ABSTRACT
BACKGROUND & AIMS: Desmoid tumors (DT) are an important cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP). DT development might be related to the type and approach of colectomy. We aimed to compare DT development after colectomy with ileorectal anastomosis (IRA) and proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: We performed an international historical cohort study in patients with FAP who underwent IRA or IPAA between 1961 and 2020. The primary outcome was the incidence of abdominal DT (either mesenteric, retroperitoneal, or abdominal wall). Patients with a DT diagnosis before or at colectomy were excluded. Time to DT was considered censored at an eventual secondary proctectomy after IRA. We used multivariable Cox regression modelling to adjust for potential confounders. RESULTS: We analyzed data from 852 patients: 514 after IRA and 338 after IPAA (median follow-up, 21 and 16 years, respectively). DTs were diagnosed in 64 IRA patients (12%) and 66 IPAA patients (20%). The cumulative DT incidence at 5 and 10 years was 7.5% and 9.3% after open IRA and 4.7% and 10.9% after laparoscopic IRA. These estimates were 13.6% and 15.4% after open IPAA and 8.4% and 10.0% after laparoscopic IPAA. The postoperative risk was significantly higher after IPAA (P < .01) in multivariable analysis, whereas approach did not significantly influence the risk. CONCLUSIONS: The risk of developing an abdominal DT was found to be significantly higher after IPAA than after IRA. Postoperative DT risk should be taken into account when choosing between IRA and IPAA in FAP.
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PURPOSE: The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome. METHODS: Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants. RESULTS: The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS). CONCLUSION: The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.
Subject(s)
Adenomatous Polyposis Coli , Genetic Testing , Humans , Genetic Testing/methods , Genetic Variation , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Germ-Line Mutation/genetics , Germ CellsABSTRACT
BACKGROUND: Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. METHODS: A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%). RESULTS: One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. CONCLUSION: These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres.
Subject(s)
Adenocarcinoma , Adenomatous Polyposis Coli , DNA Glycosylases , Stomach Neoplasms , Humans , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/therapy , Adenomatous Polyposis Coli/diagnosis , Stomach Neoplasms/genetics , Stomach Neoplasms/therapy , Stomach Neoplasms/diagnosis , Adenocarcinoma/genetics , Adenocarcinoma/therapy , Adenocarcinoma/diagnosis , DNA Glycosylases/genetics , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Neoplastic Syndromes, Hereditary/diagnosis , Europe , Adenomatous Polyps/genetics , Adenomatous Polyps/therapy , PolypsABSTRACT
OBJECTIVE: A constitutional disease-causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%-60% of patients with juvenile polyposis syndrome (JPS). The aim of this study was to characterize the clinical course and polyp burden in children with DCV-positive JPS compared to DCV-negative JPS. METHODS: Demographic, clinical, genetic, and endoscopic data of children with JPS were compiled from eight international centers in the ESPHGAN/NASPGHAN polyposis working group. RESULTS: A total of 124 children with JPS were included: 69 (56%) DCV-negative and 55 (44%) DCV-positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range) follow-up of 4 (2.8-6.4) years. DCV-positive children were diagnosed at an older age compared to DCV-negative children [12 (8-15.7) years vs. 5 (4-7) years, respectively, p < 0.001], had a higher frequency of family history of polyposis syndromes (50.9% vs. 1.4%, p < 0.001), experienced a greater frequency of extraintestinal manifestations (27.3% vs. 5.8%, p < 0.001), and underwent more gastrointestinal surgeries (16.4% vs. 1.4%, p = 0.002). The incidence rate ratio for the development of new colonic polyps was 6.15 (95% confidence interval 3.93-9.63, p < 0.001) in the DCV-positive group compared to the DCV-negative group, with an average of 12.2 versus 2 new polyps for every year of follow-up. There was no difference in the burden of polyps between patients with SMAD4 and BMPR1A mutations. CONCLUSIONS: This largest international cohort of pediatric JPS revealed that DCV-positive and DCV-negative children exhibit distinct clinical phenotype. These findings suggest a potential need of differentiated surveillance strategies based upon mutation status.
