Current Problems in Surgery 53 (2016) 212–217

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Current Problems in Surgery

journal homepage: www.elsevier.com/locate/cpsurg

In Brief
Lee F. Starker, MD, PhDa, Peter A. Prieto, MD, MPHa,
J. Spencer Liles, MDb, Hop S. Tran Cao, MDc,
Elizabeth G. Grubbs, MD, MSa, Jeffrey E. Lee, MDa,
Nancy D. Perrier, MDa, Paul H. Graham, MDa,n

Endocrine incidentalomas

The practice of endocrine surgery involves specialized management of benign and malignant
disorders of the thyroid, parathyroids, adrenals, and endocrine pancreas. The routine use of
laboratory testing and diagnostic imaging in the contemporary practice of medicine bring many
of the diseases of the endocrine system to the attention of the clinician before the development
of any clinical symptoms. The discovery of an asymptomatic adrenal nodule is commonly
referred to as an adrenal incidentaloma, and like adrenal pathology, many of the other endocrine
disorders could be similarly labeled as endocrine incidentalomas. Much of the modern day
practice of endocrine surgery involves the evaluation of these incidental findings to determine
which patients may benefit from operative management.
The most common surgically managed incidental endocrine disorder encountered is the
thyroid nodule. Thyroid nodules are ubiquitous in the general population, and they are
commonly discovered on physical examination as well as increasingly by a variety of diagnostic
imaging modalities. The main consideration during the evaluation of the incidental thyroid
nodule is the exclusion of a thyroid carcinoma from the more common benign nodule. The
prevalence of thyroid carcinoma has increased over the past decades and is now the fifth most
common malignancy in women, making the proper evaluation of an incidental thyroid nodule
essential.

From the a Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX; b University
of South Alabama, Mobile, AL; and c Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine,
Houston, TX; n Address reprint requests to Paul H. Graham, MD, MPH, Department of Surgical Oncology, University of
Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1484, Houston, TX 77030.
E-mail address: phgraham@mdanderson.org (P.H. Graham)

http://dx.doi.org/10.1067/j.cpsurg.2016.04.002
0011-3840/& 2016 Published by Elsevier Inc.

