New Approaches for Early Detection of Ulcerative Colitis (UC) Associated Cancer and Surgical Treatment of UC Patients

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1 New Approaches for Early Detection of Ulcerative Colitis (UC) Associated Cancer and Surgical Treatment of UC Patients Toshiaki Watanabe, M.D., Ph.D. Department of Surgery, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo, , Japan. Summary Introduction The number of ulcerative colitis (UC) patients in Japan has been increasing. Previous studies show colonoscopic surveillance to be useful for the early detection of UCassociated colorectal cancers. Recently, studies show that chromoendoscopy is useful for performing a targeted biopsy instead of a step biopsy to improve the efficacy of surveillance. Another approach to improve the efficacy of surveillance is to identify molecular markers for high-risk patients. A microarray analysis might be useful for the selection of highrisk patients. A prospective randomized controlled study is presently being conducted in Japan to compare the efficacy of a step biopsy and a target biopsy. Long-standing Ulcerative colitis (UC) patients are at high-risk for developing colon cancer. The cumulative risk of developing UC-associated colon cancer increases with the duration and extent of the disease. The cumulative risk for developing colon cancer 10, 20 and 30 years after the onset of the disease is 2%, 8% and 18%, respectively. 1 Previous studies show that surveillance is important for the early detection of UCassociated neoplasm. Patients with total colitis and disease that has lasted over seven to ten years are at risk of cancer and surveillance colonoscopy is performed on such patients. 1-4 Surveillance is important for the early detection of UC-associated neoplasms. However, most of these studies have been reported from Western countries. This study examined the usefulness of such surveillance among Japanese UC patients. UC-associated colon cancer in Japan Key words: Ulcerative colitis, Colon cancer, Dysplasia, Microarray, Prediction The number of UC patients in Japan has been increasing since 1980s and the number of reported Address for reprints and correspondence; Toshiaki Watanabe, Department of Surgery, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo, , Japan. Tel: , Fax: , toshwatanabe@yahoo.co.jp 217

2 Toshiaki Watanabe Figure 1 Number of UC patients in Japan Figure 3 Frequency of early cancer Figure 2 Number of UC-associated colorectal cancers in Japan patients with UC-associated colon cancer in the Japanese literature shows an increase in recent years (Figure 1, 2). 5 Surveillance for early detection of UCassociated neoplasms has been conducted since Surveillance colonoscopy was performed for 217 longstanding UC patients and identified a total of 20 patients with cancer and/or dysplasia. 4 This series demonstrated the same tendency as observed in Western countries and that the cumulative risk for developing colon cancer and/or dysplasia 10, 20 and 30 years after onset of the disease was 3.1%, 10.0%, 15.6%, respectively. 4 A review of the published reports of UC-associated colon cancers in Japan revealed a total of 312 patients who developed UC-associated colon cancers to have been reported as of the year These patients were divided into two groups, the Surveillance group or the Non-surveillance group. The Surveillance group included completely asymptomatic patients whose lesions had been detected by surveillance colonoscopy (91 cases). On the other hand, patients, whose lesions were detected because of symptoms due to UC-associated cancers, such as ileus, palpable tumor etc., were classified as the Non-surveillance group (60 cases). The Surveillance group showed a significantly higher frequency of early cancer than the Non-surveillance group (55% vs. 4%, p<0.05; Figure 3). On the other hand, the frequency Figure 4 Frequency of lymph node metastasis Figure 5 Frequency of distant metastasis of both lymph node metastasis (26% vs. 70%, p<0.05) and distant metastasis (15% vs. 48%, p<0.001) was significantly lower in the Surveillance group than in the Non-surveillance group (Figure 4,5). These results suggested that colonoscopic surveillance may be useful for the early detection of UC-associated cancers. 218

