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THYROID
Volume 22, Number 3, 2012
Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2010.0154
Background: Although clinically evident metastases of nonthyroid malignancies (NTMs) to the thyroid gland are
uncommon, it is important to suspect them in patients who present with a new thyroid mass and a history,
however far back, of prior malignancy. In fact, metastases from NTMs to the thyroid gland have been reported in
1.4%3% of all patients who have surgery for suspected cancer in the thyroid gland. Here we review the
literature over the last decade regarding this topic.
Summary: Based on recent literature, the most common NTMs that metastasize to the thyroid gland are renal cell
(48.1%), colorectal (10.4%), lung (8.3%), and breast carcinoma (7.8%), and sarcoma (4.0%). Metastases of NTMs to
the thyroid are more common in women than men (female to male ratio = 1.4 to 1) and in nodular thyroid glands
(44.2%). The mean and median intervals between diagnosing NTMs and their metastases to thyroid gland are
69.9 and 53 months, respectively. In 20% of cases the diagnosis of the NTM and its metastases to the thyroid was
synchronous. Recent reports indicate that there is a higher frequency of sarcoma metastasizing to the thyroid
gland than reported in prior years. Fine-needle aspiration biopsy (FNAB) of thyroid masses is useful in diagnosis
of thyroid metastases. However, this requires information about the NTM so that the proper antibodies can be
used for immunohistochemical analysis; therefore it is of lesser utility if the NTM is occult. In patients with
preexisting thyroid pathology the FNAB diagnosis can be more difficult due to more than one lesion being
present.
Conclusions: It is important to keep in mind that the thyroid gland can be a site of metastases for a variety of
tumors when evaluating a thyroid nodule, especially in a patient with a prior history of malignancy. In patients
with thyroid lesions and a history of malignant disease, regardless of time elapsed since the initial diagnosis of
the primary neoplasm, disease recurrence or progression of malignancy must be considered until proven
otherwise.
Introduction
258
259
Sources of metastases to the thyroid gland
The most frequently reported (n = 180) NTM was RCC.
Following RCC, the next most common NTMs were colorectal, lung, and breast carcinoma (see Supplementary Table S2)
(712,15110). Melanoma is another common malignancy that
can metastasize to the thyroid gland. The same number of
melanoma (n = 15) and sarcoma (n = 15) cases metastasizing
to the thyroid gland were reported, each accounting for
4.0% of metastases from NTMs to the thyroid gland in the last
decade. There were isolated reports of various cancers, including urothelial sarcomatoid, bladder cancer, endometrial
adenocarcinoma and carcinosarcoma, neuroendocrine cancers, meningioma, gastrointestinal stromal tumor, intraductal
papillary-mucinous carcinoma of the pancreas, ovarian cancer,
undifferentiated carcinoma of the nasopharynx, testicular seminoma, and uterine carcinoma metastasizing to the thyroid gland.
Interval between primary diagnosis
and thyroid metastases
Metastases of primary tumors can be divided into two categories: synchronous and metachronous. Synchronous indicates that the tumors are detected at the same time as the
thyroid metastases whereas metachronous indicates that the
thyroid metastases are detected some time after the NTM was
first noted. Thyroid metastases can present decades after
initial diagnosis and treatment for a NTM, making diagnosis
of metastases to the thyroid gland even more difficult. The
recent literature reflects this, with the longest interval being 21
years between the initial diagnosis of foregut neuroendocrine
carcinoma and metastases to the thyroid gland (20). In another patient, metastases of liposarcoma to the thyroid occurred more than 20 years after the initial diagnosis (21). In
our review we noted 261 cases of metachronous metastases;
the mean interval between discovery of the primary tumor
and the thyroid metastases was 69.9 months (5.8 years) and
the median was 53 months, or 4.4 years. In other reviews,
mean disease-free intervals of 6.8, 9.4, 10.3, and < 2 years were
noted (9,10,17,18). Regarding synchronous metastases, there
were 69 cases (20.9%) of synchronous diagnosis of the NTM
and their thyroid metastases. In some of these cases, discovery
of the thyroid metastases led to diagnosis of the primary
malignancy. NTMs that presented synchronously with thyroid metastases are shown in Table 1. The most common of
these was RCC. In some reports the primary malignancy was
very advanced when diagnosed.
