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

Abstract

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly-moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10-100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least 3-4 times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or <2-fold response to stimulation. The measurement of calcitonin in fine-needle aspirate washout (FNA-CT) and calcitonin immunocytochemical staining from thyroid nodules are ancillary methods that may significantly improve MTC diagnosis. The present review examines the gray areas in the interpretation of calcitonin measurement in order to provide a tool to clarify the origin of calcitonin secretion and differentiate the behavior of the two-faced Janus of neuroendocrinology: intra-thyroid (MTC) and extra-thyroid NENs.

Calcitonin-secreting neuroendocrine neoplasms of the lung: a systematic review and narrative synthesis

“…There are multiple other neuroendocrine neoplasms causing diarrhoea such as gastrinomas, VIPomas, glucagonomas, somatostatinomas and the carcinoid syndrome, as well as medullary thyroid cancer and hypercalcitonaemia secreted from the pancreas causing Verner-Morrison syndrome (20). In the reported cases, when patients with CTN secreting lung NENs have clinical symptoms, there is usually co-secretion of other biologically-active substances, and it is these substances which most likely explain the symptoms rather than the raised CTN (2,3,5,7,20).…”

“…Endocrine PNS is the term used when PNS is from ectopic secretion of a hormone, and can lead to diagnostic uncertainty, as it can manifest with symptoms identical to a neoplasm in the expected site of origin. (4,6,7).…”

“…The ectopic secretion of biological substances such as peptides, amines or cytokines isec more commonly seen by neoplasms that are formed in the gut ( 2 , 4 , 5 ). Endocrine PNS is the term used when PNS is from the ectopic secretion of a hormone, and can lead to diagnostic uncertainty, as it can manifest with symptoms identical to a neoplasm in the expected site of origin ( 4 , 6 , 7 ).…”

“…MTC is a NEN originating from the thyroid and associated with eutopic secretion of CTN. However, CTN can also be raised due to chronic renal failure, pernicious anaemia, hepatic cirrhosis, various medications, extra-thyroid neoplasms, false-positive CTN assay laboratory results, lower respiratory tract infections, smoking, chronic inflammatory conditions of the lung, and any condition increasing gastrin or calcium such as hyperparathyroidism or Zollinger-Ellison syndrome ( 7 , 8 , 10 , 11 ). These conditions tend to cause a moderate rise in CTN compared to MTC.…”

“…There is speculation that neuroendocrine cells are the origin of lung NENs, but as we do not yet have evidence of the events of early cell change into neoplasm, this cannot be claimed definitively ( 16 ). However, around 25% of lung carcinomas (mainly small and large cell lung carcinomas) can develop neuroendocrine features and may be associated with endocrine PNS ( 7 , 14 ). The development of an endocrine PNS may be what initially leads to the diagnosis of a carcinoma, or its recurrence in cases of patients with known malignancy ( 4 , 18 ).…”