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.

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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

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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).

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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

The severe form of acute lower respiratory tract infection that affects the pulmonary parenchyma in one or both lungs is known as pneumonia. It is a common disease and a potentially serious infectious disease with considerable morbidity and mortality. Pneumonia is the sixth leading cause of death and the only infectious disease in the top ten causes of death in the United States.Pneumonia can be classified into 2 types based on how the infection is acquired: Community-acquired pneumonia (CAP): Most common type Nosocomial pneumonia Hospital-acquired pneumonia (HAP) Ventilator-associated pneumonia (VAP) Healthcare-associated pneumonia (HCAP) Community-acquired pneumonia is diagnosed in non-hospitalized patients or a previously ambulatory patient within 48 hours after admission to the hospital. CAP is further divided into "typical" and "atypical."HAP develops more than 48 hours after hospital admission. Patients who are mechanically ventilated for more than 48 hours after endotracheal intubation can develop pneumonia known as VAP. HCAP occurs in ambulatory patients who are not hospitalized and have had extensive healthcare contact within the last 3 months.

Typical Bacterial Pneumonia

Abstract Many medical trainees will encounter a case of sudden cardiac death (SCD) during their medical training and observe the unpleasant task of disclosing the tragic news to the family of the victim. Although the majority of deaths will affect middle-aged and elderly individuals, occasionally a young, apparently healthy person falls victim, making the experience even more poignant. The devastating impact associated with the missed opportunity to save a young life cannot be overestimated. The majority of SCDs in the young are secondary to previously quiescent, inherited cardiac diseases. However, a significant proportion may be preventable if the clinical symptoms, family history and electrocardiogram are interpreted appropriately. All clinicians should have a basic understanding of conditions predisposing to SCD in the young, and recognize the need to evaluate first-degree relatives who may be at risk in an effort to prevent further catastrophes. This article outlines the epidemiology of SCD and provides an overview of the commonest implicated cardiac pathologies, as well as the necessary investigations and management of surviving first-degree relatives when appropriate.

Sudden Cardiac Death

The alveolar gas equation is used to calculate alveolar oxygen partial pressure as it is not possible to collect gases directly from the alveoli. The equation is helpful in calculating and closely estimating the PaO2 inside the alveoli. The variables in the equation can affect the PaO2 inside the alveoli in different physiological and pathophysiological states. Alveolar Gas Equation PAO2 = (Patm - PH2O) FiO2 - PaCO2/RQ Patm is the atmospheric pressure (at sea level 760 mm Hg), PH2O is partial pressure of water (approximately 45 mm Hg). FiO2 is the fraction of inspired oxygen. PaCO2 is partial pressure of carbon dioxide in alveoli (in normal physiological conditions around 40 to 45 mmHg). RQ is the respiratory quotient. The value of the RQ can vary depending upon the type of diet and metabolic state. RQ is different for carbohydrates, fats, and proteins (average value is around 0.82 for the human diet). Indirect calorimetry can provide better measurements of RQ by measuring the VO2 (oxygen uptake) and VCo2 (carbon dioxide production).RQ = amount of CO2 produced/amount of oxygen consumedAt sea level, the alveolar PAO2 is: PaO2 = (760 - 47) 0.21 - 40/0.8 = 99.7 mm Hg. The 3 major variables of the equation are the atmospheric pressure, amount of inspired oxygen, and levels of carbon dioxide. Each has an important clinical significance and can help explain different physiological and pathophysiological states.

Sandeep Sharma

Papers

Juvenile polyposis syndrome

Typical Bacterial Pneumonia

Sudden Cardiac Death

Alveolar Gas Equation

Osler-Weber-Rendu Disease (Hereditary Hemorrhagic Telangiectasia, HHT)