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Rectal cancer after sulindac therapy for a sporadic adenomatous colonic polyp
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Copyright © 1998 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 93, No. 11, 1998 ISSN 0002-9270/98/$19.00 PII S0002-9270(98)00511-5
Rectal Cancer After Sulindac Therapy for a Sporadic Adenomatous Colonic Polyp N. Matsuhashi, M.D., A. Nakajima, M.D., K. Shinohara, M.D., T. Oka, M.D., and Y. Yazaki, Ph.D. Third Department of Internal Medicine, Second Department of Surgery, and Department of Pathology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
specimen revealed a tubular adenoma with moderate atypia. He was treated with oral sulindac (300 mg/day) for 4 months in an open label study of sulindac therapy for sporadic adenomatous colorectal polyps (1). Informed consent was obtained before the therapy. After therapy, the diameter of the polyp decreased to 8 mm, and the polyp was removed endoscopically 15 days after the course of sulindac therapy had ended. Histological examination of the resected polyp showed a tubular adenoma with moderate atypia and no evidence of cancer. The cut end of the resected polyp was negative for adenomatous tissue, and the resection was considered complete. Sixteen months after the polypectomy, follow-up colonoscopy revealed a new elevated lesion in the midrectum, where no abnormality had been noted previously (Fig. 1). The lesion had a sessile configuration, with a diameter of 10 mm and an elevation of 3 mm. The tumor was removed endoscopically. Histologic examination revealed a moderately differentiated adenocarcinoma, with no areas of adenoma (Fig. 2). Massive submucosal infiltration by the cancer was observed histologically, as was venous infiltration. Therefore, an anterior rectal resection with lymph node dissection was performed. Macroscopically, no remaining cancer tissue was detected in the resected specimen. However, histologic examination revealed microscopic venous invasion by the cancer tissue in a vein approximately 6 mm from the polypectomy site (Fig. 3), although there was no cancer tissue in the mucosal or submucosal tissue at the site of the polypectomy. In addition, one of eight resected lymph nodes contained metastatic cancer (data not shown). Eventually, the patient underwent a partial hepatectomy due to a liver metastasis 33 months after the second polypectomy. Formalin-fixed, paraffin-embedded tissue samples were stained immunohistochemically for cyclooxygenase-2 (COX-2) and the mutant p53 product. The biopsy specimen obtained before sulindac therapy was negative for mutant p53 (not illustrated) and positive for COX-2 (Fig. 4A). The polyp resected 15 days after conclusion of sulindac treatment also was negative for mutant p53 (not illustrated) and positive for COX-2 (Fig. 4B). The rectal cancer was homogeneously and strongly positive for both mutant p53 protein (not illustrated) and COX-2 (Fig. 4C). Control noncancer-
Like adenomatous polyps in familial adenomatous polyposis, some sporadic colorectal polyps have been reported to regress in response to sulindac administration. However, a rapidly growing invasive rectal cancer developed in one of 15 patients with sulindac-treated sporadic adenomatous colorectal polyps 16 months after sulindac treatment. In this patient, both the adenomatous polyp that responded partially to sulindac and the rectal cancer developing after sulindac therapy showed immunostaining for cyclooxygenase-2. Although short term sulindac therapy seems to be able to cause some adenomatous colorectal polyps to regress, 4 months of sulindac therapy may not reliably prevent colorectal cancer development in these patients. (Am J Gastroenterol 1998;93:2261–2266. © 1998 by Am. Coll. of Gastroenterology)
INTRODUCTION The regression of sporadic adenomatous colorectal polyps in response to sulindac administration has been reported previously (1), although other studies have failed to demonstrate significant regression (2– 4). Because the ultimate aim of such therapy is to prevent the formation of colorectal cancers, the long term effects of such therapy are clinically important. However, the long term outcome of sulindac therapy on sporadic colorectal polyps has not been reported previously. Following our previous study using sulindac therapy for sporadic adenomatous colorectal polyps (1), follow-up colonoscopy was performed 7–22 months after the cessation of sulindac administration in 10 of the 15 treated patients. In one of them, a rapidly growing rectal cancer developed after sulindac therapy. CASE REPORT A 62-yr-old Japanese man had a positive stool occult blood test during a routine examination. A barium enema study revealed a 15-mm colonic polyp in the mid-sigmoid colon. Histological examination of an endoscopic biopsy Received Dec. 1, 1997; accepted Apr. 27, 1998. 2261
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FIG. 1. Endoscopic appearance of a newly developed rectal cancer.