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The initial step in the assessment of an incidental thyroid nodule is determining whether the
nodule is functional, or autonomously overproducing thyroid hormone, as this provides
important information regarding the overall risk of malignancy. Measurement of serum thyroid
function tests, including thyroid stimulating hormone (TSH) and free thyroxine (T4) levels,
provides a quick assessment of hormonal status. A TSH level suppressed to below normal limits
is consistent with biochemical hyperthyroidism and can be the result of diffuse thyroid
hyperfunction, solitary toxic adenomas, or toxic multinodular goiters. Radioiodine thyroid
scintigraphy is used to differentiate between unifocal and diffuse sources of hyperfunction, as
well as to identify separate nonfunctioning “cold” nodules that may warrant further diagnostic
evaluation. Thyroid nodules demonstrating autonomous hormone production typically carry a
low risk of harboring a thyroid malignancy. Additional measurement of thyrotropin receptor
antibodies or thyroid stimulating immunoglobulins can help distinguish between different
forms of autoimmune thyroiditis and toxic multinodular goiters. Therapy is then directed toward
the identified source of hormone excess, with surgical resection commonly performed for
solitary toxic adenomas and toxic goiters. Graves thyrotoxicosis is treated with antithyroid
medications, radioactive iodine ablation, or surgery. The particular modality is dependent on
patient comorbidities (ie, ophthalmopathy and pregnancy), response to prior treatment (eg,
neutropenia and elevated liver transaminases), and preference.
Incidental thyroid nodules discovered in the setting of normal to high TSH levels require
further diagnostic evaluation to assess their malignant potential. Ultrasound is the imaging
modality of choice to characterize nonfunctioning thyroid nodules. Certain sonographic features
are common to primary thyroid carcinomas, including increased nodular size, hypoechogenicity
in comparison to the surrounding thyroid parenchyma, hypervascularity, and the presence of
calcifications or irregular margins. When seen in combination, these features can infer up to a
97% risk of malignancy. A sonographic evaluation also provides an opportunity to fully stage the
adjacent central and lateral neck compartments for any lymphadenopathy concerning for
locoregional metastasis.
Thyroid nodules displaying any of the earlier suspicious features warrant diagnostic
evaluation by tissue biopsy. Because nodules in the incidental setting are unlikely to be
palpable, ultrasound-guided fine-needle aspiration (FNA) is the diagnostic procedure of choice.
Diagnostic categorization of aspirate samples is according to the classification scheme provided
through the 2007 National Cancer Institute Thyroid FNA State of the Science Conference. The
diagnostic spectrum spans from benign to malignant categories, with indeterminate cytologic
categories (atypical cells of undetermined significance, follicular lesion of undetermined
significance, follicular neoplasm, and suspicious for malignancy) inferring variable risks of
harboring thyroid malignancy. Separate molecular testing of FNA samples can be performed to
further classify the risk of malignancy in indeterminate nodules and avoid unnecessary
diagnostic surgery. Various proprietary point mutation and gene fusion panels are used to test
for common mutations specific to thyroid carcinoma and may be helpful to rulein malignancy.
Alternatively, samples assessed for recognizable patterns on messenger RNA gene expression
panels help rule out malignancy. Both techniques are commercially available to clinical providers,
and the results of the molecular testing should be interpreted in conjunction with the clinical
setting, imaging characteristics, and cytopathology results to guide management decisions.
Surgical management of the thyroid nodule is dependent on clinical symptoms, imaging
characteristics, and cytology results. Interval repeat biopsy or thyroid lobectomy should be
considered following nondiagnostic biopsies to render a definitive diagnosis. Clinically
symptomatic benign nodules or those with significant interval growth during surveillance
warrant consideration of excision. Indeterminate thyroid nodules should undergo repeat FNA
with or without molecular marker testing or proceed directly to diagnostic thyroid lobectomy.
Patients with low-risk indeterminate cytology and no clinical risk factors can be considered for
serial surveillance without resection, but short-interval surveillance is recommended. Malignant
cytology should prompt appropriate staging and surgical evaluation. Total thyroidectomy is the
standard treatment of thyroid carcinoma, although lobectomy may be sufficient treatment of
unifocal carcinomas smaller than 4 cm in size lacking specific risk factors such as a first-degree

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214 L.F. Starker et al. / Current Problems in Surgery 53 (2016) 212–217

