Metastatic neoplasms to the thyroid diagnosed by fine-needle aspiration/core needle biopsy: Clinicopathologic and cytomorphologic correlation

Case 1: Metastatic pulmonary squamous cell carcinoma

A 63-year-old female was previously diagnosed with inoperable pulmonary SCC 7 months prior and was treated with radiation therapy to slow the progression of tumor growth. She presented to our facility with shortness of breath secondary to a pleural effusion. Physical examination revealed a diffusely enlarged thyroid and cervical lymphadenopathy which was confirmed by an ultrasound and computerized tomographic (CT) scan of the neck. A radiologist performed an ultrasound guided biopsy of a 2.0 cm right thyroid lobe lesion with a fine needle. The ROSE imprint cytology was highly cellular and comprised of irregular disordered clusters of overlapping tumor cells with nuclear pleomorphism and high nuclear-cytoplasmic (N:C) ratios [Figure 1a]. In addition, there were scattered isolated spindled cells with elongated nuclei forming tadpole configurations [Figure 1b]. The nuclei were hyperchromatic and occasionally multinucleated with nuclear membrane irregularities. Nucleoli were indistinct. With Diff-Quik staining, their cytoplasm was dense and glassy blue–purple with distinct cell borders and occasional vacuolization [Figure 1b]. The cell block preparation demonstrated irregular tumor nests with abundant eosinophilic cytoplasm, prominent intercellular junctions, and scattered dyskeratotic cells [Figure 1c]. Immunohistochemical stains were positive for cytokeratin (CK) 5/6 [Figure 1d] and p63 [Figure 1e] and negative with thyroid transcription factor-1 (TTF-1) [Figure 1f] confirming the diagnosis of metastatic SCC. Three months later, the patient succumbed to her disease.

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Figure 1

Metastatic pulmonary squamous cell carcinoma to thyroid. (a) Disordered tumor clusters with overlapping nuclei, nuclear pleomorphism, and high nuclear-cytoplasmic ratios on fine-needle aspiration (×400, Diff-Quik stain). (b) Spindled tumor cells with enlongated hyperchromatic nuclei and dense glassy cytoplasm on fine-needle aspiration (×1000, Diff-Quik stain). (c) Cell block showing metastatic squamous cell carcinoma (×400, H and E) immunopositive for cytokeratin 5/6 (d), p63 (e), and negative for thyroid transcription factor-1 (f) (×200)

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Case 2: Metastatic nasopharyngeal squamous cell carcinoma

A 61-year-old male with a history of nasopharyngeal SCC diagnosed a decade previously was recently found to have a malignant melanoma on the dorsal tongue surface. On further examination, the patient was also noted to have enlargement of the right thyroid and submandibular gland. FNA and CNB of the right thyroid nodule and submandibular gland were performed. The cytology of the submandibular gland showed metastatic melanoma. The Pap-stained FNA smear of the thyroid revealed frequent elongated spindled forms with dense orangeophilic to green–blue cytoplasm [Figure 2a]. The nuclei varied significantly in size and shape and exhibited hyperchromatism with occasional pyknotic nuclei and indistinct nucleoli. Diff-Quik-stained smears also demonstrated single as well as loose cellular aggregates of tumor, with irregular hyperchromatic nuclei, dense basophilic cytoplasm, and sharply demarcated cell borders [Figure 2b]. Tumor diathesis was identified in the background [Figure 2a and b]. The cell block sections and thyroid CNB [Figure 2c] showed metastatic SCC, confirmed with positive immunohistochemical stains for CK5/6 [Figure 2d] and p63 [Figure 2e]. Staining with p16 was negative [Figure 2f]. Both of the patient's tumors, namely the SCC and the melanoma, subsequently progressed in the neck, leading to airway compromise. The patient passed away 11 months after thyroid metastasis.

