Progression and Management of Duodenal Neoplasia in Familial Adenomatous Polyposis: A Cohort Study.

OBJECTIVE: To describe the natural history and outcomes of surveillance of duodenal neoplasia in familial adenomatous polyposis (FAP). BACKGROUND: Duodenal cancer is the most common cause of death in FAP. METHODS: Cohort study of patients prospectively enrolled in an upper endoscopic surveillance protocol from 1982 to 2012. The duodenum was assessed by side-viewing endoscopy and classified as stage 1 to 5 disease. Endoscopic and/or operative interventions were performed according to stage. RESULTS: There were 218 patients in the protocol (98 with advanced stage). They had a median of 9 endoscopies (range: 2-25) over a median of 11 years (range: 1-26). Median age at diagnosis of stage 3 disease (adenoma: 2.1-10 mm) was 41 years and stage 4 disease (adenoma >10 mm) was 45 years. Median time from first esophagogastroduodenoscopy to stage 4 disease was 22.4 years. The risk of stage 4 disease was 34.3% [95% confidence interval (CI) 23.8-43.4] at 15 years. In multivariate analysis, sex, type of colorectal surgery, years since colorectal surgery, and stage were significantly associated with risk of progression to stage 4 disease. Five of 218 (2.3%) patients developed duodenal cancer at median age of 58 years (range: 51-65). The risk of developing duodenal cancer was 2.1% (95% CI: 0-5.2) at 15 years. CONCLUSIONS: Patients with advanced duodenal polyposis progress in the severity of disease (size and degree of dysplasia); however, the rate of progression to carcinoma is slow. Aggressive endoscopic and surgical intervention, especially in the presence of large polyps and high-grade dysplasia, appears to be effective in preventing cancer deaths in FAP.

Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder most often caused by mutation in the endoglin or ALK1 genes. A distinct syndrome combines the clinical features of HHT and juvenile polyposis (JP) and has been associated with SMAD4 mutation. The aim of this study was to describe the phenotype of patients with JP-HHT and SMAD4 mutations and to compare this phenotype with HHT or JP patients with mutations other than SMAD4. METHODS: Patients prospectively enrolled in the Toronto HHT and JP databases who underwent genotyping were included. The phenotypic characteristics of JP-HHT patients with SMAD4 mutations and patients with mutations other than SMAD4 were analyzed and compared. RESULTS: Three hundred and fifty-eight patients underwent genetic testing (HHT, n = 332; JP, n = 26). Among fourteen patients identified with SMAD4 mutations, ten met the clinical diagnostic criteria for both JP and HHT (71%). Patients with SMAD4 mutations had 100% penetrance of the polyposis phenotype. All patients with JP and SMAD4 mutation had features of HHT. Three JP-HHT patients developed early onset colorectal cancer (CRC) (mean age 28 years). JP-HHT patients with SMAD4 mutation had a significantly higher rate of anemia than HHT patients with mutations other than SMAD4. CONCLUSIONS: Patients with HHT and SMAD4 mutations are at significant risk of JP and CRC. The gastrointestinal phenotype is similar to JP patients without SMAD4 mutation. It is essential for HHT patients to undergo genetic testing to determine if they have SMAD4 mutations so that appropriate gastrointestinal screening and surveillance for JP and CRC can be completed.

Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly.

The FAP self-concept scale (adult form).

UNLABELLED: Familial Adenomatous Polyposis (FAP) is a dominantly inherited disorder characterized by multiple colorectal adenomas associated with a 100% risk of early colorectal cancer. A diagnosis of FAP may alter a person's self-concept, which in turn may impact on an individual's quality of life and screening behaviors. PURPOSE: The purpose of the study was to develop and validate a scale for measuring the impact of being diagnosed with FAP on an individual's self-concept. METHODS: The study was conducted in two phases: Phase (1) Item generation and refinement, and Phase (2) Scale selection and initial validation. Adults age 18 and older. RESULTS: During Phase 1, scale items were generated through individual interviews and two professionally led focus groups. In Phase 2, 132/200 (66%) participants completed the 41-item candidate scale and a battery of standardized validating measures. The mean age of participants was 48 (12.2) years (range 21-74), 57% were female, 72% were married and 69% were Anglo-Canadian. The study resulted in a 23-item valid and reliable scale, Cronbach's alpha = .92, inter-item correlation = .34, total variance explained = 52.6%, low correlation with social desirability, and expected relationships with the other validating measures. Factor analysis resulted in three subscales representing the dimensions of stigma, self-esteem and mastery. CONCLUSIONS: A promising new scale for measuring self-concept among adults with FAP has been developed. The instrument has potential use as a clinical screening tool and a research measure that will contribute to the empirical and theoretical literature.

