Brandie Leach

Defining Phenotypes and Cancer Risk in Hyperplastic Polyposis Syndrome

BACKGROUND: Hyperplastic polyposis syndrome is a rare syndrome of colorectal cancer predisposition. Patterns of inheritance of hyperplastic polyposis syndrome are not obvious and the clinical definition is relatively arbitrary. We hypothesize that there are multiple phenotypes included in what is currently called hyperplastic polyposis syndrome. We performed this review of a large series of patients who presented with multiple serrated polyps to look for clinical patterns that may confirm our hypothesis. METHODS: Hereditary colorectal cancer, colonoscopy, and clinical databases from a single institution were queried for patients meeting the following criteria: 1) ≥20 serrated colorectal polyps; 2) ≥5 serrated polyps proximal to the sigmoid; 3) ≥2 serrated polyps ≥10 mm in size; 4) any serrated polyps in a person with at least one first-degree relative who has hyperplastic polyposis syndrome. Records were reviewed for demographics, polyp details, and personal or family history of colorectal extracolonic malignancy. RESULTS: One-hundred fifteen patients were included. Median age at diagnosis was 62 years and 56% were male. Ninety-seven percent were white. Twenty-five percent of patients had a personal history and 38% had a family history of colorectal cancer. Twenty-eight percent of patients had a personal history and 54% had a family history of extracolonic cancer. Phenotype analysis identified 3 patterns: relatively few large, right-sided polyps (n = 55), many small left-sided polyps (n = 18), and a combination of both left- and right-sided polyps (n = 42). The right-sided phenotype had more sessile serrated polyps and tended to develop colorectal cancer at a younger age. CONCLUSIONS: There are at least 3 different but overlapping clinical phenotypes within hyperplastic polyposis. Recognizing this clinical heterogeneity is important in defining underlying genetic causes.

Lynch syndrome screening in newly diagnosed colorectal cancer in general pathology practice: from the revised Bethesda guidelines to a universal approach.

Abstract Objective. Lynch syndrome (LS) is the most common hereditary form of colorectal cancer (CRC). The revised 2004 Bethesda guidelines were developed to identify potential LS patients. This study aimed to retrospectively evaluate utilization and adequacy of the guidelines in general pathology practice and to determine if a universal LS screening approach increased the potential LS detection rate in newly diagnosed CRCs. Material and Methods. Included were 445 primary CRCs surgically resected from November 2006 to March 2009, when reflex microsatellite instability (MSI) testing was based on histomorphology and age as well as 145 CRCs resected from July 2009 to July 2010 when a universal LS testing paradigm was used. Reflex MSI testing rates and MSI testing results were determined. Results. The overall LS screening rate from November 2006 to March 2009 was 34.8%, and the extrapolated microsatellite instability-high (MSI-H) rate was 8.5% (38/445). Strict adherence to the revised Bethesda guidelines, that is, without testing CRC diagnosed in patients ‡60 years, would have missed 26 (68.4%) MSI-H CRCs. The overall LS screening rate from July 2009 to July 2010 was 76.3% and the MSI-H rate was 20.6% (30/145). Compared with the MSI tested group, the untested group had more CRCs removed by local excision (22.2% vs. 4.8%, p = 0.00035). Conclusion. The revised Bethesda guidelines are inadequate for LS screening when personal and family cancer history is not available to the pathologist, a universal screening paradigm greatly increased the rate of MSI testing and MSI-H CRC detection and CRCs less likely to be screened for LS were those diagnosed in locally excised specimens.

Upper and lower gastrointestinal findings in PTEN mutation-positive Cowden syndrome patients participating in an active surveillance program

OBJECTIVES:Cowden syndrome (CS), associated with germline PTEN mutations, is an autosomal-dominant disorder with increased frequencies of thyroid and breast cancers. Recent reports document the occurrence of gastrointestinal (GI) polyps and increased risk of colon cancer in PTEN mutation carriers. Studies to date, however, have not been based on mutation carriers undergoing active, systematic, routine-interval GI surveillance. Our objective is to document the upper and lower GI findings in CS patients undergoing such an active GI surveillance program.METHODS:In a 5-year period, 3,000 consecutive patients were referred to our high-risk GI cancer clinic for various reasons. Of these 3,000, 10 met full-blown clinical criteria for the diagnosis of CS. Individuals with identified PTEN mutations underwent annual upper and lower endoscopy surveillance programs using dual white light and narrow-band imaging. All biopsies including archived materials were reviewed by a single dedicated GI pathologist.RESULTS:Ten PTEN mutation carriers from different ethnic backgrounds were invited and all participated in the active GI surveillance program. Eight patients had colonic polyps, mostly hyperplastic (eight patients) and hamartomatous (five patients), but also adenomatous (three patients), ganglioneuromatous (three patients), and juvenile polyps (two patients). One patient (10%) had an early-onset rectal cancer (aged 44 years), which was null for PTEN expression on immunohistochemistry. All patients had gastric polyps and nine (90%) had duodenal polyps, mostly hyperplastic and hamartomatous. Additional three patients (30%) had adenomatous duodenal polyps.CONCLUSIONS:PTEN mutation–positive CS patients have a higher frequency of upper GI polyps than previously believed. They appear prone to develop adenomatous upper and lower tract dysplastic polyps and cancer. Thus, the polyps encountered during upper or lower endoscopy in these patients should not be automatically considered innocent hamartomas without malignant potential. Active surveillance programs in specialized centers should be considered in these patients.

