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Clear cell papulosis of the skin is a rare condition; to our knowledge only 12 cases have been reported. Here, we report for the first time a case of clear cell papulosis with cytokeratin 7 expression and provide a comprehensive literature review. A 16-month-old girl presented with 3 hypopigmented lesions in the pubic region that were 3 to 9 mm in diameter; 1 lesion was papular, and the other 2 were macular. A skin biopsy revealed acanthosis with a proliferation of clear cells along the basal and suprabasal layers of the epidermis occurring in small clusters and singly. The cells had round to oval regular nuclei with abundant to moderate lightly eosinophilic to clear cytoplasm and intracytoplasmic mucin. Immunostaining produced positive results for carcinoembryonic antigen, AEl /3, epithelial membrane antigen, cell adhesion molecule 5.2, and cytokeratin 7 and negative results for gross cystic fluid disease protein, Si 00, and FIMB-45. Clear cells of clear cell papulosis are mucin-positive and S100-negative glandular- secretory epithelial cells with histogenetic features of Toker cells of nipple and Paget cells. Immunohistochemical features support an eccrine secretory cell origin because the clear cells are consistently and strongly positive for carcinoembryonic antigen, positive for cell adhesion molecule 5.2, and negative or rarely positive for gross cystic fluid disease protein. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

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.)

The dysplasia grading of Barrett's esophagus (BE), based on the histomorphological assessment of formalin-fixed, paraffin-embedded (FFPE) tissue, suffers from high interobserver variability leading to an unsatisfactory prediction of cancer risk. Thus, pre-analytic preservation of biological molecules, which could improve risk prediction in BE enabling molecular and genetic analysis, is needed. We aimed to evaluate such a molecular pre-analytic fixation tool, PAXgene-fixed paraffin-embedded (PFPE) biopsies, and their suitability for histomorphological BE diagnostics in comparison to FFPE. In a ring trial, 9 GI pathologists evaluated 116 digital BE slides of non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinomas (EAC) using virtual microscopy. Overall quality, cytological and histomorphological parameters, dysplasia criteria, and diagnosis were analyzed. PFPE showed better preservation of nuclear details as chromatin and nucleoli, whereas overall quality and histomorphologic parameters as visibility of basal lamina, goblet cells, and presence of artifacts were scored as equal to FFPE. The interobserver reproducibility with regard to the diagnosis was best for NDBE and EAC (κ F  = 0.72-0.75) and poor for LGD and HGD (κ F  = 0.13-0.3) in both. In conclusion, our data suggest that PFPE allows equally confident histomorphological diagnosis of BE and EAC, introducing a novel tool for molecular analysis and parallel histomorphological evaluation., (© 2022. The Author(s).)

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.

