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

in European Journal of Endocrinology
View More View Less
  • 1 Department of Experimental Medicine ‘Sapienza’ University of Rome, Rome, Italy
  • 2 Dept PROMISE, UOC Malattie Endocrine, del Ricambio e della Nutrizione, University of Palermo, Palermo, Italy
  • 3 Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
  • 4 Department of Diagnostic and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
  • 5 Department of Advanced Biomedical Sciences, Pathology Section University ‘Federico II’, Naples, Italy
  • 6 Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy
  • 7 Oncological Endocrinology Unit, Regina Elena National Cancer Institute, Rome, Italy
  • 8 Neuroendocrinology Unit, Neuromed Institute, IRCCS, Pozzilli, Italy
  • 9 Dept of Clinical Medicine and Surgery, University ‘Federico II’, Naples, Italy

Correspondence should be addressed to E Giannetta; Email: elisa.giannetta@uniroma1.it

† (Details of the Nike group are presented in the Acknowledgements section)

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 three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or <two-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-th9yroid NENs.

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 three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or <two-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-th9yroid NENs.

Introduction

Calcitonin is produced by parafollicular C cells located mainly in the thyroid, but also present in the lung, bladder, small intestine, liver, thymus and parathyroid glands (1). An elevated calcitonin serum level, while not a pathognomonic sign (2), suggests a medullary thyroid cancer (MTC). However, renal insufficiency, hyperparathyroidism, neuroendocrine neoplasms (NENs) and non-neuroendocrine carcinomas (lung, colon, breast, and prostate carcinomas) as well as various drugs can increase serum calcitonin levels (3). NENs often express peptide(s) or amine(s), especially insulin, gastrin, and serotonin. Calcitonin-secreting NENs have been described in various organs including the lung, pancreas, larynx, bladder and ovaries (3, 4, 5, 6, 7, 8). Their frequency may be underestimated, as serum calcitonin measurement or immunohistochemical staining for calcitonin is not routinely performed on NENs of various origins, and even when calcitonin serum levels are measured, an elevated level may be misinterpreted as MTC, especially in patients with thyroid nodules, leading to unnecessary thyroidectomies.

We performed an up-to-date critical review taking into account the results of published studies on calcitonin measurement in both thyroid and extra-thyroid NENs. The primary search was carried out via PubMed, EMBASE, and the Cochrane Library (until April 2020), while other articles and guidelines were retrieved from related papers or those referenced in these papers. The search was restricted to reports published in English.

The ontology of calcitonin

Origins

Calcitonin was named for its role in maintaining normal calcium tone, first described in 1962 by Douglas Harold Copp and B. Cheney (9). It was initially thought to originate from the parathyroid gland, but was later realized to be secreted by parafollicular cells of the thyroid gland (10). According to current understanding, parafollicular cells are part of the neuroendocrine system and originate from primordial C cells of the neural crest (11). These cells move to the lower pharyngeal arch, reaching the ultimobranchial bodies, and colonize the middle third of each lateral lobe of the thyroid gland. They are typically found scattered within thyroid follicles, lying inside the basement membrane but not reaching the follicular lumen, known as an intrafollicular position. Occasionally, they occur in clusters in the interfollicular connective tissue stroma, called a parafollicular/interfollicular position. Contrary to current understanding, new findings suggest that neuroendocrine cells of the mammalian thyroid gland are derived from foregut endoderm (12). This discovery adds weight to the argument that MTC should be reclassified to the family of NENs of endodermal origin (12).

Calcitonin secretion and main functions

Calcitonin is a 32 amino acid polypeptide hormone composed by a disulfide bridge and an amidated C-terminus. Its release is stimulated by elevated serum calcium and gastrin secretion (13). It acts through the calcitonin receptor (CTR), a seven-transmembrane class II G protein-coupled receptor linked to multiple signal transduction pathways (14). One of the most important pathways is coupled with adenylyl cyclase-cAMP-PKA signal transduction. However, CTRs are also coupled to the phospholipase A2, C, and D enzyme pathways. These can be activated by the coupling of CTRs to multiple G-proteins, generating the release of Ca+2 from intracellular stores (15). Chen et al. demonstrated that calcitonin bound to CTRs stimulates Shc phosphorylation and Erk1/2 activation by parallel Gi- and protein kinase C-dependent mechanisms (16).

Although the biological function of calcitonin has been well established in animals such as fish, reptiles and birds, the same is not true in humans. Neither high (as in metastatic medullary thyroid cancer) nor low values (as after total thyroidectomy) produce any clinical effects in humans, and the biological role of human calcitonin remains elusive. In contrast, in in vitro experimental models, calcitonin exerts important physiologic effects on the tubular epithelium of the kidney and on osteoclasts. It reduces serum calcium and phosphate levels, acting in the tubules by promoting diuresis and decreasing resorption. In bone, it has been demonstrated to impair osteoclast function and consequently reduce both bone resorption and serum calcium levels through three main mechanisms: reduced osteoclast motility, inhibition of carbonic anhydrase II – a key enzyme in bone resorption – and prevention of osteoclast precursor differentiation into their mature form. The effect on bone is temporary; in fact, osteoclasts retract and ‘escape’ the effects of continuously administered calcitonin within 24–48 h (14, 17). The efficacy of calcitonin in calcium regulation is lower than that of other antagonist calcium-regulating hormones such as calcitriol and parathyroid hormone.

Types of calcitonin, pro-calcitonin and molecular aspects miRNAs

Mature human calcitonin originates from the calcitonin-I (CALC-I) gene, one of four genes (from CALC-I to CALC-IV) with nucleotide sequence homologies (18). The transcript of the CALC-I gene, located on the short arm of chromosome 11, generates mRNA that contain six exons, calcitonin precursor and CGRP-I (17). The CALC-I gene is processed in three mRNAs by tissue-specific alternative splicing: CT-I (exons from 1 to 4) in thyroid parafollicular cells, CT-II (exons from 1 to 3, partial 4, 5 and 6) in the liver, and CGRP-I (all exons except 4) in neural tissues (19). The polypeptide CT-I precursor, known as pre-procalcitonin (Pre-PCT), is a peptide comprising 141 amino acids. Early in post-translational processing Pre-PCT is cleaved by an endopeptidase in the amino terminus region after the first 25 amino acids, resulting in a 116 amino acid polypeptide called PCT (20). The amino acid sequence of PCT is subsequently cleaved by a convertase enzyme to generate the nPCT of 57 amino acids at the N-terminal, the immature non-amidated calcitonin of 33 amino acids centrally, and the calcitonin carboxyl-terminal peptide-I (CCP-I) of 21 amino acids at the C-terminal (21).

CT-II precursor differs from CT-I precursor only in the last eight amino acids, which produce specific C-terminal peptides (CCP-II). CGRP-I precursor is translated in the N-terminal region into mature CGRP-I, a potent vasodilator that stimulates glomerular filtration, and a cryptic peptide (22). Finally, post-translational amidation produces mature calcitonin, considered to be immunoreactive. Interestingly, thyroid parafollicular cells and neuroendocrine cells in the lungs and bowel produce PCT as well as calcitonin (23). PCT is not secreted into blood, but may be released during bacterial infections and is widely used as a marker in such situations (24). It is also considered a useful biomarker in the diagnosis and follow-up of MTC (25). In healthy individuals all these component peptides, including PCT, are present at very low serum concentrations, and are produced by the neuroendocrine cells in the lungs and thyroid gland (26).

Recent papers have studied the possible relationship between calcitonin or PCT and miRNAs (27, 28, 29, 30). miRNAs are implicated in biological processes such as cellular differentiation, proliferation, and apoptosis; they are stable and can be detected in clinical samples and used as biomarkers for the early diagnosis of several diseases (31). miR-323 is reportedly highly expressed in MTC and some articles support its role in thyroid malignancies (32), but conversely, a recent study found no significant relationship between miR-323 and serum calcitonin levels in MTC patients with or without RET mutation (28). In contrast, there was a statistically significant negative association between miR-224 expression and serum calcitonin levels on diagnosis in a large cohort of MTC patients (27). miR-224 can in fact be considered an independent prognostic marker, given its significant association with patient survival (27). Finally, miR-125b regulates PCT expression by mediating the transcriptional activity of STAT3 in human monocytes (30). miR-125b enhances the production of total STAT3 and phosphorylated STAT3 while reducing the PCT expression of CT (33). A very interesting future research field could be investigation of the correlation between overexpressed miRNAs and PCT or calcitonin levels in MTC and NENs, their biological effects in the pathogenesis of human cancers and their use as prognostic biomarkers in MTC patients.

Tissue expression of calcitonin

A broad spectrum of NENs expresses calcitonin in their tissue. In the last 30 years it has been established that not only is calcitonin not specific for MTC, but that some MTCs do not express it at all, making their pathologic classification unclear (34). They were initially referred to as ‘atypical medullary thyroid carcinomas’, then as ‘calcitonin-negative neuroendocrine tumors of the thyroid’ or ‘non-medullary neuroendocrine tumors of the thyroid’.

Several cases of extra-thyroid calcitonin-expressing NENs have been described over the years. Prostate cancers with NE dedifferentiation have also been reported. In one of the first studies, 53 prostate cancer cases were analyzed for neuroendocrine dedifferentiation: eight of them were found to express neuroendocrine markers and, of these, two were immunoreactive for calcitonin (35). In a later case series of 42 specimens of radical prostatectomy (36), the presence of calcitonin-positive neuroendocrine cells was demonstrated in normal tissue: levels were lower in hyperplastic nodules of benign prostatic hyperplasia and markedly reduced in cases of prostate cancer. This finding conflicted with those observed in both established prostate cancer cell lines and tissue from human primary tumors (37, 38). These authors not only observed higher calcitonin mRNA expression in cancer compared to normal and hyperplastic tissues, but they also localized its expression within the tissue. It was more common in the basal epithelial cells than in the luminal epithelium and stromal prostate compartment in benign and low-grade cancers, while it was detected throughout the luminal epithelium in higher grade tumors (Gleason score 7–10), and with a stronger signal. Furthermore, tumor progression has been associated with a loss of spatial specificity and increased intensity of staining: cases with higher expression were those that displayed metastatic disease and poor prognosis (39). However, calcitonin may have a predictive and therapeutic role as well as a potential diagnostic and prognostic role in prostate cancer. Experiments on cell lines revealed that calcitonin expression is associated with chemoresistance to etoposide, dexamethasone and selenite through activation of the Akt-survivin pathway that establishes apoptosis resistance (38).

The second most common site for calcitonin-expressing NENs is the larynx, with more than 80 cases described in the last 30 years. In a case series of 20 laryngectomy specimens (40), non-neoplastic neuroendocrine cells accounted for around 5% of the total number of epithelial cells in laryngeal tissue, mostly located in the middle layer of the respiratory epithelium of the ventricle and subglottic region. The specimens were all reactive to chromogranin A and synaptophysin, but not to calcitonin. Laryngeal NENs are rare (around 0.6% of laryngeal malignancies), but they account for 59% of non-squamous carcinomas arising in this site. They are usually large cell neuroendocrine carcinomas and, like MTC, are often associated with stromal amyloid and TTF1 (albeit focal in laryngeal tumors) and calcitonin immunoreactivity (in 80% of cases) (41). Differential diagnosis between thyroid and laryngeal primary forms is thus based on the integration of clinical, biochemical and radiological data (42). Over 90% of laryngeal NENs arise near the aryepiglottic fold, arytenoid or false vocal cord, while thyroid NENs invade the subglottis or trachea, sparing the supraglottis. Skin metastases are more common in laryngeal neurendocrine carcinomas than in medullary thyroid carcinomas (40).

Calcitonin expression is common in pancreatic NENs (pNENs) (Fig. 1), but most of our knowledge comes from single case reports where the finding was consequent to the discovery of inappropriately high serum calcitonin levels. A recent study explored the effective frequency of calcitonin tissue expression and assessed the clinicopathological features of this subgroup of pNENs (25 out of 229 cases) (43). More than 10% of them showed various proportions of calcitonin immunostaining, independently of their functional state. In functioning tumors, calcitonin was co-expressed almost exclusively with insulin. A possible explanation is that calcitonin belongs to the same amylin/islet amyloid polypeptide superfamily that is co-secreted with insulin. However, no differences in clinicopathological parameters were seen compared to non-calcitonin expressing tumors. Differential diagnosis between primitive pancreatic MTC and MTC metastasized to the pancreas may be based on the detection of TTF1 immunoreactivity in the latter but not in the former.

Figure 1
Figure 1

Histopathological features of a calcitonin-secreting pancreatic NEN (A). A neuroendocrine neoplasm of the pancreas can be seen in the lower part of this field. It was composed of mid-sized cells with nuclei characterized by ‘salt and pepper’ chromatin and granular eosinophilic cytoplasm. (Hematoxylin and eosin stain, 100× magnification). One year later, this neoplasm caused distant metastasis to the adrenal gland. (B and C) Cells were diffusely immunoreactive to chromogranin (B) and focally to calcitonin (C) staining (100× magnification) d. Ki67 Labeling index was around 5% in a ‘hot spot’ area (400× magnification).

