Management of hereditary colorectal cancer: BSG/ACPGBI/UKCGG guideline

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  We recommend that the moderate risk category of family history of CRC (FHCC) is the minimum threshold for a referral from primary care (GRADE of evidence: very low; Strength of recommendation: strong)

  
  


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  We recommend that individuals with an FHCC, which meets this referral criterion, be referred to a specialist familial CRC clinic in secondary or tertiary care (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We recommend that patients should be referred to a specialist service which includes access to constitutional genetic testing in the presence of either deficient mismatch repair (MMR) (with no evidence of MLH1 promoter methylation or BRAF V600E), or polyposis. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  There are insufficient clinical data to develop specific guidance for patients with very rare conditions such as polymerase proofreading associated polyposis (PPAP), or NTHL1-associated polyposis (NAP); therefore, we suggest patients with these syndromes should be referred to multidisciplinary expert centres for clinical management. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We recommend that hospitals which diagnose or manage patients at hereditary CRC risk should ensure clinical pathways to facilitate their care, and processes to monitor the quality of the service. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We recommend that individuals at increased familial CRC risk receive specialist knowledge and are aware of patient/support organisations and discussion with regard to lifestyle and participation in research projects. (GRADE of evidence: very low; Strength of recommendation: strong)

  
  

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  We recommend that for all patients referred from primary care for assessment for an FHCC, MMR status should be assessed in tumour tissue from a close affected family member. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We recommend that a reported family history of polyposis should be verified by a review of histopathology and/or endoscopy reports which confirm the presence of a minimum of 10 adenomas or serrated lesions in an FDR. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We recommend that patients with a moderate familial CRC risk should have a one-off colonoscopy at age 55 years. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We recommend that subsequent colonoscopic surveillance should be performed as determined by post-polypectomy surveillance guidelines. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We suggest that in high-risk families (a cluster of 3× FDRs with CRC across >1 generation) a 5 yearly colonoscopy should be performed from age 40 years until age 75 years. (GRADE of evidence: moderate; Strength of recommendation: weak)

  
  

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  We recommend that individuals with LS should be advised that regular use of daily aspirin reduces CRC risk. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We suggest that people with LS should be offered research opportunities to take aspirin daily at different dosages. If they decline research participation they may be advised on their choices regarding the dose of aspirin, risks and benefits of long-term aspirin use and ensure their medical practitioner is aware of their intake. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  There is insufficient evidence of the benefit of chemoprophylaxis in polyposis syndromes. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We suggest that individuals at increased familial risk of CRC should be strongly encouraged not to smoke, to maintain a normal body mass index (BMI), to moderate their consumption of red and processed meat, and to exercise regularly. (GRADE of evidence: low; Strength of recommendation: weak)

  
  

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  We recommend that colonoscopy is the gold standard diagnostic and preventative method of surveillance for people with a hereditary risk of CRC. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We recommend that all surveillance colonoscopies are performed by endoscopists who consistently achieve BSG colonoscopy KPI (key performance indicators) minimum standards, specifically caecal intubation rate, adenoma/polyp detection rate and comfort score. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We suggest high-quality, high-definition white light endoscopy is the preferred modality for colonoscopy surveillance. Chromoendoscopy (virtual or dye-based) does not offer a clear advantage over high definition white light examination for colonoscopic surveillance, apart from in the context of determining the multiple polyp phenotype. (GRADE of evidence: moderate; Strength of recommendation: weak)

  
  


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  We suggest a repeat colonoscopy performed by an expert endoscopist is indicated in the event of a previously failed colonoscopy, with efforts made to both improve patient experience and to ensure procedure completion, given the advantages of colonoscopic surveillance. If colonoscopy is not possible then consider CT colonography. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We suggest that if the bowel preparation for colonoscopy is inadequate or if the examination is incomplete then a repeat colorectal surveillance procedure should be arranged within 3 months. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  There is insufficient evidence to recommend other methods of surveillance for those with familial CRC risks such as FIT (faecal immunochemical test), MR or CT colonography. (GRADE of evidence: low; Strength of recommendation: strong)

  
  

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  We recommend that for all people when first diagnosed with CRC, testing using immunohistochemistry (IHC) for MMR proteins or microsatellite instability is used to identify tumours with deficient DNA MMR, and to guide further sequential testing for LS. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We recommend that colonoscopic surveillance should be performed at a 2 yearly interval for all LS patients. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We recommend that the age of onset of surveillance colonoscopy should be stratified according to the LS-associated gene. We recommend colonoscopy from age 25 years for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. There are insufficient data to support the stratifying age of onset of surveillance by gender. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We suggest that for LS patients with MLH1 or MSH2 mutations who develop colon cancer or colonic neoplasia not amenable to endoscopic control, the decision to perform segmentally versus total/near-total colectomy should balance the risks of metachronous cancer, the functional consequences of surgery, the patient’s age and patient’s wishes. (GRADE of evidence: Moderate; Strength of recommendation: strong)