ous rectal mucosa obtained at the time of rectal resection was negative for both COX-2 (Fig. 4D) and mutant p53 (not illustrated). DISCUSSION Colorectal cancers develop in several different settings, including sporadic adenomatous polyps, familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal
AJG – Vol. 93, No. 11, 1998 cancer (HNPCC), and flat cancers. The respective genes implicated in FAP and HNPCC are APC and mismatch repair genes (mainly hMLH1 and hMSH2). Additionally, sequential genetic changes have been postulated in the adenoma-carcinoma sequence occurring in sporadic adenomatous polyps (5). However, little is known about genetic and epigenetic changes in flat cancers. In Western countries, most colorectal cancers are thought to develop from adenomatous polyps following the adenoma-carcinoma sequence, whereas flat cancers are considered relatively rare (6, 7). On the other hand, in reports from Japan, 10 –20% of colorectal cancers have been flat cancers (8, 9). The reason for this regional difference has not been elucidated, but several hypotheses have been proposed (10 –13). One is that colorectal cancer in Japan is biologically different from analogous tumors in the West. Another possibility is failure to discover flat lesions in Western studies. A third possibility is that pathological criteria for the diagnosis of cancer differ between Japan and the West; the significance of any difference would depend on the detailed characteristics of flat cancers. The rectal cancer described in this report was sessile and essentially flat in contour. In addition, the tumor contained no adenomatous components, and was homogeneous both
FIG. 2. Histology of the endoscopically resected rectal polyp (hematoxylin and eosin, 340). It consisted of a homogeneous, moderately differentiated adenocarcinoma, and no adenoma tissue was detected within it.
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FIG. 3. Histology of the surgically resected rectum (hematoxylin and eosin, 3100). In the submucosal layer about 6 mm distant from the polypectomy site, a small venous invasion was noted.
morphologically and immunohistochemically. These findings strongly suggest that the cancer developed as a flat lesion, not from an adenomatous polyp. Because such tumors often are difficult to detect endoscopically, the flat lesion may have been overlooked in previous endoscopic examinations. Both nonpolypoid cancers and nonpolypoid adenomas are referred to as flat lesions, but the relationship between them has not been determined. In the adenoma-carcinoma sequence, a point mutation of ras is thought to occur as a relatively early event (14), a view that has been borne out in both sporadic adenomatous polyps and FAP (15). However, a marked difference in the frequency of the ras mutation has been observed between polypoid lesions and flat lesions. Specifically, 40 –70% of adenomatous polyps and polypoid cancers have been reported to be associated with a ras mutation, whereas only 0 – 40% of flat adenomas or flat cancers have such a mutation (16 –19). Some authors maintain that these findings suggest that flat cancers arise from flat adenomas. In contrast, little difference is evident between frequencies of a p53 mutation in polypoid and flat lesions; in both configurations, the p53 mutation is observed frequently in cancer tissues, much less in adenoma with
high-grade atypia, and only rarely in adenoma with mild to moderate atypia (18). Like the ras mutation, frequency of the p53 mutation does not differ significantly between sporadic adenomatous polyps and FAP (20). On the other hand, another study argued that flat adenomas are not major precursors of flat cancers, because 1) 90% of flat cancers include no adenomatous component; 2) follow-up study of 13 flat adenomas failed to show transformation to cancer; 3) the distribution of flat adenomas is notably different from that of flat cancers; and 4) the macroscopic configuration of cancers with invasion into the muscle layer is similar to that of flat cancers (8). The study concluded that most colorectal cancers arise as flat cancers. In the same report, 80% of polypoid cancers were associated with adenomatous components, which supports the significance of the adenoma-carcinoma sequence in polypoid cancers. Little is known about flat lesions in HNPCC, but some HNPCC patients reportedly develop flat adenomas, which have been suggested to be precursors of colorectal cancers (21). Some evidence favors adenomas as precursor lesions for cancer in HNPCC (13). In one report, residual adenomas were found in 12% of HNPCC cancers, a rate similar to that
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FIG. 4. Immunohistochemical staining for COX-2 (3200). A: A colonoscopic biopsy specimen before sulindac therapy was positive for COX-2. B: A polypectomy specimen 15 days after the course of sulindac treatment also was positive. C: A rectal cancer developing 16 months later was strongly positive for COX-2. D: The noncancerous mucosa in the surgically resected rectum (control) was negative for COX-2.
