Association between hepatic angiosarcoma and end-stage renal disease: nationwide population-based evidence and enriched mutational signature of aristolochic acid exposure.

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.

A Single-Institute Experience with C-ros Oncogene 1 Translocation in Non-Small Cell Lung Cancers in Taiwan.

(1) Background: The C-ros oncogene 1 (ROS1) gene translocation is an important biomarker for selecting patients for crizotinib-targeted therapy. The aim of this study was to understand the incidence, diagnostic algorithm, clinical course and objective response to crizotinib in ROS1 translocated lung non-small cell lung cancers (NSCLCs) in Taiwan. (2) Methods: First, we retrospectively studied the ROS1 status in 100 NSCLC samples using break-apart fluorescent in situ hybridization (FISH) and immunohistochemical (IHC) staining to establish a diagnostic algorithm. Then, we performed routine ROS1 IHC tests in 479 NSCLCs, as crizotinib was available from 2018 in Taiwan. We analyzed the objective response rate and the survival impact of crizotinib. (3) Results: Four ROS1 translocations were clustered in epidermal growth factor receptor (EGFR) wild-type adenocarcinomas but not in cases with EGFR mutations. Strong ROS1 expression was positively correlated with ROS1 translocation (p < 0.001). NSCLCs with ROS1 translocation had a poor prognosis compared to those without ROS1 translocation (p = 0.004) in the pre-crizotinib stage. Twenty NSCLCs were detected with ROS1 translocation in 479 wild-type EGFR specimens from 2018. Therefore, the incidence of ROS1 translocation is approximately 4.18% in EGFR wild-type NSCLCs. In these 20 ROS1 translocation cases, 19 patients received crizotinib treatment, with an objective response rate (ORR) of 78.95% (confidence interval = 69.34% to 88.56%), including 1 complete response, 14 partial responses, 3 stable cases and 1 progressive case. Overall survival and progression-free survival were better in the 19 ROS1-translocated NSCLCs of the prospective group with crizotinib treatment than the four ROS1-translocated NSCLCs of the retrospective group without crizotinib treatment. (4) Conclusions: ROS1-translocated NSCLCs had a poor prognosis and could have a beneficial outcome with crizotinib.

The clinicopathological and molecular analysis of gastric cancer with altered SMARCA4 expression.

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.

Subtraction of Epstein-Barr virus and microsatellite instability genotypes from the Lauren histotypes: Combined molecular and histologic subtyping with clinicopathological and prognostic significance validated in a cohort of 1,248 cases.

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.

Comparative Tissue Proteomics of Microdissected Specimens Reveals Novel Candidate Biomarkers of Bladder Cancer.

More than 380,000 new cases of bladder cancer are diagnosed worldwide, accounting for ∼150,200 deaths each year. To discover potential biomarkers of bladder cancer, we employed a strategy combining laser microdissection, isobaric tags for relative and absolute quantitation labeling, and liquid chromatography-tandem MS (LC-MS/MS) analysis to profile proteomic changes in fresh-frozen bladder tumor specimens. Cellular proteins from four pairs of surgically resected primary bladder cancer tumor and adjacent nontumorous tissue were extracted for use in two batches of isobaric tags for relative and absolute quantitation experiments, which identified a total of 3220 proteins. A DAVID (database for annotation, visualization and integrated discovery) analysis of dysregulated proteins revealed that the three top-ranking biological processes were extracellular matrix organization, extracellular structure organization, and oxidation-reduction. Biological processes including response to organic substances, response to metal ions, and response to inorganic substances were highlighted by up-expressed proteins in bladder cancer. Seven differentially expressed proteins were selected as potential bladder cancer biomarkers for further verification. Immunohistochemical analyses showed significantly elevated levels of three proteins-SLC3A2, STMN1, and TAGLN2-in tumor cells compared with noncancerous bladder epithelial cells, and suggested that TAGLN2 could be a useful tumor tissue marker for diagnosis (AUC = 0.999) and evaluating lymph node metastasis in bladder cancer patients. ELISA results revealed significantly increased urinary levels of both STMN1 and TAGLN2 in bladder cancer subgroups compared with control groups. In comparisons with age-matched hernia urine specimens, urinary TAGLN2 in bladder cancer samples showed the largest fold change (7.13-fold), with an area-under-the-curve value of 0.70 (p < 0.001, n = 205). Overall, TAGLN2 showed the most significant overexpression in individual bladder cancer tissues and urine specimens, and thus represents a potential biomarker for noninvasive screening for bladder cancer. Our findings highlight the value of bladder tissue proteome in providing valuable information for future validation studies of potential biomarkers in urothelial carcinoma.

