THYROID CANCER AND NODULES

THYROID
Volume 22, Number 3, 2012
Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2010.0154

Metastases to the Thyroid:

A Review of the Literature from the Last Decade
Alice Y. Chung, Thuy B. Tran, Kevin T. Brumund, Robert A. Weisman, and Michael Bouvet

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

espite its abundant arterial supply, the thyroid

gland receives few metastatic deposits. In 1931, Willis
proposed two hypotheses for why this is the case: (1) fast arterial flow through the thyroid discourages adhesion of malignant cells, and (2) the high oxygen saturation and iodine content
of the thyroid gland inhibit the growth of malignant cells (1). In
the ensuing 70 years after Willis first hypothesized why metastases of NTMs to the thyroid gland are rare, their prevalence in
various reports has been variable (24). Prior to 2000, several
large clinical series demonstrated that clinically significant
NTM are infrequent occurrences. Chen et al. retrospectively
identified only 10 cases of isolated NTM over an 8-year period
within a single institution (5). McCabe et al. reported 17 patients
over a 23-year period while a large series from the Mayo clinic
only identified 14 patients over a 55-year period (4,6).

On the other hand, some suggest that although clinically

apparent metastases of NTMs to the thyroid gland are uncommon, they are no longer considered to be rare. Metastases
from NTMs to the thyroid gland have been reported in 1.4%
3% of all patients who have surgery for thyroid malignancy
(3,711). The most commonly reported NTMs leading to
clinically discovered metastases to the thyroid are renal cell
carcinoma (RCC), and lung, colorectal, and breast carcinoma
(7,1012). Older autopsy studies report a wide range of
prevalences, from 1.9% to 24%, for metastases of NTMs to the
thyroid (10,11). In autopsy studies, the most frequently encountered NTMs that metastasize to the thyroid are breast,
lung, and melanoma (11,13).
One question that has been addressed in the literature is
whether metastases from NTMs have more of a predilection
for abnormal thyroid glands compared with normal glands. If
the hypothesis of Willis is correct, diseased thyroid glands

Department of Surgery, University of California San Diego, San Diego, California.

258

METASTASES TO THE THYROID

with reduced blood flow and lower iodine concentrations
should be more susceptible to metastases. In 2000, Kameyama
et al. reported only five cases of carcinoma metastatic to a
thyroid adenoma in the literature, thus suggesting that tumorto-tumor metastases are rare occurrences (14). In 2005 Peteiro
et al. also noted that metastases to a preexisting thyroid neoplasm are rare (15). However, other studies have shown that
metastases to the thyroid occur more frequently in diseased
glands (16). In particular, in a series by Heffess et al. using the
Endocrine Registry of the Armed Forces, 42% of patients with
thyroid metastases from NTMs were noted in glands with
adenomas or thyroiditis (17).
Here we review the literature between 2000 and 2010 on
metastases from NTMs to the thyroid gland. Although historically metastases to the thyroid gland were considered to
be an uncommon but potentially lethal diagnosis, their
prevalence, ease of diagnosis, and appropriate management
remain controversial. The purpose of this study was to investigate the prevalence, and primary sites of metastases of
NTMs of the thyroid gland and their relationship to survival.
We also examined the role of fine-needle aspiration biopsy
(FNAB) in the diagnosis of thyroid metastases. To our
knowledge, this is the first comprehensive review in recent
years of the patterns and behavior of metastases of NTMs to
the thyroid gland.
Review
A review of the English-language literature from January
2000 to early 2010, and selected other articles, was conducted
for articles pertaining and relevant to metastases from NTMs
to the thyroid gland (1131). We searched PubMed for all
reported cases of metastases to the thyroid from January 2000
until early 2010 using any combination of keywords from the
following categories: primary malignancy (kidney, breast,
melanoma, lung, colon, rectum, sarcoma, bladder, neuroendocrine, pancreatic, ovarian, cervical testicular, uterine) and
abnormal thyroid glands (adenoma, goiter, multinodular
goiter, nodule, thyroiditis, Graves disease, hyperthyroidism,
hypothyroidism). A combination of these terms was used to
select relevant articles on metastases to the thyroid gland.
Cases in which thyroid metastases was discovered by autopsy were excluded. A total of 372 cases were reported
during this period. Many retrospective chart reviews and
case series published during this period included cases that
occurred before this date range in the analysis. Our review
also included two previously unreported cases, presented
here as illustrative cases, that occurred in this period (see
Supplementary Table S1; Supplementary Data are available
online at www.liebertonline.com/thy) (712,14112,115117,
124126).
Demographic distribution
Of the total of 374 NTMs with metastases to the thyroid, 207
were in women and 151 were in men, a female to male ratio
of *1.4. In 16 cases, the gender of the patient was not noted
usually because the focus was on cytology and histopathology. Age was reported in 194 cases. The mean age was 59
years (range: 26 to 87) and the median was 60 years. In individual case series the mean ages were 62, 64.6, 64.9, 67, and 52
years (9,10,1719).