TABLE 1 Characteristics of Rectal Cancers Developing After Sulindac Therapy
Case
Primary Disorder
Age, Gender
Ref. 38 Ref. 39 Present case
FAP FAP sporadic polyp
53, F 68, F 66,M
Sulindac Treatment Dose
Duration (months)
450mg 300mg 450m
28 15 4
Response of Poyps (no polyp) diappeared regressed
Developed Rectal Cancer Period* (months)
Shape
Size
Invasion
Histology
28 15 20
large pelvic mass flat, ulcerated sessile
4.2 cm 1 cm
direct direct, LN direct, LN, V
mod mod mod
*Period after start of suindac administration (months). FAP 5 familial ademomatous polyposis; LN 5 lymph nodes; V 5 vein; mod 5 moderately differentiated adenocarcinoma.
of adenoma occurrence in the general population (22). Another survey of endoscopically detected colorectal cancer in HNPCC patients reported that nine of 12 such cancers were associated with adenoma (23). However, adenomas in HNPCC are reported to have a much greater tendency toward malignant transformation (“aggressive adenoma”) (24), which has been linked to defects in gene mismatch repair. However, little is known about cancer-related genes apart from mismatch repair genes in HNPCC. A few studies of HNPCC have reported that the frequencies of mutation in K-ras and p53 are much lower than in sporadic colorectal cancer (25, 26). This implies that colon cancer in HNPCC may largely follow a distinct pathogenetic mechanism that
involves genes different from those altered in sporadic tumors. Indeed, a transforming growth factor–b type II receptor mutation has been reported to occur significantly more frequently in HNPCC than in non-HNPCC lesions (27, 28). These findings suggest that development of most HNPCC tumors involves genetic changes different from those occurring in the adenoma-carcinoma sequence. Concerning mismatch repair genes, microsatellite instability is characteristic of tumors in HNPCC and replication errors begin in an early stage of carcinogenesis in that disorder. Such instability also occurs in non-HNPCC cancers, but in later stages (28). Many studies, especially short-term ones (about 2–12
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months), have indicated that sulindac exerts a regressive effect on FAP polyps (29 –37). However, less is known about the long term efficacy of such therapy. To date, several studies investigating the long term efficacy of the therapy have been published (30 –37). These studies indicate that polyp regression is observed especially during the first few months of treatment. However, the polyps tend to recur after the discontinuation of the drug or, in some studies, after prolonged sulindac administration (31–34, 36). To date, development of rectal cancer after sulindac therapy for FAP polyps has been reported in two cases (38, 39). The cancer described in this report was strikingly similar in several aspects to those two reported rectal cancer cases (Table 1). First, the shape of the three cancers was not polypoid; all formed broad-based masses. Second, all three cancers grew rather rapidly. The two previously reported cancers developed and grew within several months. Furthermore, these three cancers had invaded into venous and lymphatic vessels within a short period. Third, none of the three cancers contained any detectable adenomatous components, although the complete details of the previous cases were not reported. In the present case, the cancer was homogeneous, based on its morphology by hematoxylin and eosin staining and p53 and COX-2 immunostaining. It is difficult to assume that these cancers developed from adenomatous polyps. These cancers apparently developed de novo independently of the adenoma-carcinoma sequence, growing as flat cancers from their onset. The mechanism of the adenoma-inhibitory effect of sulindac is still unclear, but the main pharmacological effect of nonsteroidal antiinflammatory drugs (NSAIDs), including sulindac, is inhibition of cyclooxygenase (COX). Several studies have implied that COX-2 inhibition is important in NSAID-mediated antineoplastic effects (40 – 43), although some other studies have reported evidence that a COX-2independent mechanism also is at work in the NSAIDmediated antitumor effect (44 – 49). Therefore, tissue COX-2 expression was of great interest in the present case, in which both the initial adenomatous polyp and the rectal cancer immunostained for COX-2. The polyp might have been negative or minimally positive for COX-2 staining during sulindac treatment, but in that case the 15-day period after sulindac treatment may have permitted the adenomatous tissue to recover COX-2 expression. In the present study, sulindac therapy resulted in partial regression of an adenomatous polyp, but could not prevent cancer development. The COX-2 positive polyp responded to sulindac, supporting involvement of COX-2 inhibition in polyp regression. However, whether the rectal cancer could have been prevented if sulindac treatment had been continued for a prolonged period remains unknown. At present, the exact relationship between sulindac administration and the development of rectal cancer is not clear. Further investigation will be necessary concerning not only the genetic and epigenetic characteristics of flat tumors, but also the ability of NSAIDs to prevent such tumors.
