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Background and Aims: When treating undifferentiated-type early gastric cancer (UD-EGC) that is limited to the mucosa (clinically T1a), endoscopic submucosal dissection (ESD) can be considered if the tumor is 2 cm or less and is not ulcerated. However, there is insufficient evidence to determine the relationships between tumor size and oncological safety of ESD in UD-EGC., Methods: The pathology reports of Korean patients who were diagnosed with UD-EGC (n = 5286) were retrospectively reviewed. The cumulative incidence of lymph node metastasis (LNM) according to tumor size was evaluated in subgroups. The tumor-size cut-off was identified as the upper limit of the 95% confidence interval (CI) of cumulative LNM incidence that did not exceed 1.0%., Results: We identified 1516 patients with non-ulcerated T1a tumors ≤2 cm in size. Among patients without lymphatic invasion, 1.5% (95% CI 0.91-2.16%) had LNM. In patients with poorly differentiated tubular adenocarcinoma (PD), LNM increased from 0 to 0.74% based on a tumor size of 1.0 cm. Regardless of tumor size, smaller percentages of undifferentiated-type (UD) and poorly cohesive carcinoma (PCC) patients experienced LNM than did those with PD. In non-ulcerated mucosal cancer without lymphatic invasion and tumor size ≤0.9 cm, no LNM was observed in patients with UD (95% CI 0-0.53%), PCC (95% CI 0-0.59%), or PD (95% CI 0-0.86%) histologic type., Conclusion: In patients diagnosed with non-ulcerated T1a UD-EGC, ESD can be performed if the tumor size is 0.9 cm or less, regardless of histologic type., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 and TP53 (54.5%), followed by FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia [BilIN]), but a substantial proportion was subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. Combined analysis with metastatic tumors (n=11) identified branching evolution in nine patients (81.8%). Of these, eight patients (88.9%) had a total of 11 subclones expanded at least sevenfold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4 , ROBO1 , and DICER1 . In mutational signature analysis, six mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors., Competing Interests: MK, HN, SA, JK, SL, SA, JL, JY, HK, KK, KS, JL, SK, JK, YK, KL, YY, JK, JC, HH, JL No competing interests declared, (© 2022, Kang, Na et al.)

