Metastatic Carcinoma to the Thyroid Gland: A SingleInstitution 20-Year Experience and Review of the Literature

Parnian Ahmadi Moghaddam & Kristine M. Cornejo &

Ashraf Khan

# Springer Science+Business Media New York 2013

Abstract The thyroid gland is an uncommon site for meta-static disease but cases have been well-documented in theliterature, particularly in autopsy series. A retrospective re-view of surgical pathology and autopsy pathology databasefor patients with metastatic carcinoma to the thyroid wasperformed at the University of Massachusetts Medical Cen-ter between January 1993 to January 2013. We identified atotal of 10 patients with metastatic carcinoma to the thyroid;6 were in surgical pathology specimens out of a total of 1,295thyroid carcinoma (0.46 %) and 4 were diagnosed at autopsyout of a total of 2,117 (0.19 %) autopsy cases during thisperiod. Cases with direct extension of the tumor into thethyroid from local primary sites such as larynx, esophagusor soft tissues of the neck were excluded. The primarytumors in these cases comprised of four lung carcinomas,three colorectal carcinomas, a renal cell carcinoma, a pleuralmalignant mesothelioma, and an unknown primary. There-fore, it is important to keep intrathyroidal metastases in thedifferential diagnosis when evaluating a thyroid nodule,particularly in patients with a previous history of malignan-cy. Furthermore, a literature review reveals over 1,400 caseshave been previously reported, with the most common ma-lignancies from the kidney (34 %), lung (15 %), gastrointes-tinal tract (14 %), and breast (14 %).

Keywords Metastatic carcinoma . Intrathyroidalmetastasis . Malignant mesothelioma . Breast carcinoma .

Lung adenocarcinoma . Tumor-to-tumor metastasis

Introduction

Thyroid involvement by metastatic disease is an uncommonbut well-documented occurrence. Metastatic disease to thethyroid gland is usually not detected in clinical practice butfound at autopsy due to widespread involvement or directinvasion from a primary neck or mediastinal neoplasm [1, 2].The overall incidence of metastases to the thyroid in autopsyseries with a known primary ranges from 1–24 % [2–10].Patients found to have thyroid metastases at autopsy withouta known primary range from 0.5–2.8 % [11]. Furthermore,metastatic carcinoma to the thyroid has been reported in0.05–1.4 % of patients undergoing evaluation for thyroidcancer [12, 13]. Therefore, metastatic disease should be con-sidered in the differential diagnosis in patients with a priorhistory of cancer with new thyroid nodules or thyromegaly[14]. We report a 20-year experience at our institution inwhich we identified 10 cases of metastatic disease to thethyroid gland, of which 4 were found at autopsy and 6 diag-nosed during evaluation of surgical pathology specimens in-cluding biopsy and lobectomy/thyroidectomy. We have alsoreviewed the literature for metastatic carcinoma to the thyroid.

Case Reports

A retrospective review of our surgical and autopsy pathology filesover the period from January 1993 to January 2013 identified 10cases (post-mortem examination, n=4; thyroidectomy, n=1,lobectomy, n=3, thyroid biopsy, n=2) (Table 1). Patients withdirect extension of tumor from primary head and neck lesionswere excluded. All lesions were confirmed to be of metastaticorigin by histomorphology and immunohistochemistry. In

Parnian Ahmadi Moghaddam and Kristine M. Cornejo contributedequally to this study and are considered as co-first authors.

Electronic supplementary material The online version of this article(doi:10.1007/s12022-013-9257-8) contains supplementary material,which is available to authorized users.

P. A. Moghaddam :K. M. Cornejo :A. Khan (*)Department of Pathology, University of Massachusetts MedicalSchool, Biotech 3, One Innovation Drive,Worcester, MA 01605, USAe-mail: Ashraf.Khan@umassmemorial.org

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addition, patient demographics and follow-up information wascollected.

