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The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP-NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP-NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP-NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP-NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix., (© 2024 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Notably, the incidence of lung cancer among never-smokers, predominantly women, has been rising in recent years. Among the various implicated risk factors, human papilloma virus (HPV) may play a role in the development of NSCLC in a certain subset of patients. The prevalence of high-risk HPV-DNA within human neoplastic lung cells varies across the world; however, the carcinogenetic role of HPV in NSCLC has not been completely understood. Bloodstream could be one of the routes of transmission from infected sites to the lungs, along with oral (through unprotected oral sex) and airborne transmission. Previous studies reported an elevated risk of NSCLC in patients with prior HPV-related tumors, such as cervical, laryngeal, or oropharyngeal cancer, with better prognosis for HPV-positive lung cancers compared to negative forms. On the other hand, 16% of NSCLC patients present circulating HPV-DNA in peripheral blood along with miRNAs expression. Typically, these patients have a poorly differentiated NSCLC, often diagnosed at an advanced stage. However, HPV-positive lung cancers seem to have a better response to target therapies (EGFR) and immune checkpoint inhibitors and show an increased sensitivity to platinum-based treatments. This review summarizes the current evidence regarding the role of HPV in NSCLC development, especially among patients with a history of HPV-related cancers. It also examines the diagnostic and prognostic significance of HPV, investigating new future perspectives to enhance cancer screening, diagnostic protocols, and the development of more targeted therapies tailored to specific cohorts of NSCLC patients with confirmed HPV infection.

Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine tumors) through the identification of specific essential genes, crucial molecular pathways, regulators, and effects of the tumoral microenvironment. Target therapies have been developed to cure oncology patients refractory to traditional treatments, introducing the concept of precision medicine. Preliminary data on PitNETs are derived from preclinical studies conducted on cell cultures, animal models, and a few case reports or small case series. This study comprehensively reviews the principal pathways involved in aggressive PitNETs, describing the potential target therapies. A search was conducted on Pubmed, Scopus, and Web of Science for English papers published between 1 January 2004, and 15 June 2023. 254 were selected, and the topics related to aggressive PitNETs were recorded and discussed in detail: epigenetic aspects, membrane proteins and receptors, metalloprotease, molecular pathways, PPRK, and the immune microenvironment. A comprehensive comprehension of the molecular mechanisms linked to PitNETs' aggressiveness and invasiveness is crucial. Despite promising preliminary findings, additional research and clinical trials are necessary to confirm the indications and effectiveness of target therapies for PitNETs.

Background: The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients., Methods: The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management., Discussion: The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols., Ethics Committee Approval Number: 5420 - 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore Ethics Committee., Trial Registration: clinicaltrial.gov - NCT05802771., (© 2023. The Author(s).)

Pancreatic neuroendocrine neoplasms (panNENs) are a rare yet diverse type of neoplasia whose precise clinical-pathological classification is frequently challenging. Since incorrect classifications can affect treatment decisions, additional tools which support the diagnosis, such as machine learning (ML) techniques, are critically needed but generally unavailable due to the scarcity of suitable ML training data for rare panNENs. Here, we demonstrate that a multi-step ML framework predicts clinically relevant panNEN characteristics while being exclusively trained on widely available data of a healthy origin. The approach classifies panNENs by deconvolving their transcriptomes into cell type proportions based on shared gene expression profiles with healthy pancreatic cell types. The deconvolution results were found to provide a prognostic value with respect to the prediction of the overall patient survival time, neoplastic grading, and carcinoma versus tumor subclassification. The performance with which a proliferation rate agnostic deconvolution ML model could predict the clinical characteristics was found to be comparable to that of a comparative baseline model trained on the proliferation rate-informed MKI67 levels. The approach is novel in that it complements established proliferation rate-oriented classification schemes whose results can be reproduced and further refined by differentiating between identically graded subgroups. By including non-endocrine cell types, the deconvolution approach furthermore provides an in silico quantification of panNEN dedifferentiation, optimizing it for challenging clinical classification tasks in more aggressive panNEN subtypes.

