Crohn's Disease Features in Anastomotic Biopsies from Patients With and Without Crohn's Disease: Diagnostic and Prognostic Value.

Endoscopic evidence of disease activity is a critical predictor of clinical relapse in patients with Crohn's disease (CD), and histologic disease activity is evolving as a similarly important end point for patient management. However, classical morphologic features of CD may overlap with postoperative inflammatory changes, confounding the evaluation of anastomotic biopsies. There is a clear unmet need for better characterization of diagnostic and clinically significant histologic features of CD in these surgically altered sites. We evaluated ileocolonic and colocolonic/rectal anastomotic biopsies performed at 3 academic institutions in patients with and without CD. The biopsies were blindly assessed for CD histologic features and correlated to clinical and endoscopic characteristics. In CD patients, the presence of each feature was correlated with the subsequent clinical exacerbation or relapse. We obtained anastomotic biopsies from 208 patients, of which 109 were operated on for CD and 99 for another indication (neoplasia [80%], diverticular disease (11%), and other [9%]). Mean time since surgery was 10 years (0-59; 14 years for CD [1-59], 6 years for non-CD [0-33]). Endoscopic inflammation was noted in 52% of cases (68% for CD and 35% for non-CD). Microscopic inflammation was present in 74% of cases (82% for CD and 67% for non-CD). Only discontinuous lymphoplasmacytosis (P < .001) and pyloric gland metaplasia (P = .04) occurred significantly more often in CD patients. However, none of the histologic features predicted clinical disease progression. In subset analysis, the presence of histologic features of CD in nonanastomotic biopsies obtained concurrently in CD patients was significantly associated with relapse (P = .03). Due to extensive morphologic overlap between CD and postoperative changes and the lack of specific histologic features of relapse, biopsies from anastomotic sites are of no value in predicting clinical CD progression. Instead, CD activity in biopsies obtained away from anastomotic sites should be used for guiding endoscopic sampling and clinical management.

Pancreatic Cancer Progression in a Patient With Lynch Syndrome Receiving Immunotherapy: A Cautionary Tale.

Pancreatic ductal adenocarcinomas (PDACs) with DNA mismatch repair deficiency (MMRd) respond preferentially to immune checkpoint inhibitors (ICIs). However, a subset of MMRd PDACs does not respond to these agents. This report describes a patient with PDAC who experienced rapid disease progression suggestive of hyperprogressive disease. The case involved a 63-year-old man carrying a pathogenic germline PMS2 mutation who developed metastatic PDAC. His tumor showed isolated loss of PMS2 expression by immunohistochemistry (IHC). He was treated with pembrolizumab, but his disease rapidly progressed. Whole-genome and transcriptome sequencing of a liver metastasis biopsy, acquired at disease progression, showed a retained wild-type PMS2 allele and hallmarks of microsatellite stability, including low tumor mutational burden and low MSIsensor score. PCR-based microsatellite instability (MSI) testing of the treatment-naïve tumor showed microsatellite stability. The ICI-treated tumor had a lower density of CD8+ T-cell infiltration than the treatment-naïve tumor, which is contrary to the expected evolution with ICI responsiveness. Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.

A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.

BACKGROUND: Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. METHODS: Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype-phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. RESULTS: This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. CONCLUSIONS: Our genotype-phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention.

Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia.

A patient received a diagnosis of adenocarcinoma of the ampulla of Vater at 34 years of age. Two decades later, adenomatous polyps were found, followed by multiple primary invasive adenocarcinomas of both the colon and the stomach. Premature chromatid separation and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities, were detected in his cells. We identified a germline homozygous intronic mutation, c.2386-11A→G, in the spindle-assembly checkpoint gene BUB1B, which creates a de novo splice site that is favored over the authentic (i.e., preferentially used) site. Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers and provide evidence for the interdependency of the APC protein (encoded by the adenomatous polyposis coli gene) and the BUBR1 protein (encoded by BUB1B) in humans. (Funded by the Turner Family Cancer Research Fund and others.).

The impact of incidental gastrointestinal stromal tumours on patients undergoing resection of upper gastrointestinal neoplasms.

BACKGROUND: Emerging data suggest asymptomatic gastrointestinal stromal tumours (GISTs) of the upper gastrointestinal (UGI) tract are not uncommon. We sought to determine their incidence in patients undergoing resection for UGI neoplasms and their impact on surgical and adjuvant treatment. METHODS: We accessed a database prospectively listing all patients undergoing resection of non-GIST neoplasms of the stomach and esophagus at a single university centre over a 4.5-year period and reviewed pathology reports for the presence of synchronous GISTs in the UGI tract. We compared patient demographic and tumour characteristics, operative procedures and postoperative outcomes. RESULTS: In all, 207 patients undergoing gastrectomy or esophagectomy for non- GIST neoplasms were included. We identified 15 synchronous GISTs in the UGI tract of 11 (5.3%) patients (1 preoperatively, 4 intraoperatively and 10 on final pathology), with an average age of 67 years. Most patients were men. Additional resections were required for GISTs identified pre- or intraoperatively. Final pathology revealed completely resected c-kit positive tumours of an average size of 0.5 (range 0.1-4.0) cm with low or very low risk of malignant potential. No patients received adjuvant therapy for the GISTs. After a median follow-up of 11 (range 2-36) months, 5 patients died from their primary cancer, 3 were alive with primary cancer recurrence, and 3 were alive without disease. No patients experienced GIST recurrence. CONCLUSION: Incidentally finding a synchronous GIST during resection of UGI neoplasms is not uncommon; it may alter surgical treatment but is unlikely to impact longterm survival.