Case #1

A 43-year-old female was diagnosed with poorly differenti-ated invasive ductal carcinoma of the left breast with metas-tases to the axillary and supraclavicular lymph nodes. Thepatient underwent neoadjuvant chemotherapy and left mod-ified radical mastectomy with axillary node dissection. Later,the patient underwent adjuvant radiotherapy to the left chestwall and regional lymph nodes. Ayear later, she developed alarge left pleural effusion secondary to metastasis to the chestwall accompanied with progressive liver failure and expiredsoon afterwards. Post-mortem evaluation revealed poorlydifferentiated carcinoma of the left breast and chest wall withwidespread metastatic disease to the contralateral breast,thyroid gland, bilateral lungs, left pleura, spleen, liver, uter-us, cervix, pericardium, stomach, esophagus, and lymphnodes with extensive lymphovascular involvement. Micro-scopic examination of the thyroid revealed numerous foci ofpoorly differentiated carcinoma, which histologically resem-bled the primary breast cancer (Fig. 1a). Immunohistochem-ical stains revealed the tumor was positive for cytokeratin(CK) 7 and mammoglobin, supporting the diagnosis.

Case #2

A 51-year-old female presented with progressive dyspneaand chest CT scan showed a large mass-like opacity withinvasion into the mediastinum with subcarinal and medias-tinal lymphadenopathy, bilateral adrenal gland enlargementand lesions within the liver and bony thorax concerning formetastatic disease. The patient was subsequently diagnosed

with pulmonary hypertension and atrial fibrillation likelydue to pericardial irritation from the probable malignancy.The patient soon expired and post-mortem examinationrevealed poorly differentiated carcinoma most prominentwithin the lung, favoring a lung primary. The tumor wasalso noted to invade the mediastinum with metastatic in-volvement to the thyroid gland, contralateral lung, bilateralpleura, liver, bilateral ovaries, bilateral adrenal glands, andlymph nodes. Histologically, the thyroid was involved byanaplastic tumor cells consistent with poorly differentiatedcarcinoma, which infiltrated in between thyroid follicles(Fig. 1b). The tumor cells stained positively with CK7and TTF-1 and negative for thyroglobulin, confirming thediagnosis.

Case #3

A 69-year-old male presented with a neck mass, which wasinitially diagnosed as a Hurthle cell neoplasm in the left lobeof the thyroid gland by fine-needle aspiration (FNA). He hada history of malignant mesothelioma for which he underwentextrapleural pneumonectomy with diaphragmatic recon-struction on the right side about 1.5 years before recognitionof the thyroid mass. Subsequently, he underwent left thyroidlobectomy. Microscopic examination revealed multiple mi-croscopic foci of tumor cells that were strongly reactive withcalretinin, WT1, CK5/6, and negative for TTF-1, p63, CK19,HBME-1, and thyroglobulin supporting the diagnosis ofmetastatic malignant mesothelioma (Fig. 1c).

Case #4

A 62-year-old female with no previous history of malignan-cy presented with a thyroid nodule in the right lobe. An FNA

Table 1 Patients with thyroid metastases at the University of Massachusetts Medical Center (01/1993–01/2013)

Age Sex Primary lesion Time to thyroidmetastasis

Procedure for Dx ofmetastasis

Treatment of thyroidmetastasis

Prognosis

66 F Renal cell carcinoma 6 years Lobectomy Lobectomy LTF

43 F Breast carcinoma Unknown Autopsy N/A DOD at 13 m

51 F Lung carcinoma Unknown Autopsy N/A DOD at diagnosis

66 F Lung carcinoma Unknown Biopsy Chemo and Rads DOD at 12 m

54 F Lung carcinoma 4 days Autopsy N/A DOD at diagnosis

69 M Malignantmesothelioma

18 m Lobectomy Lobectomy NED at11 months

44 F Colorectal carcinoma 48 m Biopsy Unknown LTF

75 M Colorectal carcinoma Unknown Total thyroidectomy Total thyroidectomy and RND LTF

62 F Unknown Unknown Lobectomy Lobectomy LTF

57 M Lung carcinoma unknown Autopsy N/A DOD at diagnosis

Chemo chemotherapy, DOD died of disease, DX diagnosis, LTF lost to follow-up, m months, N/A not applicable, NED no evidence of disease, radsradiation, RND radical neck dissection

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was performed and revealed highly atypical cells suspicious for amalignancy. One month later, a right lobectomy was performedwhich revealed a 3.5×3.0×3.0-cmwell-circumscribed, white-tansolid nodule. The tumor cells formed solid sheets and werefound to be mucicarmine and pan-CK positive and negativefor calcitonin and thyroglobulin, favoring a poorly differenti-ated carcinoma of unknown primary (Fig. 1d). Patient was lostto follow-up.

