Best practices of handling, processing, and interpretation of small intestinal biopsies for the diagnosis and management of celiac disease: A joint consensus of Indian association of pathologists and microbiologists and Indian society of gastroenterology.

The Indian Association of Pathologists and Microbiologists (IAPM) and Indian Society of Gastroenterology (ISG) decided to make a joint consensus recommendation for handling, processing, and interpretation of SI biopsies for the diagnosis and management of celiac disease (CD) recognizing the inhomogeneous practice of biopsy sampling, orientation, processing, and interpretation. A modified Delphi process was used to develop this consensus document containing a total of 42 statements and recommendations, which were generated by sharing the document draft, incorporating expert's opinion, followed by three cycles of electronic voting as well as a full-day face-to-face virtual ZOOM meeting and review of supporting literature. Of the 42 statements, 7 statements are on small intestinal (SI) biopsy in suspected patients of CD, site and the number of biopsies; 7 on handling, fixative, orientation, processing, and sectioning in pathology laboratories; 2 on histological orientation; 13 statements on histological interpretation and histological grading; 3 on the assessment of follow-up biopsies; 2 statements on gluten-free diet (GFD)-nonresponsive CD; 4 on challenges in the diagnosis of CD; 2 statements each on pathology reporting protocol and training and infrastructure in this area. The goal of this guideline document is to formulate a uniform protocol agreed upon both by the experienced pathologists and gastroenterologists to standardize the practice, improve the yield of small bowel biopsy interpretation, patients' compliance, overall management in CD, and generate unified data for patient care and research in the related field.

Histomorphological analysis of gastric polyps.

INTRODUCTION: Incidence of gastric carcinoma and gastric polyps is on rise all over the world. Chronic atrophic gastritis to intestinal metaplasia progressing to adenocarcinoma has been documented pathway for gastric carcinogenesis. Another pathway for gastric carcinoma is adenoma carcinoma sequence similar to colon cancer. AIM: To study prevalence, endoscopic, and histomorphological features of gastric polyps. METHODS AND MATERIAL: This was retrospective analysis of gastric polyps from 2012 to 2019 in consecutive 10,800 upper gastrointestinal endoscopies. Demographic, endoscopic, and histopathological data were obtained from hospital records. All gastric polyps were classified as per standard histologic criteria. Additional histological features noted were presence of dysplasia, focus of adenoma, or malignancy. RESULTS: The prevalence of gastric polyps was 434 (4%) of 10,800 upper gastrointestinal endoscopies. Majority of polyps were found in the last 4 years (277: 63.8%). Mean age was 55.4 years with male to female ratio 1:1.2. Most of the polyps (94.9%) were less than 1 cm, located in gastric antrum. Multiple polyps were seen in 20.9% cases. On histopathology, fundic gland polyps were most common (147: 33.8%), followed by hyperplastic (128: 29.4%) polyps. Adenomatous polyps were nine (2%); of these, two cases of hyperplastic polyps and one each of fundic gland polyp and benign epithelial polyp showed adenomatous foci. CONCLUSION: Fundic gland polyps were the most common polyps. With rising incidence of gastric carcinoma, identification of gastric polyps on endoscopy with biopsy can prevent progression to carcinogenesis.

Risk factors for inflammatory bowel disease: A prospective multi-center study.

INTRODUCTION: Environmental risk factors have been associated with inflammatory bowel disease (IBD). With rising incidence, it is important to know risk factors associated with IBD in our population. This study was aimed to evaluate risk factors for IBD from western India. METHODS: This was prospective, multi-center case-control study which included 1054 patients with IBD of which 765 (72.5%) were ulcerative colitis (UC) and 289 (27.4%) Crohn's disease (CD). Asymptomatic individuals without a history of any major illness served as controls. The questionnaire containing risk factors for IBD was given to patients and control group. Odds ratio and 95% confidence interval were calculated for each variable. RESULT: Significant numbers of patients with CD were from rural area. Rural environment (OR 1.071, 0.82-1.38 and OR 1.441, 1.02-2.02), higher education (OR 1.830, 1.52-2.19 and OR 1.519, 1.16-1.97), professional by occupation (OR 1.754, 1.46-2.09 and OR 1.293, 0.99-1.67), annual family income >100,000 Indian national rupees (OR 2.185, 1.52-3.13 and OR 4.648, 3.10-6.95), history of appendectomy (OR 3.158, 1.71-5.80 and OR 3.158, 1.71-5.80), and family history of IBD (OR 4.510, 2.19-9.25 and OR 3.972, 1.58-9.96) were the risk factors for UC and CD, respectively. Vegetarian diet was protective factor for UC (OR 0.29, 0.27-0.39) and risk for CD (OR 1.179, 0.88-1.57). Smoking and chronic alcoholism were not found to be the risk factors. CONCLUSION: This study highlights association between socioeconomic, dietary factors, appendectomy, and family history as risk factors for IBD.

