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Malignancies of upper gastrointestinal tract are aggressive, and most locally advanced unresectable and metastatic cancers are managed by a combination of surgery and neoadjuvant/adjuvant chemotherapy and radiotherapy. Current therapeutic recommendations include targeted therapies based on biomarker expression of an individual tumor. All G/gastro-esophageal junction (GEJ) cancers should be tested for HER2 status as a reflex test at the time of diagnosis. Currently, testing for PDL 1 and mismatch repair protein status is optional. HER2 testing is restricted to adenocarcinomas only and endoscopic biopsies, resections, or cellblocks. Facilities should be available for performing validated immunohistochemical stains and in-situ hybridization techniques, and importantly, pathologists should be experienced with preanalytical and analytical issues and scoring criteria. Genomic profiling via next-generation sequencing (NGS) is another strategy that assess numerous mutations and other molecular events simultaneously, including HER2 amplification, MSS status, tumor mutation burden, and neurotrophic tropomyosin-receptor kinases gene fusions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Positive human epidermal growth factor 2 (HER2) expression and its predictive clinicopathological features remain unclear in Sri Lankan gastric cancer (GC) patients. Here, we aimed to determine GC HER2 status predictors by analyzing associations between clinicopathological features and HER2 expression using immunohistochemistry (IHC) and silver in situ hybridization (SISH)., Methods: During this 4-year prospective study, clinicopathological data were collected from participants in the National Hospital of Sri Lanka. HER2 IHC and SISH were performed using commercial reagents. Using chi-square tests, associations of HER2-IHC/SISH with clinicopathological features were analyzed., Results: Overall, 145 GC patients were included, 69 had gastrectomies and 76 had biopsies. Positive HER2 expression by IHC was associated with age <60 years, high T stage (assessed pathologically in resections and radiologically in biopsies), high nuclear grade, tumor necrosis, mitosis >5/high-power field, with additional perineural invasion and lymphovascular invasion in resections. These features, excluding lymphovascular invasion but including male sex, were associated with HER2 expression by SISH., Conclusions: Age <60 years, high nuclear grade, tumor necrosis, and perineural invasion are associated factors of HER2 status. These could be used to triage GC patients for HER2 status testing in limited resource settings where IHC/SISH analysis is costly.

Aims: To determine the clinicopathological features of pyloric gland adenomas (PGA) that arise in the duodenum., Methods and Results: Fifty-seven cases of duodenal PGA were identified and analysed from 56 patients. Clinicopathological and immunohistochemical analyses were performed. PGA tend to occur in older individuals (median age = 73.5), with a slight female predominance (25 males, 31 females). PGA arise more commonly in the proximal duodenum (68.75% in D1, 25% in D2 and 6.25% in D3) and usually present as mucosal nodules (98.2%) or plaques (1.8%), with a mean size of 14.8 mm. There is associated gastric heterotopia in 22.8% of cases. PGA showing features of high-grade dysplasia were significantly larger in size than PGA, showing only low-grade dysplasia (23.1 versus 8.7 mm; P = 0.0001) and more likely to show a tubulovillous rather than a pure tubular architecture (P = 0.025). In our series, 10 of 56 patients had intramucosal or invasive carcinoma associated with the duodenal PGA (17.9%). Three of these carcinomas showed lymph node metastasis. Following definitive treatment, local recurrence occurred in only three patients., Conclusions: Duodenal PGA tend to occur in the proximal duodenum of older individuals. Larger size and tubulovillous architecture correlates with high-grade dysplasia and associated adenocarcinoma. The low recurrence rate of these lesions would suggest that endoscopic management is appropriate, provided that the lesion can be completely resected., (© 2019 John Wiley & Sons Ltd.)

Human epidermal growth factor receptor 2 (HER2) status determines gastric/gastroesophageal junction (GEJ) adenocarcinomas that benefit from targeted therapy; hence, HER2 testing has become a routine practice. Accurate HER2 testing is fundamental to select eligible patients who will benefit from HER2-targeted treatment. The reported HER2-positive rate in gastric/GEJ cancers ranges from 4.4% to 53.4%, and HER2-positive tumors are considered to have more-aggressive biologic behavior and tumor recurrence. Main modalities of HER2 testing in clinical practice include immunohistochemistry (IHC) for protein expression and in situ hybridization (ISH) for gene amplification. Many technical pitfalls affect the accuracy of HER2 result. Additionally, several issues in HER2 testing are related to the tumor biology, sample selection, interpretation of IHC and ISH results, and confirming HER2 status. Therefore, gastric/GEJ adenocarcinoma-specific HER2 testing protocols have been developed and standardized to minimize the impact of these preanalytical and analytical factors and to enhance reproducibility of HER2 testing results. This review provides up-to-date practical guidance to clinicians on accurate HER2 testing and interpretation of results in gastric/GEJ adenocarcinoma., (Copyright © 2019 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

An esophagogastrectomy is a surgical procedure that is performed for treatment of confirmed localized esophageal and esophagogastric junction adenocarcinoma. Proper macroscopic assessment and cut-up technique is essential to ensure that the overall assessment is correct and reproducible. Here, we describe a standard for macroscopic assessment and dissection to be used for routine handling of esophagogastrectomy specimens in the clinical laboratory.

