Little data exist on the colorectal phenotype of patients with Lynch Syndrome. The present study evaluated colonoscopic findings in patients with LS confirmed by germline testing. These individuals were followed by serial colonoscopy with an average interval between procedures of 1.7 years and an average of more than 9 years of follow-up representing the longest follow-up study, to our knowledge, to date.
The overall cumulative risk of colorectal neoplasm in LS patients in the present study group was 43% by age 40. Mecklin et al (10
) calculated a similar risk with over 40% of males and over 30% of females with colorectal neoplasms. These rates are strikingly different from the general population in which 1–2% of patients have colorectal adenomas by age 40 (11
In young adulthood, clinical differentiation between patients with Lynch Syndrome and oligopolyposis syndromes (such as attenuated familial adenomatous polyposis and MYH associated polyposis) is difficult to make. Although colorectal neoplasms are thought to be limited in LS, the present study revealed that the cumulative average number approaches 7.0±6.8 by age 80. However, the mean cumulative number of colorectal neoplasms was 1.3±0.5 and 2.2±1.8 in those affected before age 30 and 50, respectively. Consequently, patients under 30 years old with 3 or more (>2 SD from mean) or under 50 with 6 or more colorectal neoplasms likely have a polyposis syndrome rather than LS. This information can help guide appropriate management and genetic testing. Cumulative number of colorectal neoplasms by age has not otherwise been studied in LS patients with germline mutations except for the report of Liljegren et al (12
). This investigator noted a mean of 1.9 colorectal polyps among a cohort of 108 patients with assumed HNPCC and at risk family members with a mean age of 44.3 yrs at last surveillance colonoscopy.
Polyp dwell time is defined as the duration of the adenoma carcinoma sequence from normal colorectal mucosa to colorectal cancer. In sporadic colorectal cancer, this period is considered, from a variety of sources but more from expert opinion, to be about 10 years (13
). In LS, the polyp dwell time is estimated to be much shorter (8
) but has never been calculated. Nevertheless, screening and surveillance guidelines recommend colonoscopy every 1 to 2 years starting at age 20–25 and then annually after 40 years old (9
). In the present investigation, the polyp dwell time for development of an advanced adenoma was 33 months and for colorectal cancer 36 months. In addition, the mean age of adenoma and colorectal cancer diagnosis was similar in our study, further arguing for a very short colorectal cancer dwell time. This rapid progression to malignancy in LS supports the previous frequent screening/surveillance recommendations and argues for annual colonoscopy in germline affected individuals even at young age. Of note, the dwell time analysis is limited since missed small or flat adenomas on one colonoscopy could proceed to advanced adenomas or colorectal cancer on the next endoscopy. Although not statistically significant, there was a shorter dwell time for proximal compared to distal colorectal cancer. This finding could support the hypothesis that right-sided tumors were missed by colonoscopy.
Investigators have determined that patients with LS develop primarily right-sided colorectal cancer. The present study had a similar overall distribution of colorectal cancer with 22 of 31 cancers found in the right colon. However, evaluation of the location of all colorectal neoplasms in this study revealed that women have predominantly left-sided compared to men with right-sided neoplasms, and this difference was marginally statistically significant when adjusted for age and mutation type. There was no association between germline mutation type and location of neoplasia.
Thirty-one cancers were detected among 24 patients. In this retrospective study, 23 of 24 colorectal cancer patients were still alive at 5 years with a survival rate of 96%. Similarly, Jarvenin et al found a 100% survival rate at 5 years in patients with colorectal cancer in the screened group vs 57% in the nonscreened group (11
). This strikingly positive survival rate likely reflects both the effect of screening/surveillance and a less aggressive biology of this malignancy.
The findings in this retrospective investigation are limited by several considerations. A small number of patients were evaluated in this study. This factor might account for failure to find statistical significance in analysis of colorectal neoplasia distribution by mutation type or the chance occurrence of a high risk of colorectal cancer in women. As in other retrospective studies, selection bias can influence the data. Although complete information was obtained and verified on all participants, the accuracy of the data was dependent on the medical record. In our investigation, the patients came to a specialized center for management, and, consequently, the element of referral bias cannot be discounted; although none of the patients were enrolled in the study because of colorectal neoplasia. The above factors could have influenced results such as the cumulative risk of colorectal neoplasia and mean cumulative number of neoplasia per patient by age at colonoscopy. Nevertheless, this study attempted to mitigate these factors by extensively investigating a genetically confirmed group of Lynch Syndrome patients with prolonged colonoscopy follow-up.
In summary, by age 50 the majority of Lynch Syndrome patients have been affected by colorectal neoplasia. Left-sided colorectal neoplasia is common especially in females and should not dissuade the clinician from the diagnosis of LS. A burden of 3 or more colorectal neoplasms by age 30 or 6 or more by age 50 probably indicates a polyposis syndrome rather than LS. These guidelines can help determine the appropriate genetic testing to conduct. Polyp dwell time for advanced neoplasia is very rapid in patients with LS. This argues for annual and not biennial colonoscopic screening/surveillance in these patients and pedigrees. Finally, the excellent colorectal cancer 5 year survival in the present study supports literature data that colonoscopy screening/surveillance is a life saving tool.