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Introduction: Half of all patients with testicular germ cell tumors (GCTs) present with metastases to retroperitoneal lymph nodes or visceral organs. Inguinal metastases (I/Ms) are very rare. We aimed to evaluate the relative frequency and clinical features of I/Ms and look for predisposing factors. Methods: A cohort of 740 GCT patients treated between 2010 and 2022 was analyzed. The frequency of I/M and their clinical features were statistically compared among the subgroups. Results: Eight patients had I/M, with a median age of 55 years, all of whom had primary seminoma and six had previous groin surgery. The relative frequency of I/M is 1.1% and 8.3% in the GCT patient cohort and the metastasized seminoma subgroup, respectively. All patients were cured, six underwent surgery and additional chemotherapy, and two received cisplatin-based chemotherapy alone. Discussion: I/Ms occur in approximately 1% of GCT patients. Prior groin surgery, bulky retroperitoneal metastases, and possibly histology of seminoma represent risk factors for I/M. The presence of I/M does not adversely affect prognosis, and all cases can be cured with standard therapeutic measures. Lymph node excision may be required to establish the diagnosis. In patients with risk factors, follow-up examinations should include the groins. [ABSTRACT FROM AUTHOR]

Homozygous 9p21 deletions usually result in a complete loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression visualizable by immunohistochemistry (IHC). MTAP deficiency has been proposed as a marker for predicting targeted treatment response. A tissue microarray including 2,710 urothelial bladder carcinomas were analyzed for 9p21 deletion by fluorescence in situ hybridization and MTAP expression by IHC. Data were compared with data on tumor phenotype, patient survival, intratumoral lymphocyte subsets, and PD-L1 expression. The 9p21 deletion rate increased from pTaG2 low (9.2% homozygous, 25.8% heterozygous) to pTaG2 high (32.6%, 20.9%; p < 0.0001) but was slightly lower in pTaG3 (16.7%, 16.7%) tumors. In pT2-4 carcinomas, 23.3% homozygous and 17.9% heterozygous deletions were found, and deletions were tied to advanced pT (p = 0.0014) and poor overall survival (p = 0.0461). Complete MTAP loss was seen in 98.4% of homozygous deleted while only 1.6% of MTAP negative tumors had retained 9p21 copies (p < 0.0001). MTAP loss was linked to advanced stage and poor overall survival in pT2-4 carcinomas (p < 0.05 each). The relationship between 9p21 deletions/MTAP loss and poor patient prognosis was independent of pT and pN (p < 0.05 each). The 9p21 deletions were associated with a noninflamed microenvironment (p < 0.05). Complete MTAP loss is strongly tied to homozygous 9p21 deletion, aggressive disease, and noninflamed microenvironment. Drugs targeting MTAP-deficiency may be useful in urothelial bladder carcinoma. MTAP IHC is a near perfect surrogate for MTAP deficiency in this tumor type., (© 2024 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Objective: There is a shortage of established prognostic biomarkers in bladder cancer. One candidate is tumour protein 63 (p63), a transcription factor of the p53 gene family that is expressed in the normal urothelium. Recently proposed RNA expression-based molecular classifiers of bladder cancer identified high p63 expression as a component of a basal/squamous subtype linked to poor patient prognosis., Methods: In this study, p63 protein expression was analysed by immunohistochemistry on more than 2500 urothelial bladder carcinomas in a tissue microarray format to determine its relationship with clinicopathological parameters of disease progression and patient outcome., Results: Nuclear p63 staining was seen in all cells of normal urothelium and at elevated levels in pTaG2 tumours. The rate of p63 positive cases and the staining intensity was lower in pTaG3 tumours (93.2%, p  < 0.0001 for pTaG3 vs. pTaG2) and markedly lower in pT2-4 carcinomas (83.5%, p  = 0.0120 for pT2-4 vs. pTaG3). Within 1018 pT2-4 carcinomas treated by cystectomy, low p63 expression was linked to nodal metastasis ( p  = 0.0028) and overall survival ( p  = 0.0005). The association with survival was independent of pT and pN ( p  = 0.0081). p63 expression was associated with GATA3 expression ( p  < 0.0001), a luminal cell type marker associated with favourable disease. A joint analysis of p63 and GATA3 did not suggest that GATA3 could provide additional prognostic information., Conclusion: The independent prognostic role of reduced p63 expression in advanced urothelial carcinomas suggests that p63 could be a useful biomarker to distinguish pT2-4 urothelial carcinomas., Competing Interests: The recombinant rabbit monoclonal p63 antibody, clone MSVA‐063R, was obtained from MS Validated Antibodies GmbH, Hamburg, Germany (owned by a family member of GS)., (© 2024 The Author(s). BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

