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Background: Transperitoneal laparoscopic adrenalectomy (TLA) is the most frequently chosen approach in adrenal surgery. At present, impact of obesity on patient outcomes following adrenal surgery is frequently under discussion. We intended to offer updated evidence thanks to a comparison between intraoperative and perioperative outcomes in non-obese and obese patients, who underwent TLA for benign or malignant adrenal diseases., Methods: Our systematic review made use of Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Articles of interest turned out from a search with PubMed/MEDLINE, Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials-CENTRAL), Web of Science (Science and Social Science Citation Index), and Scopus databases. We evaluated two groups of outcomes: intraoperative (operative time, intraoperative complications rate, estimated blood loss (EBL), transfusion rate, conversion to open surgery rate) and postoperative (overall postoperative complications rate, major postoperative complications rate, length of hospital stay). RevMan (Computer program) Version 5.4 was used to perform the meta-analysis. The heterogeneity of the included studies in the meta-analysis was assessed by using the I2 statist., Results: The 8 included comparative studies (1,646 patients: 995 non-obese versus 651 obese) had a time frame of approximately 30 years (1994-2020) and an observational nature. Meta-analysis showed no differences in terms of operative time, intraoperative complications rate, EBL, transfusion rate, conversion to open surgery rate, overall postoperative complications rate, major (Clavien-Dindo ≥ III) postoperative complications rate, length of hospital stay between non-obese and obese populations., Conclusions: We can say that obesity does not impact TLA safety and effectiveness. Due to biases among meta-analyzed studies (small overall sample size and small number of events analyzed, in particular), careful interpretation is needed to interpret our results. Additional randomized, possibly multi-center trials may contribute to confirm our results.

Among cardiac tumors, angiosarcoma is the most common primary malignancy, with a relatively higher prevalence in young male adults and a weak dominance in the right atrium as a primary site of growth. It is characterized by rapid infiltration of cardiac structures and possible metastasis to mediastinal and distant organs. The patient may be asymptomatic until advanced phases. It therefore has a poor prognosis. Diagnosis requires the use of multimodality imaging, including echocardiography, computed tomography (CT), cardiac magnetic resonance and positron emission tomography. The definitive diagnosis is based on histological examination. We report the case of a young male adult who was referred to the cardiology department for a syncopal event 5 h after cocaine assumption. During the diagnostic work-up, a chest X-ray was performed, showing multiple pulmonary lesions, which were evaluated with a chest CT highlighting the presence of a cardiac mass in the right atrium and ventricle. For this reason, a complete cardiological evaluation was performed. The clinical and instrumental suspicion of a malignant cardiac tumor was confirmed by multimodality imaging and finally by histological examination.

Chromatin modifiers are emerging as major determinants of many types of cancers, including Anaplastic Large Cell Lymphomas (ALCL), a family of highly heterogeneous T-cell lymphomas for which therapeutic options are still limited. HELLS is a multifunctional chromatin remodeling protein that affects genomic instability by participating in the DNA damage response. Although the transcriptional function of HELLS has been suggested, no clues on how HELLS controls transcription are currently available. In this study, by integrating different multi-omics and functional approaches, we characterized the transcriptional landscape of HELLS in ALCL. We explored the clinical impact of its transcriptional program in a large cohort of 44 patients with ALCL. We demonstrated that HELLS, loaded at the level of intronic regions of target promoters, facilitates RNA Polymerase II (RNAPII) progression along the gene bodies by reducing the persistence of co-transcriptional R-loops and promoting DNA damage resolution. Importantly, selective knockdown of HELLS sensitizes ALCL cells to different chemotherapeutic agents, showing a synergistic effect. Collectively, our work unveils the role of HELLS in acting as a gatekeeper of ALCL genome stability providing a rationale for drug design., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells and/or tumor-associated macrophages results in inhibitory signals to the T-cell receptor pathway, consequently causing tumor immune escape. PD-L1/PD-L2 are currently used as predictive tissue biomarkers in clinical practice. Virtually PD-L1 levels expressed by tumor cells are associated with a good response to immune checkpoint blockade therapies targeting the PD-1/PD-L1 axis. These therapies restore T-cell antitumor immune response by releasing T-lymphocytes from the inhibitory effects of tumor cells. Immune checkpoint therapies have completely changed the management of patients with solid cancers. This therapeutic strategy is less used in hematological malignancies, although good results have been achieved in some settings, such as refractory/relapsed classic Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Variable results have been obtained in diffuse large B-cell lymphoma and T-cell lymphomas. Immunohistochemistry represents the main technique for assessing PD-L1 expression on tumor cells. This review aims to describe the current knowledge of PD-L1 expression in various types of lymphomas, focusing on the principal mechanisms underlying PD-L1 overexpression, its prognostic significance and practical issues concerning the evaluation of PD-L1 immunohistochemical results in lymphomas.

Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is essential for the development and diagnosis of CML; on the other hand, the majority of Ph-negative MPNs are characterized by generally mutually exclusive mutations of Janus kinase 2 ( JAK2 ), calreticulin ( CALR ), or thrombopoietin receptor/myeloproliferative leukemia ( MPL ). CALR mutations have been described essentially in JAK2 and MPL wild-type essential thrombocythemia and primary myelofibrosis. Rarely coexisting CALR and MPL mutations have been found in Ph-negative MPNs. BCR::ABL1 translocation and JAK2 mutations were initially considered mutually exclusive genomic events, but a discrete number of cases with the combination of these genetic alterations have been reported. The presence of BCR::ABL1 translocation with a coexisting CALR mutation is even more uncommon. Herein, starting from a routinely diagnosed case of CALR -mutated primary myelofibrosis subsequently acquiring BCR::ABL1 translocation, we performed a comprehensive review of the literature, discussing the clinicopathologic and molecular features, as well as the outcome and treatment of cases with BCR::ABL1 and CALR co-occurrence., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zanelli, Fragliasso, Loscocco, Sanguedolce, Broggi, Zizzo, Palicelli, Ricci, Ambrogi, Martino, Aversa, Coppa, Gentile, Gozzi, Caltabiano, Koufopoulos, Asaturova, Cimino, Cavazza, Orcioni and Ascani.)

There is an ongoing need for biomarkers that could reliably predict the outcome of BC and that could guide the management of this disease. In this setting, we aimed to explore the prognostic value of the transcription factor P63 in patients with muscle-invasive bladder cancer (MIBC) having undergone radical cystectomy. The correlation between P63 expression and clinicopathological features (tumor stage, nodes involvement, patterns of muscularis propria invasion, papillary architecture, anaplasia, concomitant carcinoma in situ, lymphovascular invasion, perineural invasion, necrosis) and molecular subtyping (basal and luminal type tumors) was tested in 65 radical cystectomy specimens and matched with cancer-specific survival (CSS) and overall survival (OS). P63-negative tumors displayed significantly higher rates of pattern 2 of muscularis propria invasion (50% vs. 14%, p = 0.002) and variant histology (45% vs. 19%, p = 0.022) compared to P63-positive ones. According to the combined expression of CK5/6 and CK20 (Algorithm #1), P63-positive and P63-negative tumors were mostly basal-like and double-negative, respectively ( p = 0.004). Using Algorithm #2, based on the combined expression of CK5/6 and GATA3, the vast majority of tumors were luminal overall and in each group ( p = 0.003). There was no significant difference in CSS and OS between P63-positive and P63-negative tumors, but the former featured a trend towards longer OS. Though associated with pathological features harboring negative prognostic potential, P63 status as such failed to predict CSS and OS. That said, it may contribute to better molecular subtyping of MIBC.

Introduction: The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC., Aims: In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways., Results: Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC., Conclusion: Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2 -positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient's treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zanelli, Bisagni, Sanguedolce, Broggi, Fragliasso, Zizzo, Palicelli, Martino, Cresta, Caprera, Corsi, Gentile, Gozzi, Trombetta, Parente, Caltabiano, Koufopoulos, Cimino, Cavazza, Fraternali Orcioni and Ascani.)

Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive anaplastic lymphoma kinase-negative (ALK-) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK- ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK- ALCL.

