This article appears in the following Annals of Oncology issue: ESMO Clinical Recommendations [View the issue table of contents]
ESMO clinical recommendations |
Familial colorectal cancer risk: ESMO Clinical Recommendations
1 The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden
2 Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
3 Service of Medical Oncology, Portuguese Institute of Oncology, Lisbon, Portugal
* Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations{at}esmo.org
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introduction |
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 Top introduction familial colorectal cancerLynch syndrometreatment(attenuated) familial...notereferences |
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Colorectal cancer (CRC) is a multifactorial disease and the etiology is complex. It involves dietary and other environmental factors, and in between 15 and 30% of cases, inherited genetic factors are significant. Approximately 5% of all colorectal cancers occur in the setting of a well described inherited syndrome like Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer; HNPCC), (Attenuated) Familial Adenomatous Polyposis ((A)FAP), and MUTYH-associated polyposis (MAP).
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familial colorectal cancer |
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In families with clustering of CRC, but without evidence for one of the inherited syndromes, we deal with familial colorectal cancer. Subjects with one first degree relative (FDR) with CRC diagnosed at age >50 years, have a relative risk of developing CRC of 2–3. Subjects with two (or more) FDRs with CRC diagnosed at any age, or with one FDR with CRC diagnosed before the age of 50 years, have a relative risk of 4–6 for developing CRC.
Colonoscopic surveillance at 3- to 5-year intervals is advised for subjects with a moderately increased risk of developing CRC (RR > 4), starting 5–10 years before the first diagnosis of CRC or >45 years [III, C].
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Lynch syndrome |
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incidence
Lynch syndrome is an autosomal dominant disease and is responsible for around 3% of all CRC cases. It is caused by a mutation in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2.
diagnosis
The MMR defect leads to instability at microsatellites of tumour DNA that is called microsatellite instability (MSI). This feature can be found in >90% of colon cancers associated with Lynch syndrome. With immunohistochemical (IHC) analysis using antibodies against the four MMR proteins, loss of protein expression of the causative gene can be shown.
Currently, the Amsterdam II/Revised Bethesda criteria (Table 1) are used to select patients with CRC for MSI and/or IHC analysis of the tumour and those with evidence of MSI or loss of MMR expression are offered mutation analysis. In families with a high probability of having a mutation (Amsterdam II criteria, computer models), IHC is the best first step because it may direct mutation analysis. In other families either MSI or IHC analysis might be used as the first step. In case of loss of expression of MLH1/PMS2, additional tests (BRAFV600E and methylation analysis of MLH1 promotor) should be performed to exclude hypermethylation of the MLH1 promotor. The results of pedigree analysis and MSI/IHC analysis should be discussed in a multidisciplinary setting (pathologist, clinical/molecular geneticist, gastroenterologist, surgeon, medical oncologist, etc.) [C].
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staging and risk assessment
Carriers of an MMR–gene mutation have a high risk of developing CRC (cumulative risk of 30–80%), endometrial cancer (cumulative risk of 30–60%) and other associated cancers (cumulative risk <10–15%). The cancers observed in Lynch syndrome families are diagnosed at an unusually early age (mean age CRC 45 years) and may be multiple (synchronous or metachronous CRC present in 30% of cases). CRC is in about two-thirds of cases located in the proximal part of the colon. The carcinogenesis in Lynch syndrome is accelerated and the progression from colorectal adenoma to carcinoma may take <3 years.
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treatment |
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Topintroductionfamilial colorectal cancerLynch syndrometreatment(attenuated) familial...notereferences |
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surgical management of colorectal cancer
Before resection of a colon tumour it is important to visualize the complete colon because of the risk of a synchronous tumour. The reported risk of developing a second colon tumour after treatment of a primary colorectal cancer in Lynch syndrome was 16% after 10 years of follow-up. Regarding the treatment of CRC in patients from Lynch syndrome families, the decision has to be individualized. The option of extensive resection should be discussed in young patients (e.g. <50 years) [III, C].
chemotherapy
Currently, at least three chemotherapeutic agents have been proven to be effective in the treatment of colorectal cancer, i.e. 5FU with or without leucovorin, oxaliplatin and irinotecan (CPT11). Unfortunately, the effectiveness of the chemotherapeutic agents in patients with MSI-H or Lynch syndrome tumours is unknown. Prospective clinical trials are needed before definitive recommendations can be given [III].
surveillance
Periodic examination by colonoscopy leads to detection of colorectal cancer at an earlier stage, to a 63% reduction of the risk of CRC and to a significant reduction of the mortality associated with CRC [II, B]. A 3-year interval is proven to be (at least partly) effective [II, B]. In view of the observation of advanced CRC detected 2–3 years after colonoscopy, the optimal surveillance interval probably lies between 1 and 2 years [III, C]. Surveillance should start between ages 20 and 25 years. Decisions on the upper age limit of surveillance depend on the patient's general state of health and should be made on an individual basis. After colectomy surveillance of the rectum should be continued [III, C].
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(attenuated) familial adenomatous polyposis and MUTYH-associated adenomatous polyposis |
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incidence
FAP is an autosomal dominant condition caused by APC mutations and is responsible for 1% or less of all CRC cases. In 15–20%, the cases are de novo without clinical or genetic evidence of FAP in the parents. MAP is an autosomal recessive condition caused by bi-allelic mutations in the MUTYH gene. Mutations were found in 26–29% of patients with 10–100 adenomas and in 7–29% of patients with 100–1000 adenomas.
diagnosis
FAP.
