| Abstract|| |
Small cell variant of medullary thyroid carcinoma (MTC) is a rare variant. In the past, primary thyroid lymphomas were thought to be small cell MTC (SCMTC). However, with the advent of immunohistochemistry, it was realized that SCMTC is rare. Our patient presented with neck mass for 1 year with an outside laboratory report of neoplastic lesion. His serum calcitonin levels were normal, but serum carcinoembryonic antigen (CEA) levels were high. He underwent total thyroidectomy and was diagnosed to have small cell variant of MTC. Immunohistochemistry for AE1/AE3 and CEA were positive while calcitonin was negative. The patient underwent radiotherapy but developed metastasis 3 months later. Thus, SCMTC is a rare and aggressive variant of MTC. In the absence of raised serum calcitonin levels, raised serum CEA levels are helpful. It is necessary to identify this rare variant as it connotes a poor prognosis and should be treated aggressively.
Keywords: Calcitonin, carcinoembryonic antigen, medullary, small cell, thyroid
|How to cite this article:|
Verma A, Kane S, Vinarkar S, D'Cruz AK. Small cell medullary thyroid carcinoma: A diagnostic dilemma. Indian J Pathol Microbiol 2017;60:562-4
| Introduction|| |
Medullary thyroid carcinoma (MTC) comprises 5%–10% of thyroid malignancies and is a malignant neoplasm of parafollicular C cells. MTC can be sporadic or hereditary. Histologically, various cell types and morphological patterns have been described. Among them, small cell MTC (SCMTC) is a rare variant. Historically, before the era of immunohistochemistry, SCMTC got clubbed with primary thyroid lymphomas under the broad category of anaplastic and undifferentiated thyroid carcinomas., Immunohistochemical markers are helpful in distinguishing this entity from other small round cell tumors. We present a case of SCMTC, which caused a diagnostic dilemma in a young male. We present this case due to its rare histological presentation, paucity of literature, and also to discuss the importance of serum tumor markers.
| Case Report|| |
A 23-year-old male presented with a large swelling on the neck anteriorly for 1 year. The swelling moved with deglutition and measured approximately 12 cm × 10 cm. His serum T3, T4, TSH, calcium, and calcitonin levels were within normal limits, but his carcinoembryonic antigen (CEA) level was 590 ng/mL (reference range: 0–3.0 ng/mL). Fine needle aspiration cytology (FNAC) performed at an outside laboratory was suggestive of a neoplastic lesion.
Ultrasonography showed a large hypoechoic mass involving both the lobes and the isthmus. Positron emission tomography–contrast-enhanced computed tomography (PET-CECT) scan showed a large enhancing low-grade fludeoxyglucose avid (SUVmax 3.4) thyroid mass with bulky mediastinal and bilateral cervical nodes.
The patient underwent total thyroidectomy with lymph node dissection. Grossly, a large lobulated mass measuring 15 cm × 10 cm was seen involving the entire thyroid. The cut surface was grayish white, solid, and fleshy [Figure 1]. On microscopy, a malignant tumor was seen arranged in nests and solid sheets comprising of small, loosely cohesive cells having scanty cytoplasm [Figure 2]. Amyloid deposition and necrosis were not seen. Lymph nodes were metastatic.
|Figure 1: Gross Specimen: A large, lobulated, solid, and firm grayish mass involving the entire thyroid|
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|Figure 2: (a) Tumor arranged in cohesive nests and sheets (×100), (b) diffusely infiltrating small blue round cells (×200), (c) small blue round cells with scanty cytoplasm and inconspicuous nucleoli (×400), (d) lymph node metastasis (×100)|
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On immunohistochemistry, the tumor was diffusely and strongly positive for AE1/AE3 and CEA, focally for CK7, synaptophysin, CD56, and CD99 (MIC2) while they were negative for calcitonin, NUT, P63, P40, and chromogranin [Figure 3]. Occasional tumor cells showed positivity for TTF1. Reverse transcription polymerase chain reaction (RT-PCR) for EWSR1-FLI1 gene rearrangement was negative. Thus, after extensive histological, immunohistochemical, and molecular evaluation, a diagnosis of SCMTC was made. The patient was tested for RET proto-oncogene germline mutation by Sanger sequencing but was negative.