Hematological neoplasms sharing a blastic morphology may involve the skin. The skin may be either the primary site of occurrence of hematological malignancies with blastic features or cutaneous lesions are the first manifestation of an underlying systemic malignancy. The assessment of skin biopsies of hematological neoplasms with blastic features poses diagnostic problems and requires expert hematopathologists considering a wide range of differential diagnoses. The precise diagnosis of diseases sharing blastic features but with different outcomes and requiring distinct therapies is essential for patient management. The present paper mainly focuses on cutaneous involvement of the blastoid variant of mantle cell lymphoma and lymphoblastic lymphoma of B-cell or T-cell origin. The relevant literature has been reviewed and the clinical aspects, pathological features, prognosis, and therapy of both blastoid mantle cell lymphoma and lymphoblastic lymphoma involving the skin are discussed. A focus on other hematological entities with blastic features, which may involve the skin, to be taken into consideration in differential diagnosis is also given.

Background and Objectives: Anterior rectal resection (ARR) represents one of the most frequently performed methods in colorectal surgery, mainly carried out for rectal cancer (RC) treatment. Defunctioning ileostomy (DI) has long been chosen as a method to "protect" colorectal or coloanal anastomosis after ARR. However, DI does not rule out risks of more or less serious complications. A proximal intra-abdominal closed-loop ileostomy, the so-called virtual/ghost ileostomy (VI/GI), could limit the number of DIs and the associated morbidity., Materials and Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Meta-analysis was performed by use of RevMan [Computer program] Version 5.4., Results: The five included comparative studies (VI/GI or DI) covering an approximately 20-year study period (2008-2021). All included studies were observational ones and originated from European countries. Meta-analysis indicated VI/GI as significantly associated with lower short-term morbidity rates related to VI/GI or DI after primary surgery (RR: 0.21, 95% CI: 0.07-0.64, p = 0.006), fewer dehydration (RR: 0.17, 95% CI: 0.04-0.75, p = 0.02) and ileus episodes after primary surgery (RR: 0.20, 95% CI: 0.05-0.77, p = 0.02), fewer readmissions after primary surgery (RR: 0.17, 95% CI: 0.07-0.43, p = 0.0002) and readmissions after primary surgery plus stoma closure surgery (RR: 0.14, 95% CI: 0.06-0.30, p < 0.00001) than the DI group. On the contrary, no differences were identified in terms of AL after primary surgery, short-term morbidity after primary surgery, major complications (CD ≥ III) after primary surgery and length of hospital stay after primary surgery. Conclusions : Given the significant biases among meta-analyzed studies (small overall sample size and the small number of events analyzed, in particular), our results require careful interpretation. Further randomized, possibly multi-center trials may be of paramount importance in confirming our results.

Molecular subtyping of bladder cancer (BC) aims to capture the biological heterogeneity of this complex disease in order to provide better patient risk stratification. Immunohistochemical (IHC) markers are regarded as promising surrogates to classify BCs into luminal and basal subtypes in routine practice. We investigated the correlation between the molecular subclassification, assessed through IHC, and the conventional prognostic variables of a cohort of 93 muscle-invasive BCs (MIBCs), with a focus on the pattern of muscularis propria (MP) invasion, and evaluated their association with outcome. Basal, luminal, double-positive (DP), and double-negative (DN) phenotypes were identified according to the coordinate expression of 1 basal (CK5/6) and 2 luminal (CK20, GATA3) markers, and accounted for 33.3%, 32.3%, 3.2%, and 31.2% (Scheme #1) and 9.7%, 60.2%, 26.9%, and 3.2% (Scheme #2). There was a significant association between the pattern of MP invasion and the molecular subtypes according to Scheme #2, in that all 8 basal and DN cases, as well as 83% of DP cases, had a non-infiltrative invasion pattern. No consistent differences were observed in terms of OS and CSS between the molecular subtypes obtained through surrogate IHC markers. In keeping with previous studies, we report the correlation between the identification of BC subtypes and the presence of morphological prognostic factors, supporting the need for a comprehensive pathological evaluation, including clinicopathological and molecular parameters, in order to improve the diagnosis and management of MIBC.

Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included.

Bladder cancer (BC) is a heterogeneous disease from a molecular, morphological, and clinical standpoint. HER2 is a known oncogene involved in bladder carcinogenesis. Assessing HER2 overexpression as a result of its molecular changes in a routine pathology practice using immunohistochemistry might be a useful adjunct in several scenarios, namely (1) to correctly identify flat urothelial lesions and inverted urothelial lesions in the diagnostic setting; (2) to provide prognostic hints in both non-muscle invasive (NMI) and muscle invasive (MI) tumors, thus supplementing risk stratification tools, especially when evaluating higher-risk tumors such as those with variant morphology; (3) to improve antibody panels as a surrogate marker of BC molecular subtyping. Furthermore, the potential of HER2 as a therapeutic target has been only partly explored so far, in light of the ongoing development of novel target therapies.