Subject(s)
Bone Morphogenetic Protein Receptors, Type I , Intestinal Polyposis , Mutation , Neoplastic Syndromes, Hereditary , Phenotype , Smad4 Protein , Humans , Smad4 Protein/genetics , Bone Morphogenetic Protein Receptors, Type I/genetics , Child , Male , Female , Intestinal Polyposis/genetics , Intestinal Polyposis/congenital , Adolescent , Neoplastic Syndromes, Hereditary/genetics , Child, Preschool , Follow-Up StudiesABSTRACT
While constitutional pathogenic variants in the APC gene cause familial adenomatous polyposis, APC c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the APC I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the APC I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.
Subject(s)
Adenomatous Polyposis Coli , Colorectal Neoplasms , Humans , Genetic Predisposition to Disease , Adenomatous Polyposis Coli/genetics , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Genes, APC , Risk Factors , Jews/geneticsABSTRACT
BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.
Subject(s)
Colorectal Neoplasms , Endoscopy , Humans , Genetic Testing , Colorectal Neoplasms/diagnosisABSTRACT
BACKGROUND: Long-term pouch surveillance outcomes for familial adenomatous polyposis (FAP) are unknown. We aimed to quantify surveillance outcomes and to determine which of selected possible predictive factors are associated with pouch dysplasia. METHODS: Retrospective analysis of collected data on 249 patients was performed, analyzing potential risk factors for the development of adenomas or advanced lesions (â≥â10âmm/high grade dysplasia (HGD)/cancer) in the pouch body and cuff using Cox proportional hazards models. Kaplan-Meier analyses included landmark time-point analyses at 10 years after surgery to predict the future risk of advanced lesions. RESULTS: Of 249 patients, 76â% developed at least one pouch body adenoma, with 16â% developing an advanced pouch body lesion; 18â% developed an advanced cuff lesion. Kaplan-Meier analysis showed a 10-year lag before most advanced lesions developed; cumulative incidence of 2.8â% and 6.4â% at 10 years in the pouch body and cuff, respectively. Landmark analysis suggested the presence of adenomas prior to the 10-year point was associated with subsequent development of advanced lesions in the pouch body (hazard ratio [HR] 4.8, 95â%CI 1.6-14.1; Pâ=â0.004) and cuff (HR 6.8, 95â%CI 2.5-18.3; Pâ<â0.001). There were two HGD and four cancer cases in the cuff and one pouch body cancer; all cases of cancer/HGD that had prior surveillance were preceded by ≥â10-mm adenomas. CONCLUSIONS: Pouch adenoma progression is slow and most advanced lesions occur after 10 years. HGD and cancer were rare events. Pouch phenotype in the first decade is associated with the future risk of developing advanced lesions and may guide personalized surveillance beyond 10 years.