Case #5

A 66-year-old female with a history of prior thyroid surgeryfor non-malignancy presented with a cough and underwent achest CT scan which revealed a 4.5-cm mass in the rightupper lobe with hilar lymphadenopathy and a neck mass,concerning for a malignancy. A biopsy of the neck mass wasperformed and revealed thyroid parenchyma infiltrated bysheets and nests of poorly differentiated carcinoma (Fig. 1e).The tumor cells were found to be immunoreactive for CK7,TTF-1, and mucin and negative for CK20, thyroglobulin andcalcitonin supporting a lung primary. The patient underwentchemotherapy and radiation and died of disease 12 monthsafter diagnosis.

Case #6

A 44-year-old female with a previous history of colorectalcarcinoma diagnosed 4 years prior presented with a thyroidnodule. The patient had already been diagnosed with meta-static disease to the lung and abdominal wall a year beforepresentation. Thyroid biopsy revealed sheets of hyperchro-matic pleomorphic cells with mitoses and scattered glandularformation, consistent with metastatic carcinoma from her

colorectal primary (Fig. 1f). Unfortunately, the patient waslost to follow-up

Case #7

A 75-year-old male with a history of both a colorectal andlung carcinoma presented with a right thyroid nodule withcervical lymphadenopathy. The patient underwent a totalthyroidectomy with a modified radical neck dissection.Gross examination revealed a large 4.0-cm necrotic mass,which completely replaced the right lobe of the thyroid.Histologically, the tumor was comprised of infiltratingglands forming cribiform structures, with necrosis consistent

Fig. 1 Histology of metastatic tumors to the thyroid. a Poorly differ-entiated breast carcinoma that surrounded follicles (H&E, ×200). bPoorly differentiated lung carcinoma forming nests located betweenfollicles (H&E, ×200). c Metastatic malignant mesothelioma: Papillaryfronds lined by cuboidal tumor cells which infiltrated thyroid paren-chyma (H&E, ×200). d A well-circumscribed nodule comprised oftumor cells with vesicular nuclei and scant cytoplasm of unknownprimary (right), pushing against uninvolved thyroid parenchyma (left)(H&E, ×200). e Sheets of anaplastic tumor cells consistent with thepatient's lung carcinoma (H&E, ×200). f Thyroid parenchyma withtumor cells forming glands which were similar to the patient's primarycolorectal carcinoma (H&E, ×200). g Gland forming tumor cells withareas of cribiform formation and necrosis, histologically similar tothe patient's primary colorectal carcinoma (H&E, ×200). h A well-circumscribed nodule comprised of lobules of tumor cells with clearcytoplasm and centrally placed nuclei consistent with metastatic renalcell carcinoma (H&E, ×200). i Thyroid parenchyma with islands ofpleomorphic tumor cells with large, hyperchromatic nuclei consistentwith the patient's primary lung carcinoma (H&E, ×200). j Infiltratingsheets of hyperchromatic pleomorphic cells consistent with the patient'sanaplastic large cell lung carcinoma (H&E, ×200). For complete im-munohistochemical results, please see the respective case histories

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with metastases from his known primary colorectal adeno-carcinoma (Fig. 1g). The patient was lost to follow-up.

Case #8

A 66-year-old female with a history of renal cell carcinomadiagnosed 6 years prior, presented for surgical evaluation of aright thyroid nodule. A right lobectomy was performed andrevealed a 5.0-cm well-circumscribed mass. Histologic exam-ination revealed lobules of tumor cells with clear cytoplasm,separated by fibrovascular septae (Fig. 1h). Immunostainsrevealed the tumor cells were positive for Pan-CK andEMA, and negative for thyroglobulin, consistent with meta-static renal cell carcinoma. The patient was lost to follow-up.