Psychosocial impact of Peutz-Jeghers Syndrome.

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant inherited cancer predisposition syndrome and gastrointestinal hamartomatous polyposis syndrome characterized by the presence of distinct perioral freckling. To date, we have not found any tool that specifically assesses the psychosocial impact of PJS on patients. We developed a PJS quality of life questionnaire using expert opinions of 3 cancer genetic counselors and a survey of patients with PJS through recruitment of participants involved in a support group over the internet. We measured and compared our questionnaire results to the widely used Center for Epidemiologic Studies and Depression Scale (CES-D) and the Short Form 36 (SF-36). We recruited 38 patients for our study. Volunteers were mailed a consent form, the self-administered CES-D, SF-36 and our developed PJS questionnaire and were instructed to return the completed questionnaires by mail. Results showed that PJS patients suffer from mild depression even though physically they did not feel impacted by their condition compared to the general population. However, having PJS caused them to alter many important life decisions. The PJS Questionnaire correlated with data obtained from analysis of CES-D, as well as the SF-36. More uniquely, it provided specific information regarding the burden of disease and quality of life in patients affected with Peutz-Jeghers syndrome. Its ability to do so for other polyposis syndrome populations remains to be studied. These results are important in developing plan of care for these patients regarding genetic counseling and surveillance strategies for PJS patients.

A large novel deletion in the APC promoter region causes gene silencing and leads to classical familial adenomatous polyposis in a Manitoba Mennonite kindred.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by the inheritance of germline mutations in the APC tumour suppressor gene. The vast majority of these are nonsense and frameshift mutations resulting in a truncated protein product and abnormal function. While APC promoter hypermethylation has been previously documented, promoter-specific deletion mutations have not been reported. In a large Canadian Mennonite polyposis kindred, we identified a large novel germline deletion in the APC promoter region by linkage analysis and MLPA. By RT-PCR and sequence analysis, this mutation was found to result in transcriptional silencing of the APC allele. A few genetic disorders have been characterized as over-represented in the Manitoba Mennonite population, however, the incidence of cancer has not been recognized as increased in this population as compared to other Manitoba ethnic groups. This study strengthens the likelihood that this novel APC promoter mutation is linked to this unique population as a founder mutation.

Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients.

OBJECTIVES: MYH is a member of the DNA base excision repair (BER) pathway and mutations of this gene predispose to the development of colorectal neoplasia in an autosomal recessive transmission pattern. Our objective was to determine the significance of MYH mutations in a series of Canadian patients with multiple adenomas. METHODS: We screened for germline MYH mutations (by dHPLCO) in 20 clinic-based multiple adenoma patients who were adenomatous polyposis coli (APC) mutation-negative. Suspected mutations were confirmed by sequence analysis. RESULTS: Six of 20 (30%) patients carried pathogenic biallelic MYH mutations, 1 Y165C homozygote and 5 compound heterozygotes of other sequence variants. We identified three novel variants, Q377X, 1314delA, and P281L, which are likely pathogenic. Twenty-nine relatives of the Y90X/1103delC compound heterozygous carrier were also screened for germline MYH mutations, and 1 homozygous and 14 heterozygous carriers were identified. CONCLUSIONS: Among patients with multiple adenomas, biallelic MYH mutations account for approximately 30% of APC mutation negative cases and two thirds of these carry mutations other than the "common" Y165C and G382D variants. Clinical screening algorithms which focus only on the Y165C and G382D alleles are inadequate since additional pathogenic mutations may be identified by screening the entire gene.

Staging intra-abdominal desmoid tumors in familial adenomatous polyposis: a search for a uniform approach to a troubling disease.

INTRODUCTION: Desmoid tumors are a clinical problem in 12 to 15 percent of patients with familial adenomatous polyposis. There is no predictably effective treatment for intra-abdominal desmoid tumors, which sometimes cause significant complications by their effects on the ureters or bowel. The relative rarity and the clinical heterogeneity of intra-abdominal desmoid tumors make randomized studies difficult to do. In this article a staging system is proposed to make multi-institutional studies easier. METHODS: Intra-abdominal desmoid tumors can be staged according to their size, clinical presentation and growth pattern. CONCLUSION: A way of staging intra-abdominal desmoid tumors is proposed to facilitate stratification by disease severity during collaborative studies of various treatments.