Citation: European Journal of Endocrinology 183, 6; 10.1530/EJE-20-0506

The immunohistochemical expression of calcitonin was also assessed in pheochromocytomas (44, 45, 46), an unusual form of NEN. Reactivity confined to cellular groups was observed in 34% of sporadic forms, in 43% of forms occurring in the context of multiple endocrine neoplasia (MEN) syndrome and in 25% of other forms and syndromes (e.g. von Hippel Lindau).

Calcitonin measurement

Methods

Calcitonin can be detected in the blood using several methods. It was first measured by radioimmuno assay (RIA), using polyclonal antibodies able to recognize mature and immature monomers of calcitonin and other circulating forms (precursors of calcitonin and degradation products) (47). However, this method lacks both specificity and sensitivity, leading to its replacement by two-sided immuno radiometric assays (IRMAs). This improved specificity through the use of two monoclonal antibodies that recognize two different specific epitopes in calcitonin (48). The first antibody, labeled with I125 tracer, binds the calcitonin region in the 11–17 amino acid sequence, while the second binds the solid phase and the amino-terminal (26–32) region. The calcitonin molecules are captured in a sandwich complex, whose radioactivity is directly proportional to the calcitonin content. The limit of detection of this assay is 2.5 pg/mL (48).

However, plasma calcitonin levels are increasingly analyzed by a specific sandwich enzyme-linked immunoassay (ELISA) technique. Since 2000, test manufacturers have moved from radiolabeled systems to fluorescent and chemiluminescent tests, which have been used for MTC identification (49). The chemiluminescence test (ILMA) minimizes cross-reactivity and recognizes the monomeric form of serum calcitonin, enabling the early identification of patients with recurrent MTC (50). ILMA also uses two monoclonal antibodies, but unlike IRMA, they recognize the 11–23 and 21–32 regions and the limit of detection is 1 pg/mL. This makes it more efficient than IRMA, especially for detecting low serum concentrations (49).

In some cases, heterophilic antibodies interfere with calcitonin measurement, leading to a false positive or falsely higher result. Two-site immunometric chemiluminescent assays (ICMAs), which are highly specific for monomeric calcitonin, avoid this problem (51). Despite this, a recent case report found falsely high calcitonin levels with ICMA due to heterophilic antibody interference, and in the same paper a literature review revealed a number of cases of heterophilic antibody interference with ICMA, IRMA and chemiluminescence assay (CLIA) (52). When calcitonin levels are altered due to interference, as in the case of heterophilic antibodies or macrocalcitonin (53), a calcitonin stimulation test (calcium and/or pentagastrin test) or a dilution test (lack of linearity) could be considered.

Recent years have seen the development of numerous automated calcitonin assays, such as those produced by Nichols Institute Laboratories (NID), Diagnostic Product Corporation (DPC) and DiaSorin (DS). Their clinical and analytical quality have been evaluated in many papers, revealing discrepancies in the identification of immunoreactive calcitonin, and important differences in their limits of detection (54). Camacho et al. developed a new method for the measurement of serum calcitonin, an immunofluorometric assay (IFMA) with a limit of detection of 1 pg/mL (55). It is based on two monoclonal antibodies, one linked to the solid phase and specific for the 11–23 amino acid sequence, and the other biotinylated and specific for the 17–32 amino acid sequence (55).

The latest assay developed to measure serum calcitonin is electrochemiluminescence immunoassay (ECLIA). This is a sandwich immunoassay based on streptavidin-biotin technology. One of the calcitonin-specific antibodies is biotinylated and binds to streptavidin-coated microparticles. The second antibody, labeled with a ruthenium complex, is used for calcitonin detection. The automated ECLIA assay benefits from a shorter test time and broader measurement range, thereby enabling the prompt, accurate diagnosis of calcitonin-related diseases (54, 56).

Interpretation of calcitonin levels

Normal calcitonin levels according to age, gender, and lifestyle habits

Calcitonin levels should be interpreted according to age and gender (57). They are normally higher in the pediatric population. Using a CLIA (Immulite 2000 XPi, from Siemens Diagnostics), Castagna et al. showed in a group of 2740 pediatric subjects aged up to 16 years that mean serum calcitonin levels were higher during the first and second year of life (9.81 ± 8.8 pg/mL, range 2.0–48.9, and 4.56 ± 2.64 pg/mL, range 2.0–14.7, respectively) compared to older ages (58). The highest levels of all were observed in babies under 6 months (11.3 ± 9.5 pg/mL, range 2.0–48.9). Calcitonin levels dropped significantly from the third year of life, becoming similar to those in adults. No difference between the genders was seen in this population (58). A limitation of this study might be the method, as calcitonin was only detected in 38.5% of the analyzed samples.

In a very recent study, Eckelt et al. used the more sensitive ECLIA (Cobas System, Roche Diagnostics GmbH) to assess calcitonin levels in a cohort of 6090 samples from Caucasian pediatric subjects aged up to 18 years, finding detectable calcitonin levels in 89.5% of samples (59). In accordance with the previous study, the highest levels were observed in newborns aged under 3 months (mean 21.3 ± 10.3 pg/mL, range 6.1–72.7 in boys, and 18.2 ± 6.6 pg/mL, range 8.4–40.0 in girls). It also confirmed that calcitonin levels drop rapidly between 1 month and 4 years for boys and 5 years for girls. In contrast with Castagna et al., Eckelt et al. found that calcitonin levels decreased moderately between 4/5 years and 9.5 years, converging to the reference range for adults starting from 12.5 years for boys and 13 years for girls (59). The authors also found significantly higher calcitonin levels in boys than girls from the second year of life.

Gender differences in calcitonin levels have also been observed in healthy adults (54, 57). A recent prospective study evaluating 783 healthy subjects (398 women and 385 men) by ECLIA showed median calcitonin levels of 0.8 pg/mL (range <0.5–1.8, peak 12.7 pg/mL) in women and 3 pg/mL (range 1.6–5.0, peak 18.0 pg/mL) in men (54). All these studies confirmed the recommendation in the American Thyroid Association (ATA) guidelines that serum calcitonin concentrations should be interpreted in the setting of gender-specific reference intervals (60). This difference is because men have twice as many C cells as women (61).

Lifestyle habits may be linked to moderate hypercalcitoninemia. In men, smoking was associated with significantly higher calcitonin levels (>10 pg/mL, peak=21.4 pg/mL) compared to non-smokers (57). Female smokers also showed higher calcitonin levels than non-smokers, although the difference was not significant. Alcohol consumption also seems to affect calcitonin concentrations. Acute alcohol ingestion results in increased plasma calcitonin levels (62), whereas contrasting results are reported for chronic alcohol use (63, 64). However, physical activity does not seem to have a noticeable effect on basal calcitonin concentration (65, 66).

False positives and false negatives

Elevated serum calcitonin levels are highly sensitive for MTC, but they are not highly specific (Table 1). Several drugs can stimulate calcitonin secretion (Table 1): for example, proton pump inhibitors (PPI) induce calcitonin secretion after 2-4 months of treatment, through an increase in gastrin hypersecretion (67, 68). Furthermore, several thyroid and non-thyroid diseases may be associated with low-moderate increases in serum calcitonin concentrations. Up to 49% of C-cell hyperplasia (CCH) cases are associated with slightly elevated basal (between 10 and 20 pg/mL) and stimulated (<560 pg/mL) calcitonin levels (54, 57, 69). Follicular and papillary thyroid carcinomas could also be associated with CCH and slightly high calcitonin levels (70, 71). Cases have also been reported of benign multinodular goiter with false positive calcitonin associated with neither CCH nor MTC in surgical specimens (72, 73). Discordant data are reported for chronic autoimmune thyroiditis (74, 75, 76). However, case series have reported moderately high calcitonin levels in patient subgroups, probably caused by progressive C-cell damage due to lymphocytic infiltration (76, 77) or, in 20% of patients in one case series, by CCH (61).

Table 1

Factors associated with low-moderately elevated serum calcitonin levels in non-medullary thyroid carcinoma.

Drugs
 PPI
 Glucocorticoids
 Beta-blockers
 Glucagon
 Enteroglucagon
 Pancreozymin
 CGRP inhibitors, used for migraine treatment
Non-thyroid non-tumor diseases
 Hypergastrinemia (chronic anthropic gastritis, Zollinger-Ellison syndrome)
 Hypercalcemia (including hyperparathyroidism)
 Pseudohypoparathyroidism
 Chronic renal insufficiency
 Pernicious anemia
 Hepatic cirrhosis
 Pancreatitis
 Inflammatory states (including sepsis)
Non-thyroid neoplasms
 NENs (including pheochromocytoma, paraganglioma, entero-pancreatic NEN, insulinoma, esophageal NEN, small cell lung carcinoma)
 Breast cancer
Methodology
 Heterophilic antibodies
 Macrocalcitonin

CGRP, calcitonin gene-related peptide; NENs, neuroendocrine neoplasms; PPI, proton pump inhibitors.

Among non-thyroid non-tumor diseases (Table 1), all conditions causing hypergastrinemia (such as atrophic gastritis and gastrinoma) or hypercalcemia (such as hyperparathyroidism) are strongly associated with high serum calcitonin levels (2, 68). Hypergastrinemia and hypercalcemia are, in fact, strong calcitonin secretagogues, and both are used in stimulatory tests to assess calcitonin secretion. In contrast, elevated calcitonin levels in patients with chronic renal insufficiency are related to lower calcitonin clearance (78).

Several types of tumors, including breast cancer and NENs, may also be associated with ectopic calcitonin secretion (2) (Table 1). Hypersecretion of calcitonin by NENs is rare; in fact, in functional NENs, calcitonin secretion is less common than other hormone secretions causing endocrine paraneoplastic syndromes (79). Table 2 summarizes the main features of the calcitonin.-secreting NENs reported in the literature (1, 5, 7, 40, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94). Pancreatic, laryngeal and lung NENs are most frequently associated with hypercalcitoninemia, but calcitonin secretion has also been described in duodenal, esophageal, cutaneous and paranasal NENs. The signs and symptoms of calcitonin-secreting NENs are usually due to mass effect, although calcitonin can cause diarrhea in some patients (especially in diseases with a high tumor burden). Diarrhea is usually secretive, and can also occur at night and while fasting (93).

Table 2

Calcitonin secreting NENs reported in the literature.

ReferenceCases (n)Organ-histologyAgeSexSymptomsBasal calcitoninTreatmentPost-treatment CTOutcome
Value (peak after ST)Normal range
(42)1Larynx – moderately differentiated NET59MNeck mass, painful s.c. nodules50 pg/mL (56.6)0–10Surgery; octreotide: 30 mg/4 weeks; everolimus: 10 mg/dayN/APartial response after 15 months follow-up
(93)1Pancreas – well differentiated NET (metastatic)59MChronic diarrhea, weight loss of 4 kg>2000 pg/mLNAOctreotide: 30 mg/4 weeks (increased to /2 weeks); everolimus: 10 mg/day; radioembolization; ondansetronPersistently elevatedStable disease after 5 years follow-up
(81)1Esophagus – well differentiated NET (not metastatic)41FMild dysphagia, feeling of food getting stuck570 pg/mL0–5Endoscopic resection and cervical lymph node dissectionNormalizedFree of disease after 2 years follow up
(5)2Pancreas – well differentiated NET (non-metastatic and metastatic)53MVague abdominal discomfort253 pg/mL0–10Distal pancreatectomyNormalizedFree of disease after 2 years follow-up
78FAsymptomatic126 pg/mL0–10Distal pancreatectomy and liver metastasectomyNormalizedFree of disease after 2 years follow-up
(1)219 lung; 10 pancreas; 1 stomach; 1 appendix – 10 well differentiated and 2 poorly differentiated (all metastatic)52 (37–86)**M: 12

F: 9
8/24 diarrhea (6 also with carcinoid syndrome)> 100 pg/mL (higher in poorly differentiated and in high grade tumors)14 resections of primary tumors + median of 2 (1–6) lines of treatment1 case: decreased after SSA, 8/11 patients increased (highest value before death)NA
(7)1Larynx – poorly differentiated adenocarcinoma with neuroendocrine features57MPainful neck mass, otalgia, odynophagia, and hoarseness157 pg/mL0–8Total laryngectomy, bilateral neck dissection + RT35 pg/mLMetastasis appearance after 6 months (calcitonin increased to 320 pg/mL)
(86)1Pancreas – well differentiated NET (metastatic to liver)38MUnintentional weight loss, sweating and fatigue1137 pg/mL0–8.5Octreotide: 20 mg/4 weeks + 2 cycles of PRRT (yttrium-90-DOTATOC)After SSA: 612 pg/ml