Metastatic Crohn's Disease.

Metastatic cutaneous involvement is a rare extraintestinal manifestation of Crohn's disease. Presence of cutaneous noncaseating granulomas that are anatomically noncontiguous in location with a fistula or the gastrointestinal tract is a diagnostic hallmark. We present a case of inflammatory bowel disease initially diagnosed as ulcerative colitis, but later manifesting as intra-abdominal abscesses and ulcerated cutaneous lesions that on biopsy proved to be metastatic Crohn's disease. The patient promptly responded to corticosteroid therapy.

Frequency of colonic adenomatous polyps in a tertiary hospital in Mumbai.

INTRODUCTION: Incidence of colorectal carcinoma is increasing all over world. There is limited data on colorectal polyps from India. We evaluated the histomorphological features of colorectal polyps and determined risk stratification in adenomatous polyps. METHODS: In 4970 consecutive colonoscopies, colorectal polyps were detected in 515 cases (10.3 %). Polyps were classified using standard histological criteria. Each polyp was evaluated for presence of dysplasia. Adenomatous polyps were classified as low-risk adenomas (1-2 tubular adenomas <10 mm) and high-risk adenomas characterized by villous histology, high-grade dysplasia, size ≥10 mm, or ≥3 adenomas. RESULTS: Of 515 colorectal polyps, 270 (52.4 %) were adenomatous, followed by 78 (15.1 %) inflammatory, 78 (15.1 %) hyperplastic, 32 (6.2 %) hamartomatous polyps, 25 (4.8 %) benign epithelial polyps, 5 (0.9 %) cap polyps, 5 (0.9 %) lipomatous polyps, 3 (0.5 %) angiomatous polyps, 4 (0.7 %) lymphoid, and 15 (2.9 %) cases with adenocarcinoma masquerading as polyps. Mean (SD) age with colorectal polyps was 54.8 (33.0) years while for adenomatous polyps, 59.5 (14.8) years with male to female ratio of 2:1. Majority of adenomatous polyps 124 (45.9 %) were tubular adenomas present in rectosigmoid. High-grade dysplasia was found in 38 (14 %) adenomas. One hundred and fifty-five (57.4 %) were high risk of which majority were villous adenomas and nine (7.2 %) tubular adenomas. CONCLUSION: The most common colorectal polyps found during routine colonoscopy were 270 adenomatous (52.4 %) cases. Of these, 155 (57.4 %) adenomatous polyps were high-risk category. Population prevalence data of colonic polyps in general population beyond the age of 50 years needs to be obtained.

Polycystic Pancreas.

Polycystic disease of the pancreas is a very rare entity with very few cases reported in the literature. We report a symptomatic case of polycystic pancreas associated with pheochromocytoma that was treated surgically.

Immunoglobulin IgG4 and autoimmune hepatitis.

INTRODUCTION: IgG4 disease has been characterised by lymphoplasmacytic inflammation, rich in IgG4 plasma cells, elevated serum IgG4 and clinical improvement with steroid therapy. There is limited information about IgG4 plasma cells in autoimmune hepatitis (AIH). Aim of this study was to determine IgG4 plasma cells in autoimmune hepatitis and its impact on clinical course and treatment outcome. MATERIAL METHODS: Liver biopsies from 40 patients with AIH before therapy were subjected to IgG4 immunostaining. Clinical history, liver function tests and response to immunosuppressive therapy were recorded. Patients were monitored for 4 weeks. Liver biopsy from 23 non AIH patients served as control. Depending on the presence of IgG4 plasma cells on immunohistochemistry, patients of autoimmune hepatitis were grouped into IgG4 positive (group A) and IgG4 negative (group B). Both groups were compared before and after immunosuppressive therapy for clinicopathological features. RESULTS: Tissue IgG4 plasma cells > 5 per high power field (hpf) were seen in 10/40 (25%) and > 10 per hpf in 4/40 (10%) cases of AIH. None of the cases from control group (non AIH) were positive for IgG4 plasma cells. Group A patients were significantly younger than group B. (p < 0.05). There were no differences in histological severity but liver enzymes, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly higher in group A than group B. Post treatment biochemical improvement was similar in both groups. CONCLUSION: IgG4 positive AIH patients were younger with more abnormal liver enzymes. There was no difference in histology and response to treatment in both groups.

