Optimal Intraoperative Assessment of Gastric Margins.

OBJECTIVES: Intraoperative pathology consultation (IOC) to assess margins is frequently requested during surgery of the stomach and gastroesophageal junction. METHODS: We studied 110 consecutive patients undergoing gastrectomy with IOC margin assessment. RESULTS: Gastric margins at IOC utilized the most blocks but were least often positive. In 64% of patients, the entire gastric margin was examined using average six blocks; representative sections were examined in 25% of patients using two blocks. There was no difference in patient outcome between those who had entire vs representative sections of margin examined. Gross variables showing strongest associations with positive margins were tumor size and tumor distance to margin. Tumors sized greater than 2.3 cm had significantly increased risk of positive margin, and tumor distance greater than 4.5 cm to margin was associated with negative margins. CONCLUSIONS: We conclude representative sections of the closest gastric margin are sufficient to ensure R0 resection in the majority of cases.

Unique causes of esophageal inflammation: a histopathologic perspective.

Gastroenterologists frequently perform endoscopic esophageal mucosal biopsies for pathologic diagnosis in patients experiencing symptoms of esophagitis. The more common causes of esophagitis diagnosed on esophageal mucosal biopsy include reflux esophagitis, eosinophilic esophagitis, and infectious esophagitis caused by Candida albicans, herpes simplex virus, and/or cytomegalovirus. However, there are several causes of esophagitis seen less frequently by pathologists that are very important to recognize. We discuss unique types of esophageal inflammation, including acute bacterial esophagitis, esophageal manifestations of dermatologic diseases, medication-induced esophageal injury, and sloughing esophagitis; and we review their clinical and histopathologic features.

ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells.

Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle. Moreover, in histone 2B-GFP mice, the 2B-GFP label was retained in Tsp cells, indicative of a slow-cycling phenotype. Human Tsp cells displayed a distinct gene-expression profile that was enriched for genes overexpressed in Trm cells. In mice, proteins encoded by Tsp signature genes, including nuclear receptor subfamily 4 group A member 1 (NR4A1) and ATP-binding cassette (ABC) transporters, influenced the function and differentiation of Trm cells. Responses to adoptive transfer of human Tsp cells into immune-deficient mice and plerixafor therapy suggested that human Tsp cell mobilization could be manipulated as a potential cellular therapy. These data identify a distinct subset of human T cells with a quiescent/slow-cycling phenotype, propensity for tissue enrichment, and potential to mobilize into circulation, which may be harnessed for adoptive cellular therapy.

Pathology of premalignant colorectal neoplasia.

Colorectal cancer is a heterogeneous oncological disease that develops through several molecular pathways. Each pathway is associated with specific neoplastic precursor lesions. Classification of colorectal polyps and the molecular features of associated colorectal cancers have undergone significant changes. An understanding of colorectal carcinogenesis and the molecular features of colorectal carcinomas is now regarded as necessary for personalized treatment and management of patients with colon cancer, and even for patients undergoing screening colonoscopy for early detection and prevention of colorectal cancer. In the present review, we describe the pathological and molecular features of epithelial precursor lesions involved in the early phases of colorectal carcinogenesis.

Clinical, pathologic, and outcome study of hyperplastic and sessile serrated polyps in inflammatory bowel disease.

There is evidence that some cancers in patients with inflammatory bowel disease (IBD) develop via the serrated pathway of carcinogenesis. This study examined the clinicopathological features and outcome of 115 IBD patients (65 with ulcerative colitis, 50 with Crohn disease), all with at least 1 serrated polyp at endoscopy or colon resection, including the presence of synchronous and metachronous conventional neoplastic lesions (dysplasia or adenocarcinoma), over an average follow-up period of 56.4 months. Conventional neoplasia was categorized as flat dysplasia (low or high grade), sporadic adenoma, adenoma-like dysplasia-associated lesion or mass, or adenocarcinoma. Overall, 97% of patients had at least 1 hyperplastic polyp (HP), 6% had a sessile serrated adenoma/polyp, and none had a traditional serrated adenoma. Eight patients (7%) had a synchronous conventional neoplastic lesion; only 1 had flat dysplasia (1%) and 2 had adenocarcinoma (2%). Thirteen patients developed a metachronous conventional neoplastic lesion, with 8 developing their conventional neoplasm within an area of previous or concurrent colitis; only 1 patient developed flat dysplasia (1%), and none developed adenocarcinoma. A higher proportion of patients with both an HP and a synchronous conventional neoplastic lesion at index developed a metachronous conventional neoplastic lesion, compared with those with an index HP only (25% versus 7%). These results suggest that IBD patients (both ulcerative colitis and Crohn disease patients) with HP have a very low risk of developing a conventional neoplastic lesion (flat dysplasia or adenocarcinoma) that would warrant surgical resection.

