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.
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.
The pathological identification of lymph node (LN) metastasis is demanding and tedious. Although convolutional neural networks (CNNs) possess considerable potential in improving the process, the ...ultrahigh-resolution of whole slide images hinders the development of a clinically applicable solution. We design an artificial-intelligence-assisted LN assessment workflow to facilitate the routine counting of metastatic LNs. Unlike previous patch-based approaches, our proposed method trains CNNs by using 5-gigapixel images, obviating the need for lesion-level annotations. Trained on 5907 LN images, our algorithm identifies metastatic LNs in gastric cancer with a slide-level area under the receiver operating characteristic curve (AUC) of 0.9936. Clinical experiments reveal that the workflow significantly improves the sensitivity of micrometastasis identification (81.94% to 95.83%, P < .001) and isolated tumor cells (67.95% to 96.15%, P < .001) in a significantly shorter review time (-31.5%, P < .001). Cross-site evaluation indicates that the algorithm is highly robust (AUC = 0.9829).
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.
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.
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 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 mTOR pathway and LOH of the tuberous sclerosis complex genes is a frequent pathogenesis in hepatic AMLs.
Immunotherapy is a highly promising approach for the treatment of gastric cancer, the third-leading cause of overall cancer death worldwide. In particular, tumor-infiltrating lymphocytes and ...peripheral blood mononuclear cells are believed to mediate host immune responses, although this activity may vary depending on the activation status and/ or their microenvironments. Here, we examined the expression of a specific zinc finger transcription factor, Helios (IKZF2), in gastric tumor-infiltrating lymphocytes by immunohistochemistry and the correlation with survival. Segregation of gastric cancer patients into high- vs. low-Helios-expressing tumor-infiltrating lymphocytes showed those with high expression to exhibit longer survival in gastric cancer patients, Helicobacter pylori-infected gastric cancer patients and advanced stage (III–IV) gastric cancer patients. In particular, Helios expression was an independent factor for survival in advanced gastric cancer patients. We performed immunofluorescence staining to detect Helios expression in tumor-infiltrating lymphocytes and peripheral blood mononuclear cells. We found that Helios is expressed more in CD4+ T cells and little in CD8+ T cells in infiltrated lymphocytes in gastric cancer. In summary, we believe that the study of specific characteristics of tumor-infiltrating lymphocytes can delineate the interactions of immune and tumor cells to improve upon immunotherapy strategies.
Ethmoid or sphenoid intestinal-type adenocarcinomas (ITACs) form a distinct subtype of sinonasal adenocarcinomas that occur less than 1 case/100,000/yr. They have obvious exposure relationship to ...hardwood or leather dusts, infrequent metastasis, but a relatively high local-recurrence rate. They locate at sinuses close to vital structures listed as high-risk areas in surgeries. Even in expert hands, a craniofacial resection is associated with non-negligible mortality and morbidity. Management of these tumors, first or recurrent, needs to weigh these consequences versus the survival, regional-recurrence, and distant-recurrence rates. Due to the rareness of ethmoid or sphenoid ITACs, accurate overall survival and local- or regional-recurrence rates across diverse treatments are unclear. The aim of this study is to report the overall statistics of this cancer and the relationship between enrollment year versus age, recurrence, and survival.
Systemic review and meta-analysis with 1126 cases across various treatments in the literature.
Here, we show that patients of ethmoid or sphenoid ITACs had overall local-, regional-, and distant-recurrence rates of 32.2%, 2.2%, and 10.3%, respectively, with a 5-year overall survival rate of 66.2%. The results present a significant correlation between age, local-recurrent rate, or overall survival rate versus enrollment year.
This suggests that recent patients of ethmoid or sphenoid ITACs may present at an older mean age, have a lower local-recurrence rate, and have a better 5-year survival rate than before. There was a shifting trend of treating ethmoid ITACs from external approach to endoscopic resection. Clinicians may want to weigh mortality and morbidity rates of external surgeries and these data to share or decide a solution.
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