To identify useful markers for prognostic and therapeutic purposes, The Cancer Genome Atlas (TCGA) provided a molecular classification of gastric cancers (GCs). Previous studies have used immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) to define immunophenotypic surrogate markers of the molecular alterations. Some critical issues concerning the correct definition of immunophenotypic groups have emerged in these studies that employed tissue microarrays (TMAs). We performed an immunophenotypic classification by evaluating MLH1, p53, HER2, E-cadherin, and Epstein-Barr virus (EBV) on the whole section of the surgical GC samples compared to most of the studies conducted on TMAs. We also investigated the immunohistochemical expression of PD-L1, a known therapeutic target. We identified the following immunophenotypic groups: EBV (2.9%); mismatch repair deficient (MMR-D) (7.2%); overexpressed p53 and/or HER2+ (61.4%); aberrant E-cadherin (11.4%); and normal pattern (17.1%). The use of surgical samples emphasized that some immunohistochemical markers were not useful for properly classifying the GC specimens. We can state that EBV (significantly correlated to PD-L1 expression) and MMR-D GCs are well-defined groups, mutually exclusive, and easily assessable with IHC and CISH, and could be candidates for immunotherapy with PD-1/PD-L1 inhibitors. As regards p53, our findings suggest that IHC assessment may be responsible for a misclassification of GC groups. Immunohistochemical evaluation of E-cadherin needs to be standardized, particularly in terms of the heterogeneous cytoplasmic/membranous staining pattern. Whether to consider the normal-pattern group as a separate category remains to be clarified. Because GC specimens with known therapeutic targets account for only 40%, we suggest reviewing the immunophenotypic classification to find new therapeutic targets, such as PD-L1, MLH1, and HER2.

<b><i>Background:</i></b> The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy. <b><i>Summary:</i></b> In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays. <b><i>Key Messages:</i></b> The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.

A 61-year old man with coeliac disease and chronic lack of appetite, malabsorption and weight loss, despite the gluten-free diet, was operated because of a sub-diaphragmatic free air due to a small-bowel pneumatosis cystoides intestinalis (PCI). The jejunum showed granulomatous lesions with a honeycombed appearance of air cysts in the submucosa/subserosa. We found overexpression of peptide YY (PYY) into only the jejunum with PCI, while the expression was very weak or absent in the tissue without cysts. One year after surgery, he had no abdominal pain or PCI recurrence. The above chronic symptoms were plausibly attributable to the PYY.

ObjectivesDifferential diagnosis between pancreatic ductal adenocarcinoma (PDAC) and benign mimickers can be very difficult on small histological samples, such as fine needle aspiration biopsies (FNAB). We aimed to investigate the diagnostic value of immunostaining for IMP3, Maspin, S100A4, S100P, TFF2, and TFF3 in FNAB pancreatic lesions.MethodsWe prospectively enrolled 20 consecutive patients with suspected PDAC, collecting FNABs at our department between 2019 and 2021.ResultsThree of the 20 enrolled patients resulted negative for all immunohistochemical markers, while all the others were positive for Maspin. All other immunohistochemistry (IHC) markers had sensitivity and accuracy of less than 100%. On the basis of the IHC, the preoperative diagnosis on FNAB was nonmalignant lesions in the IHC negative cases and PDAC in the others. All patients subsequently underwent surgery for the pancreatic solid mass demonstrated by imaging techniques. The concordance between the preoperative and postoperative diagnosis was 100%; all IHC negative samples were diagnosed on surgical specimens as chronic pancreatitis and Maspin-positive samples as PDAC.ConclusionsOur results demonstrate that even in the presence of little histological material, such as FNAB, the use of Maspin alone is sufficient to discriminate between PDAC and nonmalignant pancreatic lesions, with 100% accuracy.

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