The interval between diagnosing NTMs and discovering their metastases to the thyroid gland was longest in
patients with sarcomas (mean 75 months) and shortest in
patients with lung cancer (mean 4.5 months). Table 2 indicates that the mean intervals between when NTMs were
discovered and when thyroid metastases were noted was
68 months for RCC, 48.2 months for breast cancer, 41.5
months for colorectal cancer, and 20.9 months for malignant melanoma.
Metastases to abnormal thyroid glands
Most of the literature does not indicate whether there were
coexisting or preexisting thyroid conditions in cases of metastases of NTM to the thyroid. Of the 156 cases in which this was
indicated there were 69 (44.2%) in which thyroid metastases
260
CHUNG ET AL.
Table 1. Nonthyroid Malignancies Presenting
Synchronously with Secondary Metastasis
to the Thyroid Gland
Primary malignancy
References
RCC
25
Lung
Colorectal
Melanoma
Esophageal SCC
Cholangioca
Bronchial carcinoid
Breast
Unknown digestive
Other and unknown
Total
15
5
3
3
2
2
2
2
10
69
(9,11,17,18,3941,115,116),
this study
(7,9,11,22,39,4245)
(7,9,24,27,46,112)
(9,32,47)
(39,118)
(39,48)
(49,50)
(15,55)
(9)
(7,9,35,51,85,117,119)
Interval
(months)
References
68
41.5
4.5
48.2
75
20.9
(8,9,17,25,39,41,5365,115117)
(12,23,24,27,39,46,6673,112)
(7,14,22,39,43,53,76)
(8,11,15,19,39,53,7780,116)
(11,21,38,39,5054)
(11,29,32,47,53,7375)
36.3
(18,68,81)
a
Leiomyosarcoma (n = 6), liposarcoma (n = 4), malignant adenomyoepithelioma (n = 1), malignant fibrous histiocytoma (n = 1),
phyllodes tumor (n = 1), intimal sarcoma (n = 1), and paraganglioma
(n = 1).
Follicular adenoma(s)
Other thyroid nodule
Goiter
Multinodular goiter
15
10
26
8
23
9
1
5
2
1
2
6
86
219
References
(15,17,2527)
(3136)
(2730,111114),
this study
(6,16,17,24,3739)
(29)
(6,7,23,78,83)
(59,115)
(62)
(16,84)
(17,28)
261
and histological examination of the specimen revealed metastatic deposits within the gland (24,28). Sixty patients were
incidentally found to have thyroid metastases via screening
exams such as screening or staging positron emission tomography (PET) scans, computed tomography (CT) scans,
Octreoscan (82), or neck ultrasound. In the two cases presented later, the first presented with symptomatic dysphagia
and the second by staging CT.
FNAB in diagnosis of thyroid metastases
FNAB has become an important and useful tool in diagnosis of thyroid pathology, including diagnosis of malignant
metastases to the thyroid gland. However, FNAB may not
yield a definitive diagnosis in all cases. Of the 167 patients
who underwent preoperative FNAB there were 123 cases
(73.7%) where this yielded the correct diagnosis of thyroid
metastases. In the 40 cases (24.0%) where the FNAB diagnosis
was incorrect, primary thyroid malignancy was the diagnosis
in 13 patients, benign follicular nodule in 7 patients, normal
thyroid in 14 patients, and inconclusive in 6 patients. There
were a few cases of concomitant primary thyroid malignancy
and metastases of NTM to the thyroid. In these FNAB diagnosed the primary thyroid malignancy but not the metastases
to the thyroid. In one study there was a patient in whom
FNAB had to be repeated five times before the correct diagnosis was established.
As shown in Table 4, the most common NTMs for which
FNAB or their thyroid metastases did not make the correct
diagnosis were esophagus (50%), cervix (33%), RCC (28.5%),
and malignant melanoma (20%). NTMs for which thyroid
FNAB generally provided the correct diagnosis were breast
(94.7%), lung (90.1%), colorectal cancer (88.5%), and sarcoma
(87.5%). As noted, thyroid metastases from squamous cell
carcinoma of the esophagus were especially difficult to diagnose by FNAB. One report described a patient, with esophageal cancer with metastases to the thyroid gland, who was
incorrectly diagnosed as having a primary pure squamous
cell carcinoma of the thyroid, a very rare condition.