Subject(s)
Adenoma , Adenomatous Polyposis Coli , Colonic Pouches , Humans , Retrospective Studies , Colonic Pouches/adverse effects , Adenomatous Polyposis Coli/pathology , Adenoma/epidemiology , Adenoma/etiology , Adenoma/pathology , Risk FactorsABSTRACT
BACKGROUND: Attenuated familial adenomatous polyposis is characterised by low number (≤100) and delayed development of colorectal adenomas. Various definitions have been used, and genotype-phenotype correlations have been suggested. OBJECTIVE: We aimed to evaluate phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and assess familial variability. DESIGN: This is a retrospective study. SETTINGS: This study was conducted at a tertiary polyposis registry. PATIENTS: Individuals with attenuated familial adenomatous polyposis were identified. Phenotypic group was defined as 100 or fewer adenomas at age 25 years and genotypic group was defined as a variant in the adenomatous polyposis coli region associated with attenuated familial adenomatous polyposis. Pathology polyp count was used for patients who had undergone surgery and endoscopic polyp count for those with intact colon. MAIN OUTCOME MEASURES: We evaluated phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and familial variability. RESULTS: A total of 69 patients were identified in the phenotypic group, of whom 54 (78%) had a pathogenic variant in the attenuated regions of the adenomatous polyposis coli gene. Forty-eight (70%) had intact colon (median age at last colonoscopy 43 [25-73] years; median endoscopic polyp count 20 [0-100]) and 21 (30%) had undergone colectomy (median age at surgery 45 [25-54] years; median pathology polyp count 43 [3-100]). Eighty-three patients were identified in the genotypic group of which 54 (65%) had attenuated phenotype. Inter- and intrafamilial variability were observed. LIMITATIONS: This study was limited by its retrospective nature and single-center experience. CONCLUSION: Phenotype in familial adenomatous polyposis lies on a spectrum and is determined in part by genotype and age at adenoma count. Diagnosis of attenuated familial adenomatous polyposis should be based on phenotype; genotype is not a reliable indicator. Management should be personalized according to the phenotype of each individual. See Video Abstract at http://links.lww.com/DCR/B775. POLIPOSIS ADENOMATOSA FAMILIAR ATENUADA UN DIAGNSTICO FENOTPICO PERO TRMINO OBSOLETO: ANTECEDENTES:La poliposis adenomatosa familiar atenuada se caracteriza por un número bajo (≤100) y desarrollo retardado de adenomas colorrectales. Se han utilizado varias definiciones y se han sugerido correlaciones genotipo-fenotipo.OBJETIVO:Nuestro objetivo es evaluar la correlación fenotípica y genotípica en pacientes con presunta poliposis adenomatosa familiar atenuada y evaluar la variabilidad familiar.DISEÑO:Este es un estudio retrospectivo.AJUSTE:Este estudio se realizó en un registro terciario de poliposis.PACIENTES:Se identificaron individuos con poliposis adenomatosa familiar atenuada. El grupo fenotípico se definió como ≤100 adenomas a la edad de 25 años y el grupo genotípico se definió como una variante en la región de poliposis coli adenomatosa asociada con poliposis adenomatosa familiar atenuada. Se utilizó el recuento de pólipos en patología para los pacientes que se habían sometido a cirugía y el recuento de pólipos endoscópico para los que tenían el colon intacto.PRINCIPALES MEDIDAS DE RESULTADO:Evaluamos la correlación fenotípica y genotípica en pacientes con presunta poliposis adenomatosa familiar atenuada y variabilidad familiar.RESULTADOS:Un total de 69 pacientes se identificaron en el grupo fenotípico de los cuales 54 (78%) tenían una variante patogénica en las regiones atenuadas del gen de la poliposis coli adenomatosa. Cuarenta y ocho (70%) tenían colon intacto (edad media en la última colonoscopia 43 [25-73] años; mediana del recuento de pólipos endoscópicos 20 [0-100]) y 21 (30%) se habían sometido a colectomía (edad edia en el momento de la cirugía 45 [25-54] años; mediana del recuento de pólipos patológicos 43 [3-100]). Se identificaron 83 pacientes en el grupo genotípico de los cuales 54 (65%) tenían fenotipo atenuado. Se observó variabilidad inter e intrafamiliar.LIMITACIONES:Este estudio estuvo limitado por su naturaleza retrospectiva y la experiencia de un solo centro.CONCLUSIÓNES:El fenotipo en la poliposis adenomatosa familiar se encuentra en un espectro, determinado en parte por el genotipo y la edad en el momento del recuento de adenomas. El diagnóstico de poliposis adenomatosa familiar atenuada debe basarse en el fenotipo; el genotipo no es un indicador confiable. El manejo debe personalizarse según el fenotipo de cada individuo. Consulte Video Resumen en http://links.lww.com/DCR/B775.