OncomiR miR-96 and miR-182 promote cell proliferation and invasion through targeting ephrinA5 in hepatocellular carcinoma.

EphrinA5, a member of the ephrinA subclass, is downregulated in hepatocellular carcinoma (HCC) and acts as a tumor suppressor. However, the upstream regulation mechanism of ephrinA5 remains unclear. In this study, we tried to identify and characterize the roles of miR-96 and miR-182 in the regulation of ephrinA5 expression in HCC. The expression levels of miR-96 and miR-182 were examined in 47 paired HCC and para-tumoral liver tissues using quantitative real-time RT-PCR. The luciferase reporter assay and western blotting were employed to dissect the association between miR-96/182 and ephrinA5 expression. Moreover, cells were treated with synthetic miR-96/182 precursors and inhibitors to assess their effects on HCC cell growth and migration. It was found that both miR-96 and miR-182 were upregulated in HCC compared to para-tumoral normal tissues. The expression of miR-96 and miR-182 was inversely associated with ephrinA5 protein levels. Furthermore, both miR-96 and miR-182 directly targeted the 3'UTR of the ephrinA5 mRNA and suppressed protein translation. The suppression of miR-96 and miR-182 led to reduced HCC cell proliferation and migration by negatively regulating ephrinA5 expression. In conclusion, miR-96 and miR-182 may act as oncomiRs in HCC by suppressing the expression of ephrinA5 and may play important roles in hepatocarcinogenesis. © 2015 Wiley Periodicals, Inc.

HER2 testing in paired biopsy and excision specimens of gastric cancer: the reliability of the scoring system and the clinicopathological factors relevant to discordance.

BACKGROUND: Inclusion of trastuzumab in chemotherapy regimens is advantageous for patients with advanced or metastatic gastric cancer who overexpress HER2. Therefore, accurate assessment of HER2 status in tumor tissue is critical when weighing treatment options. METHODS: We examined HER2 expression in 180 paired endoscopic biopsy and surgical excision specimens of gastric cancers via immunohistochemistry (IHC). Equivocal IHC results (IHC 2+) were resolved by HER2 fluorescence in situ hybridization (FISH). The relationships of several clinical and pathological features with discordant HER2 results in paired specimens were determined. RESULTS: Fourteen biopsy specimens and surgical specimens (7.8%) were HER2-positive. Discordant HER2 IHC scores were observed in 90 paired specimens (50%) and 8 paired specimens (4.4%) had discordant results. The kappa coefficients for an HER2 diagnostic algorithm were 0.264, 0.339, and 0.690 for IHC scores, IHC categories, and final results, respectively (p < 0.001). Discordant HER2 results were significantly associated with discordant tumor differentiation in the paired biopsy and excision specimens (p = 0.01). Intratumoral heterogeneity did not predict HER2 discordance. There was no association between HER2 discordance and the number of biopsy tissue fragments (p = 0.764). CONCLUSIONS: Hofmann's HER2 scoring system is a fairly reliable tool for evaluating HER2 status in biopsy and excision specimens. Discordant HER2 results in paired specimens were observed in a small percentage of gastric cancers. Testing all available specimens should be considered in order to eliminate discrepancies, especially when discordant tumor differentiation is observed.

Alterations of the mTOR pathway in hepatic angiomyolipoma with emphasis on the epithelioid variant and loss of heterogeneity of TSC1/TSC2.

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 mTOR 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 ß-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 mTOR pathway and LOH of the tuberous sclerosis complex genes is a frequent pathogenesis in hepatic AMLs.

Impact of epidermal growth factor receptor protein and gene alteration on Taiwanese hepatocellular carcinomas.

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.

Anaplastic lymphoma kinase translocation is correlated with anaplastic lymphoma kinase expression and mutually exclusive with epidermal growth factor receptor mutation in Taiwanese non-small cell lung cancer.

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.

Utility of fluorescence in situ hybridization for ploidy and p57 immunostaining in discriminating hydatidiform moles.

