Approximately 5% of all colorectal cancers (CRCs) are associated with a hereditary syndrome, where a germline mutation in a key tumor suppressor or DNA repair gene produces a cancer predisposition that can be inherited. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common of the hereditary CRC syndromes, accounting for about 3% of all CRC cases. HNPCC includes many families affected by Lynch syndrome, but overlap exists between these two terms. HNPCC is defined clinically by family history criteria, whereas Lynch syndrome is diagnosed genetically by the presence of an inherited mutation in a DNA mismatch repair (MMR) gene. Not all patients with Lynch syndrome fulfill HNPCC criteria, and not all HNPCC families have Lynch syndrome. Both syndromes confer an increased risk for colorectal and extracolonic cancers starting at an early age, and because they are both autosomal dominantly inherited, each first-degree relative of an affected person carries a 50% chance of having the disease. Physicians need to understand these syndromes to appropriately identify, diagnose, and educate affected families. Surgical decision making is based on knowledge of cancer risk, the natural history of the disease, risks of surgery, and the effects of the proposed surgery on quality of life. This chapter presents an overview of HNPCC/Lynch syndrome and provides a practical approach to its clinical management.
Historical Perspective and Clarification of Terms
In 1913, Alfred Warthin presented a large pedigree of a family in Michigan that had a predominance of colorectal and extracolonic cancers, many occurring at a young age. This report of “Family G” supported the concept that cancers can occur in families as an inherited condition and set the stage for study of inherited cancers. In 1966, Henry Lynch used the term “cancer family syndrome” in a report on two Midwestern families with an abundance of colorectal, endometrial, and gastric cancers. To distinguish this syndrome from familial adenomatous polyposis, which was the only recognized hereditary colorectal cancer syndrome at the time, the term hereditary nonpolyposis colorectal cancer (HNPCC) was introduced. HNPCC was defined by clinical criteria to facilitate research into the syndrome. The Amsterdam criteria were established in 1991 by the International Collaborative Group on HNPCC ( Table 59-1 ). In 1999, the Amsterdam criteria were revised to include extracolonic cancers as qualifying criteria, and these Amsterdam II criteria have become the way to define HNPCC (see Table 59-1 ).
|Amsterdam I||Amsterdam II||Amsterdam-like|
|3 or more family members, one of whom is a first-degree relative of the other two, with colorectal cancer |
2 or more successive affected generations
1 or more of the colorectal cancers diagnosed before age 50 years
Familial adenomatous polyposis is excluded
|Same criteria as for Amsterdam I, but cancers not limited to colorectal cancer |
Qualifying lesions also include hereditary nonpolyposis colorectal cancer–related cancers: endometrial, ovarian, gastric, small bowel, ureter, renal pelvis, pancreas, biliary tract, brain, sebaceous adenomas/adenocarcinomas
|Same criteria as for Amsterdam II, but qualifying lesions also include high-risk adenomas: high-grade dysplasia, >1 cm, and/or 3 or more adenomas found upon a single endoscopic examination|
In 1993, germline mutations in DNA MMR genes were found to be the genetic cause of HNPCC in many families. However, it became apparent that only about 60% of HNPCC families carry a germline MMR gene mutation. These genetically defined patients are diagnosed as having Lynch syndrome. Only about 80% of Lynch syndrome families fit the Amsterdam criteria, and thus at least 20% of cases are missed with reliance on these criteria to screen for Lynch syndrome. In families that fulfill the Amsterdam II criteria, the suspicion of Lynch syndrome is raised and genetic counseling and testing are indicated; however, Amsterdam II criteria in themselves do not define Lynch syndrome. That is a genetic definition. Patients from families who meet Amsterdam criteria but have microsatellite stable tumors (i.e., intact MMR) have familial colorectal cancer type X (FCC X), which carries a lower cancer risk than does Lynch syndrome. This distinction is important for appropriate clinical management. When discussing Lynch syndrome and HNPCC, it is important to use the correct definitions to allow for the proper classifications of the different phenotypes and genotypes.
Genetic and Molecular Cause of Lynch Syndrome
Lynch syndrome is caused by inactivation of one of four DNA mismatch repair genes: MLH1, MSH2, MSH6, or PMS2 . These genes encode proteins that function as heterodimers (MLH1/PMS2 and MSH2/MSH6) to recognize and repair nucleotide mismatches that occur during DNA replication. Approximately 90% of Lynch syndrome cases are caused by an inherited mutation in MLH1 or MSH2 . Rarely, Lynch syndrome can also result from an inherited deletion in the EPCAM gene, which silences expression of MSH2 . Inherited germline hypermethylation of MLH1 , resulting in silencing of its expression, has also been reported but is very rare.
Lynch syndrome is inherited in an autosomal-dominant pattern. When a child inherits the mutated allele from the affected parent, normal MMR function is maintained by the wild-type allele inherited from the unaffected parent. However, with sporadic loss of the wild-type allele, MMR function is lost. Because DNA mismatch errors tend to occur in areas of repeating nucleotide bases called microsatellites, unrepaired errors accumulate in these regions and lead to microsatellite instability in tumors. Panels of microsatellite markers have been established to assess tumor DNA microsatellite stability, the most common of which includes five markers. If two or more are unstable, the tumor is considered microsatellite instability high (MSI-H)—evidence of DNA MMR deficiency. About 90% of all Lynch syndrome tumors are MSI-H. In contrast, about 15% of sporadic colorectal tumors are MSI-H, resulting from epigenetic loss of MLH1 via DNA promoter hypermethylation.