Effect of H. pylori density by histopathology on its complications and eradication therapy.

INTRODUCTION: Helicobacter pylori (H. pylori) infection causes chronic gastritis and is a major risk factor for duodenal and gastric ulceration, gastric adenocarcinoma, and primary gastric lymphoma. Increased gastric bacterial density may lead to increased levels of inflammation and epithelial injury. AIMS AND OBJECTIVES: 1) To study the effect of H. pylori density by histological changes in stomach. 2) To study the effect of H. pylori density on the efficacy of standard triple drug eradication treatment. 3) To study the effect of H. pylori density on the complication related to H. pylori. MATERIAL AND METHODS: All the patients visiting gastroenterology OPD with the symptoms of dyspepsia not responding to proton pump inhibitor or having alarm symptoms were subjected to upper GI endoscopy and biopsy. If H. pylori was present they were included in the study. The patients were given standard 14 day triple antibiotic combination for H. pylori eradication. H. pylori eradication was confirmed by urea breath test after six weeks of completion of treatment. RESULTS: Out of 250 patients screened, 120 patients enrolled in the study. On clinical history 41.5% patients had symptoms of heart burn where as 63.3% patients had dyspeptic symptoms. Success rate of anti H. pylori triple drug therapy was 80%. Rate of eradication was significantly lower among the patients with higher H. pylori density (p < 0.05) on histopathology by Sydney classification. Duodenal ulcer, Gastric ulcer and gastric erosion were noted in higher frequencies among the patients with higher H. pylori density (p < 0.05). CONCLUSION: H. pylori density by histopathology correlates with the complication related to H. pylori i.e. duodenal ulcer, reflux esophagitis and antral erosions. It also correlates with the success of the standard triple drug eradication treatment.

Association of genetic variants with anti-tuberculosis drug induced hepatotoxicity: a high resolution melting analysis.

BACKGROUND: Tuberculosis (TB) treatment remains a challenge owing to the high incidence of drug induced hepatotoxicity (DIH). Apart from environmental factors, single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs), nuclear receptors (NRs) and transporter proteins (TPs) contribute to DIH. In the present study, we report known and novel SNPs in a total of seven genes of DMEs, NRs and TPs with high resolution melting (HRM) technique. METHODS: DNA samples of 185 TB patients of Western Indian population, of which 50 showed DIH, were analyzed. Grouping of the temperature-shifted difference plots obtained from the DNA melt curves enables identification of known and novel SNPs. Representative samples of each group were sequenced. RESULTS: We report 18 novel SNPs, of which 3 are in 5'-UTR, 14 in exonic and 1 in intronic region. Of the SNPs in exons, 7 non-synonymous, 3 synonymous and 4 deletion mutations were observed. Among the known SNPs, CYP2E1 wild-type, NAT2(∗)5 mutant and NAT2(∗)6 heterozygous genotypes were associated with DIH (p<0.05). Among the novel SNPs, group 2 of SLCO1B1 showed a significant association (p<0.05). CONCLUSIONS: While several SNPs showed borderline p values between 0.05 and 0.15, the confidence in association can be improved further by using larger data sets.

Association of GST null genotypes with anti-tuberculosis drug induced hepatotoxicity in Western Indian population.