3 New Approaches for Early Detection of Ulcerative Colitis... New strategies to improve the efficacy of surveillance 1. Chromoendoscopy and pit pattern diagnosis The current reported guidelines suggest that a large number of biopsy specimens should be taken during the surveillance colonoscopic examination. More than 30 biopsy specimens are needed according to these guidelines. 6,7 Taking a large number of biopsy specimens does not seem to be an ideal method, and, therefore, Kiesslich et al. reported the usefulness of chromoendoscopy during surveillance colonoscopy in order to more effectively obtain biopsy specimens. 8 They performed a randomized, controlled trial to test whether chromoendoscopy might facilitate the early detection of intraepithelial neoplasias (IN) and colitisassociated colon carcinomas (CRC) in UC. A total of 165 patients were randomized to undergo conventional colonoscopy or colonoscopy with chromoendoscopy using 0.1% methylene blue. Circumscript lesions in the colon were evaluated according to a modified pit pattern classification. They showed that more targeted biopsies were possible with chromoendoscopy, and significantly more IN were detected in the chromoendoscopy group (32 vs. 10; P = 0.003). They used the modified pit pattern classification and demonstrated both the sensitivity and specificity for differentiation between non-neoplastic and neoplastic lesions to be 93%. They concluded that chromoendoscopy with methylene blue is a novel tool for the early detection of IN and CRC in patients with UC. Another series also confirmed that UC-associated neoplasias show a neoplastic pit pattern. However, there were also non-neoplastic lesions, which showed neoplastic pit patterns. 9 In other word, the false positive rate was higher in that series than Kiesslich s study. One problem in applying pit pattern diagnosis in UCassociated neoplasm is the pit pattern classification. The original pit pattern classification was proposed to classify early neoplastic lesions in the large bowel such as adenoma, intramucosal carcinoma or carcinoma with submucosal invasion. 10 Therefore, it is sometimes difficult to classify lesions using the conventional classification criteria when performing a pit pattern diagnosis in UC-associated neoplasms. Kudo et al. are now proposing a new classification of pit pattern for the diagnosis of UC-associated lesions. However, this classification is not used in clinical practice at the present time. Further study is needed to confirm the real efficacy of chromoendoscopy and the pit pattern diagnosis for application in surveillance colonoscopy. 2. Molecular markers to select high risk patients Another approach to improve the efficacy of surveillance is to identify new markers of selecting individuals at high risk for the development of colon cancer. More effective and intensive follow-up can be performed if patients at a higher risk of cancer can be selected. Several previous studies have shown that specific gene alterations are already present in nonneoplastic mucosa in UC patients with cancer and/or dysplasia These genes include p14, p16, ER and hmlh1. Alterations of these genes are also present in sporadic colon cancers. Histologically nonneoplastic mucosa already has genetic alterations similar to those in sporadic cancers. This suggests that patients who are at high risk for developing cancer and/ or dysplasia may already have specific gene alterations in nonneoplastic mucosa. Therefore, a DNA microarray analysis was conducted to determine whether a gene expression analysis is useful for identifying UC-associated neoplasms. Recent advances in DNA microarray technology have made it possible to analyze the expression level of thousands of genes simultaneously The gene expression profiles were compared between nonneoplastic rectal mucosa in UC patients and sporadic colon cancers. Furthermore, the expression profiles of UC-associated colon cancers were compared with those of sporadic colon cancers to identify and characterize UC-associated neoplasms. Fifty-three UC (UC-group) and 60 sporadic colon cancer patients (Sporadic-Ca group) were examined. Specimens were obtained from nonneoplastic rectal mucosa from all UC cases for RNA extraction. Ten UC cases had colon cancer and/or dysplasia and in six of these cases specimens were also obtained from cancer. The gene expression profiles in these specimens were examined using a GeneChip microarray. A two-way unsupervised hierarchical clustering algorithm was used to order samples using gene expression data from genes. The gene expression of nonneoplastic rectal mucosa in UC and sporadic cancer were clustered into two distinct groups (Figure 6). Genes related to immune response (CD74, CD28, CD80, CD86, HLA- DPA1, HLA-DQB2/3, HLA-DRA, and TLR1) or signal 219

