines
from the European Neuroendocrine Tumor Society (ENETS), which largely mirror

773
the eligibility criteria for the NETTER-1 trial, are outlined in the table (table 4) [70].
We agree with these guidelines.
Risks
Radiation-related issues — Following each treatment, radiation activity persists
at low levels for several weeks following each treatment because of ongoing decay
of the administered radionuclide [71]. While this activity is not harmful to others, it
can be picked up by sensitive radiation detectors at international airports and
border crossings [72]. Patients need to be provided with a card that they carry at
all times after each treatment course, detailing the treatment they have received.
Myelotoxicity and therapy-related myeloid neoplasms — The most serious
long-term toxicity associated with PRRT is irreversible myelotoxicity and therapy-
related myeloid neoplasms, including MDS, acute leukemia, myeloproliferative
neoplasms (MPN), or any type of myeloid neoplasm. The available data from
studies with long-term follow-up suggest a rate of MDS of approximately 2.0
percent and a rate of acute leukemia of approximately 0.5 percent [66,73-76]:
●In a systematic review of 28 reports totaling 7334 patients who were treated
with PRRT for a NET, the incidence of therapy-related myeloid neoplasms was
variable, with a mean of 2.61 percent (standard deviation 4.38 percent) [76].
The median time of developing a treatment-related myeloid neoplasm was
variable, but most were diagnosed after one year of completing PRRT.
Information on prior radiotherapy or chemotherapy was mostly not reported,
so risk factors could not be addressed.
●The incidence and course of any persistent hematologic dysfunction were
addressed in a Dutch multicenter report that systematically followed 274
patients with gastroenteropancreatic NETs for at least five years following
treatment with 177Lu-Dotatate; the intended cumulative dose was 29.6 GBq
(800 millicuries) [73]. Eleven patients (3.7 percent) had persistent hematologic
dysfunction post-treatment; these included eight with a hematologic
neoplasm (four MDS, one acute myeloid leukemia, one MPN, and two
MDS/MPN) and three with bone marrow failure characterized by cytopenias
and bone marrow aplasia. The median latency period was 41 months after
the first PRRT cycle. No risk factors for persistent hematologic dysfunction
could be identified.
Advanced age, the presence of bone metastases, and heavy pretreatment are
reported to increase the risk of secondary myelodysplasia, although there is
controversy as to whether prior treatment with alkylating agents, such
as temozolomide, increases risk [77].
Given the risk and the poor prognosis after a diagnosis of therapy-related myeloid
neoplasms, clinicians should closely monitor patients with periodic complete blood

774
counts (CBC) after PRRT [78]. We suggest obtaining a CBC with differential at least
every six months and prompt referral to a hematologist if abnormalities are
detected. (See "Therapy-related myeloid neoplasms: Epidemiology, causes,
evaluation, and diagnosis" and "Therapy-related myeloid neoplasms: Management
and prognosis".)
Glomerular damage — Renal radiation may result in glomerular damage. Rates of
nephrotoxicity as assessed by increases in creatinine during therapy were low
during therapy (1 percent, grade 2 (table 5) in another Dutch report of 209 patients
treated with 177Lu-Dotatate [79]. Following treatment, the average annual decrease
in creatinine clearance was 3.4 percent, and no patient had an annual decrease in
renal function of >20 percent. No risk factors for renal toxicity could be identified.
However, rates of nephrotoxicity may be higher depending on the means of
assessment. An analysis of kidney function over time using 99mTc-
diethylenetriaminepentaacetic acid (DTPA) clearance to accurately assess
glomerular filtration rate (GFR) in 74 consecutive patients with
gastroenteropancreatic NETs undergoing PRRT with 177Lu-Dotatate noted slight
renal impairment (GFR loss >2 mL/min/m2 per year) in 43 percent [80]. By contrast,
there was only one case of grade 3 or worse nephrotoxicity as assessed by serum
creatinine (table 5) (1.3 percent).
Should the somatostatin analog be continued? — The added benefit of
combining a long-acting somatostatin analog with PRRT and continuing a
somatostatin analog as maintenance therapy compared with PRRT alone is not
established. At least some data from a retrospective analysis of 168 patients
treated at a single institution for unresectable gastroenteropancreatic NETs
suggest that combined therapy is associated with significantly better median PFS
(48 versus 27 months) and overall survival (91 versus 47 months) [81] compared
with PRRT alone. For patients with a functional NET, we continue therapy with a
somatostatin analog during and after PRRT. For patients with a nonfunctional NET,
we typically continue therapy with the somatostatin analog, although we consider
stopping it for a patient with a nonfunctional NET whose disease is progressing
unequivocally on somatostatin analog therapy. This approach is consistent with
guidelines from the European Society for Medical Oncology (ESMO) [82].
Retreatment — Further treatments with 177Lu-Dotatate can be administered if
patients experience progression after a reasonable period of disease response or
stability (typically defined as greater than 12 months). Repeat treatments often
consist of two cycles each, and limited data indicate a median time to progression
of approximately 17 months [83]. Although the maximal tolerated dose has not
been clearly established, a total cumulative radiation dose of approximately 1600

775
millicuries (eight courses of 200 millicuries each) is considered a reasonable
lifetime limit at some institutions [84].
Iobenguane I-131 — Benefit also has been suggested for systemic radionuclide
therapy using iodine-131-labeled iobenguane (iobenguane I-131 [therapeutic], also
known as metaiodobenzylguanidine [MIBG] or 131I-MIBG) [85,86] in patients with
metastatic gastroenteropancreatic NETs who have evidence of iobenguane uptake,
as determined by iobenguane I-123 (diagnostic) scanning. While iobenguane I-131
has been licensed by regulatory authorities in some countries [87] and has been
approved for treatment of pheochromocytoma/paraganglioma and
neuroblastoma in the United States, in our view, its use for the treatment of
GINETs remains investigational.
Iobenguane is a compound resembling norepinephrine that is accumulated by
some NETs. In two separate retrospective series, biochemical (5-HIAA) responses
were observed in 37 percent of patients with gastroenteropancreatic NETs treated
with iobenguane I-131, and objective radiographic responses were noted in 15 and
28 percent, respectively [86,88]. In one report, symptomatic improvement was
reported by 27 of 48 patients (56 percent) [88].
However, the benefit of iobenguane I-131 (therapeutic) was subsequently called
into question in a nonrandomized comparison of outcomes with iobenguane I-131
in 30 patients with carcinoid syndrome or tumor symptoms (fever, pain) attributed
to the NET versus unlabeled iobenguane in 20 patients with carcinoid syndrome
who were not suitable for treatment with the radioactive compound [89]. The rate
of symptom response was identical in both groups (60 percent), though symptom
response was not accompanied by either a biochemical or radiographic response
in any patient.
INTERFERONThe role of interferon alfa (IFNa) in the modern treatment of
advanced GINETs is uncertain. While IFNa is an option for patients with advanced
GINETs who have worsening symptoms while on treatment with somatostatin
analogs or who are intolerant of somatostatin analog therapy, widespread
acceptance of this agent for the treatment of advanced GINETs has been limited by
the potential for severe side effects.
Consensus guidelines from the North American Neuroendocrine Tumor Society
(NANETS) do not recommend use of IFNa unless no other options are available,
due to the relatively lower level of evidence supporting its use and its side effect
profile [90]. Updated National Comprehensive Cancer Network (NCCN) guidelines
no longer endorse the use of IFNa for patients with progressive metastases for
whom there are no other treatment options [13]. Guidelines from the European
Neuroendocrine Tumor Society (ENETS) include IFNa as a second-line therapy in
refractory carcinoid syndrome and as an agent to consider as an antiproliferative
776
option in midgut NETs for which limited therapy options exist [91]. We agree with
these guidelines.
IFNa has been used as a treatment for advanced NETs for several decades.
Interferon (IFN) receptors are expressed in neuroendocrine neoplasms [92]. IFNs
can exert antitumor effects via stimulation of T cells, induction of cell cycle arrest,
and/or inhibition of angiogenesis [93,94]. The ability of IFNa to control the
secretion of tumor products led to its initial use in patients with carcinoid
syndrome [95].
In large, retrospective series, low-dose IFNa reduces symptoms of hormonal
hypersecretion in 40 to 70 percent of patients with GINETs and induces tumor
stabilization in 20 to 40 percent [16,23,96-107]. As with somatostatin analogs,
tumor regression is less common, although it is reported in up to 20 percent of
patients in some studies [16,95,97,99-102,106].
IFNa doses have ranged from 3 to 9 million units (MU) and have been
administered subcutaneously from three to seven times per week. The usual dose
is 3 to 5 MU three times weekly [108]. IFNa is somewhat myelosuppressive, and the
dose is often titrated in individual patients to achieve a total leukocyte count of
3000/microL.
Use of IFNa is limited by severe side effects, including fatigue, depression,
myelosuppression, flu-like symptoms, weight loss, and alteration of thyroid
function [109]. For better tolerability, pegylated IFN (80 to 150 mcg per week
subcutaneously) may be considered for symptomatic patients who are refractory
to somatostatin analogs and other forms of therapy (eg, everolimus) and who do
not tolerate conventional IFNa, although the data in patients with NETs are quite
limited [48,110] and pegylated IFN is not approved for this indication.
Interferon alfa plus a somatostatin analog — Relatively few prospective studies
have evaluated IFN in combination with somatostatin analogs compared with
somatostatin analogs alone, and the results are conflicting:
●In a prospective trial of 68 patients with liver metastases who were
randomly assigned to initial therapy with octreotide (100 mcg twice daily,
increased to 200 mcg three times daily for persistent carcinoid symptoms)
alone or with IFNa, both treatments were equally effective at reducing
urinary 5-hydroxyindoleacetic acid (5-HIAA) levels [111]. However, patients
receiving combined therapy had a significantly reduced risk of tumor
progression when compared with patients receiving octreotide alone,
suggesting that the addition of IFN had a significant antitumor effect.
(See "Diagnosis of carcinoid syndrome and tumor localization", section on
'Urinary excretion of 5-HIAA'.)

777
 ●On the other hand, two other randomized trials have not demonstrated
improvements in tumor response or time to radiologic disease progression
with combined therapy as a first-line treatment for progressive GINETs:
•The comparable efficacy of lanreotide, IFNa, or combined therapy was
evaluated in a prospective randomized trial involving 80 therapy-naive
patients with documented progressive metastatic GINETs [23]. Objective
partial response rates were comparably low in all three groups (4, 4, and 7
percent for lanreotide, IFN, and combined therapy, respectively), and the
number of patients who achieved disease stabilization was not
substantially higher with combined therapy (28, 26, and 18 percent for
lanreotide, IFN, and the combination, respectively).
•Similar findings were noted in a second trial in which 109 patients with
progressive metastatic GINETs were randomly assigned to octreotide with
or without IFNa [112]. At 3, 6, and 12 months, rates of objective partial
response were low (3, 2, and 6 percent, respectively) and similar with
octreotide alone and plus IFNa. There were also no significant differences
between the two groups in the rates of stable disease at the three time
points, time to treatment failure, or long-term survival.
These studies, however, were likely underpowered to detect significant differences
between the arms. Nevertheless, We suggest initiating therapy for symptomatic
patients with a somatostatin analog alone rather than a combination of a
somatostatin analog and IFNa. The combination of octreotide plus either IFNa
or bevacizumab was evaluated in a large randomized study performed by the
Southwest Oncology Group (SWOG) and the North American Intergroup (SWOG
S0518). (See 'Treatments targeting tumor angiogenesis' above.)
CYTOTOXIC CHEMOTHERAPYThe benefit of cytotoxic chemotherapy for
advanced GINETs continues to be debated. In general, we do not consider that any
cytotoxic chemotherapy regimen represents a standard approach for treatment of
advanced GINETs. This position is consistent with published guidelines from the
European Neuroendocrine Tumor Society (ENETS), North American
Neuroendocrine Tumor Society (NANETS), and European Society for Medical
Oncology (ESMO) [11,12,82]. Consensus-based guidelines from the National
Comprehensive Cancer Network (NCCN) suggest that anticancer agents, such
as capecitabine, dacarbazine, fluorouracil (FU), and temozolomide, can be
considered in patients with progressive metastases from a GINET for whom there
are no other treatment options, although they emphasize the rarity of objective
radiologic responses and the lack of a demonstration of a progression-free
survival (PFS) or overall survival benefit in robust clinical trials [13]. Regimens that
have demonstrated evidence of activity in preliminary reports of phase II studies
778
include oxaliplatin plus short-term infusional FU plus leucovorin (FOLFOX), and
temozolomide plus capecitabine; however, in our view, confirmatory studies are
needed to better define the activity of these regimens and to assess whether
response may differ depending on primary site.
Among patients with well-differentiated GINETs, single-agent therapy with
fluoropyrimidines, streptozocin, dacarbazine, and doxorubicin is associated with
only modest response rates [113-115]. As an example, single
agent capecitabine (1000 mg/m2 twice daily for 14 days every three weeks) was
studied in a small phase II trial of 19 patients with metastatic NETs (12 arising in
the gut, one in ovary, and six unknown) [114]. Although there were no radiologic
partial or complete responses, 13 (68 percent) achieved stable disease
radiographically, which lasted >12 months in four patients; there were two
patients with a >50 percent decrease in the tumor marker chromogranin A (CGA)
from baseline. Median PFS was 9.9 months, but median overall survival was 36.5
months. Other chemotherapeutic agents, such as the taxanes, topotecan,
and gemcitabine, are relatively inactive as single agents [116-119].
Most studies in advanced GINETs have focused on streptozocin-based regimens
(table 6):
●An early Eastern Cooperative Oncology Group (ECOG) trial randomly
assigned 118 patients to streptozocin plus either FU
or cyclophosphamide [120]. Response rates (objective radiographic tumor
regression or decreased urinary 5-hydroxyindoleacetic acid [5-HIAA]) were
similar (33 and 26 percent FU and cyclophosphamide, respectively), as was
survival. Toxicity was prominent in both regimens.
●A subsequent ECOG trial increased the dosing interval between cycles
of streptozocin/FU, comparing this regimen with doxorubicin alone [121].
Although this streptozocin/FU regimen was somewhat better tolerated than
the one used in the earlier study, the response rate was similar to
doxorubicin alone (22 versus 21 percent), as was survival. More recently,
streptozocin/FU was compared with doxorubicin/FU in a randomized trial of
249 patients with advanced NETs [122]. The radiographic response rate was
similar with the two regimens (16 percent each), although there was a slight,
but statistically significant, median survival benefit associated with
streptozocin/FU (24 versus 16 months). However, PFS was short (4.5 months),
and over one-third of the patients receiving streptozocin developed mild to
moderate renal toxicity.
The relatively modest response rates of these regimens, together with the
reported toxicity, have led many to question their utility in the routine treatment of
patients with advanced GINETs [11]. As such, they are rarely utilized in this setting.

779
Dacarbazine and temozolomide — In a Southwest Oncology Group (SWOG) study
of 56 patients with metastatic GINETs receiving single agent dacarbazine, the
overall tumor response rate was 16 percent [115]. Toxicity was a concern; 88
percent of patients reported nausea and/or vomiting. In another report of second-
line dacarbazine following treatment with streptozocin/FU or doxorubicin/FU, the
response rate was only 8 percent [122].
Temozolomide is an oral analog of dacarbazine that is generally better tolerated.
Although temozolomide is active in pancreatic NETs, its single-agent activity
appears more limited in GINETs. In a retrospective series that included 44 patients
with GINETs, only one (2 percent) had an objective tumor response [123]. The
majority of these patients had primary GINETs. By contrast, 18 of 53 (34 percent)
patients with pancreatic NETs had an objective response to treatment with
temozolomide.
Several reports have suggested that temozolomide may be active in some patients
with bronchial or thymic NETs [124,125]. However, a phase II study of
temozolomide plus bevacizumab reported no objective responses among 19
patients with advanced NETs, four of whom had bronchial NETs [126]. (See "Lung
neuroendocrine (carcinoid) tumors: Treatment and prognosis", section on
'Cytotoxic chemotherapy'.)
Small studies have suggested activity for the combination
of temozolomide and capecitabine in some GINETs:
●In one retrospective study of 18 patients with metastatic, well-differentiated
NETs, there was one complete radiographic response and one partial
response among four patients with GINET. Notably, one of the responses was
in a patient with a duodenal NET [127].
●In a report of preliminary results from a phase II trial
of capecitabine plus temozolomide presented at the 2014 American Society
of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, 4 of 12
patients with metastatic NETs originating in various sites were reported as
having experienced partial responses [128]. However, the primary sites of
these tumors were not reported, and the trial had not yet completed full
accrual.
Larger, prospective studies are clearly needed to better assess the potential
activity of temozolomide and capecitabine in GINETs and to assess whether activity
may differ depending on primary tumor site.
Oxaliplatin-based regimens — Antitumor activity has been suggested for
oxaliplatin-based combinations, although the total number of treated patients has
been small. One combined analysis included data from two phase II trials totaling
76 patients with well-differentiated pancreatic NET (n = 28) or nonpancreatic NET

780
(carcinoid cohort, n = 42), or poorly differentiated neuroendocrine carcinoma (n =
6) who were treated with oxaliplatin plus bevacizumab and either capecitabine (n =
40) or short-term infusional FU plus leucovorin (n = 36) [129]. Overall, FOLFOX plus
bevacizumab resulted in an objective response in 3 of 22 patients in the carcinoid
cohort (14 percent, median PFS 19.3 months). Oxaliplatin plus capecitabine and
bevacizumab was associated with an objective response in 1 of 20 patients (5
percent) and a median PFS of 19.1 months in the carcinoid cohort.
While these regimens may have activity in GINETs, the data are too limited to draw
any conclusions as to the relative contributions of a fluoropyrimidine, oxaliplatin,
or bevacizumab.
Capecitabine plus bevacizumab — Activity for capecitabine in combination
with bevacizumab was suggested in a multicenter phase II trial, in which 49
patients with progressive, metastatic GINETs (82 percent originating in small
bowel, the remainder in the cecum, rectum, and stomach) received bevacizumab
(7.5 mg/kg every three weeks) with capecitabine (1000 mg/m2 twice daily days 1 to
14 every 21 days) [130]. The median treatment duration was 13.8 months. At 24
months maximum follow-up, the tumor control rate was 88 percent (partial
response in 18 percent, stable disease in 70 percent), and the median PFS was 23.4
months. However, grade 3 or 4 treatment-related toxicity was experienced by 84
percent of patients, mainly digestive; 31 percent developed grade 3 or 4
hypertension.
IMMUNOTHERAPYThe role of immunotherapy with immune checkpoint
inhibitors is just beginning to be studied in patients with well-differentiated NETs.
Limited data suggest that anti-programmed cell death 1 (PD-1) antibodies have
minimal activity as single-agent therapy:
●The efficacy of the anti-PD-1 antibody spartalizumab (PDR001) was evaluated
in a multicenter phase II trial that enrolled 116 patients, including 33 with
pancreatic NET, 32 with GINET, 30 with thoracic NET, and 21 with poorly
differentiated gastroenteropancreatic neuroendocrine carcinoma (NEC) [131].
In a preliminary report presented at the 2018 European Society for Medical
Oncology (ESMO) meeting, the overall radiographic response rate was 7.4
percent among all well-differentiated NETs (pooled) and 0 percent in patients
with GINET. However, the stable disease rate in patients with well-
differentiated NET was 55.8 percent, and it was 59.4 percent in patients with
GINET [132].
●Activity of pembrolizumab in patients with programmed cell death 1 ligand
(PD-L1)-positive advanced NET was evaluated in the KEYNOTE-028 study,
which enrolled 16 patients with pancreatic NET and 25 patients with a
nonpancreatic NET of GI origin (n = 7), lung (n = 9), or other site (n = 9).
781
 Overall, three patients with nonpancreatic NETs (12 percent, 95% CI 3-31
percent) had objective responses; the stable disease rate in these patients
was 60 percent (n = 15) [133]. Only one of the pancreatic NETs responded.
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors:
Systemic therapy options to control tumor growth and symptoms of
hormone hypersecretion", section on 'Immunotherapy'.)
The activity of pembrolizumab was also evaluated in the phase II KEYNOTE-
158 trial, which included a cohort of 107 patients with well- and moderately
differentiated NET whose disease had progressed or who were intolerant of
one or more lines of standard therapy [134]. PD-L1 expression was present in
16 percent of patients. Primary sites of disease included the pancreas (n =
40), small intestine (n = 25), other gastrointestinal sites (n = 18), lung (n = 14),
and other organs (n = 10). The overall response rate was low and included
four partial responses (3.7 percent), and the median progression-free survival
was 4.1 months. Partial responses were noted in three patients with
pancreatic NET and in one with an unknown primary; all responding tumors
were PD-L1 negative. Two of the responding patients had a sustained
response approaching two years.
Trials are ongoing to evaluate checkpoint inhibitors in combination with other
immunomodulatory agents, including vascular endothelial growth factor (VEGF)
pathway inhibitors [135-137]. Eligible patients should be encouraged to enroll.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMICThe
coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of
cancer care. Important issues include balancing the risk from cancer treatment
versus harm from COVID-19, minimizing the number of clinic and hospital visits to
reduce exposure whenever possible, mitigating the negative impacts of social
distancing on delivery of care, and appropriately and fairly allocating limited health
care resources. These and other recommendations for cancer care during active
phases of the COVID-19 pandemic are discussed separately. (See "COVID-19:
Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
Initial therapy
●Somatostatin analogs are highly effective in controlling the symptoms
associated with advanced gastrointestinal neuroendocrine tumors (GINETs).

782
 In addition, somatostatin analogs have also been shown to control tumor
growth. (See 'Somatostatin analogs' above.)
●We suggest initiating therapy with a somatostatin analog for patients who
are not already on a somatostatin receptor (SSTR) analog for carcinoid
syndrome and who have a high tumor burden (Grade 2B). (See "Metastatic
well-differentiated gastroenteropancreatic neuroendocrine tumors:
Presentation, prognosis, imaging, and biochemical monitoring", section on
'Somatostatin receptor-based imaging techniques'.)
●For patients with metastatic disease that appears completely resectable in
the absence of extrahepatic metastases, diffuse bilobar involvement, or
compromised liver function, we suggest resection rather than medical
therapy (Grade 2B). (See 'General approach to the patient' above
and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Surgical resection'.)
●For patients with asymptomatic, advanced, unresectable GINETs and small-
volume disease, we suggest observation alone rather than early
administration of a somatostatin analog (Grade 2B). (See 'Somatostatin
analogs' above.)
Progressive disease
●For patients with clinically meaningful tumor progression who are not
already on a somatostatin analog, we suggest initiating treatment with a
long-acting somatostatin analog (Grade 2B). Treatment with a long-acting
somatostatin analog is also reasonable in patients with evidence of
biochemical progression of disease with a rising urinary 5-
hydroxyindoleacetic acid (5-HIAA) level, particularly if there is evidence of
carcinoid heart disease. (See 'Somatostatin analogs' above.)
●We suggest hepatic arterial embolization, chemoembolization, or
radioembolization rather than medical therapy alone as a palliative technique
for symptomatic patients with hepatic-predominant unresectable disease
(Grade 2C). (See 'General approach to the patient' above and "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control
tumor growth and symptoms of hormone hypersecretion", section on
'Hepatic arterial embolization'.)
●For most patients with GINETs and progressive disease despite a long-acting
somatostatin analog who are not eligible for liver-directed therapy, we
suggest everolimus rather than dose escalation of the long-acting
somatostatin analog (Grade 2B). (See 'Everolimus' above.)

783
However, dose escalation of the long-acting somatostatin analog is an option
for patients with indolent disease after an initial response or a prolonged
duration of stability with standard-dose somatostatin analog therapy.
(See 'Dose-escalated therapy' above.)
For patients with a somatostatin-receptor-positive GINET, treatment with
peptide receptor radioligand therapy (PRRT) using a radiolabeled
somatostatin analog such as lutetium Lu-177 dotatate (177Lu-Dotatate), where
it is available, is another reasonable option, either at the time of progression
on the somatostatin analog or following progression on everolimus. There
are no data specifically comparing 177Lu-Dotatate with everolimus in patients
progressing on long-acting somatostatin analog therapy, and the choice of
therapy in this situation should be based on the availability of 177Lu-Dotatate
and patient preference. For patients with midgut NETs whose disease is
highly avid on SSTR imaging, 177Lu-Dotatate could be considered prior to
everolimus, depending on availability and patient preference.
(See 'Radiolabeled somatostatin analogs' above.)
●Interferon alfa (IFNa) may be an option for patients with advanced GINETs
who have worsening symptoms or evidence of disease progression and for
whom there are no other treatment options. (See 'Interferon' above.)
●The benefit of cytotoxic chemotherapy for advanced, low-grade GINETs
continues to be debated. Regimens that have demonstrated evidence of
activity in preliminary reports of phase II studies include oxaliplatin plus
short-term infusional fluorouracil plus leucovorin (FOLFOX),
and temozolomide plus capecitabine; however, confirmatory studies are
needed to better define the activity of these regimens and to assess whether
response may differ depending on primary site. (See 'Cytotoxic
chemotherapy' above.)

784
Metastatic well-differentiated pancreatic
neuroendocrine tumors: Systemic therapy options
to control tumor growth and symptoms of
hormone hypersecretion
Authors:
Jennifer Ang Chan, MD, MPH
Matthew Kulke, MD
Thomas E Clancy, MD
Section Editor:
Richard M Goldberg, MD
Deputy Editor:
Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 10, 2021.
INTRODUCTIONNeuroendocrine cells are distributed widely throughout the
body, and neuroendocrine neoplasms of these dispersed cells can arise at many
sites. The classification and nomenclature of neuroendocrine neoplasms arising
within the digestive system has evolved over the past two decades (see "Pathology,
classification, and grading of neuroendocrine neoplasms arising in the digestive
system", section on 'Classification and terminology'):
Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies
characterized by variable but most often indolent biologic behavior. Clinical
behavior and prognosis correlate closely with histologic differentiation and grade,
as assessed by mitotic count and/or Ki-67 labeling index (table 1) [1].
(See "Pathology, classification, and grading of neuroendocrine neoplasms arising
in the digestive system", section on 'Classification and terminology'.)

Systemic treatment approaches to control tumor growth and symptoms related to

hormone hypersecretion for patients with advanced or metastatic well-
differentiated NET arising in the pancreas will be reviewed here. Systemic therapy
options for patients with advanced or metastatic well-differentiated
gastrointestinal tract NET (carcinoid) are discussed elsewhere, as are the clinical
presentation, imaging, biochemical monitoring, pathology, and classification of
gastroenteropancreatic NET; localization and treatment of pancreatic NET;
evaluation and management of NET of unknown primary site; management of
symptoms of functioning pancreatic NET; local management options to control

785
tumor growth and symptoms of hormone excess for well-differentiated metastatic
gastroenteropancreatic NET; and the evaluation and management of patients with
high-grade gastroenteropancreatic neuroendocrine carcinoma.

●(See "Metastatic well-differentiated gastrointestinal neuroendocrine

(carcinoid) tumors: Systemic therapy options to control tumor growth".)
●(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring".)
●(See "Pathology, classification, and grading of neuroendocrine neoplasms
arising in the digestive system".)
●(See "Classification, epidemiology, clinical presentation, localization, and
staging of pancreatic neuroendocrine neoplasms".)
●(See "Neuroendocrine neoplasms of unknown primary site".)
●(See "Insulinoma".)
●(See "Management and prognosis of the Zollinger-Ellison syndrome
(gastrinoma)".)
●(See "Glucagonoma and the glucagonoma syndrome".)
●(See "Somatostatinoma: Clinical manifestations, diagnosis, and
management".)
●(See "VIPoma: Clinical manifestations, diagnosis, and management".)
●(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone
hypersecretion".)
●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

CLASSIFICATION AND BIOLOGIC BEHAVIORThe World Health

Organization (WHO) classifies all gastroenteropancreatic NETs into low-grade (G1),
intermediate-grade (G2), and high-grade (G3) categories based on mitotic count
and proliferative index (Ki-67) (table 1) [1]. Poorly differentiated NETs are G3
neuroendocrine carcinomas. (See "Pathology, classification, and grading of
neuroendocrine neoplasms arising in the digestive system", section on '2010 and
2019 World Health Organization classification'.)

As a group, well-differentiated gastroenteropancreatic NETs are generally indolent

malignancies with a prolonged natural history. However, clinical behavior is
heterogeneous, as evidenced by the following observations:

●NETs arising in the tubular gastrointestinal tract and pancreas may have
similar characteristics on routine histologic evaluation, but they have a
different pathogenesis and biology [2]. Pancreatic NETs in general pursue a
somewhat more aggressive course than do other gastrointestinal tract NETs
786
 [3], although, conversely, most systemic agents have been associated with
higher response rates among patients with pancreatic NETs than in those
with gastrointestinal NET. (See "Metastatic well-differentiated gastrointestinal
neuroendocrine (carcinoid) tumors: Systemic therapy options to control
tumor growth".)
●G2 gastroenteropancreatic NETs have a slightly worse prognosis than do G1
NETs [4]. Although they are classified and treated similarly at present, as new
treatment modalities become available, it is likely that the histologic grade of
a well-differentiated NET will affect the selection of appropriate treatment.
●By contrast, poorly differentiated neuroendocrine carcinomas have a rapidly
progressive clinical course and a poor prognosis. They are generally treated
with platinum-based chemotherapy regimens according to guidelines
established for small cell lung carcinoma. (See "High-grade
gastroenteropancreatic neuroendocrine neoplasms".)
●There is a small subset of well-differentiated tumors with a proliferative rate
that places them in the high-grade category (G3 NETs). These tumors have a
clinical behavior that is midway between G2 NETs and neuroendocrine
carcinomas. Management is discussed in detail elsewhere. (See "High-grade
gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade,
well-differentiated tumors (NET G3)'.)
GENERAL APPROACH TO THE PATIENTThe majority of patients with
advanced pancreatic NETs have liver metastases [5]. Most tumors (between 50 and
75 percent) are nonfunctioning and are not associated with a hormonal syndrome.
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms", section on 'Clinical presentation'.)
●Symptoms of hormone secretion – Patients with symptoms of hormone
hypersecretion from a well-differentiated pancreatic NET should be managed
with somatostatin analogs and other agents as appropriate to the specific
syndrome. In general, initial therapy for insulinomas consists of
carbohydrates and diazoxide, which directly inhibits the release of insulin
from insulinoma cells. Careful monitoring is necessary in insulinoma patients
when initiating therapy with somatostatin analogs, which may paradoxically
worsen hypoglycemia due to decreased secretion of counterregulatory
hormones. Everolimus can also be highly effective in improving glycemic
control in patients with insulinoma. For patients with gastrinoma, high doses
of oral proton pump inhibitors are the treatment of choice. Somatostatin
analogs may be helpful for refractory cases.
(See "Insulinoma" and "Management and prognosis of the Zollinger-Ellison
syndrome (gastrinoma)".)
787
●Potentially resectable disease – For patients who have potentially
resectable metastatic disease, resection may provide prolonged control of
symptoms and tumor growth. Although the majority of patients recur, even if
resection is complete, metastasectomy is generally preferred over medical
therapy for patients with potentially resectable liver metastases.
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local
options to control tumor growth and symptoms of hormone hypersecretion",
section on 'Surgical resection'.)
●Unresectable disease – Somatostatin analogs and the molecularly targeted
agents everolimus and sunitinib have been shown to improve progression-
free survival (PFS) duration relative to supportive care alone in patients with
metastases from a nonfunctioning pancreatic NET. For patients with low-
volume disease who are asymptomatic, we suggest waiting until disease
progression or development of symptoms related to tumor bulk before
beginning systemic therapy. For most patients with a metastatic pancreatic
NET who are felt to require therapy, somatostatin analogs may be preferred
over a molecularly targeted agent as initial therapy because of the more
favorable side effect profile. (See 'Benefits' below.)
●Therapy at progression – If an initial approach of observation is chosen,
initiation of a somatostatin analog should be considered at the time of
progression.
For patients with radiologic disease progression despite use of a
somatostatin analog at standard doses, therapeutic options for those with
hepatic-predominant disease include noncurative surgical debulking and
nonsurgical liver-directed therapy (eg, transarterial bland embolization,
chemoembolization, or radioembolization). (See "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control
tumor growth and symptoms of hormone hypersecretion", section on
'Hepatic-predominant metastatic disease' and "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control
tumor growth and symptoms of hormone hypersecretion", section on
'Surgical resection' and "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Nonsurgical liver-directed therapy'.)
For patients with more widespread disease that is not eligible for liver-
directed therapy, systemic therapy options include everolimus, sunitinib,
cytotoxic chemotherapy, peptide receptor radioligand therapy (PRRT; eg,
lutetium-177 [177Lu] dotatate), or dose-escalated somatostatin analog therapy.
Studies evaluating the optimal sequencing of therapy have not been

788
conducted. Furthermore, interpretation of an attempted network meta-
analysis to rank the relative efficacy and toxicity of a variety of systemic
therapies for NETs is limited due to variability in patient populations,
variability in eligibility and response criteria, a lack of trials directly comparing
active treatments, as well as unclear efficacy of the comparator arm in some
cases (such as interferon) [6,7]. (See 'Molecularly targeted therapy' below
and 'Cytotoxic chemotherapy' below and 'Peptide receptor radioligand
therapy' below.)
Randomized trials comparing different systemic therapy approaches are
needed, and eligible patients should be encouraged to enroll in available
trials, such as the following:
•A European phase III trial, SEQTOR (NCT02246127), is comparing the
efficacy and safety of chemotherapy (fluorouracil and streptozotocin)
followed by everolimus versus everolimus followed by fluorouracil and
streptozotocin in patients with advanced and progressive pancreatic NETs.
•Other clinical trials are examining the sequencing of PRRT, including a
randomized phase II trial of PRRT with 177Lu dotatate
versus sunitinib (NCT02230176) for progressive disease.
•In addition, the phase III COMPETE trial is evaluating PRRT with 177Lu
edotreotide versus everolimus (NCT03049189).
If trial participation is not available or desired, the following represents our
approach to treatment:
•For patients who are highly symptomatic from tumor bulk or who have
rapidly enlarging metastases, we suggest chemotherapy rather than
molecularly targeted therapy or a dose-escalated somatostatin analog.
For most patients, we suggest the combination
of capecitabine and temozolomide (CAPTEM) rather than temozolomide
alone. In the absence of comparative trials, the choice of CAPTEM over a
streptozocin-containing regimen should be individualized, taking into
account the convenience of oral rather than intravenous treatment,
performance status, and the anticipated side effect profile of both
combinations. (See 'Dacarbazine and temozolomide-based
regimens' below.)
•The molecularly targeted agents everolimus and sunitinib improve PFS
duration relative to supportive care alone in patients with metastases
from a nonfunctioning pancreatic NET, and these drugs represent an
appropriate option for patients whose disease has progressed while
receiving a somatostatin analog. The choice of agent is often based on the

789
 expected side effect profile, which differs between these two agents.
(See 'Sunitinib' below and 'Everolimus' below.)
•PRRT using radiolabeled somatostatin analogs is an option for patients
with disease that expresses somatostatin receptors (as defined by nuclear
imaging) and has progressed on therapy including at least a somatostatin
analog. Although clinical trials are being planned, there are no data yet
specifically comparing PRRT with other therapeutic agents, and the choice
of therapy in this situation should be based on the availability of PRRT,
expected side effect profiles, and patient comorbidities and preference.
(See 'Lutetium-177 dotatate' below.)
•Another option for patients with indolent disease after an initial response
or a prolonged duration of stability with standard-dose somatostatin
analog therapy is dose escalation of the somatostatin analog.
(See 'Control of tumor growth' below.)
If dose escalation is not chosen, the benefit of continuing therapy with a
standard-dose long-acting somatostatin analog in patients whose disease
has progressed while receiving such therapy is not well defined. For
patients with nonfunctional tumors who experience unequivocal
radiographic progression on a somatostatin analog and for whom a
switch in therapy is planned, we would discontinue the somatostatin
analog. For patients with functional tumors, we continue the somatostatin
analog to minimize the effects of hormone secretion.
The following sections will discuss systemic treatment options to control
symptoms related to tumor bulk, or hormone hypersecretion and tumor growth
for well-differentiated pancreatic NETs. Local treatment options for
gastroenteropancreatic NETs, including resection and liver-directed therapy (such
as embolization), are discussed in detail elsewhere, as are systemic therapy for
well-differentiated gastrointestinal tract NETs and treatment approaches for high-
grade gastroenteropancreatic neuroendocrine carcinomas. (See "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control tumor
growth and symptoms of hormone hypersecretion" and "Metastatic well-
differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic
therapy options to control tumor growth" and "High-grade gastroenteropancreatic
neuroendocrine neoplasms".)
SOMATOSTATIN ANALOGSSomatostatin is a 14-amino acid peptide that
inhibits the secretion of a broad range of hormones in vivo. Somatostatin and
analogs of somatostatin (such as octreotide and lanreotide) act by binding to
somatostatin receptors (SSTRs), which are expressed on the majority of NETs [8].