17p13 deletions including TP53 and other genes represent a common cause for reduced/lost p53 function in tumor cells. In this study, we analyzed the impact of 17p13 (TP53) deletions and p53 expression on tumor aggressiveness and patient prognosis in urothelial carcinoma. The 17p13 copy number status was analyzed by fluorescence in situ hybridization (FISH) on more than 2700 urothelial bladder carcinomas in a tissue microarray format. 17p13 deletion data were compared to p53 expression data measured by immunohistochemistry (IHC) in a previous study. Different types of p53 alterations were compared with tumor phenotype and clinical outcome data. Deletions of 17p13 occurred in 23% of 2185 analyzable carcinomas. The fraction of tumors with 17p13 deletions increased from pTa G2 low (9%) to pTa G3 (24%, p < 0.0001). In muscle-invasive carcinomas, 17p13 deletions were associated with advanced pT stage (p = 0.0246), but unrelated to patient prognosis (p > 0.5). 17p13 deletions were significantly related to p53 immunostaining (p = 0.0375). 17p13 deletions were most common in tumors with complete lack of p53 staining (31%), which supports the concept that many of these tumors have a complete loss of p53 function (p53 null phenotype). 17p13 deletions were also increased in tumors with high p53 staining (25%). In conclusion, 17p13 deletions were most commonly seen in p53 negative cancers, supporting their role as a cause for the p53 null phenotype in urothelial cancer. The association of 17p13 deletions with high grade and advanced pT stage may reflect increasing genomic instability going along with stage and grade progression., (© 2024 The Author(s). Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Introduction: Trophoblast cell surface antigen 2 (TROP2; EpCAM2) is a transmembrane glycoprotein which is closely related to EpCAM (EpCAM; EpCAM1). Both proteins share partial overlapping functions in epithelial development and EpCAM expression but have not been comparatively analyzed together in bladder carcinomas. TROP2 constitutes the target for the antibody-drug conjugate Sacituzumab govitecan (SG; TrodelvyTM) which has been approved for treatment of metastatic urothelial carcinoma by the United States Food and Drug administration (FDA) irrespective of its TROP2 expression status., Methods: To evaluate the potential clinical significance of subtle differences in TROP2 and EpCAM expression in urothelial bladder cancer, both proteins were analyzed by multiplex fluorescence immunohistochemistry in combination with a deep-learning based algorithm for automated cell detection on more than 2,700 urothelial bladder carcinomas in a tissue microarray (TMA) format., Results: The staining pattern of TROP2 and EpCAM were highly similar. For both proteins, the staining intensity gradually decreased from pTa G2 low grade (TROP2: 68.8±36.1; EpCAM: 21.5±11.7) to pTa G2 high grade (64.6±38.0; 19.3±12.2) and pTa G3 (52.1±38.7; 16.0±13.0, p<0.001 each). In pT2-4 carcinomas, the average TROP2 and EpCAM staining intensity was intermediate (61.8±40.9; 18.3±12.3). For both proteins, this was significantly lower than in pTa G2 low grade (p<0.001 each) but also higher than in pTa G3 tumors (p=0.022 for TROP2, p=0.071 for EpCAM). Within pT2-4 carcinomas, the TROP2 and EpCAM staining level was unrelated to pT, grade, UICC-category, and overall or tumor-specific patient survival. The ratio TROP2/EpCAM was unrelated to malignant phenotype and patient prognosis., Conclusion: Our data show that TROP2 and EpCAM expression is common and highly interrelated in urothelial neoplasms. Despite of a progressive loss of TROP2/EpCAM during tumor cell dedifferentiation in pTa tumors, the lack of associations with clinicopathological parameters in pT2-4 cancer argues against a major cancer driving role of both proteins for the progression of urothelial neoplasms., Competing Interests: The recombinant EpCAM antibody clone MSVA-326R, the recombinant TROP2 antibody clone MSVA-733R, the recombinant panCK antibody clone MSVA-000R were provided by MS Validated Antibodies GmbH owned by a family member of GS., (Copyright © 2024 Müller, Plage, Elezkurtaj, Mandelkow, Huang, Lurati, Raedler, Debatin, Vettorazzi, Samtleben, Hofbauer, Furlano, Neymeyer, Goranova, Ralla, Weinberger, Horst, Roßner, Schallenberg, Marx, Fisch, Rink, Slojewski, Kaczmarek, Ecke, Hallmann, Koch, Adamini, Lennartz, Minner, Simon, Sauter, Zecha, Schlomm and Bady.)