Intravascular lymphoma is a form of lymphoid malignancy characterized by neoplastic cells growing almost exclusively within the lumina of small- to medium-sized blood vessels. Most cases are of B-cell origin with rare cases of natural killer or T-cell lineage. Extranodal sites are affected, mainly the skin and central nervous system, although any organ may be involved. Intravascular NK/T-cell lymphoma deserves special attention because of its clinicopathologic features and the need for adequate immunophenotyping combined with clonality test for a proper diagnosis. Moreover, intravascular NK/T-cell lymphoma is strongly linked to Epstein-Barr virus (EBV), which is considered to play a role in tumorigenesis and to be responsible for the aggressive behavior of the disease. In this paper, we review the current knowledge on this rare lymphoma and, in particular, the most recent advances about its molecular landscape. The main distinguishing features with other EBV-related entities, such as extranodal NK/T-cell lymphoma, EBV-positive primary nodal T/NK-cell lymphoma, and aggressive NK-cell leukemia, are discussed to help pathologists obtain the correct diagnosis and consequently develop an adequate and prompt therapy response.

Primary vitreoretinal lymphoma (PVRL), a rare aggressive malignancy primarily involving the retina and/or the vitreous, is a major diagnostic challenge for clinicians (who commonly misdiagnose it as chronic uveitis) as well as for pathologists (for biological and technical reasons). Delays in diagnosis and treatment are responsible for visual impairments and life-threatening consequences, usually related to central nervous system involvement. The identification of lymphoma cells in vitreous fluid, obtained by vitrectomy, is required for diagnosis. Of note, the scarcity of neoplastic cells in small volumes of vitreous sample, and the fragility of lymphoma cells with degenerative changes caused by previous steroid use for presumed uveitis makes diagnosis based on cytology plus immunophenotyping difficult. Interleukin levels, immunoglobulin heavy chain or T-cell receptor gene rearrangements, and MYD88 mutation are applied in combination with cytology to support diagnosis. We aim to describe the current laboratory technologies for PVRL diagnosis, focusing on the main issues that these methods have. In addition, new emerging diagnostic strategies, such as next-generation sequencing analysis, are discussed. The genetic profile of PVRL remains largely unexplored. Better knowledge of genetic alterations is critical for precision medicine interventions with target-based treatments of this lymphoma for which no standardised treatment protocol currently exists.

Pediatric thymomas are extremely rare and slow-growing malignant tumors. The recent publication of the first Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) stage classification and updated treatment guidelines for thymomas has prompted us to perform a review of the literature on pediatric thymomas. A search of English-language articles in the PubMed, Cochrane, Web of Science, and Embase databases was conducted. Additional articles were identified through reference lists of retrieved publications. Thirty-two articles involving 82 pediatric thymomas were included. Males comprised 60% of patients, and 13% manifested myasthenia gravis (MG). Histotype B1 (45%) and stage I (52% Masaoka-Koga and 71% UICC/AJCC TNM) were the most frequent. Of note is the possibility that the lack of cases with mixed histologies in the reviewed publications might be related to a sampling issue, as it is well known that the more sections are available for review, the more likely it is that the majority of these neoplasms will show mixed histologies. Both staging systems showed a gradual increase in the percentage of cases, with more advanced stages of disease moving from type A to B3 thymomas. Complete surgical resection (R0) was the main therapeutic approach in Masaoka-Koga stage I (89%) and UICC/AJCC TNM stage I (70%) thymomas. Advanced stages of disease and incomplete surgical resection were most often associated with recurrence and death. An association between stage and outcome, and completeness of resection and outcome, was found. Interestingly, though an association between histotype and staging was found, this does not take into account the possibility of mixed histologies which would reduce the clinical impact of histologic subtyping over staging.