|Figure 3: (a) CD56 – Focal positive (×200), (b) carcinoembryonic antigen – Diffusely positive (×100), (c) Synaptophysin – Focal positive (×400), (d) AE1/AE3 – Diffusely positive (×100), (e) CK7 – Focal positive (×100), (f) TTF1 – Focal positive with positive thyroid follicle (×400), (g) Calcitonin – Negative (×400), (h) MIC-2 – Focal positive (×200), (i) P40 – Negative (×200), (j) chromogranin (×200)|
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Postoperatively, the patient received radiotherapy for 2 months but refused chemotherapy. Three months after completing the radiotherapy, he presented with subcutaneous nodules on the left arm, right axilla, and abdominal wall measuring 0.2–1 cm. FNAC was performed on the left arm nodule which confirmed metastasis. Following this, the patient was again advised chemotherapy which he refused and was lost to follow-up.
| Discussion|| |
MTC on histology classically presents as epithelioid cells with plasmacytoid appearance arranged in an organoid pattern. Spindle cell morphology is also seen focally. However, rare cytological variants include giant cell, clear cell, oncocytic, and small cell. Other patterns seen are papillary, follicular, and rarely paraganglioma like. In the past, SCMTC was included under undifferentiated thyroid carcinoma. However, with the introduction of immunohistochemistry, various studies concluded that >90% of small cell undifferentiated carcinomas were primary thyroid lymphomas. Few of them were insular thyroid carcinoma, and the primary SCMTC was actually a rare entity., Rosai et al. described that small cells can be seen focally in classical MTC and rarely in its pure form.
Elevated serum calcitonin and CEA levels are helpful in making a preoperative diagnosis of MTC but occasionally can be normal., Rare cases of MTC with normal serum calcitonin and negative immunohistochemistry for calcitonin have also been described. As seen in our case, elevated CEA level helps as a tumor marker in such cases. It is also helpful in monitoring the patients on follow-up., Eusebi et al. described two cases of calcitonin-free neuroendocrine carcinoma and labeled them as oat cell carcinoma considering them to be a distinct entity from MTC. While few authors consider them to be poorly differentiated calcitonin-free MTC, some authors consider tumor cell-dedifferentiation as a cause of calcitonin negativity and probably SCMTC also represents dedifferentiated MTC. These tumors are also known to behave aggressively and have poor prognosis.,, Such cases may show negative calcitonin with positive CEA.
The differential diagnoses considered were (1) SCMTC, (2) small cell carcinoma, (3) poorly differentiated thyroid carcinoma (PDTC), (4) metastatic neuroendocrine tumor, and (5) primitive neuroectodermal tumor (PNET). Metastasis was ruled out based on PET-CECT findings. Small cell carcinoma was ruled out due to lack of crushing, nuclear pleomorphism, nuclear molding, and individual cell necrosis. PDTC was not further considered due to positivity for the neuroendocrine markers and only occasional cell expressing TTF1. Since the tumor was diffusely positive for AE1/AE3 and CD99, Adamantinoma-like Ewing family of tumors (AEFT) was considered as a differential diagnosis. RT-PCR for EWSR1-FLI1 gene rearrangement was negative and ruled out AEFT. AEFTs are a recently described entity in the head and neck region and show EWSR1-FLI1 gene rearrangement in all cases.
Like conventional MTC, SCMTC should be treated with surgery, adjuvant radiotherapy, and chemotherapy, especially in cases with extensive local or metastatic disease. Patients with intrathyroid paraganglioma would only require excision of the tumor while those patients with metastasis may qualify for palliative care. Patients with small cell carcinoma or PNET would undergo surgical excision followed by chemotherapy.,
SCMTC is a distinct but rare subtype. Small cells, lack of amyloid, normal serum calcitonin, and negative calcitonin on immunohistochemistry do not rule out MTC. In this scenario, immunohistochemistry and serum CEA are equally helpful as calcitonin, and it is crucial to realize that serum CEA is as good a tumor marker as calcitonin is., Even though CEA is not specific, one should consider a diagnosis of MTC with raised CEA in the absence of calcitonin., Hence, it is important to document this rare entity to increase the awareness among the pathologists as well as the surgeons and medical oncologists.
| Conclusion|| |
SCMTC is a rare histological entity. We report this case as it caused a diagnostic dilemma, and enough literature was not available on this issue. Hence, more reports and studies are necessary to know about the biological behavior and genetic mutations. Such cases must be investigated appropriately, treated aggressively, and use CEA as a tumor marker for diagnosis and surveillance if calcitonin is not elevated.
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Conflicts of interest
There are no conflicts of interest.
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Dr. Shubhada Kane
Department of Pathology, 8th Floor, Annexe Building, Tata Memorial Centre, Dr. E Borges Road, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]