Neoplastic lesions of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) are gastric phenotype. GAPPS was reported in 2011 as a new autosomal dominant gastric polyposis syndrome characterized by involvement of the gastric body/fundus with sparing of the antrum by multiple polyps, reported to be primarily fundic gland polyps (FGPs), with progression to dysplasia and adenocarcinoma of intestinal type. Our series consists of 51 endoscopic biopsies and 5 gastrectomy specimens from 25 patients belonging to a previously defined GAPPS family. Slides were reviewed and further stains performed. Endoscopy was abnormal in 15 of the 25 patients: carpeting polyposis of the gastric body and fundus in 14 and a gastric mass without polyposis in one. The most common polypoid lesion (seen in 12 patients) was a disorganized proliferation of specialized/oxyntic glands high up in the mucosa involving the attenuated foveolar region around the gastric pits, which we have termed "hyperproliferative aberrant pits". Well developed FGP were seen in 10 patients. Established neoplastic lesions seen in 9 patients were: (1) discrete gastric adenomas, (2) multifocal "flat" dysplasia in the setting of hyperproliferative aberrant pits +/- FGPs, (3) adenomatous tissue associated with adenocarcinoma. All cases of dysplasia were of gastric phenotype based on morphology and mucin immunohistochemistry., In Conclusion: (1) the spectrum of gastric pathology associated with GAPPS is wider than previously reported, (2) the earliest microscopic clue is the finding of hyperproliferative aberrant pits, and (3) the dysplasia is gastric phenotype and the subsequent adenocarcinoma may follow the gastric pathway of carcinogenesis.

This Australian human epidermal growth factor receptor 2 (HER2) testing program aimed to analyse >800 cases tested in a coordinated setting to further evaluate the criteria to establish HER2 status in advanced gastric and gastro-oesophageal junction (GOJ) cancer. Heterogeneity, and minimum number of biopsy fragments for reliable HER2 assessment were also examined in a subset of samples. Five laboratories tested 891 samples referred to determine HER2 status for potential anti-HER2 treatment. Cancer site, specimen type (endoscopic biopsy/resection/metastases), immunohistochemistry (IHC) score, HER2 gene and CEP17 copy number (CN) and HER2:CEP17 ratios were recorded. Samples were derived from stomach (53.1%), GOJ (28.2%) or metastases (18.5%). IHC for HER2 and dual probe HER2:CEP17 in situ hybridisation (ISH) were performed in parallel. A stringent definition (SD) of HER2 positivity was used (IHC2+/3+ plus CN>6 and ratio>2) and compared with other published criteria. HER2 positive rate was 13.9% (114/820) by SD, and 12.9-16.0% using other definitions. There was higher concordance between IHC and HER2 CN by ISH than with ratio. The HER2 positive rate was significantly higher in GOJ samples than others (p = 0.03) and in endoscopic biopsies than resections (p = 0.047). In a subset of 98 positive cases, 39 (39.8%) showed heterogeneity, and in 282 endoscopic biopsies positivity rate plateaued at five tumour fragments, suggesting this is the minimum number of biopsies that should be examined., (Copyright © 2017 Royal College of Pathologists of Australasia. All rights reserved.)

Background: HER2 protein expression indicates adverse prognosis in gastric adenocarcinoma (GCa). GCa HER2 positivity ranges from 10 to 22.8%. Similar data are scarce in South Asia and unavailable in Sri Lanka., Aim: To evaluate HER2 protein expression, its clinicopathological relationship and survival in a Sri Lankan GCa cohort., Methods: One hundred consecutive GCa patients were recruited prospectively for 2 years. Histological diagnosis was confirmed on endoscopic biopsies/gastrectomy specimens. Clinicopathological and overall survival data were collected. HER2 expression was assessed using immunohistochemistry. 2+ and 3+ scores were considered positive. HER2 expression and clinicopathological parameters were analyzed by Chi-squared test and multivariate analysis with logistic regression using SPSS-21. Kaplan-Meier method and log-rank test were used for survival analysis., Results: Study includes 56 biopsies and 44 resections. Male/female ratio was 1.9:1. Mean age of diagnosis was 61.1 years (range 32-82). Majority tumors were proximally located (58%). HER2 positivity was 9%. Even though intestinal subtype predominated HER2 positivity was mostly among diffuse variant (14.8%). In multivariate analysis, mitotic count >5/hpf, high nuclear grade and tumor necrosis were significantly associated with HER2 positivity, while poor differentiation, signet cells, extracellular mucin, perineural invasion and pathological nodal metastasis (all p < 0.05) showed a correlation in univariate analysis. Mean follow-up duration was 37.4 weeks (range 0-104). HER2 positivity was associated with a significantly lower median overall survival (p = 0.046)., Conclusion: GCa HER2 positivity was 9%, associated with a lower median overall survival. Adverse histological features had a positive correlation with HER2 positivity. These histological features could direct patients for confirmatory HER2 testing in limited resource settings.