790
The ability of octreotide and lanreotide to inhibit the secretion of peptides from
NET cells is mediated mainly through SSTR-2 and SSTR-5.
The presence of SSTRs can be determined by diagnostic imaging using a
radiolabeled somatostatin analog (indium-111 [111-In] pentetreotide [OctreoScan]
or PET using gallium Ga-68 DOTATATE [Ga-68 DOTATATE] or gallium Ga-68
DOTATOC [Ga-68 DOTATOC]). While either imaging with 111-In pentetreotide or
Ga-68 DOTATATE/Ga-68 DOTATOC can be used to assess SSTR status in patients
with NETs, the higher sensitivity of Ga-68 DOTATATE and Ga-68 DOTATOC PET
suggests that they may be the preferred option in certain clinical scenarios,
particularly in patients with smaller tumor volume. In general, uptake of
radiotracer by the tumor is predictive of a response to therapy with somatostatin
analogs. However, in some cases (eg, miliary disease), diagnostic imaging may be
negative even if SSTRs are present on the tumor. In such cases, a trial of
somatostatin analog therapy can be considered even in the presence of a negative
scan. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine
tumors: Presentation, prognosis, imaging, and biochemical monitoring", section
on 'Somatostatin receptor-based imaging techniques'.)
Benefits
Patients with symptoms from hormone secretion — Patients with metastases
from functioning pancreatic NETs (which account for 10 to 30 percent of all
pancreatic NETs [9]) often become symptomatic from hormone hypersecretion
rather than from tumor bulk. For those who have octreotide-avid disease,
symptoms of hormonal excess can often be well controlled with somatostatin
analogs.
In series that include patients with only pancreatic NETs or combined series of
patients with functioning gastroenteropancreatic NETs (gastrointestinal NETs and
pancreatic NETs), somatostatin analogs provide symptom control in over 60
percent [10-18]. However, symptomatic benefit is dose-related, and also differs
according to the type of functioning NET:
●Somatostatin analogs are highly effective in controlling the symptoms
associated with VIPomas (watery diarrhea) and glucagonomas (especially
improvement in the characteristic rash, necrolytic migratory erythema)
[19,20]. (See "VIPoma: Clinical manifestations, diagnosis, and
management" and "Glucagonoma and the glucagonoma syndrome".)
●Efficacy has also been shown for somatostatinomas [21,22], although the
effects are may be less dramatic than with VIPomas and glucagonomas.
(See "Somatostatinoma: Clinical manifestations, diagnosis, and
management", section on 'Somatostatin analogue'.)

791
 ●Insulinomas and gastrinomas represent the most common types of
functioning pancreatic NET, but the role of somatostatin analogs in
controlling hormone-related symptoms is somewhat limited:
•Efficacy of somatostatin analogs for insulinomas with hypoglycemia is
unpredictable [23-28], and somatostatin analogs should be used with
caution in this setting. Only approximately one-half of these tumors
express SSTRs and derive benefit from such therapy. Furthermore,
somatostatin analogs may paradoxically result in transient worsening of
hypoglycemia, presumably due to simultaneous inhibition of glucagon
secretion. In general, initial therapy for insulinomas often consists of
dietary modification. Treatment with everolimus may improve glycemic
control in patients with insulinoma. Treatment with diazoxide, which
directly inhibits the release of insulin from insulinoma cells, is another
option. (See "Insulinoma", section on 'Medical therapy to control
symptomatic hypoglycemia'.)
•The role of somatostatin analogs in patients with hormone-related
symptoms from gastrinoma is also limited. High doses of oral proton
pump inhibitors are the treatment of choice, as they are able to effectively
control the hypergastrinemia-related gastric acid overproduction.
Somatostatin analogs may be helpful in refractory cases.
(See "Management and prognosis of the Zollinger-Ellison syndrome
(gastrinoma)".)
Currently available somatostatin analogs include octreotide and lanreotide. Highly
symptomatic patients may be initiated on short-acting octreotide with rapid
transition to a long-acting formulation and subsequent titration of dose to
optimize symptom control while the LAR formulation is starting to take effect.
However, a depot preparation (Sandostatin LAR) has largely eliminated the need
for daily octreotide injections and is now considered a standard approach for
symptomatic treatment of advanced NETs [29,30]. Many clinicians initiate therapy
with the depot preparation for most patients and do not give an initial dose of
short-acting octreotide. Sandostatin LAR is typically initiated at a dose of 20 mg IM
monthly with gradual dose escalation as needed for optimal symptom control [31].
Patients may use additional short-acting octreotide for breakthrough symptoms
while doses are being titrated; therapeutic levels of octreotide are not reached
until 10 to 14 days after the initiation of the LAR injection.
Lanreotide, another long-acting somatostatin analog, can be administered once
monthly using a deep subcutaneous injection and appears to have similar efficacy
to octreotide [14-16].

792
Control of tumor growth — In addition to controlling symptoms associated with
hormone hypersecretion, somatostatin analogs have also been shown to control
tumor growth. Given the variable and sometimes indolent disease course of some
pancreatic NETs, the optimal time to initiate treatment with a somatostatin analog
in asymptomatic patients remains uncertain. We suggest initiation of a
somatostatin analog in patients with unresectable, asymptomatic, well-
differentiated pancreatic NET and a high tumor burden, an approach that is
consistent with guidelines from the European Neuroendocrine Tumor Society
(ENETS) [30], North American Neuroendocrine Society (NANETS) [32], and the
National Comprehensive Cancer Network (NCCN) [33]. For patients with
asymptomatic, advanced, unresectable pancreatic NET and small-volume disease,
we suggest initial observation alone rather than early administration of a
somatostatin analog. In such patients, we initiate somatostatin analog therapy if
there is evidence of clinically meaningful tumor progression.
Past studies have indicated that few patients with advanced
gastroenteropancreatic NET (<10 percent) have objective tumor shrinkage with
somatostatin analogs [30,34-37], even when limited to subgroups with progressive
disease at the time of treatment initiation [11-13,34,38-40]. However, more reports
have demonstrated that, in addition to an improvement in symptoms, treatment
with somatostatin analogs may be associated with disease stabilization and
significant prolongation of progression-free survival (PFS) [41-43]. Whether
somatostatin analogs also increase overall survival is not yet known, although a
correlation between PFS and overall survival in patients with advanced NET treated
with single-agent somatostatin analog therapy has been shown [44].
Median duration of PFS and overall survival depends on several factors, including
primary tumor location, Ki-67 percent, extent of liver metastases, presence of bone
and/or peritoneal metastases, and the presence of symptoms when initiating
treatment. A nomogram has been developed to estimate PFS in patients with well-
differentiated gastroenteropancreatic NETs based upon these and other factors
[45].
The PROMID study, which was the first randomized study demonstrating an
antiproliferative effect of somatostatin analogs in NET, included patients with
metastatic small intestinal NET who were treated with octreotide LAR versus
placebo [41]. Because the study was limited to patients with small intestinal NET,
applicability of these results to patients with pancreatic NET was uncertain.
(See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid)
tumors: Systemic therapy options to control tumor growth".)
However, support for the antiproliferative effect of somatostatin analogs in
pancreatic NET was provided by the phase III CLARINET trial, which

793
compared lanreotide versus placebo in 204 patients with advanced well- or
moderately differentiated, nonfunctioning gastroenteropancreatic NET, including
both gastrointestinal NET and pancreatic NET (45 percent of all enrollees) [42].
Patients were randomly assigned to receive either 120 mg lanreotide Autogel (n =
101) or placebo (n = 103) every four weeks for 96 weeks or until progressive
disease (PD) or death. The trial’s primary end point was PFS as determined by
Response Evaluation Criteria in Solid Tumors (RECIST) criteria (table 2). All patients
had avid disease on somatostatin-receptor scintigraphy. Most patients (96 percent)
had no tumor progression by RECIST criteria in the three to six months before
randomization; approximately one-half had pancreatic primary sites. Compared
with placebo, there was a highly significant advantage in PFS with the use of
lanreotide. At a time-point of two years following initiation of treatment, median
PFS was not reached with lanreotide compared with 18 months with placebo
(hazard ratio [HR] for progression or death 0.47; 95% CI 0.30-0.73). Estimated rates
of 24-month PFS were 65 versus 33 percent. There were no significant differences
in quality of life or overall survival. The most common treatment-related adverse
effect was diarrhea (26 versus 9 percent in the lanreotide and placebo groups,
respectively). Based upon these data, lanreotide has been approved in the United
States for the treatment of patients with unresectable, well- or moderately
differentiated, locally advanced or metastatic gastroenteropancreatic NET.
The mechanisms by which somatostatin analogs control tumor growth may result
from direct antiproliferative effects, including cell cycle inhibition and pro-
apoptotic effects, and indirect antiproliferative effects, including inhibition of
tumor angiogenesis and the release of trophic growth hormones
[46]. Octreotide LAR and lanreotide are first-generation agents that primarily
target SSTR-2 and SSTR-5; benefit for the addition of the second-generation
somatostatin analog pasireotide, which targets multiple SSTR subtypes, with
greater binding affinity for SSTR-1, SSTR-3, and SSTR-5, and lower affinity for SSTR-
2, could not be shown in a randomized phase II trial of everolimus with or without
pasireotide [47].
Dose-escalated therapy — Dose escalation is an option at the time of initial
disease progression on a long-acting somatostatin analog, but it is not our
preferred option. The benefits of escalating the dose and/or frequency of a
somatostatin analog for disease control are not well established, and clinical
practice is variable. At least some data suggest the potential for prolonged periods
of stable disease when the dose intensity is increased (eg, by using higher than
standard doses or reducing the dosing interval) after an initial period of long-
acting somatostatin analog use [48,49]. However, whether this reflects indolent
biology rather than an intrinsic dose-response relationship is not clear.

794
Furthermore, how this strategy compares with other systemic treatments for
disease control after progression on a long-acting somatostatin analog (eg,
peptide receptor radioligand therapy) is not known. (See 'Peptide receptor
radioligand therapy' below.)
Side effects — Somatostatin analogs are usually well tolerated, and side effects
are generally mild [50,51]. Approximately one-third of patients may have mild
nausea, abdominal discomfort, bloating, loose stools, and fat malabsorption
during the first weeks of therapy, after which time, symptoms tend to subside. Use
of pancreatic enzyme supplements can ameliorate symptoms associated with
pancreatic insufficiency. Mild glucose intolerance may occur due to transient
inhibition of insulin secretion. Somatostatin analogs reduce postprandial
gallbladder contractility and delay gallbladder emptying; up to 25 percent of
patients develop asymptomatic gallstones or sludge within the first 18 months of
therapy [51].
CYTOTOXIC CHEMOTHERAPYWell-differentiated pancreatic NETs are clearly
responsive to cytotoxic chemotherapy (table 3). For patients who are highly
symptomatic from tumor bulk or who have rapidly enlarging metastases, we
suggest chemotherapy rather than molecularly targeted therapy or a somatostatin
analog because of the higher objective response rate. For most patients, we
suggest the combination of capecitabine and temozolomide (CAPTEM) rather than
temozolomide alone. In the absence of comparative trials, the choice of CAPTEM
over a streptozocin-containing regimen should be individualized, taking into
account the convenience of oral rather than intravenous treatment, performance
status, and the anticipated side effect profile of both combinations.
Dacarbazine and temozolomide-based regimens — Dacarbazine is an alkylating
agent (like streptozocin), with activity against pancreatic NET. In an Eastern
Cooperative Oncology Group (ECOG) phase II trial of dacarbazine in 42 patients
with advanced pancreatic islet cell carcinomas, the objective response rate was 33
percent [52]. As with streptozocin, the toxicity of dacarbazine-based regimens has
limited their widespread use.
Temozolomide is a less toxic orally active analog of dacarbazine with activity in
pancreatic NET [53]:
●In prospective studies, temozolomide has been combined
with thalidomide, bevacizumab, or everolimus, with overall response rates of
24 to 45 percent (table 3) [54-56]. In these studies, temozolomide has
generally been administered using a dose-intense regimen of 150
mg/m2 daily for seven days on an every-other-week schedule. Prophylaxis
for Pneumocystis jirovecii pneumonia is recommended in light of the
lymphopenia associated with long-term use of temozolomide according to
795
 this schedule. The relative contribution of temozolomide and the agent used
in combination with it to the observed antitumor activity is unclear.
●Retrospective series and preliminary reports of a randomized phase II trial
have also reported promising activity with CAPTEM in patients with
pancreatic NET (table 3):
•In a retrospective series of 143 patients who were treated with CAPTEM,
the response rate was 54 percent [57].
•Benefit of CAPTEM relative to temozolomide alone was shown in the
phase II ECOG-American College of Radiology Imaging Network (ACRIN)
study 2211, which randomly assigned 144 patients with unresectable or
metastatic pancreatic NET and progressive disease within the past 12
months to temozolomide alone (200 mg/m2 daily on days 1 through 5
every 28 days) or capecitabine (750 mg/m2 twice daily on days 1 through
14) plus temozolomide (200 mg/m2 orally daily on days 10 through 14),
also given in 28-day cycles [58]. On-protocol treatment was prespecified as
13 cycles, after which time patients could receive any treatment at
investigator discretion. In a preliminary report presented at the 2018
American Society of Clinical Oncology (ASCO) meeting, at a median follow-
up of 29 months, median progression-free survival (PFS), the primary
endpoint, was significantly better with combined therapy (22.7 versus 14.4
months, hazard ratio 0.58, 95% CI 0.36-0.93). Median overall survival was
38 months for temozolomide alone and had not been reached for the
combined therapy group. The objective response rate was higher for
combined therapy (33 versus 28 percent, p = 0.47), as was the disease
control rate (objective response plus stable disease; 82 versus 68 percent).
Treatment-related grade 3 or 4 adverse effects were twice as common
with combined therapy (44 versus 22 percent); the most common were
neutropenia (13 versus 4 percent), nausea and vomiting (8 versus 0
percent), diarrhea (8 versus 0 percent), and fatigue (8 versus 1 percent).
Role of MGMT expression — As has been noted in patients with glioblastoma,
there appears to be a correlation between expression of methylguanine DNA
methyltransferase (MGMT) and temozolomide responsiveness in advanced NET.
MGMT is an enzyme that is responsible for DNA repair induced by alkylating agent
chemotherapy. (See "Initial treatment and prognosis of newly diagnosed
glioblastoma in adults", section on 'Temozolomide'.)
●In one study, of 21 patients treated with temozolomide-based regimens,
none of the 16 with intact MGMT expression (including all 13 carcinoid
tumors) responded to treatment, while four of the five patients whose

796
 tumors lacked MGMT expression (all with pancreatic NET) had a radiologic
response [59].
●A second larger retrospective series also reported an association between
MGMT status and response to alkylating agents
(including temozolomide, dacarbazine, and streptozotocin-based regimens)
in patients with NET [60]. In this study, the association between MGMT status
and response to alkylating agents was observed in patients with either
gastrointestinal or pancreatic NET.
MGMT status, however, has not yet been prospectively validated as a predictor of
response in NET, and variability in the techniques and criteria used to assess
MGMT status preclude its current use as a routine clinical test to select patients
for temozolomide therapy. (See "Metastatic well-differentiated gastrointestinal
neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor
growth", section on 'Dacarbazine and temozolomide'.)
Streptozocin combinations — Streptozocin-based combination therapy has been
a historical treatment standard for patients with advanced pancreatic NET (table 3).
Antitumor efficacy can be illustrated by the following data:
●In an early randomized trial, streptozocin plus doxorubicin had a combined
biochemical and radiologic response rate of 69 percent and a median survival
of 2.2 years [61].
●A retrospective analysis of 84 patients with either locally advanced or
metastatic pancreatic NET treated with streptozocin, fluorouracil (FU),
and doxorubicin and using current standard response criteria reported a 39
percent objective radiographic response rate and a median survival duration
of 37 months [62].
●Another retrospective analysis of 96 patients with pancreatic NETs treated
with streptozocin plus FU reported an objective response rate of 43 percent,
and an additional 41 percent had stable disease as the best response [63].
While streptozocin-based regimens are clearly active in patients with advanced
pancreatic NETs, widespread use has been limited by a relatively cumbersome
administration schedule and by concerns about toxicity, which can include
myelosuppression, nausea, hair loss, and renal dysfunction [64].
Oxaliplatin-containing regimens — Reports suggest antitumor activity for some
oxaliplatin-based regimens in pancreatic NET [65,66]:
●A combined analysis of two phase II trials examining oxaliplatin-
fluoropyrimidine chemotherapy plus bevacizumab in advanced NET suggests
antitumor activity for these regimens. The analysis included a study
examining the efficacy of oxaliplatin plus short term infusional FU
and leucovorin (FOLFOX) with bevacizumab (n = 36) and another

797
 examining capecitabine in combination with oxaliplatin and bevacizumab (n =
40) [65]. The best overall responses based on Response Evaluation Criteria in
Solid Tumors (RECIST) criteria in 12 patients with pancreatic NET treated with
FOLFOX-bevacizumab included 50 percent with a partial response and 50
percent with stable disease. The outcomes in 16 patients with pancreatic NET
treated with capecitabine with oxaliplatin and bevacizumab were 18.8
percent with a partial response and 69 percent with stable disease.
●The contribution of bevacizumab to these results is unclear; similar benefit
has been shown with capecitabine plus oxaliplatin alone [66].
MOLECULARLY TARGETED THERAPYFor patients with advanced pancreatic
NETs whose disease has progressed on a somatostatin analog and who are not
symptomatic from tumor bulk that would benefit from cytoreduction, we suggest
treatment with a molecularly targeted agent (everolimus or sunitinib).
Progress in the understanding of the molecular biology of pancreatic NETs has
revealed elevated expression of several cellular growth factors and their receptors
(including vascular endothelial growth factor [VEGF] and the VEGF receptor
[VEGFR]), and involvement of the mammalian Target of Rapamycin (mTOR) in
pancreatic neuroendocrine tumorigenesis [67-69]. Many receptors like VEGFR
function as tyrosine kinases (TKs). The finding in preclinical models that disruption
of VEGFR signaling pathways inhibits neuroendocrine cell growth has prompted a
number of clinical trials evaluating small molecule TK inhibitors
(eg, sunitinib, sorafenib, pazopanib, and cabozantinib) and monoclonal antibodies
(MoAbs) that target VEGF in patients with advanced NET.
Studies have demonstrated antitumor activity associated with bevacizumab (an
anti-VEGF MoAb), and several TK inhibitors that inhibit VEGFR, as well as the mTOR
inhibitor everolimus. As has been seen with cytotoxic chemotherapy, these agents
appear to be more active in pancreatic NET than in advanced gastrointestinal NET
(carcinoid). (See "Metastatic well-differentiated gastrointestinal neuroendocrine
(carcinoid) tumors: Systemic therapy options to control tumor growth", section on
'Molecularly targeted therapy'.)
Small molecule antiangiogenic TK inhibitors
Sunitinib — Sunitinib is a multi-targeted tyrosine kinase (TK) inhibitor that has
shown activity against a range of signaling pathways and growth factors/receptors
including VEGFR 1, 2, and 3 as well as PDGFR alpha and beta, KIT, glial cell-line
derived neurotrophic factor, RET, FMS-like tyrosine kinase-3 (FLT3), and colony-
stimulating factor receptor (CSF-1R).
In an initial phase II trial, sunitinib (50 mg daily for four of every six weeks) was
administered to 109 patients with advanced NET [70]. Of 61 patients with
pancreatic NET, 11 (18 percent) had a partial response, and 68 percent had
798
prolonged periods of stable disease; median time to tumor progression (TTP) was
7.7 months. Rates of symptom control for patients with functioning tumors and
refractory symptoms were not reported.
Continuous administration of sunitinib (37.5 mg daily) was compared with placebo
in a phase III trial of 171 patients with progressing pancreatic NET [71]. Accrual
was stopped prematurely prior to the first preplanned interim efficacy analysis.
Median progression-free survival (PFS) was significantly longer with sunitinib (11.4
versus 5.5 months). There were eight objective responses with sunitinib (versus
none in the placebo group), two of which were complete. Hand-foot skin reaction
and hypertension of any grade occurred in 23 and 26 percent of patients receiving
sunitinib, respectively, and the most common grade 3 or 4 adverse events in this
group were neutropenia (12 percent) and hypertension (10 percent). Despite these
side effects, there were no differences in the quality-of-life index with sunitinib.
Rates of symptom control for patients with functioning tumors and refractory
symptoms were not reported. In a later report, median overall survival favored
sunitinib (38.6 versus 29.1 months), but the difference was not statistically
significant, potentially due to crossover from placebo to sunitinib in 69 percent of
the control group [72].
Largely based upon these data, sunitinib was approved in the United States for the
treatment of progressive, well-differentiated pancreatic NET in patients with
unresectable, locally advanced, or metastatic disease. Side effects may include
hypertension, proteinuria, and other forms of renal toxicity, arterial
thromboembolism, left ventricular dysfunction, and clinical heart failure, thyroid
dysfunction, bleeding, myelosuppression, hand-foot skin reaction, delayed wound
healing, hepatotoxicity, and muscle wasting. These side effects and their
management are discussed in detail elsewhere. (See "Cutaneous adverse events of
molecularly targeted therapy and other biologic agents used for cancer therapy",
section on 'VEGFR/PDGFR inhibitors' and "Toxicity of molecularly targeted
antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly
targeted antiangiogenic agents: Cardiovascular effects".)
Although few data are available, sunitinib provided control of refractory symptoms
due to tumor hormone production in two patients with VIPomas [73]. By contrast,
blood glucose concentrations were not increased in a single patient treated with
sunitinib for a functioning metastatic insulinoma [74]. Furthermore, worsening
hypoglycemia in patients with insulinoma and development of hypoglycemia in
patients with a previously nonfunctioning pancreatic NET related to
hyperinsulinemia have been reported [74-76].

799
Sorafenib and pazopanib — Two other orally active antiangiogenic TK
inhibitors, sorafenib and pazopanib, have demonstrated modest activity in
pancreatic NET in phase II studies:
●Sorafenib, which targets VEGFR-2 and PDGFR-beta, was evaluated in 43
patients with pancreatic NET [77]. In a preliminary analysis, responses were
observed in 9 percent of the 41 evaluable patients.
●Pazopanib, which targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha and
beta, as well as KIT, was evaluated in a prospective study of 51 patients with
advanced NET (29 with pancreatic NET and 22 with carcinoid) on stable doses
of octreotide-LAR [78]. Patients received pazopanib at a dose of 800 mg daily.
The response rate among patients with well-differentiated pancreatic NET
was 22 percent.
Cabozantinib — Cabozantinib, which targets VEGFRs, MET, AXL, and RET, was
evaluated in a prospective study of 61 patients with advanced NETs (20 pancreatic
and 41 gastrointestinal NETs). Patients started at a dose of 60 mg of cabozantinib
daily. In a preliminary report, the response rate was 15 percent for patients with
pancreatic NETs, with an encouraging median PFS of 21.8 months [79]. The
CABINET trial, a randomized placebo-controlled phase III study, is currently
enrolling patients and will evaluate the efficacy of cabozantinib in patients with
advanced pancreatic and gastrointestinal NETs after prior therapy
with everolimus (NCT03375320).
Lenvatinib — Lenvatinib, which targets VEGFRs as well as fibroblast growth factor
(FGF) receptors, was studied in the phase II TALENT trial of 111 patients with
advanced NETs (55 pancreatic and 56 gastrointestinal) [80]. All of the pancreatic
NET patients had progressed after being treated with a targeted agent
(everolimus in 69 percent, sunitinib in 29 percent). The objective response rate was
44 percent for the pancreatic NETs, and the median duration of response was 19.9
months (range 8.4 to 30.8).
mTOR inhibitors
Everolimus — Several nonrandomized studies have explored the activity
of everolimus, with and without octreotide [81-83]. The activity of everolimus (10
mg daily) in pancreatic NET was initially explored in an international multicenter
phase II trial of 160 patients, 45 of whom also received treatment with concurrent
octreotide at the discretion of the investigators [81]. Median PFS was longer in
patients who received octreotide plus everolimus compared with everolimus alone
(17 versus 9.7 months), but whether the addition of octreotide contributed to the
higher PFS is unclear since the study did not randomly assign patients to receive
octreotide.

800
Everolimus monotherapy (10 mg daily) was compared with best supportive care
alone in the placebo-controlled RADIANT-3 trial of 410 patients with advanced
progressing pancreatic NET [84]. Everolimus was associated with a significant
prolongation in median PFS (11 versus 4.6 months, hazard ratio [HR] for
progression 0.35, 95% CI 0.27 to 0.45). There were confirmed objective partial
responses (as defined by Response Evaluation Criteria in Solid Tumors [RECIST]
v1.0 (table 2)) in 5 percent of patients receiving everolimus versus 2 percent of the
placebo group. Drug-related adverse events were mostly grade 1 or 2, and
included stomatitis (64 versus 17 percent of the placebo group), rash (49 versus 10
percent), diarrhea (34 versus 10 percent), fatigue (31 versus 14 percent), and
infections (23 versus 6 percent), predominantly of the upper respiratory tract. The
most common grade 3 or 4 drug-related adverse events were stomatitis (7
percent), anemia (6 percent), and hyperglycemia (5 percent). In a later analysis,
median survival favored everolimus (44 versus 37.7 months), but the difference
was not statistically significant [85]. The high rate of crossover of patients from
placebo to everolimus (85 percent) may have confounded the ability to detect a
difference in overall survival.
Largely based upon these data, everolimus was approved in the United States for
the treatment of progressive NET of pancreatic origin in patients with
unresectable, locally advanced, or metastatic disease.
Everolimus causes hyperglycemia, particularly in those with preexisting
hyperglycemia. In analysis of data from the RADIANT-3 trial described above, the
frequency of severe (grade 3 or 4) hyperglycemia was higher in those with
preexisting diabetes mellitus or baseline hyperglycemia (15 versus 3 percent in
those without diabetes or baseline hyperglycemia) [86]. Interestingly, rates of
grade 3 or 4 hyperglycemia were similar in those with glucagonoma versus those
without glucagonoma (9.1 versus 7.8 percent). (See "Glucagonoma and the
glucagonoma syndrome", section on 'Laboratory abnormalities'.)
Largely because of this effect, everolimus may be of particular value in patients
with functioning insulinomas and refractory hypoglycemia [87-90]. In one report,
four patients with malignant insulinoma and refractory hypoglycemia normalized
their glucose levels during everolimus therapy; two had an objective antitumor
response [87]. Clinical improvement in the other two patients who had stable
disease as the best response suggests a possible direct effect of the drug on
insulin production and/or release. (See "Insulinoma".)
Though rare, everolimus has been associated with serious, adverse events,
including pneumonitis [90]; tolerance should be carefully monitored during
therapy. (See "Pulmonary toxicity associated with antineoplastic therapy:
Molecularly targeted agents", section on 'Everolimus'.)

801
Everolimus plus bevacizumab — Both VEGF pathway and mTOR inhibitors are
active in pancreatic NET. The benefit of adding bevacizumab to everolimus was
addressed in a phase II trial in which 150 patients with locally advanced or
metastatic pancreatic NET were randomly assigned to everolimus alone (10 mg by
mouth daily) or with concurrent bevacizumab (10 mg/kg IV every two weeks) [91].
In a preliminary report presented at the 2015 American Society of Clinical
Oncology (ASCO) meeting, combination therapy was associated with significantly
higher response rate (31 versus 12 percent) and superior PFS (16.7 versus 14
months), but no overall survival benefit. Combined therapy was also associated
with higher rates of serious grade 3 or higher toxicity, including diarrhea (14
versus 3 percent), hyponatremia (11 versus 3 percent), and hypertension (41
versus 12 percent). This combination warrants further investigation.
Temsirolimus — In a phase II study of 37 patients with progressive NET treated
with the mTOR inhibitor temsirolimus, only 1 of 15 patients with pancreatic NET
had an objective response, but 67 percent attained disease control (which included
stable disease for at least two months) [92]. Higher baseline tumor levels of mTOR
predicted for better outcomes.
Encouraging early results were noted in a phase II trial of temsirolimus (25 mg IV
weekly) plus the anti-VEGF monoclonal antibody bevacizumab (10 mg/kg every
other week) in 56 patients with RECIST criteria progression within seven months of
study entry [93]. A confirmed partial response was documented in 23 patients (41
percent), and 44 (79 percent) remained progression free at six months. The most
common grade 3 or 4 toxic effects related to therapy were hypertension (21
percent), hyperglycemia (14 percent), fatigue (16 percent), neutropenia, and
headache (7 percent each).
PEPTIDE RECEPTOR RADIOLIGAND THERAPY
Radiolabeled somatostatin analogs — Targeted radiotherapy using radiolabeled
somatostatin analogs is a reasonable option for patients with disease that
expresses somatostatin receptors (SSTRs) and has progressed on therapy
including at least a somatostatin analog.
Traditional external beam radiotherapy is beneficial for patients with painful bone
metastases but has little utility for the more common visceral metastases. There
has been substantial interest, however, in targeted radiotherapy using systemic
administration of radiolabeled somatostatin analogs [94-104]. The most frequently
used radionuclides for targeted radiotherapy include yttrium-90 (90Y) and lutetium-
177 (177Lu), which differ from one another in terms of emitted particles, particle
energy, and tissue penetration [105-107].
Radioembolization using 90Y-radiolabeled glass or starch microspheres is a
different procedure that is a local ablative treatment administered via the hepatic
802
artery. Use of radioembolization to treat advanced NETs is discussed elsewhere.
(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to
control tumor growth and symptoms of hormone hypersecretion", section on
'Technique and outcomes'.)
Most of the series reporting efficacy and toxicity with radiolabeled somatostatin
analogs have included both pancreatic NET and gastrointestinal NET
[105,106,108,109].
Yttrium-90 dotatoc — The most extensive experience with 90Y dotatoc comes from
a large single-institution series of 1109 patients with metastatic
gastroenteropancreatic NET and disease progression within 12 months of study
entry, with visible tumor uptake on pretreatment SSTR scintigraphy [108]. After the
initial dose, additional treatment cycles were withheld if there was tumor
progression or permanent toxicity; otherwise, patients were offered retreatment.
The specific interval was not specified. The median number of courses
administered was two (range 1 to 10).

Overall, 378 patients (34 percent) had a "morphologic" response (defined as any
measurable decrease in the sum of the longest diameters of all pre-therapeutically
detected tumor lesions by computed tomography [CT], magnetic resonance
imaging [MRI], or ultrasound), 172 (15 percent) had a biochemical response
(defined as any post-treatment decrease in a tumor marker that had
demonstrated progression prior to enrollment), and 329 (29.7 percent) improved
symptomatically. The median survival from diagnosis was 94.6 months. Longer
survival correlated with responses by any of the above criteria. Transient grade 3
or 4 hematologic toxicities developed in 142 (12 percent), and loss of renal function
was the main dose-limiting toxicity. In all, 103 patients (9 percent) had permanent
grade 4 or 5 (fatal, n = 35) renal toxicity. Older age, low baseline glomerular
filtration rate, and high kidney uptake score were associated with severe
nephrotoxicity.

Lutetium-177 dotatate — At least some data suggest that 177Lu dotatate

outperforms 90Y dotatoc [107]. In a registry-based series of 450 patients with
pancreatic or gastrointestinal NET, 54 percent were treated with 177Lu dotatate
alone, 17 percent were treated with 90Y dotatoc alone, and combined therapy was
administered to 29 percent [107]. The median progression-free survival (PFS) for
the entire group was 41 months (27 months with 90Y dotatoc alone, 40 months
for 177Lu dotatate, and 50 months for combined therapy). The nonrandomized
nature of this series precludes drawing conclusions regarding the relative efficacy
of these approaches; however, long-term side effects of peptide receptor
radioligand therapy (PRRT) may include loss of renal function, pancytopenia, and
803
myelodysplastic syndrome, although rates of severe (grade 3 or worse) toxicity are
reported to be low (1 percent or less) [107].
Efficacy results with 177Lu dotatate alone are available from the following reports:
●In one series of 443 Dutch patients with gastroenteropancreatic or lung NET,
the objective response rate was 39 percent of whom an additional 43 percent
had stable disease [110]. At a median follow-up of 78 months, median PFS
was 29 months, median time to tumor progression was 36 months, and
median overall survival was 63 months. Response rates were particularly high
in pancreatic NET, ranging from 52 percent for nonfunctioning tumors to 62
percent for functioning gastrinomas, insulinomas, and VIPomas. The safety
analysis included 610 patients who had received a cumulative dose of at least
100 millicuries (3.7 gigabecquerels). Acute treatment-related toxicity included
grade 3 or 4 thrombocytopenia in 5 percent, lymphopenia in 50 percent, and
elevated aminotransferases in 3 percent. Long-term toxicity included acute
leukemia in four patients (0.7 percent, three fatal) and myelodysplastic
syndrome in nine (1.5 percent, five fatal). There was no therapy-related long-
term renal or hepatic failure.
●In a meta-analysis of 15 studies in combined populations of gastrointestinal
and pancreatic NETs, totaling 872 patients with metastatic disease, the
pooled objective response rate following a course of 177Lu dotatate was 28
percent (95% CI 21-35 percent), and the pooled disease control rate was 79
percent (95% CI 76-82 percent) [111]. Early adverse effects were minimal,
including nausea, vomiting, fatigue, and hormonal disorders.
●In addition to these data, among patients with advanced midgut NET, the
benefits of 177Lu dotatate were shown in the NETTER-1 trial, which
demonstrated significant improvement in objective response rate, PFS, and
overall survival with 177Lu dotatate compared with high-dose long-
acting octreotide in patients whose disease had progressed on standard-
dose somatostatin analog therapy (median PFS not reached versus 18
months) [109]. These data are discussed in more detail elsewhere.
(See "Metastatic well-differentiated gastrointestinal neuroendocrine
(carcinoid) tumors: Systemic therapy options to control tumor growth",
section on 'Radiolabeled somatostatin analogs'.)
Largely based on data from the NETTER-1 trial, in January 2018, the US Food and
Drug Administration (FDA) approved 177Lu dotatate for the treatment of
somatostatin-receptor-positive gastroenteropancreatic NET, including those
arising in the pancreas [112]. The recommended dose is 7.4 gigabecquerels (200
millicuries) as an intravenous infusion over 30 minutes every eight weeks for a
total of four doses [113].

