Updates in the advances of sporadic medullary thyroid carcinoma: from the molecules to the clinic

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy that originates in parafollicular cells. It is well-known that a quarter of MTC are involved in hereditary multiple endocrine neoplasia type 2 syndromes, whereas most MTC are sporadic. Unlike the commonly encountered gastrointestinal or pulmonary neuroendocrine tumors, most sporadic MTCs have distinct genetic alterations featured by somatic changes of either Rearranged during Transfection (RET) or RAS point mutation. The increasing application of next-generation sequencing, whole-exome sequencing, and other molecular detection techniques enables us to understand MTC comprehensively concerning its detailed molecular changes and their clinical correlations. This article reviews the advances in genetic alterations and their prognostic impact in sporadic MTC among different populations and discusses the associated tumor immune microenvironments and the potential role of immunotherapy targeting PD-L1/PD-1 in treating MTC. Furthermore, the current multikinase inhibitor targeting therapy for sporadic MTC has been summarized here and its efficacy and drug toxicity are discussed. Updates in advance of the role of calcitonin/procalcitonin/calcitonin-related polypeptide alpha (CALCA) gene transcripts in diagnosing and handling MTC are also mentioned. The treatment of advanced MTC is still challenging and might require a combination of several modalities.