Aims: Rare gastric lesions composed of a combined proliferation of chief and oxyntic cells have been variably called adenocarcinoma of fundic gland type and oxyntic gland polyp/adenoma. Herein, we present a series of cases that show a morphological spectrum of chief and oxyntic cell proliferations., Methods and Results: Routine and consultation cases were collated from five institutions. Information regarding site, size, endoscopic appearance, clinical history and medication use, when available, was accrued, as was the histological features and immunoprofiles. A total of 12 cases were collated. Age ranged from 39 to 81 years. All the lesions were located in the fundus; seven of eight were polypoid lesions endoscopically. Lesions were primarily solitary, averaged 4.6 mm in diameter (largest 9 mm) and comprised >50% chief cells. The predominant architectural pattern was of anastomosing and solid and clustered glands or a mixture of these patterns. Lesions were limited mainly to the mucosa, although two showed submucosal involvement. None had known metastatic disease., Conclusions: This series included lesions that were previously described as gastric adenocarcinoma of fundic gland type and oxyntic gland polyp/adenoma. They are located exclusively in the fundus and composed predominantly of chief cells with low-grade cytology and appear to show a morphological continuum., (© 2015 John Wiley & Sons Ltd.)

HER2 is amplified/overexpressed in a subset of gastric and gastro-oesophageal junction cancers. Addition of anti-HER2 therapy has been shown to provide survival benefit in this setting. However, there are limited data assessing the concordance of HER2 status between primary and metastatic sites.A total of 113 samples from 43 paired primary and metastatic tumours were tested for HER2 status, by immunohistochemistry (IHC) for protein expression and silver in situ hybridisation (SISH) for gene amplification.Primary sites tested included endoscopic biopsies (n = 30) and resections (n = 24). Metastatic samples included lymph nodes (n = 29), peritoneal effusions (n = 21) and miscellaneous sites (n = 9). The overall HER2+ rate was 11%. Of 41 (95%; 95% CI 88.5-100%) concordant cases, 38 were HER2- and three were HER2+. There were two (5%) discordant cases, one of which showed heterogeneity of HER2 expression.This series confirms a high concordance rate of 95%, supporting that testing of primary tumours and metastases is equally valid and providing clinical rationale for the addition of anti-HER2 therapy in HER2+ disseminated disease.

HER2 testing on effusions of metastatic gastric carcinoma may provide a valuable alternative to testing on primary biopsies. This study assessed the feasibility of this method by immunohistochemistry (IHC) and silver in situ hybridization (SISH). Cell blocks from 46 effusions from metastatic gastric carcinoma were examined. IHC was scored using the modified criteria of Hofmann et al. An average of ≥6 signals per nucleus was considered amplification on SISH. Results were compared with histological specimens to assess HER2 status concordance. Cell blocks showed a poorly cohesive pattern in 30 (65%), aggregates in 7 (15%), and mixed pattern in 9 (20%). Seven (15%) showed an IHC 2+/3+ reaction with a membranous pattern, appearing more granular than in histology. Three (7%) showed HER2 amplification on SISH. In 18 cases (39%), HER2 status was compared with histological specimens, showing 100% concordance. Difficulties were encountered in distinguishing malignant cells from reactive mesothelial cells in 12 (26%). This study supports the feasibility of HER2 assessment on effusions. The incidence of HER2 positivity (7% with SISH+ and IHC 2+/3+) was lower than reported in histological samples. Further refinement and validation will enhance the use of this method in clinical practice and overcome difficulties encountered., (© 2014 Wiley Periodicals, Inc.)