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Figure 2

Nasopharyngeal squamous cell carcinoma to thyroid. (a) Spindled tumor cells with dense orangeophilic to green–blue cytoplasm on fine-needle aspiration (×1000, Pap). (b) Tumor cells with well-demarcated cell boundaries, dense basophilic cytoplasm, and hyperchromatic nuclei on fine-needle aspiration (×1000, Diff-Quik). (c) Cell block showing metastatic squamous cell carcinoma (×400, H and E), immunopositive for cytokeratin 5/6 (d), p63 (e), and negative for p16 (f) (×200)

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Case 3: Metastatic renal cell carcinoma

A 69-year-old female with no significant prior medical history presented with an asymptomatic 2.0 cm right thyroid mass. She was referred to the radiology department where an ultrasound-guided CNB was performed. The ROSE imprint cytology was of moderate cellularity and contained multiple cellular clusters that were loosely cohesive [Figure 3a]. The cells displayed hyperchromatic, mostly ovoid nuclei with indistinct cytoplasmic borders. Partially denuded tumor nuclei with occasional nucleoli were also observed [Figure 3b]. The tumor cytoplasm was abundant and extensively vacuolated [Figure 3a]. The background also contained numerous clear extracellular vacuoles [Figure 3b]. The CNB showed aggregates of tumor cells with abundant clear cytoplasm consistent with metastatic renal cell carcinoma (RCC) [Figure 3c]. Immunohistochemical stains were positive for RCC [Figure 3d], CD10 [Figure 3e], and PAX2 [Figure 3f]. A subsequent abdominal CT scan revealed a 6.9 cm left kidney mass. A radical nephrectomy confirmed the diagnosis of Fuhrman nuclear grade 2 renal cell cancer.

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Figure 3

Metastatic renal cell carcinoma to thyroid. (a) Tumor cells with abundant clear, vacuolated cytoplasm, and enlarged hyperchromatic nuclei on rapid on-site evaluation imprint cytology (×1000, Diff-Quik). (b) Partially denuded tumor nuclei amidst a background of abundant clear extracellular vacuoles (×1000, Diff-Quik). (c) Core needle biopsy showing metastatic clear cell renal carcinoma (×400, H and E) with positive CD10 (d), PAX2 (e), and RCC (f) (×200)

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Case 4: Metastatic pancreatic adenocarcinoma

A 61-year-old male with increasingly severe abdominal pain and weight loss over a 2-month period underwent imaging studies which detected a possible pancreatic pseudocyst as well as omental thickening. He presented to our facility with progressing severity of his symptoms and mild icterus. On physical exam, he was found to have abdominal distension as well as a 2.0 cm right thyroid nodule. Ascitic fluid drainage as well as an ultrasound-guided biopsy of the thyroid was performed, the latter utilizing FNA and CNB. The cytology demonstrated a cellular smear with clusters featuring three-dimensionality and overlapping [Figure 4a]. The nuclei exhibited anisonucleosis with mostly rounded contours, finely dispersed chromatin, and occasional nucleoli. Frequent mucin vacuoles were encountered. There were also single dyscohesive tumor cells containing abundant cytoplasmic mucin with peripherally displaced nuclei [Figure 4b]. On CNB sections, infiltrative ductal glands showed focal mucin production [Figure 4c]. The tumor cells were positive for CK7 [Figure 4d] and cancer antigen 19-9 (CA 19-9) [Figure 4e] and negative for TTF-1 [Figure 4f] as well as CK20 and CDX-2, consistent with metastatic pancreatic adenocarcinoma. The patient expired 1 month later.

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Figure 4

Metastatic pancreatic adenocarcinoma to thyroid. (a) Three-dimensional tumor clusters with prominent mucin vacuoles on fine-needle aspiration (×1000, Pap). (b) Single tumor cells with abundant intracytoplasmic mucin on fine-needle aspiration (×1000, Pap). (c) Core needle biopsy showing metastatic pancreatic adenocarcinoma (×200, H and E) with positive cytokeratin 7 (d), cancer antigen 19-9 (e), and a negative thyroid transcription factor-1 (f) (×200)

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Case 5: Metastatic olfactory neuroblastoma