Objectives: Lung cancer is increasingly diagnosed as a second cancer. Our goal was to analyse the characteristics and outcomes of early-stage resected lung adenocarcinomas in patients with previous cancers (PC) and correlations with adenocarcinoma subtypes., Methods: We retrospectively reviewed data of patients radically operated on for stage I-II lung adenocarcinoma in 9 thoracic surgery departments between 2014 and 2017. Overall survival (OS) and time to disease relapse were evaluated between subgroups., Results: We included 700 consecutive patients. PC were present in 260 (37.1%). Breast adenocarcinoma, lung cancer and prostate cancer were the most frequent (21.5%, 11.5% and 11.2%, respectively). No significant differences in OS were observed between the PC and non-PC groups (P = 0.378), with 31 and 75 deaths, respectively. Patients with PC had smaller tumours and were more likely to receive sublobar resection and to be operated on with a minimally invasive approach. Previous gastric cancer (P = 0.042) and synchronous PC (when diagnosed up to 6 months before lung adenocarcinoma; P = 0.044) were related, with a worse OS. Colon and breast adenocarcinomas and melanomas were significantly related to a lower incidence of high grade (solid or micropapillary, P = 0.0039, P = 0.005 and P = 0.028 respectively), whereas patients affected by a previous lymphoma had a higher incidence of a micropapillary pattern (P = 0.008)., Conclusions: In patients with PC, we found smaller tumours more frequently treated with minimally invasive techniques and sublobar resection, probably due to a more careful follow-up. The impact on survival is not uniform and predictable; however, breast and colon cancers and melanoma showed a lower incidence of solid or micropapillary patterns whereas patients with lymphomas had a higher incidence of a micropapillary pattern., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Introduction: Prolactin-secreting pituitary tumors (PRL-omas) are generally benign neoplasia. However, a percentage of cases show aggressive behavior. Prognostic markers may allow for the identification of aggressive cases. In this study, we investigated the prognostic role of galectin-3 and the estrogen receptor alpha (ERα), as predictive biomarkers of aggressiveness and poor prognosis., Patients and Methods: A mono-centric and retrospective study was conducted on consecutive cases of PRL-omas that underwent first line treatment with surgery and were followed-up for at least five years. The immunohistochemical expression of ERα and galectin-3 was investigated in each case., Results: 36 patients were enrolled. Galectin-3 resulted positive in 11 patients (30.6%). The median expression of ERα was 85% (IQR: 37). Among the group of 21 patients who underwent radical surgery (58.3%), recurrence occurred in 12 cases (33.3%). 27 patients were treated post-surgery with a dopamine agonist (DA) (12 for recurrence and 22 for a history of partial surgery). 13 patients (48.1%) were responsive to DA. Six of 11 cases positive for galactin-3 underwent partial surgery (54.5%, p<0.001). Recurrence occurred in all five cases that underwent radical surgery, which were also positive for galectin-3 (p=0.03). Galectin-3 resulted positive in 9 patients resistant to DA treatment (81.1%, p=0.01). ERα expression was lower in tumors positive for galectin-3 (p<0.001), with mitotic activity (p=0.012), with higher Ki67 Li (p<0.001), and in males with post-surgical recurrence (p<0.001)., Conclusion: Galectin-3 and ERα play as markers of aggressiveness and prognosis in PRL-omas and may be tested to identify the aggressive forms of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bima, Chiloiro, Giampietro, Gessi, Mattogno, Lauretti, Anile, Rindi, Pontecorvi, De Marinis and Bianchi.)

Pancreatic neuroendocrine tumors (PanNETs) display variable aggressive behavior. A major predictor of survival is tumor grade based on the Ki67 proliferation index. As information on transcriptomic profiles of PanNETs with different tumor grades is limited, we investigated 29 PanNETs (17 G1, 7 G2, 5 G3) for their expression profiles, mutations in 16 PanNET relevant genes and LINE-1 DNA methylation profiles. A total of 3050 genes were differentially expressed between tumors with different grades ( p < 0.05): 1279 in G3 vs. G2; 2757 in G3 vs. G1; and 203 in G2 vs. G1. Mutational analysis showed 57 alterations in 11 genes, the most frequent being MEN1 (18/29), DAXX (7/29), ATRX (6/29) and MUTYH (5/29). The presence and type of mutations did not correlate with the specific expression profiles associated with different grades. LINE-1 showed significantly lower methylation in G2/G3 versus G1 tumors ( p = 0.007). The expression profiles of matched primaries and metastasis (nodal, hepatic and colorectal wall) of three cases confirmed the role of Ki67 in defining specific expression profiles, which clustered according to tumor grades, independently from anatomic location or patient of origin. Such data call for future exploration of the role of Ki67 in tumor progression, given its involvement in chromosomal stability.

