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OBJECTIVE: Our study aimed to confirm the expression of the endocannabinoid system in the human epithelial ovarian tumors, assessing the immunohistochemical expression of Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase in benign, borderline and malignant tumors. MATERIALS AND METHODS: Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase immunohistochemical expression was determined in 118 epithelial ovarian tumors sequentially treated during the last decade in our department: 36 benign, 34 borderline and 48 malignant neoplasms. Cannabinoid Receptor type 1 and Fatty Acid Amide Hydrolase expression resulted predominantly weak-moderate in the benign and borderline forms. RESULTS: concerning malignant tumors, Cannabinoid Receptor Type 1 expression resulted predominantly moderate-strong in Type I tumors and negative-weak in Type II tumors. Fatty Acid Amide Hydrolase expression resulted, instead, independent by the tumor types. Furthermore, there was no significant difference in the Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase expression relatively to the tumoral stages. CONCLUSIONS: The present study confirmed a variable expression of the endocannabinoid system in human ovarian tumors. Cannabinoid Receptor Type 1 expression was significantly different in malignant epithelial ovarian tumors according to dualistic model of ovarian carcinogenesis. Thus, in the most aggressive types II ovarian tumors, Cannabinoid Receptor Type 1 expression resulted predominantly negative or weak.

Following publication of the original article [1], the authors identified an error in the author name of Federica Zito Marino. ● The incorrect author name is: Federico Zito Marino ● The correct author name is: Federica Zito Marino The author group has been updated above and the original article [1] has been corrected.

In the era of precision medicine, the identification of several predictive biomarkers and the development of innovative therapies have dramatically increased the request of tests to identify specific targets on cytological or histological samples, revolutionizing the management of the tumoral biomaterials. The Food and Drug Administration (FDA) has recently approved a selective neurotrophic tyrosine receptor kinase (NTRK) inhibitor, larotrectinib. Contemporarily, the development of multi-kinase inhibitors with activity in tumors carrying TRK fusions is ongoing. Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes result in constitutive activation and aberrant expression of TRK kinases in numerous cancer types. In this context, the identification of tumors harboring TRK fusions is crucial. Several methods of detection are currently available. We revise the advantages and disadvantages of different techniques used for identifying TRK alterations, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and next generation sequencing-based approaches. Finally, we propose a diagnostic algorithm based on histology and the relative frequency of TRK fusions in each specific tumor, considering also the economic feasibility in the clinical practice.

Purpose: ATTRACTION-2 trial assessed the role of Nivolumab as a new standard treatment for Asian patients with pretreated metastatic gastric cancer (mGC). The aim of this analysis was to evaluate the safety and efficacy of Nivolumab in a real-life Western population, considering the lack of evidence to date. Patients and Methods: Patients progressed after ≥2 chemotherapy regimens and able to receive Nivolumab (3 mg/kg q14) were eligible for the analysis. Results: 16 patients received Nivolumab as third (81.3%) or fourth line (18.7%) from September 2017 to July 2019. The safety was in line with the literature and only one patient discontinued treatment due to persistent hematological toxicity. Overall response rate and disease control rate were 18.7% and 31.2%, respectively. Median duration of response was 5 months. With a median follow-up of 21 months, median OS was 6 months (7, 21 and 22 months in the responders) and median PFS 3 months. PD-L1 and microsatellite status were retrospectively collected in 12 patients. All the major responders were MSI, although no statistically significant difference in OS or PFS was observed according to molecular analysis. Conclusion: Nivolumab is feasible and effective in Western patients with mGC. Further investigation is urgently needed also in non-Asians.

Introduction: Anaplastic large cell lymphoma (ALCL) is a rare mature T-cell non-Hodgkin’s lymphoma characterized by large and pleomorphic neoplastic CD30-positive T cells. ALCL includes different subtypes with different clinical and biological features: systemic ALCL, primary cutaneous ALCL, breast implant-associated ALCL (BIA-ALCL). Anaplastic lymphoma kinase (ALK) is overexpressed and rearranged in some systemic cases. Diagnosis of ALCL may be challenging on cytological samples, but the correct diagnosis is mandatory for the management of the patient. Methods: A retrospective series of 12 ALCLs diagnosed by cytology is reported. Cytological samples included lymph nodes and skin lesions fine needle aspiration cytology, peritoneal effusion, and periprosthetic fluid. Microscopic evaluation was performed on direct smears, cell-block sections, and cytocentrifugated slides. Immunocytochemistry was performed on cell-block sections, direct smears, and cytocentrifugated slides. Molecular evaluation by fluorescent in-situ hybridization (FISH) was performed on cell-block sections. Results: The series included 4 ALK+ ALCLs, 5 ALK− ALCLs, and 3 BIA-ALCLs. FNAC was performed on lymph nodes in 8 cases and on skin lesion in 1 case. In this last case, a peritoneal effusion was also evaluated. Breast periprosthetic fluids were evaluated in 3 cases. A large immunocytochemical panel was performed in each case, and FISH in 3 cases, demonstrating ALK rearrangement in a case of ALK+ ALCL. A final diagnosis was rendered in all cases. In the case of skin lesion, the differential diagnosis between systemic ALCL and primary cutaneous ALCL was possible. Conclusion: The cytological diagnosis of ALCL may be challenging, and the proper management of the collected sample is mandatory. The rapid on-site evaluation and the realization of a cell block are strongly recommended. Immunocytochemistry is mandatory for the diagnosis and a large antibodies panel is needed as differential diagnosis includes many different neoplasms. FISH may be useful to evaluate ALK rearrangements. When properly managed, cytology can lead to a reliable final diagnosis of ALCL.

