Margaret O'Malley

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.

Screening for Thyroid Cancer in Patients With Familial Adenomatous Polyposis

Objective:Clarify the incidence of thyroid cancer in patients with Familial adenomatous polyposis (FAP) in a prospective study of thyroid neck US screening. Background:FAP is a hereditary disease predisposing to cancer in multiple organs, including the thyroid. However, routine thyroid screening for FAP patients is not generally practiced in the United States. Here, we report the initial results of a prospective thyroid cancer screening program in patients with FAP. Methods:At the time of yearly gastrointestinal follow-up, every FAP patient in our registry was offered thyroid ultrasound (US) performed by experienced endocrine surgeons. Clinical findings related to thyroid disease were analyzed for those patients who completed screening from August 2008 to December 2009. Results:Of 192 screened FAP patients, 72 (38%) had thyroid nodules and 5 (2.6%) had thyroid cancer. Three of 5 patients with FAP and thyroid cancer were women. Four of 5 patients had the multifocal papillary type with mean size 15 mm. Clinical history and neck exam did not detect any of the 5 cancers. Conclusion:The incidence of thyroid cancer among FAP patients is high. Medical history and exam are inadequate to identify patients with thyroid cancer, thus thyroid screening with US is warranted.

The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome.

BACKGROUND:Juvenile polyposis syndrome is a dominant GI polyposis syndrome defined by ≥5 GI juvenile polyps or ≥1 juvenile polyps with a family history of juvenile polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥3 criteria including clinical manifestations or a family history, are present. A juvenile polyposis–hereditary hemorrhagic telangiectasia overlap syndrome has previously been reported in 22% of patients with juvenile polyposis due to a SMAD4 mutation. OBJECTIVE:Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our juvenile polyposis SMAD4 patients. DESIGN, PATIENTS, AND SETTING:This was a cohort study of juvenile polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (≥3 criteria diagnostic; 2 criteria suspect of). MAIN OUTCOME MEASURES:Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in juvenile polyposis SMAD4 patients. RESULTS:Forty-one juvenile polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally. LIMITATIONS:There was a single, tertiary referral center. CONCLUSIONS:Nearly all juvenile polyposis SMAD4 patients have the overlap syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in juvenile polyposis. Health care providers must be cognizant of the juvenile polyposis–hereditary hemorrhagic telangiectasia overlap syndrome and the implications for management of these patients.

Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal vascular structures that may present as epistaxis, telangiectasias, and/or arteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and SMAD4) are members of the TGFβ pathway. Other syndromes associated with abnormalities in TGFβ signaling include Marfan syndrome, Loeys–Dietz syndrome and related disorders. These disorders have aortic disease as a prominent finding. While there are case reports of patients with HHT and aortopathy (dilatation/aneurysm, dissection, and rupture), this has not been systematically investigated. We conducted a retrospective chart review to determine the prevalence of aortopathy in an HHT cohort. Patients from a single institution were identified who met the Curacao Criteria for a clinical diagnosis of HHT and/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. Two‐dimensional echocardiograms were reviewed by a single pediatric cardiologist, and data were collected on demographics, genotype, HHT features, aortic root measurements, past medical history, and family history. Z scores and nomograms were utilized to identify abnormal results. Twenty‐six patients from 15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were included in the analysis. Aortopathy was found in 6/26 (23%) patients; all had SMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence of aortopathy. These data suggest that aortopathy could be part of the spectrum of SMAD4‐induced HHT manifestations. Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations.