Discrimination between complete moles (CMs), partial moles (PMs), and hydropic abortions (HAs) is important as the risk of persistent gestational trophoblastic disease (GTD) differs for each condition. We evaluated whether ancillary fluorescence in situ hybridization (FISH) with a set of chromosome enumeration probes (CEP) for chromosomes X, Y, and 17 and p57 immunostaining could improve the clinical diagnosis. Forty-one products of conception (POC) were reclassified according to clinical performance, morphology, p57 immunostaining results, and FISH results. The accuracy of histological examination alone was 85% for the original diagnosis. FISH analysis showed diploidy in 19 of 20 CMs and triploidy in 4 of 6 PMs. The concordance rate was 92.5% on using the CEP probes. p57 Staining was negative in all CMs and positive in all PMs and HAs. Chromosomal abnormality was detected in 3 cases of HA by using FISH. In conclusion, combined p57 immunostaining and FISH with a set of 3 CEP probes for chromosomes X, Y, and 17 could be useful in the classification of hydatidiform moles.

Reappraisal of TLE-1 immunohistochemical staining and molecular detection of SS18-SSX fusion transcripts for synovial sarcoma.

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.

Factors associated with the survival of patients with primary small cell carcinoma of the kidney.

BACKGROUND: Primary small cell carcinoma (SCC) of the kidney is rare, and the factors associated with the survival of these patients are yet to be elucidated. PATIENTS AND METHODS: We collected data on patients who were admitted to our hospital for SCC of the kidney in the last 22 years and of those in studies in the literature. Clinical characteristics were summarized using descriptive statistics. The associations of these factors with survival were evaluated using Cox regression models, and the hazard ratio of death was calculated. RESULTS: This study included 45 patients (8 admitted to our hospital and 37 from studies in the literature) with SCC of the kidney. The overall median survival time was 9.9 months (range 6.9-31.6). Data on demographics, clinical symptoms, tumor staging, and tumor characteristics recorded at the time of diagnosis were not associated with survival. Among the different treatment modalities applied, cisplatin-based chemotherapy afforded a strong survival advantage (hazard ratio = 0.35, p = 0.022). However, patients with early local recurrence (hazard ratio = 19.13, p = 0.012) and early distant metastasis (hazard ratio = 10.93, p = 0.003) after primary treatment showed significantly poor survival. CONCLUSIONS: Patients with primary SCC of the kidney generally presented with large, advanced-stage tumors and showed poor survival. Early detection of the tumor, use of cisplatin-based chemotherapy, and careful follow-up for local recurrence or frequent metastasis within 6 months after the primary treatment could be important for improving overall patient survival.

Clinicopathological analysis of ß-catenin and Axin-1 in solid pseudopapillary neoplasms of the pancreas.

BACKGROUND: Solid pseudopapillary neoplasm (SPN) is a distinct pancreatic neoplasm and has characteristic, aberrant nuclear expression of ß-catenin in most cases. However, alterations in components of the Wnt pathway, other than the ß-catenin (CTNNB1) gene mutation, have not been identified. In this study, we investigated the status of Axin-1, the spectrum of mutations in the CTNNB1 gene, and the clinicopathological features of SPNs. MATERIALS AND METHODS: We collected 27 SPNs from 25 patients. A tissue microarray was constructed to perform immunohistochemistry for ß-catenin, E-cadherin, and Axin-1. The CTNNB1 and AXIN1 gene mutations were analyzed by DNA sequencing. Finally, the clinicopathological features of SPNs were analyzed for association with the CTNNB1 mutations and the Axin-1 alterations. RESULTS: All 27 SPNs expressed nuclear immunoreactivity of ß-catenin and exhibited a lack of membranous decoration of E-cadherin. All SPNs harbored CTNNB1 gene mutations. No alterations were present in the AXIN1 gene, and the immunohistochemical analysis revealed weak or absent reactivity of Axin-1 in the cytosol. All cases with a codon-37 CTNNB1 mutation had weak Axin-1 immunoreactivity in the cytoplasm (P = 0.018). No other significant correlation was found between clinicopathological parameters, CTNNB1 mutations, and Axin-1 alterations. CONCLUSIONS: Nuclear ß-catenin immunoexpression is characteristic for SPNs and corresponds to the CTNNB1 mutation. The Wnt pathway is involved in the tumorigenesis of SPNs, primarily through the alteration of ß-catenin. Despite the absence of any identifiable genetic mutation, a low level of Axin-1 in the cytoplasm might contribute to the aberrant distribution of ß-catenin in SPNs.

Ligands and Beyond: Mechanosensitive Adhesion GPCRs.

