Sporadic calcitonin-negative medullary thyroid carcinoma is not more aggressive than its classic counterpart: case report and review of the literature

Objective: medullary thyroid carcinoma (MTC) with normal serum basal calcitonin (calcitonin-negative MTC) is uncommon. The exact mechanism for this paradox is unclear. It has been suggested that the loss of ability to secrete calcitonin is due to tumor cell dedifferentiation and may confer a worse prognosis. Methods: we describe a 45-year-old woman with a sporadic 4.5-cm well-differentiated MTC, who despite having normal preoperative serum basal calcitonin and poor calcitonin immunostaining in tumor cells, remains in remission 5 years after total thyroidectomy with bilateral central neck dissection. Out of the 20 patients with calcitonin-negative MTC reported to date, we include 16 patients with clinical disease at presentation to determine if they fare worse than their classic MTC counterparts. We try to correlate the extent of calcitonin immunostaining with the degree of tumor differentiation to determine if poor tumor calcitonin immunoreactivity is an indicator of tumor cell dedifferentiation. Results: Seven and 9 patients with calcitonin-negative MTC had poorly-differentiated and well-differentiated tumors, respectively. Four patients in the former group died from metastatic MTC within 3 years of the diagnosis. The status of the 2 living patients with known follow-up information was one with N1 disease and one in remission. In the well-differentiated group, 2 patients had N1M1 disease and 7 patients were in remission. According to the number of tumor cells immunoreactive to calcitonin, the 15 patients with known data were classified in 3 groups: 1+ group (only few tumor cells stained weakly for calcitonin), 7 patients; 2+ group (many tumor cells stained focally for calcitonin), 2 patients; and 3+ group (most tumor cells stained strongly for calcitonin), 6 patients. The level of calcitonin immunoreactivity did not correlate with the patient’s clinical status. Conclusion: the degree of tumor differentiation is a far better predictor of outcome than the extent of calcitonin immunoreactivity and poor tumor calcitonin staining is not necessarily an indicator of tumor cell dedifferentiation

Two synchronous paraneoplastic endocrine syndromes in a 53-year-old male with broadly metastatic widely invasive Hürthle cell carcinoma

Unlike medullary thyroid carcinomas, follicular cell-derived thyroid malignancies have rarely been associated with paraneoplastic endocrine syndromes. An ultrarare case of a middle-aged man with heavily treated broadly metastatic radioactive iodine-refractory widely invasive Hürthle cell carcinoma (HCC) of the thyroid with two synchronous paraneoplastic endocrine syndromes, T3 thyrotoxicosis and hypercalcemia of malignancy, is discussed here. The levothyroxine-induced T3 thyrotoxicosis was a gradual process that became more noticeable as the tumor burden, refractory to different modalities of therapy, expanded. The 1,25-dihydroxyvitamin-D-mediated hypercalcemia, on the other hand, developed in a manner of weeks, as it usually happens. It is important to emphasize that in patients with metastatic Hürthle cell and follicular carcinomas of the thyroid, on TSH suppressive therapy, the unexplained and progressive decline in FT4 and rise in FT3 levels, resulting in an elevated FT4/FT3 ratio, could be an indication of augmented type 1 (D1) and/or type 2 (D2) deiodinase expression in tumoral tissue, causing an increased conversion from the prohormone T4 into the active metabolite T3 via outer ring deiodination

Primary high-grade calcitonin-negative neuroendocrine carcinoma of the thyroid: a very rare cancer

Most medullary thyroid carcinomas (MTCs) are low grade and produce calcitonin. There are some calcitonin-negative MTCs that produce only calcitonin gene-related peptide (CGRP). Rarely, MTCs are negative for calcitonin and CGRP peptides, but contain their corresponding mRNAs. Primary thyroid neuroendocrine neoplasms other than MTCs are extremely rare. We describe a primary high-grade neuroendocrine carcinoma that was negative for CGRP and calcitonin at both the protein and mRNA levels. A 42-year-old woman presented with a rapidly enlarging thyroid mass replacing most of the left lobe and isthmus. A computed tomography-guided core-needle biopsy was performed. The tumor was composed of sheets of small-to-medium sized epithelial cells. The cells were immunoreactive for pancytokeratin, synaptophysin, CD56 and thyroid transcription factor-1, but negative for CK7, CK20, CD45, CD99, ERG, chromogranin A, thyroglobulin, calcitonin, CGRP and carcinoembryonic antigen. The Ki-67 proliferation index was ~90%. In situ hybridization was negative for calcitonin mRNA. The patient was initially diagnosed as having a small cell carcinoma. She was treated with cisplatin and etoposide (VP16), followed by radiation therapy. Given the excellent clinical course, the tumor was reviewed and reclassified as a high-grade neuroendocrine carcinoma (non-small-cell type). Heretofore, only a few other similar high-grade neuroendocrine tumors with negative markers of C-cell derivation have been reported. In our case, the patient is cancer free five years after diagnosis, but in the other cases, the outcome was poor