SMAD4 mutation and the combined syndrome of juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia

Juvenile polyposis syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Recently, reports of the combined syndrome of JPS and HHT have been described in individuals with mutations in the SMAD4 gene, whose product—SMAD4—is a critical intracellular effector in the signalling pathway of transforming growth factor β (TGFβ). This report describes a 24-year-old man who presented to the Respiratory Institute after colectomy for JPS with a SMAD4 mutation and who was subsequently diagnosed to have HHT with asymptomatic cerebral and pulmonary arteriovenous malformations (AVMs). Patients with JPS due to a SMAD4 mutation should be screened for the vascular lesions associated with HHT, especially occult AVMs in visceral organs, which may potentially present catastrophically with serious medical consequences.

Hereditary colorectal cancer syndromes and genetic testing

Colorectal cancer (CRC) is a leading cause of cancer and cancer deaths in the Western world. Approximately 5–10% of CRC are hereditary, due to a defined genetic cause. Individuals and families affected with a hereditary CRC syndrome exhibit benign and malignant extra‐intestinal tumors, require aggressive cancer screening and benefit from management by a multi‐disciplinary team of professionals. The clinical manifestations, genetic causes and current management of patients with hereditary colon cancer syndrome is provided. J. Surg. Oncol. 2015 111:103–111.

The prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis syndrome patients with SMAD4 mutations

Background Juvenile Polyposis Syndrome (JPS) is defined by the presence of ≥ 5 colorectal juvenile polyps or any number of juvenile polyps in an individual with a family history of JPS. Genetic alterations including either point mutations or large rearrangements in BMPR1A or SMAD4 are found in 50% of affected individuals. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease diagnosed upon the presence of epistaxis, visceral arteriovenous malformations (AVM) or mucutaneous telangiectasias. HHT is diagnosed when there are ≥ 3 manifestations and is suspected when there are at least 2 manifestations. Most HHT cases are caused by a germline mutation in ALK1 or ENG ,m embers of the TGFb signaling pathway. Approximately 22% of patients with Juvenile Polyposis Syndrome (JPS) due to a SMAD4 mutation have been reported to also have HHT [1]. Most prior publications have few patients and no systematic approach to screening, so the true incidence of the combined JPS/HHT syndrome is not known. Our aim was to determine the prevalence of HHT in our patients with JPS with a SMAD4 mutation including those who underwent systematic screening for AVM’s. Methods JPS patients were identified from a comprehensive polyposis database using Cologene© software. Families carrying a germline SMAD4 mutation were studied by screening affected patients for cutaneous telangiectases and with cardiac bubble ECHO, CAT scan chest, or MRI of brain for other AVMs. Results

The community uptake of an online CRC risk assessment and its utility to assess for a potential hereditary colon cancer syndrome

Purpose The identification of individuals with Hereditary Non Polyposis Colorectal Cancer (HNPCC) in the population is suboptimal. Causes include lack of physician recognition or failure to take an accurate family history. While colorectal cancer (CRC) in HNPCC is preventable by annual colonoscopy it is underutilized in part by lack of physician recommendation or poor understanding of personal risk of disease. We developed an online CRC risk assessment (http://www.clevelandclinic.org/score) incorporating family and personal history of adenomas and CRC which generated a pedigree, risk category and screening recommendations based on ACG guidelines. Modifiable lifestyle factors were also assessed and personalized recommendations were provided to minimize neoplasia due to those factors. We assessed the feasibility and online uptake of this tool and determined the proportion of high risk individuals who meet criteria suspicious for HNPCC. Methods The assessment included questions on demographics, use of previous CRC screening, and family and personal history of adenomas and CRC in 3 generations. Height, weight, age > or < 50, race, smoking exposure, physical activity, and dietary habits assessed. Risk categories included average, low, medium, and high.

High risk clinic for hereditary colorectal neoplasia: a focus for patient care and an opportunity for clinical research

Background Patients with hereditary colorectal neoplasia and their families need specialized care to plan for appropriate surveillance and to ensure that they receive the most favorable treatment. This involves coordinating multidisciplinary appointments on the same day to minimize inconvenience to patients. We have established a special high risk clinic for these patients and their families. In this study we are reporting our activity for the last 5 years. Methods Initially the clinic ran one morning a month but has grown in the last 2 years adding another half day session. Requests for appointments were triaged by registry coordinators. Patients with syndromes of hereditary colorectal neoplasia were eligible for this clinic if the necessary appointments included multiple physicians. The clinic is staffed by one of three colorectal surgeons, one gastroenterologist, one genetic counselor, one hepatobiliary/upper GI surgeon and often by a clinical geneticist.