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ACKNOWLEDGMENTS This paper was supported in part by a Grant-in-Aid for Exploratory Research from the Ministry of Education, Science, Sports, and Culture of Japan. Reprint requests and correspondence: Nobuyuki Matsuhashi, M.D., The Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
REFERENCES 1. Matsuhashi N, Nakajima A, Fukushima Y, et al. Effects of sulindac on sporadic colorectal adenomatous polyps. Gut 1997;40:344 –9. 2. Hixson LJ, Earnest DL, Fennerty MB, et al. NSAID effect on sporadic colon polyps. Am J Gastroenterol 1993;88:1652– 6. 3. Ladenheim J, Garcia G, Titzer D, et al. Effect of sulindac on sporadic colonic polyps. Gastroenterology 1995;108:1083–7. 4. DuBois RN. Nonsteroidal anti-inflammatory drug use and sporadic colorectal adenomas. Gastroenterology 1995;108:1310 – 4. 5. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759 – 67. 6. Sugarbaker JP, Gunderson LL, Wittes RE. Colorectal cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and practices of oncology. Philadelphia: JB Lippincott, 1985:800 –3. 7. Owen DA. Flat adenoma, flat carcinoma, and de novo carcinoma of the colon. Cancer 1996;77:3– 6. 8. Kuramoto S, Oohara T. How do colorectal cancers develop? Cancer 1994;75(suppl):1534 – 8. 9. Tada S, Iida M, Matsumoto T, et al. Small flat cancer of the rectum: clinicopathologic and endoscopic features. Gastrointest Endosc 1995; 42:109 –13. 10. Colton CG, Sivak MV Jr. Flat adenomas and cancers. Gastrointest Endosc 1995;42:182– 4. 11. Bond JH. Small flat adenomas appear to have little clinical importance in Western countries. Gastrointest Endosc 1995;42:184 –7. 12. Driman DK, Riddell RH. Flat adenomas and flat carcinomas: Do you see what I see? Gastrointest Endosc 1994;40106 –9. 13. Lynch HT, Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 1996;78:1149 – 67. 14. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. New Engl J Med 1988;319:525– 32. 15. Ando M, Takemura K, Maruyama M, et al. Mutations in c-K-ras 2 gene codon 12 during colorectal tumorigenesis in familial adenomatous polyposis. Gastroenterology 1992;103:1725–31. 16. Yamagata S, Muto T, Uchida Y, et al. Lower incidence of K-ras codon 12 mutation in flat colorectal adenomas than in polypoid adenomas. Jpn J Cancer Res 1994;85:147–51. 17. Yamagata S, Muto T, Uchida Y, et al. Polypoid growth and K-ras codon 12 mutation in colorectal cancer. Cancer 1995;75:953–7. 18. Yukawa M, Fujimori T, Maeda S. Comparative clinicopathological and immunohistochemical study of ras and p53 in flat and polypoid type colorectal tumours. Gut 1994;35:1258 – 61. 19. Fujimori T, Satonaka K, Yamamura-Idei Y, et al. Non-involvement of ras mutations in flat colorectal adenomas and carcinomas. Int J Cancer 1994;57:51–5. 20. Kikuchi-Yanoshita R, Konishi M, Ito S, et al. Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res 1992;52:3965–71. 21. Watanabe T, Muto T, Sawada T, et al. Flat adenoma as a precursor of colorectal carcinoma in hereditary nonpolyposis colorectal carcinoma. Cancer 1996;77:627–34. 22. Love RR. Adenomas are precursor lesions for malignant growth in nonpolyposis hereditary carcinoma of the colon and rectum. Surg Gynecol Obstetr 1986;162:8 –12. 23. Lynch HT, Smyrk T, Jass JR. Hereditary nonpolyposis colorectal cancer and colonic adenomas: aggressive adenomas? Sem Surg Oncol 1995;11:406 –10. 24. Sankila R, Aaltonen LA, Jarvinen HJ, et al. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology 1996;110:682–7.