Background and Objectives : Surgery remains the only possible curative treatment for advanced gastric cancer (AGC). Peritoneal metastases are estimated to occur in approximately 55-60% AGC patients. Greater omentum is the most common metastatic area in AGC. At present, omentectomy alone or bursectomy are usually carried out during gastric cancer surgery. We performed a meta-analysis in order to evaluate long-term and short-term outcomes among AGC patients, who have undergone radical gastrectomy with or without complete omentectomy (CO). Materials and Methods : We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed by use of RevMan (Computer program) Version 5.4. Results : The eight included studies covered an approximately 20 years long study period (2000-2018). Almost all included studies were retrospective ones and originated from Asian countries. Meta-analysis indicated gastrectomy without CO as significantly associated with longer 3-year (RR: 0.94, 95% CI: 0.90-0.98, p = 0.005) and 5-year overall survivals (OS) (RR: 0.93, 95% CI: 0.88-0.98, p = 0.007). Moreover, we found longer operative time (MD: 24.00, 95% CI: -0.45-48.45, p = 0.05) and higher estimated blood loss (MD: 194.76, 95% CI: 96.40-293.13, p = 0.0001) in CO group. Conclusions : Non-complete omentectomy (NCO) group had a statistically greater rate in 3-year and 5-year OSs than the CO group, while the CO group had significantly longer operative time and higher estimated blood loss than the NCO group. Further randomized, possibly multi-center trials may turn out of paramount importance in confirming our results.

Collision metastasis is a rare phenomenon of concomitant localization of 2 or more different tumors in the same lymph node. In most cases, primary malignancies are synchronous carcinomas arising in the same organ or area of the body. A 82-year-old man presented with hematuria and acute renal failure; he had undergone dermatological consultation ten months ago because of a large deep brown skin lesion in his dorso-lumbar region, which was not excised upon patient's request. He underwent radical cystectomy with extended pelvic lymphadenectomy due to nonpapillary high-grade urothelial carcinoma, with focal squamous features, infiltrating the bladder wall and prostate gland. In one left iliac lymph node, small foci of metastatic urothelial carcinoma (positive for P63 and CK34betaE12) were close to melanoma cells (positive for HMB45). The patient refused further treatment and died of metastatic disease 12 months after cystectomy. There is no specific clinical feature for nodal collision metastasis. A polymorphic histologic appearance poses the suspect, but immunohistochemical stains are needed to define the primary tumors. Collision metastases are thought to carry a poor prognosis. Their clinical relevance is linked to the fact that the patient faces 2 different metastatic tumors that may require specific multidisciplinary approach once diagnosed as metastatic. We present, to the best of our knowledge, the first case of collision nodal metastasis from bladder cancer and melanoma, and describe its clinical and histopathological characteristics to raise awareness on this rare occurrence, which portends a poorer prognosis than each single tumor., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Introduction: In central nervous system neurodegenerative disorders, stem cell-based therapies should be considered as a promising therapeutic approach. The safe use of human Neural Stem Cells (hNSCs) for the treatment of several neurological diseases is currently under evaluation of phase I/II clinical trials. Clinical application of hNSCs require the development of GMP standardized protocols capable of generating high quantities of reproducible and well characterized stem cells bearing stable functional and genetic properties., Aim: The aim of this study was to evaluate possible instabilities or modifications of the microsatellite loci in different culture passages because high culture passages represent an in vitro replicative stress leading to senescence. Experimental method: The hNSCs were characterized at different culture time points, from passage 2 to passage 25, by genetic typing at ten microsatellite loci., Conclusion: We showed that genetic stability at microsatellite loci is maintained by the cells even at high passages adding a further demonstration of the safety of our hNSCs GMP culture method., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Colovesical fistulas (CVFs) account for approximately 95% enterovesical fistulas (EVFs). About 2/3 CVF cases are diverticular in origin. It mainly presents with urological signs such as pneumaturia and fecaluria. Diagnostic investigations aim at confirming the presence of a fistula. Although conservative management can be chosen for selected individuals, most patients are mainly treated through surgical interventions. CVF represents a challenging condition, which records high rates of morbidity and mortality. Our systematic review aimed at achieving deeper knowledge of both indications, in addition to short- and long-term outcomes related to CVF management., Evidence Acquisition: We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Pubmed/MEDLINE, Embase, Scopus, Cochrane Library and Web of Science databases were used to search all related literature., Evidence Synthesis: The 22 included articles covered an approximately 37 years-study period (1982-2019), with a total 1365 patient population. CVF etiology was colonic diverticulitis in most cases (87.9%). Pneumaturia (50.1%), fecaluria (40.9%) and urinary tract infections (46.6%) were the most common symptoms. Abdomen computed tomography (CT) scan (80.5%), colonoscopy (74.5%) and cystoscopy (55.9%) were the most frequently performed diagnostic methods. Most CVF patients underwent surgery (97.1%) with open approach (63.3%). Almost all patients had colorectal resection with primary anastomosis with or without ostomy and 53.2% patients underwent primary repair or partial/total cystectomy. Four percent anastomotic leak, 1.8% bladder leak and 3.1% reoperations rates were identified. In an average 5-68-month follow-up, overall morbidity, overall mortality and recurrences rates recorded were 8-49%, 0-63% and 1.2%, respectively., Conclusions: CVF mainly affects males and has diverticular origin in almost all cases. Pneumaturia, fecaluria and urinary tract infections are the most characteristic symptoms. Endoscopic tests and imaging are critical tools for diagnostic completion. Management of CVFs depends on the underlying disease. Surgical treatment represents the final approach and consists of resection and reanastomosis of offending intestinal segment, with or without bladder closure. In many cases, a single-stage surgical strategy is selected. Perioperative and long-term outcomes prove good.