After PRRT: 336 pg/ml
Stable disease and symptoms free after 7 years follow-up
(80)1Lung – large cell neuroendocrine carcinoma47FWeight loss, abdominal pain303 pg/mL0–10CHT (cisplatin etoposide) + 1 cycle PRRTAfter CHT: 152.3 pg/mLPR after CHT; died of pneumonia after 1 cycle PRRT
(94)1Duodenum – well differentiated NET63FAsymptomatic114 pg/mL0–11.5SurgeryNormalizedFree of disease
(90)2Pancreas – histology NA70FFinal stage: cachexia, general weakness625 pg/mL (no increase after PG test)0–20Patient refused treatmentNADOD
Pancreas – NET69FAbdominal pain103 (no increase after PG test)0–5Octreotide: 20 mg/4 weeks for 2 months; left- pancreatectomy, splenectomy, cholecystectomy atypical liver-resection of one metastasis86.9 pg/mL (not radically resected tumors)NA
(40)1Larynx – moderately differentiated NEC57Mhoarseness, dysphagia, voice change, foreign-body sensation in the throatElevated (after metastasis: 599 pg/mL)Laryngectomy and neck dissectionNAAfter 27 months: DOD
(88)51 mediastinal tumor of undetermined origin – poorly differentiated45FNA54.0 pg/mL (55.7)0–10NANAAfter 7 months: DOD
1 larynx – moderately differentiated large cell NEC61MNA16.3 mg/mL (29.2)0–10NANAAfter 32 months: DOD
3 lung – small cell NEC66MNA585 mg/mL (651)0–10NANAAfter 22 months: DOD
71MNA44.7 mg/mL (49.1)0–10NANAAfter 21 months: DOD
71MNA42.9 mg/mL (43.4)0–10NANAAfter 1 month: DOD
(87)1Lung – well differentiated NET58MNA730 pg/mL (758)Surgery + RT (for primary tumor); CHT for subsequent thyroid metastasisNormalization after CHTAfter 52 months: DOD
(83)1Larynx – moderately differentiated NEC69MHoarseness970 pg/mL0–300Partial laryngectomy + RT; surgery for subsequent local recurrence45 pg/mL (rising to 1210 pg/mL after recurrenceFree of disease
(91)1Larynx – atypical carcinoid55MHoarseness and dysphagia3790 pg/mL (6378)0–100RT + CHT + left neck dissection; total laryngectomy for recurrence; CHT for metastasisNAAfter 3 years: DOD
(89)1Lung – well differentiated neuroendocrine carcinoma72FAnterior chest discomfort340 pg/mL25–120Surgery105 pg/mLAfter 6 months: bone metastases
(92)1Larynx – poorly differentiated NEC54MHoarseness1200 pg/mL (1500)0–200SurgeryNANA
(84)*1Skin – Merkel cell carcinomaNAFNAElevatedSurgeryNormalization after cutaneous surgeryNA
(85)1Paranasal sinus – undifferentiated carcinoma70MLeft nasal bleeding4600 pg/mgNART + CHT; CHT for metastasisNAAfter 2 months: bone metastasis

*Full text not available (only data from abstract); ** median (range).

CHT, chemotherapy; DOD, died of disease; NA, not available; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; ST, stimultion test; RT, radiotherapy; SSA, somatostatin analogs. .

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). False negative results may also be caused by immunoassay interference, due to incorrectly stored serum or very high calcitonin levels (Hook effect) (97, 98).

In conclusion, all the above mentioned conditions should be considered before diagnosing a calcitonin-secreting NEN.

Basal and stimulated CT: the importance of gender-specific cut-offs

The routine measurement of serum calcitonin is controversial, as there are various doubts over its real advantage in the consistent detection of MTC. The ATA guidelines on MTC (60) and thyroid nodules (82) do not offer any definitive recommendations for or against calcitonin measurement in the diagnostic work-up of thyroid nodules. Conversely, several European authors support its use for the early diagnosis of MTC, enabling curative surgery and improved survival (99, 100). Although calcitonin values higher than 100 pg/mL are strongly suspicious of malignancy (60), MTCs may also be diagnosed in patients with lower values.

To improve the diagnostic performance of calcitonin assay, a calcitonin stimulation test may be applied in patients with moderately elevated values. However, there is no definitive basal or stimulated calcitonin cut-off values that consistently and accurately discriminate between MTC and other conditions associated with elevated calcitonin levels. The reasons for this lie in various unsolved questions, mainly in relation to differences in inter-laboratory and inter-assay calcitonin measurements. Indeed, current guidelines (60) recommend each center adopts its own cut-off value for basal and stimulated calcitonin.

Several studies describe the prevalence of MTC in patients with thyroid nodular disease and elevated basal calcitonin values. Although they did not all adopt the same cut-off value to identify patients with possible MTC, most reported that more than 40% of patients with basal calcitonin above 10–30 pg/mL had MTC (99, 101, 102, 103, 104, 105, 106). However, due to the retrospective design of the studies and the heterogeneity of the sample populations, significantly lower (from 3.6 to 22.7%) (77, 107, 108) or even higher (94.7%) rates of MTC were reported by other authors (103) adopting the same cut-off values.

To improve diagnostic performance, it may be helpful to evaluate calcitonin values after stimulation with pentagastrin or calcium. Given the limited availability of pentagastrin in recent years, calcium stimulation may be a valid alternative to predict the presence of MTC in patients with elevated basal calcitonin. As noted above, there is no unique basal calcitonin threshold predictive of the presence of MTC, and stimulated calcitonin may also fail to correctly diagnose MTC, especially when it leads to only mildly increased calcitonin levels. In fact, the stimulated calcitonin values observed in patients with MTC may also be reached in patients with CCH (109). For instance, pentagastrin-stimulated calcitonin values between 10 and 205 pg/mL have been found with both MTC and CCH (102).

In healthy individuals with no history of thyroid disease, calcium administration led to calcitonin elevation up to 119 and 85.7 pg/mL in males and females, respectively (110). Post-operative findings of MTC ranged from 100% to as low as 26.3% in patients indicated for thyroidectomy due to a pentagastrin-stimulated calcitonin level above 100 pg/mL (77, 99, 102, 103, 106, 107, 108, 109, 111, 112). For this reason, the fold increase after stimulation is more reliable than the absolute value of stimulated calcitonin, since stimulated calcitonin values are at least three to four times higher than the basal values in patients with MTC (97).

Stimulated calcitonin in thyroid NENs (MTC) the calcium stimulation test

The calcium stimulation test has some noteworthy features. It promotes calcitonin increase to a greater extent than pentagastrin, the peak is achieved 2 min after calcium injection, and males have higher calcium-stimulated calcitonin levels than females (54, 101, 104, 113, 114). Table 3 summarizes the main characteristics of the published studies on calcium-stimulated calcitonin cut-offs for differentiating MTC from non-MTC (including CCH), or MTC from normal tissue, in comparison with the diagnostic accuracy of basal calcitonin. Colombo et al. identified basal calcitonin >18.7 and >68 pg/mL and stimulated calcitonin >184 and >1620 pg/mL in females and males respectively as the best levels to distinguish MTC from non-MTC patients (101). In this study there was no difference in the diagnostic power of pentagastrin and calcium stimulation (101). Furthermore, on C-cell immunohistochemical examination, a stimulated calcitonin value <50 pg/mL corresponded to a mean of 30 cells per 10 fields, whereas a higher stimulated value was associated with a mean of 400 cells per 10 fields, often displaying a diffuse and nodular distribution pattern (101).

Table 3

Cut-offs of basal and calcium -stimulated CT.

Reference

Study population

Aim

Cut-off bCT (pg/mL)

Se (%)

Sp (%)

PPV (%)

NPV (%)

Ca stimulation test: dose and infusion

Timing of blood samples

Cut-off sCT (pg/ml)

Se (%)

Sp (%)

PPV (%)

NPV (%)

(90)40 pts with nodular goiter1.Differentiating MTC from non-MTCM: 681001001001002.3 mg/kg of elemental Ca infused at 10 mL/min0, 2, 5 and 15 minM: 16207510010099.9
F: 18.7100100100100F: 18410092.96.6100
2.Differentiating MTC+CCH vs normalM: 4.61001001001002.3 mg/kg of elemental Ca infused at 10 mL/min0, 2, 5 and 15 minM: 19290.9100100100
F: 2100100100100F: 32.6100100100100
(93)91 pts with thyroid nodules1.Differentiating MTC from non-MTCM: 6883.310010092.92.3 mg/kg of elemental Ca infused at 5 mL/min, min. time of 3 min0, 2, 5 and 10 minM: 54477.885.468.489.2
F: 2681.897.994.792F: 7910076.668.7100
2.Differentiating MTC+CCH from normalM: 892.88068.676.92.3 mg/kg of elemental Ca infused at 5 mL/min, minimum time of 3 min0, 2, 5 and 10 minM: 1928693.87164.7
F: 1091.993.77588.5F: 5594.693.777.488.9
(104)54 pts with thyroid nodules and sCT >100Differentiating MTC from CCH17.4806355852.3 mg/kg of elemental Ca infused in 3 min0, 1, 2, 3 and 5 min452858659 6079 89
M: 452758075100
F: 27410074
(105)41 pts with thyroid nodules and 10<bCT<100Differentiating MTC from non-MTC24.6*10074.3401002.5 mg/kg of elemental Ca infused at 10 mL/min0, 2, 5 and 10 min10010042.823100
47#5010010092.1186*1006030100
655.2#33.310010098.7
M: 544°

F: 79°
83.362.827.795.6
M: 452§

F: 274§
66.68036.393.3
≤ 452§5088.542.891.1
(106)149 consecutive pts with thyroid nodules1.Differentiating MTC from non-MTCM: 4353100100672.5 mg/kg of elemental Ca infused in 30 s0, 2, 3 and 5 minM: 15004810010065 76
F: 238110010083F: 78069100100
bCT+ Ca5510010068
sCT8110010083
2.Differentiating MTC N1a or N1bM: 10010029381002.5 mg/kg of elemental Ca infused in 30 s0, 2, 3 and 5 minM: 5011002938 29100
F:23100223010F:34110019100
3.Differentiating MTC N1bM: 10010074531002.5 mg/kg of elemental Ca infused in 30 s0, 2, 3 and 5 minM: 7411002628 26100 100
F:851005740100F:34110018100

*Lowest concentration obtained for patients with medullary thyroid carcinoma minus interassay variability; #Highest concentration obtained for patients without medullary thyroid carcinoma plus interassay variability; °cut-off proposed by Mian et al.; §cut-off proposed by Papadakis et al.

bCT, basal calcitonin; CCH, C cell hyperplasia; F, female; M, male; MTC, medullary thyroid carcinoma; NPV, negative predictive value; Pts, patients; PPV, positive predictive value; sCT, stimulated calcitonin; Se, sensitivity; Sp, specificity .

Mian et al. found that the best calcium thresholds for the identification of MTC were >26 and >68 pg/mL for basal calcitonin and >79 and >544 pg/mL for stimulated calcitonin in females and males, respectively, with similar diagnostic accuracy (104). Papadakis et al. identified different cut-off values, finding calcium-stimulated calcitonin >452 pg/mL in 75% of males with MTC and >274 pg/mL in 100% of females with MTC (115). Surprisingly, an appreciable number of patients with stimulated calcitonin levels >100 pg/mL presented differentiated thyroid carcinoma of follicular origin (115).

Rosario et al. did not find MTC in any patient with basal calcitonin ≤24.6 pg/mL or stimulated calcitonin ≤186.5 pg/mL, and all patients without MTC had basal calcitonin <47 pg/mL and stimulated calcitonin <655.2 pg/mL. MTC was found in 25% of patients with basal calcitonin between 24.6 and 47 pg/mL (116). The authors also applied the cut-offs proposed by Mian et al., obtaining 83.3% sensitivity and 62.8% specificity, and by Papadakis et al., obtaining 67% sensitivity and 80% specificity (116). There was no agreement on the best cut-off values between series, and none offered both sensitivity and specificity ≥85% (116).

Niederle et al. recently found MTC in all females and males with either basal calcitonin >23 and >43 pg/mL or calcium -stimulated calcitonin >780 and >1500 pg/mL, respectively (114). In this study early-peak stimulated calcitonin was found in CCH or cases with a low tumor burden (114). Pentagastrin stimulation was also used, with a similar diagnostic power (114). The same group confirmed these basal and calcium -stimulated calcitonin cut-offs in a recent publication (117), and showed that combining the two values (basal plus stimulated) did not improve diagnostic accuracy (117). They also found that a basal calcitonin cut‐off of >85 pg/mL for females and >100 pg/mL for males showed 100% sensitivity for diagnosing lateral neck lymph node metastasis.

Unfortunately, the available studies on calcitonin values after calcium administration adopted different calcium infusion protocols, with elemental calcium doses ranging from 2.3 to 2.5 mg/kg and i.v. infusion times from 30 s to 5–10 mL/min. Furthermore, the timing of the blood samples was not standardized (taken at various times between 0, 1, 2, 3, 5, 10 and 15 min). Calcium infusion was associated with fewer and less intense adverse effects than pentagastrin, was well tolerated and was preferred by patients (101). The side effects commonly reported were warm feeling or flushing, headache, paresthesia in the extremities or lips, abdominal cramping, urinary urgency and nausea (101, 116). In any case, continuous cardiac monitoring should be performed during the test to ensure prompt intervention in the event of cardiac alterations, as reported in one male subject (118). Although the standard protocol and the best cut-offs for calcium-stimulated calcitonin are still controversial, when a gender-specific cut-off is used this cheap, well-tolerated test promises to differentiate between various C-cell diseases and enable the early diagnosis of MTC in selected patients with mildly elevated basal calcitonin.