Subject(s)
Adenoma , Adenomatous Polyposis Coli , Colorectal Neoplasms , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/surgery , Colorectal Neoplasms/pathology , Humans , Phenotype , Retrospective StudiesABSTRACT
AIM: Total colectomy with ileorectal anastomosis (TC-IRA) is a surgical option for patients with familial adenomatous polyposis (FAP). Regular endoscopic surveillance of the rectum is recommended to prevent rectal cancer. We aimed to document polyp progression in the rectum following TC-IRA and evaluate the role of polypectomy during surveillance. METHOD: Patients with FAP who underwent TC-IRA between 1990 and 2017 were identified. Demographic, endoscopic and genetic data were retrieved. Cumulative rectal adenoma (polyp) counts were obtained, whilst accounting for any polypectomies during the study period. The rate of polyp progression and factors influencing secondary proctectomy were evaluated. RESULTS: One hundred and ninety-nine patients fulfilled our inclusion criteria, of which 44% were male. The median age at colectomy was 19 (range 11-70) years and median preoperative rectal polyp count was 7 (range 0-50). All patients had an APC pathogenic variant, of which 151 (79%) were 5' of the mutation cluster region (MCR), 19 (10%) in the MCR, six (3%) were 3' of the MCR and 15 (8%) had a gross deletion. After a median follow-up of 8.6 (range1-27) years and a median of 11 (range 2-37) flexible sigmoidoscopies per patient, the median rate of polyp progression was 5.5 polyps/year (range 0-70.2). There was no evidence of polyp regression. Eight (4%) patients underwent secondary proctectomy for neoplasia, of which one (0.5%) had rectal adenocarcinoma. A total of 13,527 polyps were removed, a median of 35 polyps/patient (range 0-829). The rate of polyp progression was not significantly associated with genotypic or phenotypic factors. CONCLUSION: Progression of rectal adenoma burden following TC-IRA appears to be slow and dependent on the length of follow-up. In the modern era of stringent endoscopic surveillance and therapeutic procedures such as cold snare polypectomy, the rate of secondary proctectomy and the risk of rectal cancer after TC-IRA are very low. These findings are important when counselling patients with regard to the choice of surgery for FAP and implementing endoscopic surveillance.
Subject(s)
Adenoma , Adenomatous Polyposis Coli , Colonic Polyps , Rectal Neoplasms , Adenoma/surgery , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/surgery , Adolescent , Adult , Aged , Anastomosis, Surgical , Child , Colectomy , Colonic Polyps/surgery , Colonoscopy , Humans , Ileum/surgery , Male , Middle Aged , Rectal Neoplasms/surgery , Rectum/surgery , Young AdultABSTRACT
BACKGROUND: Patients with familial adenomatous polyposis (FAP) are at increased risk of developing gastric adenomas. There is limited understanding of their clinical course and no consensus on management. We reviewed the management of gastric adenomas in patients with FAP from two centers. METHODS: Patients with FAP and histologically confirmed gastric adenomas were identified between 1997 and 2018. Patient demographics, adenoma characteristics, and management/surveillance outcomes were collected. RESULTS: Of 726 patients with FAP, 104 (14â%; 49 female) were diagnosed with gastric adenomas at a median age of 47 years (range 19â-â80). The median size of gastric adenomas was 6âmm (range 1.5â-â50); 64 (62â%) patients had adenomas located distally to the incisura. Five patients (5â%) had gastric adenomas demonstrating high-grade dysplasia (HGD) on initial diagnosis, distributed equally within the stomach. The risk of HGD was associated with adenoma size (Pâ=â0.04). Of adenomasâ>â20âmm, 33â% contained HGD. Two patients had gastric cancer at initial gastric adenoma diagnosis. A total of 63 patients (61â%) underwent endoscopic therapy for gastric adenomas. Complications occurred in three patients (5â%) and two (3â%) had recurrence, all following piecemeal resection of large (30â-â50âmm) lesions. Three patients were diagnosed with gastric cancer at median follow-up of 66 months (range 66â-â115) after initial diagnosis. CONCLUSIONS: We observed gastric adenomas in 14â% of patients with FAP. Of these, 5â% contained HGD; risk of HGD correlated with adenoma size. Endoscopic resection was feasible, with few complications and low recurrence rates, but did not completely eliminate the cancer risk.
