Editorial Article

Focus on Medullary Thyroid Cancer

Irene Faccio1, Loris Bertazza1, Caterina Mian1, Susi Barollo1, Raffaele Pezzani1,2,*
1OU Endocrinology, Department of Medicine (DIMED), University of Padova, via Ospedale 105, 35128 Padova, Italy 2AIROB, Associazione Italiana per la Ricerca Oncologica di Base, Padova, Italy
*Corresponding author:

Raffaele Pezzani, PhD, OU of Endocrinology, Department of Medicine (DIMED), University of Padova, Via Ospedale, 105, 35128 Padova, Italy. Phone: +390498213018, Fax: +39049657391, Email:raffaele.pezzani@unipd.it

Keywords:

Medullary thyroid cancer, Thyroid, Tyrosine kinase

Medullary Thyroid Cancer (MTC) comprises about 5-10% of all thyroid tumors [1]. It generates from parafollicular cells or C cells, characterized by the ability to produce calcitonine (CT), a hormone regulating calcium and phosphorus metabolism. Symptoms are often scarce and non-specific, such as a sudden change in voice, sore throat, difficulty swallowing, and sometimes an enlargement of thyroid. Late symptoms are severe diarrhoea and skin flushes in the face, which often occur when CT levels are already raised [1,2]. Most of MTC includes sporadic cases (75%) and presents as unilateral masses that may metastasize at lymph nodes, conversely hereditary forms (25%) show genetic basis and may appear as bilateral or multifocal mass [2]. Hereditary MTC is an autosomal dominant disorder form and may present alone (FMTC, Familiar Medullary Thyroid Carcinoma) or as part of Multiple Endocrine Neoplasia (MEN). The latter is subdivided into MEN1 and MEN2, but MTC is only characteristic of the second form, in turn split into form 2A, which is marked by pheochromocytomas and hyperplasia/adenoma of the parathyroid as well as MTC, and in the form 2B, which show pheochromocytomas and marfanoid body habit beyond MTC. The association of MTC and MEN 2B is considered more aggressive than MTC with MEN2A or sporadic form [3].

From a genetic point of view, MTC can be derived from a germline mutation in RET (REarranged during transfection) gene that encodes for a trans membrane tyrosine kinase receptor. Because of the mutation, the receptor is constitutively activated, causing continuous proliferation and inducing cell migration [4]. The strong dependence on RET mutation in hereditary MTC has led clinicians to require genetic screening, because depending on the location of the mutation it is possible to classify patients into risk classes [5].

The diagnosis of MTC is essentially based on CT, a serum marker normally found at about 10 pg/ml, while in patients with MTC it can reach values greater than 50 pg/ml. In association with CT, also CEA (carcinogenic embryonic antigen) values can be assessed, as they can improve patient follow-up [6]. Currently surgery is the main treatment for MTC and is characterized by total thyroidectomy in association with laterocervical and central lymph node dissection. After the operation, the CT level should be tested: if the serum levels return to physiological concentrations, patients can be define biochemically cured (still monitored over time) [7]. In case of CT level decrease (but higher than normal), MTC is considered as biochemically persistent and it is assumed that a remote producing metastasis is present. This biochemically persistent disease can be hardly removed, nonetheless patients can take advantage of pharmacological treatments [8]. Recently, FDA (Food and Drug Administration) and EMA (European Medicinal Agency) approved two drugs for the treatment of advanced and metastatic MTC, Vandetanib and Cabozantinib, both tyrosine kinase inhibitors (TKIs). They can act as cytostatic on RET and VEGFR blocking proliferation, migration and limiting neoplasia growth. These drugs induce a relative increase in mean survival, but have severe side effects and sometimes treatment fails, probably due to cancer cells escape to tyrosine kinase inhibitory effects [9]. For these reasons, it is attempted to delay treatment with TKI as much as possible and to use the minimum dose with maximum effect. Researchers are therefore exploring new compounds with different molecular targets in order to control tumor progression and reducing cancer growth. Furthermore novel approaches will focus on drugs combinations to target multiple pathways simultaneously and to avoid drug resistance [6]. New compounds in MTC preclinical models are also being evaluated (and have been evaluated [10]) in our laboratory; in particular, we are trying to modulate FGFR pathway with a specific TKI, tested in association with one of the authorized drugs for MTC, Cabozantinib.

MTC is a rare tumor with good prognosis, even though a small proportion shows aggressive behaviour or metastases requiring aggressive treatments. Available pharmacological therapies are insufficient and sometimes ineffective, but clinical and preclinical research is striving to find effective compounds to fight against this challenging malignancy.

The author declares no conflict of interest.

1. Rajabi S, Hedayati M (2017) Medullary Thyroid Cancer: Clinical Characteristics and New Insights into Therapeutic Strategies Targeting Tyrosine Kinases. Mol Diagn Ther pp1-17.
2. Maxwell JE, Sherman SK, O'Dorisio TM, Howe JR (2014) Medical management of metastatic medullary thyroid cancer. Cancer 120: 3287-3301.
3. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, et al. (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2, J clinical endocrinol metab 86: 5658-5671.
4. Mian C, Sartorato P, Barollo S, Zane M, Opocher G (2012) RET codon 609 mutations: a contribution for better clinical managing, Clinics 67: 33-36.
5. Accardo G, Conzo G, Esposito D, Gambardella C, Mazzella M, et al. (2017) Genetics of medullary thyroid cancer: An overview, Int J surgery 41: S2-S6.
6. Ernani V, Kumar M, Chen AY, Owonikoko TK (2016) Systemic treatment and management approaches for medullary thyroid cancer. Cancer Treat Rev 50: 89-98.
7. Machens A, Dralle H (2015) Surgical Treatment of Medullary Thyroid Cancer, Recent results in cancer research. Fortschritte der Krebsforschung. Recent Results Cancer Res 204: 187-205.
8. Azar FK, Lee SL, Rosen JE (2015) Medullary thyroid cancer: an update for surgeons, Am surg 81: 1-8.
9. Hadoux J, Schlumberger M (2017) Chemotherapy and tyrosine-kinase inhibitors for medullary thyroid cancer, Best practice & research. Clin endocrinol metab 31: 335-347.
10. Bertazza L, Barollo S, Radu CM, Cavedon E, Simioni P, et al. (2015) Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells. J cell mol med19: 2244-2252.

Citation: Faccio I, Bertazza L, Mian C, Barollo S, Pezzani R (2017) Focus on Medullary Thyroid Cancer. J Diabetes Care Endocrinolo 1:e002.

Published: 10 November 2017

Copyright:

© 2017 Faccio et al.. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.