Pseudomelanosis of stomach, duodenum, and jejunum.

Pseudomelanosis is a rare finding during upper gastrointestinal endoscopy, and is most commonly seen in the duodenum. Involvement of other organs in the upper gastrointestinal tract is extremely rare, with only 1 reported case involving the stomach, duodenum, and jejunum. We present a case of a 60-year-old woman with mild anemia and hematemesis, who was found to have characteristic speckled pattern of gray-black pigmentation on endoscopic examination. To the best of our knowledge, this is the second reported case of pseudomelanosis involving the stomach, duodenum, and jejunum.

A humanized mouse model of autoimmune insulitis.

Many mechanisms of and treatments for type 1 diabetes studied in the NOD mouse model have not been replicated in human disease models. Thus, the field of diabetes research remains hindered by the lack of an in vivo system in which to study the development and onset of autoimmune diabetes. To this end, we characterized a system using human CD4(+) T cells pulsed with autoantigen-derived peptides. Six weeks after injection of as few as 0.5 × 10(6) antigen-pulsed cells into the NOD-Scid Il2rg(-/-) mouse expressing the human HLA-DR4 transgene, infiltration of mouse islets by human T cells was seen. Although islet infiltration occurred with both healthy and diabetic donor antigen-pulsed CD4(+) T cells, diabetic donor injections yielded significantly greater levels of insulitis. Additionally, significantly reduced insulin staining was observed in mice injected with CD4(+) T-cell lines from diabetic donors. Increased levels of demethylated ß-cell-derived DNA in the bloodstream accompanied this loss of insulin staining. Together, these data show that injection of small numbers of autoantigen-reactive CD4(+) T cells can cause a targeted, destructive infiltration of pancreatic ß-cells. This model may be valuable for understanding mechanisms of induction of human diabetes.

Pathology of diseases that cause upper gastrointestinal tract bleeding.

Acute and chronic bleeding from the upper gastrointestinal tract is a common indication for endoscopy and hospitalization and is associated with significant morbidity and mortality. The causes of upper gastrointestinal bleeding are numerous and can result in both acute and chronic hemorrhage. The aim of this article is to examine the pathologic features of various diseases associated with upper gastrointestinal tract bleeding.

MUC expression in hyperplastic and serrated colonic polyps: lack of specificity of MUC6.

Previous studies have shown that hyperplastic and serrated polyps of the colon show variable degrees of gastric and intestinal differentiation. MUCs are a class of approximately 20 genes that encode high-molecular-weight glycoproteins, or mucopolysaccharides, that are widely expressed in epithelial cells and show organ specificity. The role of MUC in serrated carcinogenesis is unknown. One previously published study suggested that expression of MUC6 is specific for sessile serrated adenoma/polyps (SSA/Ps) and thus can be used to distinguish these lesions from hyperplastic polyps (HPs). However, data from our group suggest that MUC antibodies are not reliable in this differential diagnosis. The aims of this study were to systematically evaluate the expression of MUCs in serrated colon polyps and to determine the efficacy of MUC expression in differentiating HPs from SSA/Ps specifically. Routinely processed specimens from 182 serrated polyps [58 HPs, 46 SSA/Ps, 59 SSA/Ps with dysplasia (SSA/P-D), 19 traditional serrated adenomas, and 38 conventional tubular or tubulovillous adenomas (CAs)] were immunohistochemically stained with MUC1, MUC2, MUC5AC, and MUC6, and scored for extent, intensity, and location of staining within the polyps. HPs were further subclassified into goblet cell type (N=18), microvesicular type (N=21), and mucin-depleted type (N=19). The data were compared between the different polyp groups and between polyps from different anatomic locations in the colon. MUC1, MUC2, MUC5AC, and MUC6 were expressed in 27%, 100%, 100%, and 72% of serrated polyps overall. These antibodies were positive in 32%, 100%, 100%, and 43% of CAs. Expression levels of MUC1, MUC2, and MUC5AC were not significantly different between any of the polyp subgroups or between serrated polyps and CAs. Both SSA/P and SSA/P-D showed a significantly higher percentage of polyps that stained with MUC6, and a greater degree and intensity of staining for this peptide in comparison with HPs. Overall, 91% of SSA/Ps and 84% of SSA/P-Ds were positive for MUC6 in comparison with 60% of HPs (P<0.001 and P=0.02, respectively). Although polyps from both the left and right colon from each polyp group showed positivity for MUC6, a significantly higher proportion of SSA/P-Ds and traditional serrated adenomas from the right colon showed MUC6 positivity compared with those from the left. No differences were noted in MUC6 staining between each of the 3 HP subgroups. On the basis of these data, we conclude that SSA/P and SSA/P-D show increased expression of MUC6 compared with HPs; however, because of overlap in the presence, degree, and intensity of staining, use of MUC6 to differentiate HPs from SSA/P or SSA/P-D in individual cases is not reliable because of a lack of specificity. Differences in MUC6 expression between right-sided and left-sided colonic polyps supports the theory that there may be biological differences in the progression of malignancy in different portions of the colon with regard to the serrated pathway of carcinogenesis.