family history of thyroid carcinoma or personal history of radiation therapy to the head and
neck. The extent of resection is dependent on clinical risk factors, nodule size, imaging
characteristics, the presence of any suspicious lymphadenopathy, histologic variant, and patient
and surgeon preference.
Continued surveillance is recommended for benign thyroid nodules, although the risk of
malignant transformation is considered to be less than 2%. A repeat ultrasound is typically
performed 6-12 months following the initial evaluation, after which surveillance intervals can be
extended to 2-5 years for stable and benign nodules. Most of the thyroid nodules would
demonstrate some growth over time, but significant interval growth would be considered to
include those nodules with an interval increase in volume of 50% or more. Substantial growth or
the development of new suspicious sonographic features warrants repeat FNA or excision.
Primary hyperparathyroidism (PHPT) is one of the most common etiologies of hypercalcemia.
It is often discovered incidentally on routine biochemical testing and predominately affects
women in the fifth and sixth decades of life. PHPT is caused by excess parathyroid hormone
(PTH) secretion by 1 or more abnormal parathyroid glands despite normal to high serum
calcium levels. Over time, the persistently elevated serum calcium and PTH levels can lead to
multiple deleterious, systemic effects. Because PHPT is potentially curable by surgical
intervention, accurate diagnosis, and management of the disease are paramount.
The differential diagnosis of hypercalcemia is extensive, and common etiologies to be
excluded in the evaluation of PHPT include hypercalcemia of malignancy, excessive calcium
intake or milk-alkali syndrome, calcium-altering medications (ie, lithium and thiazide
diuretics), and inherited hypercalcemic disorders (ie, familial hypocalciuric hypercalcemia).
True PHPT is diagnosed by an intact PTH level above the upper limit of assay in the
setting of normal to high serum calcium levels. It should be distinguished from multiple
secondary causes of hyperparathyroidism, in which high levels of PTH may be an appropriate
response to common disorders such as calcium malabsorption, vitamin D deficiency, or chronic
kidney disease.
Parathyroidectomy should be considered for all cases of symptomatic PHPT, but often the
incidental biochemical diagnosis precedes many of the clinical manifestations of the disease that
would otherwise bring a patient to medical attention. The classic constitutional, neuropsychia-
tric, renal, and skeletal abnormalities of PHPT may be absent or nonspecific at the time of initial
diagnosis, necessitating evaluation for separate objective factors to identify those asymptomatic
individuals for whom parathyroidectomy may be beneficial. These factors, as described through
expert consensus guidelines from the International Workshop on Asymptomatic Primary
Hyperparathyroidism, include serum calcium levels greater than 1 ng/dL above the upper limit
of assay, age younger than 50 years, a history or presence of nephrolithiasis or nephrocalcinosis,
24-hour urinary calcium levels greater than 400 mg, estimated glomerular filtration rate less
than 60 mL/min, radiographic evidence of an atraumatic vertebral fracture, or bone density
measurements consistent with osteoporosis. Those patients meeting any of the earlier criteria
should be evaluated for surgery.
The standard approach to parathyroid surgery has traditionally been a bilateral cervical
exploration with visual comparison of all parathyroid glands for identification and resection of
any abnormal gland(s). Because the majority of cases of PHPT are the result of the adenomatous
transformation of a single parathyroid gland, a focused surgical approach is feasible in many
cases. A minimally invasive parathyroidectomy uses preoperative imaging to localize abnormal
parathyroid glands for a targeted surgical approach with minimal neck dissection. This
localization is achieved by the use of multiple specialized, preoperative imaging studies,
including ultrasound, sestamibi scintigraphy, and multiphase computed tomography (CT).
Additionally, the incorporation of serial intraoperative PTH (ioPTH) assays into the operative
management helps confirm successful resection of all hyperfunctioning parathyroid glands with
up to 97% accuracy when 10-minute postexcision ioPTH levels appropriately decrease by at least
50% from preincision baseline values. The traditional bilateral cervical approach is used for cases
with nonlocalizing imaging, failure of ioPTH levels to appropriately correct, multigland disease,
or surgeon preference.