A 50-year-old female previously underwent resection and radiation for olfactory neuroblastoma of the left nasal sinuses. She presented to our facility 7 years later with metastases to the left parotid, left parapharyngeal fat space, left submandibular region, facial bones, neck, and axillary lymph nodes. Furthermore, ultrasound of the neck revealed multiple enlarged bilateral nodules in the thyroid. A FNA was performed under ultrasound guidance. The ROSE imprint cytology was comprised of multiple highly cellular smears containing clusters and single monotonous cells [Figure 5a]. The nuclei were enlarged and hyperchromatic with granular chromatin, mostly smooth nuclear contours, and nuclear molding. Nucleoli were inconspicuous. The nuclei were surrounded by abundant fibrillary matrix with indistinct cellular borders [Figure 5a]. At the periphery, the crowded tumor clusters exhibited fibrillary or neuropil-like processes [Figure 5b and inset]. Homer–Wright rosettes were not observed. Thyroidectomy revealed metastatic olfactory neuroblastoma [Figure 5c], which was further confirmed by positive immunoperoxidase stains for CD56 [Figure 5d], chromogranin [Figure 5e], synaptophysin [Figure 5f], and neuron specific enolase.

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Figure 5

Metastatic olfactory neuroblastoma to thyroid. (a) Hyperchromatic tumor nuclei with nuclear molding surrounded by fibrillary matrix on fine-needle aspiration (×1000, Diff-Quik). (b) Crowded cellular aggregates with fibrillary neuropil-like processes on fine-needle aspiration (×400, Diff-Quik). (c) Thyroidectomy showing organoid tumor nests among remnant follicles (×200, H and E) with positive CD56 (d), chromogranin (e), and synaptophysin stains (f) (×200)

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Cytology of metastatic squamous cell carcinomas to the thyroid

Lung cancers, as well as head and neck carcinomas, are common sources of metastases to the thyroid representing up to 43% and 40% of cases, respectively [Table 4].[717] Of the 42 cases of metastatic lung carcinomas diagnosed by thyroid FNA and/or CNB including ours,[4567121718] 14 (33%) cases were SCCs.[4671012] Of the 45 metastatic head and neck cancers, 25 (56%) cases were SCCs.[79101215171820] Specifically examining all metastatic SCCs to the thyroid, 44% were from the head and neck region,[79101215171820] 28% had their origin in the lung,[467101112] 23% were from the esophagus,[241218] 3.5% from the uterine cervix,[10] and 1.8% were from skin.[12] One differential diagnostic cytologic entity to keep in mind is squamous metaplasia, which may be seen in a wide variety of lesions.[23] Squamous metaplasia has been associated with cystic thyroid lesions, including intrathyroidal lymphoepithelial lesions and cysts, epidermoid cysts, thyroglossal duct remnants, and branchial cleft cysts. It may also be present in chronic lymphocytic (Hashimoto’s) thyroiditis and may represent modified Hurthle cells. It can also be seen in malignant lesions such as papillary, anaplastic, squamous, mucoepidermoid carcinoma, or carcinomas with thymus-like differentiation. Cytomorphologically, squamous metaplasia may exhibit abundant benign squamous cells which are predominantly anucleate, with occasional single or groups of nucleated cells. However, diagnostic challenges occur when there is mild-to-moderate squamous atypia with increased N:C ratios and nuclear membrane irregularities amidst a mixed inflammatory background, usually in the setting of Hashimoto's thyroiditis or cystic change. However, frankly malignant squamous cells are rarely encountered in these situations.

Another entity which must be considered in the differential diagnosis is anaplastic (undifferentiated) thyroid carcinoma with squamous differentiation.[24] In general, most cases of anaplastic thyroid carcinoma contain a heterogeneous tumor cell population comprised of epithelioid, spindled, squamous, and multinucleated giant cells. However, tumors with a single cell population may be encountered, consisting only of malignant squamous cells. In fact, Jin et al.[24] reported a case initially interpreted as anaplastic thyroid carcinoma that was later determined to be a metastatic SCC from an unknown source. Therefore, in the absence of reliable clinical history, it may be difficult to differentiate cases of metastatic SCC from anaplastic thyroid carcinoma.