Characteristics of Benign and Malignant Thyroid Disease in Familial Adenomatous Polyposis Patients and Recommendations for Disease Surveillance

BACKGROUND Familial adenomatous polyposis (FAP) is a hereditary colon cancer syndrome that involves multiple extracolonic organs, including the thyroid. Several studies have estimated the rate of thyroid cancer in FAP to occur at five times the rate of the general population, but no current consensus defines screening for thyroid cancer in this cohort. This study seeks to define the features of benign and malignant thyroid disease in FAP patients, to compare thyroid cancer cases found through screening with those found incidentally, and to propose disease surveillance recommendations. METHODS Prospective screening for early thyroid cancer detection with thyroid ultrasound (US) was performed on FAP patients at the time of annual colonoscopy since November 2008. Clinical and US data were reviewed to characterize the observed thyroid nodules. Nonscreening-detected cases (NSD) were found through review of the colon cancer registry database. RESULTS Eighteen NSD were found, compared with 15 screening-detected (SD) cases, out of 205 total patients screened (Mage=42 years; 55% female). The mean tumor size was larger in the NSD group than the SD group (p=0.04), and they tended to demonstrate more positive lymph nodes and more complications than the SD group. In the screened cohort, at least one thyroid nodule was detected in 106 (51.7%) patients, with 90% of these seen on initial exam. A total of 40/106 (37.7%) patients required fine-needle aspiration biopsy of a dominant nodule (Msize=14 mm), and 28/40 (70%) of these were performed at the first US visit. Suspicious US features were present in 16/40 (40%) patients, including five sub-centimeter nodules. Cytology and/or nodule US was abnormal in 15/205 screened patients, leading to surgery and revealing 14 papillary and one medullary thyroid cancer. CONCLUSIONS Given the age and sex distribution of the screened cohort, this study reveals a higher-than-expected prevalence of both benign and malignant thyroid disease in the FAP population. Additionally, SD cases seemed to consist of smaller-sized cancers that required less radical therapy compared to NSD cases. Since it was found that the initial US in the screening program accounted for the majority of detected nodules (90%) and biopsies (70%), baseline and subsequent thyroid US surveillance is recommended in all FAP patients.

Desmoids and genotype in familial adenomatous polyposis.

BACKGROUND: Desmoid disease can be a serious, life-threatening complication of familial adenomatous polyposis. The ability to predict patients at increased desmoid risk is important, but a convincing genotype-phenotype correlation for desmoid formation has not yet been described. PURPOSE: The aim of this study is to assess the relationship between desmoid disease and genotype in patients with familial adenomatous polyposis. DESIGN: This is a cohort study. PATIENTS: All patients with familial adenomatous polyposis and a documented pathogenic APC mutation in themselves or a first-degree relative were selected. MAIN OUTCOMES MEASURES: The comparison of genotype and the presence, stage, and site of desmoid disease are the primary end points of this study. RESULTS: Three hundred twenty-three patients from 219 families were identified. Mutations spanned the length of the gene, from codon 213 to codon 2051. Desmoid disease was diagnosed in 77 patients from 68 families. Desmoid disease was found in 14.9% of patients with a mutation 5′ of codon 400, 23.2% of patients with a mutation from codon 401 to 1400, and in 37.1% of those with a mutation 3′ of 1400. All patients with 5′ mutations had stage I or II abdominal desmoid disease, and all tumors were stable or shrinking. Twelve percent of patients who had desmoid disease with mutations between codons 400 and 1400 had stage III or IV desmoid disease, and 5 of 42 (12%) tumors were growing at the time of the study. There had been 2 desmoid-related deaths. Almost half (44%) of patients who had desmoid disease with mutations 3′ of codon 1400 had stage III or IV disease. Three of 14 tumors were growing (21%), and there were 4 desmoid-related deaths. LIMITATIONS: This study was conducted at a tertiary referral center, and there was no systematic surveillance for desmoids. CONCLUSION: Desmoid disease occurs in patients who have familial adenomatous polyposis with almost any APC mutation, although there is an increased propensity in those with a 3′ mutation. The incidence and severity of the desmoid disease are related to the site of the mutation.