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a "consensus" classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic and predictive characteristics. In order to implement molecular subtyping (MS) as a risk stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The second part of this review deals with the pathological and clinical features of the molecular clusters, both in conventional and divergent urothelial carcinoma, with a focus on the role of IHC-based subtyping.

Bladder cancer (BC) is a heterogeneous disease with highly variable clinical and pathological features, and resulting in different outcomes. Such heterogeneity ensues from distinct pathogenetic mechanisms and may consistently affect treatment responses in single patients. Thus, over the last few years, several groups have developed molecular classification schemes for BC, mainly based on their mRNA expression profiles. A "consensus" classification has recently been proposed to combine the published systems, agreeing on a six-cluster scheme with distinct prognostic and predictive features. In order to implement molecular subtyping as a risk-stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The first part of this review deals with the steps resulting in the development of a molecular subtyping of BC, its prognostic and predictive implications, and the main features of immunohistochemical markers used as surrogates to stratify BC into pre-defined molecular clusters.

Background and Objectives : Gastrectomy with D2 lymphadenectomy is the standard surgical treatment with curative intent for patients with gastric cancer (GC). Over the last three decades, surgeons have been increasingly adopting laparoscopic surgery for GC, due to its better short-term outcomes. In particular, laparoscopic gastrectomy (LG) has been routinely used for early gastric cancer (EGC) treatment. However, LG suffers from technical limitations and drawbacks, such as a two-dimensional surgical field of view, limited movement of laparoscopic tools, unavoidable physiological tremors and discomfort for operating surgeon. Therefore, robotic surgery has been developed to address such limitations. Materials and Methods : We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines in order to investigate the benefits and harms of robotic gastrectomy (RG) compared to the LG. PubMed/MEDLINE, Scopus, Cochrane Library (Cochrane Database of Systematic Re-views, Cochrane Central Register of Controlled Trials-CENTRAL) and Web of Science (Science and Social Science Citation Index) databases were used to search all related literature. Results : The 7 included meta-analyses covered an approximately 20 years-study period (2000-2020). Almost all studies included in the meta-analyses were retrospective ones and originated from Asian countries (China and Korea, in particular). Examined overall population ranged from 3176 to 17,712 patients. If compared to LG, RG showed both operative advantages (operative time, estimated blood loss, number of retrieved lymph nodes) and perioperative ones (time to first flatus, time to restart oral intake, length of hospitalization, overall complications, Clavien-Dindo (CD) ≥ III complications, pancreatic complications), in the absence of clear differences of oncological outcomes. However, costs of robotic approach appear significant. Conclusions : It is impossible to make strong recommendations, due to the statistical weakness of the included studies. Further randomized, possibly multicenter trials are strongly recommended, if we want to have our results confirmed.

Neuroendocrine neoplasms (NENs) are a group of disease entities sharing common morphological, ultrastructural and immunophenotypical features, yet with distinct biological behavior and clinical outcome, ranging from benign to frankly malignant. Accordingly, a spectrum of therapeutic options for each single entity is available, including somatostatin analogues (SSA), mTOR-inhibitors, peptide receptor radionuclide therapy (PRRT), non-platinum and platinum chemotherapy. In the last few decades, several attempts have been made to better stratify these lesions refining the pathological classifications, so as to obtain an optimal correspondence between the scientific terminology and, the predictive and prognostic features of each disease subtype, and achieve a global Classification encompassing NENs arising at different anatomical sites. The aim of this review was to analyze, compare and discuss the main features and issues of the latest WHO Classifications of NENs of the lung and the digestive system, in order to point out the strengths and limitations of our current understanding of these complex diseases.