Subject(s)
Adenoma , Adenomatous Polyposis Coli , Stomach Neoplasms , Adenoma/surgery , Adenomatous Polyposis Coli/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Neoplasm Recurrence, Local , Stomach Neoplasms/surgery , Young AdultABSTRACT
AIM: This study aimed to determine the clinical presentation, management and outcomes for patients with ileoanal pouch cancer. METHOD: Patients who were diagnosed with ileoanal pouch cancer were identified from our polyposis registry (1978-2019) and operative and referral records (2006-2019). Details of presentation, endoscopic surveillance, cancer staging and management were retrieved from hospital records. RESULTS: Eighteen patients were identified (12 with ulcerative colitis, one with Crohn's disease, three with familial adenomatous polyposis [FAP], two with dual diagnosis of FAP and inflammatory bowel disease). The median time from pouch formation to cancer diagnosis was 16.5 years (range 5-34 years) and the median age of the patient at pouch cancer diagnosis was 54 years (range 35-71 years). Eleven of the 18 patients were undergoing surveillance. Four of five FAP patients developed pouch cancer whilst on surveillance. Eight patients were asymptomatic at the time of pouch cancer diagnosis. Two patients had complete clinical response following chemoradiotherapy. Fourteen patients underwent pouch excision surgery (eight with exenteration). Median survival was 54 months; however, only eight patients had outcomes available beyond 24 months follow-up. CONCLUSIONS: Pouch cancer can occur in patients despite routine surveillance and without symptoms, and survival is poor. Centralization of 'high-risk' patients who require surveillance is recommended and a low threshold for referral to centres that can provide expert investigation and management is advised.
Subject(s)
Adenomatous Polyposis Coli , Colitis, Ulcerative , Colonic Pouches , Crohn Disease , Proctocolectomy, Restorative , Adenomatous Polyposis Coli/surgery , Adult , Aged , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/surgery , Colonic Pouches/adverse effects , Crohn Disease/surgery , Humans , Middle Aged , Proctocolectomy, Restorative/adverse effectsABSTRACT
Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.
Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , Population Surveillance , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/prevention & control , Adenomatous Polyposis Coli/therapy , Colonoscopy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , DNA Glycosylases/genetics , Family Health , Humans , Intestinal Polyposis/congenital , Intestinal Polyposis/genetics , Intestinal Polyposis/therapy , Ireland , Life Style , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Peutz-Jeghers Syndrome/genetics , Peutz-Jeghers Syndrome/therapy , Referral and Consultation/standards , Risk Factors , United KingdomABSTRACT
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.
Subject(s)
Neoplastic Syndromes, Hereditary , Stomach Neoplasms , HumansABSTRACT
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.
Subject(s)
Intestinal Polyposis , Neoplastic Syndromes, Hereditary , Adult , Bone Morphogenetic Protein Receptors, Type I/genetics , Germ-Line Mutation , Humans , Intestinal Polyposis/congenital , Intestinal Polyposis/diagnosis , Intestinal Polyposis/epidemiology , Intestinal Polyposis/genetics , Neoplastic Syndromes, Hereditary/epidemiology , Neoplastic Syndromes, Hereditary/genetics , Retrospective Studies , Smad4 Protein/genetics , Surveys and QuestionnairesABSTRACT
OBJECTIVES: Prophylactic colectomy at a premalignant stage is the cornerstone of management of familial adenomatous polyposis (FAP). Before surgery, colonoscopy surveillance is recommended in children with FAP. This study aimed to examine the natural history of FAP in children by evaluating adenoma progression and factors influencing timing of colectomy. METHOD: Patients with FAP younger than 18 years at first surveillance colonoscopy and who had undergone more than 1 colonoscopy were identified. Demographic, endoscopic, genetic, and surgical data were retrieved. Cumulative adenoma (polyp) counts were obtained while accounting for any polypectomies during the study period. The rate of polyp progression and factors influencing the timing of colectomy were evaluated. RESULTS: Eighty-four patients (50% boys; mean age at first colonoscopy 13 years [standard deviation 1.97]) were identified, of which 83 had a family history of FAP. At first colonoscopy, 67 (79%) had <100 adenomas and 29 (35%) had colonic polyps identified despite rectal sparing. The median rate of polyp progression per patient was 12.5âpolyps/year (range 0-145). Of the 45 (54%) patients who had undergone surgery, 41 (91%) underwent colectomy with ileorectal or ileodistal sigmoid anastomosis. Polyp progression did not alter the choice of surgical intervention in any patient. CONCLUSION: Our results suggest that adenoma number remains relatively stable in the majority of children under surveillance. Tailored surveillance intervals according to phenotype are a more appropriate strategy as recommended by recently published guidelines.