Immunohistochemistry (IHC) is usually able to differentiate between primary thyroid malignancy and secondary
malignancy. Thyroglobulin antibody staining is particularly
useful, except in certain cases of anaplastic thyroid cancer (81).
Immunostaining of a thyroid mass, especially if traditional
histopathology is equivocal, is especially important in the
patient with known history of malignancy. In this setting the
appropriate antibodies can be selected for IHC based on
References
RCC
Colorectal
Breast
Sarcoma
Lung
Melanoma
Esophagus
Cervix
42
26
19
8
11
5
4
3
71.4
88.5
94.7
87.5
90.9
80
50
66
28.6
11.5
5.3
12.5
9.1
20
50
33
(8,9,18,25,33,3941,6165,81,8587,117)
(12,24,27,39,46,56,6773,8892,112)
(8,15,19,39,7779,93,94)
(30,34,38,39,50,54,95,111)
(7,22,36,39,42,45,57,96,124)
(52,71,79,97,124)
(39,46)
(19,39)
262
from 2000 to 2010, there was a female sex predominance of
1.4:1. We also noted that the mean age of presentation was 59
years. This is younger than reported in most of the past retrospective chart studies. Given that the majority of our cases
were reported in the form of case reports and that malignancy
and metastases are unusual in younger patients, it is possible
that there was a bias toward reporting younger patients
which would skew downward the mean age of presentation
that we calculated.
RCC was responsible for almost half (i.e., 48.1%) of metastases of NTMs to the thyroid gland in the past decade, confirming that RCC is the most common extra-thyroidal cancer
to metastasize to the thyroid gland. Similarly, in recent reports, lung, colorectal, and breast carcinomas were the next
most common extra-thyroidal cancers that metastasized to the
thyroid. This is also consistent with earlier studies. Melanoma, esophageal carcinoma, and stomach carcinoma are also
relatively prominent among extra-thyroidal cancers that metastasize to the thyroid (39). The biggest contrast between the
earlier and more recent literature was for sarcomas. We
identified 15 cases of sarcoma metastasizing to the thyroid
gland in the literature of the past decadethis represented 4%
of metastases of NTMs. In contrast, earlier studies did not
report sarcoma to be a common NTM metastasizing to the
thyroid gland (2,4,6,125). The true rate for sarcomas was
previously thought to be underestimated by 50% because
tabulations in the early versions of the population-based databases only included sarcomas arising in soft tissues, but not
those arising in specific organs such as the skin and organ sites
(126,127). The higher number of sarcomas in the last decade
may be attributed to the recent shifts in the World Health
Organization diagnostic criteria and classification of soft tissue sarcomas (114). Further, the use of modern diagnostic
techniques, increase in number of radiation treatments, and
greater awareness may account for the higher than previously
reported cases of sarcomas.
The time to detection of thyroid metastases after the primary
tumor diagnosis was variable in our review, but was often long,
similar to the earlier literature. We noted, however, short intervals between diagnosis of the primary tumor and thyroid
metastases for both lung cancer and melanoma, consistent with
the aggressive nature of these tumors. In addition, while the
early literature noted that thyroid metastases tend to occur after
or along with widespread metastases (11), our review of recent
literature indicated that 40.3% of metastasis were solitary to the
thyroid gland alone. This reinforces the concept that metastases
to the thyroid should be seriously considered in patients having
only a thyroid nodule and a history of extra-thyroidal malignancy (66). The two cases presented at the end of this review
illustrate how the work-up of a thyroid nodule in a patient with
a history of a prior malignancy can lead to the correct diagnosis
of metastases to the thyroid gland.
