No abstract

Choroidal melanoma (CM), despite its rarity, is the most frequent intraocular malignancy. Over time, several histological variants of CM have been distinguished, including spindle A and B cell, fascicular, epithelioid and necrotic type. However, they have been progressively abandoned as having no prognostic value and currently, the American Joint Committee of Cancer (AJCC) classification identifies three CM cell types: spindle, epithelioid and mixed cell type. Other rare histological variants of CM include: (i) diffuse melanoma; (ii) clear cell; and (iii) balloon cell melanoma. Immunohistochemically, CMs are stained with Human Melanoma Black 45 (HMB45) antigen, S-100 protein, Melan-A (also known as melanoma antigen recognized by T cells 1/MART-1), melanocyte inducing transcription factor (MITF), tyrosinase, vimentin, and Sex determining region Y-Box 10 (SOX10). Several genetic and histopathological prognostic factors of CM have been reported in the literature, including epithelioid cell type, TNM staging, extraocular extension, monosomy 3 and 6p gain and loss of BAP-1 gene. The aim of this review was to summarize the histopathological, immunohistochemical and genetic features of CM, establishing “the state of the art” and providing colleagues with practical tools to promptly deal with patients affected by this rare malignant neoplasm.

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10–15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.

Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endometrial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors.

The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage >II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist.