Calcitonin negative Medullary Thyroid Carcinoma: a challenging diagnosis or a medical dilemma?

Abstract

Background Medullary thyroid carcinoma is a neuroendocrine tumor belonging form a malignant growth of the thyroid parafollicular C-cells, representing from 1 to 10% of all thyroid cancer. The biochemical activity of medullary thyroid carcinoma includes the production of calcitonin and carcinoembryogenic antigen, which are sensitive tumor markers, facilitating the diagnosis, follow-up and prognostication. The diagnosis is reached through the identification of high basal calcitonin serum level or after pentagastrin stimulation test. Medullary thyroid carcinoma is able to produce other relevant biomarkers as procalcitonin, carcinoembryionic antigen and chromogranin A. In Literature are described few cases of medullary thyroid carcinoma without elevation of serum calcitonin, an extremely rare event. The aim of this study was to analyse the presentation, the main features and therapeutic management of medullary thyroid carcinoma associated with negative serum calcitonin levels. Methods Using the PubMed database, a systematic review of the current Literature was carried out, up to February 2018. Finally, nineteen articles met our inclusion criteria and were selected according to the modified Newcastle-Ottawa scale. Results Fourty-nine patients with definitive pathology confirming medullary thyroid carcinoma and with calcitonin serum level in the normal range were identified (24 female, 24 male and not reported gender in 1 case). Mean age was 51.7 years. Serum calcitonin levels were reported for 20 patients with a mean value of 8.66 pg/mL and a range of 0.8–38 pg/mL. Despite the low or undetectable calcitonin serum level, at immunochemistry in almost the half of the cases reported by the Authors, the tumors presented diffuse or focal positivity for calcitonin and carcinoembryionic antigen, while was reported a chromogranin A positivity in 41 of the 43 tested patients. Conclusions Calcitonin negative medullary thyroid carcinoma is an extremely rare pathology. The diagnosis and the surveillance is often challenging and delayed, due to the lack of elevation of serum markers as calcitonin and carcinoembryionic antigen. Further studies are needed, to better define options for management of non secretory medullary thyroid carcinoma and to identify new and reliable biomarkers associated to diagnosis and relapse of this medical dilemma.

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus

“…Diarrhea is usually secretive, and can also occur at night and while fasting (93). False negatives have also been reported in rare cases of calcitonin-negative MTC (95), all of which were sporadic. One case has been described of familial MTC characterized by a germline RET 611 mutation associated with somatic DICER1 mutations causing normal calcitonin levels (96).…”

Calcitonin negative medullary thyroid cancer in ectopic thyroid tissue: a rare diagnosis in an unusual location

“…Pro-CT and CT gene-related peptide (CGRP) are new alternative biomarkers which have shown diagnostic value in non-secretory MTC. 1 Pro-CT is the precursor of CT and has been shown to be a sensitive, reliable alternative to CT and is currently of most diagnostic use. 4 CGRP is secreted by MTC but also non-neoplastic C cells, and therefore may be of most use as an adjunct to diagnosis.…”

“…4 CGRP is secreted by MTC but also non-neoplastic C cells, and therefore may be of most use as an adjunct to diagnosis. 1…”

“…5 Like other neuroendocrine tumours, MTC can also produce a range of relevant biomarkers, such as procalcitonin (Pro-CT), neuron-specific elonase and chromogranin A (CgA). 1 Calcitonin negative medullary thyroid cancer (CNMTC) has been described in the literature; however, it is considered rare and often proves to be a challenging clinical and pathological diagnosis.…”

Calcitonin Revisited in 2020

“…Very rarely, other non C cell-derived tumors, such as carcinoids or small cell lung cancers, may also be accompanied by very elevated CT levels (6). Lower CT values (between 10-40 pg/mL), although considered pathological, are more difficult to be interpreted, because normal range varies function of sex and the commercial kit used and slightly increased CT levels may be found in other nonmalignant conditions (certain cases of autoimmune thyroiditis, chronic renal failure, chronic pulmonary disease, acute trauma, pregnancy, hypercalcemia, hypergastrinemia, hypercatecholaminemia, type 1A pseudohypoparathyroidism, mastocytosis, sepsis) (4,6,7,9,10).…”