Stephen J. Lanspa

Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (∼30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRCs proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir‐Torre variant). LS explains only 10–25% of familial CRC.

Attenuated familial adenomatous polyposis (AFAP) a phenotypically and genotypically distinctive variant of FAP

Background. The usual manifestation of familial adenomatous polyposis (FAP) is hundreds or thousands of colonic adenomas. The authors previously described a colon cancer‐prone syndrome characterized by fewer adenomas (1–100), most located in the proximal colon, and upper gastrointestinal lesions, particularly fundic gland polyps and duodenal adenomas. The colonic adenomas are often flat rather than polypoid, a feature emphasized in earlier reports with the term “hereditary flat adenoma syndrome.” The syndrome has an autosomal dominant pattern of inheritance and is linked to the adenomatous polyposis coli [APC] locus at 5q.

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I & II): Genetics, pathology, natural history, and cancer control, part I

Hereditary nonpolyposis colorectal cancer (HNPCC) is common, accounting for about 4-6% of the total colorectal cancer burden. It is heterogeneous and appears to be delineated into two clinical subsets, Lynch syndromes I and II. Lynch syndrome I is characterized by an autosomal dominantly inherited proclivity to early onset colonic cancer with proximal predominance and an excess of multiple primary colonic cancer. Lynch syndrome II has all of these features plus extracolonic cancer sites, the most common of which is endometrial carcinoma. The lack of premonitory physical signs or biomarkers of HNPCC makes diagnosis difficult. A careful family history, tempered by an understanding of the clinical and pathologic features of HNPCC, is the key to its assessment. This paper reviews HNPCCs natural history, its integral extracolonic cancer associations, its differential diagnosis, surveillance, and management strategies. Attention is focused upon the need for biomarker research in the interest of improving control of HNPCC.

Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II)

Approximately 5 to 6 percent of the total colorectal cancer burden is accounted for by hereditary nonpolyposis colorectal cancer (HNPCC). Because clinical premonitory signs such as those seen in familial polyposis coli (FPC) are lacking, the clinician must recognize clinical findings and family history typical of HNPCC. The authors have described colorectal cancer expression from a survey of ten HNPCC kindreds. Kindred members with colorectal cancer differed significantly (P<.05) from patients with sporadic colorectal cancer: 1) mean age of initial colon cancer diagnosis was 44.6 years; 2) 72.3 percent of first colon cancers were located in the right colon, and only 25 percent were in the sigmoid colon and rectum; 3) 18.1 percent had synchronous colon cancers; and 4) 24.2 percent developed metachronous colon cancer, with a risk for metachronous lesions in ten years of 40 percent. Affecteds and their first-degree relatives should undergo early intensive education and surveillance. In families with an early age of onset, colonoscopy should begin at age 25, and biannually thereafter, with fecal occult blood testing of the stool semiannually. Third-party carriers must become more responsive to the costly surveillance measures required for these otherwise healthy patients.

Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population

PURPOSE: This clinical case review aimed to identify phenotypic variations in colorectal and extracolonic cancer expression between hereditary nonpolyposis colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the general population. METHODS: Colorectal cancer onset and site distribution were compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and 1,189 patients from the general population. Synchronous and metachronous cancer rates, tumor stage, extracolonic cancer incidence, and survival were also compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years for MLH1, MSH2, and the general population, respectively (P<0.001). More proximal and fewer distal colon cancers were noted in HNPCC than the general population (P<0.001,P=0.04). Site distribution showed disparity of rectal cancers (8 percent MLH1vs. 28 percent MSH2;P=0.01) based on genotypes. Overall, synchronous colorectal cancer rates were 7.4, 6.7, and 2.4 percent for MLH1, MSH2, and the general population, respectively (P=0.016). Annual metachronous colorectal cancer rates were 2.1, 1.7, and 0.33 percent for MLH1, MSH2, and the general population, respectively (P=0.041). Colorectal cancer stage presentation was lower in HNPCC than the general population (P=0.0028). Extracolonic cancers were noted in 33 percent of MSH2 patients, compared with 12 percent of MLH1 patients and 7.3 percent of the general population with colorectal cancers (P<0.001). Combined MLH1 and MSH2 ten-year survival was 68.7 percent compared with 47.8 percent for the general population (P=0.009 stage stratified, hazard ratio 0.57). CONCLUSION: The presence of rectal cancer should not preclude the diagnosis of HNPCC, because the incidence of rectal cancer in MSH2 was comparable with that in the general population. Phenotypic variations, including the preponderance of extracolonic cancers in MSH2 patients, did not result in survival differences between genotypic subgroups. These phenotypic features of HNPCC genotypes may have clinical significance in the design of specific screening, surveillance, and follow-up for affected individuals.

Colon cancer genetics

The terms “hereditary,” “sporadic,” and “familial” colorectal cancer (CRC) suggest a knowledge of causation; however, current understanding of CRC does not permit categorization of differing CRC risks in accord with their cause per se. Despite these serious shortcomings, these terms are defined operationally on the basis of a family history of cancer, and when available, additional phenotypic information. The sporadic type occurs in the absence of a family history of CRC in a first‐degree relative. The familial type occurs when at least one first‐degree relative has CRC. Both these categories require the exclusion of hereditary CRC. In the case of hereditary CRC, this type is defined as a family history of CRC occurring in a pattern that indicates autosomal‐dominant inheritance, which also may involve certain phenotypic signs (depending on the specific disorder, i.e., florid adenoma‐tous polyps, benign and malignant extracolonic lesions, cancer of unusually early onset, and multiple primary cancer, particularly synchronous and metachronous CRC). Although this operational classification does not produce etiologically homogeneous groups, it is believed to have pragmatic utility with respect to planning targeted surveillance and management strategies. Because of the distinctive natural history of CRC in hereditary syndromes, it is of paramount clinical importance to identify hereditary CRC when it does occur. Even in patients with no evidence of hereditary CRC syndrome, their family history may be second only to age in determining the best CRC screening program for those who are asymptomatic. In an attempt to provide a perspective on the clinical evaluation of CRC risk, research was reviewed on pathologic features and biomarkers that may be related to CRC causes, especially the genetic basis of CRC susceptibility. The long‐term objective of studies on the genetic epidemiology of CRC is primary and secondary prevention through development of targeted management and surveillance recommendations (based on an understanding of CRC causation) that is relevant to hereditary, familial, and sporadic CRC.