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Surgical cure of PHPT is determined by return of normal systemic calcium balance. Persistent
hyperparathyroidism occurs when calcium levels fail to normalize within 6 months of
parathyroidectomy and is most commonly the result of incomplete resection of all
hyperfunctioning parathyroid tissue. Return of PHPT after at least 6 months of normal calcium
balance is most consistent with recurrent disease from residual parathyroid tissue. In either
situation, the biochemical diagnosis should be reconfirmed, and the potential benefit of any
reoperative surgery weighed against the increased risks of recurrent laryngeal nerve injury and
permanent hypoparathyroidism. Patients demonstrating appropriately sustained eucalcemia
following parathyroidectomy should be monitored long term with annual calcium screening.
An adrenal incidentaloma is an adrenal lesion larger than 1 cm in size identified
unexpectedly on imaging studies obtained for separate indications. Adrenal nodules are present
in up to 10% of the general population and are commonly identified by routine abdominal
imaging. Most of the adrenal incidentalomas are benign, lipid-rich adrenocortical adenomas that
require no surgical intervention, but a small portion consist of hormonally functional tumors,
adrenocortical carcinomas (Acc), or extra-adrenal metastases. A thorough biochemical
assessment and imaging characterization are therefore needed to distinguish between
nonsurgical and surgical adrenal pathology.
Functional tumors of the adrenal gland can affect any level of the adrenal cortex or medulla.
Excess production of serum aldosterone, cortisol, androgens, or catecholamines can lead to a
variety of clinical manifestations among patients, but in the incidental setting, hormonal excess
may be identified solely through biochemical screening. As a result, a full baseline adrenal
biochemical assessment should be performed to identify subclinical functional tumors.
Any hormone abnormality identified on the initial screening panel may require further
confirmatory testing. Hypercortisolism because of a cortisol-producing adenoma is identified by
abnormal results on at least 2 of 3 screening studies, including overnight dexamethasone
suppression tests, midnight salivary cortisol levels, and 24-hour urinary cortisol levels. Primary
hyperaldosteronism is confirmed most commonly by 24-hour urine aldosterone concentrations
following 3 days of oral salt loading or by serial serum aldosterone levels following intravenous
isotonic saline infusion. Additionally, adrenal venous sampling is regularly performed following
biochemical confirmation of primary hyperaldosteronism to distinguish between bilateral and
unilateral sources of aldosterone excess, even in the setting of a unilateral adrenal nodule. Both
plasma and urine metanephrines are used to diagnose pheochromocytomas with high
sensitivity and specificity, but indeterminate results can be confirmed through clonidine-
suppression testing.
In addition to determining hormonal status, the malignant potential of an adrenal
incidentaloma should be assessed. An incidentaloma’s specific imaging phenotype provides
valuable information regarding the risk of malignancy. A feature linked to the risk of malignancy
is the overall size of the adrenal lesion. Lesions larger than 4 cm in greatest dimension
demonstrate a greater than 90% sensitivity for adrenocortical carcinoma, and resection of lesions
larger than 4 cm is commonly practiced to exclude malignancy. Large lesions should not be
presumed malignant though as absolute size carries a lower specificity for malignancy.
Conversely, a benign nature is not implicit for lesions smaller than 4 cm in size as multiple cases
of small ( o4 cm) carcinomas have been reported in the literature.
Instead, further information should be gleaned from an adrenal mass specific imaging study
of the adrenal mass. CT is the predominant imaging modality used for assessing adrenal
incidentalomas and provides particularly useful information on multiphase imaging. Benign
adrenal lesions typically demonstrate well-demarcated, rounded borders, homogenous
densities, and low ( o10) Hounsfield units on unenhanced CT phases. Additionally, delayed CT
phases typically demonstrate more than 50% intravenous contrast washout at 10 minutes.
Suspicious adrenal tumors (eg, ACC, pheochromocytomas, and metastases) demonstrate
hypervascularity, heterogenous texture, higher 410 Hounsfield units on unenhanced phases,
and o 50% intravenous contrast washout at 10 minutes.
The decision to pursue resection of an incidentaloma is based predominantly on the
hormonal status and concerning imaging features of the lesion and less on an actual tissue

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216 L.F. Starker et al. / Current Problems in Surgery 53 (2016) 212–217