Objective: Management of covert submucosal invasive cancer (SMIC) discovered after piecemeal endoscopic mucosal resection (pEMR) of large (>20 mm) non-pedunculated colorectal polyps is challenging. The residual cancer risk is largely unknown. We sought to evaluate this in a large tertiary referral cohort., Design: Cases of covert SMIC following pEMR were identified and followed. Oncological outcomes after surgery were divided based on residual intramural cancer, lymph node metastases (LNM) or both. Risk factors for residual intramural cancer and LNM were analysed based on the original pEMR histological variables. Risk parameters were analysed with respect to low and high-risk variables for residual intramural cancer and LNM., Results: Among 3372 cases of large non-pedunculated colorectal polyps, 143 cases of covert SMIC (4.2%) were identified. 109 underwent surgical resection. Histological analysis of pEMR histology was available in 98 of 109 (90%) cases. 62 cases (63%) had no residual malignancy. 36 cases had residual malignancy (residual intramural cancer n=24; LNM n=5; both n=7). All cases of residual intramural cancer could be identified by a R1 histological deep margin. Cases with poor differentiation (PD) and/or lymphovascular invasion (LVI) had a high risk of LNM (12/33), with a very low risk without these criteria (<1%; 0/65). Cases at low risk for LNM with R0 deep margin have a low risk of residual intramural cancer (<1%; 0/35)., Conclusion: The majority of cases of large non-pedunculated colorectal polyps with covert SMIC following pEMR will have no residual malignancy. The risk of residual malignancy can be ascertained from three key variables: PD, LVI and R1 deep margin., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recalibrating diagnostic thresholds or using alternative labels may mitigate overdiagnosis and overtreatment of papillary microcarcinoma (mPTC). We aimed at identifying and collating relevant epidemiological evidence on mPTC, to assess the case for recalibration and/or new labels. Methods: We searched EMBASE and PubMed databases from inception to December 2020 for natural history, autopsy, diagnostic drift, and diagnostic reproducibility studies. Where a relevant systematic review was pre-identified, only new articles were additionally included. Non-English articles were excluded. One author screened titles and abstracts. Two authors screened full text articles, performed quality assessments, and extracted data. We undertook narrative synthesis of included evidence (pooled estimates from systematic reviews and single estimates from primary studies). Results: One systematic review of patients undergoing active surveillance found that after 5 years of follow-up, 5.3% (95% confidence interval [CI 4.4-6.4%]) of the mPTC lesions had increased in size by ≥3 mm, and 1.6% [CI 1.1-2.4%] of patients had lymph node metastases. Among 7 new primary studies (including 3 updates on 2 studies included in the systematic review), 1-5% of patients undergoing active surveillance had lymph node metastases after a median follow-up of 1-10 years. One systematic review found that subclinical thyroid cancer incidentally discovered at autopsy is relatively common, with a pooled prevalence of 11.2% [CI 6.7-16.1%] among studies that examined the whole thyroid. Four diagnostic drift studies evaluated the new classification of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Three studies of cases previously diagnosed as papillary thyroid cancer found 1.3-2.3% were reclassified as NIFTP (reclassifications were from follicular variation of papillary thyroid cancer [FVPTC]). One study of 48 cases previously diagnosed as mPTC found that 23.5% were reclassified as NIFTP. Thirteen reproducibility studies of papillary thyroid lesions found substantial variation in the histopathological diagnosis of thyroid lesions, including FVPTC and NIFTP classifications (no study evaluated mPTC). Conclusions: This review supports consideration of recalibrating diagnostic thresholds and/or alternative labels for low-risk mPTC.

The increasing use of gastrointestinal endoscopic procedures has led to the recognition by histopathologists of non-conventional (or special-type) dysplasias of the gastrointestinal tract. These lesions can be recognised in association with prevalent underlying gastrointestinal conditions, such as Barrett oesophagus, chronic atrophic gastritis, and inflammatory bowel disease. The diagnosis of these special types can be challenging, and their biological behaviours are not fully characterised. The aim of this review is to provide a global view of non-conventional dysplastic lesions observed in the various segments of the tubular gastrointestinal tract and describe their salient features. Furthermore, as the clinical implications of these various subtypes have not been broadly tested in practice and are not represented in most management guidelines, we offer guidance on the best management practices for these lesions., (© 2020 John Wiley & Sons Ltd.)

Background: Colitis is a significant complication of immune checkpoint inhibitors (ICI). Currently, clinical and endoscopic severity are used to guide therapy., Aims: To investigate associations between clinical, endoscopic, and histological features with outcomes METHODS: We identified 149 patients from seven institutions with biopsy-proven ICI colitis. Biopsies were evaluated for histological features including the Geboes score, and the Robarts histopathological index (RHI) was calculated. Clinical, endoscopic, and histological data were tested for associations with biological use and adverse colitis outcomes (biological-refractory colitis, colectomy or death from colitis)., Results: Three mutually exclusive histological patterns were identified: acute colitis, chronic active colitis and microscopic colitis. Microscopic colitis was associated with older age (68.5 vs 61 years for acute colitis pattern, P = 0.02) and longer time to colitis (5.5 vs 3 months for the other patterns, P = 0.05). Biological use was associated with earlier time to colitis (2 vs 3 months, P = 0.04) and higher RHI (18 vs 12, P = 0.007). On multivariate analysis, RHI ≥14 was associated with biological use with an odds ratio of 4.5 (95% CI 1.4-13.8; P = 0.01). Adverse colitis outcomes were associated with shorter time to colitis (2 vs 3 months, P = 0.008) and higher RHI (24 vs 14, P = 0.001). On multivariate analysis, RHI ≥24 was associated with adverse colitis outcomes with an odds ratio 9.5 (95% CI 2.1-42.3 P = 0.003)., Conclusion: Histological activity as measured by RHI is the only factor independently associated with biological use and adverse colitis outcomes. Prospective studies are needed to validate these findings to determine if histological activity should be incorporated into therapeutic algorithms., (© 2020 John Wiley & Sons Ltd.)

