Whole Genome Sequencing Applied in Familial Hamartomatous Polyposis Identifies Novel Structural Variations.

Hamartomatous polyposis syndromes (HPS) are rare cancer-predisposing disorders including Juvenile polyposis (JPS), Peutz-Jeghers (PJS) and PTEN hamartomatous syndromes (PHS). Penetrant mutations in corresponding genes (SMAD4, BMPR1A, STK11, PTEN and AKT1), are usually diagnosed via a next-generation-sequencing gene panel (NGS-GP) for tailored surveillance and preimplantation testing for monogenic disorders (PGT-M). Five probands with HPS phenotype, with no genetic diagnosis per genetic workup, underwent whole-genome sequencing (WGS) that identified structural genetic alterations: two novel inversions in BMPRA1 and STK11, two BMPR1A-deletions, known as founders among Bukharan Jews, and BMPR1A microdeletion. BMPR1A inversion was validated by "junction fragment" amplification and direct testing. PGT-M was performed via multiplex-PCR and enabled successful birth of a non-carrier baby. WGS may be considered for HPS patients with no NGS-GP findings to exclude structural alterations.

Juvenile polyposis: Focus on less described manifestations.

Juvenile polyposis represents an heterogeneous disease as different genetic dominant backgrounds have been evidenced leading to different clinical presentations. It is associated in some patients with a different syndrome, Hereditary Hemorragic Telangiectasia, justifying a complementary and different management. Recent international recommendations help in managing this very rare disease, and this management should probably be restricted to expert centers able to take care of the multiple manifestations and risks of these patients and families. This paper will focus on the poorly known and evaluated aspects of juvenile polyposis, excluding the colonic involvement and epidemiology that are addressed in a different article of this issue.

Clinicopathological characteristics of colorectal serrated polyposis syndrome (SPS): results of a multicenter study by the SPS Study Group in Japan.

BACKGROUND: Serrated polyposis syndrome (SPS), a type of colorectal polyposis characterized by multiple serrated polyps, is associated with a high risk of colorectal carcinoma (CRC). This study aimed to clarify the clinicopathological characteristics of SPS in Japan. METHODS: We investigated the clinicopathological characteristics of patients with SPS from the "Multicenter Study on Clinicopathological Characteristics of SPS (UMIN 000032138)" by the Colorectal Serrated Polyposis Syndrome (SPS) Study Group. In this study, patients were diagnosed with SPS based on the 2019 World Health Organization (WHO) SPS diagnostic criteria. RESULTS: Ninety-four patients were diagnosed with SPS in 10 institutions between January 2001 and December 2017. The mean number (± standard deviation [SD]) of resected lesions per patient was 11.3 ± 13.8. The mean age at diagnosis of SPS was 63.3 ± 11.6 years, and 58 patients (61.7%) were male. Eighty-seven (92.6%) and 16 (17.0%) patients satisfied WHO diagnostic criteria I and II, respectively. Nine patients (9.6%) satisfied both criteria I and II. Carcinoma (T1-T4) were observed in 21 patients (22.3%) and 24 lesions. Of the 21 patients with CRC, 19 (90.4%) satisfied diagnostic criterion I, 1 (4.8%) satisfied diagnostic criterion II, and 1 (4.8%) satisfied diagnostic criteria I and II. There was no notable difference in the prevalence of CRC among patients who met diagnostic criterion I, II, and both I and II. CONCLUSIONS: Patients with SPS have a high risk of CRC and should undergo regular surveillance colonoscopy. Raising awareness of this syndrome is crucial.

Clinical and Endoscopic Characteristics of Chinese Cronkhite-Canada Syndrome Patients: A Retrospective Study of 103 Cases.

INTRODUCTION: Cronkhite-Canada syndrome (CCS) is a rare non-inherited disease characterized by extensive gastrointestinal (GI) polyposis and ectodermal dysplasia. So far, most of CCS related literatures are published as single case report or reviewed with limited case numbers. Our study was to update the clinical and endoscopic characteristics of Chinese CCS patients. METHODS: This retrospective study was conducted in 103 Chinese CCS patients (102 cases from literatures and 1 case from our department). Their clinical and endoscopic data were collected, and statistical analyses were performed. RESULTS: (1) In Chinese population, people aged 50-70 years (62.62%) had a high incidence of CCS, and the ratio of male-to-female was 2.68:1. (2) The diverse range of GI manifestations was observed in all the patients, and almost all the patients had at least 1 symptom of ectodermal dysplasias. (3) All CCS patients presented multiple polyps in the GI tract except esophagus, and the size and appearance of polyps were diverse. Congestion, edema, and erosion were very common on the surface of polyps (96.83%) and the surrounding mucosa (85.71%). (4) The common pathological features of polyps were hyperplastic polyps (49.25%) and tubular adenomatous polyps (44.78%). The prevalence of cancer was 5.97% in Chinese CCS patients. CONCLUSIONS: Middle-aged and elderly people are the high-risk group. Various GI symptoms are observed in Chinese patients; the typical endoscopic finding is multiple small sessile polyps. These GI polyps have a chance of malignant potential. Long-term endoscopic surveillance and follow-up are recommended for the Chinese CCS patients.