Quality of life in adults diagnosed with familial adenomatous polyposis and desmoid tumor.

PURPOSE: The purpose of this study was to examine the health-related quality of life in a sample of Canadian adults diagnosed with familial adenomatous polyposis and desmoid tumor. METHODS: The study was conducted in two parts. Seven individuals participated in a focus group prior to a mail-out survey. A cross-sectional mail-out survey was administered to eligible individuals who were actively followed at the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital. RESULTS: Forty-one individuals (25 female and 16 male) were available to be contacted by the registry coordinator and 23 questionnaire packages were completed, resulting in a 56.1 percent participation rate. The results of this study demonstrated a reduced health-related quality of life for individuals living with familial adenomatous polyposis and desmoid tumor for over 10 years. The main predictors of health-related quality of life in this analysis included marital status (married vs. not married), prior knowledge of desmoid tumor in the family, and current level of hopelessness (R(2) = 0.856, df = 13, F = 26.8, P < 0.001). The qualitative content analysis of themes from the focus group indicated that ongoing medical uncertainty and lack of information from health care professionals, isolation, and family communication were the main challenges in living with desmoid tumors. CONCLUSIONS: The findings from this study suggest that ongoing education of health care professionals is warranted and that information and support interventions may be beneficial to this clinical population.

Genotype and phenotype of patients with both familial adenomatous polyposis and thyroid carcinoma.

The incidence of thyroid carcinoma in familial adenomatous polyposis (FAP) is thought to be 1%-2%, with the majority of cases being female. We have investigated the phenotype and genotype of 16 patients with FAP associated thyroid carcinoma. Among 1194 FAP patients studied in two high risk registries in North America (Familial Gastrointestinal Cancer Registry, Toronto and University California, San Francisco), 16 (1.3%) unrelated patients with FAP associated thyroid cancers were identified. Adenomatous polyposis coli (APC) gene testing was performed in 14 of the 16 cases. The average age of diagnosis for FAP and thyroid carcinoma was 29 years (range 17-52 years) and 33 years (range 17-55 years), respectively. All FAP patients except 1 had more than 100 colonic adenomas. Extracolonic manifestations, beside thyroid cancer, were presented in 81% (n = 13) of the patients, including gastric and duodenal polyps, desmoid tumor, osteoma, epidermoid cyst, sebaceous cyst and lipoma. Colorectal cancer was diagnosed in 38% (n = 6) of the patients. The pathology of the FAP associated thyroid cancer was predominantly papillary carcinoma. Germline mutations were identified in 12 of 14 patients tested. Mutations proximal to the mutation cluster region (1286-1513) were detected in 9 cases. Thyroid cancer in our FAP population was rare, predominantly in females and showed papillary carcinoma histology. Additionally, thyroid cancer in our patients occurred in the setting of classic FAP phenotype. Germline mutations were located predominantly outside the APC mutation cluster region.

Slow progression of periampullary neoplasia in familial adenomatous polyposis.

Variable endoscopic surveillance protocols and treatment strategies have been proposed for periampullary neoplasia in familial adenomatous polyposis (FAP), primarily because of the lack of long-term, prospective natural history data. A total of 115 patients with FAP were followed prospectively for 10 years with periodic side-viewing upper gastrointestinal endoscopy by a single surgeon. The appearance of the duodenum was classified as stages 1 to 5. Statistical analysis included one-way analysis of variance for age comparisons between stage groupings and Kaplan-Meier analysis for the lifetime risks of having a particular stage of duodenal polyposis. Eighty-seven patients had multiple endoscopies over an average of 6.6 years. Thirty-three subjects had a change in stage, within an average time of 3.9 years at an average age of 41 years. The risk of having stage 3 or 4 duodenal neoplasia increased exponentially after the age of 40. The degree of dysplasia did not correlate with stage at initial classification. Progression of neoplasia in the duodenum of patients with FAP is slow. The severity of duodenal polyposis increases with age and is not influenced by the initial stage. The average time for progression of adenoma to carcinoma is likely long.