Although metastases to the thyroid gland may be associated with a poor prognosis, some suggest that early detection
and aggressive surgical and medical treatment may improve
survival in a small percentage of patients (3). Unfortunately,
in one study it was noted that the overall survival time was
not significantly different in cancer patients with metastases
to the thyroid gland compared with those without thyroid
metastases; it was concluded that the clinical course of patients with metastases from NTMs to the thyroid gland depends on the extent of disease dissemination and the stage of
CHUNG ET AL.
the primary tumor rather than its spread to the thyroid gland
(10). Further experience should be analyzed to determine the
effect of thyroid gland metastases on prognosis, and the
benefit of surgical resection. At present the literature is
equivocal regarding the impact of surgical management on
survival time. Some authors have documented longer survival in patients surgically treated versus those nonsurgically
treated (8,10). In selected patients total thyroidectomy is the
mainstay of surgical intervention, despite the difficulty in
knowing how beneficial thyroidectomy is in patients with
NTMs. In carefully selected patients where the tumor is confined to one lobe hemithyroidectomy may be appropriate as it
is likely to achieve complete resection and be associated with
less morbidity.
In this review, 44.2% of metastases of NTMs to the thyroid
gland occurred in glands with abnormalities such as primary thyroid neoplasms and benign thyroid conditions. This
supports the hypotheses that abnormal thyroid glands that
have been altered by goiters, neoplasms, or thyroiditis are
more vulnerable to NTMs, presumably due to abnormal
blood supply resulting in decreased oxygen content and iodine content (1,119,128). One should suspect metastatic
disease to the thyroid gland in a patient with preexisting
thyroid gland abnormalities and perform the appropriate
diagnostic assays to avoid a delay in diagnosis of NTM to the
thyroid gland.
Whether there is a cause-and-effect relationship between
Graves diseases and metastases to the thyroid gland is unclear. Mete et al. reported a case of a patient with a history of
endometrial carcinosarcoma who presented with thyrotoxicosis, heat intolerance, and enlarging neck mass. She underwent bilateral thyroidectomy and pathologic analysis
documented Graves disease on the left and a carcinosarcoma
metastases in the right thyroid lobe (98). They postulated that
cancer antigens of malignant cells invading thyroid tissue
may have triggered cytokines, leading to thyroiditis. Another
hypothesis for why Graves disease might occur in patients
with metastases of NTMs to the thyroid gland is that thyroid
destruction and release of thyroid autoantigens may trigger
autoimmunity (98). However, there are few reports of patients
with a history of Graves disease who were affected by metastases to the thyroid gland. In fact, Graves disease may be
protective against metastases to the thyroid gland because of
its enhanced blood flow.
Early detection and surgical intervention, if indicated, may
prevent local recurrence and the development of complications
such as thyrotoxicosis, respiratory compromise, and extension
into local structures such as the recurrent laryngeal nerve and
trachea. This is especially true in RCC, where metastases to the
thyroid gland have a propensity to extend into the jugular
veins (19). The majority of cases (74.9%) initially present with
clinical manifestations such as a new neck mass, neck swelling,
and dysphagia. However, 25.1% are incidentally noted on
physical examination or imaging studies to have metastases of
NTMs to the thyroid gland. Some authors have suggested that
the screening chest CT in patients being followed up with
cancers should be a thyroid-chest CT not to miss thyroid metastases (25). It is likely that increasing use of imaging technologies, such as PET, have led to the increase frequency of
detected metastases of NTMs to the thyroid gland.
Although RCC was the most common source of metastases
to the thyroid gland, we noted that the FNAB did not yield the
263
for homatropine methylbromide-45 (HMB-45) and thought to
possibly represent early micrometastases. A PET scan done at
an outside hospital showed no evidence of active disease and
no adjuvant treatment was given at this point. The history
was positive for hypothyroidism and levothyroxine treatment. A thyroid ultrasound was performed one year later.
This showed a complex nodule in the right lobe measuring
2.1 2.3 cm containing multiple cystic regions. Thyroid stimulating hormone (TSH) at the time was 1.07 lIU/dL (normal
range: 0.355.50 lIU/L), T4 was 11.2 mcg/dL (normal range:
4.511.2 mcg/dL), and free thyroxine (fT4) was 1.57 ng/dL
(normal range: 0.91.8 ng/dL). FNAB of the right thyroid
nodule at this time was consistent with nodular goiter.