Stimulated calcitonin in extra-thyroid NENs

Elevated calcitonin may also be caused by extra-thyroid NENs (Table 2). In a multicenter prospective study for the analytical performance and clinical validation of basal serum calcitonin concentrations, more than 10% of NENs had serum calcitonin concentrations above the 97.5th percentile (54). For basal calcitonin in the gray area, a confirmatory stimulation test should help in differential diagnosis with MTC (104). Calcitonin-secreting NENs can be distinguished from C-cell diseases by their non-response to the stimulation test (104), although no specific cut-offs for stimulated calcitonin in this setting have been suggested in the literature. In fact, only a handful of case reports and small case series have reported calcitonin values after pentagastrin stimulation in calcitonin-secreting NENs (Table 2). The first published case was of a man with a laryngeal NEN that showed a poor response to pentagastrin, with basal calcitonin 1200 ng/L (the authors reported <200 ng/L as normal) and stimulated calcitonin 1500 and 1100 ng/L at 3 and 5 min, respectively, after pentagastrin administration (92). In contrast, in a second case, again involving a man with a laryngeal NEN, calcitonin levels doubled from 3790 pg/mL at baseline (normal value <10 pg/mL) to 6378 pg/mL 5 min after pentagastrin stimulation (91). In a prospective study on the suitability of pentagastrin stimulation in differential diagnosis of NENs of the foregut, Machens et al. found that a less than two-fold increase in serum calcitonin levels was significantly correlated with both non-MTC NENs (one mediastinal and one laryngeal NEN) and small cell lung carcinoma (SCLC) (3 cases) (88). Immunostaining of tissue specimens for calcitonin was positive in the patients with mediastinal and laryngeal NEN, but negative in the two SCLC patients with adequate tissue samples. Similarly, another case of lung NET showed no increase in calcitonin levels after pentagastrin (730 pg/mL at baseline, 758 pg/mL after stimulation) (87), nor did two cases of women with pNENs (90).

The unavailability of pentagastrin in most countries has led to the need to standardize other stimulation tests, including for the differentiation of calcitonin-secreting NENs from MTC. In a recent case report (42) calcium-stimulated calcitonin was included in the diagnostic work-up of a calcitonin-secreting laryngeal NEN. The basal calcitonin was 50 pg/mL (normal value <10 pg/mL), increasing to a peak of 56.6 pg/mL 10 min after calcium infusion. The calcium test was considered negative because of the low calcitonin peak value, even though the baseline value was five times higher than the normal range. This result, together with the negative measurement of calcitonin in the fine-needle aspirate washout (FNA-CT), suggested that the calcitonin production was extra-thyroid in origin; this was confirmed by the histological thyroid examination.

The measurement of basal and stimulated calcitonin should therefore be included in the differential diagnosis between thyroid and extra-thyroid NENs, but further studies are needed to define the specific cut-offs.

Calcitonin measurement in fine-needle aspirate washout

Ultrasound-guided fine-needle aspiration cytology (FNAC) of a thyroid nodule is often used for the preoperative diagnosis of MTC, although its diagnostic accuracy is not as high as for papillary thyroid carcinoma (PTC), because of the low cellularity, variety of cellular morphologies, and non-typical cell shapes that could be present in MTC (119, 120, 121). The reported accuracy of FNAC in diagnosing MTC in patients with nodules ranges from 50 to 85% (120, 121, 122, 123). Several studies found that the FNA-CT from thyroid nodules may significantly improve the sensitivity of MTC diagnosis (123, 124, 125, 126, 127). De Crea et al. used CLIA (Liaison XL, DiaSorin) to measure calcitonin, finding that the highest sensitivity and accuracy for MTC diagnosis by FNA-CT was achieved with cut-off values of >10.4 pg/mL and FNA-CT/serum calcitonin ratio >1.39. The authors showed that the FNA-CT/serum calcitonin ratio was particularly useful in patients with extremely high serum calcitonin levels, as these are potentially caused by peripheral blood contamination of needle washout fluid, with improved accuracy over both FNA-CT alone (9% vs 85%) and FNAC alone (90 vs 85%) (123). A more recent study measured FNA-CT levels by ECLIA with the Elecsys calcitonin test system (Roche Diagnostics), reporting a cut-off value for FNA-CT of 21.0 pg/mL, leading to 100% sensitivity and 100% specificity in distinguishing MTC-nodules from non-MTC nodules (127).

The diagnostic accuracy of FNA analysis has been reported to be markedly increased by immunocytochemistry for calcitonin in the FNA specimen, particularly when cytological morphology is ‘unusual’ in the presence of elevated serum calcitonin levels. However, this procedure is limited by technical concerns about the great pre-analytical variability and the need for samples with adequate cellularity, and it is not specific for MTC (CCH is a false positive) (124). Based on this evidence, the ATA guidelines recommend that when FNA findings are inconclusive or suggestive of MTC, calcitonin should be measured in the FNA washout fluid and immunocytochemical staining should be performed in the FNA sample to detect the presence of markers such as calcitonin, chromogranin and CEA and the absence of thyroglobulin (Grade B Recommendation) (60).

Clinical significance

As reported in a recent systematic review on 72 368 patients from 16 studies, only 0.32% of patients with thyroid nodules were diagnosed with MTC (128). Given this low prevalence, even though the sensitivity and specificity of basal and stimulated CT are very high, the need for routine CT measurement in patients with thyroid nodules is still under debate (128).

Based on the available evidence, we propose a diagnostic algorithm for patients with thyroid nodules and high calcitonin serum levels, reported in Fig. 2. After excluding any interferences, we recommend confirming high calcitonin levels by repeating measurements. If calcitonin levels normalize after eliminating confounding factors, diagnostic procedures may be stopped; otherwise, further examinations depend on their levels. For calcitonin >100 pg/mL, thyroid ultrasound is mandatory to identify suspicious thyroid nodules, which require subsequent FNAC and CT-FNA, while immunocytochemistry for calcitonin is considered optional. For borderline values (10–100 pg/mL), a calcium stimulation test could be helpful. Although cut-off values vary in different studies, the result can be assessed in relation to the increase from the baseline. A stimulated calcitonin value less than twice the baseline is not suggestive of MTC and supports the execution of whole-body imaging. A value of three-four times the baseline, reaching a peak >80 pg/mL in women and >100 pg/mL in men, is very suggestive of MTC and therefore requires FNAC and CT-FNA.

Figure 2
Figure 2

Diagnostic algorithm for patients with high serum calcitonin levels. Current guidelines recommend that each center adopts its own cut-off value for basal CT. List of abbreviations: WB, whole body.

Citation: European Journal of Endocrinology 183, 6; 10.1530/EJE-20-0506

In our opinion, like that of other authors (76, 99, 107, 111), CT serum testing in the context of thyroid nodule evaluation enables the early diagnosis of a potentially more aggressive tumor and improves sensitivity of the FNAC, which actually confirms the diagnosis of MTC in less than 50% of patients (120). Our opinion is supported by the fact that the high reliability and sensitivity of the new immunochemiluminometric CT measurement completely eliminates cross-reactivity with procalcitonin and other related peptides, which leads to falsely elevated serum CT levels (heterophilic antibodies and macrocalcitonin) in up to 3.7% of cases (57).

Conclusions

The interpretation of increased serum calcitonin is still a gray area in endocrinology given the many confounding factors, the multiple assays and protocols for stimulation tests, the different cut-offs for both basal and stimulated calcitonin, and above all, its possible secretion by both non-neuroendocrine and neuroendocrine neoplasms. While a higher calcitonin serum level suggests MTC, it is not a pathognomonic sign. A careful diagnostic evaluation of all patients presenting with hypercalcitoninemia is therefore essential for an accurate early diagnosis identifying the thyroidal or extra-thyroidal origin of the secretion, essential for its correct management.

Declarations of interest

Andrea Isidori is an Associate Editor of European Journal of Endocrinology. He was not involved in the editorial or peer review process for this paper, on which he is listed as an author. The other authors have nothing to disclose.

Funding

Ministerial research project PRIN2017Z3N3YC.

Author contribution statement

E Gi, V G, B A, E Gu, P M conceived and designed the review. E Gi, V G, B A, P M, C S, T F, G P collected the data and co-wrote the manuscript. E Gu conceived the tissue expression section and Fig. 1. A M I, A A L C and A F contributed to the revision of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

This review is part of the ‘NIKE’ project (Neuroendocrine tumors Innovation Knowledge and Education) led by Prof Annamaria Anita Livia Colao and Prof Antongiulio Faggiano, which aims to increase knowledge of NETs. We would like to acknowledge the project coordinators. Diego Ferone (Genoa) and Andrea M Isidori (Rome), and all those who contributed: Manuela Albertelli (Genoa), Filomena Bottiglieri (Naples), S Campione (Naples), Federica de Cicco (Naples), Alessandra Dicitore (Milan), Giuseppe Fanciulli (Sassari), Francesco Ferraù (Messina), Marco Gallo (Turin), Federica Grillo (Genova), Erika Grossrubatscher (Milan), Andrea Lania (Rozzano), Fabio Lo Calzo (Naples), Erika Messina (Messina), Roberta Modica (Naples), Giovanna Muscogiuri (Naples), Luca Pes (Cagliari), Genoveffa Pizza (Naples), Riccardo Pofi (Rome), Carmen Rainone (Naples), Paola Razzore (Turin), Laura Rizza (Rome), Manila Rubino (Milan), Rosaria Maddalena Ruggeri (Messina), Emilia Sbardella (Rome), Franz Sesti (Rome), Giovanni Vitale (Milan) and Maria Chiara Zatelli (Ferrara). We wish to thank the NETTARE Unit – NeuroEndocrine Tumor TAsk foRcE of ‘Sapienza’ University of Rome, Italy, led by Prof Andrea Lenzi, Prof Andrea M. Isidori and Prof Elisa Giannetta, for integrating the patient’s multidisciplinary clinical, diagnostic and therapeutic management and follow-up. Finally, we would like to thank Marie-Hélène Hayles MITI for revision of the English text.

References

  • 1

    Nozieres C, Chardon L, Goichot B, Borson-Chazot F, Hervieu V, Chikh K, Lombard-Bohas C & Walter T Neuroendocrine tumors producing calcitonin: characteristics, prognosis and potential interest of calcitonin monitoring during follow-up. European Journal of Endocrinology 2016 174 335341. (https://doi.org/10.1530/EJE-15-0917)

    • Search Google Scholar
    • Export Citation
  • 2

    Toledo SP, Lourenco Jr DM, Santos MA, Tavares MR, Toledo RA & Correia-Deur JE Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma. Clinics 2009 64 699706. (https://doi.org/10.1590/S1807-59322009000700015)

    • Search Google Scholar
    • Export Citation
  • 3

    Schneider R, Waldmann J, Swaid Z, Ramaswamy A, Fendrich V, Bartsch DK & Schlosser K Calcitonin-secreting pancreatic endocrine tumors: systematic analysis of a rare tumor entity. Pancreas 2011 40 213221. (https://doi.org/10.1097/MPA.0b013e3182015f5d)

    • Search Google Scholar
    • Export Citation
  • 4

    Blaustein A Calcitonin secreting struma-carcinoid tumor of the ovary. Human Pathology 1979 10 222228. (https://doi.org/10.1016/s0046-8177(7980010-6)

    • Search Google Scholar
    • Export Citation
  • 5

    Giannetta E, Gianfrilli D, Pozza C, Lauretta R, Graziadio C, Sbardella E, Baroli A, Caronna R, Chirletti P & Lenzi A et al. Extrathyroidal calcitonin secreting tumors: pancreatic neuroendocrine tumors in patients With multinodular goiter: two Case Reports. Medicine 2016 95 e2419. (https://doi.org/10.1097/MD.0000000000002419)

    • Search Google Scholar
    • Export Citation
  • 6

    Hakeem AH, Pradhan S, Bhele S & Tubachi J Primary calcitonin-secreting neuroendocrine carcinoma of the supraglottic larynx. Ear, Nose, and Throat Journal 2015 94 E34E35. (https://doi.org/10.1177/014556131509400104)

    • Search Google Scholar
    • Export Citation
  • 7

    LaBryer L, Sawh R, McLaurin C & Scofield RH Calcitonin-secreting neuroendocrine carcinoma of larynx with metastasis to thyroid. Case Reports in Endocrinology 2015 2015 606389. (https://doi.org/10.1155/2015/606389)

    • Search Google Scholar
    • Export Citation
  • 8

    Mascolo M, Altieri V, Mignogna C, Napodano G, De Rosa G & Insabato L Calcitonin-producing well-differentiated neuroendocrine carcinoma (carcinoid tumor) of the urinary bladder: case report. BMC Cancer 2005 5 88. (https://doi.org/10.1186/1471-2407-5-88)

    • Search Google Scholar
    • Export Citation
  • 9

    Copp DH & Cheney B Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood. Nature 1962 193 381382. (https://doi.org/10.1038/193381a0)

    • Search Google Scholar
    • Export Citation
  • 10

    Foster GV, Baghdiantz A, Kumar MA, Slack E, Soliman HA & Macintyre I Thyroid origin of calcitonin. Nature 1964 202 13031305. (https://doi.org/10.1038/2021303a0)

    • Search Google Scholar
    • Export Citation
  • 11

    Donoghue PC, Graham A & Kelsh RN The origin and evolution of the neural crest. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 2008 30 530541. (https://doi.org/10.1002/bies.20767)

    • Search Google Scholar
    • Export Citation
  • 12

    Johansson E, Andersson L, Ornros J, Carlsson T, Ingeson-Carlsson C, Liang S, Dahlberg J, Jansson S, Parrillo L & Zoppoli P et al. Revising the embryonic origin of thyroid C cells in mice and humans. Development 2015 142 35193528. (https://doi.org/10.1242/dev.126581)

    • Search Google Scholar
    • Export Citation
  • 13

    Erdogan MF, Gursoy A & Kulaksizoglu M Long-term effects of elevated gastrin levels on calcitonin secretion. Journal of Endocrinological Investigation 2006 29 771775. (https://doi.org/10.1007/BF03347369)

    • Search Google Scholar
    • Export Citation
  • 14

    Masi L & Brandi ML Calcitonin and calcitonin receptors. Clinical Cases in Mineral and Bone Metabolism 2007 4 117122.