Large-cell neuroendocrine carcinomas of the lung (LCNECs) are rare tumors representing 1-3% of all primary lung cancers. Patients with LCNEC are predominantly male, older, and heavy smokers. Histologically, these tumors are characterized by large cells with abundant cytoplasm, high mitotic rate, and neuroendocrine immunohistochemistry-detected markers (chromogranin-A, synaptophysin, and CD56). In 2015 the World Health Organization classified LCNEC as a distinct subtype of pulmonary large-cell carcinoma and, therefore, as a subtype of non-small cell lung carcinoma (NSCLC). Because of the small-sized tissue samples and the likeness to other neuroendocrine tumors, the histological diagnosis of LCNEC remains difficult. Clinically, the prognosis of metastatic LCNECs is poor, with high rates of recurrence after surgery alone and overall survival of approximately 35% at 5 years, even for patients with early stage disease that is dramatically shorter compared with other NSCLC subtypes. First-line treatment options have been largely discussed but with limited data based on phase II studies with small sample sizes, and there are no second-line well defined treatments. To date, no standard treatment regimen has been developed, and how to treat LCNEC is still on debate. In the immunotherapy and targeted therapy era, in which NSCLC treatment strategies have been radically reshaped, a few data are available regarding these opportunities in LCNEC. Due to lack of knowledge in this field, many efforts have been done for a deeper understanding of the biological and molecular characteristics of LCNEC. Next generation sequencing analyses have identified subtypes of LCNEC that may be relevant for prognosis and response to therapy, but further studies are needed to better define the clinical impact of these results. Moreover, scarce data exist about PD-L1 expression in LCNEC and its predictive value in this histotype with regard to immunotherapy efficacy. In the literature some cases are reported concerning LCNEC metastatic patients carrying driver mutations, especially EGFR alterations, showing targeted therapy efficacy in this setting of disease. Due to the rarity and the challenging understanding of LCNEC, in this review we aim to summarize the management options currently available for treatment of LCNEC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ferrara, Stefani, Simbolo, Pilotto, Martini, Lococo, Vita, Chiappetta, Cancellieri, D’Argento, Trisolini, Rindi, Scarpa, Margaritora, Milella, Tortora and Bria.)