BACKGROUND: The first line anti-tubercular (anti-TB) treatment normally involves isoniazid, rifampicin, pyrazinamide, and ethambutol. Clearance of these drugs depends on the activity of several enzymes such as N-acetyl transferase 2, cytochrome P450 oxidase and glutathione S-transferase (GST). Some of these enzymes are highly polymorphic leading to significant inter-individual variation in their activity thereby increasing the risk of drug induced hepatotoxicity (DIH). AIM: To investigate the possible association of anti-TB DIH with genetic polymorphism of GST genes in Western Indian population. MATERIAL AND METHODS: A prospective case-control study was undertaken on patients who received anti-TB treatment. Cases (n = 50) were distinguished from controls (n = 246) based on occurrence of DIH during anti-tubercular treatment. A multiplex polymerase chain reaction was employed to identify homozygous null mutation at GSTM1 and GSTT1 loci. Results. Homozygous null mutation in GSTM1 gene alone or in both GSTM1 and T1 genes was found to be significantly associated with anti-TB DIH at p < 0.02 and p < 0.007, respectively, in our study population. CONCLUSIONS: This is the first study to report GSTM1 null and combined GSTM1 and T1 null genotypes to be risk factors of anti-TB DIH in Western Indian population. Screening of patients for these genotypes prior to anti-TB regimen would provide better control of hepatotoxicity.

Association of N-acetyltransferase 2 and cytochrome P450 2E1 gene polymorphisms with antituberculosis drug-induced hepatotoxicity in Western India.

BACKGROUND AND AIM: Tuberculosis (TB) is a major public health problem in India. Despite the treatment availability and monitoring, drug-induced hepatotoxicity (DIH) is a serious concern and can lead to discontinuation of treatment. Anti-TB DIH is well known and can aggravate because of pharmacokinetic and pharmacodynamic interactions. Genetic polymorphism in the drug-metabolizing enzyme genes is an important factor that predisposes certain fraction of the population to drug-induced toxicity. The purpose of this study was to assess the association of N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) gene polymorphism with anti-TB DIH in Western Indian population. METHODS: A prospective cohort study of 215 patients taking treatment against TB was performed. The NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism methods. Logistic regression model was used to calculate odds ratio at 95% confidence interval and their respective P values. RESULTS: The risk of anti-TB DIH was significantly higher in slow acetylator (SA) than in intermediate and rapid acetylator of NAT2 genotypes (odds ratio: 2.3, P = 0.01). We also observed the homozygous point mutation at position 481, associated with higher risk of hepatotoxicity (P < 0.01). The major haplotype NAT2*4 seems to provide protection in DIH compared with non-DIH TB patients (P = 0.04). However, we did not find a significant association between CYP2E1 genotypes and anti-TB DIH. CONCLUSION: Increased susceptibility to isoniazid (INH)-induced hepatotoxicity due to presence of NAT2 SA polymorphism was demonstrated in Western Indian population. NAT2 genotyping can therefore serve as an important tool for identifying patients predisposed to anti-TB DIH.

Portal hypertensive polyps: distinct entity.

INTRODUCTION: Gastric mucosal changes in portal hypertension (PH) are well known, but gastroduodenal polyps in PH are rarely described. AIM: This study aims to estimate prevalence of upper gastrointestinal (GI) polyps in patients with PH of any etiology and to evaluate the role of angiogenesis in portal hypertensive polyps. MATERIAL AND METHODS: This is a retrospective analysis of all patients undergoing upper GI endoscopy to compare the etiology of the polyps in the portal hypertensive group vs. those without PH. The diagnosis of polyps was done using standard histological criteria. Another part of the study consisted of prospective analysis of vascular proliferative marker CD 34 and morphometry in 47 patients. RESULTS: A total of 3,811 upper GI endoscopies were done of which 121 patients (3.2 %) had polyps in upper GI tract. In patients with PH (=631), polyps were noted in 16, portal hypertensive polyps in 9, hyperplastic in 6, and fundic gland polyp in 1. In the patients without PH (n = 3,180), polyps of various etiologies were noted in 105 patients. The prevalence of polyps of all causes was similar in both groups (2.5 % vs. 3.3 %, p = 0.3957). Prevalence of hyperplastic polyps was similar in PH (0.95 %) and non-PH group (1.3 %). On immunohistochemistry, PH polyps and PH gastric mucosa had significantly higher vessel diameter of >50 µm, increased vascular density as compared to non-portal hypertensive polyps (PHP) and normal gastric mucosa. CONCLUSION: PHP are definite identifiable lesion in patients of cirrhosis with PH. PHP are probably related to increased angiogenesis in gastric mucosa.

Intraductal tubulopapillary neoplasm of the bile duct: potential origin from peribiliary cysts.