Prevalence of occult gynecologic malignancy at the time of risk reducing and nonprophylactic surgery in patients with Lynch syndrome

OBJECTIVE The primary aim of this study was to determine the prevalence of occult gynecologic malignancy at the time of risk reducing surgery in patients with Lynch Syndrome. A secondary aim was to determine the prevalence of occult gynecologic malignancy at the time of surgery for non-prophylactic indications in patients with Lynch Syndrome. METHODS A retrospective review of an Inherited Colorectal Cancer Registry found 76 patients with Lynch syndrome (defined by a germline mutation in a DNA mismatch repair gene) or hereditary nonpolyposis colorectal cancer (HNPCC) (defined by Amsterdam criteria) who had undergone hysterectomy and/or salpingo-oophorectomy for a prophylactic or non-prophylactic indication. Indications for surgery and the prevalence of cancer at the time of each operation were reviewed. RESULTS 24 of 76 patients underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy for Lynch syndrome or HNPCC. In 9 of these patients, a benign indication for surgery was also noted. 4 of 24 patients (17%, 95% CI = 5-38%) were noted to have cancer on final pathology. 20 of 76 patients (26%) undergoing operative management for any indication were noted to have occult malignancy on final pathology. CONCLUSIONS Patients should be counseled about the risks of finding gynecologic cancer at the time of prophylactic or non-prophylactic surgery for Lynch syndrome and HNPCC, and the potential need for additional surgery.

Desmoid tumors do not prevent proctectomy following abdominal colectomy and ileorectal anastomosis in patients with familial adenomatous polyposis.

BACKGROUND: Elective proctocolectomy has been recommended for patients at high risk of desmoids based on the possibility that cancer in a retained rectum may be unresectable because of desmoid disease. There are no data to support the reality of this concern. OBJECTIVE: The aim of this study was to see how often proctectomy was prevented by desmoids. DESIGN: This retrospective, descriptive, database study was augmented by chart review. SETTING: This study was conducted at a hereditary colorectal cancer clinic in a tertiary referral center. PATIENTS: Those presenting for proctectomy after colectomy and ileorectal anastomosis for familial adenomatous polyposis were selected. INTERVENTIONS: Patients underwent a proctectomy. MAIN OUTCOME MEASURES: The primary outcomes measured were the rate of proctectomy, rate of IPAA, and the incidence of desmoid disease. RESULTS: Sixty- seven patients, 34 men and 33 women, underwent an operation with the intent of performing proctectomy. Mean age at surgery was 39.7 years, an average of 175 months from ileorectal anastomosis. Indications for proctectomy were uncontrollable adenomas in 56, cancer in 8, and high-grade dysplasia in 3. Proctectomy was always possible. Ileal pouch-anal anastomosis was planned in 62 patients; 54 had this operation. Desmoid disease was found in 26 patients (38.8%) and influenced surgery in 13 cases, stopping pouch-anal anastomosis in 8. One patient had no resection, 2 had a pouch-low rectal anastomosis, and 5 had proctectomy and ileostomy. Proctectomy and ileostomy was planned in 5 patients and performed in all. LIMITATIONS: This is a retrospective review from a single institution. CONCLUSION: The fear of an unresectable rectum or an impossible pouch-anal anastomosis should not be an indication for proctectomy in patients with low rectal polyp counts but a high risk for desmoid disease.

Correspondence to Vorselaars et al. Thoracic Aorta Dilation in Patients With Hereditary Hemorrhagic Telangiectasia Due to SMAD4 Gene Mutation

Correspondence to Vorselaars et al. Thoracic Aorta Dilation in Patients with Hereditary Hemorrhagic Telangiectasia Due to SMAD4 Gene Mutation Brandie Heald,* Christina Rigelsky, Rocio Moran, Lisa LaGuardia, Margaret O’Malley, Carol A. Burke, and Kenneth Zahka Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio Sanford R Weiss Center for Hereditary Colorectal Cancer Neoplasia, Cleveland Clinic, Cleveland, Ohio Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio Pediatric Cardiology, Cleveland Clinic, Cleveland, Ohio Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio

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.