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)

RCC, renal cell carcinoma; SCC, squamous cell carcinoma.

occurred in glands that were also otherwise abnormal. These

abnormalities included primary thyroid neoplasms and benign
thyroid conditions. Malignant metastases were most commonly found concomitantly with goiters and follicular thyroid
adenomas (Table 3). Notably, several cases, including the first
of two cases reported later in this review, occurred in the setting
of a preexisting multinodular goiter or thyroid nodule. In some
reports thyroid metastases were suspected because there was
enlargement of a preexisting nodule or goiter (2227,111,112).
The most commonly reported NTMs to metastasize to an abnormal thyroid gland were RCC (n = 14), lung (n = 3), and sarcoma (n = 3). Several retrospective chart reviews noted the
presence of an abnormal thyroid gland but did not state the
NTM that metastasized to the thyroid. We noted 1.9% of NTMs
that metastasized to the thyroid gland were from an unknown
primary malignancy (see Supplementary Table S2).
Much of the literature did not indicate what the thyroid
function was of patients with metastatic disease to the thyroid. There were 170 reports that did contain this information.
Most patients were euthyroid (n = 149; 87.6%). Hypothyroidism, when it occurred, was related to massive infiltration of
the thyroid by a malignant tumor (13). When thyrotoxicosis
occurs, it is likely due to the leakage of the hormones into the
peripheral blood resulting from damage to the thyroid gland
Table 2. Interval Between Diagnosis of Primary
Malignancy to Known Metastasis to the Thyroid Gland
Primary
malignancy
RCC
Colorectal
Lung
Breast
Sarcomaa
Malignant
melanoma
Cervical

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).

Table 3. Types of Abnormal Thyroid Glands

Involved in Metastasis to the Thyroid
Preexisting or coexisting
thyroid disease

Follicular adenoma(s)
Other thyroid nodule
Goiter
Multinodular goiter

15
10
26
8

Other nonspecified goiter

Primary thyroid malignancy
Follicular cell carcinoma
Papillary cell carcinoma
Hurthe cell carcinoma
Oncocytic carcinoma
Hashimotos thyroiditis
Chronic thyroiditis
None
Not mentioned, unknown

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)

In some cases, abnormal thyroid glands had more than one

abnormality.

by neoplastic embolization (10,111,120). Five patients were

hypothyroid and eight patients were hyperthyroid at the time
of NTM diagnosis. Six patients (3.5%) had a history of hyperthyroidism and 4.1% had history of hypothyroidism. Notable all six patients with a history of hyperthyroidism prior to
NTM diagnosis were euthyroid at the time of NTM diagnosis.
Interestingly, among all the patients without a previous history of thyroid disease, three patients (1.8%) presented with
thyrotoxicosis at time their NTM was diagnosed. In these
cases, thyrotoxicosis was attributed to destruction of the
thyroid gland by the malignancy, thereby causing uncontrolled release of thyroxine (T4). Two patients had the sick
euthyroid syndrome. Three patients were euthyroid but had
slightly increased serum thyroglobulin concentrations.
Concomitant thyroid and extrathyroidal metastases
There were 293 cases for which information was provided
as to whether there were also metastases to extra-thyroidal
tissues. Of those there were 118 (40.3%) in which there were no
extra-thyroidal metastases. In 175 cases (59.7%), extra-thyroidal
metastases were either previously present or discovered when
metastases to the thyroid gland were first noted.
Presentation and diagnosis of thyroid metastases
In 338 cases information was provided regarding how the
metastases to the thyroid gland were diagnosed. The majority
of patients presented with clinical complaints (n = 253) such as
new or enlarging thyroid nodule, enlarged thyroid gland,
neck swelling, dysphagia, dysphonia, and cough. Four
patients presented, in a dramatic manner, with a rapidly
enlarging thyroid gland and respiratory compromise requiring emergency thyroidectomy or emergency tracheostomy
(16,31,65,112). There were 84 cases (24.9%) in which the presentation was incidental, including the second patient described later in this review. Twenty-five patients were
diagnosed in the course of a routine physical exam that revealed either a new thyroid nodule or thyromegaly. In two
patients, thyroidectomy was performed for other indications