Estimated Prevalence of Cronkhite-Canada Syndrome, Chronic Enteropathy Associated With SLCO2A1 Gene, and Intestinal Behçet's Disease in Japan in 2017: A Nationwide Survey.

BACKGROUND: Cronkhite-Canada syndrome (CCS), chronic enteropathy associated with SLCO2A1 gene (CEAS), and intestinal Behçet's disease (BD) are classified as intractable intestinal disorders in Japan. However, the national prevalence of these diseases remains unknown. We performed a nationwide survey to estimate the patient numbers and prevalence rates of these diseases throughout Japan in 2017. METHODS: We conducted a mail-based survey targeting hospitals across Japan to estimate the annual numbers of patients with CCS, CEAS, and intestinal BD in 2017. Using a stratified random sampling method, we selected 2,979 hospital departments and asked them to report the number of patients who met specific diagnostic criteria. The total number of patients for each disease was estimated by multiplying the reported numbers by the reciprocal of the sampling rate and response rate. The corresponding prevalence rates per 1,000,000 population were calculated based on the mid-year population of Japan in 2017. RESULTS: The overall survey response rate was 68.1% (2,029 departments). The estimated numbers of patients with CCS, CEAS, and intestinal BD were 473 (95% confidence interval [CI], 357-589), 388 (95% CI, 289-486), and 3,139 (95% CI, 2,749-3,529), respectively; the prevalence rates per 1,000,000 population were 3.7 (male: 4.0; female: 3.5), 3.1 (male: 3.0; female: 3.1), and 24.8 (male: 24.5; female: 25.0), respectively. The male-to-female ratios were 1.10, 0.94, and 0.93 for patients with CCS, CEAS, and intestinal BD, respectively. CONCLUSIONS: Estimates of the national prevalence of CCS, CEAS, and intestinal BD in Japan were generated and found to be higher than those previously reported.

Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers.

PURPOSE: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. METHODS: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. RESULTS: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). CONCLUSION: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.

A Multi-Institutional Cohort of Therapy-Associated Polyposis in Childhood and Young Adulthood Cancer Survivors.

Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20-33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair-deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening.

Juvenile Polyps in Denmark From 1995 to 2014.

BACKGROUND: Juvenile polyps in the large bowel are rare but the most common type of polyp in children. The prevalence and incidence are unknown, and few studies exist on the occurrence in adults. They are considered not to harbor any malignant potential unless they are part of the hereditary juvenile polyposis syndrome. OBJECTIVE: We aimed to study the demographics of juvenile polyps in Denmark in a 20-year period from 1995 to 2015 in both adults and children. This is the first report on the occurrence, anatomic localization, and reoccurrence of these polyps in a whole population. DESIGN: Data from all of the patients who had been diagnosed with 1 or more juvenile polyp from January 1, 1995, until December 31, 2014, were obtained. SETTINGS: The study was conducted based on patients registered in the nationwide pathological register in Denmark, the Danish Pathology Data Bank. PATIENTS: We detected a total of 1772 patients who had 2108 juvenile polyps removed (male = 946; female = 826). MAIN OUTCOME MEASURES: We noted the sex, age, number, reoccurrence, and localization of polyps. RESULTS: Of the detected juvenile polyps ≈75% were detected in adults and ≈25% in children. Approximately 96% of the patients had a single juvenile polyp without reoccurrence, 1% fulfilled the diagnostic criteria for juvenile polyposis syndrome (more than 5 polyps), and 5% had multiple juvenile polyps (2-5 polyps). The incidence in the Danish population can be estimated to be between 1:45,000 and 1:65,000. LIMITATIONS: Miscoding or misclassification in the register cannot be ruled out. We only have data for the 20-year period, limiting the evaluation of reoccurrence, and no data for the endoscopic removal procedures. CONCLUSIONS: We conclude that juvenile polyps are rare, with the majority found in adults, and most often found as a single juvenile polyp. A subgroup of patients have juvenile polyposis syndrome, which requires follow-up.