804
The optimal selection of candidates for 177Lu dotatate is not established. Guidelines
from the European Neuroendocrine Tumor Society, which largely mirror the
eligibility criteria for the NETTER-1 trial, are outlined in the table (table 4) [114]. We
agree with these guidelines.
The limitations of 177Lu dotatate at present include the complexity of
administration, the lack of trials comparing this agent with other systemic
therapies, and the lack of widespread availability.
Long-term toxicity — The most serious long-term toxicity associated with PRRT is
irreversible myelotoxicity and therapy-related myeloid neoplasms, including
myelodysplastic syndrome, acute leukemia, myeloproliferative neoplasms, or any
type of myeloid neoplasm. The available data from studies with long-term follow-
up suggest a rate of myelodysplastic syndrome of approximately 2 percent and a
rate of acute leukemia of approximately 0.5 percent. Given the risk and the poor
prognosis after a diagnosis of therapy-related myeloid neoplasms, clinicians
should closely monitor patients with periodic complete blood counts (CBC) after
PRRT [115]. We suggest obtaining a CBC with differential at least every six months,
and prompt referral to a hematologist if abnormalities are detected.
(See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid)
tumors: Systemic therapy options to control tumor growth", section on
'Myelotoxicity and therapy-related myeloid neoplasms'.)
Should the somatostatin analog be continued? — The added benefit of
combining a long-acting somatostatin analog with PRRT compared with PRRT
alone is not established. All patients in the NETTER-1 trial continued receiving the
long-acting somatostatin analog during and after PRRT. At least some data from a
retrospective analysis of 168 patients treated at a single institution for
unresectable gastroenteropancreatic NETs suggest that combined therapy is
associated with significantly better median PFS (48 versus 27 months) and overall
survival (91 versus 47 months) [109,116] compared with PRRT alone.
For patients with a functional NET, we continue therapy with a somatostatin
analog during and after PRRT. For patients with a nonfunctional NET, we typically
continue therapy with the somatostatin analog, although we consider stopping it
for a patient with a nonfunctional NET whose disease is progressing unequivocally
on somatostatin analog therapy. This approach is consistent with guidelines from
the European Society for Medical Oncology [117].
Iobenguane I-131 — Benefit also has been suggested for systemic radionuclide
therapy using iodine-131-labeled iobenguane (iobenguane I-131) in individuals
with metastatic gastroenteropancreatic NET whose tumors express the
norepinephrine transporter and take up iobenguane, as determined by
scintigraphy using radiolabeled iobenguane [118]. There are different iobenguane

805
nuclides used for therapeutic and diagnostic purposes. Iobenguane I-131
(therapeutic) is also known as metaiodobenzylguanidine (MIBG or 131I-MIBG);
iobenguane expression is demonstrated by uptake on iobenguane I-123
(diagnostic) scintigraphy. While iobenguane I-131 has been licensed by regulatory
authorities in some countries and is approved in the United States for treatment of
pheochromocytoma/paraganglioma and neuroblastoma, in our view, its use for
the treatment of gastroenteropancreatic NET remains investigational.
Iobenguane is a compound resembling norepinephrine that is accumulated by
some NETs. In retrospective series, biochemical responses were observed in 37
percent of patients with gastroenteropancreatic NET treated with iobenguane I-
131, objective radiographic responses were noted in 28 percent, and symptomatic
improvement was reported by 27 of 48 patients (56 percent) [119].
In another report, iobenguane I-131 (therapeutic) was "beneficial" in 73 percent of
20 patients with metastatic gastroenteropancreatic NETs (including eight with
pancreatic NETs) [120]. Treatment was judged beneficial if clinical status improved,
laboratory tests for secreting tumors improved by >20 percent, tumor progression
was halted, the size of the most significant localization had decreased by >25
percent, and the dose of analgesic and cold somatostatin analog therapy could be
lowered. Treatment was well tolerated, and only one patient had severe
pancytopenia. Notably, at 12 months, 7 of the 14 responders were again
symptomatic.
IMMUNOTHERAPYThe role of immunotherapy with immune checkpoint
inhibitors is just beginning to be studied in patients with well-differentiated NETs.
Early data suggest that anti-programmed cell death 1 (PD-1) antibodies have
minimal activity as single-agent therapy. As examples:
●The efficacy of the anti-PD-1 antibody spartalizumab (PDR001) was evaluated
in a phase II multicenter trial that enrolled 116 patients, including 33 with
pancreatic NETs, 32 with gastrointestinal NETs, 30 with thoracic NETs, and 21
with poorly differentiated gastroenteropancreatic neuroendocrine
carcinomas [121]. In a preliminary report presented at The 2018 European
Society for Medical Oncology (ESMO) meeting, the clinical activity of
spartalizumab was notable in patients with thoracic NETs (partial response
rate 20 percent) but appeared marginal in other cohorts, including well-
differentiated pancreatic NETs (partial response rate 3 percent, stable disease
rate 55 percent).
●Activity of pembrolizumab in patients with programmed cell death 1 ligand
(PD-L1)-positive advanced NET was evaluated in the KEYNOTE-028 study,
which enrolled 16 patients with pancreatic NETs and 25 patients with
gastrointestinal (n = 7), lung (n = 9), or other site (n = 9) NETs. Only one
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 patient with a pancreatic NET had an objective response (6 percent); the
stable disease rate in the 14 patients who were evaluable for response was
88 percent [122].
The activity of pembrolizumab was also evaluated in the phase II KEYNOTE-
158 trial, which included a cohort of 107 patients with well- and moderately
differentiated NET whose disease had progressed or who were intolerant of
one or more lines of standard therapy [123]. PD-L1 expression was present in
16 percent of patients. Primary sites of disease included the pancreas (n =
40), small intestine (n = 25), other gastrointestinal sites (n = 18), lung (n = 14),
and other organs (n = 10). The overall response rate was low and included
four partial responses (3.7 percent), and the median progression-free survival
(PFS) was 4.1 months. Partial responses were noted in three patients with
pancreatic NET and in one with an unknown primary; all responding tumors
were PD-L1 negative. Two of the responding patients had a sustained
response approaching two years.
Trials are ongoing to evaluate checkpoint inhibitors in combination with other
immunomodulatory agents, including vascular endothelial growth factor (VEGF)
pathway inhibitors [124-126]. Eligible patients should be encouraged to enroll.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMICThe
COVID-19 pandemic has increased the complexity of cancer care. Important issues
include balancing the risk from cancer treatment versus harm from COVID-19,
minimizing the number of clinic and hospital visits to reduce exposure whenever
possible, mitigating the negative impacts of social distancing on delivery of care,
and appropriately and fairly allocating limited health care resources. These and
other recommendations for cancer care during active phases of the COVID-19
pandemic are discussed separately. (See "COVID-19: Considerations in patients
with cancer".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Well-differentiated
gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONSNeuroendocrine precursor cells are
distributed widely throughout the body, and neoplasms of these dispersed cells,
which are termed neuroendocrine tumors (NETs), can arise at many sites. The
World Health Organization (WHO) classifies all gastroenteropancreatic NETs into
low-grade, intermediate-grade, and high-grade categories based on mitotic count
and proliferative index (Ki-67) (table 1). Poorly differentiated neuroendocrine
carcinomas are all high-grade tumors. (See "Pathology, classification, and grading

807
of neuroendocrine neoplasms arising in the digestive system", section on '2010
and 2019 World Health Organization classification'.)
Well-differentiated gastroenteropancreatic NETs have been traditionally referred
to as carcinoids when they arise within the tubular gastrointestinal tract and
pancreatic NETs (islet cell tumors) when they arise in the pancreas or, in the case
of gastrinoma, the proximal duodenum. Although gastrointestinal and pancreatic
NETs are morphologically similar on routine histologic evaluation, they differ in
terms of pathogenesis, biology, and response to therapy. Systemic treatment
options for advanced gastrointestinal NETs are discussed in detail elsewhere.
(See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid)
tumors: Systemic therapy options to control tumor growth".)
●Initial therapy
•Most patients with symptoms of hormone hypersecretion from a
pancreatic NET other than insulinoma or gastrinoma should be managed
with somatostatin analogs and other agents, as appropriate to the specific
syndrome. (See 'Benefits' above and "VIPoma: Clinical manifestations,
diagnosis, and management", section on 'Somatostatin
analogs' and "Somatostatinoma: Clinical manifestations, diagnosis, and
management" and "Glucagonoma and the glucagonoma syndrome",
section on 'General measures'.)
However, somatostatin analogs may worsen glycemic control in
insulinoma. Initial therapy for insulinomas consists of dietary
modifications. Treatment with diazoxide, which directly inhibits the
release of insulin from insulinoma cells, can be considered, as can
treatment with everolimus, which has been reported to be highly effective
in improving glycemic control in patients with insulinoma.
(See "Insulinoma", section on 'Medical therapy to control symptomatic
hypoglycemia'.)
For patients with gastrinoma, high doses of oral proton pump inhibitors
are the initial treatment of choice. Somatostatin analogs are may be
helpful for refractory cases. (See "Management and prognosis of the
Zollinger-Ellison syndrome (gastrinoma)".)
For asymptomatic patients with low-volume disease, we suggest
observation alone rather than early administration of a somatostatin
analog. In such patients, we initiate somatostatin analog therapy at the
time of clinically meaningful disease progression. (See 'Control of tumor
growth' above.)
•For most patients with hepatic metastases that are resectable with
curative intent, in the absence of extrahepatic metastases, diffuse bilobar

808
 involvement, or compromised liver function, we suggest resection rather
than medical therapy (Grade 2C). (See 'General approach to the
patient' above and "Metastatic gastroenteropancreatic neuroendocrine
tumors: Local options to control tumor growth and symptoms of hormone
hypersecretion", section on 'Surgical resection'.)
●Progressive disease and/or symptomatic from tumor bulk
•For patients who require therapy because of progressive disease or
symptoms related to hormone production, and who are not already
receiving treatment with a somatostatin analog, we suggest initiation of
therapy with a somatostatin analog (Grade 2A); for those who are already
receiving treatment with a somatostatin analog, we suggest a molecularly
targeted agent, either everolimus or sunitinib (Grade 2A). Somatostatin
analogs, everolimus, and sunitinib have all been shown to improve
progression-free survival (PFS) compared with best supportive care alone,
although none have been compared directly with each other. In the
absence of comparative trials, the choice of initial agent may be
influenced by the expected toxicity profile. Given the favorable toxicity
profile, we suggest a somatostatin analog as an appropriate first choice
for many patients and reserve use of a targeted agent if there is
subsequent disease progression (Grade 2C). Everolimus may be of
particular value in patients with functioning insulinomas and refractory
hypoglycemia because of its association with hyperglycemia. (See 'Small
molecule antiangiogenic TK inhibitors' above and 'Everolimus' above.)
•For patients who are highly symptomatic from tumor bulk and who have
rapidly enlarging metastases, we suggest chemotherapy as an initial
treatment because of the higher objective response rate compared with
other approaches (Grade 2C). For most patients, we suggest the
combination of capecitabine and temozolomide (CAPTEM) rather than
temozolomide alone (Grade 2B). In the absence of comparative trials, the
choice of CAPTEM over a streptozocin-containing regimen should be
individualized, taking into account the convenience of oral rather than
intravenous treatment, performance status, and anticipated side effect
profiles. (See 'Streptozocin combinations' above and 'Dacarbazine and
temozolomide-based regimens' above.)
•Hepatic arterial embolization is a reasonable alternative approach to
systemic therapy for patients with hepatic predominant disease,
particularly those who are symptomatic, who are not candidates for
surgical resection. (See "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and

809
symptoms of hormone hypersecretion", section on 'Hepatic arterial
embolization'.)
•For patients with a somatostatin-receptor-positive pancreatic NET,
peptide receptor radioligand therapy (PRRT) using a radiolabeled
somatostatin analog such as lutetium-177 (177Lu) dotatate is a reasonable
option, either at the time of progression on a somatostatin analog or
following progression on other agents, including everolimus, sunitinib, or
cytotoxic chemotherapy. Although clinical trials are underway, there are
no data yet specifically comparing 177Lu dotatate with other therapeutic
agents, and the choice of therapy in this situation should be based on
availability of 177Lu dotatate and patient preference. (See 'Radiolabeled
somatostatin analogs' above.)
•Another option for patients with indolent disease after an initial response
or a prolonged duration of stability with standard-dose somatostatin
analog therapy is dose escalation of the somatostatin analog.
(See 'Control of tumor growth' above.)

810
Parathyroid carcinoma
Authors:
Ghada El-Hajj Fuleihan, MD, MPH
Andrew Arnold, MD
Section Editor:
Marc K Drezner, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 11, 2021.
INTRODUCTIONParathyroid carcinoma is a rare cause of primary
hyperparathyroidism, which is usually caused by a parathyroid adenoma and
occasionally by primary parathyroid hyperplasia. Other rare causes are parathyroid cyst
and ectopic secretion of parathyroid hormone (PTH) from a nonparathyroid tumor.
Compared with patients with parathyroid adenomas, patients with parathyroid
carcinomas are more likely to have symptoms, a neck mass, bone and kidney disease,
marked hypercalcemia, and very high serum parathyroid hormone concentrations. This
topic will provide an overview of parathyroid carcinoma. Other aspects of primary
hyperparathyroidism are discussed elsewhere.
●(See "Primary hyperparathyroidism: Clinical manifestations".)
●(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)
●(See "Primary hyperparathyroidism: Management".)
●(See "Preoperative localization for parathyroid surgery in patients with primary
hyperparathyroidism".)
●(See "Parathyroid cysts".)
●(See "Parathyroid exploration for primary hyperparathyroidism".)
●(See "Pathogenesis and etiology of primary hyperparathyroidism".)
INCIDENCEParathyroid carcinoma is a rare cause of hyperparathyroidism [1]. In a
systematic review of 22,225 cases of primary hyperparathyroidism reported between
1995 and 2003, parathyroid carcinoma accounted for 0.74 percent of the cases [2]. In a
retrospective study of two European cohorts of patients with primary
hyperparathyroidism, the frequency of parathyroid carcinoma ranged from 0.3 to 2.1
percent [3].
From 1988 to 2003, 224 patients with parathyroid carcinoma were identified by the
Surveillance, Epidemiology, and End Results (SEER) cancer registry data [4]. During
this time period, the incidence of parathyroid carcinoma increased from 3.58 to 5.73 per
10 million population. The increase was accompanied by a significant decrease in the
proportion of patients with large (≥4 cm) tumors and increase in proportion with negative
lymph nodes, suggesting that earlier diagnosis may account for the increased
incidence. From 2000 to 2012, the incidence rate for parathyroid carcinoma (SEER
database) was 0.36, and there was a decrease in the incidence rate between 2000 to
2002 and 2010 to 2012 [5]. In a nation-wide cohort study from Korea (2002 to 2017),

811
there was an increase in age-adjusted incidence rates, from 3.8 to 6.6 per 10 million
person-years [6], mirroring earlier increments noted in Western populations.
The occurrence of parathyroid carcinoma in patients with multiple endocrine neoplasia
type 1 (MEN1) is very rare; only one case was reported in a series of 348 cases of
MEN1 (0.28 percent) from the Mayo Clinic from 1977 to 2013 [7]. Similarly, in a
retrospective review of 291 cases of MEN1 at MD Anderson, 242 patients had
hyperparathyroidism, and of those, two (0.8 percent) had parathyroid carcinoma
[8]. Another retrospective study at a teaching hospital in Peking from 1999 to 2019
identified 153 cases of MEN1-associated primary hyperparathyroidism, of which only
one (0.7 percent) was a parathyroid carcinoma [9]. (See "Multiple endocrine neoplasia
type 1: Clinical manifestations and diagnosis".)
MOLECULAR PATHOGENESIS
HRPT2/CDC73 — Mutation of the HRPT2 (also called CDC73) tumor suppressor gene
has been recognized to play a central role in the molecular pathogenesis of parathyroid
carcinoma. HRPT2 is located on chromosome 1 and encodes parafibromin, a protein
whose function remains under investigation but appears to involve regulation of gene
expression and inhibition of cell proliferation. Studies have confirmed the presence
of HRPT2 mutations in both the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and
sporadic parathyroid carcinoma, as well as their rare presence in isolated familial
hyperparathyroidism [10,11].
●HPT-JT – Inactivating germline mutations in the HRPT2 gene are responsible for
an autosomal dominant type of familial hyperparathyroidism, HPT-JT [12].
Patients with HPT-JT are predisposed to ossifying fibromas of the jaw, cystic and
neoplastic renal lesions, uterine tumors, and parathyroid neoplasia with an
increased risk of parathyroid cancer. Parathyroid carcinoma was reported to occur
in approximately 15 percent of patients with HPT-JT [13]. In HPT-JT, all
parathyroid glands are at risk for tumor development, but the tumors can occur
asynchronously over many years.
●Sporadic parathyroid carcinoma – Sporadic (nonfamilial) parathyroid
carcinomas frequently bear HRPT2 mutations [11,14,15]. One of two original
studies reported HRPT2 mutations in 10 of 15 sporadic parathyroid cancers [14],
and the other identified such mutations in four of four carcinomas [15]. Most
mutations were somatic and clonal [14], implying a selective advantage (attesting
to their pathogenetic importance).
Unsuspected germline mutations were also discovered in a substantial minority of
patients who presented clinically with sporadic parathyroid carcinoma, suggesting
that some of these individuals may have HPT-JT or a phenotypic variant [14]. This
recognition that family members of some patients with apparently sporadic
parathyroid cancer are also at risk for this malignancy created a new indication for
genetic testing. (See 'Genetic testing' below.)
Although a wide range of mutation frequencies (13 to 100 percent) have been
reported across studies, likely related to sample size issues and/or inconsistencies
in inclusion criteria, HRPT2 mutations have generally been detectable in a
majority of clearly malignant sporadic parathyroid carcinomas [16]. Conversely,
intragenic inactivating mutations of HRPT2 in otherwise unselected, typical
sporadic parathyroid adenomas are extremely rare [17].
812
 Somatic HRPT2 intragenic mutations tend to be found only rarely in non-HPT-JT-
related atypical parathyroid neoplasms that lack the classical invasive or
metastatic features of carcinomas [18], but higher frequencies have also been
reported [19]. The clinical utility of immunohistochemical detection of the
parafibromin protein in distinguishing parathyroid carcinoma from atypical
parathyroid adenomas is uncertain [20-22].
Other genes — Application of whole exome sequencing and other next-generation
sequencing (NGS) methods have importantly expanded the landscape of genomic
alterations in parathyroid carcinoma [23-28].
●Germline variants – Certain germline missense variants of the parathyroid
transcription factor gene GCM2 have been proposed to cause familial isolated
hyperparathyroidism (FIHP) and have also been associated with sporadic primary
hyperparathyroidism [29]. The penetrance and clinical significance of detecting
these variants (in FIHP kindreds or in the general population) require further study,
especially because some variants have relatively high population allele
frequencies compared with CDC73 or MEN1 mutations [29,30]. However, as
these variants may contribute to an increased risk of accentuated or aggressive
primary hyperparathyroidism phenotypes, including multigland disease or even
parathyroid carcinoma [31,32], it seems prudent to bear this potential risk in mind
for known GCM2 variant-carriers while further investigation proceeds and more
definitive information is acquired.
●Somatic mutations – Recurrent somatic driver mutations were found in several
established cancer genes not previously implicated in this disease; notably, these
include PI3K/AKT/MTOR pathway alterations in more than 20 percent of cases
[23,24,28] and cyclin D1 amplification in almost 30 percent, the latter reinforced by
candidate gene analysis [33].
These discoveries may prove to be important clinically in that some
metastatic/surgically incurable parathyroid cancers can carry tumor-specific
mutations against which new targeted therapeutic agents may already exist. For
example, the presence of a PIK3CA or MTOR mutation, or
of CCND1 amplification, raises the possibility that treatment with new drugs,
initially designed to target such mutations in other tumor types, could be effective
in these selected parathyroid carcinomas [23]. In some cases, a high tumor
mutation burden could suggest a vulnerability to immune checkpoint inhibitors
[27]. (See 'Novel precision/molecularly targeted cancer therapy' below.)
A major caveat in interpreting some of the NGS studies is that diagnostic inclusion
criteria for carcinoma were not always clear or consistent, and some differed from
other studies in not requiring local invasion or metastases. Other concerns
requiring cautious interpretation in specific instances include use of formalin-fixed
paraffin-embedded (FFPE) material known to cause sequence artifacts; lack of
matched normal control samples, potentially obfuscating somatic versus rare
germline mutations; and technical issues of data acquisition, variant calling, and
annotation. Ultimately, clinical trials will be needed to validate the actionability of
reported molecular targets in parathyroid carcinoma [34].
CLINICAL PRESENTATIONThe major clinical manifestations of parathyroid
carcinoma can be summarized from several small studies [21,35-38]:
813
 ●Mean age – 44 to 54 years (equivalent incidence in males and females)
●Mean serum calcium concentration – 14.6 to 15.9 mg/dL (3.7 to 4.0 mmol/L)
●Serum calcium concentration above 14 mg/dL (3.5 mmol/L) – 65 to 75 percent
●Mean serum parathyroid hormone (PTH) concentrations 5- to 10-fold higher than
the upper limit of normal
●Parathyroid crisis – 12 percent
●Neck mass – 34 to 52 percent
●Bone disease – 34 to 73 percent
●Renal disease – 32 to 70 percent
●Pancreatitis – 0 to 15 percent
●No symptoms – 2 to 7 percent
Predilection for a single inferior gland has been noted in case series [39,40].
Multiglandular parathyroid carcinoma is extremely rare [41].
Up to one-third of subjects have lymph node metastases at initial presentation, and one-
third have distant metastases, usually to liver and bone [40].
●Comparison with clinical manifestations of benign parathyroid disease –
Although there is overlap in the clinical and biochemical presentation of benign
parathyroid disease and parathyroid carcinoma, there are some features that
increase the likelihood of parathyroid cancer [42]. Whereas benign
hyperparathyroidism is more common in females (3:1), the incidence of
parathyroid cancer is equal between the two sexes. Compared with patients with
parathyroid adenomas, patients with parathyroid carcinomas are more likely to
have symptoms, larger tumor size, bone and kidney disease, marked
hypercalcemia, and very high serum PTH concentrations (5- to 10-fold higher than
the upper limit of normal) [21,35-38].
A retrospective study of 311 cases of primary hyperparathyroidism, of which nine
were parathyroid carcinomas, demonstrated that PTH levels less than four times
the upper limit of normal and a tumor weight <1.9 g made the likelihood of
parathyroid carcinoma essentially zero [43]. (See "Primary hyperparathyroidism:
Clinical manifestations".)
●Atypical presentations – Although most patients with parathyroid carcinoma
have hypercalcemia, some patients remain normocalcemic; these patients often
present with a neck mass. Nonfunctioning parathyroid carcinomas are rare, with
32 cases reported [44,45]. In a review of 17 such cases, patients were reported to
be diagnosed at a more advanced stage of disease, and their tumors may be
more aggressive [46]. Frequent locations for metastases include the lungs,
cervical lymph nodes, liver, and bone [47]. In contrast to patients with functional
parathyroid cancers, patients with nonfunctional tumors die from mass effect and
tumor burden rather than from hypercalcemia [48].
DIAGNOSISParathyroid carcinoma should be suspected in a patient with primary
hyperparathyroidism who presents with parathyroid crisis (or marked hypercalcemia and
very high parathyroid hormone [PTH] concentrations) or a neck mass. The diagnosis of
parathyroid carcinoma is typically made at the time of surgery to correct severe
hyperparathyroidism.
Although the classic pathologic features of a trabecular pattern, mitotic figures, thick
fibrous bands, and capsular and vascular invasion, when present, are highly suggestive
814
of parathyroid carcinoma [49,50], the two criteria upon which a more definitive diagnosis
of parathyroid cancer can be made are:
●Local invasion of contiguous structures
or
●Lymph node or distant metastases
Gross invasion beyond the capsule and including extracapsular vascular invasion
appear to correlate best with cancer diagnosis [21]. The use of an immunohistochemical
panel that includes parafibromin, galactin-3, PGP9.5, and Ki67 has been suggested
from a small series to aid in diagnosis of parathyroid carcinoma, with a sensitivity of 80
percent and specificity of 100 percent [22].
Although preoperative localization studies help plan the operative approach in patients
who have a biochemically confirmed diagnosis of hyperparathyroidism, they do not
reliably distinguish parathyroid carcinoma from adenoma. (See "Preoperative
localization for parathyroid surgery in patients with primary hyperparathyroidism",
section on 'Imaging modalities'.)
In some cases, it may not be possible to differentiate parathyroid adenoma or
carcinoma at the time of initial surgery. There may be pathological features suggestive
of, but insufficient for, diagnosing carcinoma. These tumors are called atypical
parathyroid adenomas [51]. Local recurrence or the occurrence of distant metastases at
subsequent follow-up ultimately determines the correct diagnosis.
GENETIC TESTINGA subset of patients with sporadic parathyroid cancer has
clinically unsuspected germline HRPT2/CDC73 mutations [14], and such mutations
carry important implications for management of the patient and/or for early detection or
prevention of parathyroid malignancy in family members [14]. The following are general
principles and management guidelines only and are not intended to supplant the need
for endocrine and medical genetic evaluation of specific individuals and their families
who are ascertained in this way. Genetic counseling is strongly recommended.
Indications — Genetic testing for germline HRPT2 mutation is clinically appropriate in
most patients with sporadic parathyroid carcinoma, particularly if there are family
members who could benefit from the genetic diagnosis. Genetic HRPT2 testing is also
indicated when parathyroid carcinoma occurs in a setting of known familial
hyperparathyroidism [10], or when features suggestive of hyperparathyroidism-jaw
tumor syndrome (HPT-JT) are present in the index patient.
It is not known whether germline HRPT2 testing may be indicated in patients with
sporadic "atypical" parathyroid adenomas, which exhibit clinical or pathological features
suggestive of, but insufficient for, diagnosing carcinoma. Such an indication has been
suggested [18] and deserves further study. There is no role for HRPT2 germline testing
in patients with typical sporadic parathyroid adenomas.
Genetic diagnosis of a germline HRPT2 inactivating mutation in a patient with sporadic
parathyroid carcinoma indicates that such a patient may have classic HPT-JT,
expressing its initial manifestation, or phenotypic variants, such as familial isolated
hyperparathyroidism, or a form of HPT-JT with altered penetrance of the component
features. Pending additional data on variant syndromes ascertained in this fashion, one
must conservatively assume they carry a similarly amplified risk of parathyroid cancer
(15 percent), as is found in classic HPT-JT.
HRPT2 mutation present
815
 ●Index patient – For the proband (index patient) with apparently sporadic
parathyroid cancer, management of the existing malignancy would typically not be
altered by genetic diagnosis of HRPT2 mutation. However, this genetic diagnosis
would mean that all parathyroid glands remain at increased risk for developing
entirely new tumors, themselves potentially malignant. Thus, in several situations,
such as recurrent hyperparathyroidism after seemingly successful surgery or
worsened hypercalcemia in the face of apparently stable metastatic tumor burden,
knowledge of an HPRT2 mutation would caution against the assumption that the
original tumor is entirely responsible and could focus surgical attention on
previously normal parathyroids in the neck or mediastinum.
●Family members – If the index patient proves to have a detectable pathogenic
germline mutation, then relatives at risk can be definitively tested (also less
expensively) for the presence or absence of that specific mutation. One major
benefit of testing is the reassurance provided to relatives who prove to have not
inherited the mutation, diminishing anxiety as well as ongoing costs of disease
surveillance.
For relatives who did inherit the mutation, their heightened risk of parathyroid
malignancy mandates careful clinical attention, beginning with immediate
biochemical testing for primary hyperparathyroidism followed by surgery for those
whose biochemical screen is suggestive or diagnostic of primary
hyperparathyroidism. (See 'Resectable disease' below.)
For individuals who carry the HRPT2 mutation but have no evidence of
hyperparathyroidism, a program of prospective surveillance is recommended. The
optimal way to conduct such surveillance remains uncertain and will be informed
by ongoing clinical experience, emerging data on disease penetrance, and
available therapies. For now, we think a reasonable approach would be
measurement of serum calcium and parathyroid hormone (PTH) every six months,
maintaining a high level of suspicion in interpreting results and a low threshold for
proceeding to parathyroid surgery. The sensitivity of such screening may be
enhanced by use of ionized calcium measurements, while specificity may be
enhanced by maintenance of adequate vitamin D status.
HRPT2 mutation absent or unknown — This is a less helpful and less definitive result
than a positive test would be because even among families with classic HPT-JT, up to
40 percent have no detectable mutation [10,12]. Such families may still have
occult HRPT2 mutations that evade detection because only the coding region of the
gene is generally sequenced, and inactivating mutations would be expected to occur in
noncoding regions in some families.
Therefore, a negative test does not provide strong reassurance that the index patient
with sporadic parathyroid carcinoma is HRPT2 mutation free. Under these
circumstances, the likelihood of a familial syndrome might gain clinical support by jaw,
kidney, and uterine imaging. Overall, however, this uninformative genetic test result
means that the patient and family may still be at risk for harboring an occult mutation
and should be treated and followed accordingly. Genetic counseling to assess the
diminished, but not negligible, level of risk may be especially helpful in this setting.
How does one approach the patient with sporadic carcinoma for whom genetic testing
will not or cannot be done, perhaps because of expense or personal choice? Jaw and

816
kidney imaging of the patient and family may provide helpful information, but all family
members who might have inherited the proband's potentially mutant HRPT2 allele
would be considered to be at risk and in general be subjected to the surveillance as
described above. Genetic counseling expertise is an essential component of the
decision-making.
STAGINGParathyroid carcinoma is included in the newest release (eighth edition,
2017) of the tumour, node, metastases (TNM) cancer manual from the combined
American Joint Committee on Cancer (AJCC) and the Union for International Cancer
Control (UICC) (table 1) [52]. However, they acknowledge that available data on tumor
characteristics and prognosis are so limited that proposing a staging system at this time
would be premature. They propose and define specific variables to be ascertained and
recorded prospectively to facilitate development of a formal staging system in the future.
Three studies have shown that tumor size was a better predictor of prognosis than
lymph node status [53-55]. In a retrospective review of patients with parathyroid
carcinoma from the National Cancer Database from 1985 to 2006, the main prognostic
factors in 733 identified cases (mean age 56 years) for 5 and 10 years overall survival
were age at diagnosis, male sex, and tumor size, but not lymph node involvement, nor
node dissection [53].
TREATMENTThe primary treatment of parathyroid carcinoma is surgery. When the
tumor is no longer amenable to surgical intervention, treatment becomes focused on the
control of hypercalcemia with medical therapy, which can include bisphosphonates,
calcimimetic agents, or denosumab. Treatment with radiotherapy and chemotherapy
has been disappointing.
Resectable disease — Surgery is the mainstay of therapy for both the initial treatment
of parathyroid carcinoma and for the treatment of locally recurrent or metastatic
disease.
Extent of resection
●Preoperatively suspected parathyroid cancer – When the diagnosis of
parathyroid cancer is suspected or known preoperatively, initial surgery should
include parathyroidectomy or en-bloc resection of the parathyroid mass and any
adjacent tissues that have been invaded by tumor [39]. In the Surveillance,
Epidemiology, and End Results (SEER) registry, 78.6 percent of patients had a
simple parathyroidectomy and 12.5 percent underwent en-bloc resection [4].
En-bloc resection could include the ipsilateral thyroid lobe, paratracheal alveolar
and lymphatic tissue, the thymus or some of the neck muscles, and in some
instances, the recurrent laryngeal nerve [35-38]. Some [56,57], but not all [38],
centers recommend ipsilateral lymph node dissection. There is no consensus
about the benefit of elective neck dissection of the central compartment [34,58]. It
is important to avoid capsular violation or tumor spillage. (See "Parathyroid
surgery for inherited syndromes", section on 'HPT-JT' and "Parathyroid surgery for
inherited syndromes", section on 'Extent of resection'.)
●Postoperatively diagnosed – In some cases, it is impossible to differentiate
parathyroid adenoma from carcinoma at the time of diagnosis or initial surgery. If
the diagnosis of parathyroid carcinoma is made postoperatively, reoperation with
ipsilateral thyroidectomy is frequently performed [56,57,59]. If a parathyroid tumor
appears to be well demarcated (not invading surrounding tissue) but is found on
817
pathological examination to invade adjacent tissue, reoperation to remove all
tumor tissue is recommended because there are no pathologic criteria that
distinguish a carcinoma that will follow an indolent course from one with a more
aggressive course.
●Surgical approach for HRPT2 mutation carriers – Given the rarity of HRPT2-
related disorders, the lack of controlled studies, and varying findings in different
reports of surgical experience (each with small numbers of cases), there is no
consensus on the optimal surgical approach for HRPT2 mutation carriers. The
optimal approach to initial parathyroid surgery in hyperparathyroid patients with
known HRPT2 mutation should take into account the substantial malignant
potential, tempered by the expectation from classic HPT-JT that most tumors will
still be benign, together with the increased risk of multiglandular disease,
asynchrony in tumor development, and observations that tumors can occasionally
be nonfunctional [46,48,60].
We generally advise that bilateral exploration be performed, identifying all
parathyroid glands. This advice is strongly dependent on the availability of a highly
experienced parathyroid surgeon. Grossly abnormal or suspicious-appearing
glands should be resected, bearing in mind the risk of malignancy. Resection itself
should be selective, and it seems reasonable for the surgeon to leave in situ any
normal-appearing glands, marking their location to facilitate possible future
operations.
An alternative, more limited surgical approach has also been advocated, more
akin to the type of focused exploration commonly performed for typical parathyroid
adenomas. This approach might be expected to carry a lower risk of surgical
complications compared with bilateral exploration, and it can be successful in
that HRPT2 mutation carriers may often have developed a tumor in only one gland
at the time of initial parathyroidectomy. On the other hand, this latter approach
runs the risk of missing tumors, including potentially aggressive lesions, in
additional parathyroid glands that may have evaded detection with preoperative
imaging and may also be nonfunctional or poorly functional [60,61].
(See "Parathyroid surgery for inherited syndromes", section on 'HPT-JT'.)
Total parathyroidectomy has been advocated by some clinicians
for HRPT2 mutation carriers with hyperparathyroidism, given that all their
parathyroid tissues have increased malignant potential. Currently, we do not favor
this approach, because of the considerable morbidity associated with
management of lifelong hypoparathyroidism, the significant but non-overwhelming
penetrance of malignancy, and the expectation that prospective surveillance
should identify tumors sufficiently early to prevent death from metastatic cancer.
Prophylactic total parathyroidectomy could gain more support if/when treatment
modalities for hypoparathyroidism improve (eg, with availability of inexpensive and
easily administered PTH replacement therapy).
●Metastatic disease – Because nonsurgical therapies for parathyroid carcinoma
have had disappointing results, surgical resection of distant metastases (bone and
lung) has been performed in some circumstances, primarily to debulk tumor as
palliation of the effects of hypercalcemia [62,63].

818
 ●Recurrent disease – Patients with recurrent parathyroid carcinoma can also be
treated surgically. Most recurrences occur within the neck [64]. Resection of
lesions in the neck (as well as lungs and liver) will often result in significant
palliation of hypercalcemia. However, these reoperations are associated with
substantial morbidity. As an example, in one series of 18 patients who underwent
28 reoperations, complications, most commonly recurrent laryngeal nerve palsies,
occurred in 9 of the 28 procedures (32 percent) [65]. Preoperative localizing
studies are recommended to minimize morbidity. (See "Preoperative localization
for parathyroid surgery in patients with primary hyperparathyroidism".)
Preoperative medical management — Prior to surgery, patients should receive
medical therapy to lower elevated calcium levels and correct other metabolic
disturbances [66]. Acute hypercalcemia due to parathyroid carcinoma is treated similarly
to hypercalcemia due to any other cause. The treatment of hypercalcemia is reviewed in
detail elsewhere. (See "Treatment of hypercalcemia", section on 'Severe
hypercalcemia'.)
Postoperative management
Monitoring serum calcium — The postoperative management of patients with
parathyroid carcinoma should include close monitoring of the patient's serum calcium
concentration. Patients in whom the preoperative serum calcium is very high may
develop the "hungry bone syndrome" after the tumor is completely removed and,
therefore, need large doses of intravenous calcium and oral calcitriol (see "Hungry bone
syndrome following parathyroidectomy in end-stage kidney disease patients"). As the
bones heal, the requirements for calcium and calcitriol decrease.
Role of adjuvant radiation therapy — In the absence of definitive data, we do not
routinely administer adjuvant radiation, particularly because it may be difficult to
differentiate atypical parathyroid adenomas from carcinoma at the time of initial surgery
(see 'Diagnosis' above). In addition, radiation may increase the difficulty of subsequent
neck surgery, often necessary in patients with parathyroid carcinoma.
The experience with adjuvant radiation therapy is limited to small observational studies,
which are often limited by selection bias [1,40,67-70]. As examples:
●In one series of 26 patients with locally invasive disease followed for a mean of
7.9 years (range 2 to 21), only one of six patients who had adjuvant radiation
therapy had a local relapse, compared with 10 of 20 who had not received
radiation therapy [40].
●In a series of 57 patients from the Mayo Clinic who had surgical resection,
locoregional disease progression occurred in 25 patients (44 percent) at a median
follow-up of 27 months. On univariate analysis, surgical margin status was a
predictor of locoregional progression. Four patients who were treated with surgery
and adjuvant radiation therapy with doses of 66 to 70 Gy had no recurrence at 60
months of follow-up [70]. The surgical margins were negative in three of these
patients and within 2 mm in one patient. It is possible, therefore, that these
patients were not at risk for locoregional disease progression.
●In an analysis of the National Cancer Database for patients with parathyroid
carcinoma who underwent surgery between 2004 and 2016, 126 (14 percent)
received external beam radiotherapy (EBRT) [71]. EBRT was not associated with
a difference in overall survival. In addition, the overall survival of the subset of

819
 patients with completely resected localized disease and who also received EBRT
(49 of 517, 10.5 percent) was not improved.
Unresectable disease — When parathyroid carcinoma is widely disseminated and no
longer amenable to surgical resection, the prognosis is generally poor. In this setting,
major morbidity and mortality result from severe hypercalcemia. Adequately controlling
hypercalcemia can prolong survival [67]. In addition, palliative radiation therapy for bone
metastases or locoregional disease has been reported [70].
Controlling hypercalcemia — Hypercalcemia is the principal cause of morbidity and
mortality from parathyroid carcinoma [35-37]. In patients with unresectable disease,
palliative treatment to control severe hypercalcemia is indicated. The initial treatment of
hypercalcemia in patients with parathyroid carcinoma is similar to management in
patients with hypercalcemia due to other causes and includes hydration with infusion
of saline to restore fluid volume and intravenous bisphosphonates. (See "Treatment of
hypercalcemia" and 'Bisphosphonates' below.)
As the disease progresses, hypercalcemia typically becomes refractory to
bisphosphonates. The addition or substitution of cinacalcet, which acts by a different
mechanism of action than bisphosphonates, has been reported to successfully control
hypercalcemia in some patients. The development of nausea and vomiting may limit
dose escalation. (See 'Calcimimetics' below.)
Denosumab is an option for patients who have hypercalcemia refractory to both
bisphosphonates and cinacalcet. (See 'Denosumab' below.)
Bisphosphonates — The initial treatment of hypercalcemia in patients with parathyroid
carcinoma includes saline hydration and intravenous bisphosphonates. Among currently
available bisphosphonates, intravenous zoledronic acid or pamidronate are the
preferred agents for the treatment of hypercalcemia due to parathyroid carcinoma.
Pamidronate has been reported to improve hypercalcemia in individual cases of
parathyroid carcinoma [72,73]. One would therefore predict that the
bisphosphonate zoledronic acid, which is more potent than pamidronate in treating
hypercalcemia of malignancy [74], would also be effective for hypercalcemia due to
parathyroid carcinoma, although this effect has not yet been documented. The
administration and dosing of bisphosphonates to treat hypercalcemia due to parathyroid
carcinoma are the same as those to treat other causes of hypercalcemia.
(See "Treatment of hypercalcemia".)
Calcimimetics — For patients with hypercalcemia that is refractory to
bisphosphonates, the addition or substitution of a calcimimetic drug (eg, cinacalcet) may
be beneficial. Calcimimetic drugs reduce parathyroid hormone (PTH) secretion by
increasing the sensitivity of the calcium-sensing receptor [75,76]. Cinacalcet, a longer-
acting calcimimetic drug, is approved by the US Food and Drug Administration (FDA)
for the treatment of hypercalcemia in parathyroid cancer, secondary
hyperparathyroidism associated with renal failure, and severe hypercalcemia in patients
with primary hyperparathyroidism unable to undergo parathyroidectomy. (See "Primary
hyperparathyroidism: Management", section on 'Calcimimetics' and "Management of
secondary hyperparathyroidism in adult dialysis patients", section on 'Calcimimetics'.)
In a 16-week, open-label study of 29 patients with inoperable parathyroid
carcinoma, cinacalcet (dose titrated to achieve calcium ≤10 mg/dL or up to 90 mg four
times daily) successfully reduced serum calcium concentration by at least 1 mg/dL in 62

820
percent of patients [76]. Mean PTH levels decreased but not significantly. Adverse
events (nausea, vomiting, headache, dehydration) were common and resulted in
discontinuation in five patients.
The initial dose of cinacalcet is 30 mg twice daily. The dose can be increased
sequentially every two to four weeks (60 mg twice daily, 90 mg twice daily, 90 mg three
times or four times daily), depending upon the serum calcium level and tolerance of the
drug. Nausea and vomiting often limit the ability to increase the dose of the drug. Serum
calcium and phosphorous should be monitored within one week of dose initiation or
adjustment. If a maintenance dose is achieved, serum calcium and phosphorous can be
monitored every one to two months.
Denosumab — Denosumab is an option for patients with parathyroid cancer who have
hypercalcemia refractory to bisphosphonates and cinacalcet. It is a potent inhibitor of
bone resorption. In case reports, denosumab, typically used as monotherapy, effectively
controlled refractory hypercalcemia in patients with parathyroid cancer previously
treated with surgery, bisphosphonates, calcium receptor agonist, and dacarbazine [77-
80]. In one patient, high-dose (120 mg) monthly denosumab was required to reduce
severely elevated serum calcium levels [81]. Stabilization of serum calcium may last for
a few weeks or as long as two years [80].
Novel precision/molecularly targeted cancer therapy — Some metastatic/surgically
incurable parathyroid cancers can carry tumor-specific mutations
(eg, PIK3CA or MTOR mutations) against which new targeted therapeutic agents may
already exist. (See 'Other genes' above.)
For a tumor this rare, future case reports of such therapeutic interventions will be
valuable, and most importantly, these prospective applications of "precision medicine"
must be rigorously tested [34,58]. Inclusion of parathyroid carcinoma patients in
"basket" clinical trials of new targeted agents, in which eligibility is based on the
presence of a particular driver mutation without regard to the tissue/histologic origin of
the tumor, should be seriously considered when clinically appropriate.
Chemotherapy — In general, attempts to reduce tumor burden with chemotherapy
have been disappointing [67]. Given the rarity of parathyroid carcinoma, chemotherapy
has been difficult to evaluate systematically, and there are no prospective randomized
trials. Various agents, either alone or in combination, have resulted in rare responses.
One patient with pulmonary metastases responded to treatment with dacarbazine, 5-
fluorouracil, and cyclophosphamide with normalization of serum calcium for 13 months
[67], while another with recurrent disease responded to dacarbazine alone with a two-
month normalization of serum calcium [82].
Biotherapy — Biologic agents based on gene products such as parafibromin, an
inhibitor of cell proliferation in parathyroid neoplasia, telomerase inhibitors such as
azidothymidine, and immune therapy constitute novel emerging therapies with
encouraging in vitro results and may prove useful clinically in the future [39].
COURSE AND OUTCOMEHypercalcemia is the principal cause of morbidity and
mortality from parathyroid carcinoma [35-37]. The carcinomas grow very slowly in most
patients but can occasionally be aggressive [83]. It appears that the disease typically
follows one of three courses: one-third of patients are cured at initial or follow-up
surgery, one-third recur after a prolonged disease-free survival but may be cured with
reoperation, and one-third of patients experience a short and aggressive course [59].
821
Patients should be followed for the possibility of recurrence with measurement of serum
calcium and parathyroid hormone (PTH) levels initially every six months and then
annually. If there is biochemical evidence of recurrence, other tests that may be
indicated to identify the sites of disease include neck ultrasound, computed tomography
(CT), magnetic resonance imaging (MRI), and fludeoxyglucose-positron emission
tomography (FDG-PET). There is no role for imaging in patients in whom calcium and
PTH levels are normal.

As noted, the recurrence rate is high, even after seemingly successful surgery. In one
study, as an example, among 22 patients who had normal serum calcium
concentrations after surgery, the recurrence rates at 1, 5, and 10 years were 27, 82,
and 91 percent, respectively [37]. In this and several other older studies, the combined
5- and 10-year survival rates varied from 50 to 70 and 13 to 35 percent, respectively
[35-37], with a mean survival time of six to seven years [35,36].
However, survival may be improving. The National Cancer Database survey (1985 to
1995) reported 5- and 10-year survival rates of 55.5 and 49 percent, respectively, in
their series of 286 patients [84]. An updated report from 1985 to 2006 with a total of 733
evaluable patients revealed 5- and 10-year overall survival rates of 82.3 and 66 percent,
respectively [53], results that are consistent with reports from the Surveillance,
Epidemiology, and End Results (SEER) cancer registry (1988 to 2003 and 2000 to
2012) with 10-year survival rates of 64.8 and 65.4 percent, respectively [4,5]. Young
age, female sex, recent year of diagnosis, smaller tumor size, and absence of distant
metastases were associated with improved survival [53,84,85].
SUMMARY AND RECOMMENDATIONS
●Clinical presentation – Parathyroid carcinoma is a rare cause of primary
hyperparathyroidism, which is usually caused by a parathyroid adenoma and
occasionally by primary parathyroid hyperplasia. Compared with patients with
parathyroid adenomas, patients with parathyroid carcinomas are more likely to
have symptoms, a neck mass, bone and kidney disease, marked hypercalcemia,
and very high serum parathyroid hormone concentrations. (See 'Clinical
presentation' above.)
●Diagnosis – The diagnosis of parathyroid cancer is typically made at the time of
surgery to correct severe hyperparathyroidism. The classic pathologic features of
a trabecular pattern, mitotic figures, thick fibrous bands, and capsular and
vascular invasion, when present, are highly suggestive of parathyroid carcinoma,
but definitive diagnosis depends on the presence of invasion into surrounding
tissues or distant metastasis. In some cases, it may not be possible to diagnose
parathyroid carcinoma at the time of hyperparathyroidism presentation or initial
surgery. Local recurrence or the occurrence of distal metastases at subsequent
follow-up ultimately determines the correct diagnosis. (See 'Diagnosis' above.)
●Genetic testing – Some patients with apparently sporadic parathyroid carcinoma
have germline HRPT2/CDC73 mutations, and genetic evaluation can play an
important role in management of such patients and family members. (See 'Genetic
testing' above.)
●Treatment

822
•Resectable disease – Surgery is the mainstay of therapy for both the initial
treatment of parathyroid carcinoma and for the treatment of locally recurrent or
metastatic disease. Treatment with radiotherapy and chemotherapy has been
disappointing. (See 'Resectable disease' above.)
•Unresectable disease – When parathyroid carcinoma is widely disseminated
and no longer amenable to surgical resection, the prognosis is generally poor.
In this setting, major morbidity and mortality results from severe
hypercalcemia. Adequately controlling hypercalcemia can prolong survival.
(See 'Unresectable disease' above.)
•Controlling hypercalcemia – The initial treatment of hypercalcemia in
patients with parathyroid carcinoma is similar to management in patients with
hypercalcemia due to other causes and includes hydration with infusion
of saline to restore fluid volume and intravenous bisphosphonates. As the
disease progresses, hypercalcemia typically becomes refractory to initial
medical therapy. The addition or substitution of cinacalcet has been reported to
successfully control hypercalcemia in some patients. Denosumab is an option
for patients who have hypercalcemia refractory to both bisphosphonates and
cinacalcet. (See 'Controlling hypercalcemia' above.)
•Novel molecularly targeted therapy – Some patients with disseminated
disease carry potentially actionable somatic mutations in their tumors, which
could lead to their consideration for trials of specifically targeted therapeutic 

823
Parathyroid cysts
Author:
Ghada El-Hajj Fuleihan, MD, MPH
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: May 21, 2020.
INTRODUCTIONPrimary hyperparathyroidism is usually caused by a
parathyroid adenoma, occasionally by primary parathyroid hyperplasia, and rarely
by a parathyroid cyst or parathyroid carcinoma. Parathyroid cysts are rare lesions
of the neck or mediastinum, with over 300 cases reported in the literature [1-8]. In
a review of 6621 patients who had neck ultrasound investigations performed at a
single center from 2003 to 2007 (mainly for evaluation of thyroid diseases), a
parathyroid cyst was diagnosed in five cases [6].

This topic will provide an overview of parathyroid cysts. Other aspects of primary
hyperparathyroidism are discussed elsewhere.

●(See "Pathogenesis and etiology of primary hyperparathyroidism".)

●(See "Primary hyperparathyroidism: Clinical manifestations".)
●(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)
●(See "Primary hyperparathyroidism: Management".)
●(See "Preoperative localization for parathyroid surgery in patients with
primary hyperparathyroidism".)
●(See "Parathyroid exploration for primary hyperparathyroidism".)
●(See "Parathyroid carcinoma".)

CLASSIFICATIONParathyroid cysts can be divided in five categories based

upon the presumed mechanism of cyst formation [9]:
●Developmental, arising from vestigial remnants of the third and fourth
branchial clefts
●Developmental, arising from vestigial remnants of Kursteiner canals
●Coalescence of microcysts into macrocysts
●Degeneration of an adenoma, or rarely carcinoma, into a pseudocyst
●Accumulation of fluid in the parathyroid gland, forming a retention cyst

824
CLINICAL PRESENTATIONA parathyroid cyst may present as an
asymptomatic neck mass or may be discovered as an incidental finding during
neck surgery or imaging procedures (carotid ultrasonography, neck computed
tomography [CT], magnetic resonance imaging [MRI], chest radiography)
performed for unrelated reasons [1,10]. They more commonly occur in the fourth
and fifth decade of life, although pediatric cases have rarely been described
[3,8,11]. In over 85 percent of cases, they are located in the neck, usually involving
the lower parathyroid glands, whereas the rest can occur between the mandible
and mediastinum [12]. They may occasionally have an intrathyroidal location [13].
Although these cysts vary in size, on average measuring 3 to 5 cm, cysts as large as
10 to 12 cm have been reported [3,8,12]. They do not take up radioiodine or
technetium and thus appear as "cold" nodules on thyroid radionuclide scans [14].
MRI, CT, and ultrasound demonstrate the cystic nature of the lesion (image 1).
Local symptoms depend on the size and location in the neck. When large
parathyroid cysts are located in the mediastinum, they can cause dyspnea,
dysphagia, or hoarseness [3,15]. Acute airway compromise due to hemorrhage in
a mediastinal cystic parathyroid adenoma has been reported [16]. In a review of 93
patients with mediastinal parathyroid cysts, 9.5 percent had evidence of recurrent
nerve injury [9].
Parathyroid cysts are usually nonfunctional [8,17]. In a systematic review of 359
cases, 62 percent of patients with parathyroid cysts had normal serum calcium,
phosphorus, and parathyroid hormone (PTH) levels [8]. In another review of 1769
case records of parathyroid surgeries, there were 48 cystic parathyroid lesions, of
which 41 were functional parathyroid lesions [18]. The large predominance of
functional parathyroid cysts in the latter study probably reflects referral bias of
patients with primary hyperparathyroidism to an endocrine surgical referral center
[18].
Functional cysts occur more often in men and are more likely to be secondary to
degenerative changes in a parathyroid tumor. The clinical presentation of
functioning parathyroid cysts is similar to that of nonfunctioning cysts
(asymptomatic or compressive symptoms depending on size and location). Some
patients may have symptoms of primary hyperparathyroidism [3]. Although the
majority of functional parathyroid cysts cause mild hypercalcemia, patients may
present with symptoms of acute parathyroid crisis [1,3,5], as illustrated by the
following cases:
●In one study, 11 of 325 patients who underwent parathyroid surgery had
parathyroid cysts. Two of the 11 patients had very high serum concentrations
of calcium (17.1 and 14.1 mg/dL [4.3 and 3.5 mmol/L], respectively) and PTH,
as well as nausea and altered consciousness [17]. In both patients, large
825
 areas within the cyst showed acute and chronic organization consistent with
cystic degeneration of a parathyroid adenoma.
●Severe hypercalcemia (16 to 23 mg/dL [4 to 5.75 mmol/L]) and very high
serum PTH concentrations (333 to 1472 pg/mL), a profile typical of
parathyroid carcinoma, have been reported in other cases [5,19-21]. In two
cases, a giant tumor of the mandible [21] and an expansile rib lesion were
described [9], presumably developing in response to markedly elevated PTH
values.
A discussion on acute parathyroid crisis is located elsewhere. (See "Primary
hyperparathyroidism: Clinical manifestations", section on 'Parathyroid crisis'.)
DIAGNOSISA parathyroid cyst should be suspected in a patient who has a cystic
mass in the neck or mediastinum that yields water-clear fluid on aspiration.
Elevated parathyroid hormone (PTH) concentration in aspirated cyst fluid is
diagnostic. In case series, intact PTH measurement in the cystic fluid ranged from
80 to over 4,000,000 pg/mL [1,3-5,7]. In patients with nonfunctioning parathyroid
cysts, serum PTH and calcium are normal, whereas they are elevated in patients
with functioning parathyroid cysts. The mechanism by which cystic PTH levels
reach the peripheral circulation is unknown.
Diagnostic evaluation — The evaluation of a neck mass includes history, physical
examination, an imaging study, and, usually, fine-needle aspiration (FNA) biopsy.
The location of the mass may suggest a specific etiology. Masses in the central
neck most commonly represent tissue that is thyroid or parathyroid in origin
(parathyroid less common). The most commonly used imaging techniques include
ultrasound and contrast computed tomography (CT). Microcysts of the parathyroid
gland are primarily found in aging glands, often incidentally noted on autopsy [2].
Generally, they have little clinical significance. Macrocysts of the parathyroid gland
are larger than 1 cm, and these require clinical investigation.
●Fine-needle aspiration – FNA biopsy is the preferred diagnostic approach
for most neck masses and is typically performed using a 25- or 27-gauge
needle on a 20 mL syringe. Image-guided (typically ultrasound) FNA is
preferable to palpation-guided FNA and is the only option for nonpalpable
lesions. (See "Evaluation of a neck mass in adults", section on 'Imaging
studies' and "Evaluation of a neck mass in adults", section on 'Diagnostic
studies'.)
The initial cytologic evaluation is to rule out a thyroid cyst, which is far more
common than a parathyroid cyst. The nature of the aspirate may suggest a
particular etiology. Thyroid cyst fluid is more often straw colored.
Hemorrhagic or pink-colored fluid may be found in cystic thyroid nodules
that contain thyroid cancer, and chocolate-colored fluid suggests
826
 hemorrhage in a thyroid nodule that occurred at least one week before
aspiration. The absence of colloid on cytologic analysis increases the
suspicion that the mass is not of thyroid origin [10]. In such cases,
measurement of thyroglobulin in the aspirate can differentiate thyroid from
nonthyroid lesions (thyroglobulin present in the former, absent in the latter)
[10]. (See "Cystic thyroid nodules", section on 'Fine-needle aspiration'.)
Water-clear fluid on aspiration in the absence of cellular material is
suggestive of a parathyroid cyst. In such cases, the aspirate should be
submitted for measurement of intact PTH. Elevated PTH concentration in
aspirated cyst fluid is diagnostic of a parathyroid cyst [22].
●Laboratory studies – If a cystic mass is determined to be a parathyroid cyst,
serum intact PTH and calcium should be measured to determine
functionality.
Differential diagnosis — The differential diagnosis of parathyroid cysts includes
thyroglossal duct cyst, branchial cleft cyst, cystic thyroid lesion, and parathyroid
carcinoma [2]. In contrast to parathyroid cysts:
●Thyroglossal duct cysts are usually in the midline and move with deglutition.
(See "Thyroglossal duct cysts and ectopic thyroid".)
●Branchial cleft cysts are usually present in childhood and typically are
located just inferior to the angle of the mandible and anterior to the
sternocleidomastoid muscle. (See "Differential diagnosis of a neck mass",
section on 'Branchial cleft cyst'.)
●Thyroid cysts have elevated thyroglobulin levels, but not elevated PTH levels.
(See "Cystic thyroid nodules".)
●The histopathologic examination of a cystic parathyroid carcinoma shows
capsular and blood vessel invasion. (See "Parathyroid carcinoma".)
Imaging modalities such as CT and ultrasound cannot differentiate parathyroid
cysts from thyroid cysts, and many parathyroid cysts can be intrathyroidal and may
be mistaken for cold thyroid nodules [2,23]. Although sestamibi scan can be
positive [20], it is not reliable (eg, negative in two of two cases of functioning
parathyroid cysts [23], and positive in the case of a thymic cyst [24]).
PATHOLOGYParathyroid cysts are histopathologically characterized by a
smooth inner surface wall with a membranous lining, a solitary layer of cuboidal
epithelium, and parathyroid tissue within the cyst wall [2,12]. They are rarely
malignant. However, atypical cystic parathyroid adenoma is a very unusual clinical
entity that may exhibit some pathologic features of carcinoma, but angioinvasion
and/or metastases are not present [20]. No specific molecular changes have been
reported in parathyroid cysts.

827
TREATMENTThe treatment of parathyroid cysts is based upon clinical
experience and data presented in case series.
Functioning cysts
●Symptomatic – The optimal treatment of symptomatic functioning
parathyroid cysts is surgical resection. Resection can be achieved through a
cervical approach in all cysts located in the neck and in over two-thirds of
mediastinal cysts. Thoracotomy or median sternotomy may be required for
some mediastinal cysts [9]. Robotic resection of a mediastinal parathyroid
cyst has been described [25]. Patients with functioning large cysts may be
more likely to develop postoperative symptomatic hypocalcemia [18].
(See "Parathyroid exploration for primary hyperparathyroidism", section on
'Postoperative hypocalcemia'.)
●Asymptomatic – For the treatment of asymptomatic functioning
parathyroid cysts, we use the serum calcium concentration to guide therapy.
In the absence of data specifically related to asymptomatic functioning
parathyroid cysts, the criteria for surgical intervention are the same as for
patients with asymptomatic primary hyperparathyroidism. We suggest
surgical intervention for asymptomatic individuals who meet the criteria used
to guide surgical intervention in patients with asymptomatic
hyperparathyroidism (table 1). For asymptomatic individuals who do not
meet the criteria, we observe for symptoms and/or the development of
indications for surgery. We measure serum calcium annually. (See "Primary
hyperparathyroidism: Management", section on 'Monitoring' and "Primary
hyperparathyroidism: Management", section on 'Candidates for surgery'.)
Nonfunctioning cysts
●Symptomatic – Patient with symptoms of compression typically require
surgery. For other patients with symptomatic nonfunctioning parathyroid
cysts, aspiration of cyst fluid may be curative [1,3]. Surgical resection is an
option for symptomatic recurrence after repeated aspiration. Ultrasound-
guided percutaneous ethanol ablation is an alternative to surgery in centers
where these procedures are performed routinely. However, such procedures
could result in fibrosis and recurrent laryngeal nerve palsy [2].
●Asymptomatic – Asymptomatic patients with nonfunctioning parathyroid
cysts may require no therapy. Patients should be monitored for the
occurrence of symptoms (due to an enlarging parathyroid cyst). In such
cases, aspiration and/or surgical resection may be required. For patients who
remain asymptomatic, we obtain an ultrasound and serum calcium level in
one year, and then less frequently thereafter.

828
In one case series, curative percutaneous aspiration of cyst fluid was achieved in
10 of 14 patients with nonfunctioning parathyroid cysts, nine with a single
aspiration and one requiring a second aspiration [1]. Four of the 14 underwent
surgical resection for recurrence of the cyst 6 to 48 months after the initial
aspiration [1]. In another series with mean follow-up of 19 months, simple
aspiration was successful in 4 of 12 patients (with a 98 percent reduction in cyst
volume), and recurrence occurred in eight patients [4].
Ethanol ablation resulted in a significant volume reduction of the cyst, with
cosmetic and symptomatic improvement in the eight patients who had recurrence
after simple aspiration; two patients required more than one ethanol ablation
treatment. No major complications were reported in this series. However, such
techniques can be complicated by recurrent laryngeal nerve palsy and fibrosis in
surrounding soft tissues, increasing the risk of subsequent surgical procedure in
the event of lack of response or recurrence. (See "Cystic thyroid nodules", section
on 'Ethanol ablation'.)
SUMMARY AND RECOMMENDATIONS
●Primary hyperparathyroidism is usually caused by a parathyroid adenoma,
occasionally by primary parathyroid hyperplasia, but only rarely (<1 percent)
by a parathyroid carcinoma or parathyroid cyst. (See 'Introduction' above.)
●Parathyroid cysts are most often located in the neck, but can also occur in
the mediastinum. Most are nonfunctional and present as a neck mass or may
be discovered as an incidental finding during neck surgery or imaging
procedures performed for unrelated reasons. Functional cysts are more likely
to be secondary to degenerative changes in a parathyroid adenoma.
Although the majority of functional parathyroid cysts cause mild
hypercalcemia, patients may present with symptoms of acute parathyroid
crisis. (See 'Clinical presentation' above.)
●Elevated parathyroid hormone (PTH) concentration in aspirated cyst fluid is
diagnostic. (See 'Diagnosis' above.)
●The differential diagnosis of parathyroid cysts includes thyroglossal duct
cyst, branchial cleft cyst, thyroid cyst, and parathyroid carcinoma.
(See 'Differential diagnosis' above.)
●The optimal treatment of symptomatic functioning parathyroid cysts is
surgical resection.
Treatment of asymptomatic functioning parathyroid cysts depends on the
serum calcium concentration. For asymptomatic individuals who meet the
criteria used to guide surgical intervention in patients with asymptomatic
primary hyperparathyroidism, we suggest surgical intervention rather than
observation (table 1) (Grade 2C). For asymptomatic patients who do not meet
829
the criteria, we monitor for symptoms and/or the development of indications
for surgery. (See 'Functioning cysts' above and "Primary
hyperparathyroidism: Management", section on 'Candidates for surgery'.)
●Patients with nonfunctioning parathyroid cysts and symptoms of
compression typically require surgery. For patients with symptoms other
than compression, initial aspiration of cyst fluid may be curative. For patients
with recurrence of symptoms after repeated aspiration, we suggest surgical
excision (Grade 2C). Ultrasound-guided percutaneous ethanol ablation is an
alternative to surgery in centers where these procedures are performed
routinely. However, such procedures could result in fibrosis and recurrent
laryngeal nerve palsy. (See 'Nonfunctioning cysts' above.)
Asymptomatic patients with nonfunctioning parathyroid cysts may require no
therapy. Patients should be monitored for the occurrence of symptoms (due
to an enlarging parathyroid cyst). For patients who remain asymptomatic and
normocalcemic, we obtain an ultrasound and serum calcium level in one
year, and then less frequently thereafter, depending on physical exam and
documented radiologic growth. (See 'Nonfunctioning cysts' above.)

830
Pathogenesis and etiology of primary
hyperparathyroidism
Authors:
Ghada El-Hajj Fuleihan, MD, MPH
Andrew Arnold, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Mar 31, 2021.
INTRODUCTIONParathyroid hormone (PTH) is one of the two major hormones
modulating calcium and phosphate homeostasis, the other being calcitriol (1,25-
dihydroxyvitamin D). The minute-to-minute regulation of serum ionized calcium is
exclusively regulated through PTH, maintaining the concentration of this cation
within a narrow range, through stimulation of renal tubular calcium reabsorption
and bone resorption. PTH secretion is, in turn, regulated by serum ionized calcium
acting via an exquisitely sensitive calcium-sensing receptor (CaSR) on the surface
of parathyroid cells.

Primary hyperparathyroidism is characterized by abnormal regulation of PTH

secretion by calcium, resulting in hypersecretion of PTH relative to the serum
calcium concentration. Experimental findings have advanced our understanding of
the pathophysiology and causes of primary hyperparathyroidism. This topic will
review these observations, beginning with a brief review of the basic aspects of
PTH and calcium homeostasis.

Other aspects of primary hyperparathyroidism are reviewed elsewhere.

●(See "Primary hyperparathyroidism: Clinical manifestations".)

●(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)
●(See "Primary hyperparathyroidism: Management".)
●(See "Preoperative localization for parathyroid surgery in patients with
primary hyperparathyroidism".)
●(See "Parathyroid exploration for primary hyperparathyroidism".)

831
PARATHYROID HORMONE AND CALCIUM HOMEOSTASISSerum
ionized calcium concentrations are normally maintained within the very narrow
range that is required for the optimal activity of the many extracellular and
intracellular processes regulated by calcium. The minute-to-minute regulation of
the ionized calcium concentration is achieved through a tightly regulated calcium-
parathyroid hormone (PTH) homeostatic system [1]. PTH is secreted almost
instantaneously in response to very small reductions in serum ionized calcium,
which are sensed by the calcium-sensing receptor (CaSR). The increase in PTH
release raises the serum calcium concentration toward normal via three actions
(see "Parathyroid hormone secretion and action"):
●Increased bone resorption, which occurs within minutes after PTH secretion
increases.
●Increased intestinal calcium absorption mediated by increased production
of calcitriol, the most active form of vitamin D, which occurs days after PTH
secretion increases.
●Decreased urinary calcium excretion due to stimulation of calcium
reabsorption in the distal tubule, which occurs within minutes after PTH
secretion increases [2,3]. (See "Regulation of calcium and phosphate
balance".)

These changes result in normalization of serum ionized calcium concentrations,

which then closes the system's feedback loop.

Relationship between serum PTH and ionized calcium concentrations — There

is a steep, inverse, sigmoidal relationship between the serum ionized calcium and
parathyroid hormone (PTH) concentrations (figure 1). The response curve is
defined by the following characteristics [4]:
●The set-point, which is the calcium concentration at which there is half-
maximal inhibition of PTH secretion
●The slope of the curve at the set-point
●The maximal response of PTH to hypocalcemia
●The maximal suppression of PTH by hypercalcemia

An increase in the first three or a decrease in the last can result in hypersecretion
of PTH.

Primary hyperparathyroidism is characterized by abnormal regulation of PTH

secretion by calcium. PTH secretion in this condition is not completely autonomous
and can usually be partially inhibited by a further rise in serum calcium. If this did

832
not occur, then patients with this disorder would have higher serum calcium
concentrations than are usually found.

The increase in PTH secretion in primary hyperparathyroidism is, in part, due to an

elevation in set-point. The increase in the set-point, ranging between 15 to 30
percent above that of a normal parathyroid gland, is the major determinant of the
severity of the hypercalcemia [4]. There is, in addition, a variable change in the
slope of the calcium-PTH curve due to relative non-suppressibility of PTH secretion
[5]. The degrees of hypersecretion and non-suppressibility are a function of tumor
mass and can range from none in patients with very small adenomas to
considerable in patients with large ones. Both a functional change at the cellular
level (a reduced number of calcium receptors on the parathyroid cell) and
increased numbers of cells probably contribute to these changes in PTH secretion.
The calcium-sensing receptor — The receptor responsible for calcium sensing by
the parathyroid gland has been cloned; it is a seven transmembrane-domain,
guanosine triphosphate (GTP)-binding protein [6,7]. While germline inactivating
mutations in this gene are commonly present in patients with familial
hypocalciuric hypercalcemia (FHH), they do not appear to occur as acquired
somatic mutations in sporadic parathyroid tumors [8,9]. There may be a small
subset of patients with primary hyperparathyroidism and hypercalciuria,
responsive to parathyroid surgery, which is due to inactivating germline mutation
of the calcium-sensing receptor gene (CASR), thus expanding the phenotypic
spectrum associated with CASR mutations [10,11].
Although there seem to be no somatic mutations of the gene, expression of the
calcium-sensing protein is reduced in parathyroid adenomas and also in uremic
hyperparathyroidism [12-15] (see "Overview of chronic kidney disease-mineral and
bone disorder (CKD-MBD)"). In both instances, the reduction in expression of the
CaSR on the surface of parathyroid cells may contribute to the increase in PTH
secretion. However, PTH secretion from large adenomas may be more related to
the increased cell mass since in one series, for example, there was little correlation
between serum calcium concentrations and receptor expression [16].
(See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
Inactivating heritable mutations in the CASR gene cause FHH and are also found in
a small percentage of patients with familial isolated hyperparathyroidism (FIHP)
(see 'Familial hyperparathyroidism' below). These mutations render the receptor
(expressed in the parathyroid glands, kidneys, and other tissues) relatively
insensitive to calcium [17], causing a rightward shift in the calcium-PTH curve [18]
and increasing renal tubular reabsorption of calcium. It is important to distinguish
this familial calcium-sensing disorder from typical primary hyperparathyroidism

833
because parathyroid surgery is usually of no benefit in the former. (See "Disorders
of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and
autosomal dominant hypocalcemia" and "Primary hyperparathyroidism: Diagnosis,
differential diagnosis, and evaluation".)
INCIDENCEMany years ago, clinical presentation of hyperparathyroidism was
one of symptomatic renal or skeletal disease with moderate or severe
hypercalcemia. However, the most common clinical presentation of primary
hyperparathyroidism now is asymptomatic hypercalcemia detected by routine
biochemical screening (figure 2). (See "Primary hyperparathyroidism: Clinical
manifestations".)
The routine measurement of serum calcium with the widespread use of
multichannel biochemical screening initially led to a marked rise in the incidence of
primary hyperparathyroidism. In the local population served by the Mayo Clinic, as
an example, the annual incidence rose from 16 per 100,000 person-years before
1974 (prescreening) to a peak of 112 per 100,000 person-years several years later
and then declined with elimination of calcium from the automated chemistry panel
[19]. There was a second peak in the incidence of primary hyperparathyroidism
between 1998 and 2007 (86 per 100,000 person-years), attributed to the rise in
bone density measurements and screening for osteoporosis [20]. In the United
States, the estimated incidence of primary hyperparathyroidism between 1998 and
2010 was approximately 50 per 100,000 person-years [20,21].
Primary hyperparathyroidism can occur at any age, but the great majority of cases
occur in patients over the age of 50 to 65 years [20-22]. Women are affected twice
as often as men, probably because the increase in bone resorption that follows
menopause unmasks parathyroid gland hyperactivity. In one study, the incidence
of hyperparathyroidism was highest among Black individuals, followed by White,
Asian, Hispanic, and other persons [21].
ETIOLOGYA cause for primary hyperparathyroidism, such as irradiation or the
rare genetic abnormalities in the multiple endocrine neoplasia (MEN) syndromes,
can be identified in only a small number of patients.
Radiation exposure — A history of irradiation to the head and neck, on average
20 to 40 years before the development of hyperparathyroidism, can be obtained in
some patients [23-26]. As an example, in a cohort of cleanup workers who worked
at the Chernobyl nuclear power plant in 1986, primary hyperparathyroidism
subsequently developed in 15 of 61 workers (odds ratio compared with prevalence
in nonexposed population 63.4, 95% CI 35.7-112.5) [26]. The mean whole-body
radiation exposure ranged from 0.3 to 8.7 Gy.
Hyperparathyroidism has also been reported in patients receiving radiation for
benign conditions. The usual radiation dose given for benign conditions several
834
decades ago was low; the mean dose in one study was 0.58 Gy [27]. Nevertheless,
in this study of 2555 patients followed for up to 50 years, even doses as low as 0.5
Gy before age 16 years were associated with a small risk of primary
hyperparathyroidism. The excess relative risk (RR) is dose dependent, being
approximately 5 to 10 at 1 Gy, whether the radiation came from external X-
radiation [27] or from an atomic bomb [28]. However, the probability of primary
hyperparathyroidism at this degree of exposure is still quite low, being less than 1
percent at 35 years and approaching 5 percent after 50 years of follow-up [27].
One study compared the clinical presentation and course of hyperparathyroidism
in exposed (49 patients) and nonexposed (389 patients) patients [29]. There were
no clinically important differences with respect to presentation, pathology, or
recurrences during six years of follow-up. However, the exposed patients had
more concurrent thyroid tumors, which can make management more difficult [30].
(See "Radiation-induced thyroid disease".)
Prior radiation exposure does not appear to increase the risk of having multigland
parathyroid disease [29,31,32], nor does it preclude a minimally invasive surgical
approach, particularly for hyperparathyroid patients with evidence of single gland
disease and no concomitant thyroid nodules [33]. (See "Parathyroid exploration for
primary hyperparathyroidism".)
Radioactive iodine therapy — There are also case reports and case series that
suggest an association between radioactive iodine (RAI) therapy (for the treatment
of benign or malignant thyroid disease) and the subsequent development of
primary hyperparathyroidism [34]. However, the incidence of primary
hyperparathyroidism was not increased in a prospective study of 125 patients
treated with RAI for thyrotoxicosis [35]. (See "Radioiodine in the treatment of
hyperthyroidism" and "Differentiated thyroid cancer: Radioiodine treatment".)
Calcium intake — Because parathyroid hormone (PTH) is secreted almost
instantaneously in response to very small reductions in serum ionized calcium, it
has been hypothesized that chronically low calcium intake may increase the risk of
developing primary hyperparathyroidism by causing chronic stimulation of the
parathyroid gland. In one prospective cohort study, which followed over 58,000
female nurses for 22 years, primary hyperparathyroidism was diagnosed in 277
women [36]. The risk of developing primary hyperparathyroidism was inversely
related to calcium intake (RR 0.56, 95% CI 0.37-0.86 for women in the group with
the highest compared with lowest calcium intake). The decreased risk was
significant after adjusting for age, vitamin D intake, body mass index (BMI), and
race. Median total calcium intake (diet plus supplement) in the lowest to highest
quintiles ranged from 522 to 1794 mg daily. Limitations of the study include

835
potential inaccuracies in reporting calcium intake and in eliciting the diagnosis of
primary hyperparathyroidism. Additional studies are warranted.
Genetic or chromosomal defects — The cells in the abnormal parathyroid tissue
comprising solitary adenomas or carcinomas are usually monoclonal.
Abnormalities in key growth-controlling genes (ie, proto-oncogenes or tumor
suppressor genes) underlie the development of these parathyroid tumors. The
abnormalities include gain-of-function mutations in genes such as cyclin
D1/PRAD1 for sporadic tumors and RET  for familial tumors or loss-of-function
mutations in genes such as MEN1 or CDC73 (previous name HRPT2)  for sporadic
and familial tumors [37-40].
Cyclin D1/PRAD1 gene — Pericentric inversion on chromosome 11 results in a
relocation of the PRAD1 (parathyroid adenoma 1) proto-oncogene so that it is
juxtaposed to 5'-PTH gene promoter sequences (the gene for PTH itself is on
chromosome 11) [41-43]. PRAD1 (CCND1) encodes cyclin D1, a major regulator of
the cell cycle. A putative tissue-specific enhancer from the 5'-PTH gene region
results in overexpression of cyclin D1. Twenty to 40 percent of sporadic
parathyroid adenomas overexpress cyclin D1 [42-45].
Parathyroid cell proliferation in primary hyperparathyroidism has been
hypothesized to be a consequence of a primary defect in PTH secretory control by
calcium. However, transgenic mice in which cyclin D1 was overexpressed in the
parathyroid glands have both excessive parathyroid cell proliferation and
abnormal control of PTH secretion, suggesting that the proliferative defect is not
solely a downstream consequence of the abnormal PTH-calcium relationship [46].
In this model, the excessive proliferation preceded the PTH secretory changes
indicating that the primary tumorigenic/proliferative defects led to secondary
dysregulation of the set-point rather than vice versa [47].
MEN1 gene — MEN1 is a classic tumor suppressor gene that contributes to cell-
selective advantage through biallelic inactivation [48]. The MEN1 gene was
identified by positional cloning as the major source of predisposing germline
mutations in familial MEN1 (see "Multiple endocrine neoplasia type 1: Definition
and genetics"). It is also an important contributor to sporadic nonfamilial
parathyroid adenomas through its acquired/somatic mutation.
One report of sporadic parathyroid tumors found a somatic inactivating mutation
in the MEN1 gene in 4 of 24 (16 percent) subjects with true sporadic tumors, and all
of the tumors with this mutation had no expression of the wild-type allele [49]. In
two other studies, the corresponding proportions were 12 to 13 percent [50,51].
The mechanism by which the MEN1 gene product, a protein termed menin,
functions normally and in tumorigenesis remains an active area of investigation.