Pathology of Gastrointestinal and Liver Complications of Hematopoietic Stem Cell Transplantation.

CONTEXT.­: Despite advances in therapeutic and preventive measures, hematopoietic stem cell transplant recipients remain at risk for a variety of gastrointestinal and liver complications. OBJECTIVE.­: To detail the pathologic features of the various gastrointestinal and liver complications occurring after hematopoietic stem cell transplantation in relation to their clinical context. The specific complications covered include graft-versus-host disease, mycophenolate mofetil-induced injury, timeline of infections, neutropenic enterocolitis, gastrointestinal thrombotic microangiopathy, sinusoidal obstruction syndrome, hepatic iron overload, and the controversy around cord colitis syndrome. DATA SOURCES.­: The content of this article is based on pertinent peer-reviewed articles in PubMed, relevant textbooks, and on the authors' personal experiences. CONCLUSIONS.­: The final histopathologic diagnosis requires the integration of clinical and histologic findings and the exclusion of other competing causes of injury. Review of the clinical data, including the original disease pretransplant, the type of transplant, the timing of the gastrointestinal and/or liver manifestations, the timing of the biopsy after transplant, the presence of graft-versus-host disease in other organs and sites, the list of drug regimens, and the clinical and laboratory evidence of infection, is the key to reaching the proper histologic diagnosis.

Postchemotherapy characteristics of hepatic colorectal metastases: remnants of uncertain malignant potential.

Accepted management for colorectal cancer (CRC) involves resection of the primary neoplasm and chemotherapy; the debate continues over the most beneficial order of these components. Preoperative chemotherapy aimed at liver metastases may result in complete pathologic response and replacement of the malignancy with scar. The McGill University liver diseases database was retrospectively reviewed. Forty-one patients receiving treatment between December 2003 and August 2004 were identified, their medical records examined, and liver histology reviewed. The histology of the remnants was linked to the appearance of the lesions on preresection imaging and to the primary colorectal neoplasms. Twenty-seven of the 41 patients (66%) received preoperative chemotherapy (oxaliplatin or irinotecan). Features of the primary neoplasm that predicted resolution of the metastases were absence of tumor budding (P = 0.04), absence of a diffusely infiltrative tumor margin (P = 0.02), and loss of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase (P = 0.08). Oxaliplatin and irinotecan demonstrate beneficial effects in treating hepatic colorectal metastases and should be considered in such patients before resection. We propose the acronym RUMP to denote the remnants of uncertain malignant potential remaining. Further investigation is required to determine any correlation between the drug received and the resulting lesion.

Classic Kaposi's sarcoma presenting first with gastrointestinal tract involvement in a HIV-negative Inuit male--a case report and review of the literature.

Kaposi's sarcoma (KS) is a multicentric low-grade vascular malignancy. In North America, it is usually seen in AIDS and solid organ transplant populations. Classic KS is a subtype that traditionally occurs in elderly HIV-negative males of Mediterranean, Eastern European, and Jewish descent. Patients with classic KS characteristically present with skin lesions in the distal extremities. Involvement of the viscera is uncommon in classic KS, but may occur in the late stages of the disease. We report the first case of classic KS presenting in the gastrointestinal tract of an elderly HIV-negative Inuit male from Northern Quebec, Canada.

Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer.

The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors.

Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome.

Although the natural history of autoimmune hepatitis (AIH) has been characterized, little is known about patients who present asymptomatically. Consequently, whether they require immunosuppressive therapy with its associated complications is unclear. To compare the natural history of asymptomatic AIH with symptomatic AIH, a large cohort of patients from a single center was examined. All patients with a clinical diagnosis of AIH were reassessed using the revised criteria of the International Autoimmune Hepatitis Group. Liver histology, response to therapy, and survival were assessed. Patients asymptomatic at presentation (n = 31) had lower serum aminotransferase, bilirubin, and immunoglobulin G (IgG) values at baseline. Half of the asymptomatic patients received no therapy, and their survival was no different from that of the total cohort. Ten-year survival was 80.0% (62.5%-97.5%) in the asymptomatic group and 83.8% (75.1%-92.6%) in the symptomatic patients (P = NS). Survival to liver-related endpoints at 10 years was similar in both groups: 89.5% (75.7%-100%) asymptomatic and 83.8% (75.1%-92.6%) symptomatic patients (P = NS). Patients with cirrhosis at baseline had poorer 10-year survival (61.9% [CI 44.9%-78.9%]) than those without cirrhosis at presentation (94.0% [CI 87.4%-100%]) (P = .003) regardless of whether they presented with symptoms or whether they received immunosuppressive therapy. In conclusion, patients with AIH who are asymptomatic at presentation have a good prognosis and may not require immunosuppressive therapy. Cirrhosis on initial liver biopsy portends a poor prognosis in all patients with AIH.

The atypical colitides.

Collagenous and lymphocytic colitis are atypical colitides that should be considered in elderly patients with unexplained diarrhea. The lack of natural history data and apparent underreporting of these disorders have made the determination of true incidence difficult. Better insight into the pathogenesis and heightened awareness of these conditions will lead to earlier diagnosis and more effective treatment.

Collagenous colitis with spondyloarthropathy presenting as fibromyalgia syndrome.

Collagenous colitis is a newly recognized clinicopathologic entity that presents with diarrhea and weight loss. In some patients arthropathy may be a concomitant feature. We describe a patient whose initial presentation masqueraded as fibromyalgia with associated bowel symptoms, but who was finally diagnosed as having collagenous colitis and inflammatory spondyloarthropathy.