The aim of this study was to compare HER2 amplification, as determined by the HER2 copy number (CN) and the HER2/CEP17 ratio, with protein expression in gastric and gastro-oesophageal junction (G/GOJ) adenocarcinoma.HER2 immunohistochemistry (IHC) and silver in situ hybridisation (SISH) were performed in 185 cases. Modified gastric criteria were used for IHC scoring. HER2 and CEP17 CNs were counted in at least 20 cancer cells and the ratio calculated as per previously defined protocols. These two SISH methods were statistically compared against the different IHC scores.Thirty-four cases showed amplification, by both methods in 29, and either method in five. IHC score was 3+ in 29 cases; 26 showed amplification by both methods, one by ratio only and two were not amplified. IHC score was 2+ in 24 cases; three showed amplification by both methods and two by either. One each of IHC 1+ and 0 showed an increased ratio but not CN. The HER2 CN and ratio for IHC score 3+ compared to scores 2+, 1+ and 0 were significantly different (all p < 0.01). The CN for IHC 2+ vs IHC 1+ and IHC 0 was significantly different (both p < 0.01) but the ratio was not (p = 0.5711 and p = 0.2857, respectively). The CN and the ratio for scores 1+ and 0 were not significantly different (p = 0.9823 and p = 0.9910, respectively).The HER2 CN differentiates between the different IHC scores better than the HER2:CEP17 ratio. Cases that show IHC3+ and high CN may not require calculation of the ratio. Furthermore, consideration should be given to the CN when IHC negative cases appear amplified by the ratio only.

Trastuzumab provides a survival benefit in patients with human epidermal growth factor receptor 2 (HER2)-amplified/overexpressed advanced gastric and gastroesophageal junction cancers (GC/GJCs). However, the optimal method for testing is unclear. The aim of this study was to assess interlaboratory agreement on HER2 scoring in GC/GJC to aid the development of a robust testing algorithm for diagnostic practice in Australia. Nine laboratories assessed the HER2 status of 100 GC/GJC tissue samples by immunohistochemistry (IHC) and in situ hybridization (ISH) [chromogenic (CISH) or silver (SISH)] using both HER2 copy number and HER2:chr17 (chromosome 17) ratio. Results were compared with reference fluorescence ISH (FISH). Interlaboratory agreement on IHC3+ scoring was good (κ=0.76), and there was good/very good agreement between IHC (positivity defined as IHC3+) and ISH when HER2 copy number was used (κ=0.72 to 0.87). Agreement on CISH/SISH scoring was good/very good when HER2 copy number was used (κ=0.68 to 0.86), and agreement between CISH/SISH and FISH using HER2 copy number was very good (κ=0.88 to 0.91). Agreement was reduced when HER2:chr17 ratio was used. The good agreement for HER2 copy number determined by bright-field ISH suggests that this is the optimal method for testing in GC/GJC cases. An IHC3+ score was strongly predictive of a positive ISH result, although agreement for all IHC scores was only moderate, suggesting that IHC triage before ISH testing would be the most cost-effective strategy. However, because of the unique features of GC/GJC samples and the difficulty of ensuring consistent HER2 staining in the community setting, it is recommended that HER2 status in advanced GC/GJC be determined by both IHC and ISH in the same laboratory.

Aims: To assess human epidermal growth factor receptor 2 (HER2) status and heterogeneity using immunohistochemistry (IHC) and silver in-situ hybridization (SISH) in gastric carcinoma and dysplasia, and to correlate HER2 status between biopsy and resection specimens of gastric carcinoma., Methods and Results: Immunohistochemistry for HER2 was performed in 178 cases of gastric carcinoma, and SISH in cases showing at least 1+ reaction. HER2 positivity [European Medicines Agency (EMA) guidelines] was identified in 20.2% of carcinomas and 12.9% of high-grade dysplasia, and HER2 heterogeneity noted in 50% and 33% of these cases, respectively. IHC negative/positive reactivity and SISH results were concordant in 96.2%. SISH amplification was seen in 35.3% of IHC 2+ and in a case with previously unrecognized staining pattern. Concordance of IHC HER2 status on biopsies and gastrectomies was seen in 74.1%. False negative IHC results on either the biopsy or gastrectomy were seen in 19.4% of HER2 amplified cases., Conclusions: Human epidermal growth factor receptor 2 status in gastric carcinoma is comparable to previous studies with good concordance between IHC and SISH; all IHC 2+ and unusual patterns should be assessed with ISH studies; heterogeneity of tumour HER2 overexpression/amplification is common with possible implications for HER2 testing; and HER2 overexpression appears sufficiently specific to be considered a potential diagnostic biomarker of dysplasia., (© 2011 Blackwell Publishing Limited.)

Pyloric gland-type adenoma of the duodenum with documented malignant progression is rare. A case is presented of an 87-year-old man with bloating and nausea, who on investigation was found to have a polyp on the anteroinferior wall of the duodenal cap. Histologic examination of the polyp showed features of a pyloric gland adenoma (PGA) demonstrating the full spectrum of progression from low- to high-grade dysplasia and finally invasive adenocarcinoma. The carcinoma showed gastric-type differentiation highlighted by its mucin immunohistochemistry profile and was of advanced stage with lymph node metastasis. The literature on PGAs and the little documentations on progression to carcinoma in duodenal PGAs are reviewed.