Management of individuals with the Lynch syndrome (hereditary nonpolyposis colorectal cancer)

Lynch syndrome or HNPCC is the most common form of genetically determined colon cancer predisposition in which a specific genetic abnormality has been identified. Lynch syndrome is an autosomal dominant disorder with high penetration and accounts for approximately 3% to 4% of CRCs. Approximately 80% of cases meeting the clinical criteria for Lynch syndrome are associated with germline mutations in genes responsible for repair of DNA errors, called mismatches, that occur during DNA replication. The majority of reported germline mutations in DNA mismatch repair (MMR) genes have been associated with the MSH2 gene on chromosome 2 (40% to 50%) and the MLH1 gene on chromosome 3 (20% to 30%). Mutations in MSH6 , PMS1 , and PMS2 have also been reported. No locus has been identified, however, for many HNPCC families. The lifetime risk of CRC approaches 70% to 80% in affected individuals carrying a MMR gene mutation. During DNA synthesis, DNA polymerase may create single base-pair mismatches resulting in structural abnormalities (so-called loop-outs) involving unpaired bases. These alterations tend to occur at repetitive DNA sequences, termed microsatellites , leading to a microsatellite instability (MSI), a hallmark of CRC occurring in the setting of Lynch syndrome. The definition of HNPCC was standardized and most strictly defined by the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer. These Amsterdam criteria include (1) at least three relatives with histologically verified CRC, one of them a first-degree relative of the other two (FAP excluded); (2) at least two successive generations affected; and (3) in one of the individuals, diagnosis of CRC before age 50 years. Because these criteria do not account for the frequent occurrence of extracolonic cancers in such families (endometrial, ovary, stomach, ureter/renal, pelvis, pancreas, brain, hepatobiliary tract, small bowel, and multiple sebaceous adenomas and carcinomas and keratoacanthomas in the Muir-Torre syndrome variant of Lynch syndrome) or for small kindreds, broader clinical criteria have been developed, including the modified Amsterdam criteria (Amsterdam II) and the revised Bethesda guidelines, published by a National Cancer Institute–sponsored workshop on HNPCC ( Box 2 ). The latter include CRC with MSI-H (presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern).

In Lynch syndrome, discrete polyps, but not polyposis, may antedate the cancers. Adenomas in the proximal colon may be flat or slightly raised lesions with foci of adenomatous change confined to the upper half of a crypt (flat adenomas). Lynch syndrome is characterized by a tendency toward proximal sites of colon tumors (approximately 70% of CRCs are proximal to the splenic flexure), multiple primary malignancies (synchronous and metachronous), and a higher incidence of mucinous carcinomas. These CRCs usually appear at age 40 to 50 years, 2 decades earlier than CRC in the general population.

Individuals with Lynch syndrome are at increased lifetime risk for developing CRC compared with the general population (70% to 80% vs 6%). Several studies suggest a higher CRC risk in men compared with women and a higher risk in MLH1 mutation carriers than in MSH2 mutation carriers. Development of metachronous primary CRCs is also common in Lynch syndrome, with one study reporting a risk of 40% for a second CRC within 7 years of the first cancer. Algorithmic approaches to screening and surveillance of families with Lynch syndrome or those suspected of having Lynch syndrome have been adopted by professional societies with clinical practice guidelines for genetic testing and risk assessment for patients and families. Genetic testing and counseling is an essential part of quality care in families with known MMR gene mutations. Because 70% to 80% of CRCs in the setting of Lynch syndrome are proximal to the splenic flexure, colonoscopy is the mandated screening modality for the colon. Most guidelines suggest that screening begin at age 20 to 25 or 10 years before the youngest case in the immediate family and repeated every 1 to 2 years in at-risk individuals with MMR gene mutations (discussed later).

The evidence supporting colonoscopic surveillance in individuals with Lynch syndrome is provided by several observational studies. A 15-year observational cohort study of HNPCC families from Finland demonstrated that in 133 at-risk individuals undergoing prospective asymptomatic screening at 3-year intervals, invasive CRC incidence was reduced by 62% compared with 119 controls from the same families who did not undergo surveillance. Follow-up of these individuals demonstrated reduced mortality in those undergoing surveillance colonoscopy compared with those who did not undergo surveillance. CRC occurred in 6% of screened individuals and 16% of unscreened individuals. These rates were 18% versus 41% in MMR carriers. All CRCs in the screened group were early stage with no associated mortality versus 9 deaths in the unscreened group. Several observational studies do show, however, that interval cancers develop within a 3-year interval after colonoscopy, and a study of 114 families with proved or suspected MMR mutations suggested that a surveillance interval of 2 years or less is required is required to diagnose CRC at an early stage in these individuals. A recent study using the Dutch Lynch syndrome registry also concluded that members of Lynch syndrome families have a lower risk of developing CRC with surveillance interval of 1 to 2 years compared with interval of 2 to 3 years. These observations and the evidence that there may be an accelerated rate of colon carcinogenesis in the setting of Lynch syndrome have led to the recommendation that surveillance colonoscopy be performed every 1to 2 years in at-risk individuals. Some have recommended, based on observational data concerning cumulative cancer rates, that the surveillance interval be reduced to 1 year after age 40.

The success and cost-effectiveness of colon cancer screening and surveillance in any population is highly dependent on compliance with recommended guidelines. Quality colonoscopy requires that best practices regarding recommendations for screening and surveillance be adhered to by physicians and patients. This is not always the case. Stoffel and colleagues conducted a study using a cross-sectional questionnaire among individuals with a personal or family history of CRC who fulfilled the Bethesda guidelines for evaluation of Lynch syndrome; 181 individuals further met the Amsterdam criteria for the Lynch syndrome and/or had an identified mutation in a MMR gene. Of these high-risk individuals, 73% had what was defined as an appropriate surveillance with colonsocopies every 2 years. Of those individuals who did not meet the criteria for a proper surveillance interval, 53% had colonoscopies at 3- to 5-year intervals. Because subjects were recruited through four US genetics clinics, compliance is likely to be worse in less specialized settings. As discussed previously, interval cancer does occur despite adherence to surveillance colonoscopy. It is also important to communicate to patients that despite surveillance, there is a small risk of developing CRC. In one recent study, 6% of individuals developed CRC despite surveillance, and 10% of these cancers were at an advanced stage (Dukes C or stage III).

CRCs occurring in the setting of Lynch syndrome are often right sided and precursor adenomas are commonly flat. This has led to the common use of red flag techniques, such as chromoendosocopy, in an attempt to better detect these lesions.

High-magnification colonoscopy with chromoendoscopy using indigo carmine or methylene blue may improve the detection of neoplastic lesions in the colon of individuals with Lynch syndrome. Hurlstone and colleagues performed back-to-back colonoscopies in 25 individuals who met the Amsterdam I criteria for HNPCC. Conventional colonoscopy with targeted chromoscopy was followed by pancolonic chromoscopic colonoscopy using indigo carmine. Panchromoscopy identified significantly more adenomas than conventional chromoscopy ( P = .001) and a significantly higher number of flat adenomas ( P = .004). In a small study, LeCompte and colleagues found that indigo carmine dye spraying in the proximal colon increased adenoma detection. Stoffel and colleagues evaluated the colonic adenoma miss rate among Lynch syndrome patients undergoing surveilance colonoscopy. The mean interval since last colonoscopy was 17.5 months. They compared the sensitivity of indigo carmine panchromoendoscopy with intensive white light inspection for identifying polyps missed by an initial standard colonoscopy performed during the same visit. Chromoendoscopy detected more polyps, but after controlling for several variables, chromoendosocopy did not detect more adenomas than intensive inspection in this pilot study of 28 individuals. This trial points out the importance of controlling for withdrawal times in such studies. There was an initial adenoma miss rate of 55% with the first white light screening colonoscopy. Additional adenomas were detected by both chromoendoscopy and intensive standard colonoscopy (20-minute pull back from cecum) on a second examination.

In approximately 30% of families that meet Amsterdam I criteria for Lynch syndrome, MSI testing and testing for MMR gemline mutations is negative. These individuals develop CRC at a more advanced age and have fewer cancers than those with Lynch syndrome. In families without MMR deficiency, a less-intensive surveillance protocol is recommended with colonoscopy at 3- to 5-year intervals, starting at 5 to 10 years before the first diagnosis of CRC or at 45 years of age.

Individuals in Lynch syndrome families who test negative for a known mutation and who are asymptomatic should undergo routine screening recommended for individuals with a family history of CRC.