Low prevalence of serrated polyposis syndrome in screening populations: a systematic review.

BACKGROUND AND STUDY AIMS: The most frequently cited prevalence for serrated polyposis syndrome (SPS) is 1 in every 3000 people screened, but this value is debated. Additionally, changes in 2010 in the World Health Organization (WHO) diagnostic criteria for SPS might affect reported prevalence. An updated estimate of SPS prevalence is necessary to predict the number of cases in screening programs. PATIENTS AND METHODS: A systematic literature search was conducted in the PubMed, EMBASE, and Web of Science databases up to February 2014. Studies reporting the prevalence of SPS, as defined by WHO criteria, in screening populations were selected. RESULTS: Six studies reported prevalence of SPS in screening populations, varying from 0 to 0.66 %. The highest prevalences (0.34 % and 0.66 %) were seen in studies from screening programs with patients pre-selected by fecal blood test. Primary colonoscopy-based screening programs, that have the lowest risk of bias, reported SPS prevalences ranging from 0 to 0.09 %. Across studies, 56 patients were diagnosed with SPS of whom 3 presented with synchronous colorectal cancer at index endoscopy. CONCLUSION: The true prevalence of SPS is unclear because of the risk of bias across studies, but is likely to be below 0.09 % as derived from primary colonoscopy screening programs. The prevalence in pre-selected screening populations after positive fecal testing is higher, with reported values of 0.34 % and 0.66 %. Large and high quality primary colonoscopy screening studies, reporting SPS prevalence in adequately described populations, are necessary for better estimation of the true prevalence of SPS in average-risk patients.

Familial colorectal cancer.

Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz-Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up.

Serrated polyposis is an underdiagnosed and unclear syndrome: the surgical pathologist has a role in improving detection.

Serrated polyposis syndrome (SPS) is poorly defined and patients have an increased but unspecified risk for colorectal carcinoma through the serrated pathway. Despite this association SPS remains relatively obscure and is therefore likely underrecognized. We determined the frequency of SPS among patients with any serrated polyps (SPs) over a 6-month "index" period, and in doing so we assessed the ability of surgical pathologists to improve SPS detection. Particular attention was given to the index procedure to assess the potential predictive value of the findings resulting from a single colonoscopy. A total of 929 patients with at least 1 SP were identified, 17 of whom (1.8%) were determined to meet World Health Organization criteria for SPS. Nine patients met the first criterion (≥ 5 proximal SPs, 2 of which are > 10 mm); 4 met the third criterion (> 20 SPs of any size distributed throughout the colon); and 4 met both criteria. Although no specific SP size or number at the index procedure was clearly superior in its ability to predict SPS, > 50% of cases would be detected if a cutoff of ≥ 3 SPs or a single SP ≥ 15 mm at the index procedure is used. In summary, SPS is rare but more likely underdiagnosed. Additional studies to address the underlying genetic basis for SPS are ongoing in order to shed further light on this syndrome. Surgical pathologists are in a unique position to assist in this endeavor by identifying those patients who either meet or seem to be at high risk of meeting World Health Organization criteria.

Clinicopathological significance of synchronous carcinoma in colorectal cancer.

BACKGROUND: Synchronous colorectal carcinoma has seldom been studied in large series. The study was designed to examine the significance of colorectal synchronous carcinoma in a large cohort of patients. METHODS: The clinicopathological features of 102 patients with synchronous colorectal carcinoma were compared with 1,793 patients with solitary colorectal carcinoma. RESULTS: The prevalence of synchronous colorectal carcinoma was 3.6%. In these patients, 4% had FAP, 6% had hyperplastic polyposis, and 2% had ulcerative colitis. The index carcinoma was more likely to have higher histological grade and T stage than other carcinoma(s) in the same patient. When compared with solitary colorectal carcinoma, synchronous colorectal carcinoma was more often noted in males with coexisting FAP and in proximal location. The 5-year survival rate of patients with synchronous colorectal carcinoma was 53% and was similar to those with solitary colorectal carcinoma. CONCLUSIONS: We examined the clinicopathological features of patients with synchronous colorectal carcinomas in a large cohort of patients. Attention to these features was important for better management of this group of cancer.

Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome.

