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Hepatic angiosarcoma (HAS) is an aggressive mesenchymal malignancy that remains underexplored with respect to its etiology and mutational landscapes. To clarify the association between HAS and end‐stage renal disease (ESRD), we used nationwide data of the National Health Insurance Research Database (NHIRD) in Taiwan, covering ~99% of the population, from 2001 to 2016. To investigate molecular signatures, we performed whole‐exome sequencing (WES) in 27 surgical specimens, including nine ESRD‐associated cases. The NHIRD analysis demonstrated that HAS ranked second among all angiosarcomas in Taiwan, with the incidence rates of HAS being 0.08, 2.49, and 5.71 per 100,000 person‐years in the general population, chronic kidney disease (CKD), and ESRD patients, respectively. The standardized incidence ratios of HAS in CKD and ESRD patients were 29.99 and 68.77, respectively. In comparison with nonhepatic angiosarcoma, the multivariate regression analysis of our institutional cohort confirmed CKD/ESRD as an independent risk factor for HAS (odds ratio: 9.521, 95% confidence interval: 2.995–30.261, p < 0.001). WES identified a high tumor mutation burden (TMB; median: 8.66 variants per megabase) and dominant A:T‐to‐T:A transversion in HAS with frequent TP53 (81%) and ATRX (41%) mutations, KDR amplifications/gains (56%), and CDKN2A/B deletions (48%). Notably, ESRD‐associated HAS had a significantly higher TMB (17.62 variants per megabase, p = 0.01) and enriched mutational signatures of aristolochic acid exposure (COSMIC SBS22, p < 0.001). In summary, a significant proportion of HAS in Taiwan is associated with ESRD and harbors a distinctive mutational signature, which concomitantly links nephrotoxicity and mutagenesis resulting from exposure to aristolochic acid or related compounds. A high TMB may support the eligibility for immunotherapy in treating ESRD‐associated HAS. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Aims: In this study, we examine the clinicopathological and molecular features of gastric cancer (GC) with SMARCA4 alterations. Methods and results: We screened SMARCA4 alterations using immunohistochemistry on 1199 surgically resected GCs with information on Epstein–Barr virus (EBV), microsatellite instability (MSI) and other SWI/SNF subunits. SMARCA4, SMARCA2 and ARID1A mutations were investigated by targeted sequencing. The clinicopathological significance was determined by statistical analysis. Twenty‐seven cases (2%) with altered SMARCA4 expression were identified, exhibiting completely lost (six), reduced (nine) or heterogeneous (12) patterns. Frequent concomitant alterations of other SWI/SNF subunits were noted with an unusual discordant spatial heterogeneity. In comparison with SMARCA4‐retained GCs, SMARCA4‐lost GCs were observed more frequently in the non‐EBV/MSI subgroup (five of six) and reduced or heterogeneous SMARCA4 expression mainly occurred in EBV‐ or MSI‐associated cases (six of nine and six of 12, respectively; P < 0.001). Histologically, SMARCA4‐altered GC, irrespective of expression pattern, demonstrated divergent histomorphology, spanning tubular, poorly cohesive or mixed, neuroendocrine to solid and undifferentiated carcinoma, with a predilection to the latter two (P < 0.001). De‐differentiation‐like transition and rhabdoid features were noted in a minority of cases. For overall survival, altered SMARCA4 expression was an unfavourable prognostic factor in stage III, EBV‐associated GC and non‐EBV/MSI intestinal subtype (P ≤ 0.001). SMARCA4 or ARID1A mutations were detected mainly in SMARCA4‐lost or reduced GC, respectively. Conclusions: SMARCA4‐altered GCs are rare and have intratumoral heterogeneity, histomorphological diversity, conditional prognostic significance and various genetic drivers. SMARCA4‐lost GC may represent a genuine SMARCA4‐deficient neoplasm, but most SMARCA4‐reduced/heterogeneous cases are secondary to ARID1A collapse or associated with different genotypes. [ABSTRACT FROM AUTHOR]