In a review of 59 cases of anaplastic thyroid carcinoma diagnosed by FNA, immunohistochemical TTF-1 staining performed on 10 of their cases was entirely negative.[24] In contrast, PAX8 staining has been shown to be positive in 76% to 79% of all histologic subtypes of anaplastic thyroid cancer, while the squamous variant was positive in 100% of cases.[25] PAX8 is reported to be negative in head and neck SCCs,[2426] and positive in only 33% of pulmonary SCCs.[26] Therefore, PAX8 staining may be useful in distinguishing metastatic SCC from primary squamous cancers of the thyroid.

Cytology of metastatic renal cell carcinoma to the thyroid

Renal cell carcinoma metastatic to the thyroid has been reported extensively in the literature, with some authors suggesting that it is the most common neoplasm to metastasize to the thyroid.[6] In our literature review of metastatic tumors to the thyroid assessed by FNA and CNB, a wide range (0%–43%) of metastatic renal cell carcinoma prevalence has been reported [Table 4].[245610111213151618192021]

A diagnostic pitfall worth noting is that metastatic clear cell renal carcinoma shares cytomorphologic features with papillary thyroid carcinomas and follicular thyroid neoplasms with clear cell features.[6924] Yang et al. noted that the trabecular or insular growth pattern seen in clear cell papillary thyroid carcinoma may lead to diagnostic confusion with metastatic renal cell carcinoma.[27] However, the nuclear features of clear cell papillary thyroid carcinoma, including clear nuclei with targetoid cytoplasmic inclusions as well as intranuclear grooves, aid in readily distinguishing it from renal cell carcinoma.

In cytologic smears of follicular neoplasms with clear cell features, the tumor nuclei were small to variably sized with round features and granular chromatin.[27] The cytoplasm exhibited prominent cytoplasmic vacuolization with equally or variably sized vesicles or lipid droplets.[2728] Thus, the similarities between the clear cell follicular carcinoma and metastatic clear cell renal cell carcinoma are striking and distinguishing the two entities may be challenging.[28] Wood et al. noted that thyroid follicular neoplasms with clear cell features maintain some cytoplasmic granularity, whereas metastatic renal cell carcinomas do not.[9] In contrast, the presence of cytoplasmic glycogen and lipid would favor a metastatic renal cancer.[9] However, metastatic renal cell carcinoma with oncocytic features such as granular cytoplasm and bland nuclei may also be misinterpreted as a Hurthle cell neoplasm.[20]

Immunohistochemical staining may be employed to reliably distinguish between metastatic renal cell carcinoma and primary thyroid neoplasms with clear and granular cell features when histologic cell block material is available. Clear cell thyroid neoplasms tend to express TTF-1 uniformly and thyroglobulin in tumor cells without clear cytoplasm, whereas renal cell carcinomas express CD10 cytoplasmically and are negative for TTF-1.[24] Other markers which may be positive in clear cell renal cell carcinomas are PAX8 (92%) and PAX2 (92%).[29] In comparison, papillary thyroid carcinomas will always stain for PAX8 (100%)[26] but not PAX2 (0%).[30] The RCC marker is also not helpful in differentiating between these two entities as it is positive in both clear cell renal cell carcinoma (72%–85%)[29] and papillary thyroid carcinoma (100%).[30] Therefore, a panel of immunohistochemical stains, including TTF-1, CD10, and PAX2, may be most beneficial in distinguishing metastatic renal cell cancer from primary thyroid cancers with clear cell features.

