Dottorato in MEDICINA MOLECOLARE

Titolo della tesi: Nuove frontiere nella caratterizzazione immunofenotipica e diagnostica delle neoplasie neuroendocrine

Neuroendocrine neoplasms (NENs) are a class of rare and heterogeneous tumors that develop from neuroendocrine cells, which are spread throughout the whole body. They mainly arise in gastrointestinal and pulmonary tract. NENs can be divided in well-differentiated tumors (NETs) and poorly-differentiated carcinomas (NECs). According to proliferation index and mitotic count, they have been categorized into low (G1, Ki67<3%), intermediate (G2, Ki67 3–20%) and high (G3, Ki67>20%) grades. Generally, NENs are characterized by a relatively indolent rate of growth and by the ability to secrete peptide hormones and biogenic amines that are used as biomarkers. Specific markers for NEN diagnosis are yet to be identified. Chromogranin A (CgA), synaptophysin (Syn), 5-Hydroxyindoleacetic Acid (5-HIAA), neuronspecifc enolase (NSE) and cluster of differentiation 56 (CD56) (neural cell adhesion molecule) are currently used for immunohistochemical diagnosis. To meet this clinical need, in our study we aimed to identify novel diagnostic and prognostic biomarkers in the setting of gastro-entero-pancreatic (GEP) NENs . Particularly, our attention was focused on prognostic and clinicopathological value of CD90 expression. Thymus cell antigen 1 (Thy1), also known as cluster of differentiation (CD) 90, is a cell surface glycoprotein located on chromosome 11q22.3, anchored cell surface protein. It regulates cell adhesion, migration and proliferation, apoptosis, and cellular communication and is involved in T cell activation, wound healing, and fibrosis. CD90 is expressed in various cells such as mesenchymal and hematopoietic stem cells, neurons, endothelial cells, and fibroblasts. It has an important role in the development of various cancers, including liver, gastric, and esophageal cancers. Moreover, it has been shown that CD90 is related to cancer progression, metastasis, and poor patient survival. Methods: In this study, 16 GEP-NEN (surgical specimens and bioptical specimen) were collected in the Policlinico Umberto I Hospital. CD90 expression was evaluated by using immunohistochemistry and correlated with clinicopathologic properties. Clinical data included age at the time of diagnosis, gender, ethnicity, follow-up radiology and/or pathology, and survival. Pathological data included tumor grade, tumor size, mitotic count, Ki-67 proliferation index, lymph node status, and the status and site of distant metastases. All specimens obtained from the patients were histologically confirmed by two pathologists and divided according to the classification. Statistical analysis: Data were analyzed using the SPSS software. The relationship of Thy1 with histological and clinical factors was analyzed using χ2 test or Fisher's exact test. The overall survival was analyzed using Kaplan-Meier univariate survival analysis and log-rank tests. Multivariate analysis was performed with Cox proportional hazards model and the 95% confidence interval was calculated. Future perspectives: CD90 presents itself as a candidate marker for isolation of Cancer stem cells (CSCs). Very little is currently known about the functional mechanisms by which CD90 contributes to NEN and stem cell biology and this will be a primary aim of our future studies.