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Page 2 of 19 Matrone et al. J Cancer Metastasis Treat 2021;7:23 https://dx.doi.org/10.20517/2394-4722.2021.47

INTRODUCTION
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells,
[1,2]
which represent only the 0.1% of all thyroid cells . The peculiarity of parafollicular cells is to produce and
secrete calcitonin (CT), as well as, to a lesser extent, other peptides such as chromogranin, serotonin,
[3]
somatostatin, or calcitonin gene-related peptide . These cells are usually located in the upper and middle
thirds of the thyroid, but the hyperplastic ones are prevalently located in the middle and lower thirds of the
[4]
lateral lobes and only exceptionally in the isthmus . Because of its origin, MTC can be considered a
separate entity from differentiated thyroid carcinoma (DTC), which originates in the epithelial follicular
thyroid cells.

The prevalence of MTC is variable according to the different series, however it is generally reported as 5%-
10% of all thyroid malignancies, 0.4%-1.4% of all thyroid nodules, and less than 1% in thyroids of subjects
submitted to autopsy. For this reason, to date, MTC is officially considered a rare disease by the national
Health Institute (NIH) . Unlike DTC, MTC shows no difference in sex distribution, and the median age at
[5]
diagnosis is 45-55 years .
[6-9]

MTC can occur in a sporadic (about 75% of cases) or hereditary (25% of cases) form. In hereditary cases,
MTC can be the only clinically expressed disease [familial medullary thyroid carcinoma (FMTC)] or
associated with other endocrine neoplasia, in the context of the multiple endocrine neoplasia syndromes
(MEN types IIA and IIB), such as pheocromocytoma (PHEO) and/or hyperparathyroidism due to
parathyroid hyperplasia or multiple adenomatosis (PTHAd) . Children can only be affected by inherited
[10]
MTC, and the more aggressive is the syndrome (i.e., MEN IIB), the younger is the affected child [11-14] .

The pathogenesis of MTC is highly associated to the activation of the RET protooncogene, both in
hereditary [15-18] and in sporadic cases [19-21] . In hereditary cases, the RET protooncogene alteration is
transmitted in a dominant mendelian autosomal way and is found at germline level, while, in sporadic
cases, this alteration is somatic and found only in the tumoral cells.

Through its dissemination by both lymphatic and hematic vessels, the clinical behavior of MTC is less
favorable when compared with most DTC, however it is not as unfavorable as the anaplastic one
(ATC) [22,23] . Five-year survival rates vary from 62% to 87% according to the different series, and the 10-year
survival could decrease to 50% [24-29] . Survival is dependent on several factors, such as age at diagnosis .
[30]
However, the staging at diagnosis remains the most relevant clinical prognostic factor of survival of these
patients. When an early diagnosis is performed, and the tumor is still intrathyroidal, 90% of patients can
survive up to 35 years [29,31] .

Usually, the most common clinical presentation of a sporadic MTC is a thyroid nodule, single or in a
clinical picture of a multinodular goiter. At the diagnosis, lymph node metastases are frequent and distant
metastases are already present in about 10% of patients . In advanced metastatic cases associated with high
[32]
levels of serum CT, symptoms such as diarrhea and/or flushing syndrome could be present.

Conversely, the hereditary forms can be easily suspected according to a familial history of MTC or if the
same patient has already been diagnosed with PHEO and/or PTHAd. The presence of mucosal neurinomas
of the tongue or conjunctivas, in particular if associated to marfanoid habitus and/or skeletal alterations,
[11]
should immediately suggest the diagnosis of MEN IIB . Similarly, the detection of an interscapular
[33]
cutaneous itchy lesion, defined as cutaneous lichen amyloidosis, is highly suspicious of MEN IIA , since
this lesion is almost exclusively found in this syndrome. While thyroid function, assessed by the