METASTASES TO THE THYROID

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

the patients known malignancy. The selection of antibodies

for IHC is more challenging when the patient presents with
occult malignancy. However, in this setting careful analysis of
the thyroid metastasis may help uncover the occult tumor.
A goiter may hinder the accuracy of FNAB. To rule out and
treat metastatic disease, El Fakih et al. recommended total
thyroidectomy in patients with history of malignancy who
had developed nodular goiters (117). Wood et al. suggested
that thyroidectomy should be performed if FNAB presents a
difficult diagnosis (11). As an abnormal thyroid gland may
increase propensity for metastatic deposits, patients with
abnormal thyroid lesions should have careful clinical followup and serial neck sonographic evaluations especially if initial
FNAB is nondiagnostic or equivocal.
Discussion
The thyroid gland has a rich blood supply of *560 mL/
100 g tissue/min, which is reported to be second only to the
adrenal gland (1). A rise in the incidence of primary thyroid
cancer is well documented (113,121,122), but the prevalence of
metastases to the thyroid gland is variable in reports. Autopsy
studies have shown that the prevalence of metastases of
NTMs to the thyroid gland ranges from 1.9% to 24% (10,11).
Our review of the literature from the last decade, however,
suggests that clinically significant metastases of NTMs to the
thyroid gland are not rare.
There has always been a strong female predominance in
cases of differentiated thyroid cancer (113). A recent study
using the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) database reported a clear
difference in prevalence between men and women for differentiated thyroid cancer. They noted that the rates of differentiated thyroid cancer rise rapidly among women during
the reproductive years such that the burden among women
peaks around 40 years of age (123). However, it remains unclear whether or not there is any sex predominance for metastases to the thyroid gland. One study found no female
predominance and postulated that this reflects the pathogenic
role of parity and estrogen on primary thyroid malignancy,
whereas for secondary malignancy this is not the case (10). On
the other hand, one study by Nakhjavani et al. in fact observed
a male predominance of 3.6:1 (3). Others have noted female
predominance of metastases to the thyroid, some reporting
ratios of 1.4:1 and even 6:1 (11,17,64,81). In our review, we
noted a modestly high female to male ratio of metastases to
the thyroid gland. Of all cases of thyroid metastases reported

Table 4. Primary Malignancy and Percentage of Correct Diagnosis by Fine-Needle Aspiration

Primary malignancy

Correct FNAs (%)

Incorrect FNAs (%)

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)

FNA, fine needle aspiration.

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

METASTASES TO THE THYROID

correct diagnosis in 28.7% of patients with RCC. Other authors noted this occurrence (42,81) and, contrary to the wide
consensus that FNAB is an accurate diagnostic tool, Mijovic
et al. reported a high false negative rate of 13% (118). While
FNAB has the lowest rate of complications, FNAB yields only
cells for cytologic examination and thus inadequate sampling
is one of the major causes of false negative results. In an era in
which FNAB is the most reliable and commonly used tool to
assess a thyroid mass, this surprisingly high finding of an
incorrect FNAB is concerning. Thus, one should remain suspicious for metastatic disease to the thyroid gland when
FNAB is negative for malignant cells or indeterminate. Given
the limitations of interpreting FNAB in the setting of an occult
malignancy, surgical excision may be the most appropriate
management in patients with a history of malignancy when
FNAB is equivocal or indeterminate.
One potential limitation of reviewing literature during a
specific period is that our analysis may not accurately reflect the
current status of metastases of NTMs to the thyroid gland.
Importantly the majority of articles on this topic, those that were
published before the period that we reviewed, reported postmortem findings. It is notable that an earlier report indicated
that malignant melanoma was the predominant NTM to metastasize to the thyroid gland, accounting to 39% of all metastatic neoplasms of the thyroid at autopsy (13). In contrast,
during the period we reviewed, we noted that melanoma
comprised 4.0% of our clinical series. This difference between
these and earlier reports suggests that in many patients with
advanced malignancy metastases to the thyroid are likely clinically occult, but can be uncovered by careful autopsy studies.
Illustrative Patients
Patient 1
A 61-year-old female was diagnosed with malignant melanoma of the right leg. A wide local excision and sentinel node
biopsy was performed and three right inguinal nodes were
removed; one node was found to have rare, small aggregates
of two to three cells, which were further evaluated using
immunohistochemical staining tools. The cells were positive

