Maryam Kherad Pezhouh

Antigenic compartmentation of the cerebellar cortex in the chicken (Gallus domesticus)

The chick is a well‐understood developmental model of cerebellar pattern formation,but we know much less about the patterning of the adult chicken cerebellum. Therefore an expression study of two Purkinje cell stripe antigens—zebrin II/aldolase C and phospholipase Cβ4 (PLCβ4)—has been carried out in the adult chicken (Gallus domesticus). The mammalian cerebellar cortex is built around transverse expression domains (“transverse zones”), each of which is further subdivided into parasagittally oriented stripes. The results from the adult chicken reveal a similar pattern. Five distinct transverse domains were identified. In the anterior lobe a uniformly zebrin II‐immunopositive/PLCβ4‐immunonegative lingular zone (LZ; lobule I) and a striped anterior zone (AZ; lobules II–VIa) were distinguished. A central zone (CZ; ∼lobules VIa–VIIIa,b) and a posterior zone (PZ; ∼lobules VIIIa,b–IXc,d) were distinguished in the posterior lobe. Finally, the nodular zone (NZ; lobule X) is uniformly zebrin II‐immunoreactive and is innervated by vestibular mossy fibers. Lobule IXc,d is considered as a transitional region between the PZ and the NZ, because the vestibular mossy fiber projection extends into these lobules and because they receive optokinetic mossy and climbing fiber input. It is proposed that the zebrin II‐immunonegative P3‐ stripe corresponds to the lateral vermal B zone of the mammalian cerebellum and that the border between the avian homologs of the mammalian vermis and hemispheres is located immediately lateral to P3−. Thus, there seem to be transverse zones in chicken that are plausible homologs of those identified in mammals, together with an LZ that is characteristic of birds. J. Comp. Neurol. 518:2221–2239, 2010.

Alzheimer disease pathology in subjects without dementia in 2 studies of aging: the Nun Study and the Adult Changes in Thought Study.

Individuals with antemortem preservation of cognition who show autopsy evidence of at least moderate Alzheimer disease (AD) pathology suggest the possibility of brain reserve, that is, functional resistance to structural brain damage. This reserve would, however, only be relevant if the pathologic markers correlate well with dementia. Using data from the Nun Study (n = 498) and the Adult Changes in Thought (ACT) Study (n = 323), we show that Braak staging correlates strongly with dementia status. Moreover, participants with severe(Braak stage V-VI) AD pathology who remained not demented represent only 12% (Nun Study) and 8% (ACT study) of nondemented subjects. Comparison of these subjects to those who were demented revealed that the former group was often significantly memory-impaired despite not being classified as demented. Most of these nondemented participants showed only stage V neurofibrillary pathology and frontal tangle counts that were slightly lower than a comparable (Braak stage V) dementia group. In summary, these data indicate that, in individuals with AD-type pathology who do not meet criteria for dementia, neocortical neurofibrillary tangles are somewhat reduced and incipient cognitive decline is present. Our data provide a foundation for helping to define additional factors that may impair, or be protective of, cognition in older adults.

Histopathologic features of colitis due to immunotherapy With Anti-PD-1 antibodies

Programmed cell death protein 1 (PD-1) blocking agents are novel immunotherapeutics used for treatment of advanced-stage malignancies. They have shown promise in the treatment of several malignancies, with greater efficacy and better tolerability than cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking agents. However, as with anti-CTLA-4 agents, clinically significant colitis remains an important complication. Although there is growing awareness of the histopathologic features of anti-CTLA-4 therapy, there is little information on the pathologic features of anti-PD-1 colitis. We describe here the histopathologic findings in 8 patients who developed colitis while on anti-PD-1 monotherapy. The most common pattern of injury observed (5/8 cases) was an active colitis with neutrophilic crypt microabscesses and with prominent crypt epithelial cell apoptosis and crypt atrophy/dropout. These latter features are reminiscent of other colitides with prominent apoptosis such as acute graft-versus-host disease or certain drug-induced colitides. The remainder of cases (3/8) showed a lymphocytic colitis-like pattern, characterized by increased intraepithelial lymphocytes and surface epithelial injury. Apoptosis was also often increased in these cases but crypt atrophy/dropout was not present. In patients who experienced recurrence of anti-PD-1 colitis, histologic features were similar to the initial insult but, in addition, features of chronicity developed that mimicked inflammatory bowel disease (basal lymphoplasmacytosis and crypt architectural irregularity, and Paneth cell metaplasia in 1 case). Awareness of the clinical scenario, however, should allow pathologists to suggest anti-PD-1 colitis. Interestingly, recurrent colitis was observed in patients who had been off anti-PD-1 therapy for many months. As anti-PD-1 agents are increasingly used in oncology, we present this series to increase awareness of anti-PD-1 colitis among pathologists, to facilitate its timely diagnosis and treatment.

