Colorectal carcinoma is one of the most common cancers and one of the leading causes of cancer-related death in the United States. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Molecular testing plays an increasingly important role in the era of personalized medicine. This review article focuses on the histopathology and molecular pathology of colorectal carcinoma and its precursor lesions, with an emphasis on their clinical relevance.

/pdf/colorectal-carcinoma-pathologic-aspects-iun914la98.pdf

Colorectal carcinoma: Pathologic aspects

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not knownMethods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic componentResults: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 33 for age <40 years to 05 for age ≥70 years (equivalent to sibling relative risks of 51 to 13, respectively)Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancerImpact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models Cancer Epidemiol Biomarkers Prev; 26(3); 404-12 ©2016 AACR

/pdf/prevalence-and-penetrance-of-major-genes-and-polygenes-for-2020x9ogqs.pdf

Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Germline point mutations in the SMAD4 and BMPR1A genes have been reported in around 40% of patients with juvenile polyposis syndrome (JPS). We performed mutation analysis in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS. By direct sequencing of the two genes we identified point mutations in 30 patients (46% of typical JPS). Using MLPA we detected large genomic SMAD4 or BMPR1A deletions in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Thus, screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. Mutation analysis of the PTEN gene in the remaining 41 SMAD4 and BMPR1A mutation negative cases uncovered a point mutation in two patients (5%). We identified a strong genotype-phenotype correlation regarding gastric polyposis, gastric cancer, and hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) in JPS patients: SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) compared to patients with BMPR1A mutations (8%) (p<0.001); all seven cases of gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation carriers with gastric polyps were significantly older at gastroscopy than those without gastric polyps (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, HHT was also diagnosed clinically. In many JPS patients with identified germline mutation, the documented histologic findings encompassed a wide distribution of different polyp types, comparable to that described in hereditary mixed polyposis syndromes (HMPS).

/pdf/high-proportion-of-large-genomic-deletions-and-a-genotype-16ktjmfpoo.pdf

High proportion of large genomic deletions and a genotype–phenotype update in 80 unrelated families with juvenile polyposis syndrome

The intestinal epithelium possesses a remarkable self-renewal ability, which is mediated by actively proliferating Lgr5+ stem cells. Bone morphogenetic protein (BMP) signalling represents one major counterforce that limits the hyperproliferation of intestinal epithelium, but the exact mechanism remains elusive. Here we demonstrate that epithelial BMP signalling plays an indispensable role in restricting Lgr5+ stem cell expansion to maintain intestinal homeostasis and prevent premalignant hyperproliferation on damage. Mechanistically, BMP inhibits stemness of Lgr5+ stem cells through Smad-mediated transcriptional repression of a large number of stem cell signature genes, including Lgr5, and this effect is independent of Wnt/β-catenin signalling. Smad1/Smad4 recruits histone deacetylase HDAC1 to the promoters to repress transcription, and knockout of Smad4 abolishes the negative effects of BMP on stem cells. Our findings therefore demonstrate that epithelial BMP constrains the Lgr5+ stem cell self-renewal via Smad-mediated repression of stem cell signature genes to ensure proper homeostatic renewal of intestinal epithelium.

/pdf/bmp-restricts-stemness-of-intestinal-lgr5-stem-cells-by-4s267s4sgo.pdf

BMP restricts stemness of intestinal Lgr5+ stem cells by directly suppressing their signature genes.

Aim: Report of a series of 12 cases of juvenile polyposis coli. Methods: The study period was from 1995 to 2005. All the patients were treated by total colectomy with rectal mucosectomy and endorectal ileoanal pullthrough with or without ileal pouch formation. Covering ileostomy was avoided in all the cases. Time taken for the surgery, postoperative complications and continence were documented. Results: The mean operating time was 4.2 h (range: 4-5 h). The mean duration of hospital stay was 16.3 days (range: 15-18 days). The most common postoperative complication was pouchitis and perianal excoriation. Initially, all the patients were passing stools at an interval of 2 h, and after 3 weeks, the frequency has reduced to 6-8 stools per day. In the follow-up after 3 months, the frequency was 3-5 per day with minimal soiling. Conclusions: Single-stage total colectomy with rectal mucosectomy and endorectal ileoanal pull-through without covering ileostomy and pouch formation is a safe and definitive treatment for juvenile polyposis coli if the patient selection is appropriate.

Juvenile polyposis syndrome

Use of fibrin glue in preventing urethrocutaneous fistula after hypospadias repair

The aim of this study was to characterize a successful approach for the management of infants with long-gap esophageal atresia (EA) with tracheoesophageal fistula (TEF). The goal was to preserve the native esophagus and minimize the incidence of esophageal anastomotic leaks using fibrin glue as a sealant over the esophageal anastomosis. A total of 52 patients were evaluated in this study. Only patients in whom, gap between the two ends of the esophagus was ≥ 2 cm were selected during January 2005 to January 2007. Patients were divided in two groups on the basis of block randomization. Group A comprised the patients in whom fibrin sealant was used as reinforcement on a primary end-to-end esophageal anastomosis; in group B, fibrin glue was not used. The two groups were compared in terms of esophageal anastomotic leak (EL), postoperative esophageal stricture (ES), and mortality. The statistical analysis was done using Fisher’s exact test and the chi-squared test. The number of anastomotic leaks in group A (glue group) was about one-fifth that in group B (no glue group). The incidence of ES was almost twice as high in group B as in group A. The mortality rate was almost threefold higher in group B (no-glue group). The higher incidence of EL and ES in group B compared to group A was statistically significant. Thus, fibrin glue when used as an adjunct to esophageal anastomosis for primary repair of long-gap EA with TEF appears safe in the clinical setting and may lower the chances of esophageal leak and anastomosis-site strictures. Hence, it can diminish the mortality and morbidity of these patients.

/pdf/role-of-fibrin-glue-as-a-sealant-to-esophageal-anastomosis-qqwvlgycaf.pdf

Role of fibrin glue as a sealant to esophageal anastomosis in cases of congenital esophageal atresia with tracheoesophageal fistula.

Single-stage repair for rectovestibular fistula without opening the fourchette

Neonatal surgery is the flagship and most challenging component of pediatric surgery, which is the youngest subspeciality of surgery. Neonatal surgery carried a survival rate of only 30% three decades ago. In the last decade there has been a significant change in the scenario. Earlier recognition and referral of these anomalies, availability of neonatal intensive care, better preoperative planning, decision, and techniques have lead to the change in the management. This is an audit into the outcome of neonatal surgery from one of the largest units in India over a ten year period. This audit reveals an across the board survival of 65-70% newborns after surgery on nearly two thousand case over a ten year period. It has an important message that while pediatric surgery units expand, risk stratification of surgical newborns and their treatment in suitable units is mandatory to maintain and improve these figures to match international standards over the next decade.

Vijai D. Upadhyaya

Papers

Juvenile polyposis syndrome

Use of fibrin glue in preventing urethrocutaneous fistula after hypospadias repair

Role of fibrin glue as a sealant to esophageal anastomosis in cases of congenital esophageal atresia with tracheoesophageal fistula.

Single-stage repair for rectovestibular fistula without opening the fourchette

Neonatal surgery: a ten year audit from a university hospital.