  • 15

    Pondel M Calcitonin and calcitonin receptors: bone and beyond. International Journal of Experimental Pathology 2000 81 405422. (https://doi.org/10.1046/j.1365-2613.2000.00176.x)

    • Search Google Scholar
    • Export Citation
  • 16

    Chen Y, Shyu JF, Santhanagopal A, Inoue D, David JP, Dixon SJ, Horne WC & Baron R The calcitonin receptor stimulates Shc tyrosine phosphorylation and ERK1/2 activation. Involvement of Gi, protein kinase C, and calcium. Journal of Biological Chemistry 1998 273 1980919816. (https://doi.org/10.1074/jbc.273.31.19809)

    • Search Google Scholar
    • Export Citation
  • 17

    Felsenfeld AJ & Levine BS Calcitonin, the forgotten hormone: does it deserve to be forgotten? Clinical Kidney Journal 2015 8 180187. (https://doi.org/10.1093/ckj/sfv011)

    • Search Google Scholar
    • Export Citation
  • 18

    Wimalawansa SJ Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. Critical Reviews in Neurobiology 1997 11 167239. (https://doi.org/10.1615/critrevneurobiol.v11.i2-3.40)

    • Search Google Scholar
    • Export Citation
  • 19

    Schifter S Expression of the calcitonin gene family in medullary thyroid carcinoma. Peptides 1997 18 307317. (https://doi.org/10.1016/s0196-9781(9600169-6)

    • Search Google Scholar
    • Export Citation
  • 20

    Le Moullec JM, Jullienne A, Chenais J, Lasmoles F, Guliana JM, Milhaud G & Moukhtar MS The complete sequence of human preprocalcitonin. FEBS Letters 1984 167 9397. (https://doi.org/10.1016/0014-5793(8480839-x)

    • Search Google Scholar
    • Export Citation
  • 21

    Davies J Procalcitonin. Journal of Clinical Pathology 2015 68 675679. (https://doi.org/10.1136/jclinpath-2014-202807)

  • 22

    Gnaedinger MP, Uehlinger DE, Weidmann P, Sha SG, Muff R, Born W, Rascher W & Fischer JA Distinct hemodynamic and renal effects of calcitonin gene-related peptide and calcitonin in men. American Journal of Physiology 1989 257 E848E854. (https://doi.org/10.1152/ajpendo.1989.257.6.E848)

    • Search Google Scholar
    • Export Citation
  • 23

    Maruna P, Nedelnikova K & Gurlich R Physiology and genetics of procalcitonin. Physiological Research 2000 49 (Supplement 1) S57S61.

  • 24

    Wacker C, Prkno A, Brunkhorst FM & Schlattmann P Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet: Infectious Diseases 2013 13 426435. (https://doi.org/10.1016/S1473-3099(1270323-7)

    • Search Google Scholar
    • Export Citation
  • 25

    Trimboli P, Seregni E, Treglia G, Alevizaki M & Giovanella L Procalcitonin for detecting medullary thyroid carcinoma: a systematic review. Endocrine-Related Cancer 2015 22 R157R164. (https://doi.org/10.1530/ERC-15-0156)

    • Search Google Scholar
    • Export Citation
  • 26

    Snider Jr RH, Nylen ES & Becker KL Procalcitonin and its component peptides in systemic inflammation: immunochemical characterization. Journal of Investigative Medicine 1997 45 552560.

    • Search Google Scholar
    • Export Citation
  • 27

    Cavedon E, Barollo S, Bertazza L, Pennelli G, Galuppini F, Watutantrige-Fernando S, Censi S, Iacobone M, Benna C & Vianello F et al. Prognostic impact of miR-224 and RAS mutations in medullary thyroid carcinoma. International Journal of Endocrinology 2017 2017 4915736. (https://doi.org/10.1155/2017/4915736)

    • Search Google Scholar
    • Export Citation
  • 28

    Ehyaei S, Hedayati M, Zarif-Yeganeh M, Sheikholeslami S, Ahadi M & Amini SA Plasma calcitonin levels and miRNA323 expression in medullary thyroid carcinoma patients with or without RET mutation. Asian Pacific Journal of Cancer Prevention 2017 18 21792184. (https://doi.org/10.22034/APJCP.2017.18.8.2179)

    • Search Google Scholar
    • Export Citation
  • 29

    Le Y, Chen T, Xun K & Ding T Expression of the long intergenic non-coding RNA (lincRNA) of the NED25 gene modulates the microRNA-125b, STAT3, nitric oxide, and procalcitonin signaling pathways in patients with sepsis. Medical Science Monitor 2018 24 45554566. (https://doi.org/10.12659/MSM.907496)

    • Search Google Scholar
    • Export Citation
  • 30

    Zhang F, Fan X, Bai Y, Lu J, Zheng M, Chen J, Liu Y, Chen Z & Zhu J miR-125b regulates procalcitonin production in monocytes by targeting Stat3. Microbes and Infection 2016 18 102108. (https://doi.org/10.1016/j.micinf.2015.09.027)

    • Search Google Scholar
    • Export Citation
  • 31

    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH & Ferrando AA et al. MicroRNA expression profiles classify human cancers. Nature 2005 435 834838. (https://doi.org/10.1038/nature03702)

    • Search Google Scholar
    • Export Citation
  • 32

    Mian C, Pennelli G, Fassan M, Balistreri M, Barollo S, Cavedon E, Galuppini F, Pizzi M, Vianello F & Pelizzo MR et al. MicroRNA profiles in familial and sporadic medullary thyroid carcinoma: preliminary relationships with RET status and outcome. Thyroid 2012 22 890896. (https://doi.org/10.1089/thy.2012.0045)

    • Search Google Scholar
    • Export Citation
  • 33

    Hua S, Liu X, Lv S & Wang Z Protective effects of cucurbitacin B on acute lung injury induced by sepsis in rats. Medical Science Monitor 2017 23 13551362. (https://doi.org/10.12659/msm.900523)

    • Search Google Scholar
    • Export Citation
  • 34

    Zhou Q, Yue S, Cheng Y, Jin J & Xu H Clinical and pathological analysis of 19 cases of medullary thyroid carcinoma without an increase in calcitonin. Experimental and Toxicologic Pathology 2017 69 575579. (https://doi.org/10.1016/j.etp.2017.05.003)

    • Search Google Scholar
    • Export Citation
  • 35

    di Sant’Agnese PA & de Mesy Jensen KL Neuroendocrine differentiation in prostatic carcinoma. Human Pathology 1987 18 849856. (https://doi.org/10.1016/s0046-8177(8780060-6)

    • Search Google Scholar
    • Export Citation
  • 36

    Abrahamsson PA, Dizeyi N, Alm P, di Sant'Agnese PA, Deftos LJ & Aumuller G Calcitonin and calcitonin gene-related peptide in the human prostate gland. Prostate 2000 44 181186. (https://doi.org/10.1002/1097-0045(20000801)44:3<181::aid-pros1>3.0.co;2-l)

    • Search Google Scholar
    • Export Citation
  • 37

    Shah GV, Thomas S, Muralidharan A, Liu Y, Hermonat PL, Williams J & Chaudhary J Calcitonin promotes in vivo metastasis of prostate cancer cells by altering cell signaling, adhesion, and inflammatory pathways. Endocrine-Related Cancer 2008 15 953964. (https://doi.org/10.1677/ERC-08-0136)

    • Search Google Scholar
    • Export Citation
  • 38

    Thomas S & Shah G Calcitonin induces apoptosis resistance in prostate cancer cell lines against cytotoxic drugs via the Akt/survivin pathway. Cancer Biology and Therapy 2005 4 12261233. (https://doi.org/10.4161/cbt.4.11.2093)

    • Search Google Scholar
    • Export Citation
  • 39

    Thakkar A, Bijnsdorp IV, Geldof AA & Shah GV Profiling of the calcitonin-calcitonin receptor axis in primary prostate cancer: clinical implications and molecular correlates. Oncology Reports 2013 30 12651274. (https://doi.org/10.3892/or.2013.2583)

    • Search Google Scholar
    • Export Citation
  • 40

    Chung JH, Lee SS, Shim YS, Kim SY, Nam SY, Kim DH & Cho KJ A study of moderately differentiated neuroendocrine carcinomas of the larynx and an examination of non-neoplastic larynx tissue for neuroendocrine cells. Laryngoscope 2004 114 12641270. (https://doi.org/10.1097/00005537-200407000-00023)

    • Search Google Scholar
    • Export Citation
  • 41

    Hirsch MS, Faquin WC & Krane JF Thyroid transcription factor-1, but not p53, is helpful in distinguishing moderately differentiated neuroendocrine carcinoma of the larynx from medullary carcinoma of the thyroid. Modern Pathology 2004 17 631636. (https://doi.org/10.1038/modpathol.3800105)

    • Search Google Scholar
    • Export Citation
  • 42

    Feola T, Puliani G, Sesti F, Modica R, Biffoni M, Di Gioia C, Carletti R, Anastasi E, Di Vito V & Centello R et al. Laryngeal neuroendocrine tumor With elevated serum calcitonin: a diagnostic and therapeutic challenge. Case report and review of literature. Frontiers in Endocrinology 2020 11 397. (https://doi.org/10.3389/fendo.2020.00397)

    • Search Google Scholar
    • Export Citation
  • 43

    Uccella S, Blank A, Maragliano R, Sessa F, Perren A & La Rosa S Calcitonin-producing neuroendocrine neoplasms of the pancreas: clinicopathological study of 25 cases and review of the literature. Endocrine Pathology 2017 28 351361. (https://doi.org/10.1007/s12022-017-9505-4)

    • Search Google Scholar
    • Export Citation
  • 44

    Fukayama M, Furukawa E, Shiozawa Y, Hayashi Y & Funata N Atypical endocrine granules in atypical endocrine tumor (AET) of the lung. An immunoelectron microscopic study. Acta Pathologica Japonica 1990 40 361366. (https://doi.org/10.1111/j.1440-1827.1990.tb01573.x)

    • Search Google Scholar
    • Export Citation
  • 45

    Hartmann CA, Gross U & Stein H Cushing syndrome-associated pheochromocytoma and adrenal carcinoma. An immunohistological investigation. Pathology, Research and Practice 1992 188 287295. (https://doi.org/10.1016/s0344-0338(1181206-9)

    • Search Google Scholar
    • Export Citation
  • 46

    Moreno AM, Castilla-Guerra L, Martinez-Torres MC, Torres-Olivera F, Fernandez E & Galera-Davidson H Expression of neuropeptides and other neuroendocrine markers in human phaeochromocytomas. Neuropeptides 1999 33 159163. (https://doi.org/10.1054/npep.1999.0012)

    • Search Google Scholar
    • Export Citation
  • 47

    Tobler PH, Tschopp FA, Dambacher MA, Born W & Fischer JA Identification and characterization of calcitonin forms in plasma and urine of normal subjects and medullary carcinoma patients. Journal of Clinical Endocrinology and Metabolism 1983 57 749754. (https://doi.org/10.1210/jcem-57-4-749)

    • Search Google Scholar
    • Export Citation
  • 48

    Motte P, Vauzelle P, Gardet P, Ghillani P, Caillou B, Parmentier C, Bohuon C & Bellet D Construction and clinical validation of a sensitive and specific assay for serum mature calcitonin using monoclonal anti-peptide antibodies. Clinica Chimica Acta: International Journal of Clinical Chemistry 1988 174 3554. (https://doi.org/10.1016/0009-8981(8890365-8)