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25. Losi L, Ponz de Leon M, Jiricny J, et al. K-ras and p53 mutations in hereditary non-polyposis colorectal cancers. Int J Cancer 1997;74: 94 – 6. 26. Jeevaratnam P, Browett PJ, Van de Water NS, et al. Analysis of Ha-ras 1 allele frequencies in hereditary non-polyposis colorectal cancer. Gut 1995;36:382– 4. 27. Lu SL, Akiyama Y, Nagasaki H, et al. Mutations of the transforming growth factor-beta type II receptor gene and genomic instability in hereditary nonpolyposis colorectal cancer. Biochem Biophys Res Comm 1995;216:452–7. 28. Konishi M, Kikuchi-Yanoshita R, Tanaka K, et al. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 1996;111:307–17. 29. Waddell WR, Loughry RW. Sulindac for polyposis of the colon. J Surg Oncol 1983;24:83–7. 30. Waddell WR, Ganser GF, Cerise EJ, et al. Sulindac for polyposis of the colon. Am J Surg 1989;157:175–9. 31. Friend W. Sulindac suppression of colorectal polyps in Gardner’s syndrome. Am Fam Phys 1990;41:891– 4. 32. Charneau J, D’Aubigny N, Burtin P, et al. Micropolypes rectaux apres colectomie totale pour polypose familiale: Efficacite du sulindac. Gastroenterol Clin Biol 1990;14:153–7. 33. Labayle D, Fischre D, Vielh P, et al. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 1991;101:635–9. 34. Rigau J, Pique JM, Rubio E, et al. Effect of long-term sulindac therapy on colonic polyposis. Ann Intern Med 1991;115:952– 4. 35. Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993;328:1313– 6. 36. Tonelli F, Valanzano R. Sulindac in familial adenomatous polyposis. Lancet 1993;342:1120. 37. Winde G, Scmid KW, Schlegel W, et al. Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Dis Colon Rectum 1995;38:813–30.
AJG – Vol. 93, No. 11, 1998 38. Niv Y, Fraser GM. Adenocarcinoma in the rectal segment in familial polyposis coli is not prevented by sulindac therapy. Gastroenterology 1994;107:854 –7. 39. Lynch HT, Thorson AG, Smyrk T. Rectal cancer after prolonged chemoprevention. Cancer 1995;75:936 – 8. 40. Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995;83:493–501. 41. Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase gene expression inhuman colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107:1183– 8. 42. Oshima M, Dinchuk JE, Kargman ST, et al. Suppression of intestinal polyposis in APC716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996;87:803–9. 43. Reddy BS, Rao CV, Seibert K. Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis. Cancer Res 1996;56:4566 –9. 44. Thompson HJ, Briggs S, Paranka NS, et al. Inhibition of mammary carcinogenesis in rats by sulfone metabolite of sulindac. J Natl Cancer Inst 1995;87:125– 6. 45. Piazza GA, Rahm ALK, Krutzsch M, et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995;55:3110 – 6. 46. Alberts DS, Hixson L, Ahnen D, et al. Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase? J Cell Biochem (suppl) 1995;22:18 –23. 47. Charalambous D, O’Brien PE. Inhibition of colon cancer precursors in rat by sulindac sulfone is not dependent on inhibition of prostaglandin synthesis. J Gastroenterol Hepatol 1996;11:307–10. 48. McCracken JD, Wechter WJ, Liu Y, et al. Antiproliferative effects of the enantiomers of flurbiprofen. J Clin Pharmacol 1996;36:540 –5. 49. Hanif R, Pittas A, Feng Y, et al. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 1996;52:237– 45.