836
CDKN1B and other CDKI genes — CDKN1B encodes the p27 cyclin-dependent
kinase inhibitor (CDKI), and both somatic and germline mutations/variants in this
and other CDKI genes are present at low frequency in sporadic parathyroid
adenomas [52,53]. Not only are these genes linked to the cell cycle control
pathway that includes cyclin D1, an established parathyroid oncogene,
but CDKN1B mutation causes hyperparathyroidism in an animal model [54], and
CDKI mutations/variants are found in rare patients with MEN1-like presentations
of hyperparathyroidism [54,55]. Importantly, the CDKI findings suggest that low-
penetrance genetic variants, insufficiently robust to cause obvious familial
clustering, can predispose to sporadic, typical presentations of solitary parathyroid
adenoma.
CDC73/HRPT2 gene — Germline-inactivating CDC73 (HRPT2) mutations have been
described in a type of familial hyperparathyroidism, the hyperparathyroidism-jaw
tumor (HPT-JT) syndrome, that is associated with an increased risk of parathyroid
cancer [56]. In addition, both somatic and germline mutations of this gene have
been reported in patients with sporadic parathyroid carcinoma. The presence of
germline mutations in some of these individuals suggests that they may have the
HPT-JT syndrome or a phenotypic variant [37,57]. CDC73 mutations are not
generally a feature of typically presenting sporadic parathyroid adenomas [58] but
can, of course, be present in adenomas associated with HPT-JT syndrome.
(See "Parathyroid carcinoma".)
RET gene — Tumor-specific mutations similar to those in MEN2A or 2B (ie, gain-of-
function RET mutations) are rarely, if ever, found in sporadic primary
hyperparathyroidism. As an example, none of the known mutations occurred in 34
sporadic adenomas in one report [59,60]. (See "Classification and genetics of
multiple endocrine neoplasia type 2".)
Vitamin D receptor gene — The vitamin D receptor (VDR) gene is a natural
candidate for inactivation in parathyroid adenomas because of the well-
established action of 1,25-dihydroxyvitamin D to inhibit proliferation of
parathyroid cells in culture. While inactivating mutations of the VDR gene do not
seem to play a primary role in parathyroid gland tumorigenesis [61], vitamin D
deficiency may alter the phenotypic expression of parathyroid tumors [62].
Other candidate genes — A few genes have been reported to rarely incur somatic
mutations in sporadic parathyroid adenomas; they have not yet been shown to
drive hyperparathyroidism in experimental/model systems. These
include: CTNNB1 (b-catenin) in the Wnt signaling pathway, which has been
implicated in the development of several neoplasms including breast, prostate,
colon, pancreas, stomach, adrenal, and liver [63-68]; EZH2, a histone

837
methyltransferase implicated in malignant lymphomas [69]; ZFX, encoding a DNA-
binding zinc finger protein [70]; and POT1  [71].
Ectopic PTH gene expression — Several cases of ectopic parathyroid hormone
(PTH) production by nonparathyroid malignant neoplasms have been reported;
tumor cell expression of the PTH gene and tumoral production of PTH was directly
demonstrated in very few [72,73].
PATHOLOGIC CONDITIONS IN PRIMARY
HYPERPARATHYROIDISMThe following pathologic conditions have been
found with hyperparathyroidism [74].
Adenoma — Single adenomas account for up to 80 to 85 percent of cases of
primary hyperparathyroidism, and double adenomas are found in an additional 2
to 5 percent [75,76]. Most adenomas consist of parathyroid chief cells. They are
usually encapsulated, and 50 percent are surrounded by a rim of normal
parathyroid tissue. Some adenomas, however, are composed of oxyphil cells.
These adenomas are usually larger than chief cell adenomas.
Parathyroid hormone (PTH)-secreting adenomas are occasionally located in the
thymus gland. These tumors express a parathyroid-specific gene, GCM2, unlike
normal human thymus, which expresses neither PTH nor GCM2 [77]. This
observation suggests that these tumors are derived from parathyroid cells that
migrated during embryogenesis.
Glandular hyperplasia — In a systematic review of 215 studies including 20,225
patients, multiple-gland hyperplasia accounted for approximately 6 percent of
cases of primary hyperparathyroidism [76]. The glands are usually composed of
chief cells. Clear cell hyperplasia is very rare and is the only form in which the
upper glands are larger than the lower ones.
Carcinoma — Parathyroid carcinomas account for no more than 1 to 2 percent of
cases of hyperparathyroidism [76,78]. The diagnosis of carcinoma requires at least
one of the following: local/extracapsular invasion of contiguous structures
(although World Health Organization [WHO] criteria include vascular invasion even
if within the gland or capsule), lymph node, or distant metastases. While not
sufficient for diagnosis, characteristic histopathologic changes in parathyroid
carcinoma include fibrous trabeculae, mitotic figures, and capsular invasion.
(See "Parathyroid carcinoma".)
CONDITIONS ASSOCIATED WITH PRIMARY
HYPERPARATHYROIDISM
Familial hyperparathyroidism — Hereditary forms of hyperparathyroidism are
rare [79], and the molecular basis of the various subtypes of hereditary
hyperparathyroidism is well understood [56,79]. Probably the most common cause

838
of familial hyperparathyroidism is as part of the multiple endocrine neoplasia
(MEN) type 1 syndrome (see "Multiple endocrine neoplasia type 1: Definition and
genetics"). It can also occur as familial primary hyperparathyroidism not
associated with any other endocrine or syndromic disorder, termed familial
isolated hyperparathyroidism (FIHP); in the familial hyperparathyroidism-jaw
tumor (HPT-JT) syndrome [79], previously termed familial cystic parathyroid
adenomatosis [80]; or in MEN2A (see "Classification and genetics of multiple
endocrine neoplasia type 2"). Familial hypocalciuric hypercalcemia (FHH) and
neonatal severe hyperparathyroidism are also forms of familial
hyperparathyroidism [79], but because of the dual defect in calcium sensing at the
parathyroid gland and kidney, these syndromes are discussed separately.
(See "Disorders of the calcium-sensing receptor: Familial hypocalciuric
hypercalcemia and autosomal dominant hypocalcemia".)
FIHP is rare and, in most instances, its genetic basis appears to be distinct from
that in MEN type 1 or 2, FHH, or HPT-JT [56,79,81,82]. However, a minority of
kindreds with apparently isolated hyperparathyroidism have predisposing
mutations in either MEN1, calcium-sensing receptor (CASR), or HRPT2  (CDC73), or
may have evidence of other syndromic diagnoses [82]. In the latter study, five of 36
kindreds had inactivating mutations of the CASR gene and other features similar to
FHH, and three had the HPT-JT syndrome. None of the kindreds had MEN1
syndrome.
Patients presenting with apparently sporadic primary hyperparathyroidism at
younger ages may be at increased risk for having a familial form of
hyperparathyroidism. In a study of 86 patients (age <45 years) with clinically
nonsyndromic primary hyperparathyroidism, the results of genetic testing showed
germline mutations in susceptibility genes in eight (9.3 percent) subjects: four
with MEN1, three with CASR, and one with HRPT2  [83].
Management of patients with familial hyperparathyroidism differs from that in
sporadic hyperparathyroidism because of the variability in the presentations,
including [56,79]:
●Penetrance
●Delay in onset of symptoms
●Severity of hypercalcemia
●Propensity to parathyroid cancer (HPT-JT syndrome)
●Feasibility and accuracy in assessment of carrier status
●High recurrence rate post-parathyroidectomy
In one series of 16 patients with familial primary hyperparathyroidism, almost one-
half had severe hypercalcemia (>15 mg/dL [3.8 mmol/L]), one-third presented in
parathyroid crisis, and 75 percent had multiple abnormal parathyroid glands [84].

839
DNA testing can play a role in the diagnosis or management of the familial
hyperparathyroid syndromes, but the issues are complex and need to be
considered on an individual basis [56]. RET mutation testing is mandatory in MEN2
for prevention of metastatic medullary thyroid carcinoma, and periodic
surveillance that may include biochemical monitoring and imaging for associated
tumors is advised in MEN1 and 2, as well as in HPT-JT syndrome. Subtotal
parathyroidectomy, at times with autografting and cryopreservation, are
recommended in MEN1 and 2. The role of CDC73/HRPT2 mutation testing,
biochemical surveillance, and surgical management related to HPT-JT syndrome is
discussed separately. (See "Parathyroid carcinoma".)
Thiazide therapy — Thiazide diuretics reduce urinary calcium excretion and
therefore can cause possible transient mild hypercalcemia (up to 11.5 mg/dL [2.9
mmol/L]) (see "Etiology of hypercalcemia"). In addition, thiazide therapy can
unmask underlying primary hyperparathyroidism. Primary hyperparathyroidism is
more likely when hypercalcemia persists after drug withdrawal or when the initial
serum calcium value is above 12 mg/dL (3 mmol/L) [85].
In a population-based study of residents of Olmsted County, Minnesota, the
annual age- and sex-adjusted incidence of thiazide-associated hypercalcemia was
12.2 per 100,000 person-years (95% CI 10.6-13.8) [86]. Hypercalcemia was
identified (mostly in women [86.4 percent]) a mean of 5.2 years after initiating
thiazides, and it persisted in 71 percent of patients who discontinued the thiazide.
Among all patients with thiazide-associated hypercalcemia, 24 percent were
subsequently diagnosed with primary hyperparathyroidism. The mean maximum
serum calcium in these patients was 10.85 mg/dL (2.71 mmol/L). Patients
diagnosed with hyperparathyroidism had higher average serum calcium (10.9
versus 10.7 mg/dL [2.72 versus 2.67 mmol/L] in the overall cohort). A greater
proportion of patients with than without a formal diagnosis of primary
hyperparathyroidism had serum calcium >11 mg/dL (26 versus 10 percent). Severe
hypercalcemia was uncommon.
Although the best management strategy in patients with thiazide-induced primary
hyperparathyroidism is unclear, asymptomatic patients with unequivocal
biochemical evidence of hyperparathyroidism weeks after thiazide discontinuation
are best managed as patients with thiazide-unrelated, asymptomatic primary
hyperparathyroidism [87]. (See "Primary hyperparathyroidism: Diagnosis,
differential diagnosis, and evaluation".)
Lithium therapy — Lithium increases serum total and ionized calcium and intact
parathyroid hormone (PTH) levels within weeks, but these remain within the
normal range in most subjects [88-90]. Nevertheless, even though hypercalcemia
may not be present, lithium can induce a continued defect in calcium-PTH

840
regulation; normocalcemic patients can have a slightly raised serum PTH
concentration and an increase in mean parathyroid gland volume [91].
Although estimates vary widely, approximately 10 to 20 percent of patients
taking lithium develop hypercalcemia and hypocalciuria, and a smaller percentage
have high serum PTH concentrations [88,92,93] (see "Etiology of hypercalcemia").
In a study of 142 patients on lithium for at least 15 years, the overall prevalence of
hypercalcemia was 3.6 percent, approximately eight times that expected in the
general Swedish population. In patients with surgically verified high PTH, the
prevalence was 2.7 percent [94].
Lithium also increases the serum magnesium and decreases urinary calcium and
magnesium concentrations, findings reminiscent of familial benign hypocalciuric
hypercalcemia, a syndrome caused by inactivation mutations in the CASR [88,95].
Lithium decreases parathyroid gland sensitivity to calcium, shifting the set-point of
the calcium-PTH curve to the right [96-98].
In one study of lithium-treated patients, the value for the set-point of the serum
ionized calcium concentrations was 1.26 mmol/L, as compared with 1.21 mmol/L in
normal subjects [97]. Lithium is thought to exert an action downstream of the
CaSR itself [99,100], although the precise mechanism by which it interferes with
CaSR signaling is unknown [96,97]. (See "Disorders of the calcium-sensing
receptor: Familial hypocalciuric hypercalcemia and autosomal dominant
hypocalcemia".)
Whereas altered calcium sensing would be anticipated to result in four-gland
hyperplasia in patients with lithium-induced hyperparathyroidism, equal or greater
numbers of adenomas than hyperplasias have been reported [93,101-103]. The
median duration of lithium therapy in patients with adenomas was two years,
whereas it was 12 years in those with four-gland hyperplasia. It is possible that
lithium unmasks adenomas in patients with preexisting parathyroid lesions within
a few years of starting therapy or induces parathyroid hyperplasia with more
chronic use [101].
If the lithium can be stopped without exacerbating the psychiatric condition, the
hypercalcemia may resolve. Normalization of serum calcium is more likely to occur
one to four weeks post-lithium withdrawal in patients with a relatively short
duration of lithium use (less than a few years) [88]. It is less likely in patients
receiving lithium for more than 10 years [101]. In some patients, the serum
calcium concentration may not fall for one to four months after lithium is
discontinued [94]. Other probable predictors of calcium normalization include the
underlying parathyroid gland pathology and mass and the use of other drugs that
may also affect calcium metabolism, such as thiazide diuretics.

841
The effect of mild, lithium-induced hyperparathyroidism on the skeleton is unclear.
Two longitudinal studies of a total of 21 patients suggested significant bone
mineral loss in the forearm after a short period (three to six months)
of lithium therapy [104,105]. However, these findings were not confirmed in a
cross-sectional study of bone mineral density in the spine and the hip in 25 lithium-
treated and 25 control patients [106].
In view of the uncertainty of the effect of lithium on bone, we recommend periodic
measurement of bone mineral density of the forearm in younger patients (<45
years) and of the spine and hip in older patients who have persistent
hypercalcemia. (See "Clinical manifestations, diagnosis, and evaluation of
osteoporosis in postmenopausal women".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Primary hyperparathyroidism".)
SUMMARY
●Primary hyperparathyroidism is characterized by abnormal regulation of
parathyroid hormone (PTH) secretion by calcium. (See 'Parathyroid hormone
and calcium homeostasis' above.)
●A cause for primary hyperparathyroidism, such as irradiation or the rare
familial genetic abnormalities, can be identified in only a small number of
patients. (See 'Etiology' above.)
●Abnormalities in key growth-controlling genes (ie, proto-oncogenes or
tumor suppressor genes) underlie the development of parathyroid tumors,
which may occur sporadically or in familial patterns. The underlying genetic
abnormalities include gain-of-function changes in genes such as cyclin
D1/PRAD1 for sporadic tumors and RET for familial tumors or loss-of-function
mutations in genes such as MEN1 or CDC73 for sporadic and familial tumors.
(See 'Genetic or chromosomal defects' above.)
●Single adenomas account for approximately 80 to 85 percent of cases of
primary hyperparathyroidism. Multiple-gland hyperplasia accounts for
approximately 6 to 12 percent, double adenomas for an additional 2 to 5
percent, and parathyroid carcinoma for approximately 1 percent of cases of
primary hyperparathyroidism. (See 'Pathologic conditions in primary
hyperparathyroidism' above.)

842
Preoperative localization for parathyroid surgery
in patients with primary hyperparathyroidism
Authors:
Linwah Yip, MD
Shonni J Silverberg, MD
Ghada El-Hajj Fuleihan, MD, MPH
Section Editors:
Sally E Carty, MD, FACS
Clifford J Rosen, MD
Deputy Editor:
Wenliang Chen, MD, PhD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 27, 2021.
INTRODUCTIONPrimary hyperparathyroidism is usually caused by a solitary
benign adenoma (80 to 85 percent) but can also be due to double adenomata (2 to
5 percent), diffuse or nodular hyperplasia (10 to 15 percent), or parathyroid
carcinoma (<1 percent) [1]. An open four-gland parathyroid exploration has
traditionally been considered the gold standard for patients undergoing surgery
for primary hyperparathyroidism. However, a more focused, minimally invasive
approach to parathyroid surgery has been adopted at many centers [2,3].
Localization techniques are primarily used in patients who have biochemically
confirmed sporadic primary hyperparathyroidism to identify patients who are
candidates for a minimally invasive approach. They are also important in patients
who have persistent or recurrent disease, or who have had prior cervical
exploration and require remedial surgery. Patients with hereditary primary
hyperparathyroidism generally undergo bilateral parathyroid exploration, even in
the event of a positive localizing study, because of the high likelihood of
multiglandular disease. Localization studies, in conjunction with intraoperative
parathyroid hormone testing, can help minimize the extent of surgical dissection,
identify concurrent thyroid pathology, and detect ectopic parathyroid tissue, the
latter being a particular advantage for patients who had prior failed parathyroid
exploration. However, localization studies should not be used to diagnose or
confirm the diagnosis of primary hyperparathyroidism or determine the need for
surgery. Use of localization studies does not override the recommendation that
parathyroid surgery should only be performed by highly experienced surgeons
[2,4].

843
The techniques and role of preoperative localization in patients with primary
hyperparathyroidism will be reviewed here. Decision making regarding the role of
surgical therapy, the details of surgical management in these patients, and the
role of surgery for secondary hyperparathyroidism in patients with end-stage
kidney disease are discussed elsewhere. (See "Refractory hyperparathyroidism and
indications for parathyroidectomy in adult dialysis patients" and "Parathyroid
exploration for primary hyperparathyroidism", section on 'Focused parathyroid
exploration' and "Primary hyperparathyroidism: Management", section on
'Candidates for surgery'.)
ROLE OF PREOPERATIVE LOCALIZATIONThe diagnosis of primary
hyperparathyroidism should be made based upon biochemical findings. Imaging
studies are not used as a diagnostic tool, because of high false-positive rates,
which can range from 5 to 25 percent (table 1). In addition, a single-focus positive
imaging result does not reliably exclude the presence of multiglandular
parathyroid disease [5]. Rather, preoperative localization studies help plan the
operative approach in patients who have a biochemically confirmed diagnosis of
primary hyperparathyroidism, and in whom other pathologies have been
appropriately ruled out (eg, familial hypocalciuric hypercalcemia). For patients
undergoing initial surgery, these studies are predominantly used to determine
whether or not a patient is a candidate for a minimally invasive approach [6-8].
(See "Parathyroid hormone assays and their clinical use".)
Available radiologic expertise is an important factor in choosing the type of
localization testing to be performed. Localization images should be displayed and
available intraoperatively since review during exploration often usefully guides
successful surgery. (See 'Imaging modalities' below.)
Minimally invasive and unilateral parathyroidectomy — Preoperative
localization reduces operative time in unilateral parathyroid surgery and is
required if a minimally invasive procedure is contemplated [9-11]. The success of a
minimally invasive approach is dependent upon accurate imaging results, which
aid in limiting the dissection to the region where the adenoma has been localized.
For every parathyroid operation, the goal is cure of the biochemical condition, and,
thus, intraoperative parathyroid hormone (PTH) assay should be used to confirm
success of the operation by demonstrating a substantial drop in parathyroid
hormone level [12-14]. (See "Parathyroid exploration for primary
hyperparathyroidism", section on 'Intraoperative assessment' and "Intraoperative
parathyroid hormone assays".)
Reoperation for recurrent or persistent hyperparathyroidism — Two to 10
percent of patients undergoing surgery for hyperparathyroidism have recurrent or
persistent disease, and the likelihood of failed surgery is dependent on the length
844
of postoperative follow-up and surgeon volume [15,16]. In such cases, the
diagnosis of primary hyperparathyroidism should be confirmed biochemically, and
indications for surgery should be reevaluated. Accurate localization studies are
mandatory in patients undergoing reoperative surgery. Because of fibrosis from
the previous surgery and alterations in parathyroid gland location, the rate of
complications, such as recurrent laryngeal nerve injury, permanent
hypoparathyroidism, and persistent disease, is typically higher [17,18].
At least one preoperative imaging study should localize hyperfunctional
parathyroid tissue before proceeding with re-exploration and may include
sestamibi scan, sestamibi with single-photon emission computed tomography
(SPECT), ultrasound, and/or four-dimensional computed tomography (4D-CT)
[2,19,20]. The success rate of reoperative surgery without preoperative localization
is only 60 percent. Several observational studies have reported success rates of 95
percent or more with positive preoperative localization before reoperation
[17,21,22]. Almost 30 percent of patients undergoing reoperation have multiple
gland disease. Thus, localization studies identifying an apparent single adenoma
do not exclude the existence of abnormal parathyroid glands in other locations.
The best imaging study or combination of studies for persistent disease has not
been determined. In most reports assessing different imaging modalities,
SPECT/CT often is the first imaging study utilized in the reoperative setting and can
detect 60 to 80 percent of the abnormal glands [23,24]. A study of 90 patients who
required reoperative surgery reported high postoperative cure rates but shorter
operative times when 4D-CT was used for preoperative localization [25].
Ultrasound- or CT-guided fine needle aspiration of suspicious lesions for PTH assay
can be performed to confirm that the lesion is parathyroid tissue [26,27]. In a
study of 44 patients, fine needle aspiration with PTH assay had a specificity and
sensitivity of 100 and 70 percent, respectively [27]. Fine needle aspiration should
not be performed if the diagnosis of parathyroid cancer is considered likely, as
seeding of the cancer is a potential complication [2]. Selective arterial or venous
angiography is usually the next localization modality used if multiple noninvasive
imaging techniques fail to identify an abnormality [28-30].
Algorithms for the evaluation of patients undergoing reoperation have been
developed (figure 1) [31,32]. These algorithms, which are based upon clinical
experience, suggest performing two noninvasive procedures prior to reoperation,
one of which should be sestamibi imaging. The other is often ultrasonography, but
choice is dictated by available expertise. If the results of these studies are
concordant, surgery is performed. If the results are discordant or inconclusive, the
next step depends upon the expertise of the referral center and may include either
surgery with intraoperative monitoring of PTH or additional testing [31,32].

845
Further testing includes additional imaging (CT, MRI) or possible invasive
procedures (selective venous sampling). Several observational studies showed that
this approach allowed the identification of the offending parathyroid gland or
glands in 92 to 97 percent of reoperated cases [22,31,32].
Bilateral neck exploration — Bilateral parathyroid exploration should be planned
when imaging studies are negative or show more than one focus of activity, in
cases of secondary or tertiary hyperparathyroidism, suspected hereditary etiology,
or when concurrent thyroid pathology is present and warrants surgery. Bilateral
exploration should also be considered for male patients under the age of 30 years
because of the increased incidence of multiple endocrine neoplasia in these
patients [33]. In the hands of experienced surgeons, bilateral exploration has a
high cure rate and low morbidity [34-38]. (See "Parathyroid exploration for primary
hyperparathyroidism", section on 'Bilateral parathyroid exploration'.)
IMAGING MODALITIESAs mentioned above, imaging studies are obtained
only after biochemical confirmation of primary hyperparathyroidism and are used
predominantly to help plan the operative approach [39]. (See 'Role of preoperative
localization' above.)
Sestamibi scintigraphy (technetium-99-sestamibi scanning) combined with
sestamibi single photon emission computed tomography (SPECT) has the highest
positive predictive value of the available imaging techniques, and some prefer this
as the localizing procedure of choice for initial surgery [3,40,41]. However, SPECT is
not available at all centers, and some use planar sestamibi as the initial localizing
study. Additional complementary techniques are needed for patients with
persistent/recurrent disease or inconclusive results on sestamibi or SPECT
scanning. Imaging modalities that have also been used successfully include
ultrasound, SPECT combined with computed tomography (MIBI-SPECT-CT fusion),
four-dimensional computed tomography (4D-CT), and 11C-methionine positron
emission tomography (PET) combined with CT [28,40,42-47]. The utility of these
tests is discussed in the following sections. The sensitivity and positive predictive
value of the imaging modalities are summarized in the table (table 1).
Sestamibi scintigraphy — Technetium-99m-methoxyisobutylisonitrile (99mTc-
sestamibi or MIBI) was first used for cardiac scintigraphy and was noted to
concentrate in parathyroid adenomas. 99mTc-sestamibi is taken up by the
mitochondria in thyroid and parathyroid tissue; however, the radiotracer is
retained by the mitochondria-rich oxyphil cells in parathyroid glands longer than in
thyroid tissue [48]. Planar images are typically obtained shortly after injection of
99mTc-sestamibi and again at approximately two hours to identify foci of retained
radiotracer activity consistent with hyperfunctioning parathyroid tissue. Sestamibi
scintigraphy alone provides limited anatomic detail.
846
A negative 99mTc sestamibi scan does not negate the diagnosis of primary
hyperparathyroidism, since it occurs in 12 to 25 percent of patients with disease
[49,50]. Sestamibi scanning is often unrevealing, or misleading, in patients with
parathyroid hyperplasia, multiple parathyroid adenomas, and coexisting thyroid
disease [9,51-57]. Thyroid disease requiring surgery significantly increases both
the false positive and false negative rate of sestamibi scanning [58]. Falsely
negative scans can also be caused by calcium channel blockers that interfere with
the uptake of the isotope by parathyroid cells [55]. Other gland characteristics that
can increase the likelihood of a negative scan include small size, superior position,
and a paucity of oxyphil cells [56,57].
Sestamibi scanning for parathyroid tissue can be enhanced by combination with
three-dimensional imaging (SPECT), a subtraction thyroid scan, or fusion with
computed tomography images (MIBI-SPECT-CT) [51,59,60]. These are discussed
below.
SPECT — Sestamibi-single photon emission computed tomography (SPECT or
MIBI-SPECT) is a three-dimensional sestamibi scan that provides higher-resolution
imaging and improves the performance of sestamibi scanning (image 1). The
multidimensional images illustrate the depth of the parathyroid gland or glands in
relation to the thyroid and improve detection of ectopic glands, which facilitates
minimally invasive parathyroidectomy [54,59,61,62].
In single-institution comparison studies utilizing a variety of imaging protocols, the
addition of SPECT improves the sensitivity for identifying abnormal parathyroid
glands to 92 to 98 percent as compared with 71 to 79 percent for planar sestamibi
scintigraphy [51,54,59,61,62]. As an example, in a prospective study of 338 patients
with primary hyperparathyroidism, SPECT imaging successfully detected 96
percent of solitary adenomas and 83 percent of double adenomas [51]. However,
only 45 percent of multiglandular hyperplasias were detected.
SPECT imaging substantially reduces the likelihood of missing multiglandular
disease compared with planar imaging [5,63]. However, even with imaging
showing a clear, bright focus of increased uptake, multiglandular disease is still a
possibility [5,49,51,63]. Because SPECT imaging has a high rate (7 to 16 percent)
[5,64,65] of missed multiglandular disease, a validated adjunct to exclude
multiglandular disease such as intraoperative parathyroid hormone monitoring or
four-gland parathyroid exploration should be routinely utilized.
SPECT and CT fusion — SPECT-CT adds the ability to discriminate parathyroid
adenomas from other anatomic landmarks, which may facilitate the surgical
procedure [42,60,63,66]. In a single-institution retrospective and observational
study of 1388 patients who underwent parathyroid exploration for primary
hyperparathyroidism, SPECT-CT had greater accuracy for both single-gland disease

847
(83 versus 77 percent) and multigland disease (36 versus 22 percent) than SPECT
alone. The negative imaging rates were similar between the two imaging cohorts
(about 10 percent) [67].
Subtraction thyroid scan — Even with the addition of SPECT, distinguishing
abnormal parathyroid glands from thyroid pathology can be difficult. If necessary,
a subtraction thyroid scan can be obtained by using two radiotracers (dual isotope
scintigraphy). The use of technetium plus a second radiotracer such as 123I or
99mTc pertechnetate (thallium) permits selective imaging of the thyroid gland.
Ultrasound — Neck ultrasonography (US) is also often utilized for parathyroid
localization (image 2). Sonographic characteristics of parathyroid adenomas
include homogeneous hypoechogenicity and an extrathyroidal feeding vessel with
peripheral vascularity seen on color Doppler imaging (image 3).
US is highly sensitive in experienced hands and is inexpensive, noninvasive, and
reproducible in the operating room. In reoperative cases, intraoperative US can be
used to localize the adenoma and facilitate surgery in a previously dissected and
scarred field. However, the accuracy of ultrasound is operator dependent as the
sensitivity of ultrasound for detecting enlarged parathyroid glands ranges from 72
to 89 percent [46,68-70]. It is advantageous for experienced endocrine surgeons to
learn to perform neck ultrasound [64], and studies have shown comparable
sensitivity for localizing parathyroid adenomas compared to radiologist-performed
ultrasound (77 to 87 percent) [64,71].
As with sestamibi-based techniques, the sensitivity of ultrasound for parathyroid
adenoma localization is reduced in patients with thyroid nodules [72]. However, US
is helpful for the characterization and evaluation of any thyroid pathology,
facilitating operative planning. This is a common problem since concurrent thyroid
pathology is present in 20 to 30 percent of patients with primary
hyperparathyroidism [73]. Concurrent thyroid disease should be addressed
preoperatively (eg, with fine needle aspiration) and/or intraoperatively (eg, with
concurrent thyroidectomy). In addition, US-directed fine needle aspiration biopsy
with analysis of parathyroid hormone (PTH) levels can be helpful for confirming
suspected parathyroid lesions such as intrathyroidal adenomas or cysts [26,27].
Most experts in parathyroid surgery rely on both US and SPECT for preoperative
localization, although this varies by geography and institutional expertise
[14,74,75]. Combining 99mTc-sestamibi scintigraphy with neck ultrasound
provides high sensitivity (79 to 95 percent) for predicting the location of a single
parathyroid adenoma [62,63,76]. Sonography provides additional anatomic
information about the thyroid gland that could alter surgical management [77,78].
In a cost analysis study, initial ultrasound is the most cost-effective imaging
modality, followed by 4D-CT [79]. No imaging technique, even in combination,

848
accurately predicts multiglandular disease, and a bilateral neck exploration should
be strongly considered when the studies are discordant, equivocal, or negative
[51,80].
Disadvantages to the use of US alone include decreased accuracy in patients with
smaller parathyroid gland size, obesity, or mediastinal glands located behind the
clavicles [81].
Four-dimensional computed tomography — Four-dimensional computed
tomography (4D-CT) scans take advantage of the rapid contrast uptake and
washout that is characteristic of parathyroid adenomas for precise anatomic
localization (image 4). The primary disadvantage of 4D-CT is the radiation
exposure, which, compared with sestamibi imaging, results in a >50-fold higher
dose of radiation absorbed by the thyroid. The additional radiation leads to an
age-dependent higher risk of developing thyroid cancer; hence, the use of 4D-CT
should be highly selective in younger patients [82]. Most protocols include
noncontrast images followed by additional acquisitions (up to three) after contrast
injection. However, protocols vary by center, and some utilize fewer acquisitions to
limit the radiation exposure. In a meta-analysis inclusive of 34 published studies
that evaluated CT imaging for parathyroid adenoma localization using a wide
variety of protocols, each additional imaging acquisition resulted in a marginal
increase in the pooled sensitivity for abnormal gland lateralization (sensitivity of
single phase, 71 percent; two phase, 76 percent; three phase, 80 percent) [83].
4D-CT is particularly useful in the reoperative setting when initial imaging with
sestamibi is negative. In a study of 45 patients who had undergone previous neck
exploration, 4D-CT had 88 percent sensitivity for abnormal parathyroid glands
compared with sestamibi SPECT or neck US (54 and 21 percent, respectively) [84].
Magnetic resonance imaging — Parathyroid adenoma characteristics on
magnetic resonance imaging (MRI) include intermediate to low signal intensity on
T1 imaging and high intensity on T2 imaging. Cervical lymph nodes can also have
similar imaging characteristics, which limits the accuracy of MRI.
For reoperative surgery, MRI may provide a useful noninvasive imaging modality
to localize abnormal parathyroid tissue and does not require iodinated contrast or
exposure to ionizing radiation [85,86]. The reported sensitivity of MRI for abnormal
parathyroid tissue ranges from 40 to 85 percent [39,87,88].
Positron emission tomography and CT — The combination of 11C-methionine
positron emission tomography and computed tomography (MET-PET-CT) uses 11C-
methionine as a radiotracer to identify pathologic parathyroid glands [89-91]. A
prospective study that included 102 patients undergoing a parathyroidectomy for
primary hyperparathyroidism found that MET-PET-CT scan correctly located a
single-gland adenoma in 83 of 97 patients (86 percent), with a positive predictive

849
value of 93 percent [92]. In a small single-institution series, MET-PET-CT has also
been described as a useful option for patients who need reoperative surgery but
have initial negative imaging [93].
In Europe, 18-fluorocholine-PET-CT has been used to localize parathyroid
adenomas. In a 2019 systematic review, it had a sensitivity of 80 to 100 percent
and a specificity of 95 to 100 percent [94]. In a single US institution study of 58
patients undergoing initial parathyroid exploration with six-month cure, 18f-
fluorocholine-PET findings were associated with the highest likelihood of cure (83
percent) compared with sestamibi (28 percent) or ultrasound (37 percent) [95].
However, this technique has not been widely adopted in the United States, due to
regulatory issues and availability.
Invasive localization — Invasive procedures, such as selective venous sampling
or selective arteriography, are reserved for patients who have had prior neck
surgery and require reoperative surgery, in whom noninvasive testing has been
unrevealing. Risks associated with invasive localization procedures include groin
hematoma, anaphylaxis from the iodinated contrast, contrast-induced acute renal
failure, and stroke. They are also expensive and require an experienced
interventional radiologist to perform. Because of improvements in scanning and
ultrasonography, as noted above, the need for invasive testing has declined
substantially.
Selective venous sampling — Selective venous sampling is the most common
invasive modality used for parathyroid localization. A 1.5- to 2-fold increase in
parathyroid hormone levels obtained from representative cervical vein drainage
locations (inferior, middle, superior thyroid, thymic, and/or vertebral veins)
compared with a peripheral location is considered an abnormal elevation. Selective
venous sampling can identify hyperfunctioning parathyroid tissue when all other
imaging modalities are negative [70,96].
Selective arteriography — Selective arteriography is performed by combining
selective transarterial hypocalcemic stimulation with nonselective venous
sampling. Baseline and timed superior vena cava samplings are taken after
injection with sodium citrate to induce hypocalcemia while simultaneous
arteriography is performed. A positive localization is considered an increase in the
parathyroid hormone level to 1.4 times the baseline or a blush seen on
arteriography [70].
NEGATIVE IMAGINGNonlocalizing imaging studies should not preclude initial
surgery for patients with biochemically confirmed primary hyperparathyroidism
who meet operative criteria. In such patients, a single adenoma is still the most
likely intraoperative finding (62 to 77 percent); however, multiglandular disease is
more common than is typical in patients with primary hyperparathyroidism (20 to
850
38 percent) [55,56]. These patients require bilateral exploration by an experienced
parathyroid surgeon and the use of intraoperative parathyroid hormone
monitoring [50,97]. When compared to patients with localized studies, equivalent
long-term biochemical cure rates can be achieved, although more extensive
surgery may be needed [55,70]. (See "Parathyroid exploration for primary
hyperparathyroidism".)
It should also be mentioned that if initial imaging is negative at a medical facility
that does not commonly perform parathyroid imaging, referral to a high-volume
center should be considered. Sensitivity of localization has been reported to
increase to as high as 92 percent in higher-volume centers [47].
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Parathyroid surgery".)
SUMMARY AND RECOMMENDATIONS
●Preoperative parathyroid localization studies are useful for identifying
patients who are candidates for a minimally invasive surgical approach and
are also used to evaluate concurrent thyroid pathology.
(See 'Introduction' above.)
●Localization studies do not confirm the diagnosis of primary
hyperparathyroidism when positive or rule out the diagnosis when negative.
The diagnosis of primary hyperparathyroidism should be based upon
biochemical evaluation. Localization studies do not reliably exclude
multiglandular parathyroid disease and should not be used in order to select
patients for surgery. (See 'Introduction' above.)
●Results of localization studies, interpreted in conjunction with intraoperative
parathyroid hormone testing, can guide incision placement, minimize the
extent of surgical dissection, and locate ectopic parathyroid tissue. The latter
is particularly helpful in patients with recurrent or persistent
hyperparathyroidism after unsuccessful parathyroid exploration.
(See 'Minimally invasive and unilateral parathyroidectomy' above.)  
●For initial minimally invasive surgery, the preferred localizing imaging
studies include sestamibi scintigraphy (MIBI-SPECT imaging), ultrasound,
and/or four-dimensional computed tomography (4D-CT). The type and
number of studies ordered preoperatively are influenced by institutional and
geographical expertise, as well as other clinical considerations. Additional
complementary techniques are sometimes needed for patients with
persistent/recurrent disease. (See 'Imaging modalities' above.)
●For all patients undergoing reoperation, we recommend performing
preoperative localization (Grade 1B). We suggest obtaining at least two
851
imaging studies to assure concordance under these circumstances (Grade
2C). (See 'Reoperation for recurrent or persistent
hyperparathyroidism' above.)