Cytology of metastatic pancreatic adenocarcinoma to thyroid

Although there were no cases of metastatic pancreatic adenocarcinoma within the FNA series of metastases to the thyroid [Table 3], there are a few isolated case reports in the literature.[31323334] Interestingly, most of these articles described their cases of metastatic pancreatic adenocarcinoma that were initially misdiagnosed as putative primary thyroid cancer. Delitala et al.[31] reported a case of a 63-year-old man with pancreatic cancer who underwent FNA of a thyroid lesion. Although no cytomorphological description was given, the cytologic specimen was classified as malignant per the Bethesda criteria, and the patient was referred for possible thyroidectomy. In addition, Kelly et al.[32] described a thyroid FNA specimen containing only a small amount of “follicular” cells with papillary architecture which did not demonstrate classical features of papillary thyroid carcinoma. The case was reported as a suspected atypical papillary thyroid carcinoma. Further systemic workup also revealed a mass in the pancreas, which showed a ductal adenocarcinoma on resection. Eight weeks later, the patient underwent a total thyroidectomy, which demonstrated a metastatic adenocarcinoma with histologic features similar to pancreatic cancer. Finally, Hsiao et al.[33] reported a case of a 45-year-old male with a pancreatic mass which was radiologically suspected to be an intraductal pancreatic mucinous neoplasm. The patient developed cervical and periaortic lymphadenopathy, liver, bone, adrenal, and skin metastases as well as a rapidly growing tender thyroid mass. FNA of the thyroid produced smears of moderate cellularity with branching papillary fronds exhibiting nuclear pleomorphism. There were also aggregates of three-dimensional tumor nests, as well as individual tumor cells with prominent nucleoli and abundant cytoplasm. The background contained an amorphous mucoid substance and cellular debris. Despite the notable clinical history, the authors were not able to exclude a papillary thyroid carcinoma. Thyroidectomy was performed, which confirmed the diagnosis of a metastatic pancreatic intraductal papillary neoplasm.

In the latter two of these prior reported cases,[3233] the diagnoses of metastatic pancreatic adenocarcinoma were established only after the patients underwent thyroidectomy. Cytologic examinations of both thyroid FNA specimens led to erroneous diagnoses of atypical papillary thyroid carcinoma, due to the papillary architecture manifested by the metastases. However, in both instances, the classic nuclear features of papillary thyroid carcinoma, namely oval nuclei with fine chromatin, and intranuclear nuclear inclusions and grooves were not reported. Furthermore, in one case,[33] nuclear features incongruous with the diagnosis of papillary thyroid cancer, namely prominent nucleoli, were also noted. Therefore, careful attention to the characteristic cytodiagnostic features of papillary thyroid carcinoma is essential in achieving an accurate diagnosis.

Pancreatic cancer may also manifest with thyroid metastasis prior to a cancer diagnosis as was observed with our patient. Eriksson et al.[34] described a 54-year-old male who developed a neck skin mass and a diffusely enlarged thyroid. Thyroid FNA showed plump neoplastic cells forming acini and containing mucin surrounding follicular cells. The patient expired 8 weeks later, and postmortem examination revealed pancreatic cancer with widespread metastases.

With Eriksson's[34] study and our cases, the tumors appeared poorly differentiated, with neoplastic cells forming acini or three-dimensional clusters with nuclear overlapping, plump or abundant cytoplasm, and occasional nucleoli. Therefore, cytologic differentiation from primary poorly differentiated thyroid cancer may be difficult. However, intracellular mucin was identified in both cases, which is not usually observed in primary poorly differentiated thyroid cancer.[35] Furthermore, immunohistochemical stains may be useful in the differentiation. Delitala et al.[31] were able to perform immunohistochemistry on their patients’ subsequent thyroid CNB. Tumor staining was positive with CK19 and negative for TTF-1, confirming the diagnosis of metastatic pancreatic adenocarcinoma and thereby preventing a thyroidectomy. We also performed immunohistochemical staining on our patient's thyroid CNB, which demonstrated tumor positivity with CK7 and CA19-9 and was negative for TTF-1. In contrast, Kelly et al. and Hsiao et al.[3233] both examined only FNA specimens and were unable to perform immunohistochemical confirmation on either CNB or cell block specimens, which may have contributed to their diagnostic difficulties.

Cytology of metastatic olfactory neuroblastoma to the thyroid

We report the first known case of metastatic olfactory neuroblastoma to the thyroid diagnosed by FNA. Olfactory neuroblastoma is a rare neoplasm of neuroectodermal origin comprising only 1% to 5% of nasal cavity neoplasms.[36] Sixty-five percent of olfactory neuroblastoma patients reported in the cytologic literature had a diagnosis rendered from either a soft tissue swelling or a lymph node of the neck region,[37383940414243] indicating a predilection for locoregional spread. However, metastases to distant sites have also been reported, and cytologic exam has been employed to identify metastatic olfactory neuroblastoma in loci such as pleural fluid,[37] scalp,[38] liver, spine, and parotid.[39] In fact, our patient with nasal cavity olfactory neuroblastoma also developed extensive metastases involving the cervical and axillary lymph nodes, parotid gland, and facial bones.