The patient was followed, and a PET scan 3 years after her
initial diagnosis showed increased activity in the right common iliac chain, but no evidence of other sites of disease.
Biopsy of the mass in the right common iliac chain revealed
metastatic malignant melanoma, however the mass appeared
adherent to the iliac vessels without a good tissue plane, and it
was thought not to be resectable for purposes of a cure. She
was subsequently enrolled in a mitogen-activated protein/
extracellular signal-regulated kinase (MEK) inhibitor trial and
staging CT scan at that point showed a thyroid lesion. Thyroid
ultrasound at this time showed interval increase in the size of
the previously observed right lobe nodule and a new lesion
in the inferior pole of the right thyroid gland. Another new
2.3 mm nodule was observed in the left lobe of the thyroid.
TSH at this time was 1.32 mIU/dL, T4 was 10.6 mcg/dL. Since
the patient was enrolled in the MEK inhibitor study at that
time, the decision was made to repeat the thyroid ultrasound
in 6 months. However, she tolerated the drug poorly, and after
dose reduction, CT showed widely metastatic melanoma.
The patient was then placed on palliative chemotherapy. The
patient responded well to treatment, and PET scan then
showed no evidence of active disease. However, surveillance
PET scan 5 years after her original diagnosis showed active
disease in a right common iliac lymph node, and decision was
made to surgically remove the mass and perform a lymph
node dissection. The resection was then followed by radiation
therapy.
FIG. 1. Metastatic melanoma to the thyroid gland. (A) Coronal view of FDG whole body PET scan showing intense focal
activity (SUV 11.5) in the left neck corresponding to a large thyroid nodule seen on concurrent CT. Additionally seen is a
smaller focus of increased FDG activity (SUV 4.5) in the right neck, corresponding to a right thyroid lobe nodule seen on the
same CT. (B) Axial view of a CT thorax with contrast in a patient with metastatic melanoma to the thyroid; arrow indicating mass in left thyroid lobe measuring 2.50 2.98 cm. FDG, fludeoxyglucose; PET, positron emission tomography;
SUV, standard uptake value; CT, computed tomography.
264
CHUNG ET AL.
FIG. 2. (A) Histology of the melanoma metastases from Case 1, showing tumor cells abutting thyroid follicles (hematoxylineosin, original magnification 40). (B) High-power view of the metastatic melanoma cells, showing positive immunoreactivity to HMB-45, confirming diagnosis of metastatic melanoma (HMB-45, original magnification 400). HMB-45, homatropine methylbromide-45.
The patient then presented several months later with new
complaints of dysphagia. Physical exam at this point demonstrated a diffusely enlarged thyroid gland without a discrete nodule. CT imaging showed a new left thyroid lobe mass
and corresponding PET scan showed intense focal activity in
the left neck corresponding to this with a standard uptake
value (SUV) of 11.5 (Fig. 1). Additionally, there was a smaller
focus of increased fludeoxyglucose activity (SUV of 4.5) in the
right neck which corresponded to a right thyroid lobe nodule.
A decision was made for total thyroidectomy. Histopathology
of the thyroid showed metastatic melanoma present in the
right, left, and pyramidal lobe of the thyroid (Fig. 2A). Immunostains using the antihuman melanoma antigen markers
HMB-45 and melanoma-associated antigen recognized by
T cells (MART-1) showed focal positive staining in the tumor
in the left lobe of the thyroid, supporting metastatic melanoma (Fig. 2B). Two years after surgery, the patient died from
metastatic melanoma.
Patient 2
A 55-year-old male was admitted for a one year history of
worsening fatigue, decreased appetite, and 40-pound weight
loss. CT scan revealed a renal mass thought to be RCC, along
with nodules replacing the adrenal glands bilaterally and a
FIG. 3. (A) Gross specimen of renal cell carcinoma metastastic to the left thyroid gland, transected to show one
2.6 2.3 2.1 cm yellowish, well-circumscribed nodule. (B) Histology of renal cell carcinoma metastastic to the thyroid gland,
showing malignant cells on the lower right with hyperchromatic nuclei and clear cytoplasm characteristic of RCC (hematoxylin-eosin, original magnification 100).
265
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