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (DH/TH-HGBL) still miss an in-depth genomic characterization. To identify accompanying genetic events, we performed a pilot study on 7 cases by applying DNA microarray and targeted NGS sequencing. Interestingly, the genetic background of DH/TH-HGBL is largely overlapping with that of other high-grade/poor prognosis lymphomas. Namely, copy number abnormalities were trisomy of chromosome 7 and chromosome 8q gain, encompassing MYC . Among gene variants, those affecting transcription factors ( MYC, FOXO1 ), epigenetic modulators ( KMT2D , EZH2 and CREEBP ), and anti-apoptotic gene ( BCL2 ), were recurrent. MYC and BCL2 were mutated in 3 and 5 cases, respectively. In addition, mutations of FOXO1, previously reported in Diffuse Large B-Cell Lymphomas, were also detected. Clarifying the genomic background of this subset of high-risk lymphomas will pave the way for the clinical use of new biomarkers to: (1) monitor treatment response and; (2) consider alternative targeted therapies.

Neoplasms with plasma cell differentiation may occasionally involve the skin. Cutaneous lesions may represent the first sign of an underlying systemic plasma cell malignancy, such as multiple myeloma, or the skin itself may be the primary site of occurrence of a hematological tumor with plasma cell differentiation. Starting from examples encountered in our daily practice, we discussed the diagnostic approach pathologists and clinicians should use when faced with cutaneous lesions with plasma cell differentiation. Cases of primary cutaneous marginal zone lymphoma, localized primary amyloidosis/amyloidoma, and cutaneous manifestations (secondary either to multiple myeloma or to plasmablastic lymphoma) are discussed, focusing on the importance of the adequate patient's work-up and precise clinicopathological correlation to get to the correct diagnosis and appropriate treatment. The pertinent literature has been reviewed, and the clinical presentation, pathological findings, main differential diagnoses, treatment, and outcome of neoplasms with plasma cell differentiation involving the skin are discussed.

Competing Interests: Competing interests: None declared.

The recurrent genetic anomalies used to classify prostate cancer (PC) into distinct molecular subtypes have limited relevance for clinical practice. In consideration of WHO 2016 histological classification, which includes the introduction of Gleason Score 4 for patients with cribriform component and the definition of intraductal carcinoma as a new entity, a retrospective pilot study was conducted to investigate, by histological review, if there were any variations of Gleason Score and the incidence of intraductal carcinoma and cribriform pattern, intended as "phenotypic" markers of potentially lethal PC, among metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC) samples. Potentially predictive factors were also assessed. Among 125 cases, a variation in the Gleason Score was reported in 26% of cases. A cribriform (36%) or intraductal (2%) pattern was reported in a higher percentage. Of them, a primary Gleason pattern 4 was reported in 80% of cases. All patients with intraductal carcinoma present a BRCA2 mutation, also found in 80% of cases with a cribriform pattern. This pilot study documented some hypothesis-generating data, as the evaluation of de novo mCSPC and mCRPC as phenotypic/biologic model to be translated in clinical practice. A cribriform pattern/intraductal carcinoma might be a marker of potentially lethal PC. The high incidence of TP53 and BRCA2 mutations in de novo mCSPC may also have a therapeutic implication.

The ongoing global Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has been posing challenges to proper patients' management. Lungs are the first, and often the most affected organ by SARS-CoV-2; viral infection involves and damages both epithelial and vascular compartments, sometimes leading to severe and even fatal acute respiratory distress syndrome. Histopathological findings, mainly from post-mortem examination of COVID-19 deceased patients, have been increasingly published in the last few months, helping to elucidate the sequence of events resulting in organ injury and the complex multifactorial pathogenesis of this novel disease. A multidisciplinary approach to autopsy, including light microscopy examination along with the detection of viral proteins and/or RNA in tissue samples through ancillary techniques, provided crucial information on the mechanisms underlying the often-heterogeneous clinical picture of COVID-19.