Cytomorphological descriptions of primary olfactory neuroblastoma have been reported in the literature.[3839444546] The tumor cells were found in loose clusters and singly[38394445] and were described as being small in size and round to oval in shape.[3839383940] The nuclei were also round to oval, hyperchromatic with slight size variation, smooth nuclear membranes,[39] finely dispersed and/or granular chromatin,[3839444546] and an indistinct nucleolus.[38394446] Mahooti and Wakely[38] also described a two-cell population consisting of tumor cells with viable nuclei and others with pyknotic/karyorrhectic apoptotic nuclei. They also noted the presence of paranuclear blue bodies that indented the nuclei.[38] The cytoplasm of primary olfactory neuroblastoma has been described as scanty[383945] and having a fibrillary quality.[394546] In fact, neurofibrillary stroma was identified in 80% of the primary olfactory neuroblastomas reported in the FNA literature.[384546] In addition, rosette formation was also noted in 80% of cases.[38444546]

Most of the cases of metastatic olfactory neuroblastoma diagnosed by FNA demonstrated cytomorphologic features similar to those seen in primary olfactory neuroblastoma, including hyperchromatic nuclei with small and/or indistinct nucleoli, molding, and scant cytoplasm.[3740414243] The more defining cytologic features of olfactory neuroblastoma, namely the presence of neurofibrillary matrix and rosette formation, were identified in 72%[3740414243] and 68%[3740414243] of the cases, respectively. Although our case demonstrated neurofibrillary features, no rosettes were seen.

Poorly differentiated thyroid carcinoma may exhibit some cytomorphologic features similar to metastatic olfactory neuroblastoma. Like olfactory neuroblastoma, poorly differentiated thyroid carcinoma features isolated tumor cells alternating with groups of uniform tumor cells with round nuclei, high N:C ratios, and apoptosis.[35] However, unlike olfactory neuroblastoma, poorly differentiated thyroid carcinoma may show insular, solid, or trabecular architecture. Furthermore, only slight nuclear size variability is seen in olfactory neuroblastoma,[39] whereas poorly differentiated thyroid carcinoma may demonstrate varying degrees of nuclear atypia, with nuclear pleomorphism and anisokaryosis in the majority of the cases.[35] Finally, the cardinal features of olfactory neuroblastoma, namely, neurofibrillary stroma and rosette formation are absent in poorly differentiated thyroid carcinoma.[3839444546] Immunohistochemical staining is also useful in the distinction as poorly differentiated thyroid carcinoma is positive with TTF-1 and thyroglobulin and negative for chromogranin.[35]

Medullary thyroid carcinoma must also be considered in the cytologic differential diagnosis. The cellular architectural arrangement in cytological smears can appear similar to an olfactory neuroblastoma, with the cells appearing singly or in loosely cohesive clusters.[47] However, the cellular morphologic features in medullary thyroid carcinoma are invaluable in differentiating these two entities. While metastatic olfactory neuroblastoma demonstrates hyperchromatic nuclei with molding and high N:C ratios, medullary carcinoma exhibits eccentric nuclei with a salt and pepper chromatin pattern and abundant eosinophilic granular cytoplasm, imparting a plasmacytoid appearance. Other medullary carcinoma variants feature spindled or multinucleated tumor cells. In addition, the background may contain amyloid-like material present in the form of strings or round to oval-shaped fragments. Immunohistochemically, both olfactory neuroblastoma and medullary thyroid carcinoma stain positively with synaptophysin and chromogranin.[383941424347] Unlike olfactory neuroblastoma, calcitonin is positive in medullary thyroid carcinoma.[47] Carcinoembryonic antigen is also positive in medullary carcinoma,[47] while generally negative in olfactory neuroblastoma.[42]