Subject(s)
Adenomatous Polyposis Coli , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/surgery , Anastomosis, Surgical , Child , Colectomy , Colonoscopy , Female , Humans , Male , RectumABSTRACT
ESGE recommends that individuals with Lynch syndrome should be followed in dedicated units that practice monitoring of compliance and endoscopic performance measures.Strong recommendation, low quality evidence, level of agreement 100â%.ESGE recommends starting colonoscopy surveillance at the age of 25 years for MLH1 and MSH2 mutation carriers and at the age of 35 years for MSH6 and PMS2 mutation carriers.Strong recommendation, moderate quality evidence, level of agreement 100â%. ESGE recommends the routine use of high-definition endoscopy systems in individuals with Lynch syndrome. Strong recommendation, high quality evidence, level of agreement 100â%. ESGE suggests the use of chromoendoscopy may be of benefit in individuals with Lynch syndrome undergoing colonoscopy; however routine use must be balanced against costs, training, and practical considerations.Weak recommendation, moderate quality evidence, level of agreement 89â%.ESGE recommends definition of familial risk of colorectal cancer as the presence of at least two first-degree relatives with colorectal cancer or at least one first-degree relative with colorectal cancer before the age of 50 years.Strong recommendation, moderate quality evidence, level of agreement 92â%.ESGE recommends colonoscopy surveillance in first-degree relatives of colorectal cancer patients in families that fulfill the definition of familial risk of colorectal cancer.Strong recommendation, moderate quality evidence, level of agreement 100â%.
Subject(s)
Colonoscopy/standards , Colorectal Neoplasms, Hereditary Nonpolyposis/surgery , Colorectal Neoplasms/genetics , Disease Management , Genetic Predisposition to Disease , Societies, Medical , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Europe , HumansABSTRACT
ESGE recommends that individuals with hereditary gastrointestinal polyposis syndromes should be surveilled in dedicated units that provide monitoring of compliance and endoscopic performance measures. Strong recommendation, moderate quality of evidence, level of agreement 90â%.ESGE recommends performing esophagogastroduodenoscopy, small-bowel examination, and/or colonoscopy earlier than the planned surveillance procedure if a patient is symptomatic. Strong recommendation, low quality of evidence, level of agreement 100â%.
Subject(s)
Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/therapy , Endoscopy, Gastrointestinal , Adenomatous Polyposis Coli/genetics , Colectomy , Early Detection of Cancer , Humans , Population SurveillanceABSTRACT
The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Polyposis Working Group developed recommendations to assist clinicians and health care providers with appropriate management of patients with juvenile polyposis. This is the first juvenile polyposis Position Paper published by ESPGHAN with invited experts. Many of the published studies were descriptive and/or retrospective in nature, consequently after incorporating a modified version of the GRADE system many of the recommendations are based on expert opinion. This ESPGHAN Position Paper provides a guide for diagnosis, assessment, and management of juvenile polyposis syndrome in children and adolescents, and will be helpful in the appropriate management and timing of procedures in children and adolescents. The formation of international collaboration and consortia is proposed to monitor patients prospectively to advance our understanding of juvenile polyposis conditions.