    • Search Google Scholar
    • Export Citation
  • 49

    d’Herbomez M, Leclerc L, Vantyghem MC, Fourrier F, Proye C & Wemeau JL Clinical evaluation of a new sensitive calcitonin assay: study of specificity. Clinica Chimica Acta: International Journal of Clinical Chemistry 2001 311 149155. (https://doi.org/10.1016/s0009-8981(0100582-4)

    • Search Google Scholar
    • Export Citation
  • 50

    Engelbach M, Gorges R, Forst T, Pfutzner A, Dawood R, Heerdt S, Kunt T, Bockisch A & Beyer J Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements. Journal of Clinical Endocrinology and Metabolism 2000 85 18901894. (https://doi.org/10.1210/jcem.85.5.6601)

    • Search Google Scholar
    • Export Citation
  • 51

    Fugazzola L Stimulated calcitonin cut-offs by different tests. European Thyroid Journal 2013 2 4956. (https://doi.org/10.1159/000346020)

    • Search Google Scholar
    • Export Citation
  • 52

    Censi S, Cavedon E, Fernando SW, Barollo S, Bertazza L, Zambonin L, Zaninotto M, Faggian D, Plebani M & Mian C Calcitonin measurement and immunoassay interference: a case report and literature review. Clinical Chemistry and Laboratory Medicine 2016 54 18611870. (https://doi.org/10.1515/cclm-2015-1161)

    • Search Google Scholar
    • Export Citation
  • 53

    Alves TG, Kasamatsu TS, Yang JH, Meneghetti MC, Mendes A, Kunii IS, Lindsey SC, Camacho CP, Dias da Silva MR & Maciel RM et al. Macrocalcitonin is a novel pitfall in the routine of serum calcitonin immunoassay. Journal of Clinical Endocrinology and Metabolism 2016 101 653658. (https://doi.org/10.1210/jc.2015-3137)

    • Search Google Scholar
    • Export Citation
  • 54

    Kahaly GJ, Algeciras-Schimnich A, Davis TE, Diana T, Feldkamp J, Karger S, Konig J, Lupo MA, Raue F & Ringel MD et al. United States and European multicenter prospective study for the analytical performance and clinical validation of a novel sensitive fully automated immunoassay for calcitonin. Clinical Chemistry 2017 63 14891496. (https://doi.org/10.1373/clinchem.2016.270009)

    • Search Google Scholar
    • Export Citation
  • 55

    Camacho CP, Lindsey SC, Melo MC, Yang JH, Germano-Neto F, Valente Fde Fde O, Lima TR, Biscolla RP, Vieira JG & Cerutti JM et al. Measurement of calcitonin and calcitonin gene-related peptide mRNA refines the management of patients with medullary thyroid cancer and may replace calcitonin-stimulation tests. Thyroid 2013 23 308316. (https://doi.org/10.1089/thy.2012.0361)

    • Search Google Scholar
    • Export Citation
  • 56

    Schiettecatte J, Strasser O, Anckaert E & Smitz J Performance evaluation of an automated electrochemiluminescent calcitonin (CT) immunoassay in diagnosis of medullary thyroid carcinoma. Clinical Biochemistry 2016 49 929931. (https://doi.org/10.1016/j.clinbiochem.2016.05.006)

    • Search Google Scholar
    • Export Citation
  • 57

    d’Herbomez M, Caron P, Bauters C, Do Cao C, Schlienger JL, Sapin R, Baldet L, Carnaille B, Wemeau JLFrench Group GTE. Reference range of serum calcitonin levels in humans: influence of calcitonin assays, sex, age, and cigarette smoking. European Journal of Endocrinology 2007 157 749755. (https://doi.org/10.1530/EJE-07-0566)

    • Search Google Scholar
    • Export Citation
  • 58

    Castagna MG, Fugazzola L, Maino F, Covelli D, Memmo S, Sestini F, Fioravanti C, Ferraris Fusarini C, Scapellato C & Macchini F et al. Reference range of serum calcitonin in pediatric population. Journal of Clinical Endocrinology and Metabolism 2015 100 17801784. (https://doi.org/10.1210/jc.2014-4508)

    • Search Google Scholar
    • Export Citation
  • 59

    Eckelt F, Vogel M, Geserick M, Kirsten T, Bae YJ, Baber R, Schaab M, Thiery J, Pfaeffle R & Raue F et al. Calcitonin measurement in pediatrics: reference ranges are gender-dependent, validation in medullary thyroid cancer and thyroid diseases. Clinical Chemistry and Laboratory Medicine 2019 57 12421250. (https://doi.org/10.1515/cclm-2018-1186)

    • Search Google Scholar
    • Export Citation
  • 60

    Wells Jr SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF & Pacini F et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015 25 567610. (https://doi.org/10.1089/thy.2014.0335)

    • Search Google Scholar
    • Export Citation
  • 61

    Guyetant S, Rousselet MC, Durigon M, Chappard D, Franc B, Guerin O & Saint-Andre JP Sex-related C cell hyperplasia in the normal human thyroid: a quantitative autopsy study. Journal of Clinical Endocrinology and Metabolism 1997 82 4247. (https://doi.org/10.1210/jcem.82.1.3684)

    • Search Google Scholar
    • Export Citation
  • 62

    Rico H Alcohol and bone disease. Alcohol and Alcoholism 1990 25 345352.

  • 63

    Schuster R, Koopmann A, Grosshans M, Reinhard I, Spanagel R & Kiefer F Association of plasma calcium concentrations with alcohol craving: new data on potential pathways. European Neuropsychopharmacology 2017 27 4247. (https://doi.org/10.1016/j.euroneuro.2016.11.007)

    • Search Google Scholar
    • Export Citation
  • 64

    Vantyghem MC, Danel T, Marcelli-Tourvieille S, Moriau J, Leclerc L, Cardot-Bauters C, Docao C, Carnaille B, Wemeau JL & D’Herbomez M Calcitonin levels do not decrease with weaning in chronic alcoholism. Thyroid 2007 17 213217. (https://doi.org/10.1089/thy.2006.0216)

    • Search Google Scholar
    • Export Citation
  • 65

    Nelson ME, Meredith CN, Dawson-Hughes B & Evans WJ Hormone and bone mineral status in endurance-trained and sedentary postmenopausal women. Journal of Clinical Endocrinology and Metabolism 1988 66 927933. (https://doi.org/10.1210/jcem-66-5-927)

    • Search Google Scholar
    • Export Citation
  • 66

    Nishiyama S, Tomoeda S, Ohta T, Higuchi A & Matsuda I Differences in basal and postexercise osteocalcin levels in athletic and nonathletic humans. Calcified Tissue International 1988 43 150154. (https://doi.org/10.1007/BF02571312)

    • Search Google Scholar
    • Export Citation
  • 67

    Klinkenberg-Knol EC, Festen HP, Jansen JB, Lamers CB, Nelis F, Snel P, Luckers A, Dekkers CP, Havu N & Meuwissen SG Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety. Annals of Internal Medicine 1994 121 161167. (https://doi.org/10.7326/0003-4819-121-3-199408010-00001)

    • Search Google Scholar
    • Export Citation
  • 68

    Freston JW Omeprazole, hypergastrinemia, and gastric carcinoid tumors. Annals of Internal Medicine 1994 121 232233. (https://doi.org/10.7326/0003-4819-121-3-199408010-00012)

    • Search Google Scholar
    • Export Citation
  • 69

    Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C, Haas OA & Niederle B Sporadic hypercalcitoninemia: clinical and therapeutic consequences. Endocrine-Related Cancer 2009 16 243253. (https://doi.org/10.1677/ERC-08-0059)

    • Search Google Scholar
    • Export Citation
  • 70

    Borget I, De Pouvourville G & Schlumberger M Editorial: calcitonin determination in patients with nodular thyroid disease. Journal of Clinical Endocrinology and Metabolism 2007 92 425427. (https://doi.org/10.1210/jc.2006-2735)

    • Search Google Scholar
    • Export Citation
  • 71

    Albores-Saavedra J, Monforte H, Nadji M & Morales AR C-cell hyperplasia in thyroid tissue adjacent to follicular cell tumors. Human Pathology 1988 19 795799. (https://doi.org/10.1016/s0046-8177(8880262-4)

    • Search Google Scholar
    • Export Citation
  • 72

    Giovanella L, Suriano S, Cattaneo F & Bongiovanni M False-positive calcitonin results in patients with benign goiter. Clinical Chemistry and Laboratory Medicine 2011 50 407408. (https://doi.org/10.1515/CCLM.2011.783)

    • Search Google Scholar
    • Export Citation
  • 73

    Batista RL, Toscanini AC, Brandao LG & Cunha-Neto MB False positive results using calcitonin as a screening method for medullary thyroid carcinoma. Indian Journal of Endocrinology and Metabolism 2013 17 524528. (https://doi.org/10.4103/2230-8210.111677)

    • Search Google Scholar
    • Export Citation
  • 74

    Rosario PW & Calsolari MR Influence of chronic autoimmune thyroiditis and papillary thyroid cancer on serum calcitonin levels. Thyroid 2013 23 671674. (https://doi.org/10.1089/thy.2012.0564)

    • Search Google Scholar
    • Export Citation
  • 75

    Grani G, Nesca A, Del Sordo M, Calvanese A, Carbotta G, Bianchini M & Fumarola A Interpretation of serum calcitonin in patients with chronic autoimmune thyroiditis. Endocrine-Related Cancer 2012 19 345349. (https://doi.org/10.1530/ERC-12-0013)

    • Search Google Scholar
    • Export Citation
  • 76

    Turk Y, Makay O, Ozdemir M, Ertunc G, Demir B, Icoz G, Akyildiz M & Yilmaz M Routine calcitonin measurement in nodular thyroid disease management: is it worthwhile? Annals of Surgical Treatment and Research 2017 92 173178. (https://doi.org/10.4174/astr.2017.92.4.173)

    • Search Google Scholar
    • Export Citation
  • 77

    Karanikas G, Moameni A, Poetzi C, Zettinig G, Kaserer K, Bieglmayer C, Niederle B, Dudczak R & Pirich C Frequency and relevance of elevated calcitonin levels in patients with neoplastic and nonneoplastic thyroid disease and in healthy subjects. Journal of Clinical Endocrinology and Metabolism 2004 89 515519. (https://doi.org/10.1210/jc.2003-030709)

    • Search Google Scholar
    • Export Citation
  • 78

    Sabia R, Wagner M, Susa K, Lemke J, Rothermund L, Henne-Bruns D & Hillenbrand A Calcitonin concentrations in patients with chronic kidney disease on hemodialysis in reference to parathyroidectomy. BMC Research Notes 2019 12 439. (https://doi.org/10.1186/s13104-019-4479-6)

    • Search Google Scholar
    • Export Citation
  • 79

    Daskalakis K, Chatzelis E, Tsoli M, Papadopoulou-Marketou N, Dimitriadis GK, Tsolakis AV & Kaltsas G Endocrine paraneoplastic syndromes in patients with neuroendocrine neoplasms. Endocrine 2019 64 384392. (https://doi.org/10.1007/s12020-018-1773-3)

    • Search Google Scholar
    • Export Citation
  • 80

    Cvijovic G, Micic D, Kendereski A, Zoric S, Sumarac-Dumanovic M, Tatic S, Trivic A, Pejkovic-Stamenkovic D & Jeremic D Ectopic calcitonin secretion in a woman with large cell neuroendocrine lung carcinoma. Hormones 2013 12 584590. (https://doi.org/10.14310/horm.2002.1447)

    • Search Google Scholar
    • Export Citation
  • 81

    Fertig RM, Alperstein A, Diaz C, Klingbeil KD, Vangara SS, Misawa R, Reed J & Gaudi S Metastatic neuroendocrine tumor of the esophagus with features of medullary thyroid carcinoma. Intractable and Rare Diseases Research 2017 6 224229. (https://doi.org/10.5582/irdr.2017.01035)

    • Search Google Scholar
    • Export Citation
  • 82

    Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM & Schlumberger M et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016 26 1133. (https://doi.org/10.1089/thy.2015.0020)

    • Search Google Scholar
    • Export Citation
  • 83

    Insabato L, De Rosa G, Terracciano LM, Lupoli G, Montedoro D & Ravetto C A calcitonin-producing neuroendocrine tumor of the larynx: a case report. Tumori 1993 79 227230. (https://doi.org/10.1177/030089169307900315)

    • Search Google Scholar
    • Export Citation
  • 84

    Johannessen JV & Gould VE Neuroendocrine skin carcinoma associated with calcitonin production: a Merkel cell carcinoma? Human Pathology 1980 11 (Supplement) 586588.

