Regional Proliferative Patterns in the Colon of Patients at Risk for Hereditary Nonpolyposis Colorectal Cancer S. E. Patchett, M.D., E. M. Alstead, M.D., B. P. Saunders, M.R.C.P., S. V. Hodgson, M.D., M. J. G. Farthing, M.D. From the Digestive Diseases Research Centre, The Medical College of St Bartholomew's Hospital, and the Department of Gastroenterology, St Mark's Hospital, London, United Kingdom Patients from a hereditary nonpolyposis colorectal cancer (HNPCC) kindred (Lynch Type 1 and Type 2) have an increased risk of developing large-bowel cancer. Tumors occur at a young age and are characteristically fight-sided. Colonic mucosal proliferation is known to be increased in several groups of patients at risk of colorectal cancer. PUR- POSE: This study was performed to assess the pattern of mucosat proliferation at different sites in the colon of pa- tients at risk of HNPCC and to determine whether this pattern differs from normal patients. METHODS: Mucosal biopsies were obtained at colonoscopy from 21 patients at risk for HNPCC (16 females; mean age, 42 years) and from 7 normal patients (4 females; mean age, 38 years), and mucosal proliferation was quantified using the whole crypt mitotic count (WCMC) technique. RESULTS: In patients from HNPCC families, WCMC and crypt area were signifi- cantly greater in the cecum than in the transverse colon and left colon (P < 0.001). Compared with normal patients, WCMC in HNPCC patients was significantly greater in the cecum only (P < 0.05). A significant right-to-left shift was also observed in normal patients, but the percentage in- crease from fight to left was two-fold greater in HNPCC patients. CONCLUSIONS: These results confirm a proximal- to-distal proliferative gradient in the human colon and sug- gest that this may be exaggerated in HNPCC. This increased proximal proliferative rate may be a factor in the develop- ment of right-sided cancer in these patients. [Key words: Hereditary nonpolyposis colorectal cancer; Proliferation; Mitotic count; Colonic crypt] Patchett SE, Alstead EM, Saunders BP, Hodgson SV, Farthing MJG. Regional proliferative patterns in the colon of patients at risk for hereditary nonpolyposis colorectal cancer. Dis Colon Rectum 1997;40:168-171. H ereditary nonpolyposis colorectal cancer (HNPCC) is responsible for approximately 3 to 6 percent of all colorectal tumors and is inherited in an autosomal dominant pattern. The disease is char- Supported by the Joint Research Board, St Bartholomew's Hospital, London, United Kingdom. Presented in part at the meeting of The American Gastroenterologi- cal Association, Boston, Massachusetts, May 16 to 19, 1993. Address reprint request to Dr. Patchett: Digestive Diseases Research Centre, The Medical College of St Bartholomew's Hospital, Char- terhouse Square, London EC1 M 6BQ, United Kingdom. 168 acterized by the presence of colorectal cancer in at least three family members for two generations with at least one case occurring before the age of 50 years. 1 A subset of patients is also predisposed to extract- ionic tumors, particularly in the urogenital tract and stomach. Recently several tumor susceptibility genes respon- sible for this disorder have been characterized. Ap- proximately 90 percent of cases of HNPCC are a result of mutations in one of four mismatch repair genes. 2 An unexplained clinical observation in these patients is the predilection for cancer to develop in the right colon in contrast to sporadic cancer in which left- sided tumors predominate. In patients predisposed to colorectal cancer, an early indication of abnormal activity in crypt cells is increased proliferative activi- ty.3 Increased cellular proliferation in the normal co- ionic mucosa of patients harboring a colorectal cancer or polyp has been demonstrated by a variety of meth- ods including tritiated thymidine 4 and bromode- oxyuridine 5 labeling. In addition, some studies have shown increased rectal mucosal proliferation in pa- tients with a strong family history of colorectal cancer compared with controls. 5 To identify whether the pattern of mucosal prolif- eration throughout the colon in patients with a strong family history differs from normal patients, we have studied a group of patients from families with docu- mented HNPCC and compared them with a group of healthy controls using a novel technique for assessing intestinal crypt cell turnover. METHODS Twenty-one consecutive patients from families with HNPCC, defined according to the Amsterdam criteria 6 (16 females; median age, 40 (range, 26-62) years)