Gastric inverted polyps (GIPs) are rare gastric polyps characterized by a submucosal inverted growth of mucosal components. Because of their rarity, they are not well characterized and are diagnostically challenging. We examined 12 cases of GIPs arising in 8 male and 4 female patients (mean age: 56 y). Most GIPs (11/12, 92%) occurred as a single, rounded subepithelial lesion in the body or fundus (mean size: 14.9 mm). Histologically, GIPs consisted of gastric-type glandular epithelium and smooth muscle component, growing in an endophytic manner; however, they displayed significant morphologic variations. We classified GIPs into 3 subtypes by the following features: communication with the mucosal surface, smooth muscle boundary, and tissue organization. The defining characteristics of type 1 were a mucosal communicating structure at the center and a well-defined smooth muscle boundary, resulting in a characteristic low-magnification morphology of a round vase. Type 2 had an organized glandular proliferation with smooth muscle boundary and no central communicating structure. Type 3 GIPs had no mucosal communicating structure or smooth muscle boundary; its key histologic feature was the lobular organization pattern produced by proliferations of cystic or hyperplastic glands and smooth muscle. All type 1 GIPs exhibited coexisting adenocarcinoma (3 cases) or stromal proliferation (3 cases). Three patients with type 2 GIP had separate adenocarcinoma. None of the type 3 GIPs had accompanying carcinoma. In conclusion, GIPs are a heterogenous group showing different morphology and clinical behavior. Notably, type 1 GIP could be considered a precancerous lesion with the potential to develop adenocarcinoma., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: This multi-institutional study and a re-evaluation of the TCGA cohort explores the morphological spectrum, genetics and outcome of GI (gastrointestinal) hepatoid tumours, tumours expressing alpha-fetoprotein (AFP) and fetal-type (FT) GI adenocarcinomas., Methods: 44 tumours with evidence of hepatocellular differentiation were evaluated for morphology as well as by immunohistochemistry for AFP, HepPar1, glypican-3 and arginase-1 and by in situ hybridisation for albumin. Three categories were defined: type I (hepatoid: morphological evidence of hepatocellular differentiation), type II (FT GI adenocarcinoma: tubular profiles and subnuclear vacuolisation, resembling fetal intestine) and type III: positive for at least two hepatocyte-specific markers but lacking morphological evidence of hepatocellular differentiation. GI adenocarcinomas in the TCGA cohort were also evaluated (n=829)., Results: 18 cases were classified as type I, 19 as FT GI adenocarcinomas and 7 as type III (resembling conventional gastrointestinal carcinomas). Serum AFP was elevated in 92% of cases. 93% of tumours were positive for glypican-3, 90% for albumin and 89% for AFP. Arginase-1 was restricted to 35% of type 1 tumours. TCGA gastric tumours with elevated AFP expression showed morphological features of FT GI adenocarcinoma (70%) and were exclusively MSI stable. TCGA gastric adenocarcinomas with high AFP expression showed inferior survival on univariate and multivariate analysis., Conclusions: FT GI adenocarcinomas show a distinctive morphological and immunohistochemical profile. Gastric adenocarcinomas with elevated expression of AFP morphologically resemble FT GI adenocarcinomas, demonstrate aggressive behaviour, independent of grade and stage, and a distinct genetic profile., Competing Interests: Competing interests: The work was partially funded by a sponsored research agreement between the authors’ institution and Affymetrix, California, USA., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: The objectives of this study were to analyze the clinicopathologic features of villoglandular adenocarcinoma (VGA) of the uterine cervix, a variant of cervical adenocarcinoma with good prognosis, and to discuss the association of human papillomavirus (HPV) infection with VGA., Methods: A retrospective review of medical records was performed to identify the patients with VGA between 1999 and 2007 at the Samsung Medical Center., Results: Fifteen patients were identified among 171 women diagnosed with adenocarcinoma of the cervix. The median age was 40 years (range, 32-72 years). Four patients were treated by cone biopsy and 10 patients by hysterectomy with or without pelvic lymphadenectomy. Five patients had invasion of more than half of the depth of tumor in the cervix. Lymphovascular space invasion was present in 2 patients, one of whom also had lymph node metastases. Three recurrences were identified during the median follow-up of 64 months (range, 9-149 months). An HPV test was positive in 6 of 7 patients. Of the 6 patients with HPV infection, 2 were positive for HPV type 18, one for HPV type 6, and the remaining 3 were positive for 1 or more types of high-risk HPV., Conclusions: Although VGA has been reported to have a favorable prognosis, we observed recurrences in those patients with close margins by the tumor, lymph node metastasis, or advanced stage. Human papillomavirus DNA, mostly HPV types 16 and 18, was associated with VGA. Further studies are warranted on prognostic factors and the pathogenetic role of HPV infections.

Background: Endoscopic resection has become standard therapy for selected patients with early gastric carcinoma (EGC). However, the preoperative diagnostic accuracy for excluding submucosal (SM) invasion is not precise. Moreover, histologic features predicting SM invasion in gastric carcinomas (SMiGC) have not been studied extensively., Methods: Pre-treatment gastric biopsies from 60 patients with SM invasion who underwent endoscopic resection were reviewed and compared to 58 biopsies of lesions confirmed to be intramucosal carcinomas (IMC). For validation of the results, an independent cohort consisting of 616 gastric biopsies confirmed as EGC were analyzed. For statistical analyses, χ-square test, Fisher's exact test and multiple logistic progression tests were used., Results: In the biopsy specimens of patients with SMiGCs, differentiated histology, poorly differentiated component, wisps of muscularis mucosa, tumor cribriforming, papillary architecture, desmoplasia and intraglandular eosinophilic necrotic debris (IEND) were observed in 96.7%, 36.7%, 16.7%, 16.7%, 23.3%, 40%, and 46.7% of cases, respectively, while the same features were observed in 100%, 5.2%, 0%, 1.7%, 5.2%, 19%, and 22.4% of biopsies with IMC. In multivariate analyses, poorly differentiated component [odds ratio (OR), 9.59, p = 0.002], IEND [OR, 6.23, p = 0.012], tumor cribriforming [OR, 4.66, p = 0.03] and papillary architecture [OR, 5.52, p = 0.018] were significantly associated with the detection of SM invasion. In the validation cohort, poorly differentiated component (p = 0.003) and papillary architecture (p = 0.008) remained significant., Conclusion: Poorly differentiated component and papillary architecture are significant histopathologic predictors of SM invasion in pretreatment gastric biopsies of lesions considered for endoscopic therapy. Additional prospective studies are warranted to confirm our findings., Virtual Slide: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1588557731103084.