Mucosal Schwann cell "hamartoma": clinicopathologic study of 26 neural colorectal polyps distinct from neurofibromas and mucosal neuromas.

Colorectal polyps containing S-100-positive neural proliferations in the lamina propria that lack ganglion cells have been variously referred to as "neuromas" or "neurofibromas." However, these lesions have not been systematically examined, and whether they are associated with type 1 neurofibromatosis (NF1) or other inherited syndromes is unknown. The aim of this study was to evaluate the clinicopathologic and immunohistochemical features of these lesions, in comparison to colorectal neurofibromas from known NF1 patients. Morphologically similar lesions from 26 patients (mean age, 62 y; range, 46 to 88 y; male/female ratio, 10/16) were retrieved from surgical pathology and consult files. Clinical and endoscopic data were obtained, and immunohistochemistry for S-100 protein, glial fibrillary acidic protein, neurofilament protein (NFP), epithelial membrane antigen, claudin-1, CD34, smooth muscle actin, and KIT was performed. The findings were compared with those in mucosal biopsies of 5 submucosal neurofibromas from NF1 patients. All 26 polyps were sessile, ranging from 1 to 6 mm in size (mean, 2.5 mm). Most arose in the distal colon (15 rectosigmoid, 7 descending, 2 transverse, and 2 ascending), and were incidentally found at screening colonoscopy. After a mean follow-up of 6.5 years (range, 3 mo to 17.5 y), none of the patients developed other neural polyps, and none had evidence of NF1 or other inherited syndromes. Histologically, the lamina propria of the polyps contained a diffuse cellular proliferation of uniform bland spindle cells with elongated, tapering nuclei, abundant, dense eosinophilic cytoplasm, and indistinct cell borders, entrapping adjacent crypts. No nuclear atypia, pleomorphism, mitotic activity, or associated ganglion cells were observed. All showed strong staining for S-100 protein in essentially 100% of cells. NFP highlighted rare axons in 7 lesions. All other markers were negative. The 5 neurofibromas showed similar histologic features, but were generally less uniformly cellular, showed some intralesional heterogeneity, and showed less extensive staining for S-100 protein; all contained scattered NFP-positive axons. In summary, solitary colorectal polyps containing pure Schwann cell proliferations in the lamina propria are not associated with NF1. Distinguishing these lesions from NF1-associated neurofibromas is difficult based on histologic features; the presence of an underlying submucosal nodule or mass should be excluded endoscopically, and immunohistochemistry should be performed. Although their nature is uncertain, we propose the interim designation "mucosal Schwann cell 'hamartoma'" to avoid confusion with the neural lesions that have significant associations with inherited syndromes.

Podoplanin (D2-40) is a novel marker for follicular dendritic cell tumors.

Podoplanin, recognized by monoclonal antibody D2-40, may be a useful marker for follicular dendritic cell (FDC) tumors. Paraffin sections of 125 dendritic cell, histiocytic, and spindle cell lesions were studied, including 11 FDC tumors, 5 interdigitating dendritic cell tumors, 10 histiocytic sarcomas, 5 Langerhans cell histiocytosis, 5 sinus histiocytosis with massive lymphadenopathy, 5 inflammatory pseudotumors of lymph node or spleen, 9 nodal Kaposi sarcomas, 6 inflammatory myofibroblastic tumors (IMTs), 29 gastrointestinal stromal tumors (GISTs), and 10 cases each of malignant peripheral nerve sheath tumor, leiomyosarcoma, monophasic synovial sarcoma (SS), and solitary fibrous tumor. All FDC tumors and Kaposi sarcomas showed strong immunoreactivity for podoplanin (predominantly membranous). Podoplanin expression was only occasionally observed in the other tumor types, including 7 GISTs (24%), 2 IMTs (33%), and 3 SS (30%), and was generally weak and cytoplasmic. Reactivity for podoplanin was more common in spindle cell GISTs (5/13 [38%]) than in epithelioid or mixed-type GISTs (2/16 [13%]). Podoplanin is a highly sensitive marker for FDC tumors and may be useful to help confirm the diagnosis in conjunction with conventional FDC markers, particularly in the differential diagnosis of dendritic cell and histiocytic lesions.