852
Primary hyperparathyroidism: Clinical
manifestations
Authors:
Ghada El-Hajj Fuleihan, MD, MPH
Shonni J Silverberg, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Aug 10, 2021.
INTRODUCTIONThe most common clinical presentation of primary
hyperparathyroidism (PHPT) is asymptomatic hypercalcemia detected by routine
biochemical screening. However, the presentation may be atypical and include a
spectrum of disturbances in calcium homeostasis, ranging from symptomatic
severe hypercalcemia (parathyroid crisis) to normocalcemic PHPT.
The clinical manifestations that are directly related to PHPT will be reviewed here.
Symptoms and signs (gastrointestinal, neuromuscular, renal, and psychological)
that are likely related to hypercalcemia are also discussed elsewhere (see "Clinical
manifestations of hypercalcemia"). It should be recognized, however, that the
distinction is to some extent arbitrary.

The clinical manifestations of the familial forms of PHPT and of parathyroid cancer,
and the diagnosis and management of PHPT, are also reviewed separately.

●(See "Multiple endocrine neoplasia type 1: Clinical manifestations and

diagnosis".)
●(See "Clinical manifestations and diagnosis of multiple endocrine neoplasia
type 2".)
●(See "Parathyroid carcinoma".)
●(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)
●(See "Primary hyperparathyroidism: Management".)

CLINICAL PRESENTATIONSThe most common clinical presentation of PHPT

in Western populations is asymptomatic PHPT. Atypical presentations include
normocalcemic PHPT and parathyroid crisis. The classical manifestations of PHPT
("bones, stones, abdominal moans, and psychic groans") are uncommon in the

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United States but are still prevalent in resource-limited countries [1,2].
Nevertheless, there has been an increase in the prevalence of asymptomatic
disease even in resource-limited countries, particularly in India [3-5].
Asymptomatic primary hyperparathyroidism — Biochemical screening tests
that include measurements of serum calcium currently account for the
identification of at least 80 percent of patients with PHPT in Western countries
(figure 1) [6,7]. These patients are usually asymptomatic and have mild and
sometimes only intermittent hypercalcemia [8-11]. In most asymptomatic patients,
the mean serum calcium concentration is less than 1.0 mg/dL (0.25 mmol/L) above
the upper limit of the normal range [12]. In most patients, serum calcium and PTH
levels remain stable, although they may increase over time in a small subset (<5
percent) of subjects [13-15]. However, with time, approximately 30 percent of
patients with true asymptomatic PHPT may develop clinical manifestations of
PHPT, including skeletal manifestations, nephrocalcinosis, or kidney stones [13-16].
When carefully questioned, some patients with presumed asymptomatic PHPT
have nonspecific symptoms, such as fatigue, weakness, anorexia, mild depression,
and mild cognitive or neuromuscular dysfunction [17-21]. Thus, the differentiation
between symptomatic and asymptomatic PHPT is not always clear-cut [17].
(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)
There are no specific physical findings of PHPT. Parathyroid adenomas are rarely
palpable, and if a neck mass is palpated in a patient with PHPT, the diagnosis is
more likely to be thyroid nodule or parathyroid carcinoma (see "Parathyroid
carcinoma"). Band keratopathy (deposition of calcium phosphate in the exposed
areas of the cornea) is rare and occurs only when serum calcium and phosphate
concentrations are both high. A slit-lamp examination is usually needed to detect
the keratopathy.
Normocalcemic primary hyperparathyroidism — Increasingly, patients
undergoing evaluation for low bone density or other conditions may have
parathyroid hormone (PTH) levels drawn in the absence of hypercalcemia. In 2009,
an international panel of experts recognized this phenotype of PHPT in which PTH
levels are consistently elevated but serum total and ionized calcium levels are
normal, and all secondary causes for hyperparathyroidism have been excluded
(table 1) [22,23]. (See "Primary hyperparathyroidism: Diagnosis, differential
diagnosis, and evaluation", section on 'Diagnosis'.)
This condition is most challenging to characterize. Patients without an apparent
secondary cause may have a "forme fruste" of PHPT [24,25]. It might be expected
that early in the natural history of PHPT, elevated PTH levels would precede the
development of overt hypercalcemia. In these patients, the serum calcium

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concentration would be expected to rise above the upper limit of normal when
followed over time. However, persistent normocalcemia [25,26], intermittent
hypercalcemia [27,28], and progression to hypercalcemia [29-31] have all been
described.
In one prospective study of 37 patients with normocalcemic hyperparathyroidism,
41 percent developed evidence for progressive hyperparathyroid disease during a
median of three years (range one to eight years) of observation [29]. However, less
than 20 percent of patients became hypercalcemic during the observation period.
Instead, some persistently normocalcemic patients developed other indications of
progressive disease, such as kidney stones, hypercalciuria, bone loss, and fracture.
Furthermore, four individuals with normal serum calcium levels had successful
parathyroid surgery. In another study of 25 patients with normocalcemic
hyperparathyroidism, five patients had nephrolithiasis [32].

There are no data to suggest that all these patients will ultimately become
hypercalcemic, and over what time period. In addition, since most of these
patients were identified in the course of an evaluation for osteoporosis, fracture,
or low bone density, they may not represent an early form of asymptomatic PHPT
but could instead represent a unique phenotype of the disease. Identification of
the normocalcemic patients who represent the true clinical precursor of
hypercalcemic, asymptomatic PHPT would probably require population screening,
which we do not recommend.

Parathyroid crisis — Parathyroid crisis is rare; the risk in a patient with known

PHPT was estimated at 1 to 2 percent in two long-term studies of untreated
patients with mild PHPT [33-35]. Parathyroid crisis is characterized by severe
hypercalcemia, with the serum calcium concentration usually above 15 mg/dL (3.8
mmol/L) and marked symptoms of hypercalcemia: in particular, central nervous
system dysfunction. In some cases, the syndrome occurs in patients with
previously documented PHPT that is not severe. In others, it is the first evidence of
parathyroid disease.
In a review of 48 cases of parathyroid crisis, the numbers of females and males
were similar, the mean age was 55 years, and the mean serum calcium
concentration was 17.5 mg/dL (4.4 mmol/L) [36]. Of the 38 patients for whom
clinical information was available, the following characteristics were noted:
●Changes in mental status were common; 20 patients were comatose and the
remaining 18 were confused.
●Sixty-nine percent had bone disease, as assessed by plain radiography or
radionuclide bone scan.

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 ●Fifty-threepercent had nephrolithiasis, and 50 percent had both bone
disease and nephrolithiasis.
●Serum PTH concentrations were, on average, 20 times the upper limit of
normal.
●One-fourth of the patients were known to have had hypercalcemia at some
time in the preceding 10 years.

Other clinical problems included severe abdominal pain, nausea, vomiting, peptic
ulcer, and pancreatitis.

Another report compared 54 patients with parathyroid crisis with 460 patients
treated at the same hospital for PHPT without hypercalcemic crisis [37]. There
were more patients younger than 40 years old among those with parathyroid crisis
(20 versus 5 percent).
The mechanism for the development of parathyroid crisis is not known but may be
related to an intercurrent illness (often of a life-threatening nature), volume
depletion, or infarction of a parathyroid adenoma [36].
Classical — The classical symptoms and signs of PHPT are known as the "bones,
stones, abdominal moans, and psychic groans." They reflect the combined effects
of increased PTH secretion (table 2) and hypercalcemia (table 3). The abnormalities
associated with hyperparathyroidism are nephrolithiasis and bone disease; both
are due to prolonged PTH excess [6,38]. Symptoms attributable to hypercalcemia
include anorexia, nausea, constipation, polydipsia, and polyuria (table 3).
Symptoms in PHPT are not necessarily related to serum calcium levels [39];
however, they seem to be more common in patients in whom hypercalcemia
develops rapidly. (See 'Parathyroid crisis' above.)
Although bone disease and stone disease are the universally accepted classical
manifestations of PHPT, clinical parathyroid bone disease (osteitis fibrosa cystica)
is rarely seen in the United States today (<5 percent of patients), and the incidence
of nephrolithiasis has declined over the last few decades [6,38]. However, classical
manifestations of PHPT are still prevalent in countries such as India and China
[1,40-44]. As an example, in a study of 464 patients from the Indian PHPT registry
(based on five tertiary referral centers from four different geographic areas)
spanning from 2005 to 2015, 95 percent of patients with PHPT (mean age 41 years)
were symptomatic [41]. The most common symptoms at presentation included
bone pain (56 percent), renal calculi (31 percent), and weakness/fatigability (59
percent).
The geographical differences in the clinical manifestations of PHPT may be
explained, at least in part, by the greater prevalence of vitamin D deficiency in
some countries [7,45-47]. Vitamin D deficiency is common in patients with PHPT
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[48]. In countries where hypovitaminosis D is prevalent, PHPT may be
characterized by overt, severe clinical bone and stone disease [45,46]. Individuals
with vitamin D deficiency and hyperparathyroidism have more clinically significant
disease, including larger adenomas, higher concentrations of PTH, increased bone
turnover, and more frequent fractures [49-51].
Evaluation for and management of vitamin D deficiency in patients with PHPT are
reviewed separately. (See "Primary hyperparathyroidism: Management", section
on 'Concomitant vitamin D deficiency' and "Primary hyperparathyroidism:
Diagnosis, differential diagnosis, and evaluation", section on 'Serum vitamin D'.)
●Osteitis fibrosa cystica – The classic manifestation of PHPT bone disease is
osteitis fibrosa cystica, which is characterized clinically by bone pain and
radiographically by subperiosteal bone resorption on the radial aspect of the
middle phalanges (image 1), tapering of the distal clavicles (image 2), a "salt
and pepper" appearance of the skull (image 3), bone cysts, and brown tumors
of the long bones (image 4). Brown tumors result from excess osteoclast
activity and consist of collections of osteoclasts intermixed with fibrous tissue
and poorly mineralized woven bone. The brown coloration is due to
hemosiderin deposition.
Osteitis fibrosa cystica is now very rare in the United States. It occurs more
typically in patients with severe disease, especially those with parathyroid
carcinoma [6]. In a review of 97 cases of mild PHPT, as an example,
conventional radiography revealed signs of bone disease in only one patient
[52]. On the other hand, bone disease remains a major problem in patients
with secondary hyperparathyroidism due to chronic renal failure.
(See "Overview of chronic kidney disease-mineral and bone disorder (CKD-
MBD)".)
●Nephrolithiasis – Nephrolithiasis is the universally accepted, classical renal
manifestation of PHPT (table 4) [53]. Nephrolithiasis occurs in approximately
15 to 20 percent of patients with PHPT [6]; conversely, approximately 5
percent of patients with nephrolithiasis have hyperparathyroidism [54].
Nephrocalcinosis is less common and may represent a spectrum of the same
disease process, although most studies of PHPT have not reported its
frequency [53]. (See "Nephrocalcinosis".)
Among normocalcemic patients with nephrolithiasis, PHPT should be
suspected if the serum calcium concentration is in the high-normal range
because the hypercalcemia may be intermittent and detected only by
multiple measurements [8,54,55]. In one series of 48 patients with
nephrolithiasis and PHPT, 30 patients (63 percent) had serum calcium
concentrations between 10.2 and 11 mg/dL (2.55 and 2.75 mmol/L) [54].

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Most stones in patients with PHPT are composed of calcium oxalate [54],
although a slightly alkaline urine may favor the precipitation of calcium
phosphate stones. Contributing factors for calcium oxalate stone formation
in PHPT include hypercalciuria; hyperoxaluria; hypocitraturia; dietary risk
factors, such as a low calcium intake, high oxalate intake, high animal protein
intake, high sodium intake, low fluid intake; and a high serum calcitriol
concentration [56-58]. The high serum calcitriol concentration, caused by PTH
stimulation of renal hydroxylation of 25-hydroxyvitamin D (25[OH]D), may
contribute to both hypercalciuria and stone formation.
The presence of subclinical nephrolithiasis in asymptomatic patients is
reviewed below. (See 'Subclinical renal disease' below.)
●Neuromuscular – Complaints of weakness and fatigue are common among
patients with PHPT [19,59]. In classical PHPT, a neuromuscular syndrome
characterized by atrophy of type II muscle fibers was seen [60]. However, that
syndrome, as well as any objective evidence of myopathy or weakness, is
rarely seen today [61].
In some more severely affected patients, neuromuscular symptoms may
improve after cure. In one report, muscle strength and fine motor movement
increased four weeks after parathyroidectomy in all nine patients with PHPT
but not in a control group who underwent surgery for nodular goiter [62].
However, these reports are limited by small sample sizes.
●Neuropsychiatric – Neurobehavioral symptoms have been recognized in
patients with PHPT for almost seven decades and appear to be more
prevalent in patients with PHPT than in the general population [63-67]. These
symptoms include lethargy, depressed mood, decreased social interaction,
and cognitive dysfunction [65]. The exact prevalence of such abnormalities is
not well defined due to the lack of rigorous assessment for symptoms in
many studies, the small size of the studies, and the wide variations in the
instruments used to assess such disturbances [65].
As an example, in a case-control study comparing 39 postmenopausal
women with mild PHPT with 89 postmenopausal controls without PHPT,
symptom scores for depression and anxiety were higher, and performance
on tests of verbal memory and nonverbal abstraction was worse in women
with PHPT [66]. After parathyroidectomy, depressive symptoms, nonverbal
abstraction, and some aspects of verbal memory significantly improved.
Since 2002, four randomized clinical trials have been published, assessing the
effect of parathyroidectomy versus nonintervention in mild PHPT on, among
other things, neuropsychiatric symptoms [68-71]. Although limited
differences were shown by some, as a whole, these trials do not show a

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 consistent and convincing clinically significant improvement in the various
domains examined. These trials are reviewed in detail separately.
(See "Primary hyperparathyroidism: Management", section on
'Neuropsychiatric'.)
OTHER MANIFESTATIONS
Skeletal — Although the classical bone disease osteitis fibrosa cystica is rare
today, the skeleton remains very much a target organ in this disease. This is clear
from studies of bone density and histomorphometry in PHPT.
●Bone mineral density – Patients with asymptomatic hyperparathyroidism
may have decreased bone mineral density (BMD), in particular at more
cortical sites (forearm and hip) as compared with more trabecular sites
(spine) [72]. However, the reduction is usually small [73]. As an example, in
one study of 24 patients followed for three years, only 12 percent had bone
density at the hip and spine of more than 1.5 standard deviations (SD) lower
than age- and sex-matched normal subjects, although 52 percent had a low
score for the distal radius [74].
Randomized trials have demonstrated increased BMD following
parathyroidectomy. Measurement of BMD is an essential part of the
management of the disease, and BMD should be measured at the spine, hip,
and distal one-third forearm sites. The degree of bone loss is reflective of the
severity of hyperparathyroidism and is useful for making recommendations
for parathyroid surgery or observation with monitoring. (See "Primary
hyperparathyroidism: Management", section on 'Surgery versus nonsurgical
management' and "Primary hyperparathyroidism: Management", section on
'Subclinical bone disease'.)
●Other imaging technologies – In contrast to BMD, trabecular bone score
(TBS) and high-resolution peripheral quantitative computed tomography
(HRpQCT) reveal deterioration in indices of bone quality at the level of both
cortical and trabecular bone, thus providing insights into the
pathophysiology of fractures observed at the spine and peripheral sites [75-
85]. TBS is readily available for clinical use in patients who have a spine dual-
energy x-ray absorptiometry (DXA) BMD scan, provided the appropriate
software is installed. HRpQCT is an investigational procedure.
●Bone histomorphometry – The classical histomorphometric profile of
patients with hyperparathyroidism, the majority of whom have asymptomatic
disease, shows thin cortices with preserved trabecular bone [86]. This profile
is more pronounced in patients with concomitant vitamin D deficiency [87].
●Fractures – Most [88-95], but not all [96], studies demonstrate an increased
risk of vertebral fractures in patients with PHPT. In a meta-analysis of 12
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 studies, there was an increased risk of vertebral (odds ratio [OR] 3.00, 95% CI
1.41-6.37), forearm (OR 2.36, 95% CI 1.64-3.38), and possibly hip (OR 1.27,
95% CI 0.97-1.66) fractures [95].
The largest report of hip fracture was a population-based study of over 1800
patients with PHPT in Uppsala, Sweden [97]. There was an increase in hip
fracture in men but not in women. In a retrospective review of the 28-year
experience at the Mayo Clinic, risks of vertebral, Colles', rib, and pelvic
fractures were increased significantly, but the risk of hip fracture was
increased only marginally [92].
The impact of PHPT on fracture incidence appears related not only to site-
specific changes in areal bone density but also to the effect of the disease on
other factors related to bone quality [38]. Excess PTH would induce cortical
thinning due to endosteal bone resorption but would also increase periosteal
apposition, thus increasing bone diameter. Decreased areal bone density
would increase fracture risk, while increased bone diameter and preserved
trabecular microarchitecture would protect against fractures [38]. Since
fracture is not common in PHPT, prospective multicenter studies that capture
site-specific fractures are needed.
Subclinical renal disease — Important subclinical renal manifestations of PHPT
include (table 4):
●Asymptomatic nephrolithiasis
●Hypercalciuria
●Nephrocalcinosis
●Chronic renal insufficiency
●Abnormalities in renal tubular function (in particular, decreased
concentrating ability)
Up to 20 percent of patients with asymptomatic PHPT have an estimated
glomerular filtration rate below 60 mL/min/1.73 m2 [98-100]. The development of
renal insufficiency in PHPT is related to the degree and duration of hypercalcemia.
Mild hypercalcemia is rarely associated with renal insufficiency. In randomized
trials of two to three years duration, there is little evidence that renal function
deteriorates in patients with mild chronic hypercalcemia due to PHPT.
(See "Primary hyperparathyroidism: Management", section on 'Biochemical
abnormalities' and "Clinical manifestations of hypercalcemia", section on 'Renal
insufficiency'.)
Subclinical nephrocalcinosis and nephrolithiasis are more common in patients with
than without hyperparathyroidism [101,102]. In a retrospective review of 271 renal
ultrasounds from patients with surgically proven, asymptomatic PHPT, the
prevalence of renal stones on ultrasound performed within six months prior to

860
surgery was significantly higher than in age-matched subjects who had renal
ultrasounds for other reasons (7 versus 1.6 percent) [103]. In a cross-sectional
analyses of asymptomatic patients with PHPT, occult urolithiasis or renal
calcifications (nephrolithiasis and/or nephrocalcinosis) were identified in
approximately 20 percent of patients [104-106].
A contributing factor for stone formation in PHPT is hypercalciuria. Although PTH
directly stimulates the distal tubular reabsorption of calcium [56], this effect is
overshadowed by the increase in filtered calcium due to hypercalcemia, leading to
increased urinary calcium excretion in 35 to 40 percent of patients with PHPT. In
the cross-sectional analysis described above, occult urolithiasis was associated
with higher urinary calcium excretion; however, there was no biochemical index
that accurately predicted occult stones [104,106]. This is likely due to the limited
precision of a 24-hour urine calcium collection and to the complexity of factors that
determine stone formation. Urinary calcium concentration is only one of at least
six urinary risk factors that determine the urine saturation of the calcium salts that
lead to calcium stone formation.
Evaluation for subclinical renal disease in patients with asymptomatic PHPT is
reviewed separately. (See "Primary hyperparathyroidism: Diagnosis, differential
diagnosis, and evaluation", section on 'Renal imaging'.)
Cardiovascular — PHPT may be associated with cardiovascular disease, including
hypertension, arrhythmia, ventricular hypertrophy, and vascular and valvular
calcification, as illustrated by the following findings in observational studies [107-
109]:
●Hypertension is common in patients with PHPT, even among those with mild
disease [110-112]. The causal nature of this relationship in those without
multiple endocrine neoplasia (MEN) is unclear since hypertension does not
improve with cure of PHPT.
●Several [113-116], but not all [117,118], observational studies have reported
an association between PHPT and left ventricular hypertrophy and diastolic
dysfunction.
●Mean carotid intima-media thickness (IMT) was significantly higher in
patients with mild PHPT compared with controls (0.96 versus 0.91 mm) [119].
In addition, an indirect measure of aortic stiffness [120,121] and carotid
vascular stiffness [119] were associated with extent of PTH elevation,
suggesting that vessel stiffness may be related to the severity of
hyperparathyroidism. In adult populations, there is a moderate, graded,
positive relationship between carotid IMT and the presence of coronary
atherosclerosis. (See "Overview of possible risk factors for cardiovascular
disease", section on 'Arterial intima-media thickness'.)

861
It is uncertain if normocalcemic PHPT is also associated with cardiometabolic
changes. Preliminary data suggest an association with hypertension [122,123].
The nature of cardiovascular involvement and the extent to which abnormalities
improve postoperatively need to be further elucidated before a cause-and-effect
relationship can be established (see "Primary hyperparathyroidism: Management",
section on 'Cardiovascular'). There are no data to support routine cardiovascular
evaluation in patients diagnosed with PHPT.
The only proven association between PHPT and cardiovascular disease is in
patients with PHPT as part of multiple endocrine neoplasia type 2 (MEN2) with
pheochromocytoma. (See "Clinical manifestations and diagnosis of multiple
endocrine neoplasia type 2", section on 'Pheochromocytoma'.)
Body weight and abnormalities in glucose metabolism — A higher than normal
frequency of impaired glucose tolerance and type 2 diabetes have been reported
in some, but not all, studies of PHPT [112,120,124,125].
Patients with PHPT appear to be heavier than age-matched controls [126]. In a
meta-analysis of 13 studies of PHPT, subjects with PHPT were on average 3.3 kg
heavier than controls, and body mass index (BMI), in the four studies that reported
it, was 1.1 kg/m2 higher than controls [126]. The increased body weight may
contribute to the association of PHPT with cardiovascular disease, hypertension,
and glucose intolerance. In one trial, BMI did not change after parathyroidectomy
(versus observation) [127]. (See "Primary hyperparathyroidism: Management",
section on 'Cardiovascular'.)
Rheumatologic manifestations — Many rheumatologic abnormalities have been
described in patients with classical symptomatic PHPT, but none of these are
commonly seen in modern-day disease [128]. They include the following:
●Hyperuricemia and gout.
●Pseudogout with pyrophosphate crystals into the joint [129-133].
Calcification of articular cartilage (chondrocalcinosis), most commonly
affecting the wrists and knees, is more commonly reported than gout itself
[132,133]. Pseudogout may also be seen soon after parathyroidectomy. The
mechanism for this is unclear. (See "Clinical manifestations and diagnosis of
calcium pyrophosphate crystal deposition (CPPD) disease".)
OTHER LABORATORY FINDINGSIn addition to abnormalities in serum
calcium and parathyroid hormone (PTH), other laboratory findings may include the
following:
Hypophosphatemia — In most patients with mild PHPT, phosphate levels are not
frankly low but are instead in the lower half of the normal range. In some patients
with more severe disease, serum phosphate concentrations are low because PTH
inhibits the proximal tubular reabsorption of phosphate, leading to increased
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phosphate excretion. The decrease in reabsorption is due to reduced activity of the
sodium-phosphate cotransporter in the luminal membrane, so that entry of
filtered phosphate into the tubular cells, and therefore its return to the systemic
circulation, are decreased. (See "Hypophosphatemia: Causes of
hypophosphatemia", section on 'Primary and secondary hyperparathyroidism'.)
1,25-dihydroxyvitamin D — Patients with PHPT convert more 25-hydroxyvitamin
D (25[OH]D; calcidiol) to 1,25-dihydroxyvitamin D (calcitriol) than normal
individuals. Serum concentrations of 1,25-dihydroxyvitamin D may therefore be at
upper limits of normal or elevated [13,57].
Magnesium balance — Renal tubular reabsorption of magnesium is stimulated by
PTH but inhibited by hypercalcemia. The effects of the hypercalcemia on
magnesium excretion may be mediated via calcium-sensing receptors in the thick
ascending loop of Henle. Overall, magnesium excretion tends to be slightly
increased, and a few patients have mild hypomagnesemia. (See "Disorders of the
calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal
dominant hypocalcemia".)
Acid-base balance — High concentrations of PTH inhibit proximal tubular
bicarbonate reabsorption, which tends to cause a mild metabolic acidosis.
However, this effect is usually counterbalanced by the alkali liberated as a result of
increases in bone resorption and in tubular reabsorption of bicarbonate caused by
hypercalcemia [134,135]. Thus, metabolic acidosis is unusual in PHPT unless serum
PTH concentrations are very high or the patient has coexistent renal insufficiency.
Anemia — Patients with severe PHPT may have a normochromic, normocytic
anemia that responds to parathyroidectomy [136]. The mechanism is unclear, but
marrow fibrosis may be important [136,137]. In patients with mild disease, anemia
should not be attributed to coexisting PHPT.
Monoclonal gammopathy — There may be an association between PHPT and
monoclonal gammopathy, although data are conflicting. While the prevalence of
monoclonal gammopathy in the general adult population is approximately 1
percent, estimates in patients with PHPT have ranged from 1 to 10 percent [138-
141]. This may be an association limited to those with severe disease. As an
example, the highest prevalence (10 percent) was reported in a prospective study
of 100 cases with severe PHPT (median calcium of 12 mg/dL and PTH levels of 200
pg/mL), compared with 2 to 3 percent in two control groups (age- and sex-
matched) [141]. Of the 10 patients with monoclonal gammopathy, two were
discovered to have multiple myeloma.
There are also several single-case reports of concomitant PHPT and multiple
myeloma. Whether this truly represents an increased prevalence of this
comorbidity remains unknown [141].

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CANCERThere are conflicting data on whether PHPT is more common in patients
with cancer and/or whether it is associated with an increased risk of cancer [142-
147]. Several studies suggest a small increase in risk of death from cancer
[142,144,145], even after parathyroidectomy [144,145]. In contrast, cancer-related
mortality was lower than expected in an unselected cohort of patients with PHPT in
the community (many of whom did not undergo surgery) [143].
MORTALITYSevere classical PHPT is associated with increased mortality,
primarily due to cardiovascular disease. However, the impact of milder PHPT on
cardiovascular mortality is uncertain. Excess mortality, mostly due to
cardiovascular disease, has been reported in some [148-153], but not all
[143,154,155], studies of patients with milder forms of PHPT (relative risk [RR]
ranging from 1.2 to 2.0). Studies of European populations tend to report increased
mortality, whereas those from the United States do not. One explanation for the
incongruent mortality data is that more patients in the United States studies had
mild disease with lower serum calcium levels (mean calcium 10.9 mg/dL [2.7
mmol/L]) and fewer symptoms than patients in the European studies, where
average calcium levels were significantly higher. In some [143,155-157], but not all
[152] studies, higher serum calcium levels were associated with increased
mortality. As an example, in a multivariate analysis of the Rochester study, higher
calcium levels (≥11.2 mg/dL [2.8 to mmol/L]) were associated with worse survival
[143]. In an updated report from the same group, patients with a serum calcium
(≥10.8 mg/dL [2.7 to mmol/L]) had increased mortality [155].
In some studies, the higher mortality rate declined with time from
parathyroidectomy but persisted after surgical cure [142,149-151]. This suggests
that the disease may cause enduring damage to the cardiovascular system. The
largest study to date on this subject was conducted on 10,995 Swedish patients
with PHPT who underwent parathyroidectomy between 1958 and 1997 (identified
through the Cancer and Causes of Death Registries) [142]. Mortality, primarily
cardiovascular, was increased after surgery (standard mortality ratio of 1.2, 95%
1.19-1.27) in the overall group and persisted up to 15 years post-
parathyroidectomy. It was noted in both sexes and all age groups. However, in the
subset of 6386 patients operated on between 1985 and 1997, there was no
increase in mortality. Possible speculations for the decreased mortality in the latter
subset include a milder clinical presentation or earlier surgical intervention.
Surprisingly, a previously published Swedish study conducted on 4461 patients
operated in the same period, between 1987 and 1994, and using the same national
Swedish registries, observed an increased mortality (RR 1.7 for males and 1.85 for
females), compared with age-, sex-matched controls [149]. The reason for the
discrepancy between the two Swedish studies is unclear.
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Further studies are needed to determine whether cardiovascular mortality is truly
increased in patients with PHPT and whether that risk is affected by disease
severity and/or timing of surgical intervention [47]. (See "Primary
hyperparathyroidism: Management".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Primary hyperparathyroidism".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
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and they answer the four or five key questions a patient might have about a given
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patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topic (see "Patient education: Primary hyperparathyroidism (The

Basics)")
●Beyond the Basics topic (see "Patient education: Primary
hyperparathyroidism (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The most common clinical presentation of primary hyperparathyroidism
(PHPT) in Western populations is asymptomatic hypercalcemia detected by
routine biochemical screening. The serum parathyroid hormone (PTH)
concentration is either frankly elevated or within the normal range but
inappropriately elevated given the patient's hypercalcemia.
(See 'Asymptomatic primary hyperparathyroidism' above.)
●In 2009, an international panel of experts recognized normocalcemic PHPT
as a phenotype of PHPT in which PTH levels are consistently elevated but
serum total and ionized calcium levels are normal, and all secondary causes
for hyperparathyroidism (table 1) are excluded. Patients with normocalcemic
hyperparathyroidism typically come to medical attention in the setting of an

865
evaluation for low bone mineral density (BMD). (See 'Normocalcemic primary
hyperparathyroidism' above.)
●Parathyroid crisis, which is rare, is characterized by severe hypercalcemia,
with the serum calcium concentration usually above 15 mg/dL (3.8 mmol/L)
and marked symptoms of hypercalcemia: in particular, central nervous
system dysfunction. (See 'Parathyroid crisis' above.)
●The classical symptoms and signs of PHPT, such as osteitis fibrosa cystica
and nephrolithiasis, are due to prolonged excessive PTH secretion and
hypercalcemia. Although osteitis fibrosa cystica is rarely seen in the United
States and Europe, it is still prevalent in resource-limited countries. The
geographical differences in the clinical manifestations of PHPT may be
explained, at least in part, by the greater prevalence of vitamin D deficiency
in some countries. (See 'Classical' above.)
●Although many patients with PHPT have neuropsychologic complaints, the
extent and attribution of these symptoms to PHPT in a given patient requires
further elucidation. (See 'Classical' above.)
●Patients with PHPT may have decreased BMD, in particular at more cortical
sites (forearm and hip) as compared with more cancellous sites (spine).
(See 'Skeletal' above.)
●Important subclinical renal manifestations of PHPT include asymptomatic
nephrolithiasis, hypercalciuria, nephrocalcinosis, chronic renal insufficiency,
and several abnormalities in renal tubular function: in particular, decreased
concentrating ability (table 4). (See 'Subclinical renal disease' above.)
●The nature of cardiovascular involvement and the impact of PHPT on
cardiovascular mortality require further elucidation.
(See 'Cardiovascular' above.)

866
Primary hyperparathyroidism: Diagnosis,
differential diagnosis, and evaluation
Authors:
Ghada El-Hajj Fuleihan, MD, MPH
Shonni J Silverberg, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 16, 2020.
INTRODUCTIONThe diagnosis of hyperparathyroidism is usually first
suspected because of the finding of an elevated serum calcium concentration. If
hypercalcemia is confirmed on a repeat sample, all of its causes should be
considered (table 1). (See "Etiology of hypercalcemia".)
The serum parathyroid hormone (PTH) concentration should then be measured
using a two-site immunoradiometric sandwich assay. The diagnosis of primary
hyperparathyroidism (PHPT) is usually made by finding a PTH concentration that is
frankly elevated or within the normal range but inappropriately normal given the
patient's hypercalcemia (figure 1).

The diagnosis, differential diagnosis, and evaluation of PHPT will be discussed

here. Other aspects of PHPT are reviewed elsewhere.

●(See "Primary hyperparathyroidism: Clinical manifestations".)

●(See "Primary hyperparathyroidism: Management".)
●(See "Preoperative localization for parathyroid surgery in patients with
primary hyperparathyroidism".)
●(See "Parathyroid exploration for primary hyperparathyroidism".)
●(See "Pathogenesis and etiology of primary hyperparathyroidism".)