Definition of barrett esophagus in the United States: Support for retention of a requirement for goblet cells

Barrett esophagus (BE) predisposes patients to the development of esophageal adenocarcinoma (EAC). However, the global definition of BE is controversial. Pathologists in Europe and the United States require intestinal metaplasia (IM) within columnar-lined mucosa (CLM) in the tubular esophagus to diagnose BE, whereas in the UK and Japan only the presence of CLM is required. To aid in establishing an appropriate definition for BE, we evaluated whether IM accompanies EAC in a US patient cohort. We examined a series of 139 consecutive patients who underwent endoscopic mucosal resections or esophagectomies for EAC performed at a US tertiary care center. The resection specimens were evaluated for the presence (IM+) or absence (IM−) of IM within CLM. Ninety-seven (70%) patients were IM+. Tumors found in IM− patients tended to be advanced at the time of resection (57% pT3 or greater, IM−; 31% pT3 or greater, IM+; P=0.02) such that the tumor may have “overgrown” zones of IM. We hypothesized that changes as a result of neoadjuvant chemotherapy or radiation might mask preexisting IM. When evaluating this hypothesis, we found that 34 of 39 of treatment-naive patients were IM+. Two of the 5 IM− patients had prior IM+ biopsies resulting in 92% of treatment-naive patients who were IM+. In our US hospital population, CLM with IM in the tubular esophagus is found in association with EAC in 70% to 92% of patients. We believe that based on these data the United States definition of BE should continue to require the presence of IM.

Gastric Pyloric Gland Adenoma

Pyloric gland adenomas are rare neoplasms of the gastrointestinal tract. Gastric pyloric gland adenomas have been shown to arise in chronically damaged mucosa. The neoplastic glands have gastric pyloric gland differentiation and have a tightly packed organization with occasional cystic dilatation. The individual cells are cuboidal to columnar, with eosinophilic to amphophilic cytoplasm and either no apical mucin cap or a poorly formed apical mucin cap. The nuclei are round to oval, with occasional prominent nucleoli. Immunohistochemically, the neoplastic cells label with markers of gastric pyloric gland differentiation, including MUC6 and MUC5AC. There is limited information regarding the natural history of pyloric gland adenomas, but clinical series have described adenocarcinomas in association with gastric pyloric gland adenomas. The ideal clinical management is adequate sampling of the lesion to investigate for high-grade dysplasia and/or invasive cancer and recommendation to clinical colleagues to investigate the background mucosa for the etiology of chronic gastritis as well as potential additional neoplastic lesions. This review will focus on gastric pyloric gland adenomas.

Clinicopathologic Study of Calcifying Fibrous Tumor of the Gastrointestinal Tract: A Case Series.

Calcifying fibrous tumor (CFT) is a rare benign mesenchymal lesion known to arise at multiple body sites that may clinically mimic other more aggressive lesions in the gastrointestinal (GI) tract. In this study we describe the clinicopathologic findings of 28 GI tract CFTs. Tumors predominantly arose in middle-aged adults with a slight female predominance. The most commonly involved sites were small bowel and colon, followed by stomach and appendix. Tumors ranged from 0.3 to 9.3 cm (median 1.4 cm), and submucosa was the most commonly involved layer. All tumors were well circumscribed and unencapsulated. Microscopically, tumors were hypocellular and composed of spindle cells with abundant, haphazardly arranged hyalinized collagen. No necrosis and less than one mitosis per 10 HPF were identified in all cases. Calcification was present in most (81%) of the cases. All cases had lymphoplasmacytic inflammatory infiltrates either scattered throughout the lesion with occasional perivascular conglomeration or in the form of lymphoid aggregates. A lymphoplasmacytic cuff was usually present (81%). Immunostains showed variable CD34 immunoreactivity and variable numbers of IgG4-positive plasma cells. The lesional cells were negative for DOG-1, ALK-1, S100, C-kit, Sox10, Melan A, HMB45, desmin, CK7, and CK20, and showed cytoplasmic staining for β-catenin. Follow-up information was available in 5 cases with no recurrences reported to date (mean follow-up, 3 years). CFT is a rare benign tumor that can occur in part of the GI tract and should be distinguished from other mesenchymal tumors due to its low risk of recurrence.

Significance of Paneth Cells in Histologically Unremarkable Rectal Mucosa.