INTRODUCTION: Hyperplastic polyposis syndrome (HPS) is characterised by the presence of multiple colorectal hyperplastic polyps and is associated with an increased colorectal cancer (CRC) risk. For first-degree relatives of HPS patients (FDRs) this has not been adequately quantified. Reliable evidence concerning the magnitude of a possible excess risk is necessary to determine whether preventive measures, like screening colonoscopies, in FDRs are justified. AIMS AND METHODS: We analysed the incidence rate of CRC in FDRs and compared this with the general population through person-year analysis after adjustment for demographic characteristics. Population-based incidence data from the Eindhoven Cancer Registry during the period 1970-2006 were used to compare observed numbers of CRC cases in FDRs with expected numbers based on the incidence in the general population. RESULTS: A total of 347 FDRs (41% male) from 57 pedigrees were included, contributing 11 053 person-years of follow-up. During the study period, a total of 27 CRC cases occurred among FDRs compared to five expected CRC cases (p<0.001). The RR of CRC in FDRs compared to the general population was 5.4 (95% CI 3.7 to 7.8). Four FDRs satisfied the criteria for HPS. Based on the estimated HPS prevalence of 1:3000 in the general population the projected RR of HPS in FDRs was 39 (95% CI 13 to 121). CONCLUSIONS: FDRs of HPS patients have an increased risk for both CRC and HPS compared to the general population. Hence, as long as no genetic substrate has been identified, screening colonoscopies for FDRs seem justified but this needs to be prospectively evaluated.

Juvenile polyps: recurrence in patients with multiple and solitary polyps.

BACKGROUND & AIMS: Juvenile polyps are benign hamartomas with neoplastic potential that are the most frequent gastrointestinal polyp of childhood. Most information about juvenile polyps in childhood comes from small published series that lack detailed outcome data. We sought to identify a large cohort of children with one or more polyps and analyze clinical characteristics, including polyp recurrence, which might contribute to the development of management guidelines. METHODS: A retrospective chart review study of patients with juvenile polyps of the colon was performed. Cases were identified by searching a single hospital pathology database from 1990 to 2009 for the diagnosis of juvenile polyps. Recorded information included basic demographics, family history, genetic testing, and colonoscopy and pathology reports. RESULTS: A total of 257 children (median age, 5.6 y; 61.5% male) with juvenile polyps were identified. Among 192 patients who underwent complete colonoscopy at initial diagnosis, 117 (60.9%) had a single polyp, 75 (39.1%) had multiple polyps, 8 (4.2%) had polyps restricted to the right colon, and a total of 1653 polyps were found during 350 colonoscopy examinations. Polyps recurred in 21 of 47 (44.7%) patients after initial eradication, including 3 (16.7%) of 18 presenting with a single polyp. Neoplasia was found in 10 of 257 (3.9%) patients (right colon in 7 patients). Germline DNA abnormalities in mothers against decapentaplegic Drosophila (SMAD4), bone morphogenetic protein receptor 1A (BMPR1A), and phosphatase and tensin homolog (PTEN) were detected in 10 of 23 (43.5%) patients with multiple polyps. CONCLUSIONS: Recurrent polyp formation is common in children with juvenile polyps and occurs in patients with multiple and solitary polyps. Standardized protocols for detecting polyp recurrence, associated gene mutations, and neoplasia should be developed for children with juvenile polyps.

Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study.

BACKGROUND AND AIMS: Patients with hyperplastic polyposis syndrome (HPS) receive endoscopic surveillance to prevent malignant progression of polyps. However, the optimal treatment and surveillance protocol for these patients is unknown. The aim of this study was to describe the clinical and pathological features of a large HPS cohort during multiple years of endoscopic surveillance. METHODS: Databases were searched for patients with HPS, who were analysed retrospectively. Endoscopy reports and histopathology reports were collected to evaluate frequency of endoscopic surveillance and to obtain information regarding polyp and the presence of colorectal cancer (CRC). RESULTS: In 77 patients with HPS, 1984 polyps were identified during a mean follow-up period of 5.6 years (range: 0.5-26.6). In 27 (35%) patients CRC was detected of which 22 (28.5%) at initial endoscopy. CRC was detected during surveillance in five patients (cumulative incidence: 6.5%) after a median follow-up time of 1.3 years and a median interval of 11 months. Of these interval CRCs, 4/5 were detected in diminutive serrated polyps (range: 4-16 mm). The cumulative risk of CRC under surveillance was 7% at 5 years. At multivariate logistic regression, an increasing number of hyperplastic polyps (OR 1.05, p=0.013) and serrated adenomas (OR 1.09, p=0.048) was significantly associated with CRC presence. CONCLUSIONS: HPS patients undergoing endoscopic surveillance have an increased CRC risk. The number of serrated polyps is positively correlated with the presence of CRC in HPS, thus supporting a 'serrated pathway' to CRC. To prevent malignant progression, adequate detection and removal of all polyps seems advisable. If this is not feasible, surgical resection should be considered.