The clinical diagnosis of classical FAP is based on the identification of more than 100 colorectal adenomas. In more than 70% of these patients a mutation can be identified in the APC-gene. Predictive testing for the mutation should be offered to the first-degree relatives. Attenuated FAP is characterized by the presence of fewer adenomas and later onset of disease. The clinical diagnosis is more difficult and suggested criteria are: there should be (i) at least two patients with 10–99 adenomas at age >30 years or (ii) one patient with 10–99 adenomas at age >30 years and a first-degree relative with CRC with few adenomas, and applying for both criteria, no family members with more than 100 adenomas before the age of 30 years. In about 25% of these patients a mutation can be identified in the APC gene.
MAP.
Bi-allelic MUTYH-mutations are usually associated with an attenuated polyposis phenotype. Patients with more than 10 adenomas should be referred for genetic counselling and mutation analysis of the MUTYH-gene should be considered.
staging and risk assessment
FAP.
The severity of colonic polyposis is correlated with the site of the mutation in the APC gene. Most patients develop hundreds of colorectal adenomas during childhood and adolescence. CRC before the age of 10 years is extremely rare and there are incidental cases between ages 11 and 15 years. Without surgical intervention FAP patients almost inevitably develop CRC by the mean age of 40–50 years. The risk of rectal adenomas remains after colectomy and there is a risk of adenomas and even cancer in the pouch after proctectomy. Adenomas also develop in the upper GI tract, especially in the duodenum and if untreated, these progress to malignancy in approximately 5% of the cases. FAP patients are also at risk for several extra-intestinal malignant and benign lesions. Recommendations for surveillance and treatment of lesions outside the colorectum were recently extensively discussed. In AFAP the mean age at diagnosis of CRC is about 10–15 years later than in classical FAP. In contrast to classical FAP patients AFAP patients may develop only a few adenomas in the right part of the colon.
MAP.
CRC due to bi-allelic MUTYH mutations before the age of 30 years is extremely rare. Bi-allelic mutation carriers may develop only a few adenomas and CRC is often localized in the proximal part of the colon. Adenomas (and cancer) also develop in the duodenum. Family members with mono-allelic mutations in MUTYH are probably not at increased risk of CRC, and therefore do not need colonoscopic surveillance.
treatment
FAP.
In general, colorectal surgery is indicated if there are a large number of adenomas larger than 5 mm including adenomas showing a high degree of dysplasia. Most patients with classical FAP undergo surgery between ages 15 and 25 years. The two main options for prophylactic surgery are colectomy with ileorectal anastomosis (IRA) and proctocolectomy with ileal pouch-anal anastomosis (IPAA). The decision on the type of surgery depends on many factors including the age of the patient, the wish to have children, the risk of developing desmoids, the site of the mutation in the APC-gene (possibly) and the severity of rectal (and colonic) polyposis. An IPAA is the treatment of choice in patients with a large number of rectal adenomas (i.e. >15–20 adenomas). In patients with only a few rectal adenomas or with a polyp-free rectum both options are possible and should be discussed with the patient. In patients with multiple large (>5 mm) rectal adenomas that show a high degree of dysplasia after IRA there is an indication for proctectomy.
chemoprevention
NSAIDS and/or specific COX-2 inhibitors reduce colorectal (and duodenal) adenomas. However, whether these drugs also prevent the development of CRC is unknown. As cardiovascular side effects have recently been reported in patients using one of the specific COX-2 inhibitors caution is warranted and the use of these drugs may only be justifiable in special situations.
MAP.
In the case of a small number of adenomas endoscopical removal might be possible. If surgery is required, an IRA will be sufficient in most cases. However, if rectal polyposis is severe an IPAA is recommended.
surveillance prior to surgery in FAP
Classical FAP: Endoscopic surveillance should be continued lifelong. In asymptomatic mutation carriers surveillance with flexible sigmoidoscopy is recommended from age 10–12 years at 2 yearly intervals. Once adenomas are identified there is an indication for yearly colonoscopy. In high risk members (first-degree relatives of affected patients) from families without an identified APC-mutation, surveillance should be continued at 2 yearly intervals until age 40 years; after this age the intervals between examinations may be longer (every 3–5 years) until age 50 years [III, B].
AFAP: Colonoscopic surveillance is recommended at 2 yearly intervals starting from age 18–20 years. Once adenomas are identified there is an indication for yearly surveillance.
surveillance prior to surgery in MAP
Colonoscopic surveillance should be continued lifelong. In asymptomatic bi-allelic mutation carriers surveillance is recommended at 2 yearly intervals starting from age 18–20 years [III, B].
surveillance after surgery in FAP and MAP
Surveillance after IRA: Depending on the severity of rectal adenomas rectoscopy is recommended at intervals of 3–6 months.
Surveillance after IPAA: Pouchoscopy is recommended at intervals of 6–12 months.
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note |
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Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
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footnotes |
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Approved by the ESMO Guidelines Working Group: December 2008
Conflict of interest: Dr Vasen, Dr van der Meulen-de Jong and Dr de Vos tot Nederveen Cappel have reported no conflicts of interest; Dr Oliveira has not reported any conflicts of interest.
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references |
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