DIAGNOSIS
●Primary hyperparathyroidism (PHPT) – The most common clinical
presentation of PHPT is asymptomatic hypercalcemia. The diagnosis is
usually first suspected because of the incidental finding of an elevated serum
calcium concentration on biochemical screening tests. In addition, PHPT may
be suspected in a patient with nephrolithiasis. If hypercalcemia is confirmed,

867
 intact parathyroid hormone (PTH) should be measured concomitantly with
the serum calcium.
PHPT is diagnosed by finding a frankly elevated PTH concentration in a
patient with hypercalcemia. When the PTH is only minimally elevated or
within the normal range (but inappropriately normal given the patient's
hypercalcemia), PHPT remains the most likely diagnosis, although familial
hypocalciuric hypercalcemia (FHH), a rare disorder, is possible (figure
1 and algorithm 1). (See 'Diagnostic evaluation' below.)
●Normocalcemic PHPT – Normocalcemic PHPT is a variant of PHPT, first
recognized in 2009 by an international panel of experts [1]. Patients with
normocalcemic PHPT typically come to medical attention in the setting of an
evaluation for low bone mineral density (BMD), during which time PTH levels
are drawn and found to be elevated in the absence of hypercalcemia [2-5]. In
order to make a diagnosis of normocalcemic PHPT, certain conditions must
be met. In particular, ionized calcium levels should be normal, and all
secondary causes for hyperparathyroidism (table 2) must be ruled out.
Vitamin D deficiency and chronic kidney disease are the most common
causes of secondary hyperparathyroidism; however, the precise serum 25-
hydroxyvitamin D (25[OH]D) and estimated glomerular filtration rate (eGFR)
thresholds for defining them are not well established [6,7]. (See 'Secondary
hyperparathyroidism' below.)
DIAGNOSTIC EVALUATION
Serum calcium — A single elevated serum calcium concentration should be
repeated to confirm the presence of hypercalcemia. The total serum calcium
concentration should be used for both the initial and the repeat serum calcium
measurements. If a laboratory known to measure ionized calcium reliably is
available, some authorities prefer to measure the ionized calcium, although this
usually adds little to the diagnosis of asymptomatic primary hyperparathyroidism
(PHPT) in patients with normal serum albumin concentrations and no
abnormalities in acid-base balance [8]. (See "Diagnostic approach to
hypercalcemia", section on 'Confirm hypercalcemia'.)
One circumstance in which ionized calcium measurements are an important
adjunct to diagnosis is in patients with presumed normocalcemic PHPT. In order to
make this diagnosis, ionized calcium levels should be normal [9]. In one series, 12
of 60 patients in whom the diagnosis of normocalcemic PHPT was considered had
a raised serum concentration of ionized calcium in the presence of a normal total
serum calcium concentration [10].

868
Previous values for serum calcium should be reviewed, if available. The presence
of longstanding asymptomatic hypercalcemia is more suggestive of PHPT and, in
young individuals, also raises the possibility of familial hypocalciuric hypercalcemia
(FHH).

Serum PTH — Either intact parathyroid hormone (PTH) (second-generation PTH

assay) or PTH 1-84 assays (third-generation) should be measured concomitantly
with the serum calcium level to diagnose hyperparathyroidism [11]. Although
limited data [12] suggest that PTH is increased in a higher proportion of patients
with PHPT using the PTH 1-84 assay, several other studies have found no increase
in diagnostic utility [13,14]. (See "Parathyroid hormone assays and their clinical
use", section on 'Clinical use of PTH assays'.)
●PTH elevated – Approximately 80 to 90 percent of patients with PHPT have
serum PTH concentrations above the normal range for the assay (figure
1 and algorithm 1) [15,16]. In contrast to parathyroid cancer and secondary
hyperparathyroidism associated with renal failure, the extent of elevation in
PHPT tends to be modest, often in the range of twice the upper limit of
normal.
●PTH within normal range – Ten to 20 percent of patients have serum PTH
values that are only minimally elevated or normal [1]. These "normal" values
in the presence of hypercalcemia are inappropriately high; normal individuals
given calcium intravenously have suppressed serum PTH concentrations
(below 10 pg/mL), and patients with nonparathyroid hypercalcemia virtually
always have values below 20 to 25 pg/mL (figure 1) [17,18]. When the PTH is
minimally elevated or within the normal range (but inappropriately normal
given the patient's hypercalcemia), measurement of 24-hour urinary calcium
excretion may help distinguish PHPT from FHH (algorithm 1). (See '24-hour
urinary calcium' below.)
●PTH lower end of normal range – When PTH is below or in the lower end of
the normal range, non-PTH-mediated causes of hypercalcemia should be
investigated (algorithm 1). Occasionally, a patient with proven PHPT has a
serum intact PTH concentration in the lower half of the normal range [19]
and, very rarely, one that is undetectable [20]. In the latter report, the patient
had a biologically active PTH fragment, which was undetectable with the
intact PTH assay. (See "Parathyroid hormone assays and their clinical use",
section on 'PTH fragments'.)
24-hour urinary calcium — Measurement of 24-hour urinary calcium excretion is
not always required for the diagnosis of PHPT, but it is routinely measured in
patients with asymptomatic PHPT in order to assess the risk of renal complications

869
(when urine calcium is high) and thus determine subsequent management
(see 'Additional evaluation to determine management' below). For patients with
hypercalcemia and PTH that is only minimally elevated or inappropriately normal
given the patient's hypercalcemia, the 24-hour urinary calcium also helps to
distinguish PHPT from FHH (algorithm 1).
●Approximately 40 percent of patients with PHPT are hypercalciuric, and most
of the remaining patients have normal values [21]. An elevated urinary
calcium concentration (>200 to 300 mg/day) essentially excludes FHH.
●If calcium excretion is <200 mg/day (5.0 mmol/day), FHH or PHPT with
concomitant vitamin D deficiency are possibilities. Lower urinary calcium
values may also be seen in patients with PHPT whose calcium intake is
extremely low (algorithm 1). (See 'Serum 25-hydroxyvitamin D' below.)
●Approximately 75 percent of affected persons with FHH excrete less than
100 mg of calcium in urine daily [22]. (See 'Familial hypocalciuric
hypercalcemia' below.)

A calcium/creatinine (Ca/Cr) clearance ratio, which is equivalent to the fractional

excretion of calcium, may also be helpful. This ratio is calculated from 24-hour
urinary calcium and creatinine and total serum calcium and creatinine
concentrations using the following formula:

 Ca/Cr clearance ratio  =  [24-hour urine Ca  x  serum Cr]  ÷  [serum Ca  x  24-hour

urine Cr]

The data establishing the value of the Ca/Cr clearance ratio in differentiating FHH
from PHPT are based primarily on 24-hour urine collections. While there are
insufficient data available to prove that Ca/Cr ratios calculated from spot urines
are equivalent to those determined from 24-hour urines, in principle, the two
should reflect renal calcium handling similarly.

A value below 0.01 in a vitamin D-replete individual is highly suggestive of FHH

rather than PHPT (ratio usually >0.02). In an analysis of five large studies
combining 165 patients with FHH and 197 patients with PHPT, a Ca/Cr clearance
ratio <0.01 had a sensitivity for FHH of 85 percent, a specificity of 88 percent, and a
positive predictive value of 85 percent; a value >0.02 essentially excluded FHH [23-
25].
Many individuals with PHPT and with FHH have Ca/Cr clearance ratios between
0.01 and 0.02 [22,26]. Due to the difficulty of differentiating FHH from vitamin D-
replete PHPT when the Ca/Cr clearance ratio is between 0.01 and 0.02, some have
suggested genetic testing for FHH, where available, for such individuals.
870
[11,22,25,27]. Genetic testing for FHH is reviewed separately. (See "Disorders of the
calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal
dominant hypocalcemia", section on 'Distinction from primary
hyperparathyroidism'.)
The role of genetic testing in hereditary PHPT is reviewed below. (See 'Role of
genetic testing' below.)
Serum 25-hydroxyvitamin D — Measurement of vitamin D metabolites may be
useful to distinguish PHPT from other conditions in the following circumstances:
●Differentiation of FHH from mild PHPT with concomitant vitamin D
deficiency in individuals with concomitantly elevated serum PTH and calcium
but with normal or low 24-hour urinary calcium excretion. To do so, we
typically measure 25-hydroxyvitamin D (25[OH]D). In the latter patients,
urinary calcium excretion increases with vitamin D repletion, thereby
distinguishing it from FHH. (See "Primary hyperparathyroidism:
Management", section on 'Concomitant vitamin D deficiency'.)
●Differentiation of secondary hyperparathyroidism due to vitamin D
deficiency from normocalcemic PHPT in patients with elevated PTH and
normal serum calcium concentrations. To do so, we typically measure
25(OH)D, which is low in the former and normal in the latter.

Sometimes patients with presumed secondary hyperparathyroidism actually have

PHPT with concomitant vitamin D deficiency. In these patients, the diagnosis of
mild PHPT is obscured by vitamin D deficiency due to poor dietary intake of
vitamin D or sunlight exposure and may not be recognized until vitamin D is
repleted and hypercalcemia and/or hypercalciuria develop. PHPT with coexisting
vitamin D deficiency may be suspected when serum calcium concentrations are in
the upper half of the normal range and urinary calcium concentration is normal,
despite vitamin D deficiency.

Individuals with normocalcemic PHPT and low 25(OH)D concentrations may be

repleted with vitamin D. However, vitamin D replacement should be provided
cautiously in those with suspected concurrent PHPT, in particular in those with a
urinary calcium that is in the high-normal range, as worsening hypercalcemia and
hypercalciuria may develop. In contrast, serum and urinary calcium remain normal
and PTH normalizes after vitamin D repletion in individuals with vitamin D
deficiency-induced secondary hyperparathyroidism. (See "Primary
hyperparathyroidism: Management", section on 'Concomitant vitamin D
deficiency' and "Vitamin D deficiency in adults: Definition, clinical manifestations,
and treatment", section on 'Coexisting primary hyperparathyroidism'.)

871
Patients with PHPT convert more 25(OH)D (calcidiol) to 1,25 dihydroxyvitamin D
(calcitriol) than normal individuals. Serum concentrations of 1,25 dihydroxyvitamin
D may therefore be at upper limits of normal or elevated [28,29]. An elevated value
is not specific for diagnosis, and measurement of 1,25-dihydroxyvitamin D is not
generally needed to confirm the diagnosis.
Role of genetic testing — The majority of patients with PHPT do not require
genetic testing. Due to the difficulty of differentiating FHH from vitamin D-replete
PHPT when the Ca/Cr clearance ratio is between 0.01 and 0.02, some experts have
suggested calcium-sensing receptor (CaSR) mutation analysis for such individuals.
(See 'Familial hypocalciuric hypercalcemia' below and "Disorders of the calcium-
sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant
hypocalcemia", section on 'Distinction from primary hyperparathyroidism'.)
Genetic testing, where available, can also be performed in selected patients in
whom a familial form of PHPT is suspected, including young patients and patients
with a family history of PHPT, multigland involvement, or clinical findings
suspicious for multiple endocrine neoplasia type 1 (MEN1) [11]. Approximately 10
percent of patients with PHPT will have a mutation in 1 of 11 genes [11].
(See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis",
section on 'MEN1 mutational analysis'.)
Abnormalities in key growth-controlling genes, protooncogenes, or tumor
suppressor genes underlie the development of parathyroid tumors, which may
occur sporadically or in familial patterns. The underlying genetic abnormalities
include gain-of-function changes in genes such as cyclin D1/PRAD1 for sporadic
tumors and RET for familial tumors, or loss-of-function mutations in genes such
as MEN1 or HRPT2 for sporadic and familial tumors. (See "Pathogenesis and
etiology of primary hyperparathyroidism", section on 'Genetic or chromosomal
defects'.)
DIFFERENTIAL DIAGNOSISAlthough the most common clinical presentation
of primary hyperparathyroidism (PHPT) is asymptomatic hypercalcemia with an
elevated or high-normal intact parathyroid hormone (PTH) concentration, the
presentation may be atypical. Atypical presentations include a spectrum of
disturbances in calcium homeostasis, ranging from symptomatic severe
hypercalcemia (parathyroid crisis) to normocalcemic PHPT. Laboratory testing
often can distinguish atypical presentations of PHPT from other diseases, such as
malignancy, familial hypocalciuric hypercalcemia (FHH), and secondary
hyperparathyroidism (table 3).
In PHPT and FHH, the calcium and PTH levels are usually simultaneously elevated.
Nonparathyroid-mediated causes of hypercalcemia (table 3), including milk-alkali
syndrome, granulomatous disease, and hypervitaminosis D, are associated with
872
suppressed rather than elevated PTH concentrations. They are discussed in more
detail elsewhere. (See "Etiology of hypercalcemia" and "Diagnostic approach to
hypercalcemia".)
Malignancy — PHPT and malignancy are the most common causes of
hypercalcemia, accounting for more than 90 percent of cases (table 1). It is usually
not difficult to differentiate between them. Malignancy is often evident clinically by
the time it causes hypercalcemia, and patients with hypercalcemia of malignancy
have higher calcium concentrations and are more symptomatic from
hypercalcemia than individuals with PHPT. (See "Hypercalcemia of malignancy:
Mechanisms".)
However, it may be difficult to differentiate the two problems clinically when the
presentation is less typical. As an example, some patients with occult malignancy
may present with mild hypercalcemia. Alternatively, patients with
hyperparathyroidism can occasionally have acute onset of severe, symptomatic
hypercalcemia (parathyroid crisis). In these cases, measurement of intact PTH will
usually distinguish the two diseases. Intact PTH concentrations are generally
undetectable or very low in hypercalcemia of malignancy and are elevated or high-
normal in PHPT (table 3). It is uncommon for patients with hypercalcemia of
malignancy to have elevated PTH levels, but this finding may occur rarely in
individuals with hypercalcemia of malignancy and concomitant PHPT or in
individuals with PTH-secreting tumors, which are also rare. (See "Hypercalcemia of
malignancy: Mechanisms", section on 'Coexisting primary
hyperparathyroidism' and "Hypercalcemia of malignancy: Mechanisms", section on
'Ectopic PTH secretion'.)
Patients with parathyroid carcinomas have severe hypercalcemia and PTH levels in
the hundreds to thousands pg/mL range. (See "Parathyroid carcinoma".)
Familial hypocalciuric hypercalcemia — FHH is an autosomal dominant disorder
characterized by longstanding, mild hypercalcemia; normal or mildly elevated PTH
levels; and low urinary calcium excretion. In most cases, it is due to an inactivating
mutation in the calcium-sensing receptor in the parathyroid glands and the
kidneys [23]. A family history of hypercalcemia, especially in young children, and
the absence of symptoms and signs of hypercalcemia are characteristic of this
disorder.
Fifteen to 20 percent of patients with FHH may have a mildly elevated PTH
concentration [23,24,30,31]. In these individuals, it may be difficult to distinguish
asymptomatic PHPT from FHH. It is important to make this distinction, however,
because FHH is a benign inherited condition that typically does not require
parathyroidectomy and will not be cured by it.

873
The major feature that distinguishes FHH from PHPT is a low urine calcium
excretion and calcium/creatinine (Ca/Cr) clearance ratio (table 3). In contrast, in the
absence of hypovitaminosis D, most patients with PHPT have either normal or
elevated urinary calcium excretion. Because the calcium-sensing receptor is a
cation receptor, urinary magnesium excretion parallels calcium excretion and is
therefore low in FHH, in contrast with PHPT. Measurement of urinary magnesium
is not, however, recommended in the evaluation of PHPT or FHH. (See '24-hour
urinary calcium' above and "Disorders of the calcium-sensing receptor: Familial
hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on
'Distinction from primary hyperparathyroidism'.)
Drugs — Two drugs deserve special consideration when evaluating a patient for
hyperparathyroidism: thiazide diuretics and lithium.
Thiazide diuretics, including chlorthalidone, reduce urinary calcium excretion and
therefore can cause mild hypercalcemia (up to 11.5 mg/dL [2.9 mmol/L])
(see "Etiology of hypercalcemia"). In addition, some patients with
hyperparathyroidism may be prescribed thiazides, which may elevate the serum
calcium further and thereby unmask the hyperparathyroidism. Following
discontinuation of the drug, these individuals remain hypercalcemic, although
perhaps less so, and are found to have surgically proven hyperparathyroidism.
Thus, if a patient taking a thiazide is found to be hypercalcemic, the drug should
be withdrawn, if possible, and calcium and PTH assessed three months later.
Persistent hypercalcemia (with elevated or high-normal PTH) after drug withdrawal
suggests that the thiazide has unmasked PHPT. (See "Pathogenesis and etiology of
primary hyperparathyroidism", section on 'Thiazide therapy'.)
Lithium decreases parathyroid gland sensitivity to calcium, shifting the calcium-
PTH curve to the right (figure 2). Lithium may also reduce urinary calcium
excretion. Lithium is thought to affect calcium-PTH dynamics through an action
downstream of the calcium-sensing receptor, but the exact locus is still unknown.
Some patients taking lithium develop hypercalcemia and hypocalciuria, and a
subset of these individuals have high serum PTH concentrations. If the lithium can
be stopped without exacerbating the psychiatric condition, the hypercalcemia may
resolve. Following discontinuation, the serum calcium concentration is more likely
to normalize if the duration of lithium use had been relatively short (eg, less than a
few years), but less likely if it had been longer (eg, more than 10 years).
(See "Pathogenesis and etiology of primary hyperparathyroidism", section on
'Lithium therapy' and "Parathyroid hormone secretion and action", section on
'Lithium and PTH secretion'.)
Secondary hyperparathyroidism — Occasionally, patients with PHPT have
consistently normal total and ionized calcium concentrations (normocalcemic

874
PHPT). These patients typically come to medical attention in the setting of an
evaluation for low bone mineral density (BMD). In these cases, it may be difficult to
distinguish secondary hyperparathyroidism from early PHPT because the
biochemical findings may be similar.
Secondary hyperparathyroidism occurs when the parathyroid gland appropriately
responds to a reduced level of extracellular calcium. PTH concentrations rise, and
calcium is mobilized by increasing intestinal absorption (via increase in calcitriol)
and by increasing bone resorption. Thus, it is characterized biochemically by
elevated PTH and normal or low serum calcium concentrations. (See "Management
of secondary hyperparathyroidism in adult dialysis patients".)
Secondary hyperparathyroidism may occur in patients with renal insufficiency or
failure and impaired calcitriol (1,25 dihydroxyvitamin D) production, as well as in
individuals with inadequate calcium intake or absorption, as can occur with vitamin
D deficiency or with gastrointestinal diseases causing malabsorption (table 2).
Assessment of renal function (serum creatinine), vitamin D status (25-
hydroxyvitamin D [25(OH)D]), and calcium sufficiency (urinary calcium excretion)
may help differentiate normocalcemic primary and secondary
hyperparathyroidism. Further assessment and work-up for specific gastrointestinal
disorders is generally undertaken only when the clinical suspicion is high.
Some patients may have more than one condition leading to increased PTH
secretion. Co-existing PHPT and vitamin D deficiency is not uncommon. When this
occurs, the serum calcium level in the primary hyperparathyroid patient may be
reduced (into the normal range in some cases) due to vitamin D deficiency.
(See 'Serum vitamin D' below and "Vitamin D deficiency in adults: Definition, clinical
manifestations, and treatment", section on 'Coexisting primary
hyperparathyroidism'.)
ADDITIONAL EVALUATION TO DETERMINE MANAGEMENTFor
patients diagnosed with asymptomatic primary hyperparathyroidism (PHPT),
additional evaluation is necessary to make subsequent management decisions.
(See "Primary hyperparathyroidism: Management".)

Although patients with symptomatic PHPT should have parathyroid surgery, the
widespread identification of asymptomatic individuals raises the question of need
for and timing of surgical intervention in this population. In order to make
management recommendations for patients with asymptomatic PHPT, we
measure:

●Urinarycalcium excretion (if not previously measured)

●Serum 25-hydroxyvitamin D (25[OH]D) (if not previously measured)

875
 ●Serum creatinine and estimated glomerular filtration rate (eGFR) to assess
for renal compromise
●Bone density to determine if it is low

Some, but not all, UpToDate authors and editors also obtain imaging studies of
the:

●Kidneys to assess for occult kidney stones

●Spine to assess for asymptomatic vertebral compression fracture
The Fourth International Workshop guidelines recommended further assessment
to help in the decision regarding surgery for PHPT (table 4). This includes renal
imaging (plain radiographs or ultrasound) to determine if the patient has a
clinically silent kidney stone and vertebral imaging (spine radiograph or vertebral
fracture assessment [VFA] of dual-energy x-ray absorptiometry [DXA] image) for
subclinical vertebral fracture [32]. Urinary stone risk profile is also recommended,
but only if urinary calcium excretion is extremely elevated (>400 mg/day) and a
patient is unsure about parathyroid surgery. However, these tests are more
expensive, may not be readily available to all clinicians, and there are few data to
support their role in managing patients with PHPT. Nevertheless, these latter tests
may be helpful for making management recommendations for select patients with
asymptomatic PHPT. (See "Primary hyperparathyroidism: Management", section
on 'Candidates for surgery'.)
Urinary calcium excretion — In asymptomatic patients, the urinary calcium
excretion is helpful to assess the risk of renal complications (when urine calcium is
high) and thus determine subsequent management. The Fourth International
Workshop on Asymptomatic Primary Hyperparathyroidism guidelines
recommended surgical intervention as opposed to observation in asymptomatic
patients who have a 24-hour urinary calcium excretion >400 mg/day (>10
mmol/day). It should be noted that urinary calcium levels are considered to be
elevated at a significantly lower level of excretion (250 mg/24 hours in women and
300 mg/24 hours in men), and that there are no specific data assessing the cut-
point of 400 mg calcium excretion daily. This particular recommendation reflected
expert opinion regarding a level above which there is consensus that patients
should be sent for surgery even in the absence of other criteria. (See "Primary
hyperparathyroidism: Management", section on 'Candidates for surgery'.)
Serum vitamin D — We measure serum 25(OH)D in all patients with suspected or
diagnosed PHPT. Measurement of 25(OH)D is important to identify patients with
PHPT and vitamin D deficiency, who require vitamin D repletion. (See "Primary
hyperparathyroidism: Management", section on 'Concomitant vitamin D

876
deficiency' and "Vitamin D deficiency in adults: Definition, clinical manifestations,
and treatment", section on 'Coexisting primary hyperparathyroidism'.)
Due to the significant prevalence of vitamin D insufficiency in individuals with
PHPT, the Fourth International Workshop on Asymptomatic Primary
Hyperparathyroidism recommended measuring 25(OH)D in all patients with the
disease and repleting those with low levels (defined as ≤20 ng/mL [50 nmol/L])
prior to making any management decisions [11]. In some cases, the decision
regarding surgery will be clear despite the low vitamin D level. In such patients, it
is still advisable to replete vitamin D if this can be done safely, in order to mitigate
postoperative hypocalcemia.
Serum creatinine — The serum creatinine concentration provides information
about renal function, which can be diminished by hypercalcemia. Rather than
using serum creatinine alone, the eGFR can be estimated in patients with a stable
serum creatinine concentration. (See "Clinical manifestations of
hypercalcemia" and "Assessment of kidney function", section on 'Estimation
equations'.)
An eGFR of 60 mL/min is the threshold of chronic kidney disease for deciding
which asymptomatic individuals with PHPT may benefit from early surgical
treatment [32]. (See "Primary hyperparathyroidism: Management", section on
'Candidates for surgery'.)
Renal imaging — In several studies, clinically silent kidney stones were reported
in 7 to 21 percent of patients with asymptomatic PHPT [33-36]. Patients with
undiagnosed (subclinical) nephrocalcinosis or calcium kidney stones are regarded
as having symptomatic disease, regardless of the absence of symptoms. Thus,
these patients meet criteria for surgical intervention [32]. For patients who do not
have other overt indications for surgery, some UpToDate authors and editors
obtain renal imaging (ultrasound, computed tomography [CT], or abdominal
radiograph) to look for nephrocalcinosis or asymptomatic nephrolithiasis at the
time of the original evaluation for PHPT [3]. Ultrasound is typically the imaging
modality used.
Bone mineral density — Patients with hyperparathyroidism may have decreased
bone mineral density (BMD), in particular at more cortical sites (forearm and hip)
as compared with more trabecular (cancellous) sites (spine). Although
measurement of BMD is not required for the diagnosis of PHPT, it is an essential
part of the management of the disease, and BMD must be measured at the spine,
hip, and distal one-third forearm sites. The degree of bone loss is reflective of the
severity of hyperparathyroidism and is useful for making recommendations for
parathyroid surgery or observation with monitoring in asymptomatic patients.
(See "Primary hyperparathyroidism: Management", section on

877
'Asymptomatic' and "Primary hyperparathyroidism: Management", section on
'Subclinical bone disease'.)
Assessment for vertebral fracture — Patients with subclinical, idiopathic
vertebral compression fractures are regarded as having osteoporosis,
independent of BMD findings. Vertebral compression fractures are
underdiagnosed in all populations, and many studies have demonstrated an
increased risk of asymptomatic vertebral fractures in patients with PHPT.
(See "Primary hyperparathyroidism: Clinical manifestations", section on 'Skeletal'.)
In order to diagnose asymptomatic vertebral compression fractures, the Fourth
International Workshop guidelines recommended imaging to assess for vertebral
fracture in asymptomatic patients who do not have osteoporosis on BMD testing
(patients with clinical osteoporotic fractures or with BMD in the osteoporosis range
already meet criteria for surgery) [32]. If a vertebral fracture is present by VFA or
radiograph, parathyroidectomy is recommended. Vertebral assessment can be
performed with plain radiographs or with VFA by DXA. The latter can be done at
the time of BMD testing, at greater patient convenience, less cost, and lower
radiation exposure than conventional radiography of the spine. (See "Overview of
dual-energy x-ray absorptiometry", section on 'Vertebral fracture
assessment' and "Primary hyperparathyroidism: Management", section on
'Candidates for surgery'.)
Other tests — Other tests that may provide useful clinical information include the
following:
Biochemical renal stone prediction — For asymptomatic patients with
hypercalciuria (>400 mg/day [10 mmol/day]), the Fourth International Workshop
Guidelines on the Management of Asymptomatic Primary Hyperparathyroidism
recommended assessment of the urine composition to identify patients at highest
risk for nephrolithiasis [32]. There are no specific data to suggest that urine stone
risk profiling can predict risk of nephrolithiasis in patients with PHPT [37]. Some
experts believe that urinary calcium excretion >400 mg/day alone raises sufficient
enough concern about long-term renal complications to warrant a
recommendation for parathyroidectomy. If an asymptomatic patient with a urinary
calcium >400 mg/day is unsure about proceeding to surgery, a stone risk profile
might provide useful information for making a decision about surgery.
(See "Kidney stones in adults: Evaluation of the patient with established stone
disease", section on '24-hour urine collections'.)
For asymptomatic patients at high risk for nephrolithiasis (24-hour urinary calcium
>400 mg and high-risk urinary biochemical profile), the Fourth International
Workshop guidelines recommended parathyroidectomy [32]. (See "Primary
hyperparathyroidism: Management", section on 'Candidates for surgery'.)

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Serum phosphorus — The serum phosphorus concentration may be decreased
but typically is in the lower range of normal. Some patients have mild
hyperchloremic acidosis. (See "Primary hyperparathyroidism: Clinical
manifestations".)
Markers of bone turnover — Biochemical markers of bone turnover (collagen
crosslinks, osteocalcin, bone-specific alkaline phosphatase) are often at the upper
end of normal or mildly elevated in asymptomatic PHPT (see "Bone physiology and
biochemical markers of bone turnover"). In those with more severe disease, they
are typically high. They are only occasionally helpful in the management of
hyperparathyroidism and should not be routinely measured [8].
Localization studies — The diagnosis of PHPT is established by appropriate
biochemical testing. Localization studies with ultrasonography, technetium-99m
sestamibi, CT, or magnetic resonance imaging (MRI) scanning should not be used
to establish the diagnosis of PHPT or to determine management. Localization
studies should be performed only after a decision for surgery has been made.
Their utility is questionable when bilateral neck exploration is planned. However,
they are commonly used now, along with intraoperative parathyroid hormone
(PTH) monitoring, to facilitate unilateral exploration and minimally invasive surgery
in those with probable single gland disease. (See "Preoperative localization for
parathyroid surgery in patients with primary hyperparathyroidism".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Primary hyperparathyroidism".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

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 ●Basics topic (see "Patient education: Primary hyperparathyroidism (The
Basics)")
●Beyond the Basics topic (see "Patient education: Primary
hyperparathyroidism (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The most common clinical presentation of primary hyperparathyroidism
(PHPT) is asymptomatic hypercalcemia. The diagnosis is usually first
suspected because of the incidental finding of an elevated serum calcium
concentration on biochemical screening tests. In addition, PHPT may be
suspected in a patient with nephrolithiasis. PHPT is diagnosed by finding a
frankly elevated parathyroid hormone (PTH) concentration in a patient with
hypercalcemia. When the PTH is only minimally elevated, or within the
normal range (but inappropriately normal given the patient's hypercalcemia),
PHPT remains the most likely diagnosis, although familial hypocalciuric
hypercalcemia (FHH), a rare disorder, is possible (algorithm 1).
(See 'Diagnosis' above.)
Either intact PTH (second-generation PTH assay) or PTH 1-84 assays (third-
generation PTH assays) can be used for diagnosis of hyperparathyroidism.
(See 'Serum PTH' above.)
●Normocalcemic PHPT is a variant of PHPT. Patients with normocalcemic
PHPT typically come to medical attention in the setting of an evaluation for
low bone mineral density (BMD), during which time PTH levels are drawn and
found to be elevated in the absence of hypercalcemia. In such cases, BMD at
cortical sites may be preferentially affected. In order to make this diagnosis,
all secondary causes for hyperparathyroidism (table 2) must be ruled out, and
ionized calcium levels should be normal. (See 'Diagnosis' above and 'Bone
mineral density' above.)
●For patients with hypercalcemia and PTH that is only minimally elevated or
inappropriately normal given the patient's hypercalcemia, further evaluation
is necessary to confirm the diagnosis.
We measure urinary calcium excretion and 25-hydroxyvitamin D (25[OH]D) in
all patients with suspected PHPT (algorithm 1). Measurement of 24-hour
urine calcium excretion is helpful for distinguishing PHPT from FHH.
Measurement of 25(OH)D is not only important to distinguish PHPT from
other conditions, but also to identify patients with both PHPT and vitamin D
deficiency, who require vitamin D repletion. (See '24-hour urinary
calcium' above and 'Serum 25-hydroxyvitamin D' above.)
●Although the most common clinical presentation of PHPT is asymptomatic
hypercalcemia with an elevated or high-normal intact PTH concentration, the
880
presentation may be atypical. Atypical presentations include a spectrum of
disturbances in calcium homeostasis, ranging from symptomatic severe
hypercalcemia (parathyroid crisis) to normocalcemic PHPT. Laboratory testing
often can distinguish atypical presentations of PHPT from other diseases,
such as malignancy, FHH, and secondary hyperparathyroidism (table 3).
(See 'Differential diagnosis' above.)
●For patients diagnosed with asymptomatic PHPT, additional evaluation is
necessary to make subsequent management decisions. (See 'Additional
evaluation to determine management' above and "Primary
hyperparathyroidism: Management", section on 'Surgery versus nonsurgical
management'.)
Although patients with symptomatic PHPT should have parathyroid surgery,
the widespread identification of asymptomatic individuals raises the question
of the need for and timing of surgical intervention in this population. In order
to make management recommendations for patients with asymptomatic
PHPT, we measure urinary calcium excretion and serum 25(OH)D (if both
have not been previously measured), assess kidney function by estimated
glomerular filtration rate (eGFR), and obtain a BMD test. Some, but not all,
UpToDate authors and editors also obtain imaging of the kidneys and spine
to assess for occult kidney stones and vertebral compression fracture,
respectively. (See 'Additional evaluation to determine management' above.)
●Localization studies with ultrasonography, technetium-99m sestamibi,
computed tomography (CT), or magnetic resonance imaging (MRI) scanning
should not be used to establish the diagnosis of PHPT or to determine
management. If localization studies are performed, they should be done after
a decision for surgery has been made. (See "Preoperative localization for
parathyroid surgery in patients with primary hyperparathyroidism".)

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Primary hyperparathyroidism: Management
Authors:
Shonni J Silverberg, MD
Ghada El-Hajj Fuleihan, MD, MPH
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Aug 27, 2021.
INTRODUCTIONPrimary hyperparathyroidism (PHPT) is often recognized as a
result of biochemical screening or as part of an evaluation for decreased bone
mass. Most of the patients have serum calcium concentrations within 1 to 1.5
mg/dL (0.25 to 0.375 mmol/L) above the upper limit of normal with an elevated or
inappropriately normal PTH level. Among such patients, the majority are women
over age 50 years who are asymptomatic. This topic reviews the management of
PHPT in general and the risks and benefits of medical versus surgical management
in asymptomatic patients. The clinical manifestations and diagnosis of PHPT,
diagnostic localization of abnormal parathyroid glands, and the methods of
surgical removal are discussed in greater detail elsewhere.

The decision regarding medical versus surgical treatment does not apply to
patients who have familial hypocalciuric hypercalcemia. Patients with this disorder
have mild hypercalcemia, few if any symptoms, no evidence of end organ damage
from their disease, and no benefit from parathyroidectomy.

●(See "Primary hyperparathyroidism: Clinical manifestations".)

●(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)
●(See "Preoperative localization for parathyroid surgery in patients with
primary hyperparathyroidism".)
●(See "Parathyroid exploration for primary hyperparathyroidism".)
●(See "Disorders of the calcium-sensing receptor: Familial hypocalciuric
hypercalcemia and autosomal dominant hypocalcemia".)
SYMPTOMATICPatients with symptomatic PHPT (nephrolithiasis, fractures,
symptomatic hypercalcemia) should have parathyroid surgery, which is the only
definitive therapy. Parathyroidectomy is an effective therapy that cures the
disease, decreases the risk of kidney stones, improves bone mineral density (BMD),
882
and may decrease fracture risk and modestly improve some quality of life
measurements. (See 'Surgical procedure' below.)
Observational studies report a marked reduction in formation of kidney stones
after successful surgery [1,2]. Furthermore, over a 10-year follow-up period, all
patients with a history of nephrolithiasis who did not choose to have
parathyroidectomy had progression of disease [2]. Thus, a history of
nephrolithiasis is regarded as a clear indication for surgery.
Some patients may have nonspecific symptoms that are difficult to quantify. These
symptoms include fatigue, a sense of weakness, mild depression, and memory
impairment. Because of the largely subjective nature of these symptoms, the
distinction between asymptomatic and symptomatic PHPT is not always clear-cut.
Patients may deny symptoms, whereas a family member may say the patient has
been mildly symptomatic in some way [3-5]. Nonspecific neuropsychiatric
symptoms alone are not indications for surgery. (See 'Neuropsychiatric' below.)
If there are comorbidities, contraindications, or prior unsuccessful neck
explorations that preclude surgery, or if the patient refuses surgery, preventive
measures and adequate monitoring are important. (See 'Preventive
measures' below and 'Monitoring' below.)
In addition, for such patients who are unable to have surgery and whose primary
indication for surgery is symptomatic and/or severe hypercalcemia, (particularly
those in whom bone density is normal), we suggest cinacalcet rather than
bisphosphonates. (See 'Poor surgical candidates' below.)
ASYMPTOMATICAlthough patients with symptomatic PHPT should have
parathyroid surgery, the widespread identification of asymptomatic individuals
raises the question of need for and timing of surgical intervention in this
population [6,7]. In some patients with asymptomatic disease, surgery is not
mandatory. Most asymptomatic patients do not have progression of disease, as
defined by worsening hypercalcemia, hypercalciuria, bone disease, and/or
nephrolithiasis [8]. However, some individuals do progress and would benefit from
surgical cure. The primary goal is to identify the asymptomatic individuals at risk
for disease progression, as well as those who have features of the disease that
may improve following parathyroidectomy. These two groups of individuals would
likely benefit from surgical intervention.
Candidates for surgery — All patients with PHPT are "candidates" for surgery,
which offers the only option for cure of the disease. For asymptomatic individuals
who meet the Fourth International Workshop on Asymptomatic Primary
Hyperparathyroidism guidelines (table 1), we suggest surgical intervention as
opposed to observation [9,10]. Patients need to meet only one of the following
criteria for surgery:
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 ●Serum calcium concentration of 1.0 mg/dL (0.25 mmol/L) or more above the
upper limit of normal
●Skeletal indications
•Bone density at the hip, lumbar spine, or distal radius that is more than
2.5 standard deviations below peak bone mass (T-score <-2.5).
•Previous asymptomatic vertebral fracture (by radiograph, computed
tomography [CT], magnetic resonance imaging [MRI], or vertebral
fracture assessment).
●Renal indications
•Estimated glomerular filtration rate (eGFR) <60 mL/min.
•Twenty-four-hour urinary calcium >400 mg/day (>10 mmol/day). Some
experts suggest that a stone risk profile is a useful adjunct for making a
decision about surgery in those with urinary calcium excretion >400
mg/day, but there are limited to data to support this.
•Nephrolithiasis or nephrocalcinosis by radiograph, ultrasound, or CT.
●Age less than 50 years

Patients with asymptomatic PHPT who do not meet surgical intervention criteria
may still choose parathyroidectomy because it is the only definitive therapy.

These criteria were chosen on the basis of clinical experience and observational
and clinical trial data as to which patients are more likely to have end-organ effects
of PHPT (nephrolithiasis, skeletal involvement) if surgery is deferred and the most
benefit from surgery. The panel emphasized the need for parathyroidectomy to be
performed by surgeons who are highly experienced and skilled in the operation.