Modern management of Barrett's oesophagus and related neoplasia essentially focuses upon surveillance to detect early low-risk neoplastic lesions and offering organ-preserving advanced endoscopic therapies, while traditional surgical treatments of oesophagectomy and lymph node clearance with or without chemoradiation are preserved only for high-risk and advanced carcinomas. With this evolution towards figless invasive therapy, the choice of therapy hinges upon the pathological assessment for risk stratifying patients into those with low risk for nodal metastasis who can continue with less invasive endoscopic therapies and others with high risk for nodal metastasis for which surgery or other forms of treatment are indicated. Detection and confirmation of neoplasia in the first instance depends upon endoscopic and pathological assessment. Endoscopic examination and biopsy sampling should be performed according to the recommended protocols, and endoscopic biopsy interpretation should be performed applying standard criteria using appropriate ancillary studies by histopathologists experienced in the pathology of Barrett's disease. Endoscopic resections (ERs) are both diagnostic and curative and should be performed by clinicians who are skilled with advanced endoscopic techniques. Proper preparation and handling of ERs are essential to assess histological parameters that dictate the curative nature of the procedure. Those parameters are adequacy of resection and risk of lymph node metastasis. The risk of lymph node metastasis is determined by depth invasion and presence of poor differentiation and lymphovascular invasion. Those adenocarcinomas with invasion up to muscularis mucosae (pT1a) and those with superficial submucosal invasion (pT1b) up to 500 µ with no poor differentiation and lymphovascular invasion and negative margins may be considered cured by endoscopic resections., (© 2020 John Wiley & Sons Ltd.)

Universally accepted guidelines for diagnosis and management of any disease are desirable. Standardization of thyroid cytology reporting is aimed at guiding and improving clinical decision-making and management. However, socio-economic, and local factors and differences in disease prevalence and patterns require modification to suit local settings. 'One size fit all' approach is not possible for any disease diagnosis or management. The same concept is applicable in diagnosis and management of thyroid nodules. An additional special issue is the well-known high inter and intra-observer variability in the histological and cytological diagnosis of thyroid neoplasms. Despite this, thyroid cytology has a very significant influence in the management of thyroid diseases. An approach based on common principals with appropriate modifications that suits countries or continents is desirable and sustainable. The principals of TBSRTC have served as a framework for similar tiered classifications for reporting thyroid cytopathology. This article discusses globally available professional guidelines based on a common framework with appropriate modifications, with the universal aim of risk stratification of thyroid nodules., Competing Interests: Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-2019-catp-25). The series “Asian and Western Practice in Thyroid Pathology: Similarities and Differences” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare., (2020 Gland Surgery. All rights reserved.)

There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was undertaken on 30 tumors comprising 25 'pure' acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1 gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RET or RAF1 fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Endoscopic resection (ER) allows optimal staging with potential cure of early-stage luminal malignancies while maintaining organ preservation. ER and surgery are non-competing but complementary therapeutic options. In addition, histological examination of ER specimens can either confirm or refine the pre-procedure diagnosis. ER is used for the treatment of Barrett's related early carcinomas and dysplasias, early-esophageal squamous cell carcinomas and dysplasias, early gastric carcinomas and dysplasia, as well as low-risk submucosal invasive carcinomas (LR-SMIC) and, large laterally spreading adenomas of the colon. For invasive lesions, histological risk factors predict risk of lymph node metastasis and residual disease at the ER site. Important pathological risk factors predictive of lymph node metastasis are depth of tumor invasion, poor differentiation, and lymphovascular invasion. Complete resection with negative margins is critical to avoid local recurrences. For non-invasive lesions, complete resection is curative. Therefore, a systematic approach for handling and assessing ER specimens is recommended to evaluate all above key prognostic features appropriately. Correct handling starts with pinning the specimen before fixation, meticulous macroscopic assessment with orientation of appropriate margins, systematic sectioning, and microscopic assessment of the entire specimen. Microscopic examination should be thorough for accurate assessment of all pathological risk factors and margin assessment. Site-specific issues such as duplication of muscularis mucosa of the esophagus, challenges of assessing ampullectomy specimens and site-specific differences of staging of early carcinomas throughout the gastrointestinal tract (GI) tract should be given special consideration. Finally, a standard, comprehensive pathology report that allows optimal staging with potential cure of early-stage malignancies or better stratification and guidance for additional treatment should be provided.

Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may be under-recognized. In contrast to pancreatic ductal adenocarcinoma, most acinar cell carcinomas lack mutations in KRAS, DPC, CDKN2A or TP53, but appear to have a high incidence of gene rearrangements, with up to 20% reported to be driven by BRAF fusions. With the development of a new class of RET-specific tyrosine kinase inhibitors, which appear to have particularly strong activity against RET gene rearranged tumours, there is now considerable interest in identifying RET gene rearrangements across a wide range of cancers. RET rearrangements have been reported to occur at a very low incidence (<1%) in all pancreatic carcinomas. We postulated that given its unique molecular profile, RET gene rearrangements may be common in acinar cell carcinomas. We performed fluorescent in-situ hybridization (FISH) studies on a cohort of 40 acinar cell spectrum tumours comprising 36 pure acinar cell carcinomas, three pancreatoblastomas and one mixed acinar-pancreatic neuroendocrine tumour. RET gene rearrangements were identified in 3 (7.5%) cases and BRAF gene rearrangements in 5 (12.5%). All gene rearranged tumours were pure acinar cell carcinomas. Our findings indicate that amongst all pancreatic carcinomas, acinar carcinomas are highly enriched for potentially actionable gene rearrangements in RET or BRAF. FISH testing is inexpensive and readily available in the routine clinical setting and may have a role in the assessment of all acinar cell carcinomas-at this stage to recruit patients for clinical trials of new targeted therapies, but perhaps in the near future as part of routine care.

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.)

High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

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.)

There is increasing interest in p53 immunohistochemistry as an adjunct to haematoxylin and eosin (H&E) assessment for dysplasia in oesophageal Barrett's mucosa; however, published information on the patterns of staining remains scant. Here, we present descriptions of normal and aberrant p53 staining in non-neoplastic and dysplastic Barrett's mucosa in endoscopic mucosal resections. A retrospective series of archival endoscopic mucosal resections for biopsy proven dysplasia at our institution were retrieved for this study, comprising 28 sections from 23 patients. p53 immunohistochemistry was performed using an in-house optimised protocol and the staining pattern assessed in H&E confirmed non-neoplastic, dysplastic and neoplastic areas of Barrett's mucosa with regard to individual cell intensity and location of positive cells with respect to gland microanatomy. In non-neoplastic epithelium, normal p53 staining was weak, heterogenous and localised to the crypts. In dysplastic epithelium, p53 over-expression was seen which was of moderate to strong intensity in either a crypt predominant location or diffuse involving crypt and surface epithelium. The crypt predominant pattern was observed more commonly in low grade dysplasia while the diffuse pattern was more commonly seen in high grade dysplasia. In a minority of cases, there was complete loss of p53 staining in dysplastic epithelium and contiguous neoplasia (null phenotype). p53 immuno-expression in non-neoplastic and dysplastic Barrett's mucosa is distinctive when interpreted with regard to cell intensity and gland microanatomy. We propose that these staining patterns may assist in the interpretation of dysplasia in endoscopic biopsies of Barrett's mucosa., (Copyright © 2019 Royal College of Pathologists of Australasia. All rights reserved.)

HER2 positivity is based on the fundamental principle of amplification of the human epidermal growth factor receptor 2 (HER2) gene resulting in overexpression of the protein products . Arising from that a "HER2-positive cancer" is one that shows HER2 gene amplification and resultant protein expression as demonstrated by in situ hybridization and immunohistochemistry, respectively. Testing of the HER2 status is crucial to ensure selection of the correct patient who may benefit from target therapy for esophageal adenocarcinoma. Accurate testing is dependent on several pre-analytical and analytical factors including sample selection, laboratory techniques, and accurate interpretation of HER2 test results.