Cells respond to diverse types of mechanical stimuli using a wide range of plasma membrane-associated mechanosensitive receptors to convert extracellular mechanical cues into intracellular signaling. G protein-coupled receptors (GPCRs) represent the largest cell surface protein superfamily that function as versatile sensors for a broad spectrum of bio/chemical messages. In recent years, accumulating evidence has shown that GPCRs can also engage in mechano-transduction. According to the GRAFS classification system of GPCRs, adhesion GPCRs (aGPCRs) constitute the second largest GPCR subfamily with a unique modular protein architecture and post-translational modification that are well adapted for mechanosensory functions. Here, we present a critical review of current evidence on mechanosensitive aGPCRs.

Dedifferentiation-like tubular and solid carcinoma of the stomach shows phenotypic divergence and association with deficient SWI/SNF complex.

Gastric carcinoma showing an abrupt transition from a tubular to solid pattern is an unusual phenomenon reminiscent of dedifferentiation. The phenotypic and molecular characteristics of this transition are still unclear. We retrospectively collected 41 gastric carcinomas exhibiting dedifferentiation-like tubular to solid transition and applied an array of immunohistochemical stains, including neuroendocrine and hepatocytic markers, to delineate their lineage. The status of Epstein-Barr virus (EBV) infections, mismatch repair proteins, SWI/SNF complex proteins and p53 expression levels were examined. The clinicopathologic differences were assessed by statistical analysis. Except for 10 cases with neuroendocrine differentiation and 2 EBV-associated carcinomas, we identified 8 hepatoid carcinomas and 21 solid adenocarcinomas with loss of CDX2 and/or hep-par1 expression in solid part (12/29). A subset of solid adenocarcinoma was associated with MSI (8) and mutant p53 expression was frequent in non-MSI cases (10/13). We found hepatoid carcinomas usually harbored SMARCA2 loss (5/8), MSI-associated cases commonly had ARID1A loss (6/8), and non-MSI solid adenocarcinomas frequently showed SMARCA2/A4 loss (7/13) with a high rate of concurrent ARID1A loss (4/7). Spatial correlation between solid transition and loss of SWI/SNF complex subunits were seen in 63% of tumors (12/19). Dedifferentiation-like tubular and solid carcinoma was associated with a propensity to inferior survival outcomes (p = 0.034), especially hepatoid carcinoma and in the non-MSI/EBV intestinal subgroup. In conclusion, gastric cancer exhibiting dedifferentiation-like tubular to solid transition is a phenotypically divergent group that shares common alterations in the SWI/SNF complex.

A clinicopathological reappraisal of orbital vascular malformations and distinctive GJA4 mutation in cavernous venous malformations.

Vascular anomalies are common orbital lesions, while variations in previous nomenclature might hamper robust characterization of their clinicopathological and genetic features. We reviewed and reclassified 92 orbital vascular lesions by the modified International Society for the Study of Vascular Anomalies (ISSVA) classification with reappraising clinicopathological parameters of 4 main types of vascular malformations, including orbital venous malformation 1 (OVM1, cavernous venous malformation), OVM2 (varix), OVM3 (infiltrating venous malformation), and arteriovenous malformation (AVM). GJA4, BRAF, and KRAS mutations were assessed by Sanger sequencing. There were 90 cases of vascular malformations, consisting of 60 OVM1 (67%), 13 AVM (14%), 8 OVM2 (9%), 8 OVM3 (9%), and 1 lymphatic-venous malformation (1%). The prevailing OVM1, histologically characterized by well-delineated borders and a uniform cavernous growth pattern, predominantly occurred in intraconal space (57%, P = .019) with an older median age (49 years) and female predilection (73%). OVM2, OVM3, and AVM exhibited differences in the distributions of patients' ages and lesion locations. Sizes of lesions were significantly correlated with periorbital and intraconal/extraconal locations (P < .001). OVM1 had the lowest rate of residual and recurrent diseases (3%). GJA4 mutations were identified in 75% (44/59) of OVM1 but not in OVM2/3 and AVM. No BRAF or KRAS mutations were detected. In conclusion, the modified ISSVA scheme enables meaningful classification of orbital vascular malformations by highlighting the molecular correlation between the distinct clinicopathological features and specific GJA4 mutation in OVM1, which implies OVM1 as a unique variant of venous malformation genetically akin to cutaneous and hepatic counterparts.

Incidental Tuberculosis Epididymitis/Epididymo-orchitis: A Retrospective Analysis at a Tertiary Center in Taiwan.