Surgery versus nonsurgical management — The debate regarding treatment of

asymptomatic PHPT revolves around the effect of intervention on outcomes, such
as symptoms, bone disease, and biochemical abnormalities. Although
parathyroidectomy improves bone density and may have modest effects on some
quality-of-life symptoms, long-term, observational data and short-term,
randomized trial data clearly demonstrate that a large subgroup of patients with
asymptomatic PHPT can be followed safely without surgery because they do not
have disease progression, as evidenced by stable biochemical abnormalities and
bone mineral density (BMD) for up to a decade of observation [8]. However,
disease may progress (worsening hypercalcemia, hypercalciuria, newly diagnosed
nephrolithiasis) in as many as one-third of patients over the first years of
observation, and these patients would benefit from surgical intervention. In
addition, BMD declines in most patients observed for longer than 8 to 10 years.

884
Although these observational data are based upon a small number of patients,
they do suggest that long-term (>8 to 10 years) observation in asymptomatic
patients is not optimal for skeletal outcomes. (See 'Subclinical bone
disease' below.)
The ability to identify criteria that are predictive of disease progression would
improve management strategies, but these factors (other than age <50 years at
presentation) are as yet unknown. Proponents of surgery for asymptomatic
individuals argue that many untreated patients are lost to follow-up after 5 to 10
years and that the cost of follow-up visits and tests may ultimately exceed the
costs of surgery [11,12]. Some argue that parathyroidectomy is an attractive
strategy for nearly all patients, particularly with recent significant progress in
techniques for minimally invasive surgical extirpation [13,14]. Proponents who
favor nonoperative management for asymptomatic individuals cite the lack of
disease progression in the majority of patients and the ability to treat, if necessary,
with alternative therapies as reasons to avoid an invasive procedure. (See 'Poor
surgical candidates' below.)
Neuropsychiatric — International guidelines do not include neuropsychiatric
symptoms as a specific indication for parathyroidectomy [9,10].
Although only a minority of patients with mild PHPT have the classic symptoms of
the disease (nephrolithiasis or overt bone disease, osteitis fibrosa cystica), many
have nonspecific symptoms. These symptoms include fatigue, a sense of
weakness, mild depression, and memory impairment; their reversal after surgery
in some patients suggests that they were caused by the hypercalcemia or the
hypersecretion of parathyroid hormone (PTH) [15-24]. However, most of the
studies reporting symptomatic improvement were observational and were limited
by selection bias, inclusion of subjects with symptomatic hyperparathyroidism, or
by lack of an adequate control group or validated instruments to describe
neuropsychiatric symptoms.
Randomized trials in PHPT have been difficult to conduct and also have limitations,
including difficulty recruiting asymptomatic patients who will accept
randomization to surgery. Subjects who choose to participate may well differ from
those who decline enrollment, decreasing the generalizability of the results to all
patients with asymptomatic PHPT [25]. In addition, withdrawal rates are high due
to a variety of reasons, including discontent with initial treatment assignment.
Despite these limitations, the results of randomized trials assessing the benefit of
surgery versus observation on neuropsychiatric symptoms in individuals with
asymptomatic PHPT provide important information [26,27].
●Long-term (10 year) data on 120 subjects was reported from a prospective
randomized trial comparing surgery versus no surgery in 191 Scandinavian

885
 patients with PHPT [28]. There was modest improvement in some of the
mental domains of the Short Form 36 (SF-36) quality-of-life scale. Although
these changes were statistically significant, the treatment effects were subtle
and of uncertain clinical significance. Further, there were no significant
differences in the Comprehensive Psychopathological Rating Scale (CPRS)
between the two groups.
●In another trial, 53 of 283 potentially eligible patients (calcium between 10.1
and 11.5 mg/dL [2.52 to 2.87 mmol/L]) agreed to be randomly assigned to
surgery or observation [26,29]. At baseline, mean SF-36 Health Survey scores
were similar to published normals. Those who underwent successful surgery
(traditional neck exploration) had little change in psychosocial functioning
two years later, but there was a significant decline over time in the
observation group. After a median follow-up of 42 months, there was a
significant benefit of surgery compared with no surgery in two of nine
domains of the SF-36 survey (social functioning and emotional problems)
[29].
●In a one-year trial of 50 patients (mean calcium 10.2 mg/dL [2.55 mmol/L])
randomly assigned to observation or parathyroidectomy, there was modest
improvement in some SF-36 quality-of-life domains (bodily pain, general
health, vitality, and mental health) in patients assigned to surgery compared
with observation [27].
Taken together, these short- and long-term randomized trial data suggest minimal
to modest differences in some domains of the SF-36, favoring surgical
intervention. The fact that improvements were noted in differing domains of the
SF-36 in the different trials suggests that individual patients cannot have specific
expectations regarding surgical outcome for neuropsychiatric symptoms. In
addition, the differences were small and of uncertain clinical significance. It should
be noted that while current international guidelines do not include
neuropsychiatric symptoms as a specific indication for parathyroidectomy, more
liberal guidelines were issued by the American Association of Endocrine Surgeons
in 2016 [30]. These guidelines suggest intervention for neurocognitive and/or
neuropsychiatric symptoms that "are attributable to PHPT," although the evidence
supporting this recommendation is of low quality, and no guidance was included
as to how to determine attribution.
Subclinical renal disease — Important subclinical renal manifestations of PHPT
include asymptomatic nephrolithiasis, hypercalciuria, nephrocalcinosis, and
chronic renal insufficiency (see "Primary hyperparathyroidism: Clinical
manifestations", section on 'Subclinical renal disease'). Patients with subclinical

886
renal disease are regarded as having symptomatic disease and are candidates for
surgery, regardless of the absence of symptoms [9].
Most stones in patients with hyperparathyroidism are composed of calcium
oxalate, some have calcium phosphate or mixed calcium phosphate and oxalate. A
contributing factor for stone formation in hyperparathyroidism is hypercalciuria.
However, urinary calcium excretion per gram creatinine does not necessarily
differentiate patients with or without stones, nor does it predict the development
of kidney stones in an individual patient [31]. Nevertheless, most experts believe
that urinary calcium excretion >400 mg/day raises sufficient enough concern
about long-term renal complications to warrant a recommendation for
parathyroidectomy.
Similarly, data are lacking to support a specific threshold of renal impairment at
which parathyroidectomy should be performed. However, limited data showing
that reductions in eGFR can have adverse effects in PHPT and that patients with
eGFR <60 mL/min/1.73 m2 have improved outcomes after surgery, have led to the
recommendation that those with eGFR <60 mL/min/1.73 m2 be referred for surgery
[32,33].
Cardiovascular — Cardiovascular features of classical PHPT include hypertension,
arrhythmia, ventricular hypertrophy, vascular stiffening, and vascular and valvular
calcification. In addition, several studies in Europe have reported increased
cardiovascular morbidity and mortality in patients with otherwise asymptomatic
hyperparathyroidism. (See "Primary hyperparathyroidism: Clinical
manifestations".)
Survival benefit has been demonstrated post-parathyroidectomy in several large,
cohort studies from Sweden and Denmark [34-36]. Similarly, in a Scottish study,
risk of mortality was lower in patients with primary hyperparathyroidism who were
treated surgically versus those who did not undergo surgery [37]. However, in the
largest study published to date, the survival benefit was not observed until 15
years post-parathyroidectomy [35].

The extent to which other cardiovascular findings persist after parathyroidectomy

is unclear. The available data are mostly observational, and definitive evidence for
an improvement in cardiovascular function post-parathyroidectomy is lacking.

●A meta-analysis of 15 studies, including four randomized trials and 457

patients undergoing parathyroidectomy, supported a modest reduction in
left ventricular mass after surgery [38].
●Although hypertension is frequently seen in association with PHPT, even
among those with mild disease, the majority of observational studies indicate

887
 that hypertension is not reversible with surgical cure and should not be used
as an indication for parathyroidectomy [39,40].
There are few randomized trials with cardiovascular endpoints. In a two-year
analysis of a randomized trial of parathyroidectomy versus observation in 116
patients with asymptomatic PHPT, mean arterial and diastolic blood pressure
declined in both groups with no significant difference between groups [41]. There
were also no differences between the two groups in cardiovascular risk factors,
including lipids, adiponectin, leptin, C-reactive protein, or biochemical markers of
endothelial function (eg, vascular cell adhesion molecule 1, Von Willebrand factor).
There were only minor differences in echocardiogram findings in 49 patients in
whom echocardiography was performed (a significant reduction in diastolic
dimension of the interventricular septum and a nonsignificant reduction in left
ventricular mass, both in the parathyroidectomy group) [42]. Although data are
limited, the impact of parathyroidectomy on cardiovascular risk factors has been
mixed [43,44].
Current research is focusing on more subtle abnormalities of the cardiovascular
system. The nature of such involvement and the extent to which any abnormalities
improve postoperatively need to be elucidated before recommending surgery
based upon such considerations [10].
Subclinical bone disease — Patients with asymptomatic hyperparathyroidism
may have decreased BMD, in particular at more cortical sites (forearm and hip) as
compared with more trabecular sites (spine). In addition, observations from large
case-control and cohort studies suggest that there may be increased fracture risk
at vertebral and other skeletal sites. (See "Primary hyperparathyroidism: Clinical
manifestations", section on 'Skeletal'.)
Randomized trials have demonstrated increased BMD following
parathyroidectomy [27,29,41,45]. In one trial, lumbar spine BMD increased in the
surgical group compared with the medical observation group two years after
surgery; spine BMD remained unchanged in the medical group [45]. A similar but
nonsignificant trend was noted at the femoral neck. In another randomized trial,
BMD after two years was slightly better at the femoral neck and total hip (but not
spine) in the surgical compared with the nonsurgical group (group differences of
0.8 and 1.0 percent per year at the femoral neck and hip, respectively) [29].
Significant improvement in BMD post-parathyroidectomy has also been noted in
observational studies [2,46-49]. In one prospective study of a cohort of 121
patients with hyperparathyroidism followed for up to 10 years, there were
substantial increments in BMD of 12 to 15 percent in those who underwent
parathyroidectomy [2]. Most of the increments occurred within the first year at the
lumbar spine and within the first two years at the hip. Importantly, not only bone

888
density improves after parathyroidectomy. Using the noninvasive imaging
technology of high-resolution peripheral quantitative CT, skeletal
microarchitecture and bone strength were both found to improve through two
years after surgery [50].
In most [2,47,48,51-53], but not all [54,55], studies, the initial years of observation
without surgical intervention were not associated with progressive bone loss. In a
15-year follow-up of the prospective cohort study described above, lumbar spine
BMD remained stable in the six patients observed without intervention [8]. In
contrast, BMD started to fall at cortical sites, ultimately decreasing at the femoral
neck and distal radius by 10 and 35 percent, respectively. Although the sample size
after 10 years was limited, these data suggest that nonsurgical management of
PHPT is not a lifelong strategy and requires careful reevaluation in stable patients
after ten years [14,56].
Observational data suggest that fracture risk is decreased after parathyroidectomy
[36,57-62]. A prospective randomized study also suggested a decline in vertebral
fractures following parathyroidectomy (as compared with observation) [63].
There are very limited data from trials directly comparing parathyroidectomy with
medical therapy (eg, bisphosphonates) for the treatment of low BMD [64]. In the
short term, bisphosphonates improve bone density in patients with PHPT.
However, documentation that the bone density benefit is sustained and
accompanied by fracture reduction is lacking (see 'Bisphosphonates' below). PHPT
is a chronic disease, and patients with PHPT and osteoporosis require a long-term
solution. There is concern about the adverse effects of long-term use of
bisphosphonates. For these reasons, surgery remains the treatment of choice for
osteoporotic patients with PHPT. (See "Bisphosphonate therapy for the treatment
of osteoporosis", section on 'Duration of therapy'.)
Biochemical abnormalities — In randomized trials, there is no evidence that
renal function deteriorates in asymptomatic patients followed for two to three
years without surgery, or that it improves in asymptomatic patients who are cured
following parathyroidectomy [29,45,65]. In addition, there is little evidence that
hypercalcemia worsens in the majority of asymptomatic patients followed for two
to three years [29,45]. However, in one trial, 8 percent of asymptomatic patients
randomly assigned to observation developed worsening hypercalcemia requiring
surgery (over a two-year interval) [45].
Observational studies of longer duration (up to 15 years) report similar findings
[39,46,66-68]. Biochemical abnormalities remain stable in the majority, but
patients occasionally become spontaneously normocalcemic during follow-up, and
a small proportion develop worsening biochemical parameters requiring surgical
intervention [2,39,67,68].

889
Among 52 asymptomatic patients followed for up to 10 years, there was no change
in mean serum calcium and PTH concentrations and urinary calcium excretion (or
BMD), but one or more of these measures increased substantially in 14 patients
(27 percent) [2], and after 15 years of observation, 37 percent of patients had
evidence of disease progression [8]. These patients were younger at baseline than
those without disease progression (52 versus 60 years of age), and several became
menopausal during follow-up. Thus, younger age (<50 years) at diagnosis has been
identified as a risk factor for disease progression [69].
Surgical procedure — The goal of parathyroid surgery is excision of the
parathyroid adenoma(s) and thereby biochemical cure of PHPT. The standard
surgical approach for most patients with PHPT had been bilateral neck exploration,
usually under general anesthesia [6]. Bilateral exploration relies on visual and
weight-based estimations of gland size to distinguish a single adenoma from
multiglandular disease. However, with increased experience, improved imaging
modalities, and the use of adjuncts such as intraoperative parathyroid hormone
monitoring (IOPTH), minimally invasive parathyroidectomy (MIP) is emerging as
the procedure of choice in those with positive preoperative localization [30]. The
success of a targeted parathyroidectomy is dependent upon studies that permit
the surgeon to limit the operative field to the region where a single radiologic
focus is identified. (See "Parathyroid exploration for primary
hyperparathyroidism", section on 'Focused parathyroid
exploration' and "Preoperative localization for parathyroid surgery in patients with
primary hyperparathyroidism", section on 'Role of preoperative localization'.)
Nonoperative management — If surgery is not recommended, then it is
appropriate to recommend supportive-preventive measures with adequate
monitoring. Asymptomatic patients who do not undergo surgery require long-
term monitoring for worsening hypercalcemia, renal impairment, and bone loss.
The development of any of these findings indicates disease progression and the
need for surgical intervention. We monitor serum calcium and creatinine annually,
and bone density (hip, spine, and forearm) every one to two years
(see 'Monitoring' below). If disease progression occurs (table 1), we would suggest
surgery, as described above.
Preventive measures — A number of measures should be recommended to
patients who do not undergo surgery, including the following:
●Avoid factors that can aggravate hypercalcemia if possible, including
thiazide diuretic and lithium carbonate therapy, volume depletion, prolonged
bed rest or inactivity, and a high-calcium diet (>1000 mg/day). (See "Diuretics
and calcium balance".)
●Encourage physical activity to minimize bone resorption.

890
 ●Encourage adequate hydration (at least six to eight glasses of water per day)
to minimize the risk of nephrolithiasis.
●Maintain a moderate calcium intake (1000 mg/day) (see "Calcium and
vitamin D supplementation in osteoporosis", section on 'Primary
hyperparathyroidism'). A low calcium diet may lead to further increases in
PTH secretion and could aggravate bone disease [70]. However, in patients
with high serum calcitriol concentrations, the recommended calcium intake
has been shown to exacerbate hypercalcemia or hypercalciuria. Thus,
moderate calcium restriction (eg, <800 mg/day) is probably warranted when
the serum calcitriol concentration is high [71].
●Maintain moderate vitamin D intake (400 to 800 international units daily) to
maintain a serum 25-hydroxyvitamin D (25[OH]D) level of at least 20 or 30
ng/mL (50 or 75 mmol/L). Vitamin D deficiency stimulates PTH secretion and
bone resorption and, therefore, is deleterious in patients with PHPT.
(See 'Concomitant vitamin D deficiency' below.)
Monitoring — Periodic monitoring should be performed for disease progression
and development of indications for surgery (table 1). Measurements of serum
calcium, creatinine, and eGFR annually and bone density (hip, spine, and forearm)
every one to two years is sufficient [9]. While confirmation of the absence of
nephrocalcinosis or silent nephrolithiasis (with radiograph, ultrasound, or CT) at
the time of the original evaluation is recommended by some, routine monitoring
with serial ultrasounds is not [9]. After initial evaluation, if development of a renal
stone is suspected on clinical grounds (eg, flank pain, hematuria), renal imaging
(radiograph, ultrasound, CT) should be repeated. (See "Primary
hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on
'Renal imaging'.)
POOR SURGICAL CANDIDATESFor certain patients who meet surgical
criteria (either due to symptoms or to consensus guideline criteria) but who cannot
or will not have surgery, we prescribe medical therapy in some instances. The
following recommendations are in keeping with the Fourth International
Workshop on Asymptomatic Primary Hyperparathyroidism guidelines [9,72].
●For patients whose primary indication for surgery is symptomatic and/or
severe hypercalcemia, we typically use cinacalcet rather than
bisphosphonates, particularly for those in whom bone density is not in the
osteoporotic range.
●For individuals who are unable to have surgery and whose primary
indication for surgery is osteoporosis and risk for fracture, we suggest
bisphosphonates. Among the bisphosphonates, alendronate has been most
extensively evaluated in patients with PHPT.
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 ●If there is no need to improve bone density or to lower the serum calcium,
we do not use pharmacologic therapy.
Certain medications have been used in patients with PHPT (eg, patients who do
not meet surgical criteria, who are unable to undergo surgery, or who prefer to
avoid surgery), although they are not primarily indicated for this purpose. They
include bisphosphonates, denosumab, and estrogen plus progestin, which inhibit
bone resorption and can increase bone density and possibly lower serum calcium
concentrations in patients with hyperparathyroidism [72]. Other medications, such
as calcimimetics or vitamin D analogues, suppress parathyroid hormone (PTH)
release or counteract the effects of hyperparathyroidism at the level of the PTH
receptor and thereby reduce serum calcium.
Although thiazides may raise serum calcium levels in patients with PHPT [73,74],
low dose thiazides (eg, 12.5 mg daily) have been studied for the treatment of
hypercalciuria in poor surgical candidates [75]. Close monitoring of serum calcium
is required [75].
Bisphosphonates — For patients with PHPT and osteoporosis (or those with low
bone mineral density [BMD] that would warrant intervention) who prefer to avoid
surgery, we suggest bisphosphonates. In the short term (two years), the increases
in BMD with bisphosphonate therapy match those seen after parathyroidectomy
[76]. However, documentation that the bone density benefit is sustained and
accompanied by fracture reduction is needed. In addition, PHPT is a chronic
problem, and there is concern about the adverse effects of long-term use of
bisphosphonates (see "Bisphosphonate therapy for the treatment of
osteoporosis", section on 'Duration of therapy'). Thus, surgery remains the
treatment of choice for osteoporotic patients with PHPT.
Bisphosphonates are potent inhibitors of bone resorption and may be useful to
improve low bone mass in patients with untreated PHPT. In four studies in
which alendronate was given to patients with mild PHPT for one to two years, bone
density increased at the hip and lumbar spine [77-80] (but not radius [80]) as
compared with untreated or placebo-treated patients. As an example, in two of the
studies, lumbar spine BMD increased by 7 to 8 percent and femoral neck BMD by 4
to 5 percent in the treated patients when compared with baseline and/or the
untreated group [77,80]. In two other studies, there were small transient increases
in serum PTH concentrations and small transient decreases in serum calcium
concentrations and urinary calcium excretion in the first months of alendronate
treatment, but the values then returned to baseline for the duration of the two-
year period [78,79].
The influence of prior bisphosphonate use on postsurgical bone density
improvement, should surgery become necessary, is unknown. In studies of

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recombinant PTH for the treatment of osteoporosis, the prior administration of
some bisphosphonate blunts the improvement in BMD attained with PTH alone
(see "Parathyroid hormone/parathyroid hormone-related protein analog for
osteoporosis", section on 'Combination therapy not recommended'). Thus, bone
remodeling is necessary for the intermittent administration of recombinant PTH to
exert its beneficial effects on bone density and fracture prevention.
Calcimimetics — Cinacalcet can be used to normalize serum calcium in patients
with severe hypercalcemia who are unable to undergo parathyroidectomy [72].
●For patients who are unable to have surgery and whose primary indication
for surgery is symptomatic and/or severe hypercalcemia (particularly those in
whom bone density is normal), we suggest cinacalcet rather than
bisphosphonates.
●In such patients, we typically give cinacalcet at a dose of 30 mg twice daily.
●Serum calcium should be measured within one week after initiation or any
dose adjustment.
Calcimimetic agents activate the calcium-sensing receptor in the parathyroid
gland, thereby inhibiting PTH secretion [81]. Functions of the calcium-sensing
receptor are reviewed elsewhere (see "Disorders of the calcium-sensing receptor:
Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia").
Only one calcimimetic drug, cinacalcet, is available for the treatment of secondary
hyperparathyroidism associated with renal failure, for hypercalcemia in
parathyroid cancer, and for the treatment of severe hypercalcemia in patients with
PHPT unable to undergo parathyroidectomy. (See "Parathyroid
carcinoma" and "Management of secondary hyperparathyroidism in adult dialysis
patients", section on 'Calcimimetics'.)
Cinacalcet reduces serum calcium in the majority of patients with PHPT [72,82-86].
As an example, in a one-year trial of 78 patients with PHPT randomly assigned to
cinacalcet or placebo (12-week dose-titration, 12-week maintenance, and 28-week
follow-up phases), cinacalcet therapy normalized serum calcium in 73 percent of
subjects compared with only 5 percent in the placebo group. Serum PTH
concentrations decreased by 7.5 percent with cinacalcet but increased in the
placebo group. BMD was unchanged in both groups, and there was no significant
difference in the 24-hour urinary calcium-creatinine ratio between the two groups
[84]. In an open-label extension study, 45 patients (21 and 24 of those originally
assigned to cinacalcet and placebo, respectively) were treated with cinacalcet (30
to 50 mg twice daily) for up to 4.5 years [87]. Cinacalcet maintained normocalcemia
and reduced PTH in the majority of patients (74 to 92 percent), with no changes in
BMD.

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In a pooled analysis of data from three trials, cinacalcet was equally effective in
reducing serum calcium in patients across a broad spectrum of disease severity
[88].
Side effects most commonly reported included nausea, arthralgia, diarrhea,
myalgia, and paresthesia, occurring in 36, 30, 22, 22, and 22 percent of patients,
respectively, sometimes requiring discontinuation of the medication.
Thus, cinacalcet is not the medical equivalent of parathyroidectomy, because it is
not permanent and there is no improvement in BMD. Furthermore, PTH
concentrations do not normalize, and data are lacking on any salutary effect of
cinacalcet on nephrolithiasis.
Currently, there are no data on the effects of cinacalcet on subtle neuropsychiatric
or cognitive abnormalities in the disease or in patient-reported quality-of-life
outcomes. Thus, cinacalcet is not indicated in patients with mild asymptomatic
PHPT.
Combination antiresorptive agents and cinacalcet — Cinacalcet reduces serum
calcium in the majority of patients with PHPT but does not improve bone density,
whereas the antiresorptive agents improve bone density but do not reduce serum
calcium. There are no randomized trials evaluating the benefits and risks of
combination therapy with alendronate. In small observational studies, treatment
of patients with both drugs improved bone density and reduced serum calcium
levels [72,89,90]. A randomized, placebo-controlled study of cinacalcet
and denosumab in 45 patients (15 placebo-placebo, 16 denosumab-placebo, 14
cinacalcet-denosumab) demonstrated normalization of serum calcium in 64
percent of patients on combination therapy and an increase in spine and hip BMD
in denosumab groups comparison with placebo [91]. Thus, for patients with severe
hypercalcemia and very low bone density who are unable to have surgery,
treatment with both cinacalcet and an antiresorptive agent is an option.
Other medications
●Estrogen-progestin therapy – Although estrogen or estrogen-progestin
therapy reduces bone resorption in postmenopausal women with PHPT, it
should not be a first-line medical therapy for women with PHPT. However,
women with PHPT who choose to take estrogen-progestin therapy for
menopausal symptoms will have the added skeletal benefit. There are
significant risks associated with estrogen-progestin therapy, including
increased risks of breast cancer, stroke, and coronary heart disease.
(See "Menopausal hormone therapy: Benefits and risks" and "Treatment of
menopausal symptoms with hormone therapy".)
Estrogen-progestin therapy is beneficial in postmenopausal women with
PHPT because of its ability to reduce bone resorption. In two trials, serum

894
calcium concentrations decreased by 0.5 to 1.0 mg/dL (0.12 to 0.24 mmol/L)
and bone density increased slightly [92,93]. In a third, larger, randomized,
controlled trial, there was no change in serum calcium or PTH concentrations
with estrogen-progestin therapy [54]. In this trial, 42 women with mild
hyperparathyroidism were randomly assigned to treatment with placebo or
conjugated estrogens (0.625 mg/day) plus medroxyprogesterone acetate (5
mg/day) for two years [54]. Total body and forearm bone density fell by 2.3
and 3.5 percent, respectively, in the placebo group and increased by 1.3 and
3.4 percent, respectively, in the estrogen-progestin group. Lumbar spine and
femoral neck bone density also increased in the latter group. Twenty-three of
the 42 women then participated in an extension study for an additional two
years (total of four years) [94]. The beneficial effect of hormone therapy on
bone density persisted at year 4, with between-group differences in hip,
lumbar spine, and forearm bone density that ranged from 7 to 8.2 percent. In
addition, a small prospective trial suggested that improvements in BMD after
parathyroidectomy are most substantial in a subset of women given
concomitant menopausal hormone therapy (MHT) [95].
There are no data evaluating the effect of estrogen-progestin on fracture risk
in women with PHPT.
●Raloxifene – Raloxifene, a selective estrogen receptor modulator (SERM), is
available in many countries for the prevention and treatment of osteoporosis
(see "Selective estrogen receptor modulators for prevention and treatment of
osteoporosis"). In a short-term study of 18 postmenopausal women with
asymptomatic PHPT, raloxifene (60 mg/day for eight weeks) reduced mean
serum calcium concentration by 0.4 mg/dL at a single time point (eight
weeks) [96]. Further data are needed before recommending raloxifene for
this indication.
●Investigational – Denosumab has been used successfully to treat resistant
hypercalcemia in patients with parathyroid carcinoma, and the drug may
have the potential to improve bone at cortical sites impacted by PHPT. A
retrospective study comparing surgery with denosumab in 39 patients
reported improved BMD with denosumab, although significantly greater
increases were seen with parathyroidectomy (spine 11.2 versus 6 percent
with denosumab; total hip 7.5 versus 3.7 percent) [97]. PTH levels rose in
those treated with denosumab, but calcium levels did not decline. Another
small study demonstrated better BMD response to denosumab in older
females with PHPT compared with older females with osteoporosis but
without PHPT [98]. Further investigation of this drug in PHPT is warranted.
(See "Parathyroid carcinoma", section on 'Denosumab'.)

895
 Drugs on the horizon include calcitriol analogues that inhibit PTH secretion
directly but do not stimulate gastrointestinal calcium or phosphate
absorption [99] and drugs that block the PTH receptor [100,101].
CONCOMITANT VITAMIN D DEFICIENCYDue to the significant
prevalence of vitamin D insufficiency in individuals with PHPT, the Fourth
International Workshop on Asymptomatic Primary Hyperparathyroidism
recommends measuring 25-hydroxyvitamin D (25[OH]D) in all patients with PHPT
and repleting those with low levels (defined as ≤20 ng/mL [50 nmol/L]) [72,102].
Specific repletion recommendations are not available from clinical trial data. Until
such information becomes available, we suggest cautiously repleting vitamin D
(600 to 1000 international units daily) in patients with underlying
hyperparathyroidism, since worsening hypercalcemia and hypercalciuria have
been reported in this setting [103]. We do not favor repletion of vitamin D
deficiency in PHPT using high-dose (50,000 international units) vitamin D
preparations.
Vitamin D deficiency is common in patients with PHPT. Some individuals with
vitamin D deficiency and hyperparathyroidism have more clinically significant
disease. (See "Primary hyperparathyroidism: Clinical manifestations", section on
'Classical'.)
Vitamin D repletion may improve some of the clinical manifestations [104],
although there is concern that repleting vitamin D will worsen hypercalcemia and
hypercalciuria [105]. However, in a systematic review of nine observational studies
(547 patients with hyperparathyroidism and hypovitaminosis D), vitamin D
replacement improved serum 25-hydroxyvitamin D levels, while PTH levels were
unchanged, and there was no worsening of hypercalcemia or hypercalciuria [106].
Furthermore, in a randomized trial of cholecalciferol (2800 international units/day)
versus placebo in 46 patients with PHPT and hypovitaminosis D (mean 25[OH]D
21.6 ng/mL [54 nmol/L]), vitamin D supplementation raised the serum 25(OH)D to
37 ng/mL, while reducing parathyroid hormone (PTH) by 17 percent and improving
lumbar spine BMD [107]. There was no difference between groups in serum or
urinary calcium levels.
Regardless of the vitamin D dose, particular caution must be exercised in those
individuals with vitamin D deficiency whose urinary calcium excretion is in the
upper range of normal or frankly elevated. Once these individuals are vitamin D
replete, their urinary calcium levels can rise quickly, increasing their risk for kidney
stone formation. (See "Vitamin D deficiency in adults: Definition, clinical
manifestations, and treatment", section on 'Coexisting primary
hyperparathyroidism'.)

896
NORMOCALCEMIC HYPERPARATHYROIDISMPatients with
normocalcemic hyperparathyroidism (elevated parathyroid hormone [PTH],
normal serum albumin-adjusted calcium) typically come to medical attention in the
setting of an evaluation for low bone mineral density (BMD). In order to make this
diagnosis, certain conditions must be met. In particular, all secondary causes for
hyperparathyroidism (table 2) must be ruled out, and ionized calcium levels should
be normal. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis,
and evaluation", section on 'Secondary hyperparathyroidism'.)
The natural history of the disorder is unclear, in part because of lack of consistent
definitions for this phenotype, as well as inadequate exclusion of all secondary
causes for hyperparathyroidism. In one prospective study of 37 patients with
normocalcemic hyperparathyroidism, 41 percent developed evidence for
progressive hyperparathyroid disease during a median of three years (range one
to eight years) of observation [108]. However, less than 20 percent of patients
became hypercalcemic during the observation period. Instead, some persistently
normocalcemic patients developed other indications of progressive disease, such
as kidney stones, hypercalciuria, bone loss, and fracture. Furthermore, four
individuals with normal serum calcium levels had successful parathyroid surgery.
There are currently insufficient longitudinal data on patients with this phenotype
of PHPT to support definite guidelines for management. In practice, however,
most patients with symptomatic (ie, kidney stones, overt skeletal involvement)
normocalcemic hyperparathyroidism should undergo parathyroid surgery, as is
recommended for patients with symptomatic PHPT. Patients with asymptomatic
normocalcemic PHPT may develop symptomatic disease and, therefore, require
monitoring for disease progression and development of indications for surgery
(see 'Monitoring' above). Again, in the absence of sufficient data to support
accepted surgical criteria, experts generally consider surgery when one or more of
the current guidelines used in asymptomatic PHPT is met (table 1).
For such patients who meet surgical criteria, we routinely obtain a localization
study with ultrasonography, technetium-99m sestamibi, computed tomography
(CT), or magnetic resonance imaging (MRI) to facilitate unilateral exploration or
minimally invasive surgery. As is true for patients with PHPT, patients with
normocalcemic hyperparathyroidism and negative preoperative localization
studies require bilateral exploration by an experienced parathyroid surgeon
(see "Preoperative localization for parathyroid surgery in patients with primary
hyperparathyroidism", section on 'Negative imaging'). If osteoporosis is the only
indication for surgery, some physicians treat patients who have negative
localization studies with a bisphosphonate rather than surgery.

897
PREGNANCYPHPT is uncommon during pregnancy [109-112]. However,
moderate to severe hypercalcemia during pregnancy may carry significant
maternal and fetal risks. In case reports and case series, maternal presentation
included hyperemesis, nephrolithiasis, recurrent urinary tract infection, and
pancreatitis. Neonatal complications included hypocalcemia and tetany, secondary
to fetal parathyroid hormone (PTH) suppression, preterm delivery, low birth
weight, and fetal demise [110,113]. These outcomes are very uncommon in
pregnancies of patients with mild hypercalcemia.

As in nonpregnant patients, treatment is based upon severity and symptoms, but

consideration of gestational age is also important. When interpreting the severity
of serum calcium elevations in pregnant women, it is important to remember that
total serum calcium declines across gestation, likely due to plasma volume
expansion. The upper limit of normal for total serum calcium is 9.5 mg/dL in
pregnancy. The active, ionized calcium level does not change significantly during a
normal pregnancy.

Surgery during the second trimester is the preferred treatment for symptomatic
patients; however, observation may be appropriate in some circumstances (for
some patients with asymptomatic, very mild hypercalcemia) [114]. In one small
series, surgery was successfully performed in 15 of 16 patients during the third
trimester [115]. In pregnant patients undergoing minimally invasive parathyroid
surgery (MIP), localization is done with ultrasound rather than sestamibi. If a
woman with diagnosed PHPT plans a pregnancy, parathyroidectomy should be
done prior to conception. If a patient is followed through her pregnancy with very
mild hypercalcemia, it is important to alert neonatologists to the possibility of
hypocalcemia in the newborn (due to possible suppression of the fetal parathyroid
gland).
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Primary hyperparathyroidism".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are

898
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topic (see "Patient education: Primary hyperparathyroidism (The

Basics)")
●Beyond the Basics topic (see "Patient education: Primary
hyperparathyroidism (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Symptomatic primary hyperparathyroidism – Patients with symptomatic
primary hyperparathyroidism (PHPT) (nephrolithiasis, symptomatic
hypercalcemia) should have parathyroid surgery, which is the only definitive
therapy. Parathyroidectomy is an effective therapy that cures the disease,
decreases the risk of kidney stones, improves bone mineral density (BMD),
and may decrease fracture risk and modestly improve some quality-of-life
measurements. (See 'Symptomatic' above.)
●Asymptomatic primary hyperparathyroidism – Surgical guidelines for
asymptomatic PHPT have been developed based upon risk for end-organ
effects and disease progression, as well as upon data regarding likelihood of
improvement after surgery. Parathyroidectomy should be performed only by
surgeons who are highly experienced and skilled in the operation.
(See 'Asymptomatic' above.)
•For asymptomatic individuals who meet the Fourth International
Workshop on Asymptomatic Primary Hyperparathyroidism guidelines
(table 1), we suggest surgical intervention as opposed to observation
(Grade 2C). (See 'Candidates for surgery' above.)
•For asymptomatic individuals who do not meet surgical criteria, we
monitor serum calcium and creatinine annually and bone density (hip,
spine, and forearm) every one to two years (see 'Monitoring' above). If
disease progression occurs (table 1), we would proceed to surgery, as
described above.
Patients with asymptomatic PHPT who do not meet surgical intervention
criteria may still choose parathyroidectomy because it is the only definitive
therapy.
●Poor surgical candidates – For patients who are unable to have surgery
and whose primary indication for surgery is symptomatic and/or severe
899
hypercalcemia or osteoporosis and high risk for fracture, we recommend
medical therapy rather than observation (Grade 1B). If there is no need to
improve bone density or to lower the serum calcium, we do not use
pharmacologic therapy. (See 'Poor surgical candidates' above.)
•For such patients who are unable to have surgery and whose primary
indication for surgery is symptomatic and/or severe hypercalcemia
(particularly those in whom bone density is normal), we
suggest cinacalcet rather than bisphosphonates (Grade 2B).
(See 'Calcimimetics' above.)
•For individuals (symptomatic or asymptomatic) who are unable to have
surgery and whose primary indication for surgery is osteoporosis and risk
for fracture, we suggest bisphosphonates (Grade 2B).
(See 'Bisphosphonates' above.)
●Concomitant vitamin D deficiency – For individuals with PHPT and
concomitant vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL
[50 nmol/L]), we suggest vitamin D repletion (Grade 2C). In such individuals,
monitoring of serum and urine calcium to identify worsening hypercalcemia
and/or hypercalciuria is necessary. (See 'Concomitant vitamin D
deficiency' above.)

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