Answer: Metastatic medullary thyroid carcinoma

Histology: Microscopic examination reveals nests of relatively uniform cells with pale granular to clear cytoplasm and bland nuclei with finely dispersed chromatin. The nests are separated by delicate fibrous bands. Rare mitotic figures are evident. No necrosis is seen. The patient has a history of medullary thyroid carcinoma and presented with an elevated serum calcitonin level on routine surveillance. Immunostains performed show the neoplasm to be positive for synaptophysin, chromogranin, calcitonin, CEA, and TTF1 and to be negative for thyroglobulin, S100 and AE1/AE3.

Synaptophysin:
Chromogranin:
CEA:
Calcitonin:

Discussion: Medullary thyroid carcinoma arises from the thyroid C cells (formerly called “parafollicular cells” but they are actually intrafollicular), which produce calcitonin. These tumors can be suspected clinically due to elevated serum calcitonin, and calcitonin can serve as a useful tumor marker to monitor for recurrence. Medullary thyroid carcinomas are associated with a variety of genetic syndromes, including multiple endocrine neoplasia (MEN) type 2 (RET mutations), von HIppel-Lindau syndrome (VHL mutations), and familial medullary thyroid carcinoma syndrome (also RET mutations). C cell hyperplasia is often seen in the background thyroid parenchyma of patients with these syndromes, whereas it is not seen in sporadic cases of medullary thyroid carcinoma.

One unique feature of medullary thyroid carcinomas, not seen in this metastasis, is the presence of amyloid protein deposition admixed with the tumor. On immunohistochemistry, medullary thyroid carcinomas are positive for synaptophysin and chromogranin, calcitonin, and CEA. In addition, medullary thyroid carcinomas are positive for TTF1, but unlike follicular and papillary thyroid carcinomas, they are negative for thyroglobulin and variably positive for Pax8.

Although paragangliomas, parathyroid neoplasms and carcinoid tumors would all appear histologically similar to medullary thyroid carcinoma and are all positive for neuroendocrine markers, all of the tumors listed in the differential diagnosis would all be negative for TTF1 and calcitonin. Parathyroid carcinomas are positive for parathyroid hormone; carcinoid tumors are positive for cytokeratin; and clear cell renal cell carcinoma is positive for CAIX and RCC.

Reference(s):
– Nikiforov YE. Thyroid carcinoma: molecular pathways and therapeutic targets. Mod Pathol. 2008 May;21 Suppl 2:S37-43.
– Nonaka D, Tang Y, Chiriboga L, Rivera M, Ghossein R. Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol. 2008 Feb;21(2):192-200.