Granulomas are organised collection of activated histiocytes induced by a persistent antigen stimulus. A wide variety of antigens encountered by the gastrointestinal tract are of this nature and hence the resulting granulomatous inflammation represents a tissue reaction pattern. The potential causes can be broadly classified as infections or non-infectious immune reactions. There is also a group where a cause is never identified. Granulomas may be of varying morphological appearance, most commonly epithelioid, foreign body type, suppurative and necrotizing. This may provide a clue as to the aetiology; however, in most cases, the cause requires further inquiry. Pathologists may need to cut deeper levels to look for foreign material and apply special stains to look for microorganisms. Pathologists also need to be certain that the process is a true granuloma and not a mimic. The site of occurrence in the gastrointestinal tract and the clinical setting is often paramount in establishing the aetiology. For instance, infections are more likely the cause in developing countries or when there is immunosuppression. Similarly, granulomas in the stomach are usually due to Crohn's disease; however, it is only rarely the cause of granulomas isolated to the appendix.

Gastroenteropancreatic (GEP) neuroendocrine neoplasms can be broadly separated into well- and poorly differentiated categories. Tumours within each category have similarities in morphology and immunophenotype, but vary in grade, behaviour, molecular signature and responses to therapy. The aetiology of these differences is multifactorial. Site of origin, mucosal milieu and hereditary influences are some of the currently known factors. Given these differences, staging and grading systems continue to evolve, and the most recent World Health Organization classification of pancreatic neuroendocrine neoplasms reflects this by introducing a grade 3 neuroendocrine tumour category for morphologically well-differentiated tumours with an elevated Ki-67 proliferation index and/or mitotic count. This review aims to highlight current classification guidelines with discussion of unique site-specific features of selected GEP neuroendocrine neoplasms and an emphasis on practical issues related to daily reporting., (© 2017 John Wiley & Sons Ltd.)

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.

Background: Hereditary tumour predisposition syndromes may increase the risk for development of thyroid nodules at a young age. We present the case of an adolescent female with Cowden syndrome who had some atypical phenotypic features which overlapped with the DICER1 syndrome., Material and Methods: A 17-year-old female presented with a 3-month history of progressive right neck swelling. Fine needle cytology of the thyroid revealed a follicular neoplasm with features suggestive of follicular variant of papillary thyroid carcinoma and she underwent a hemithyroidectomy. Enlarging nodules in the remaining thyroid led to a completion thyroidectomy at 19 years of age. The patient's past medical history included an ovarian mixed malignant germ cell tumour, pulmonary nodules and cysts, renal cysts, mucocutaneous lesions, an arachnoid cyst, and a fibrous breast lesion. Macrocephaly was noted on physical examination., Results: Based on the patient's complex phenotype and young age, a hereditary predisposition syndrome was suspected and genetic testing of PTEN and DICER1 was undertaken. A heterozygous truncating germ-line PTEN mutation was identified, which combined with clinical findings, met criteria for the diagnosis of Cowden syndrome. Additional loss of heterozygosity of the wild-type PTEN allele was detected in the right thyroid lesion and ovarian tumour. No DICER1 mutations were identified., Conclusions: Genetic testing was crucial in elucidating this patient's predisposition to the early development of neoplastic and non-neoplastic conditions. Our report also highlights the phenotypic overlap between the Cowden and DICER1 syndromes and illustrates the importance of recognising the variable phenotypic features of hereditary syndromes in order to enable timely implementation of appropriate care.

Pathological assessment of tissue is the gold standard for diagnosis and staging of neoplasia and provides key prognostic information for clinical management. Proper macroscopic assessment and cut-up technique is essential to ensure that the overall assessment is correct and reproducible. Endoscopic mucosal resection is a technique used for removing early neoplastic glandular lesions of the esophagus at the level of submucosa. Here, we describe the macroscopic assessment and dissection techniques used for the routine handling of endoscopic mucosal resection 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.