Paneth cell metaplasia of the rectal epithelium is a common histologic finding in patients with chronic inflammatory bowel disease. However, the clinical significance of isolated Paneth cells in otherwise unremarkable rectal mucosa has not been extensively examined. This study examined the frequency and clinical correlates of rectal Paneth cells in 245 biopsies obtained from patients between the ages of 2 weeks to 20 years in a pediatric tertiary care facility from 2010 to 2011. The specimens comprised 193 endoscopic pinch biopsies and 52 rectal suction biopsies. All 245 cases were endoscopically and histologically unremarkable with no prominence of eosinophils, no altered mucosal architecture, and no inflammation. Paneth cells were present in 42 cases (17.1%), which is higher than previous reports. Only 1 of 42 patients with rectal Paneth cells was subsequently diagnosed with Crohn disease. In our study population, the finding of Paneth cells was associated with young age, and the incidence of Paneth cell cases decreased with increasing age (&khgr;2=13.69, P=0.0002). Constipation was the most common presenting symptom in patients with rectal Paneth cells and was highly associated with the presence of Paneth cells (odds ratio 4.5, 95% confidence interval: 2.2-9.0). Paneth cells in otherwise unremarkable pediatric rectal biopsies are not rare and frequently occur in common conditions such as idiopathic constipation.

Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis

Use of the immune checkpoint inhibitor ipilimumab is sometimes complicated by ipilimumab‐associated colitis (Ipi‐AC), an immune‐mediated colitis that mimics inflammatory bowel disease.

Low Incidence of Dysplasia and Colorectal Cancer Observed among Inflammatory Bowel Disease Patients with Prolonged Colonic Diversion

Abstract Background In inflammatory bowel disease (IBD), many scenarios call for fecal diversion, leaving behind defunctionalized bowel. The theoretical risk of colorectal cancer (CRC) in this segment is frequently cited as a reason for resection. To date, no studies have characterized the incidence of neoplasia in the diverted colorectal segments of IBD patients. Methods A retrospective cohort analysis was conducted for IBD patients identified through a tertiary care center pathology database. Patients that had undergone colorectal diversion and were diverted for ≥ 1 year were included. Incidence of diverted dysplasia/CRC was calculated for Crohn’s disease (CD) and ulcerative colitis (UC) with respect to diverted patient-years (dpy) and patient-years of disease (pyd). Results In total, 154 patients comprising 754 dpy and 1984 pyd were analyzed. Only 2 cases of diverted colorectal dysplasia (CD 1, UC 1) and 1 case of diverted CRC (UC) were observed. In the UC cohort (n = 75), the rate of diversion-associated CRC was 4.5 cases/1000 dpy (95% CI 0.11–25/1000) or 1.5 cases/1000 pyd (95% CI 0.04–8.2/1000). In the CD cohort (n = 79), no patients developed CRC, although a dysplasia rate of 1.9 cases/1000 dpy (95% CI 0.05–11/1000) or 0.77 cases/1000 pyd (95% CI 0.02–4.3/1000) was observed. All patients developing neoplasia had disease duration > 10 years and microscopic inflammation. Conclusions Diverted dysplasia occurred infrequently with rates overlapping those reported in registries for IBD-based rectal cancers. Neoplasia was undetected in patients with < 10 pyd, regardless of diversion duration, suggesting low yield for endoscopic surveillance before this time.

Refractory inflammatory bowel disease: is there a role for Epstein–Barr virus? A case controlled study using highly sensitive EBV encoded small RNA1 In Situ hybridization

A potential role for viral infections has been implicated in inflammatory bowel disease (IBD) unresponsive to medical treatment. It is well known that Epstein-Barr virus (EBV) infection can elicit a brisk mononuclear response in the gastrointestinal tract. The aim of this study was to further evaluate the role of EBV in patients with refractory IBD and compare them with nonrefractory IBD cases. Surgically resected colonic specimens from 67 patients with refractory IBD (62 with ulcerative colitis, 3 patients with Crohn disease, and 2 patients with indeterminate colitis) were retrieved. Twelve colectomy specimens from patients with ulcerative colitis who had undergone resections for dysplasia or endometriosis were included as controls. Highly sensitive EBV-encoded small RNA1 (EBER-1) in situ hybridization was performed on a representative block from each specimen. EBER-1 reactivity was graded as absent, focal, or diffuse. EBV was detected in 60% (40/67) of patients with refractory IBD compared with 25% (3/12) of the control group (P < .05). Focal EBER-1 positivity was present in 45% of cases of refractory IBD compared with 25% of controls. Diffuse EBER-1 reactivity was seen in 15% of cases of refractory IBD (10/67); none of the samples from the control group contained diffuse EBER-1 positivity. There was a positive correlation between EBER positivity and depth of inflammation and mucosal ulceration in patients with refractory IBD. Our findings suggest a potential role for EBV infection in patients with refractory IBD.