Competing Interests: None

Esophageal neuroendocrine neoplasms (E-NENs) are much rarer than other gastro-entero-pancreatic neuroendocrine neoplasms, the majority showing aggressive behavior with early dissemination and poor prognosis. Among E-NENs, exceptionally rare well differentiated neuroendocrine tumors (E-NET) and more frequent esophageal poorly differentiated neuroendocrine carcinomas (E-NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNEN) can be recognized. E-NECs usually exhibit a small cell morphology or mixed small and large cells. Esophageal MiNEN are composed of NEC component admixed with adenocarcinoma or squamous cell carcinoma. Gastric (G) NENs encompass a wide spectrum of entities ranging from indolent G-NETs to highly aggressive G-NECs and MiNENs. Among G-NETs, ECL-cell NETs are the most common and, although composed of histamine-producing cells, are a heterogeneous group of neoplastic proliferations showing different clinical and prognostic features depending on the patient's clinico-pathological background including the morphology of the peri-tumoral mucosa, gastrin serum levels, presence or absence of antral G-cell hyperplasia, and presence or absence of MEN1 syndrome. In general, NET associated with hypergastrinemia show a better outcome than NET not associated with hypergastrinemia. G-NECs and MiNENs are aggressive neoplasms more frequently observed in males and associated with a dismal prognosis., (Copyright © 2021 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Neoplasms characterized by the expression of markers of neuroendocrine differentiation in neoplastic cells are defined neuroendocrine. This broad definition comprises tumors found at different sites of the body with similar morphology but different behavior and genetic background. From a clinical standpoint neuroendocrine neoplasms may be functioning, when they give rise to unregulated secretion of hormones. Functioning tumors account for about one-third of neuroendocrine neoplasms. From a pathological standpoint neuroendocrine neoplasm are classified by cancer category, cancer families/classes, cancer types, cancer grade and cancer stage. The category identifies the cancer major trait and thus defined as neuroendocrine neoplasia (NEN) to comprise all families/classes of neuroendocrine cancer. The cancer family/types are neuroendocrine tumors (NET) as well differentiated, and neuroendocrine carcinoma (NEC) as poorly differentiated forms. Cancer grade, based on proliferation measure by mitotic count and Ki-67%, and cancer stage, based on tumor size and invasion (T), node deposits (N) and distant metastases (M), complete the pathological classification. Site-specific differences are the rule. Still missing is a genetic classification tool to complement current pathological descriptors., (Copyright © 2021 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Up to now, Italy is one of the European centers with the most active Coronavirus cases with 233,836 positive cases and 33,601 total deaths as of June 3rd. During this pandemic and dramatic emergency, Italian hospitals had also to face neoplastic pathologies, that still afflict the Italian population, requiring urgent surgical and oncological treatment. In our Cancer Center Hospital, the high volume of surgical procedures have demanded an equally high volume of intraoperative pathological examinations, but also posed an additional major challenge for the safety of the staff involved. The current commentary reports our experience in the past two months (since March 9th) for a total of 1271 frozen exams from 893 suspect COVID-19 patients (31 confirmed)., (Copyright © 2020 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Neuroendocrine neoplasia is described in almost every tissue, either in the pure endocrine organs, the nerve structures or in the so-called diffuse neuroendocrine system. The current nomenclature contains time-honored, widely accepted definitions; however, it is different according to anatomical sites. Diverse definitions may generate confusion and non-standard patient management. The International Agency for Research on Cancer - World Health Organization (IARC-WHO) proposed a framework for universal classification of neuroendocrine neoplasia. Evidence indicates that neuroendocrine cancer is composed by cells with a distinctive phenotype characterized by the expression of general and specific neuroendocrine markers. The neuroendocrine phenotype is indicated as descriptor of a unique cancer category, now recommended for all organs as neuroendocrine neoplasm. Evidence indicates that neuroendocrine neoplasia may be well or poorly differentiated, with diverse incidence and prevalence in different organs. It is proposed that the well-differentiated neoplasm is universally defined as neuroendocrine tumor (NET) and the poorly differentiated as neoplasm neuroendocrine carcinoma (NEC). Evidence indicates that a cancer grading tool based on a proliferation measure by mitotic count, Ki67 % and/or necrosis assessment is useful to predict NET patient behavior. It is proposed to utilize this tool for grading NET universally, with site-specific cut-offs to be defined. It is also acknowledged that significant biological site-specific differences exist. It is recommended that current pathology reports contain this classification together with the current traditional classifiers. This IARC-WHO common classification framework for neuroendocrine neoplasm aims at uniformizing nomenclature toward different organs and at fostering the definition of a similar site-specific gene signature.

Background: Gynecological neuroendocrine neoplasms (NENs) are extremely rare, accounting for 1.2-2.4% of the NENs. The aim of this study was to test cervical NENs for novel markers of potential utility for differential diagnosis and target therapy., Methods: All cases of our center ( n = 16) were retrieved and tested by immunohistochemistry (IHC) for 12 markers including markers of neuroendocrine differentiation (chromogranin A, synaptophysin, CD56), transcription factors (CDX2 and TTF1), proteins p40, p63, p16INK4a, and p53, somatostatin receptors subtypes (SST2-SST5) and the proliferation marker Ki67 (MIB1)., Results: All cases were poorly differentiated neuroendocrine carcinomas (NECs), 10 small cell types (small cell-neuroendocrine carcinomas, SCNECs) and 6 large cell types (large cell-neuroendocrine carcinomas, LCNECs); in 3 cases a predominant associated adenocarcinoma component was observed. Neuroendocrine cancer cells expressed at least 2 of the 3 tested neuroendocrine markers; p16 was intensely expressed in 14 (87.5%) cases; SST5 in 11 (56.25%, score 2-3, in 9 cases); SST2 in 8 (50%, score 2-3 in 8), CDX2 in 8 (50%), TTF1 in 5 (31.25%), and p53 in 1 case (0.06%). P63 and p40 expressions were negative, with the exception of one case that showed moderate expression for p63., Conclusions: P40 is a more useful marker for the differential diagnosis compared to squamous cell carcinoma. Neither CDX2 nor TTF1 expression may help the differential diagnosis versus potential cervical metastasis. P16 expression may suggest a cervical origin of NEC; however, it must be always integrated by clinical and instrumental data. The expression of SST2 and SST5 could support a role for SSAs (Somatostatin Analogues) in the diagnosis and therapy of patients with cervical NECs., Competing Interests: The authors declare no conflict of interest.