Vol. 93, No. 11, 1998 ISSN 0002-9270/98/$19.00 PII S0002-9270(98)00511-5
Rectal Cancer After Sulindac Therapy for a Sporadic Adenomatous Colonic Polyp N. Matsuhashi, M.D., A. Nakajima, M.D., K. Shinohara, M.D., T. Oka, M.D., and Y. Yazaki, Ph.D. Third Department of Internal Medicine, Second Department of Surgery, and Department of Pathology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
specimen revealed a tubular adenoma with moderate atypia. He was treated with oral sulindac (300 mg/day) for 4 months in an open label study of sulindac therapy for sporadic adenomatous colorectal polyps (1). Informed consent was obtained before the therapy. After therapy, the diameter of the polyp decreased to 8 mm, and the polyp was removed endoscopically 15 days after the course of sulindac therapy had ended. Histological examination of the resected polyp showed a tubular adenoma with moderate atypia and no evidence of cancer. The cut end of the resected polyp was negative for adenomatous tissue, and the resection was considered complete. Sixteen months after the polypectomy, follow-up colonoscopy revealed a new elevated lesion in the midrectum, where no abnormality had been noted previously (Fig. 1). The lesion had a sessile configuration, with a diameter of 10 mm and an elevation of 3 mm. The tumor was removed endoscopically. Histologic examination revealed a moderately differentiated adenocarcinoma, with no areas of adenoma (Fig. 2). Massive submucosal infiltration by the cancer was observed histologically, as was venous infiltration. Therefore, an anterior rectal resection with lymph node dissection was performed. Macroscopically, no remaining cancer tissue was detected in the resected specimen. However, histologic examination revealed microscopic venous invasion by the cancer tissue in a vein approximately 6 mm from the polypectomy site (Fig. 3), although there was no cancer tissue in the mucosal or submucosal tissue at the site of the polypectomy. In addition, one of eight resected lymph nodes contained metastatic cancer (data not shown). Eventually, the patient underwent a partial hepatectomy due to a liver metastasis 33 months after the second polypectomy. Formalin-fixed, paraffin-embedded tissue samples were stained immunohistochemically for cyclooxygenase-2 (COX-2) and the mutant p53 product. The biopsy specimen obtained before sulindac therapy was negative for mutant p53 (not illustrated) and positive for COX-2 (Fig. 4A). The polyp resected 15 days after conclusion of sulindac treatment also was negative for mutant p53 (not illustrated) and positive for COX-2 (Fig. 4B). The rectal cancer was homogeneously and strongly positive for both mutant p53 protein (not illustrated) and COX-2 (Fig. 4C). Control noncancer-
Like adenomatous polyps in familial adenomatous polyposis, some sporadic colorectal polyps have been reported to regress in response to sulindac administration. However, a rapidly growing invasive rectal cancer developed in one of 15 patients with sulindac-treated sporadic adenomatous colorectal polyps 16 months after sulindac treatment. In this patient, both the adenomatous polyp that responded partially to sulindac and the rectal cancer developing after sulindac therapy showed immunostaining for cyclooxygenase-2. Although short term sulindac therapy seems to be able to cause some adenomatous colorectal polyps to regress, 4 months of sulindac therapy may not reliably prevent colorectal cancer development in these patients. (Am J Gastroenterol 1998;93:2261–2266. © 1998 by Am. Coll. of Gastroenterology)
INTRODUCTION The regression of sporadic adenomatous colorectal polyps in response to sulindac administration has been reported previously (1), although other studies have failed to demonstrate significant regression (2– 4). Because the ultimate aim of such therapy is to prevent the formation of colorectal cancers, the long term effects of such therapy are clinically important. However, the long term outcome of sulindac therapy on sporadic colorectal polyps has not been reported previously. Following our previous study using sulindac therapy for sporadic adenomatous colorectal polyps (1), follow-up colonoscopy was performed 7–22 months after the cessation of sulindac administration in 10 of the 15 treated patients. In one of them, a rapidly growing rectal cancer developed after sulindac therapy. CASE REPORT A 62-yr-old Japanese man had a positive stool occult blood test during a routine examination. A barium enema study revealed a 15-mm colonic polyp in the mid-sigmoid colon. Histological examination of an endoscopic biopsy Received Dec. 1, 1997; accepted Apr. 27, 1998. 2261
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FIG. 1. Endoscopic appearance of a newly developed rectal cancer.