The assumption that intestinal metaplasia is a prerequisite for intraepithelial neoplasia/dysplasia and adenocarcinoma in the distal esophagus has been challenged by observations of adenocarcinoma without associated intestinal metaplasia. This study describes our experience of intestinal metaplasia in association with early Barrett neoplasia in distal esophagus and gastroesophageal junction. We reviewed the first endoscopic mucosal resection of 139 patients with biopsy-proven neoplasia. In index endoscopic mucosal resection, 110/139 (79%) cases showed intestinal metaplasia. Seven had intestinal metaplasia on prior biopsy specimens and three had intestinal metaplasia in subsequent specimens, totaling 120/139 (86%) patients showing intestinal metaplasia at some point supporting the theory of sampling error for absence of intestinal metaplasia in some cases. Those without intestinal metaplasia (13%) were enriched for higher stage disease (T1a Stolte m2 or above) supporting the assertion of obliteration of intestinal metaplasia by the advancing carcinoma. All cases of intraepithelial neoplasia and T1a Stolte m1 carcinomas had intestinal metaplasia (42/42). The average density of columnar-lined mucosa showing goblet cells was significantly less in shorter segments compared to those ≥3 cm (0.31 vs 0.51, P=0.0304). Cases where segments measured less than 1 cm were seen in a higher proportion of females and also tended to lack intestinal metaplasia. We conclude that early Barrett neoplasia is always associated with intestinal metaplasia; absence of intestinal metaplasia is attributable to sampling error or obliteration of residual intestinal metaplasia by neoplasia and those with segments less than 1 cm show atypical features for Barrett-related disease (absent intestinal metaplasia and female gender), supporting that gastroesophageal junction adenocarcinomas are heterogeneous.

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.

Assessing BRAF mutation status in thyroid fine needle aspiration (FNA) cytology samples by both immunohistochemistry (IHC) and molecular methods has been documented in recent literature. We aim to highlight issues relating to quality and quantity of cellular material and DNA extracted from cell block samples.BRAF mutation status was assessed by both molecular and IHC methods in cell block material from thyroid FNA samples over a range of diagnostic categories, and correlated with available follow-up resection specimens.Of 39 samples there were 14 cases with 'inconclusive' cytology (Bethesda diagnostic categories 3, 4 or 5) and 25 cases with malignant cytology. Follow-up information was available in 38 of 39 cases and resection material for comparison in 18 of 39 case. Detection of BRAF mutation in cell block samples by combined molecular and IHC methods showed 100% specificity and 71.4% sensitivity compared to subsequent histologically confirmed BRAF mutated papillary thyroid carcinoma. IHC detected BRAF mutation in two (8.2%) cases which were negative by molecular methods and confirmed mutation positive by IHC and molecular methods on subsequent histology. Low extracted DNA concentration did not appear to preclude detection of BRAF mutation, although cell blocks with lower tumour cell content were over-represented in cases that were wild-type on FNA material and BRAF mutant on subsequent histology.BRAF mutation detection in cell block material is feasible and highly specific for papillary thyroid carcinoma. Best results are obtained by a combination of molecular and IHC methods.

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.)

Endoscopic resection (ER) is considered the therapy of choice for intraepithelial neoplasia associated with visible lesions and T1a adenocarcinoma. Pathologists are bound to encounter specimens collected via these techniques more frequently in their practice. A standardised protocol for handling, grossing, and assessing ER specimens should be adopted to ensure that all prognostic information and characteristics influencing treatment are included in reports (see Supplementary Video Abstract, http://links.lww.com/PAT/A22). The entire specimen should be appropriately oriented, processed and assessed. An ER specimen will commonly show intraepithelial neoplasia or invasive carcinoma. There are essential features that should be recorded if invasive carcinoma is found as they dictate further management and follow-up. These features are the margin status, depth of invasion, degree of differentiation and presence or absence of lymphovascular invasion. Important features such as duplication of muscularis mucosae should be recognised to avoid misinterpretation of depth of invasion. Key diagnostic and prognostic elements that are essential for optimal clinical decisions have been included in the reporting format proposed by the Structured Pathology Reporting committee of the Royal College of Pathologists of Australasia (RCPA).