Mitotane (MTT) is an adrenolytic drug used in adjuvant and advanced treatments of adrenocortical carcinoma (ACC). Ionizing radiation (IR) is also used in adrenal cancer treatment, even though its biological action remains unknown. To provide a reliable in vivo preclinical model of ACC, we used mouse xenografts bearing human ACC to test the effects of MTT and IR alone and in combination. We evaluated tumor growth inhibition by the RECIST criteria and analyzed the cell cycle by flow cytometry (FCM). In the xenograft ACC model treated with MTT/IR in combination, we observed a marked inhibition of tumor growth, with strong tumor regression ( p < 0.0001) compared to MTT and IR given alone ( p < 0.05). The MTT results confirm its antisteroidogenic activity ( p < 0.05) in the xenograft ACC model, revealing its ability to render cancer cells more prone to radiotherapy treatment. In addition, to explain the biological effect of these treatments on the Mismatch Repair System (MMR), we interfered with the MSH2 gene expression in untreated and MTT/IR-treated H295R and SW13 cell lines. Moreover, we observed that upon treatment with MTT/IR to induce DNA damage, MSH2 gene inhibition in both the H295R and SW13 cell lines did not allow DNA damage repair, thus inducing cell death. In conclusion, MTT seems to have a radiosensitizing property and, when given in combination with IR, is able to promote neoplastic growth inhibition, leading to a significant reduction in tumor size due to cell death., Competing Interests: The authors have nothing to disclose.

Context: The treatment of acromegaly resistant to first- and second-line therapies can be extremely challenging., Design: We have described six patients who were successfully treated with a combination therapy of pasireotide and pegvisomant and compared them with a control group of patients resistant to conventional somatostatin analogs (SSAs), whose disease was controlled with other treatment, such as pasireotide (as monotherapy) or pegvisomant (as monotherapy or combined with conventional SSAs)., Results: In these six patients, acromegaly was controlled with combined pasireotide and pegvisomant treatment after failure of all other treatments. Compared with the 49 patients in the control group, these six patients had giant and invasive pituitary adenomas (at both the cavernous sinus and other structures). Although not statistically significant, higher growth hormone levels, more elevated Ki-67 expression, greater somatostatin receptor (SSTR) subtype 5 expression, and lower SSTR subtype 2 expression at the diagnosis of acromegaly were detected in patients receiving combination treatment with pasireotide and pegvisomant compared with the control group., Conclusion: Our data have reinforced the importance of personalized treatment of patients with acromegaly according to the clinical, biochemical, molecular, and morphological disease markers and suggest that combined treatment with pasireotide and pegvisomant can induce disease control in tumors with low SSTR2 expression, resistant to conventional SSAs (alone or combined with pegvisomant) and to new-generation SSAs alone (pasireotide)., (Copyright © 2019 Endocrine Society.)

No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit with immunotherapy. The immunological features of mUM were reviewed in order to understand if immunotherapy could still play a role for this disease.

Background: No standard treatment has been defined for metastatic uveal melanoma (mUM). Although clinical trials testing Nivolumab/Pembrolizumab for cutaneous melanoma did not include mUM, anti PD-1 agents are commonly used for this disease., Patients and Methods: In this prospective observational cohort single arm study, we investigated efficacy and safety of Pembrolizumab as first-line therapy for mUM. The efficacy was evaluated in terms of progression-free survival (PFS), response rate and overall survival (OS). Toxicity was also assessed., Results: Seventeen patients were enrolled. A median of 8 cycles were administered (range 2-28). Two patients achieved partial response (11.7%), 6 a disease stabilization (35.3%), whereas 9 (53%) had a progression. No complete response was observed. PFS of the overall population was 3.8 months. PFS was 9.7 months for patients with an interval higher than 5 years from diagnosis of primary tumor to metastatic disease and 2.6 months for patients with an interval lower than 5 years [p = 0.039, HR 0.2865 (95% CI 0.0869-0.9443)]. Median OS was not reached. The two responding patients were still on treatment with Pembrolizumab at the time of data analysis. Survival was 12.8 months for patients with clinical benefit, while OS for progressive patients was 3.1 months. PD-L1 expression and genomic abnormalities predictive of relapse after diagnosis of primary tumor were not associated with PFS. Toxicity was mild, without grade 3-4 side effects., Conclusions: The efficacy of Pembrolizumab does not seem particularly different when compared to other agents for mUM, but responding patients had a remarkable disease control.