ous rectal mucosa obtained at the time of rectal resection was negative for both COX-2 (Fig. 4D) and mutant p53 (not illustrated). DISCUSSION Colorectal cancers develop in several different settings, including sporadic adenomatous polyps, familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal
AJG – Vol. 93, No. 11, 1998 cancer (HNPCC), and flat cancers. The respective genes implicated in FAP and HNPCC are APC and mismatch repair genes (mainly hMLH1 and hMSH2). Additionally, sequential genetic changes have been postulated in the adenoma-carcinoma sequence occurring in sporadic adenomatous polyps (5). However, little is known about genetic and epigenetic changes in flat cancers. In Western countries, most colorectal cancers are thought to develop from adenomatous polyps following the adenoma-carcinoma sequence, whereas flat cancers are considered relatively rare (6, 7). On the other hand, in reports from Japan, 10 –20% of colorectal cancers have been flat cancers (8, 9). The reason for this regional difference has not been elucidated, but several hypotheses have been proposed (10 –13). One is that colorectal cancer in Japan is biologically different from analogous tumors in the West. Another possibility is failure to discover flat lesions in Western studies. A third possibility is that pathological criteria for the diagnosis of cancer differ between Japan and the West; the significance of any difference would depend on the detailed characteristics of flat cancers. The rectal cancer described in this report was sessile and essentially flat in contour. In addition, the tumor contained no adenomatous components, and was homogeneous both
FIG. 2. Histology of the endoscopically resected rectal polyp (hematoxylin and eosin, 340). It consisted of a homogeneous, moderately differentiated adenocarcinoma, and no adenoma tissue was detected within it.
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FIG. 3. Histology of the surgically resected rectum (hematoxylin and eosin, 3100). In the submucosal layer about 6 mm distant from the polypectomy site, a small venous invasion was noted.
morphologically and immunohistochemically. These findings strongly suggest that the cancer developed as a flat lesion, not from an adenomatous polyp. Because such tumors often are difficult to detect endoscopically, the flat lesion may have been overlooked in previous endoscopic examinations. Both nonpolypoid cancers and nonpolypoid adenomas are referred to as flat lesions, but the relationship between them has not been determined. In the adenoma-carcinoma sequence, a point mutation of ras is thought to occur as a relatively early event (14), a view that has been borne out in both sporadic adenomatous polyps and FAP (15). However, a marked difference in the frequency of the ras mutation has been observed between polypoid lesions and flat lesions. Specifically, 40 –70% of adenomatous polyps and polypoid cancers have been reported to be associated with a ras mutation, whereas only 0 – 40% of flat adenomas or flat cancers have such a mutation (16 –19). Some authors maintain that these findings suggest that flat cancers arise from flat adenomas. In contrast, little difference is evident between frequencies of a p53 mutation in polypoid and flat lesions; in both configurations, the p53 mutation is observed frequently in cancer tissues, much less in adenoma with
high-grade atypia, and only rarely in adenoma with mild to moderate atypia (18). Like the ras mutation, frequency of the p53 mutation does not differ significantly between sporadic adenomatous polyps and FAP (20). On the other hand, another study argued that flat adenomas are not major precursors of flat cancers, because 1) 90% of flat cancers include no adenomatous component; 2) follow-up study of 13 flat adenomas failed to show transformation to cancer; 3) the distribution of flat adenomas is notably different from that of flat cancers; and 4) the macroscopic configuration of cancers with invasion into the muscle layer is similar to that of flat cancers (8). The study concluded that most colorectal cancers arise as flat cancers. In the same report, 80% of polypoid cancers were associated with adenomatous components, which supports the significance of the adenoma-carcinoma sequence in polypoid cancers. Little is known about flat lesions in HNPCC, but some HNPCC patients reportedly develop flat adenomas, which have been suggested to be precursors of colorectal cancers (21). Some evidence favors adenomas as precursor lesions for cancer in HNPCC (13). In one report, residual adenomas were found in 12% of HNPCC cancers, a rate similar to that
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FIG. 4. Immunohistochemical staining for COX-2 (3200). A: A colonoscopic biopsy specimen before sulindac therapy was positive for COX-2. B: A polypectomy specimen 15 days after the course of sulindac treatment also was positive. C: A rectal cancer developing 16 months later was strongly positive for COX-2. D: The noncancerous mucosa in the surgically resected rectum (control) was negative for COX-2.