Limited studies investigated clinicopathological and prognostic significance of histologic and molecular subgroups of gastric cancer concurrently. We retrospectively enrolled 1,248 patients with gastric cancer who received radical gastrectomy with lymphadenectomy and classified these cases into the Epstein–Barr virus (EBV)‐associated and microsatellite instability (MSI)‐associated subtypes by EBV‐encoded small RNA in situ hybridization and immunohistochemical stains for DNA mismatch repair proteins, respectively. The remaining cases were categorized as the Lauren intestinal and diffuse/mixed subtypes. The clinicopathological and prognostic significance of the subtypes was examined by statistical analysis. In total, 65 (5.2%), 116 (9.3%), 496 (39.7%), 431 (34.5%) and 140 (11.2%) cases were identified as EBV‐associated, MSI‐associated, intestinal, diffuse and mixed subtypes, respectively. The EBV‐associated, MSI‐associated, intestinal and diffuse/mixed subtypes exhibited distinctive clinicopathological characteristics, including differences in age, gender, stump cancer, gastric location, tumor size, TNM stage, margin involvement, lymphatic/perineural invasion, HER2 status and recurrence pattern. The log‐rank test showed survival discrimination (p < 0.001), and the multivariate analysis identified EBV‐associated and MSI‐associated cases demonstrated better outcomes than the diffuse/mixed subtype (EBV, HR 0.464, 95% CI 0.296–0.727, p = 0.001; MSI, HR 0.590, 95% CI 0.407–0.856, p = 0.005). EBV‐associated lymphoepithelioma‐like carcinoma cases had the most favorable outcome (HR 0.138, 95% CI 0.033–0.565, p = 0.006). In different clinical groups, the subtypes exhibited survival discrepancies. The EBV‐associated and diffuse/mixed cases exhibited more favorable response to chemotherapy. In conclusion, this combined classification, in parallel with the molecular subtypes specified in the Cancer Genome Atlas study, has implications for the clinical management of gastric cancer. What's new? Gastric cancer is a heterogeneous disease from histologic and molecular viewpoints. Stratifying gastric cancer into Epstein–Barr virus‐positive, microsatellite instability‐associated and Lauren intestinal and diffuse/mixed subtypes demonstrates significant clinicopathological and prognostic discrimination, which is relevant to current genetic knowledge and clinical management. This combined molecular and histologic classification, correspondent to the molecular subtyping specified in the Cancer Genome Atlas study, is practically implementable with etiologic insight and therapeutic implications. [ABSTRACT FROM AUTHOR]

Background and Aim Epidermal growth factor receptor ( EGFR) overexpression is associated with disease progression and poor survival in a variety of solid tumors. The role of EGFR in hepatocellular carcinoma ( HCC) remains controversial. Methods One hundred thirty-eight HCCs were analyzed for total EGFR (t- EGFR) and phospho- EGFR (p- EGFR) expression and gene amplification using immunohistochemistry and fluorescence in situ hybridization. The role of EGFR was analyzed in relation to the clinicopathological features. Results Weak to strong p- EGFR immunostaining was noted in 42 of the 138 HCCs. p- EGFR expression correlated with alcoholism ( P = 0.03) and chronic hepatitis B infection ( P = 0.041). There was no correlation between t- EGFR expression and any of the clinicopathological features. Amplification of the EGFR gene was not identified in the 138 HCCs, but 39.1% of the HCCs showed balanced polysomy of both the EGFR gene and centromere 7. Moreover, 65 tumors showed > 2.2 copies per tumor cell. EGFR copy number gain ( CNG) was significantly correlated with gender ( P = 0.0491), tumor grade ( P = 0.006), and vascular invasion ( P = 0.005). HCCs with EGFR CNG also had a poor recurrence-free survival ( RFS), as compared with HCCs without EGFR CNG ( P = 0.031). When exploring the impact of gender, a significant association of EGFR CNG was found with tumor grade ( P = 0.044) and cirrhosis ( P = 0.015) exclusively in the male group only; however, the OS and RFS analysis show no significant difference between male and female groups. Conclusions EGFR CNG was related to crucial clinicopathological features and early recurrence, indicating that EGFR CNG might be a poor prognosis factor for Taiwanese HCC. [ABSTRACT FROM AUTHOR]