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

small lung nodule. CT of the thorax showed a left thyroid

hypodensity measuring 2 2 cm. A decision was made to
begin outpatient chemotherapy, with a plan to proceed with
nephrectomy if the patient showed improvement with treatment. At this time, thyroid ultrasonography was performed
and showed a 2.2 1.5 cm hypoechoic, heterogeneous mass in
the left lobe of the thyroid with well-defined margins. Thyroid
function tests were within normal limits. His fT4 was 1.17 ng/dL
(normal range 0.901.80 ng/dL) and TSH was 2.01 lIU/mL
(normal range 0.355.50 lIU/mL). FNAB of the thyroid mass
was performed and predominantly showed thyroid follicular cells with microfollicular architecture and minimal colloid suggestive of a follicular lesion or neoplasm. Also noted
was one small sheet of cells with large vacuolated cytoplasm
and mild nuclear atypia, which raised concern for the possibility of metastatic RCC. Four months following the initial
presentation, a partial nephrectomy and left adrenalectomy
was performed. The final histologic diagnosis was RCC, Fuhrman grade 3 with metastases to the left adrenal gland. The
primary neoplasm had a maximum diameter of 6.2 cm and
showed extensive necrosis and invasion into the lymphatics.
The patient was staged as pT1bNXM1, Stage IV. Six months
following the initial operation, a right adrenalectomy was performed. Histology again showed metastatic RCC. About 2
months after the adrenalectomy, the patient underwent a left

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).

METASTASES TO THE THYROID

thyroid lobectomy. Frozen section during the operation was
consistent with RCC, and a decision was made to perform
hemithyroidectomy with wide margins, as there was no evidence of disease in the contralateral lobe. The final pathologic
diagnosis was metastatic RCC (Fig. 3); immunostains showed
RCC positive, common acute lymphocytic leukemia antibody
(CD10) positive, thyroid transcription factor-1 negative, and
thyroglobulin negative, confirming the diagnosis. Two years
after surgery, the patient is doing well without evidence of
disease recurrence.
The two patient cases above illustrate the diagnostic work-up
for metastases of NTMs to the thyroid gland. The first case
shows a patient with a benign thyroid goiter who later developed metastases to the thyroid gland. This is consistent with the
concept that the persistence of thyroid abnormalities increase
the risk of metastases of NTM to the thyroid gland. The second
case illustrates a patient with RCC, the most common NTM to
metastasize to the thyroid gland, in which the correct diagnosis
depended on good cytologic sample from FNAB.
Summary and Conclusions
RCC is the common extra-thyroidal tumor to metastasize to
the thyroid gland according to both earlier and more recent
literature. It accounts for almost half of patients with this
condition. Colorectal, lung, and breast are also relatively
common sources of nonthyroid cancers that metastasize to the
thyroid. Sarcomas metastasize to the thyroid gland more
frequently than previously ascertained. It is not clear if there
has been a real change in the behavior of sarcomas with regard to metastasizing to the thyroid or this is due to differences in ascertainment between the older and more recent
literature. Females show a slight predilection for metastases to
the thyroid from nonthyroidal tumors. Nodular goiter may be
a preferential site for nonthyroid metastases compared with
normal thyroid tissue but whether this is the case is difficult to
confirm.
Clinical exam and imaging studies remain important in the
diagnosis of thyroid metastases from nonthyroid tumors. Many
patients have symptoms of compression, airway obstruction,
hoarseness, dysphagia, and a few have transient thyrotoxicosis.
There should be a high index of suspicion for thyroid metastases when a patient with history of NTM presents with a new
thyroid finding. FNAB along with IHC is a useful diagnostic
tool but may be misleading if nodular goiter is present. Therefore if the FNAB is difficult to interpret, there should be a low
threshold for repeating the biopsy and utilizing optimal ultrasound guidance if metastases from a NTM are suspected.
Author Disclosure Statement
The authors declare that no competing financial interests
exist.
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Address correspondence to:

Michael Bouvet, M.D.
Department of Surgery
University of California San Diego
Moores Cancer Center
3855 Health Sciences Drive #0987
La Jolla, CA 92093
E-mail: mbouvet@ucsd.edu