    • Search Google Scholar
    • Export Citation
  • 85

    Kameya T, Shimosato Y, Adachi I, Abe K, Ebihara S & Ono I Neuroendocrine carcinoma of the paranasal sinus: a morphological and endocrinological study. Cancer 1980 45 330339. (doi:10.1002/1097-0142(19800115)45:2<330::aid-cncr2820450222>3.0.co;2-s)

    • Search Google Scholar
    • Export Citation
  • 86

    Kovacova M, Filkova M, Potocarova M, Kinova S & Pajvani UB Calcitonin-secreting pancreatic neuroendocrine tumors: a case report and review of the literature. Endocrine Practice 2014 20 e140e144. (https://doi.org/10.4158/EP13505.CR)

    • Search Google Scholar
    • Export Citation
  • 87

    Leboulleux S, Baudin E, Young J, Caillou B, Lazar V, Pellegriti G, Ducreux M, Schaison G & Schlumberger M Gastroenteropancreatic neuroendocrine tumor metastases to the thyroid gland: differential diagnosis with medullary thyroid carcinoma. European Journal of Endocrinology 1999 140 187191. (https://doi.org/10.1530/eje.0.1400187)

    • Search Google Scholar
    • Export Citation
  • 88

    Machens A, Haedecke J, Holzhausen HJ, Thomusch O, Schneyer U & Dralle H Differential diagnosis of calcitonin-secreting neuroendocrine carcinoma of the foregut by pentagastrin stimulation. Langenbeck’s Archives of Surgery 2000 385 398401. (https://doi.org/10.1007/s004230000169)

    • Search Google Scholar
    • Export Citation
  • 89

    Sano T, Saito H, Yamasaki R, Hamaguchi K, Ooiwa K, Shimoda T, Hosoi E, Saito S & Hizawa K Immunoreactive somatostatin and calcitonin in pulmonary neuroendocrine tumor. Cancer 1986 57 6468. (doi:10.1002/1097-0142(19860101)57:1<64::aid-cncr2820570114>3.0.co;2-6)

    • Search Google Scholar
    • Export Citation
  • 90

    Schneider R, Heverhagen AE, Moll R, Bartsch DK & Schlosser K Differentiation between thyroidal and ectopic calcitonin secretion in patients with coincidental thyroid nodules and pancreatic tumors – a report of two cases. Experimental and Clinical Endocrinology and Diabetes 2010 118 520523. (https://doi.org/10.1055/s-0029-1231083)

    • Search Google Scholar
    • Export Citation
  • 91

    Smets G, Warson F, Dehou MF, Storme G, Sacre R, Van Belle S, Somers G, Gepts W & Kloppel G Metastasizing neuroendocrine carcinoma of the larynx with calcitonin and somatostatin secretion and CEA production, resembling medullary thyroid carcinoma. Virchows Archiv: A, Pathological Anatomy and Histopathology 1990 416 539543. (https://doi.org/10.1007/BF01600306)

    • Search Google Scholar
    • Export Citation
  • 92

    Sweeney EC, McDonnell L & O’Brien C Medullary carcinoma of the thyroid presenting as tumours of the pharynx and larynx. Histopathology 1981 5 263275. (https://doi.org/10.1111/j.1365-2559.1981.tb01785.x)

    • Search Google Scholar
    • Export Citation
  • 93

    Vlaemynck K, De Man M, De Man K, Hoorens A & Geboes K Neuroendocrine tumor with diarrhea: not always the usual suspects – a case report of metastatic calcitoninoma with literature review. Acta Clinica Belgica 2020 In pres. (https://doi.org/10.1080/17843286.2020.1711668)

    • Search Google Scholar
    • Export Citation
  • 94

    Huguet I, Lamas C, Vera R, Lomas A, Quilez RP, Grossman A & Botella F Medullary thyroid carcinoma and duodenal calcitonin-secreting neuroendocrine tumour: more than coincidence? Endocrinology, Diabetes and Metabolism Case Reports 2013 2013 130021. (https://doi.org/10.1530/EDM-13-0021)

    • Search Google Scholar
    • Export Citation
  • 95

    Gambardella C, Offi C, Patrone R, Clarizia G, Mauriello C, Tartaglia E, Di Capua F, Di Martino S, Romano RM & Fiore L et al. Calcitonin negative medullary thyroid carcinoma: a challenging diagnosis or a medical dilemma? BMC Endocrine Disorders 2019 19 45. (https://doi.org/10.1186/s12902-019-0367-2)

    • Search Google Scholar
    • Export Citation
  • 96

    Zhang G, Jiang Y, Zhang S, Zhao L, Fan J, Zhang Z, Ma J, Chen R & Xu Y Genetic analysis of a hereditary medullary thyroid carcinoma case with normal preoperative serum calcitonin levels. Pathology, Research and Practice 2019 215 152529. (https://doi.org/10.1016/j.prp.2019.152529)

    • Search Google Scholar
    • Export Citation
  • 97

    Elisei R & Romei C Calcitonin estimation in patients with nodular goiter and its significance for early detection of MTC: European comments to the guidelines of the American Thyroid Association. Thyroid Research 2013 6 (Supplement 1) S2. (https://doi.org/10.1186/1756-6614-6-S1-S2)

    • Search Google Scholar
    • Export Citation
  • 98

    Leboeuf R, Langlois MF, Martin M, Ahnadi CE & Fink GD ‘Hook effect’ in calcitonin immunoradiometric assay in patients with metastatic medullary thyroid carcinoma: case report and review of the literature. Journal of Clinical Endocrinology and Metabolism 2006 91 361364. (https://doi.org/10.1210/jc.2005-1429)

    • Search Google Scholar
    • Export Citation
  • 99

    Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, Miccoli P, Iacconi P, Basolo F & Pinchera A et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. Journal of Clinical Endocrinology and Metabolism 2004 89 163168. (https://doi.org/10.1210/jc.2003-030550)

    • Search Google Scholar
    • Export Citation
  • 100

    Karga H, Giagourta I, Papaioannou G, Doumouchtsis K, Polymeris A, Thanou S, Papamichael K & Zerva C Changes in risk factors and tumor node metastasis stage of sporadic medullary thyroid carcinoma over 41 years, before and after the routine measurements of serum calcitonin. Metabolism: Clinical and Experimental 2011 60 604608. (https://doi.org/10.1016/j.metabol.2010.06.004)

    • Search Google Scholar
    • Export Citation
  • 101

    Colombo C, Verga U, Mian C, Ferrero S, Perrino M, Vicentini L, Dazzi D, Opocher G, Pelizzo MR & Beck-Peccoz P et al. Comparison of calcium and pentagastrin tests for the diagnosis and follow-up of medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2012 97 905913. (https://doi.org/10.1210/jc.2011-2033)

    • Search Google Scholar
    • Export Citation
  • 102

    Gibelin H, Essique D, Jones C, Levillain P, Marechaud R & Kraimps JL Increased calcitonin level in thyroid nodules without medullary carcinoma. British Journal of Surgery 2005 92 574578. (https://doi.org/10.1002/bjs.4875)

    • Search Google Scholar
    • Export Citation
  • 103

    Iacobone M, Niccoli-Sire P, Sebag F, De Micco C & Henry JF Can sporadic medullary thyroid carcinoma be biochemically predicted? Prospective analysis of 66 operated patients with elevated serum calcitonin levels. World Journal of Surgery 2002 26 886890. (https://doi.org/10.1007/s00268-002-6613-0)

    • Search Google Scholar
    • Export Citation
  • 104

    Mian C, Perrino M, Colombo C, Cavedon E, Pennelli G, Ferrero S, De Leo S, Sarais C, Cacciatore C & Manfredi GI et al. Refining calcium test for the diagnosis of medullary thyroid cancer: cutoffs, procedures, and safety. Journal of Clinical Endocrinology and Metabolism 2014 99 16561664. (https://doi.org/10.1210/jc.2013-4088)

    • Search Google Scholar
    • Export Citation
  • 105

    Niccoli P, Wion-Barbot N, Caron P, Henry JF, de Micco C, Saint Andre JP, Bigorgne JC, Modigliani E & Conte-Devolx B Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group. Journal of Clinical Endocrinology and Metabolism 1997 82 338341. (https://doi.org/10.1210/jcem.82.2.3737)

    • Search Google Scholar
    • Export Citation
  • 106

    Scheuba C, Kaserer K, Weinhausl A, Pandev R, Kaider A, Passler C, Prager G, Vierhapper H, Haas OA & Niederle B Is medullary thyroid cancer predictable? A prospective study of 86 patients with abnormal pentagastrin tests. Surgery 1999 126 10891095; discussion 1096. (https://doi.org/10.1067/msy.2099.102268)

    • Search Google Scholar
    • Export Citation
  • 107

    Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, Crocetti U, Attard M, Maranghi M & Torlontano M et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. Journal of Clinical Endocrinology and Metabolism 2007 92 450455. (https://doi.org/10.1210/jc.2006-1590)

    • Search Google Scholar
    • Export Citation
  • 108

    Hahm JR, Lee MS, Min YK, Lee MK, Kim KW, Nam SJ, Yang JH & Chung JH Routine measurement of serum calcitonin is useful for early detection of medullary thyroid carcinoma in patients with nodular thyroid diseases. Thyroid 2001 11 7380. (https://doi.org/10.1089/10507250150500694)

    • Search Google Scholar
    • Export Citation
  • 109

    Vierhapper H, Niederle B, Bieglmayer C, Kaserer K & Baumgartner-Parzer S Early diagnosis and curative therapy of medullary thyroid carcinoma by routine measurement of serum calcitonin in patients with thyroid disorders. Thyroid 2005 15 12671272. (https://doi.org/10.1089/thy.2005.15.1267)

    • Search Google Scholar
    • Export Citation
  • 110

    Giovanella L Serum procalcitonin and calcitonin normal values before and after calcium gluconate infusion. Experimental and Clinical Endocrinology and Diabetes 2012 120 169170. (https://doi.org/10.1055/s-0031-1301290)

    • Search Google Scholar
    • Export Citation
  • 111

    Papi G, Corsello SM, Cioni K, Pizzini AM, Corrado S, Carapezzi C, Fadda G, Baldini A, Carani C & Pontecorvi A et al. Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: a multicenter study. Journal of Endocrinological Investigation 2006 29 427437. (https://doi.org/10.1007/BF03344126)

    • Search Google Scholar
    • Export Citation
  • 112

    Vierhapper H, Raber W, Bieglmayer C, Kaserer K, Weinhausl A & Niederle B Routine measurement of plasma calcitonin in nodular thyroid diseases. Journal of Clinical Endocrinology and Metabolism 1997 82 15891593. (https://doi.org/10.1210/jcem.82.5.3949)

    • Search Google Scholar
    • Export Citation
  • 113

    Doyle P, Duren C, Nerlich K, Verburg FA, Grelle I, Jahn H, Fassnacht M, Mader U, Reiners C & Luster M Potency and tolerance of calcitonin stimulation with high-dose calcium versus pentagastrin in normal adults. Journal of Clinical Endocrinology and Metabolism 2009 94 29702974. (https://doi.org/10.1210/jc.2008-2403)

    • Search Google Scholar
    • Export Citation
  • 114

    Niederle MB, Scheuba C, Gessl A, Li S, Koperek O, Bieglmayer C, Riss P, Selberherr A & Niederle B Calcium-stimulated calcitonin – the ‘new standard’ in the diagnosis of thyroid C-cell disease – clinically relevant gender-specific cut-off levels for an ‘old test’. Biochemia Medica 2018 28 030710. (doi:10.11613/BM.2018.030710] 030710.

    • Search Google Scholar
    • Export Citation
  • 115

    Papadakis G, Keramidas I, Triantafillou E, Kanouta F, Pappa T, Kaltzidou V, Tertipi A, Iordanidou L, Trivizaki E & Vecchini G et al. Association of basal and calcium-stimulated calcitonin levels with pathological findings after total thyroidectomy. Anticancer Research 2015 35 42514258.

    • Search Google Scholar
    • Export Citation
  • 116

    Rosario PW & Calsolari MR Basal serum calcitonin, after calcium stimulation, and in the needle washout of patients with thyroid nodules and mild or moderate basal hypercalcitoninemia. Hormone and Metabolic Research 2017 49 129134. (https://doi.org/10.1055/s-0042-121895)

    • Search Google Scholar
    • Export Citation
  • 117

    Niederle MB, Scheuba C, Riss P, Selberherr A, Koperek O & Niederle B Early diagnosis of medullary thyroid cancer: are calcitonin stimulation tests still indicated in the era of highly sensitive calcitonin immunoassays? Thyroid 2020 30 974984. (https://doi.org/10.1089/thy.2019.0785)

    • Search Google Scholar
    • Export Citation
  • 118

    Russo M, Scollo C, Padova G, Vigneri R & Pellegriti G Cardiac arrest after intravenous calcium administration for calcitonin stimulation test. Thyroid 2014 24 606607. (https://doi.org/10.1089/thy.2013.0394)

    • Search Google Scholar
    • Export Citation
  • 119

    Chang TC, Wu SL & Hsiao YL Medullary thyroid carcinoma: pitfalls in diagnosis by fine needle aspiration cytology and relationship of cytomorphology to RET proto-oncogene mutations. Acta Cytologica 2005 49 477482. (https://doi.org/10.1159/000326191)

    • Search Google Scholar
    • Export Citation
  • 120

    Essig GF Jr, Porter K, Schneider D, Debora A, Lindsey SC, Busonero G, Fineberg D, Fruci B, Boelaert K & Smit JW et al. Fine needle aspiration and medullary thyroid carcinoma: the risk of inadequate preoperative evaluation and initial surgery when relying upon FNAB cytology alone. Endocrine Practice 2013 19 920927. (https://doi.org/10.4158/EP13143.OR)

    • Search Google Scholar
    • Export Citation
  • 121

    Kaushal S, Iyer VK, Mathur SR & Ray R Fine needle aspiration cytology of medullary carcinoma of the thyroid with a focus on rare variants: a review of 78 cases. Cytopathology 2011 22 95105. (https://doi.org/10.1111/j.1365-2303.2010.00747.x)

    • Search Google Scholar
    • Export Citation
  • 122

    Trimboli P, Treglia G, Guidobaldi L, Romanelli F, Nigri G, Valabrega S, Sadeghi R, Crescenzi A, Faquin WC & Bongiovanni M et al. Detection rate of FNA cytology in medullary thyroid carcinoma: a meta-analysis. Clinical Endocrinology 2015 82 280285. (https://doi.org/10.1111/cen.12563)

    • Search Google Scholar
    • Export Citation
  • 123

    de Crea C, Raffaelli M, Maccora D, Carrozza C, Canu G, Fadda G, Bellantone R & Lombardi CP Calcitonin measurement in fine-needle aspirate washouts vs. cytologic examination for diagnosis of primary or metastatic medullary thyroid carcinoma. Acta Otorhinolaryngologica Italica 2014 34 399405.