OBJECTIVES: To determine the earliest noticeable manifestation and diagnosis in patients diagnosed with tuberculosis (TB) epididymitis/epididymo-orchitis incidentally and to analyze their responses to surgical and medical treatment. METHODS: Patients who underwent surgery for the preliminary impression of chronic epididymitis/epididymo-orchitis or epididymal/testicular tumor from 2000 to 2019 were included in the study. The clinical presentations, laboratory data, radiological examinations, and operative findings were analyzed retrospectively. The outcomes were assessed by the responses to anti-TB chemotherapy and post treatment radiographic evaluations. RESULTS: All of our 25 patients with a mean age of 60.6 years were diagnosed incidentally with TB epididymitis (48.0%) and TB epididymo-orchitis (52.0%) according to the histopathological findings from their surgeries. The presence of a palpable scrotal mass (76.0%), was the major presentation. Nineteen (76.0%) patients had undergone complete chemotherapy after the surgery and 15 (78.9%) patients showed complete recovery. Four (21.1%) patients had unfavorable outcomes, 3 had TB autonephrectomies and 1 required re-surgery years after complete chemotherapy. Of the 3 (12.0%) patients who did not receive chemotherapy after their surgeries, 1 had a TB relapse in the spine and lung and 1 developed bladder cancer years later. CONCLUSION: Tuberculosis epididymitis/epididymo-orchitis is difficult to diagnose. However, some clinical clues can assist including aged patients, extragenital TB histories, poor responses to antibiotic treatment and scrotal skin lesion. Complete anti-TB chemotherapy is mandatory even after the total removal of TB lesion. Supplemental surgical interventions can be considered when the symptoms are not relieved after chemotherapy. Lifespan follow-up is recommended due to high relapse rate.

Role of ADGRG1/GPR56 in Tumor Progression.

Cellular communication plays a critical role in diverse aspects of tumorigenesis including tumor cell growth/death, adhesion/detachment, migration/invasion, angiogenesis, and metastasis. G protein-coupled receptors (GPCRs) which constitute the largest group of cell surface receptors are known to play fundamental roles in all these processes. When considering the importance of GPCRs in tumorigenesis, the adhesion GPCRs (aGPCRs) are unique due to their hybrid structural organization of a long extracellular cell-adhesive domain and a seven-transmembrane signaling domain. Indeed, aGPCRs have been increasingly shown to be associated with tumor development by participating in tumor cell interaction and signaling. ADGRG1/GPR56, a representative tumor-associated aGPCR, is recognized as a potential biomarker/prognostic factor of specific cancer types with both tumor-suppressive and tumor-promoting functions. We summarize herein the latest findings of the role of ADGRG1/GPR56 in tumor progression.

The clinicopathological significance of SWI/SNF alterations in gastric cancer is associated with the molecular subtypes.

The clinicopathological significance of altered SWI/SNF complex has not been well evaluated in gastric cancer (GC). We examined SMARCA2, SMARCA4, SMARCB1 and ARID1A expression by immunohistochemistry in 1224 surgically resected GCs with subtyping into Epstein-Barr virus (EBV), microsatellite instability (MSI) and non-EBV/MSI Lauren histotypes. SWI/SNF mutations were investigated using the GC dataset of the TCGA Pan-Cancer Atlas. Clinicopathological association was assessed by statistical analysis. There were 427 cases (35%) of SWI/SNF-attenuated GC, including 344 SMARCA2 (28%), 28 SMARCA4 (2%), 11 SMARCB1 (1%) and 197 ARID1A (16%) cases. Simultaneous alterations of multiple subunits were observed. Compared to SWI/SNF-retained cases, SWI/SNF-attenuated GC exhibited a significant predilection to older ages, EBV and MSI genotypes, higher lymphatic invasion and less hematogenous recurrence (P < 0.05). SWI/SNF attenuation was an independent risk factor for short overall survival (P = 0.001, hazard ratio 1.360, 95% confidence interval 1.138-1.625). The survival impact stemmed from SMARCA2-attenuated GCs in stage III and non-EBV/MSI diffuse/mixed subtypes (P = 0.019 and < 0.001, respectively). ARID1A-lost/heterogeneous GCs were more aggressive in the EBV genotype (P = 0.016). SMARCB1 or SMARCA4 loss was not restricted to rhabdoid/undifferentiated carcinoma. In the TCGA dataset, 223 of 434 GCs (52%) harbored deleterious SWI/SNF mutations, including ARID1A (27%), SMARCA2 (9%), ARID2 (9%), ARID1B (8%), PBRM1 (7%), and SMARCA4 (7%). SWI/SNF-mutated GCs displayed a favorable outcome owing to the high percentage with the MSI genotype. In conclusion, SWI/SNF-altered GCs are common and the clinicopathological significance is related to the genotype.