  
  


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  We recommend that for LS patients with MSH6 or PMS2 mutations there is insufficient evidence for an oncological benefit of extended colectomy over segmental resection. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We suggest that when abdominal-perineal excision can be avoided, a standard low anterior resection is a reasonable option to treat rectal cancers in LS patients, even though the residual colon is at high risk of metachronous neoplasia. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We recommend that gastric, small bowel or pancreatic surveillance in LS patients is only performed in the context of a clinical trial. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We recommend screening for Helicobacter pylori in patients with LS and subsequent eradication therapy if indicated. (GRADE of evidence: low; Strength of recommendation: strong)

  
  

Lynch-like syndrome (LLS)

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  We recommend that deficient MMR tumours without hypermethylation/BRAF mutation and without a germline pathogenic variant in MMR genes should undergo somatic tumour testing with a CRC gene panel. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We recommend that if double somatic MMR pathogenic variants are identified, manage proband and their FDRs based on the FHCC. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We suggest that if no or one somatic mutation is identified, the proband and their FDRs should be managed as per LS. (GRADE of evidence: low; Strength of recommendation: weak)

  
  

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  We recommend that in patients under 30 years of age with dMMR CRC, an LS constitutional panel test should be performed, followed by tumour testing for somatic testing if constitutional testing is negative. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We recommend that in patients under 30 years of age with pMMR CRC, a constitutional CRC multiple gene panel test should be performed. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We suggest that people diagnosed with CRC under age 50 years, where hereditary CRC syndromes have been excluded, undergo standard post-CRC surveillance for 3 years, then continue 5 yearly colonoscopic surveillance until the age they are eligible for national screening. (GRADE of evidence: low; Strength of recommendation: weak)

  
  

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  We recommend a diagnosis of SPS should be made in accordance with the new WHO 2019 criteria for SPS. Since causative gene pathogenic variants for SPS have not been identified, a definitive diagnosis of SPS should be phenotype-driven. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  Other intestinal polyposis syndromes may present with serrated lesions. If (i) the patient is under 50 or (ii) there are multiple affected individuals within kindred or (iii) there is dysplasia within any of the polyps, then we suggest that other polyposis syndromes should be excluded by gene panel testing before making a definitive diagnosis of SPS. (GRADE of evidence: very low; Strength of recommendation: weak)

  
  


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  We recommend the cumulative number of serrated polyps from all endoscopic examinations should be used when applying the WHO 2019 diagnostic criteria for SPS. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We recommend that patients with SPS should have colonoscopic surveillance yearly once the colon has been cleared of all lesions >5 mm in size. If no polyps ≥10 mm in size are identified at subsequent surveillance examinations the interval can be extended to 2 yearly. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We recommend all FDRs of patients with SPS on the basis of the new WHO 2019 SPS criteria, one or two should be offered an index colonoscopic screening examination at age 40 years or 10 years before the diagnosis of the index case. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We suggest all FDRs of SPS patients have a surveillance examination every 5 years unless polyp burden indicates an examination is required earlier according to post-polypectomy surveillance guidelines. (GRADE of evidence: low; Strength of recommendation: strong)

  
  

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  We suggest an individualised approach to germline testing of patients with MCRA (defined as having 10 or more metachronous adenomas). Consider this testing for:

  
  
  
  
  
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    Patients under 60 years of age with lifetime total of ≥10 adenomas; or

    
    
  
  
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    Patients from 60 years of age with a lifetime total of:

    
    
    
    
    
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      ≥20 adenomas, or

      
      
    
    
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      ≥10 adenomas and an FHCC or polyposis

      
      
    
    
    
    
  
  
  
  

(GRADE of evidence: low; Strength of recommendation: weak)

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  We suggest that patients with a finding of 10 or more polyps (adenomas or serrated lesions) should, at their next colonoscopy, have a high-quality colonoscopic assessment with pancolonic dye spray in order to define accurately the multiple polyp phenotype. (GRADE of evidence: very low; Strength of recommendation: weak)

  
  


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  We suggest that the endoscopic management of patients with 10 or more metachronous adenomas, without MUTYH or APC gene mutations, should be individualised according to phenotype. (GRADE of evidence: very low; Strength of recommendation: weak)

  
  


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  We suggest annual colonoscopic surveillance for patients with 10 or more metachronous adenomas after the colon has been cleared of all lesions >5 mm in size. If no polyps 10 mm or greater in size are identified at subsequent surveillance examinations the interval can be extended to 2 yearly. (GRADE of evidence: very low; Strength of recommendation: weak)

  
  

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  We recommend that colonic surveillance should normally commence age 12–14 years in those confirmed to have FAP on predictive genetic testing. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We suggest that for those with FAP, intervals between surveillance colonoscopy may be individualised depending on colonic phenotype every 1–3 years. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We suggest that colonoscopy screening is performed for individuals who have an FDR with a clinical diagnosis of FAP (ie, “at-risk”) and in whom an APC mutation has not been identified, starting at age 12–14 years, and should continue on 5 yearly surveillance until either a clinical diagnosis is made and they are then managed as FAP, or they reach the age at which they can enrol in national screening. (GRADE of evidence: very low; Strength of recommendation: weak)