The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors.

Neuroendocrine tumor (NET) in adenoma of the gastrointestinal tract is a rare mixed glandular-endocrine neoplasm and has uncommonly been described mostly in the colon. Histologically, this tumor is composed of a predominant proportion of benign adenomatous component and a small portion of well-differentiated NE component. Only three cases of NET in gastric adenoma have been reported in the literature. We present 4 cases of NET in gastric adenoma mimicking invasive adenocarcinoma. The NETs were 0.62 mm to 4.1 mm in size and located at the basal lamina propria, muscularis mucosa and submucosa. Histologically, NETs consisted of nests, cords, tubules, and clusters of cells that predominantly interposed between the foveolar base without disturbing the overall polyp architecture. The lesions were completely removed by endoscopic submucosal dissection in three cases and in one case, subtotal gastrectomy was performed because endoscopic biopsy was invasive adenocarcinoma. The patients' clinical course was uneventful without an evidence of recurrence or metastasis. The recognition of NET in gastric adenoma will help avoid potential diagnostic pitfalls masquerading as invasvie adenocarcinomas posed by their infiltrative pattern into submucosa. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1688552293761001.

Simple Summary: We compared the prognosis of patients with cardia or subcardia cancer using a gastric cancer staging system and identified a significant difference in overall survival according to invasion of the esophagogastric junction. In addition, esophagogastric junction invasion was a significant independent factor reflecting a poor prognosis. Esophagogastric junction invasion should be considered for staging, and additional research is needed to apply it to gastric and esophageal cancer classification. Background: There has been no comparison of the prognoses of Korean patients who underwent curative surgery for cancer located at the cardia or subcardia of the stomach. We performed this comparison and further investigated the prognostic significance of esophagogastric junction (EGJ) invasion in patients. Methods: The medical records of patients (n = 511) who were diagnosed with cardia or subcardia cancer and underwent surgery between January 2010 and May 2019 were retrospectively reviewed. Patients were further categorized into four groups for analysis: subcardia gastric cancer (sGC; subcardia cancer without EGJ invasion; n = 97), AEG (adenocarcinoma of the esophagogastric junction) type III (subcardia cancer with EGJ invasion, n = 54), AEG type II without EGJ invasion (n = 158), and AEG type II with EGJ invasion (n = 202). We compared the overall survival of the four groups using a gastric cancer staging system and evaluated the prognostic significance of EGJ invasion with multivariate analysis. Results: The median follow-up of patients was 46.0 months (range: 0–124 months). There was significant difference in overall survival curves among the four groups (p < 0.001). Subgroup analysis showed a significant difference in overall survival between the groups with and without EGJ invasion (p < 0.001). Cancers with EGJ invasion were more frequently in the cardia (p < 0.001), had a larger size (p < 0.001), and showed a more advanced pathologic stage (stages II and III; 67.6% versus 33.7%, p < 0.001) than those without EGJ invasion. EGJ invasion and the pathologic stage were significant independent prognostic factors of overall survival in cardia and subcardia cancer patients (hazard ratio 2.24, 95% confidence interval 1.32–3.81, p = 0.003). Conclusion: The overall survival between patients with cardia or subcardia cancer was significantly different according to EGJ invasion. EGJ invasion was an independent prognostic factor and should be considered for staging. Additional research is needed to apply this feature to gastric and esophageal cancer classification. [ABSTRACT FROM AUTHOR]