Histologic Features of Lynch Tumors
Colorectal cancers arising within Lynch syndrome have distinct histologic characteristics that, when recognized in a tumor, suggest defective MMR. These characteristics include the presence of tumor-infiltrating lymphocytes, a Crohn-like lymphoid reaction, signet ring cells, mucinous components, and a lack of dirty necrosis. Some of these histologic factors have been incorporated into the revised Bethesda criteria ( Box 59-1 ) as a tool to identify which patients should undergo testing for the presence of MSI ( Figs. 59-1, 59-2, and 59-3 .)
Colorectal cancer diagnosed before age 50 years
Presence of synchronous or metachronous colorectal cancer or Lynch syndrome–associated tumors ∗
∗ Lynch syndrome–associated tumors include tumors of the colorectum, endometrium, stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel, and sebaceous glands, along with keratoacanthomas.
Microsatellite instability high–type histologic features: tumor-infiltrating lymphocytes, Crohn-like reaction, mucinous tumor, signet cell differentiation, medullary growth pattern in tumor from a patient younger than 60 years
Patient with colorectal cancer and a first-degree relative with colorectal cancer or a Lynch syndrome–associated tumor ∗ before age 50 years
Patient with colorectal cancer and two first- or second-degree relatives with colorectal cancer or a Lynch syndrome–associated tumor ∗ at any age
Diagnosing Lynch Syndrome
The first step in managing Lynch syndrome in a family is to diagnose it. Several strategies can be used to select patients for genetic testing, including clinical criteria, prediction models, and tumor testing.
Amsterdam I criteria (see Table 59-1 ) require three relatives affected with colorectal cancer, with two being first degree to the other one, in at least two consecutive generations, with one relative younger than 50 years and polyposis excluded. Amsterdam II criteria are more inclusive than Amsterdam I criteria because they include any Lynch-related cancers as qualifying events. Amsterdam II criteria are highly sensitive (85%) but poorly specific (20%). However, the shrinking size of families and the attenuation of phenotype caused by increasingly widespread colonoscopic screening is decreasing the sensitivity of family-based criteria. Therefore, we have adopted “Amsterdam-like” criteria, in which high-risk adenomas count as a qualifying lesion (see Table 59-1 ). The revised Bethesda guidelines include details of the cancers, as well as family history and age at diagnosis, and are aimed at identifying tumors suitable for MSI testing (see Box 59-1 ).
In an effort to improve the predictive accuracy of clinical criteria, several clinical computational prediction models have recently been developed and validated to determine a person’s risk for Lynch syndrome. These models include MMRpro, MMRpredict, and PREMM. They include factors such as age, gender, location of tumor, and the presence of multiple tumors or endometrial cancer, and they are available for use as Internet-based programs. Although they seem to outperform traditional clinical criteria, they do not replace a comprehensive family history and clinical acumen.
For patients who have a cancer or a large adenoma, tumor testing for MMR deficiency is a more accurate and cost-effective way of identifying potential patients with Lynch syndrome than are clinical criteria or prediction models alone. MMR deficiency is evaluated by MSI or by immunohistochemistry for expression of MMR proteins. About 90% of Lynch syndrome CRCs will be MSI-H and lack MMR protein expression. Lack of expression of a specific protein can direct germline testing for mutations to a specific gene. If MSH2 is mutated, both MSH2 and MSH6 are lost; if MSH6 is mutated, only MSH6 is lost. If MLH1 is mutated, both MLH1 and PMS2 expression are lost, but if PMS2 is mutated, then only PMS2 is lost. Depending on the findings of immunohistochemistry, the appropriate gene(s) is/are sequenced. About 15% to 18% of all colorectal cancers are MSI-H, and approximately 85% of these are attributable to acquired methylation of the MLH1 promoter not associated with Lynch syndrome. Therefore, if MLH1 expression is lost, results should be taken within the context of age and family history. Most tumors with methylation of MLH1 will have mutations in BRAF , whereas these are almost never found in Lynch tumors. Therefore, testing for BRAF mutations and MLH1 methylation can differentiate most tumors with absent MLH1 expression into Lynch syndrome and not Lynch syndrome.
Although tumor testing is the best way to identify patients for genetic testing, selection criteria for testing are debated. Limiting tumor testing by age or clinical criteria would lead to a significant number of Lynch syndrome cases being missed, and thus there is a move toward testing of all resected CRCs. In 2009, the Evaluation of Genomic Applications in Practice and Prevention Working Group recommended that samples of all newly diagnosed CRC undergo MSI and/or immunohistochemistry for MMR protein expression. These guidelines are endorsed by the Collaborative Group of the Americas on Inherited Colorectal Cancer. Recently, the National Comprehensive Cancer Network recommended universal screening of all colorectal cancers for persons younger than 70 years and for those older than 70 years who meet revised Bethesda guidelines. The Cleveland Clinic approach to universal tumor testing is summarized in Figure 59-4 .