Background The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC). Methods PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR, western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice. Results Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation. Conclusions PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.

Fine needle aspiration cytology (FNAC) can be a precious tool for the evaluation of lymphadenopathies in children and adolescents. The purpose of this study was to analyse the diagnostic accuracy of FNAC in a paediatric lymph node series. We report a series of 76 patients, aged up to 19 years, who underwent lymph node FNAC. In our series, 57 cases were diagnosed as non-neoplastic, including benign reactive hyperplasia and other inflammatory lesions, 18 cases were diagnosed as malignant and 1 case was diagnosed as suspicious for lymphoproliferative process, not otherwise specified. Sensitivity, specificity, positive predictive value and negative predictive value were 93 %, 100 %, 100 % and 98 %, respectively. Diagnostic accuracy resulted 98.6 %. FNAC is an accurate, minimally invasive method with minimal complications that allows evaluation of paediatric lymphadenopathies and a correct triage of reactive/inflammatory and neoplastic lymphadenopathies. The application of rapid on-site evaluation, the realization of a cell block and the application of ancillary diagnostic tests, including at least immunocytochemistry and flow cytometry, allows to achieve an excellent diagnostic performance.

Chromosomal rearrangements involving BCL2, BCL6 and MYC are commonly found in the most frequent B cell lymphomas, namely follicular lymphomas (FLs) and diffuse large B-cell lymphomas (DLBCLs). Particularly, BCL2-rearrangement represents a diagnostic hallmark in FLs, whereas MYC translocation can occur simultaneously with BCL2 and/or BCL6 rearrangements, defining a specific category of DLBCLs with a poorer prognosis. In this study, we aim to validate the diagnostic performance of multiplex BCL2/BCL6 FISH approach in formalin-fixed paraffin-embedded FLs and DBCLs and cytological samples of DLBCL comparing to the classic set of single break-apart probes. We collected a series of lymphomas, including 85 DLBCLs, 45 FLs and 36 other B-cell lymphoma histotypes and 16 cytological samples of DLBCLs. MYC, BCL2 and BCL6 rearrangements were previously assessed by a classic FISH test using single break-apart probes. All samples were analysed by a multiplex FISH assay. In the FL series, 38 cases showed BCL2-R; in the DLBCLs series, MYC-R was detected in 21 out of 85 DLBCL patients, BCL2-R in 10 out of 85 and BCL6-R in 33 out of 85. In the DLBCL cytological series, MYC-R was detected in 4 out of 16, BCL2-R in 4 out of 16 and BCL6-R in 1 out of 16. Notably, in FFPE, 13 double-hit lymphomas (DHLs) and 3 triple-hit lymphomas (THLs) were detected; in the cytological series, only 3 DHL cases were observed. The dual BCL2/BCL6 FISH probe test results were fully concordant with the results obtained using classic BCL2 and BCL6 single break apart. Particularly, multiplex FISH to simultaneously detect BCL2-R and BCL6-R on a single slide could find a wide application in the characterisation of double- and triple-hit DLBCLs.

Molecular heterogeneity is a frequent event in cancer responsible of several critical issues in diagnosis and treatment of oncologic patients. Lung tumours are characterized by high degree of molecular heterogeneity associated to different mechanisms of origin including genetic, epigenetic and non-genetic source. In this review, we provide an overview of recognized mechanisms underlying molecular heterogeneity in lung cancer, including epigenetic mechanisms, mutant allele specific imbalance, genomic instability, chromosomal aberrations, tumor mutational burden, somatic mutations. We focus on the role of spatial and temporal molecular heterogeneity involved in therapeutic implications in lung cancer patients.