Colorectal adenomas in the lynch syndromes. Results of a colonoscopy screening program

Forty-four asymptomatic putative Lynch syndrome patients participated in a colonoscopy screening program. There were 18 men and 26 women; mean age was 44 yr. Thirty percent of Lynch syndrome patients had at least one adenoma; 20% had multiple adenomas. In 18% of the patients, adenomas were discovered proximal to the splenic flexure. In a reference group of 88 age- and sex-matched patients, 11% had adenomas, 4% had multiple adenomas, and 1% had right-sided adenomas. Twenty-one Lynch syndrome patients had follow-up colonoscopies. Of 7 patients with adenomas on initial examinations, 6 had adenomas at follow-up. Of 14 patients with negative initial examination results, 3 had adenomas at follow-up. The prevalence of adenomas in the Lynch syndromes is greater than in an unselected reference group. The adenomas are more proximally located, corresponding to the site of cancer distribution in the Lynch syndromes. A high rate of synchronous and metachronous lesions is found. Our findings support the hypothesis that adenomatous changes are the premalignant lesion in the Lynch syndromes. We also found evidence of heterogeneity among Lynch syndrome families in adenoma incidence.

Hereditary flat adenoma syndrome: A variant of familial adenomatous polyposis?

We describe the clinical and pathologic features in four extended kindreds that are consistent with the hereditary flat adenoma syndrome (HFAS). This colon cancer susceptibility disorder is believed to be inherited as an autosomal dominant. The principal phenotypic marker is multiple colonic adenomas (usually less than 100), with a tendency for proximal location. The majority of these adenomas are flat or slightly raised and plaquelike, as opposed to polypoid. Colon cancers have typically developed in middle age and show no unusual histologic features. There are a variety of extracolonic manifestations, including adenomas and carcinomas of the small bowel and fundic gland polyps. The HFAS is contrasted with hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis (FAP) and shown to be distinct from both in the numbers and distribution of colonic adenomas and the typical age of cancer diagnosis. The clinical implications of these findings are discussed. Given its linkage to the FAP locus on 5q and the phenotypic parallels between HFAS and FAP, we conclude that HFAS is a variant of FAP.

Epidemiologic characteristics of the flat adenoma of Muto. A prospective study.

The flat adenoma is an endoscopically visible lesion that histologically consists of adenomatous change near the luminal surface of colonic tubules. We have described three families with hereditary colon cancer with later age of onset than familial adenomatous polyposis (FAP) and with multiple proximal colonic flat adenomas. These families have been linked to the FAP locus on chromosome 5. Our aim was to determine whether the flat adenoma is pathognomonic of this hereditary flat adenoma syndrome (HFAS) or merely an atypical or early tubular adenoma with occurrence in patients other than those from colon cancer-prone families. Methods: We prospectively examined a population referred for colonoscopy within a one-year period. During colonoscopy, flat adenomas were specifically sought and all lesions were removed endoscopically and evaluated histologically. Members of known hereditary colon cancer families were excluded. Results: One hundred forty-eight patients underwent colonoscopy (64 men and 84 women). Median age was 61 years. Fifty-seven patients had 157 polyps. One hundred thirty-six polyps were reviewed histologically. Thirty-five (23.6 percent) of the referred patients had adenomas, of whom twelve patients had only flat adenomas while six had both flat and other adenomas (18=12 percent of 148). The associations between flat adenoma occurrence and various predictors (sex, race, prior colonic neoplasms, family history of cancer, synchronous adenomas) were similar to those seen with other adenomas. Flat adenomas were found in nearly equal proportions of patients under or over age 61 years (11 percent and 13 percent, respectively). Other adenomas were significantly more common in the older group (6 percentvs.25 percent;P<0.002 by Fishers exact test). Conclusion: In a referral practice, the flat adenoma has the same prevalence and associated risk factors as other adenomas, except for younger age of onset. Our data suggest that the flat adenoma represents an early stage of adenoma development that is manifested in a subset of patients from the general population and that, as an isolated event, does not provide a marker for a hereditary colon cancer-prone syndrome.

Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome II)

Increasing recognition of the statistical burden posed by HNPCC (5 to 6 percent of all colorectal cancer) mandates that physicians have a better understanding of the genetics, natural history, and distinction between the hereditary site-specific variant (Lynch syndrome I) and the Cancer Family Syndrome (Lynch syndrome II). The authors report detailed cancer (all sites) family histories on two prototype families with Lynch syndrome I (Family R) and Lynch syndrome II (Family N), which have been under investigation for more than two decades. Emphasis is placed on shared clinicogenetic features; namely, early age of onset of colonic cancer (approximately age 44), multiple primary colonic cancer (24 percent of cases showed metachronous colonic cancer), predominance of proximal colonic cancer location (approximately 65 percent in the proximal colon), and vertical transmission consonant with an autosomal dominantly inherited factor. An increased predilection for extracolonic cancer, particularly endometrial carcinoma, occurs in Lynch syndrome II and is the primary basis for distinction from Lynch syndrome I. Surveillance and management programs must be wholly responsive to these natural history features.