    • Search Google Scholar
    • Export Citation
  • 124

    Trimboli P, Guidobaldi L, Bongiovanni M, Crescenzi A, Alevizaki M & Giovanella L Use of fine-needle aspirate calcitonin to detect medullary thyroid carcinoma: a systematic review. Diagnostic Cytopathology 2016 44 4551. (https://doi.org/10.1002/dc.23375)

    • Search Google Scholar
    • Export Citation
  • 125

    Boi F, Maurelli I, Pinna G, Atzeni F, Piga M, Lai ML & Mariotti S Calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in patients with primary and metastatic medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 2007 92 21152118. (https://doi.org/10.1210/jc.2007-0326)

    • Search Google Scholar
    • Export Citation
  • 126

    Diazzi C, Madeo B, Taliani E, Zirilli L, Romano S, Granata AR, De Santis MC, Simoni M, Cioni K & Carani C et al. The diagnostic value of calcitonin measurement in wash-out fluid from fine-needle aspiration of thyroid nodules in the diagnosis of medullary thyroid cancer. Endocrine Practice 2013 19 769779. (https://doi.org/10.4158/EP12420.OR)

    • Search Google Scholar
    • Export Citation
  • 127

    Kihara M, Hirokawa M, Kudo T, Hayashi T, Yamamoto M, Masuoka H, Higashiyama T, Fukushima M, Ito Y & Miya A et al. Calcitonin measurement in fine-needle aspirate washout fluid by electrochemiluminescence immunoassay for thyroid tumors. Thyroid Research 2018 11 15. (https://doi.org/10.1186/s13044-018-0059-4)

    • Search Google Scholar
    • Export Citation
  • 128

    Verbeek HH, de Groot JWB, Sluiter WJ, Muller Kobold AC, van den Heuvel ER, Plukker JT & Links TP Calcitonin testing for detection of medullary thyroid cancer in people with thyroid nodules. Cochrane Database of Systematic Reviews 2020 3 CD010159. (https://doi.org/10.1002/14651858.CD010159.pub2)

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 568 568 459
PDF Downloads 323 323 255
  • View in gallery

    Histopathological features of a calcitonin-secreting pancreatic NEN (A). A neuroendocrine neoplasm of the pancreas can be seen in the lower part of this field. It was composed of mid-sized cells with nuclei characterized by ‘salt and pepper’ chromatin and granular eosinophilic cytoplasm. (Hematoxylin and eosin stain, 100× magnification). One year later, this neoplasm caused distant metastasis to the adrenal gland. (B and C) Cells were diffusely immunoreactive to chromogranin (B) and focally to calcitonin (C) staining (100× magnification) d. Ki67 Labeling index was around 5% in a ‘hot spot’ area (400× magnification).

  • View in gallery

    Diagnostic algorithm for patients with high serum calcitonin levels. Current guidelines recommend that each center adopts its own cut-off value for basal CT. List of abbreviations: WB, whole body.

  • 1

    Nozieres C, Chardon L, Goichot B, Borson-Chazot F, Hervieu V, Chikh K, Lombard-Bohas C & Walter T Neuroendocrine tumors producing calcitonin: characteristics, prognosis and potential interest of calcitonin monitoring during follow-up. European Journal of Endocrinology 2016 174 335341. (https://doi.org/10.1530/EJE-15-0917)

    • Search Google Scholar
    • Export Citation
  • 2

    Toledo SP, Lourenco Jr DM, Santos MA, Tavares MR, Toledo RA & Correia-Deur JE Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma. Clinics 2009 64 699706. (https://doi.org/10.1590/S1807-59322009000700015)

    • Search Google Scholar
    • Export Citation
  • 3

    Schneider R, Waldmann J, Swaid Z, Ramaswamy A, Fendrich V, Bartsch DK & Schlosser K Calcitonin-secreting pancreatic endocrine tumors: systematic analysis of a rare tumor entity. Pancreas 2011 40 213221. (https://doi.org/10.1097/MPA.0b013e3182015f5d)

    • Search Google Scholar
    • Export Citation
  • 4

    Blaustein A Calcitonin secreting struma-carcinoid tumor of the ovary. Human Pathology 1979 10 222228. (https://doi.org/10.1016/s0046-8177(7980010-6)

    • Search Google Scholar
    • Export Citation
  • 5

    Giannetta E, Gianfrilli D, Pozza C, Lauretta R, Graziadio C, Sbardella E, Baroli A, Caronna R, Chirletti P & Lenzi A et al. Extrathyroidal calcitonin secreting tumors: pancreatic neuroendocrine tumors in patients With multinodular goiter: two Case Reports. Medicine 2016 95 e2419. (https://doi.org/10.1097/MD.0000000000002419)

    • Search Google Scholar
    • Export Citation
  • 6

    Hakeem AH, Pradhan S, Bhele S & Tubachi J Primary calcitonin-secreting neuroendocrine carcinoma of the supraglottic larynx. Ear, Nose, and Throat Journal 2015 94 E34E35. (https://doi.org/10.1177/014556131509400104)

    • Search Google Scholar
    • Export Citation
  • 7

    LaBryer L, Sawh R, McLaurin C & Scofield RH Calcitonin-secreting neuroendocrine carcinoma of larynx with metastasis to thyroid. Case Reports in Endocrinology 2015 2015 606389. (https://doi.org/10.1155/2015/606389)

    • Search Google Scholar
    • Export Citation
  • 8

    Mascolo M, Altieri V, Mignogna C, Napodano G, De Rosa G & Insabato L Calcitonin-producing well-differentiated neuroendocrine carcinoma (carcinoid tumor) of the urinary bladder: case report. BMC Cancer 2005 5 88. (https://doi.org/10.1186/1471-2407-5-88)

    • Search Google Scholar
    • Export Citation
  • 9

    Copp DH & Cheney B Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood. Nature 1962 193 381382. (https://doi.org/10.1038/193381a0)

    • Search Google Scholar
    • Export Citation
  • 10

    Foster GV, Baghdiantz A, Kumar MA, Slack E, Soliman HA & Macintyre I Thyroid origin of calcitonin. Nature 1964 202 13031305. (https://doi.org/10.1038/2021303a0)

    • Search Google Scholar
    • Export Citation
  • 11

    Donoghue PC, Graham A & Kelsh RN The origin and evolution of the neural crest. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 2008 30 530541. (https://doi.org/10.1002/bies.20767)

    • Search Google Scholar
    • Export Citation
  • 12

    Johansson E, Andersson L, Ornros J, Carlsson T, Ingeson-Carlsson C, Liang S, Dahlberg J, Jansson S, Parrillo L & Zoppoli P et al. Revising the embryonic origin of thyroid C cells in mice and humans. Development 2015 142 35193528. (https://doi.org/10.1242/dev.126581)

    • Search Google Scholar
    • Export Citation
  • 13

    Erdogan MF, Gursoy A & Kulaksizoglu M Long-term effects of elevated gastrin levels on calcitonin secretion. Journal of Endocrinological Investigation 2006 29 771775. (https://doi.org/10.1007/BF03347369)

    • Search Google Scholar
    • Export Citation
  • 14

    Masi L & Brandi ML Calcitonin and calcitonin receptors. Clinical Cases in Mineral and Bone Metabolism 2007 4 117122.

  • 15

    Pondel M Calcitonin and calcitonin receptors: bone and beyond. International Journal of Experimental Pathology 2000 81 405422. (https://doi.org/10.1046/j.1365-2613.2000.00176.x)

    • Search Google Scholar
    • Export Citation
  • 16

    Chen Y, Shyu JF, Santhanagopal A, Inoue D, David JP, Dixon SJ, Horne WC & Baron R The calcitonin receptor stimulates Shc tyrosine phosphorylation and ERK1/2 activation. Involvement of Gi, protein kinase C, and calcium. Journal of Biological Chemistry 1998 273 1980919816. (https://doi.org/10.1074/jbc.273.31.19809)

    • Search Google Scholar
    • Export Citation
  • 17

    Felsenfeld AJ & Levine BS Calcitonin, the forgotten hormone: does it deserve to be forgotten? Clinical Kidney Journal 2015 8 180187. (https://doi.org/10.1093/ckj/sfv011)

    • Search Google Scholar
    • Export Citation
  • 18

    Wimalawansa SJ Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. Critical Reviews in Neurobiology 1997 11 167239. (https://doi.org/10.1615/critrevneurobiol.v11.i2-3.40)

    • Search Google Scholar
    • Export Citation
  • 19

    Schifter S Expression of the calcitonin gene family in medullary thyroid carcinoma. Peptides 1997 18 307317. (https://doi.org/10.1016/s0196-9781(9600169-6)

    • Search Google Scholar
    • Export Citation
  • 20

    Le Moullec JM, Jullienne A, Chenais J, Lasmoles F, Guliana JM, Milhaud G & Moukhtar MS The complete sequence of human preprocalcitonin. FEBS Letters 1984 167 9397. (https://doi.org/10.1016/0014-5793(8480839-x)

    • Search Google Scholar
    • Export Citation
  • 21

    Davies J Procalcitonin. Journal of Clinical Pathology 2015 68 675679. (https://doi.org/10.1136/jclinpath-2014-202807)

  • 22

    Gnaedinger MP, Uehlinger DE, Weidmann P, Sha SG, Muff R, Born W, Rascher W & Fischer JA Distinct hemodynamic and renal effects of calcitonin gene-related peptide and calcitonin in men. American Journal of Physiology 1989 257 E848E854. (https://doi.org/10.1152/ajpendo.1989.257.6.E848)

    • Search Google Scholar
    • Export Citation
  • 23

    Maruna P, Nedelnikova K & Gurlich R Physiology and genetics of procalcitonin. Physiological Research 2000 49 (Supplement 1) S57S61.

  • 24

    Wacker C, Prkno A, Brunkhorst FM & Schlattmann P Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet: Infectious Diseases 2013 13 426435. (https://doi.org/10.1016/S1473-3099(1270323-7)

    • Search Google Scholar
    • Export Citation
  • 25

    Trimboli P, Seregni E, Treglia G, Alevizaki M & Giovanella L Procalcitonin for detecting medullary thyroid carcinoma: a systematic review. Endocrine-Related Cancer 2015 22 R157R164. (https://doi.org/10.1530/ERC-15-0156)

    • Search Google Scholar
    • Export Citation
  • 26

    Snider Jr RH, Nylen ES & Becker KL Procalcitonin and its component peptides in systemic inflammation: immunochemical characterization. Journal of Investigative Medicine 1997 45 552560.

    • Search Google Scholar
    • Export Citation
  • 27

    Cavedon E, Barollo S, Bertazza L, Pennelli G, Galuppini F, Watutantrige-Fernando S, Censi S, Iacobone M, Benna C & Vianello F et al. Prognostic impact of miR-224 and RAS mutations in medullary thyroid carcinoma. International Journal of Endocrinology 2017 2017 4915736. (https://doi.org/10.1155/2017/4915736)

    • Search Google Scholar
    • Export Citation
  • 28

    Ehyaei S, Hedayati M, Zarif-Yeganeh M, Sheikholeslami S, Ahadi M & Amini SA Plasma calcitonin levels and miRNA323 expression in medullary thyroid carcinoma patients with or without RET mutation. Asian Pacific Journal of Cancer Prevention 2017 18 21792184. (https://doi.org/10.22034/APJCP.2017.18.8.2179)

    • Search Google Scholar
    • Export Citation
  • 29

    Le Y, Chen T, Xun K & Ding T Expression of the long intergenic non-coding RNA (lincRNA) of the NED25 gene modulates the microRNA-125b, STAT3, nitric oxide, and procalcitonin signaling pathways in patients with sepsis. Medical Science Monitor 2018 24 45554566. (https://doi.org/10.12659/MSM.907496)