CLINICAL FEATURES AND PATHOLOGY
Florid polyposis does not occur in Lynch syndrome, but colonic adenomas (particularly right sided) have been reported to be more common than in controls: 30 % of Lynch syndrome patients have at least one colonic adenoma, and 20 % have multiple lesions, compared with 11 and 4 % in age- and sex-matched controls (Lanspa et al. 1990; Gaglia et al. 1995). Other studies have, however, suggested that the prevalence of adenomas is not greatly increased, but they develop more rapidly through the adenoma-carcinoma sequence in this disease (Jass 1995). If multiple adenomas do occur, it is very rare to find more than 50, which differentiates Lynch syndrome from FAP, in which characteristically there are more than 100 polyps. A subgroup of patients with Lynch syndrome develops flat adenomas (slightly elevated lesions with adenomatous changes confined to the colonic crypts) (Lynch et al. 1990a, b, c), although it is not clear that this subset can be distinguished by molecular means.
The MMR defect results in instability of microsatellite DNA in the Tumours, causing microsatellite instability (MSI) in over 90 % Tumours in Lynch syndrome compared with 15 % in sporadic Tumours.
The pathology of colorectal cancers in Lynch syndrome is notable for a slight overrepresentation of mucinous carcinomas, mainly well differentiated and rarely of the signet-ring cell type, with a medullary pattern in about 9 % of cases. Lymphocytic infiltration and Tumours budding with de-differentiation are more common in Lynch syndrome than in sporadic cancers, and in Lynch syndrome, there are characteristically more APC, CTNNB1, and KRAS mutations than in sporadic cancers, whereas DNA methylation and BRAF mutations are rare (Jass 2004). Interestingly, a higher level of antibody reactivity against such frameshift peptides (FSPs) can be demonstrated in patients with microsatellite unstable Lynch syndrome and healthy MMR mutation carriers than in controls, indicating that these FSPs are recognized by the patients’ T cells. This may account for the observed high levels of inflammatory response with lymphocyte infiltration in Tumours in individuals with Lynch syndrome.
The dermatological features of Muir–Torre syndrome (Smyrk et al. 2001) with sebaceous adenomas and carcinomas may occur occasionally in individuals with Lynch syndrome, but genotype-phenotype correlations are not evident, beyond the observation that MSH2 mutations are more likely to cause this than MLH1 (Lucci-Cordisco et al. 2003).
Turcot syndrome is defined as the co-occurrence of colorectal polyps and brain Tumours. This can be caused by germline mutations in the APC gene or germline mutations in one of the MMR genes. Some children have been described with adenomatous colonic polyps, primary brain Tumours, leukemia, and café-au-lait skin patches, with an autosomal recessive inheritance pattern, and the condition has been shown to be due to homozygosity or compound heterozygosity for mutations in the MMR genes MLH1, MSH2, MSH6 or PMS2 (Ricciardone et al. 1999; Whiteside et al. 2002; Menko et al. 2004, reviewed in Bandipalliam 2005).
There is evidence that colorectal cancers exhibiting MSI have a better survival than those that do not (Bubb et al. 1996; Gryfe et al. 2000), and this may also be true for those with Lynch syndrome (Sankila et al. 1996; Watson et al. 1998), although this has been disputed (Farrington et al. 2002; Clark et al. 2004).