The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase ( EML4- ALK) fusion gene is an important biomarker for target therapy. The aim of this study is to better understand the clinical and molecular features of the EML4- ALK fusion gene in lung cancer patients in Taiwan and therefore to generate an efficient algorithm for the detection of ALK translocation. In the first cohort, ALK translocation was identified in 1 adenocarcinoma from 100 lung cancer patients by using break apart fluorescent in situ hybridization ( FISH). Next, we detected 6 ALK translocations in another 40 EGFR wild type adenocarcinomas but not in 40 cases with EGFR mutation. Histological analysis revealed that solid growth with signet-ring cells or cribriform glands with extracellular mucin were noted in all the 7 ALK translocated cases. One ALK positive cancer with mucinous cribriform pattern had no ALK expression. ALK expression was correlated with ALK translocation ( p < 0.001), but not with ALK gene copy number gain ( CNG) ( P = 0.838). ALK translocation was also mutually exclusive with EGFR mutation in Taiwanese non-small cell lung cancer ( P = 0.033). These results indicate that screening tests for EGFR mutation status and/or ALK expression could help efficiently select ALK translocated patients for target therapy. [ABSTRACT FROM AUTHOR]

Aims To determine the significance of the epithelioid type and the corresponding molecular alterations in hepatic angiomyolipoma ( AML). Methods and results We retrieved 24 samples of hepatic AML to delineate the clinicopathological features and the immunohistochemical expression of components in the m TOR pathway, and employed microsatellite markers to analyse allelic imbalances in the TSC1 and TSC2 regions. Myomatous AML was the most common type, and a predominantly epithelioid cell population was observed in 50% of the samples. Two-thirds of all samples contained <20% of fat tissue. Four cases of monotypic epithelioid AML were discovered without prognostic implications. Elevated phospho-p70S6 kinase expression was noted in 19 samples in the absence of phospho- AKT activity. Loss of heterogeneity ( LOH) of TSC1/ TSC2 was found in 15 samples. As compared wityh syndromic AML samples, sporadic AML samples showed LOH of microsatellite markers to a limited extent. Only four samples had increased β-catenin expression in the context of concurrent high expression of phospho-p70S6 kinase and phospho-S6 ( P = 0.018). Conclusions The low fat content and epithelioid cytomorphology in hepatic AML potentially obstruct preoperative and pathological diagnosis. Alteration of the m TOR pathway and LOH of the tuberous sclerosis complex genes is a frequent pathogenesis in hepatic AMLs. [ABSTRACT FROM AUTHOR]

The aim of the present study was to re-evaluate TLE-1 staining and the molecular detection methods of SS18- SSX transcripts for synovial sarcoma. We analyzed TLE-1 expression in 50 molecularly confirmed synovial sarcomas and 85 other soft tissue tumors with three previously published scoring systems. In the present study, 39 to 43 synovial sarcomas showed TLE-1 nuclear staining, whereas 9-15 of 85 other soft tissue tumors showed TLE-1 staining ( P < 0.0001). The specificities of strong TLE-1 staining were 100%, 97.6% and 98.8%. The positive likelihood ratio of moderate and strong TLE-1 nuclear expression was >10 in all three scoring systems. There was no difference in TLE-1 staining between different subtypes of synovial sarcoma ( P > 0.05). Based on a comparison between conventional reverse transcription ( RT)-polymerase chain reaction ( PCR) and fluorescence in situ hybridization ( FISH), quantitative RT-PCR is a more sensitive method than conventional RT-PCR and FISH to detect t( X;18). A positive correlation between TLE-1 staining and SS18- SSX translocation was detected by conventional PCR ( P < 0.05). In conclusion, although all three scoring systems could differentiate synovial sarcoma from other soft tissue tumors, diffuse moderate to severe intensity tumors showed the highest specificity in the diagnosis of synovial sarcoma. [ABSTRACT FROM AUTHOR]