Case #9

A 54-year-old female presented to the emergency depart-ment with productive cough, progressive shortness of breath,malaise and weight loss of 6 month duration. Chest CTrevealed multiple bilateral pulmonary nodules, and medias-tinal lymphadenopathy with compression of the central air-ways. A supraclavicular lymph node biopsy was performedand an endotracheal stent was placed. Over the next fewdays, the patient rapidly deteriorated due to respiratory fail-ure and expired 4 days later. Post-mortem examination re-vealed widely disseminated poorly differentiated carcinomainvolving both lungs, the pleura, liver, thyroid, endocervix,and numerous lymph nodes with extensive lymphovascularinvasion (Fig. 1I). Immunohistochemical stains revealed thetumor cells were positive for CK7, CK5/6, BerEp4, MOC3,calretinin and negative for CK20, CDX2, TTF-1, pCEA,p63, WT1, and B72.3. Based upon the predominance oftumor in the lung and the immunohistochemical staining, apoorly differentiated lung carcinoma was favored.

Case #10

A 57-year-old man presented with odynophagia, dyspha-gia and mental status changes after 1 year of diagnosis ofstage IV metastatic non-small cell carcinoma of the lung(status post chemoradiation therapy and subsequent esoph-agitis). Physical exam showed a fixed mass (5 cm) on theright side of the neck. CT scan showed a large neck masswith invasion to the right supraclavicular region and su-perior mediastinum and expired soon after. Autopsyshowed large pleomorphic tumor cells morphologicallyconsistent with metastatic non-small cell carcinoma (highgrade anaplastic large cell type) of the right lower lobe ofthe lung with perineural invasion and involvement of thesoft tissues of the right neck, mediastinum, larynx, tra-chea, esophagus, lymph nodes, esophagus, jejunum andthyroid (Fig. 1j).

Discussion

Metastatic disease to the thyroid is an uncommon but well-documented event and accounts for 1–9 % of all thyroidmalignancies [3, 13, 15–19]. Over a 20-year period at ourinstitution, only 6 patients were diagnosed with thyroidmetastases out of 1,295 surgical pathology cases with thy-roid cancer (0.46 %) including biopsies and excisions(lobectomy/thyroidectomy). An additional 4 cases of meta-static disease to the thyroid gland were also identified onpost-mortem examination of 2,117 autopsy cases (0.19 %).One of the autopsy cases had a microscopic focus, whichcould have been missed if the thyroid was not adequatelysampled. The pathogenesis of metastatic tumor to the thyroidis either through lymphovascular spread or direct extensionfrom adjacent tissue [1, 2, 20–23]. The theory of tumorseeding the thyroid is controversial as some believe tumordeposits in the thyroid due to the rich lymphatic and bloodsupply [7, 12, 24, 25]. Others hypothesize that despite theincreased blood supply to the thyroid, which is only secondto the adrenal gland, the high flow rate and velocity preventstumor cells from depositing [2, 22, 26, 27]. In addition, thehigh iodine and oxygen content may inhibit tumor growthunless a disease process occurs such as adenomatous changeor thyroiditis, altering the parenchyma and improving theenvironment for tumor to proliferate [2, 26].

In patients with a previous history of malignancy with athyroid nodule(s), thyroiditis or thyroid enlargement, meta-static disease should be considered in the differential diag-nosis [3, 24, 28–31]. Patients with metastatic disease mostcommonly present with a thyroid nodule while a smallersubset are asymptomatic or found to have an incidentalnodule on imaging [3, 9, 11, 12, 16, 31–35]. The durationfrom initial diagnosis and treatment to diagnosis of metastat-ic disease can occur within months to years, and has beenreported over 20 years later [1, 3, 4, 9, 36–40]. On rareoccasions, thyroid involvement may be the initial presenta-tion of the malignancy [1, 34, 41].

The diagnosis of metastases is often delayed as signs andsymptoms of thyroid involvement are usually subtle witheuthyroid hormone levels [24, 25, 29, 31]. In the rare in-stances of hyperthyroidism, it is believed to occur fromdamage of the thyroid gland due to the malignant neoplasmreleasing hormones into the blood or production of thyroidhormones by tumor cells [24, 42–46]. Eventually, the paren-chymal damage and depletion of hormones may later resultin hypothyroidism, with the transient thyrotoxicosis goingunnoticed [43, 47].