diagnosis. Routine biopsy of an adrenal mass is not routinely performed because the results
often do not change the necessary course of management. An exception is in the setting of a
patient with a concurrent or prior history of an extra-adrenal malignancy at risk for adrenal
metastasis, where identification of extraadrenal tissue in an adrenal mass may appropriately
stage the patient and determine a nonsurgical course of management. Importantly, a
pheochromocytoma should be excluded before any biopsy of an adrenal mass to prevent the
possible complications of an adrenergic crisis.
Most of the adrenal incidentalomas can be excised by laparoscopic approaches. Minimally
invasive techniques, including transabdominal and retroperitoneal approaches, have beneficial
effects in postoperative pain, blood loss, length of hospitalization, and postoperative mobility
over open techniques, but their use in resection of lesions concerning for primary carcinomas
raise concern for tumor spillage and positive resection margins. Open resection remains the gold
standard for surgical treatment of adrenocortical carcinoma and demonstrates superior
recurrence-free and overall survival rates.
Adrenal incidentalomas lacking a surgical indication at the initial evaluation should be
followed for interval growth or the development of autonomous hormone production. The
optimal interval and duration of surveillance are unknown, but common practice includes repeat
abdominal imaging at 3-6 months, and then annually for 1-2 years. Repeated biochemical
assessment is recommended annually for 5 years. Incidentalomas with little or no concern for
malignancy, such as myelolipomas, simple cysts, and hematomas, do not require extended
surveillance.
Pancreatic incidentalomas encompass a wide variety of benign and malignant cystic and solid
pancreatic tumors, as well as various nonneoplastic processes. Pancreatic neuroendocrine
tumors (PNETs) and pancreatic adenocarcinoma comprise most of the solid incidentalomas, and
distinguishing between the entities is important for proper management. PNETs can also be
classified as functional and nonfunctional tumors based on the presence of excess endogenous
hormone production. In the incidental setting, patients are likely not to demonstrate any of the
clinical manifestations of a functional tumor, but an evaluation for symptoms of hormonal
excess is nevertheless important. Functional tumors of the pancreas include gastrinomas,
insulinomas, glucagonomas, vasoactive intestinal polypeptide-producing tumors, and somatos-
tatinomas. The initial laboratory assessment should target their respective hormones, as well as
chromogranin A levels, which are elevated in at up to 60% of PNETs. Other distinguishing
laboratories include CA19-9 and IgG-4, which may help differentiate pancreatic adenocarcinoma
and autoimmune pancreatitis respectively.
High-resolution cross-sectional imaging is an essential component of the diagnostic
evaluation of pancreatic incidentalomas. Pancreatic triple-phase CT imaging helps discern
among pancreatic lesions by their enhancement through noncontrasted, arterial, and venous
phases. PNETs tend to be well-vascularized tumors and enhance throughout the multiple
imaging phases. In comparison, pancreatic adenocarcinomas are typically hypovascular tumors
and appear less intense relative to the background parenchyma. In cases of small tumors or
equivocal contrast enhancement, other modalities including magnetic resonance imaging,
octreotide scintigraphy, and position emission tomography imaging can be helpful in describing
PNETs and evaluating for metastases.
Endoscopic ultrasound (EUS) is another important modality in the evaluation of pancreatic
incidentalomas, both for imaging characterization and tissue acquisition. EUS can provide
further information regarding vascular invasion and nodal involvement of pancreatic lesions.
Additionally, EUS-guided FNA can acquire tissue to help distinguish between various benign and
malignant lesions when imaging is equivocal. Biopsy samples can be sent for additional testing
including flow cytometry and Ki-67 assessment to further characterize tumor type and behavior.
The clinical behavior of PNETs is highly variable and often difficult to predict. The spectrum of
behavior is dependent on factors such as functional status, size, local invasion, lymph node
involvement, metastases, and association with various genetic syndromes. Malignant potential is
also denoted by nuclear mitotic count or Ki-67 activity. These features help determine the
appropriate surgical approach and extent of resection. The goal of surgery is for complete

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resection of the PNET while preserving sufficient pancreatic tissue for normal exocrine and
endocrine function. Traditional surgical approaches include pancreaticoduodenectomy, distal
pancreatectomy (with and without splenic preservation), and total pancreatectomy and are used
for tumors that are large (4 2 cm), locally advanced, involve the main pancreatic duct, or have
evidence of locoregional or liver metastases. Pancreas-sparing resections, including enucleation,
are appropriate for small functional tumors of low malignant potential, which do not involve the
main pancreatic duct. Enucleation of nonfunctional PNETs smaller than 2 cm in size without
overt malignant features is more debated as these tumors still carry a measurable risk of lymph
node metastases. Observation alone for nonfunctioning sporadic PNETs smaller than 2 cm in size
can be considered, particularly those which are stable on serial imaging, identified in elderly
patients or with limiting medical comorbidities, and with low Ki-67. Nonresectable advanced
disease can be managed by multiple adjuvant modalities including ablative techniques,
embolization, somatostatin analogs, molecularly targeted therapy (mechanistic target of
rapamycin and tyrosine kinase inhibitors), and systemic chemotherapy.

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