Extramedullary hematopoiesis (EMH) usually occurs in patients with severe anemia or myelofibrosis, and involvement of the serous cavities is uncommon. A total of 5 cases of peritoneal EMH are presented in patients presenting with primary gynecologic pathology including endometrial adenosarcoma (n=2), ovarian leiomyosarcoma, and ovarian endometrioid adenocarcinoma (each n=1), all of which were associated with peritoneal metastases; the remaining patient had a hemorrhagic benign ovarian cyst. All cases were associated with organizing peritoneal hemorrhage, and EMH was localized to the reactive granulation tissue. EMH was not identified within the tumor tissue in the 4 neoplastic cases. Erythroid precursors were present in all cases and granulocytic precursors and megakaryocytes were identified in two and three cases, respectively. There was no evidence of EMH in the corresponding peritoneal fluid cytology preparations examined in 4 cases. None of the patients had a significant hematological abnormality at the time of presentation or during a mean follow-up period of 35 mo (range, 2-66 mo). The mechanism of peritoneal EMH in these cases is uncertain but most likely related to tissue hemorrhage and repair as described in other sites such as dura, myocardium, and synovium. Pathologists should be aware that EMH may involve the peritoneum to avoid misinterpretation of the findings, particularly in small biopsy or cytology samples.

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.

Cronkhite-Canada syndrome is a rare protein-losing enteropathy, classically characterized by ectodermal changes and gastrointestinal polyposis. The etiology remains obscure but immune dysregulation may be important. The diagnosis of Cronkhite-Canada syndrome in the upper gastrointestinal tract is challenging, frequently resulting in delayed patient management. In this study, we described the initial clinical presentations, upper gastrointestinal endoscopic appearances, clinical follow-up, and histologic diagnoses in 7 patients who were subsequently diagnosed with Cronkhite-Canada syndrome. Histology slides were reviewed, and IgG4 immunohistochemical analysis was performed. The most common initial endoscopic impressions were antral malignancy and gastric infection, but gastroduodenal polyposis was not described. On histologic review, the main findings in the gastric mucosa were a prominent mucosal edema, a mixed inflammatory infiltrate rich in eosinophils, and architectural changes with gland dilatation and withering. In the duodenal mucosa, total or subtotal duodenal villous atrophy, inflammation, crypt distortion, and increased apoptotic bodies were the most common features. Three patients died of the disease, and 4 patients were asymptomatic at a mean follow-up of 3.5 years. No intestinal malignancy had been diagnosed. In 2 patients foci of dysplasia in colonic polyps were identified. In only 1 patient, a significant increase in IgG4-positive plasma cells was observed in a colonic polyp. In summary, we found that patients with Cronkhite-Canada syndrome have histologic features commonly found in other immune disorders of the gastrointestinal tract that may help in establishing the diagnosis and further supports the hypothesis that Cronkhite-Canada syndrome may represent an immune dysregulation syndrome, different from IgG4-related disease.

Background: The objective of this study was to develop a triage algorithm to optimize diagnostic yield from cytology, carcinoembryonic antigen (CEA), and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) testing on different components of a single pancreatic cyst fluid specimen. The authors also sought to determine whether cell block supernatant was suitable for CEA and KRAS testing., Methods: Fifty-four pancreatic cysts were triaged according to a volume-dependent protocol to generate fluid (neat and supernatant) and cell block specimens for cytology, comparative CEA, and KRAS testing. Follow-up histology, diagnostic cytology, or a combined clinicopathologic interpretation was recorded as the final diagnosis., Results: There were 26 mucinous cystic lesions and 28 nonmucinous cystic lesions with volumes ranging from 0.3 mL to 55 mL. Testing different components of the specimens (cell block, neat, and/or supernatant) enabled all laboratory investigations to be performed on 50 of 54 cyst fluids (92.6%). Interpretive concordance was observed in 17 of 17 cases (100%) and in 35 of 40 cases (87.5%) that had multiple components tested for CEA and KRAS mutations, respectively. An elevated CEA level (>192 ng/mL) was the most sensitive test for the detection of a mucinous cystic lesion (62.5%) versus KRAS mutation (56%) and "positive" cytology (61.5%). KRAS mutations were identified in 2 of 25 mucinous cystic lesions (8%) in which cytology and CEA levels were not contributory., Conclusions: A volume-based protocol using different components of the specimen was able to optimize diagnostic yield in pancreatic cyst fluids. KRAS mutation testing increased diagnostic yield when combined with cytology and CEA analysis. The current results demonstrated that supernatant is comparable to neat fluid and cell block material for CEA and KRAS testing., (Copyright © 2012 American Cancer Society.)