Distinguishing metastatic disease from a primary thyroidmalignancy on histology or cytology, may require ancillaryimmunohistochemical and molecular studies [24, 25, 29, 30,41, 48–50]. The most useful immunohistochemical markersare TTF-1 and thyroglobulin to differentiate metastases from

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a thyroid primary [11, 25, 38, 42, 51, 52]. However, only asubset (20–30 %) of anaplastic thyroid carcinomas are pos-itive for thyroid markers, making the distinction even morechallenging [3].

Fine-needle aspiration is commonly performed to evalu-ate lesions in the thyroid. As such, the incidence of metastat-ic disease found preoperatively in patients with a thyroidmass was 5.7–7.5 % [53, 54]. It was previously reported thatFNA accurately diagnosed metastatic disease in 58 % ofcases, while it identified a thyroid malignancy in approxi-mately 90 % of cases [11, 55]. This may be due to thedifficulty of distinguishing a primary from metastatic thyroidneoplasm on FNA containing anaplastic, spindle or cleartumor cells [3, 56, 57]. Due to the rarity of metastases, anexclusion work-up would not be considered unless there is a

high clinical suspicion and previous history of malignancy[54, 58]. The incidence of detecting metastatic disease hasrecently increased due to the use of CT-guided FNA andimproved imaging techniques such as the positron emissiontomography scan which may be used to monitor therapy andidentify recurrence and metastatic disease [11, 25, 32,59–65]. In addition, FNA has been found to be helpful inmaking the diagnosis in patients with a history of a primarymalignancy who presents with a thyroiditis-like picture onultrasound as imaging studies may not be diagnostic ofmetastatic disease alone [36].

The first documented case of metastatic disease to thethyroid was reported by Willis and described by Foerster in1858 [27]. Our review of the English literature confirmed atotal of 1,482 cases (Table 2). The three most common

Table 2 Summary of cases fromthe literature (please see mentaldata for references)

CNS central nervous system, GUgenitourinary, MM malignantmelanoma, NOS not otherwisespecified, OBGYN obstetric andgynecologic

Primary site of malignancy No. of cases

Kidney 509 (34 %)

Lung 222 (15 %)

Gastrointestinal 204 (14 %)

Colorectal 107

Esophageal 32

Gastric 33

Pancreaticobiliary 22

Liver 10

Breast 202 (14 %)

MM 72 (5 %)

Cutaneous 62

Non-cutaneous 10

Head and neck 70 (5 %)

Head and neck, NOS 32

Salivary gland 6

Oral/nasopharynx/larynx 32

Hematopoietic/immunologic (including thymus) 55 (4 %)

OBGYN 53 (4 %)

Uterine 12

Cervical 25

Ovarian 5

Female genital tract 11

Soft tissue 33 (2 %)

Genitourinary (non-renal) 25 (1 %)

Testes 5

Prostate 11

Bladder 9

Unknown primary 22 (1 %)

Cutaneous (non-MM) 9 (<1 %)

Endocrine (adrenal/parathyroid/paraganglioma) 5 (<1 %)

CNS (including eye) 1 (<1 %)

Total cases 1,482

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neoplasms to metastasize to the thyroid were from the kid-ney, lung, gastrointestinal tract and breast, respectively. Inprevious studies, the most common malignancies were mel-anoma, renal, breast, and lung carcinoma with the majoritybeing renal carcinoma or melanoma [1, 3, 7, 9, 12, 22, 31, 32,34, 37, 66–71]. Recently, Chung et al. reported intrathyroidalmetastases were mainly from renal cell (48.1 %), colorectal(10.4 %), and lung (8.3 %) primaries, which is similar to ourfindings [72].

Malignant mesothelioma is an aggressive tumor with apoor prognosis as the median survival is 12 months fromdiagnosis [73]. Malignant mesothelioma most commonlyspreads to the pleural cavity and neighboring organs suchas the lung and chest wall, but rarely presents with distantmetastases [74]. Intrathyroidal metastases secondary to ma-lignant mesothelioma has only been reported in two priorcases, both of which were diagnosed by FNA [74, 75]. Wereport a third case of metastatic mesothelioma to the thyroid,which is rare, as it occurs in 0.2 % of all metastaticintrathyroidal malignancies.