We report two patients with unique biliary tumors histologically similar to pancreatic intraductal tubulopapillary neoplasm (ITPN). One patient underwent right hepatectomy for a partly cystic mass in the hepatic hilum. The other patient had liver transplantation for cryptogenic cirrhosis and multiple hilar cysts detected in the explanted liver, some obliterated by papillary nodules. Histologically both tumors consisted of intracystic non-invasive and well differentiated adenocarcinoma with a papillary and tubular architecture. Associated cysts were peribiliary cysts partly lined by carcinoma cells that were continuous with the intracystic papillotubular masses. Both tumors shared the same immunophenotype: K7(+)/K20(-)/MUC1(+)/MUC2(-)/MUC5AC(-)/MUC6(+). Genetic analysis of KRAS and BRAF revealed wild type genotypes. These pathological and genetic features are similar to those of pancreatic ITPNs. This report suggested that ITPNs may rarely develop in the bile duct seemingly in association with peribiliary cysts.

Atypical histological features of ulcerative colitis.

INTRODUCTION: The diagnosis of ulcerative colitis is based on combination of clinical, endoscopic and pathological findings. However cases have been reported showing atypical endoscopic and histological features in ulcerative colitis. Hence the objective of this study was to determine the atypical features of new onset ulcerative colitis in adult population. METHODS: A total 110 newly diagnosed cases of ulcerative colitis were enrolled in the study over a period of five years. The diagnosis of ulcerative colitis was made by correlating clinical, endoscopic and histological features. Biopsies from representative areas were processed routinely. Endoscopic and histological evaluation was carried out for atypical features. RESULTS: Majority of the patients (75.4%) were between 21-50 years of age with male to female ratio of 2.2:1. A significant number of patients showed atypical endoscopic findings in the form of rectal sparing in 12 (10.9%) and skip lesions in 24 (21.8%) patients. Atypical features noted on histology included normal surface epithelium in 8 (7.3%), predominant polymorphs in 42 (38%), predominant eosinophils in 7 (6.3%), normal crypt architecture in 1 (0.9%) and well preserved goblet cells in 30 (28%) cases. CONCLUSION: A significant number of patients with new onset ulcerative colitis showed atypical pattern of disease endoscopically as well as histologically. Pathologists should be aware of these atypical findings in cases of ulcerative colitis so as to avoid misdiagnosis.

Splenic mass and isolated gastric varices: a rare presentation of a neuroendocrine tumor of the pancreas.

CONTEXT: Splenic involvement in neuroendocrine pancreatic tumors is well known but rarely presents as a primary splenic mass. CASE REPORT: A rare case of a neuroendocrine tumor involving the tail of the pancreas, splenic hilum and splenic flexure of the colon, forming a conglomerate mass and presenting as isolated gastric varices is described. A 75-year-old male presented with hematemesis and melena. Esophagogastroduodenoscopy revealed isolated gastric varices. A CT scan revealed a mass predominantly involving the spleen and a small part of the pancreas. CONCLUSION: A splenic mass with isolated gastric varices should be kept in mind as one of the presentations of a pancreatic neuroendocrine tumor.

Morphological spectrum of gastrointestinal tuberculosis.

INTRODUCTION: Gastrointestinal tuberculosis (GITB) is a great mimicker and it is often difficult to distinguish GITB from other inflammatory lesions of the intestine. AIM: This study was carried out with the objective of analysing the entire morphological spectrum of GITB. METHODS: A total of 110 diagnosed cases of GITB were included in the study. The diagnosis was based on the presence of acid-fast bacilli (AFB) on histology, caseating or non-caseating epithelioid cell granulomas (ECGs), evidence of tuberculosis at other extraintestinal sites, and all of these along with a complete response to anti-tuberculous treatment (ATT). RESULTS: The mean age was 30.9 years with M:F ratio of 1:1. On gross examination, apart from typical tuberculous lesions in the form of transverse ulcers, strictures, hyperplastic lesions and serosal tubercles, intestinal perforation (32.6%) was seen with higher frequency and ischemic bowel was also identified (7.3%). Varied morphological patterns of ECGs in the form of caseating, non-caseating, confluent, discrete and even suppurative granulomas were identified on histopathology. An important finding was the co-existence of different types of granulomas within the same case. In a significant number of cases (44.5%) granulomas were seen in a submucosal location. The predominant type of inflammation seen in the lamina propria was lymphoplasmacytic in 85.5% cases. CONCLUSION: Pathologists should be aware of the entire spectrum of gross and histopathological features of GITB, so as to avoid misdiagnosis.