4 Toshiaki Watanabe Figure 6 An unsupervised hierarchical cluster analysis. Two-way hierarchical clustering was used to order samples (columns) and array targets (rows). Nonneoplastic rectal mucosa in UC and sporadic cancer were clustered into two distinct groups. Among six UC-associated cancers, two cancers were classified in a cluster of nonneoplastic rectal mucosa of UC, while the other four cancers were classified in a cluster of sporadic cancer. Figure 7 Chromoendoscopy in ulcerative colitis patient with dysplasia. Chromoendoscopy was useful for identifying slightly elevated lesions in the rectum with dysplasia. transduction (CD2, CD3D, CD69, IL7R, CD79B, and PTPRC) showed higher expression in the nonneoplastic rectal mucosa of UC in comparison to sporadic cancer. On the other hand, apoptosis inhibitor (BIRC5), tumor suppressor gene (BRCA1), genes related to regulation of cell cycle (MKI67, CDK2, CDKN3, CCNA2, CCNB2, SKP2) or cell proliferation (SIL, IFRD2, TPX2, KIF2C, KNSL7) showed a higher expression in sporadic colon cancer than in the nonneoplastic rectal mucosa of UC. The gene expression profiles of UC-associated cancer were then compared with those of sporadic colon cancer. Interestingly, four of six UC-associated cancers were classified in a cluster of nonneoplastic rectal mucosa of UC, while the other two cancers were classified in a cluster of sporadic cancer. This may suggest that some UC-associated cancers show the characteristics of cancer while others show the characteristics similar to UC background mucosa. However, the number of 220

5 New Approaches for Early Detection of Ulcerative Colitis... patients was too small in the present study, and a further study with a larger number of patients is needed to conclude whether molecular markers are truly effective for identifying high risk patients. Future perspectives Targeted biopsies using chromoendoscopy are considered as a useful method for surveillance instead of step biopsies in Japan (Figure 7). The Japanese study group has shown that the detection rate of neoplasia by targeted biopsies is comparable to the rate obtained by step biopsy. Therefore, a prospective randomized controlled study is being conducted in Japan to compare the efficacy of both step biopsies and target biopsies. Longstanding UC patients are randomized to receive either step biopsies or targeted biopsies. Four biopsy specimens are taken from every 10 cm of the large bowel in the Step group. In addition, biopsies are taken from lesions suspected of being neoplastic. Biopsies were taken from lesions suspected of being neoplastic in the Target group. In addition, one biopsy is taken from the lower rectum even though no neoplastic change is observed. chromoendoscopy and magnified endoscopy are used when lesions are suspected of neoplasia. The trial is now ongoing and this study may be able to compare the efficacy of targeted biopsies and step biopsies. REFERENCES 1. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48: Morson BC, Pang LS. Rectal biopsy as an aid to cancer control in ulcerative colitis. Gut 1967;8: Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983;14: Hata K, Watanabe T, Kazama S, et al. Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population. Br J Cancer 2003;89: Suzuki K, Watanabe T, Hata K, Nagawa H. Colorectal cancer and surveillance in patients with ulcerative colitis. J Jpn Soc Coloproctol 2003;56: Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence. Gastroenterology 2003;124: Farrell RJ, Peppercorn MA. Ulcerative colitis. Lancet 2002;359(9303): Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;124: Hata K, Watanabe T, Motoi T, Nagawa H. Pitfalls of pit pattern diagnosis in ulcerative colitis-associated dysplasia. Gastroenterology 2004; 126(1): Kudo S, Tamura S, Nakajima T, Yamano H, Kusaka H, Watanabe H. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc 1996;44: Hsieh CJ, Klump B, Holzmann K, et al. Hypermethylation of the p16ink4a promoter in colectomy specimens of patients with longstanding and extensive ulcerative colitis. Cancer Res 1998;58: Sato F, Harpaz N, Shibata D, et al. Hypermethylation of the p14(arf) gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res 2002;62: Issa JP, Ahuja N, Toyota M, et al. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 2001;61: Brentnall TA, Crispin DA, Bronner MP, et al. Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res. 1996;56: Clarke PA, te Poele R, Wooster R, Workman P. Gene expression microarray analysis in cancer biology, pharmacology, and drug development: progress and potential. Biochem Pharmacol 2001;62: Chin KV, and Kong AN. Application of DNA microarrays in pharmacogenomics and toxicogenomics. Pharm Res 2002;19: Wong YF, Selvanayagam ZE, Wei N, et al. Expression genomics of cervical cancer: molecular classification and prediction of radiotherapy response by DNA microarray. Clin Cancer Res 2003;9: