Clinical and molecular characterization of endocrine and neuroendocrine tumors

Endocrine and neuroendocrine tumors are a heterogeneous groups of tumors which show peculiar biological pathways and clinical features. The comprehension of the peculiar biological mechanisms of endocrine and neuroendocrine cells has a relevant impact on clinical management and therapeutic strategies for these tumors. The work performed during my Doctorate thesis contributes to clarify the molecular bases and to define the clinical characteristics of thyroid tumors as well as of neuroendocrine tumors of various histotypes. For this purpose, parallel clinical and molecular investigations have been performed in different tumor models. In tumors arising from thyrocytes, the characteristic enzymatic pathway, that will incorporate iodide into tyrosyl residues, to couple iodotyrosyl residues and to secrete thyroid hormones into the blood stream, is profoundly altered in differentiated thyroid carcinomas and unexpressed in anaplastic tumors. Immunohistochemistry of thyroid samples is able to define the expression of many thyroid-specific proteins, including NIS, pendrin, Duox, Tg, TSH-R, providing information on the degree of expression and localization of proteins within the thyrocyte. Thyroid morphometry and immunohistochemistry of thyroid-specific proteins highlight that there are different kinds of follicles within a given thyroid and, among subjects, small, active follicles and proliferating thyrocytes are predominant in childhood and adolescence, providing a molecular basis to the agedependent variation in radiation doses after contamination by radioactive iodine isotopes and consequently for the risk of radiation-induced thyroid cancer. Morpho-functional data allow also to build geometrical models of thyroid and to calculate iodine distributions inside the thyroid gland and absorbed dose after exposure to 131I. In this study, it appears that, for various iodine distributions into the thyroid follicles, energy deposition is highly heterogeneous from one subject to another, and absorbed dose rates are greater in younger subjects. In neuroendocrine tumors, immunohistochemistry is of great usefulness to recognize the neuroendocrine differentiation, to differentiate neuroendocrine tumors from non-neuroendocrine tumors, pre-cancerous lesions and normal pictures, to define differentiation degree and proliferative activity, to define prognosis and predict response to receptor-targeted therapy. The comprehension of the specific biological mechanisms of each neuroendocrine tumor provides helpful information to prevent, recognize, and manage these tumors.