Hyperplastic Polyps in Hereditary Nonpolyposis Colorectal Cancer Fleur E. M. Rijcken, M.D., Tineke van der Sluis, Ing, Harry Hollema, M.D., Ph.D., and Jan H. Kleibeuker, M.D., Ph.D. Departments of Gastroenterology and Pathology, University Hospital Groningen, Groningen, The Netherlands OBJECTIVES: Hereditary nonpolyposis colorectal cancer (HNPCC) is a genetic syndrome caused by germline muta- tions in DNA mismatch repair (MMR) genes, in particular hMLH1, hMSH2, and hMSH6. Dysfunction of MMR genes leads to loss of MMR protein expression and to microsat- ellite instability (MSI). MSI is also detected in 10 –20% of sporadic colorectal cancers. Hyperplastic polyps (HP) may serve as precursor for these MSI+ sporadic colorectal can- cers. The aim of this study was to examine whether hyper- plastic polyps are also possible premalignant lesions in HNPCC. METHODS: All HPs resected from (suspected) mismatch re- pair gene mutation carriers were retrieved from a screening program database. Clinical information on patient age at colonoscopy and location of the HP was collected. MLH1, MSH2, and MLH6 protein expression was evaluated using immunohistochemistry. RESULTS: A total of 90 HPs were resected from 21 men and 19 women. The mean patient age at resection was 45.7 yr (44.7 yr in men and 46.6 yr in women). In all patients, 19 (21%) HPs were resected from the proximal colon, 23 (26%) from the distal colon, and 48 (53%) from the rectum. None of the HPs demonstrated loss of MMR protein expression. CONCLUSIONS: Mismatch repair dysfunction in HPs of HNPCC patients is apparently very rare. It seems unlikely that HPs in HNPCC patients are precursors for (MSI+) cancers in these patients. (Am J Gastroenterol 2003;98: 2306 –2311. © 2003 by Am. Coll. of Gastroenterology) INTRODUCTION There is abundant evidence supporting the classical adeno- ma-carcinoma sequence in the evolution of colorectal can- cer (1, 2). Hyperplastic polyps (HPs) have not been included in the classic model. Traditionally, HPs have been regarded as benign lesions, lacking the potential for neoplastic pro- gression. Recently, this view is has become increasingly difficult to sustain given the finding of K-ras mutations (3), transforming growth factor-RII receptor mutations (4), chromosome 1p deletions (5), and DNA microsatellite in- stability (MSI) (6) in HPs. With the discovery of the mismatch repair (MMR) genes, it has become clear that two major molecular genetic path- ways could be discerned in colorectal carcinogenesis. The first pathway, the chromosomal instability pathway, is char- acterized by allelic losses and gains and by aneuploidy. The second pathway, the microsatellite instability pathway, is characterized by an abundance of subtle DNA mutations and diploidy. Microsatellite instability is caused by inacti- vation of a DNA MMR gene. It is the molecular hallmark of hereditary nonpolyposis colorectal cancer (HNPCC), a ge- netic syndrome caused by germline mutations in DNA MMR genes, in particular hMLH1, hMSH2, and hMSH6. Microsatellite instability seems to be an early event in the carcinogenesis of HNPCC colorectal cancers, as up to 57% of colorectal adenomas from patients with HNPCC show MSI (7, 8). Microsatellite instability is also detected in 10 –20% of sporadic colorectal cancers (9, 10). However, on the basis of morphological observations and epigenetic changes, these lesions are thought to progress to cancer in a way that differs from the microsatellite instability pathway described for hereditary MSI+ tumors. Iino et al. proposed the serrated pathway in which HPs serve as precursors for sporadic MSI+ colorectal cancers (6). Under the influence of pro- moter methylation of the DNA MMR gene hMLH1, HPs may develop through serrated dysplasia into sporadic MSI+ colorectal cancer. In HNPCC, all polyps (even minute ones) are resected during screening colonoscopy. Some of these are hyperplas- tic and so, far, have been considered as “innocent bystand- ers” without any consequences for further management. However, in view of the recently described microsatellite instability and loss of expression of MMR proteins in hy- perplastic aberrant crypt foci from MMR gene mutation carriers the innocence of hyperplastic lesions in HNPCC should be questioned (11). On the other hand, Iino et al. found only two of 17 HPs in subjects with HNPCC to be microsatellite unstable (12). Jass et al. described one HNPCC patient with a mixed HPs/adenoma in contiguity with a colorectal cancer (13). The aim of this study was to examine whether HPs are possible premalignant lesions in HNPCC. The loss of ex- THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 98, No. 10, 2003 © 2003 by Am. Coll. of Gastroenterology ISSN 0002-9270/03/$30.00 Published by Elsevier Inc. doi:10.1016/S0002-9270(03)00540-9