  
  


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  We recommend upper GI surveillance for FAP patients starting at age 25 years. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We suggest that for those considered at risk, where predictive genetic testing is not possible, screening with upper GI endoscopy is not routinely recommended but should be started if/when a clinical diagnosis of FAP is made based on colorectal phenotype. (GRADE of evidence: very low; Strength of recommendation: weak)

  
  


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  We suggest that patients with congenital hypertrophy retinal pigmentation epithelium (CHRPE) be referred for a specialist ophthalmic review. Patients with bilateral and multiple CHRPE lesions should be referred for screening for FAP and considered for genetic testing and colonoscopy. (GRADE of evidence: low; Strength of recommendation: weak)

  
  

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  We recommend that for patients with FAP who are undergoing colonoscopic surveillance, relative indications for surgery are: polyps >10 mm in diameter, high-grade dysplasia within polyps and a significant increase in polyp burden between screening examinations. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We recommend that absolute indications for immediate colorectal surgery in FAP include: documented or suspected cancer or significant symptoms attributable to the polyposis. (GRADE of evidence: low; Strength of recommendation: strong)

  
  


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  We suggest that FAP patients should be counselled about the risk of postoperative desmoid disease formation. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  Consider, for FAP patients before colectomy, determining genotypes or family history of the desmoid disease which may be predictive of desmoid formation. (GRADE of evidence: very low; Strength of recommendation: weak)

  
  


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  We suggest that sulindac in combination with high-dose selective oestrogen receptor modulators may be effective in FAP patients with intra-abdominal desmoids and desmoids located at the abdominal wall. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We recommend the role of elective surgery for intra-abdominal desmoids should be restricted to treating the secondary effects of the desmoid disease, and this surgery should be performed in expert centres. (GRADE of evidence: low; Strength of recommendation: strong)

  
  

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  We recommend that colorectal surveillance is commenced in MAP commencing age 18–20 years. If surgery is not undertaken then annual surveillance is suggested. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We recommend that for monoallelic MUTYH pathogenic variant carriers, the risk of CRC is not sufficiently different to population risk to meet thresholds for screening and routine colonoscopy is not recommended. (GRADE of evidence: moderate; Strength of recommendation: strong)

  
  


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  We suggest that upper GI surveillance should be considered starting at the age of 35 years in MAP. We recommend that the surveillance interval is determined as outlined for FAP. (GRADE of evidence: low; Strength of recommendation: weak).

  
  

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  We suggest that in an asymptomatic patient with PJS, GI surveillance by upper GI endoscopy, colonoscopy and video capsule endoscopy commence at age 8 years. We recommend that small bowel surveillance should continue 3 yearly. If baseline colonoscopy and oesophagal-gastro-duodenoscopy (OGD) are normal, then they can be safely deferred until age 18 years; however, if polyps are found at baseline examination, then they should be repeated 3 yearly. An earlier investigation of the GI tract should be performed in symptomatic patients. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We suggest elective polypectomy to prevent polyp related complications. Small bowel polyps greater than 1.5–2 cm in size (or smaller if symptomatic) should be considered for elective resection to prevent intussusception. (GRADE of evidence: low; Strength of recommendation: weak)

  
  

Juvenile polyposis syndrome (JPS)

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  We suggest colonoscopic surveillance should commence from the age of 15 years or earlier if symptomatic. The surveillance interval should be 1–3 yearly, personalised according to colorectal phenotype. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We suggest that for those with a confirmed clinical or genetic diagnosis, upper GI endoscopic surveillance should start at the age of 18 years for SMAD4 mutation carriers and 25 years for BMPR1A mutation carriers and those without an identified constitutional. The surveillance interval should be 1–3 yearly, personalised according to upper GI tract phenotype. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We suggest that for those with an FDR with a clinical diagnosis of JPS and in whom a mutation has not been identified, screening of the upper GI tract is not required routinely but should be initiated if/when the clinical diagnosis is made on the basis of colonic phenotype. It may, however, be considered if there is a family history suggestive of hereditary haemorrhagic telangiectasia (HHT), even in the absence of colonic polyps. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  We suggest that patients with SMAD4 pathogenic variant should be evaluated for HHT and that those at risk of, or with a confirmed diagnosis of, HHT are best managed in conjunction with a specialist HHT centre. (GRADE of evidence: low; Strength of recommendation: weak)

  
  


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  Patients with JPS and a microdeletion involving BMPR1A and PTEN are at risk of the clinical manifestations of both JPS and PTEN-hamartoma tumour syndrome (PHTS). We suggest that they should be referred to their local genetics centre for further advice and to coordinate their surveillance needs. (GRADE of evidence: low; Strength of recommendation: weak)

  
  

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