Although uncommon, there are cases reported of tumor-to-tumor metastases in which a cancer metastasizes to aprimary thyroid neoplasm [41, 49, 76–81]. The primarythyroid neoplasm may be benign or malignant [41, 76, 77].In order to make the diagnosis of tumor-to-tumor metastases,the recipient tumor must be a true neoplasm and the donortumor must be a true metastasis without direct extension[81–83]. Of the 26 cases reported of thyroid tumor-to-tumor metastases, 14 were of malignant-to-benign and 12were of malignant-to-malignant cases (Table 3). Of the

primary thyroid malignancies, the most commonly reportedwas the follicular variant of papillary thyroid carcinoma,likely due to the rich vasculature and lymphatics associatedwith this neoplasm [41, 49, 79]. The most common benignneoplasm was a follicular adenoma [49, 76, 77, 79]. Theprimary neoplasm, whether benign or malignant, alters theconditions of the thyroid parenchyma, which in addition tothe increased vasculature of the thyroid, results in a favorableenvironment for metastatic tumor to deposit and proliferate[2, 76, 77, 84]. Tumor-to-tumor metastases should be con-sidered when there are distinctly varying or dimorphic tumorpatterns [76, 77].

The treatment options in patients with metastatic diseaseto the thyroid gland should be made based upon the condi-tion of the patient, extent of the disease, stage, and volume[9, 11, 16, 28, 85, 86]. Thyroidectomy or lobectomy isreasonable in certain instances given the low morbidity as-sociated with the procedure, particularly in patients in whichthe tumor is slow-growing, cure of the metastatic disease isexpected and for possible palliation from locally advanceddisease [1, 11, 28, 29, 60, 87–89]. In addition, some proposea more aggressive surgical approach with lymph node dis-section [29]. However, it is unclear whether surgical treat-ment may prolong patient survival. Few studies suggestsurgical intervention may provide survival advantage witha mean survival of 34 months with thyroidectomy with orwithout adjuvant therapy versus 25 months without surgicalintervention [3, 36]. However, to date, there is no conclusiveevidence that there is improvement in overall survival withsurgical resection [16, 24, 25, 28, 29, 37, 90, 91]. In addition,

Table 3 Summary of cases withtumor-to-tumor metastases

PTC papillary thyroid carcinoma

Thyroid tumor Primary tumor No. of cases

Follicular adenoma Lung 4

Renal 3

Breast 2

Colorectal 2

Prostate 1

Follicular carcinoma Cutaneous MM 1

Follicular variant of PTC Lung 3

Renal 1

Unknown 1

PTC Renal 2

Colorectal 1

Breast 1

Hurthle cell carcinoma Colorectal 1

Hurthle cell adenoma Breast 1

Renal 1

Oncocytic carcinoma Renal 1

Total no. cases 26

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most patients with thyroid metastases have widespread dis-ease, which is associated with a poor prognosis [4, 13, 52,68, 86, 92]. However, isolated metastatic disease to thethyroid has been reported [16, 22, 93, 94].

The overall prognosis of the patient may also vary withthe histologic grade and subtype of the primary neoplasm[29, 31]. Patients with metastatic renal and breast carcinomawere reported to have an average of 32 and 37 months afterthyroidectomy versus patients with lung and gastrointestinalcarcinoma with an average of 1.5 and 2 months after thy-roidectomy [31, 95]. Therefore, patients with certain malig-nancies such as renal carcinoma are associated with im-proved overall survival while others such as lung carcinomaare associated with a poorer prognosis [3, 14, 32, 34, 67].Radiation and chemotherapy is often reserved as palliativecare for patients with widespread disease or in those with co-morbidities which precludes surgical intervention [9, 14, 29,92, 96, 97].

Conclusion

Metastatic disease to the thyroid is diagnostically challeng-ing and requires a high level of suspicion. Metastatic diseaseto the thyroid gland is a much more common phenomenonthan expected, particularly in patients with a prior history ofmalignancy, despite a long interval from the time of diagno-sis. Although most patients with thyroid involvement presentwith widespread metastatic disease, occasionally there arepatients, which present with a solitary thyroid nodule. Rare-ly, thyroid metastases may be the initial presentation of theprimary malignancy. Therefore, careful clinico-pathologicalevaluation of thyroid nodules should be performed to differ-entiate a primary versus metastatic malignancy.

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