TABLE 1 Characteristics of Rectal Cancers Developing After Sulindac Therapy
Case
Primary Disorder
Age, Gender
Ref. 38 Ref. 39 Present case
FAP FAP sporadic polyp
53, F 68, F 66,M
Sulindac Treatment Dose
Duration (months)
450mg 300mg 450m
28 15 4
Response of Poyps (no polyp) diappeared regressed
Developed Rectal Cancer Period* (months)
Shape
Size
Invasion
Histology
28 15 20
large pelvic mass flat, ulcerated sessile
4.2 cm 1 cm
direct direct, LN direct, LN, V
mod mod mod
*Period after start of suindac administration (months). FAP 5 familial ademomatous polyposis; LN 5 lymph nodes; V 5 vein; mod 5 moderately differentiated adenocarcinoma.
of adenoma occurrence in the general population (22). Another survey of endoscopically detected colorectal cancer in HNPCC patients reported that nine of 12 such cancers were associated with adenoma (23). However, adenomas in HNPCC are reported to have a much greater tendency toward malignant transformation (“aggressive adenoma”) (24), which has been linked to defects in gene mismatch repair. However, little is known about cancer-related genes apart from mismatch repair genes in HNPCC. A few studies of HNPCC have reported that the frequencies of mutation in K-ras and p53 are much lower than in sporadic colorectal cancer (25, 26). This implies that colon cancer in HNPCC may largely follow a distinct pathogenetic mechanism that
involves genes different from those altered in sporadic tumors. Indeed, a transforming growth factor–b type II receptor mutation has been reported to occur significantly more frequently in HNPCC than in non-HNPCC lesions (27, 28). These findings suggest that development of most HNPCC tumors involves genetic changes different from those occurring in the adenoma-carcinoma sequence. Concerning mismatch repair genes, microsatellite instability is characteristic of tumors in HNPCC and replication errors begin in an early stage of carcinogenesis in that disorder. Such instability also occurs in non-HNPCC cancers, but in later stages (28). Many studies, especially short-term ones (about 2–12
AJG – November 1998
RECTAL CANCER AFTER SULINDAC THERAPY
months), have indicated that sulindac exerts a regressive effect on FAP polyps (29 –37). However, less is known about the long term efficacy of such therapy. To date, several studies investigating the long term efficacy of the therapy have been published (30 –37). These studies indicate that polyp regression is observed especially during the first few months of treatment. However, the polyps tend to recur after the discontinuation of the drug or, in some studies, after prolonged sulindac administration (31–34, 36). To date, development of rectal cancer after sulindac therapy for FAP polyps has been reported in two cases (38, 39). The cancer described in this report was strikingly similar in several aspects to those two reported rectal cancer cases (Table 1). First, the shape of the three cancers was not polypoid; all formed broad-based masses. Second, all three cancers grew rather rapidly. The two previously reported cancers developed and grew within several months. Furthermore, these three cancers had invaded into venous and lymphatic vessels within a short period. Third, none of the three cancers contained any detectable adenomatous components, although the complete details of the previous cases were not reported. In the present case, the cancer was homogeneous, based on its morphology by hematoxylin and eosin staining and p53 and COX-2 immunostaining. It is difficult to assume that these cancers developed from adenomatous polyps. These cancers apparently developed de novo independently of the adenoma-carcinoma sequence, growing as flat cancers from their onset. The mechanism of the adenoma-inhibitory effect of sulindac is still unclear, but the main pharmacological effect of nonsteroidal antiinflammatory drugs (NSAIDs), including sulindac, is inhibition of cyclooxygenase (COX). Several studies have implied that COX-2 inhibition is important in NSAID-mediated antineoplastic effects (40 – 43), although some other studies have reported evidence that a COX-2independent mechanism also is at work in the NSAIDmediated antitumor effect (44 – 49). Therefore, tissue COX-2 expression was of great interest in the present case, in which both the initial adenomatous polyp and the rectal cancer immunostained for COX-2. The polyp might have been negative or minimally positive for COX-2 staining during sulindac treatment, but in that case the 15-day period after sulindac treatment may have permitted the adenomatous tissue to recover COX-2 expression. In the present study, sulindac therapy resulted in partial regression of an adenomatous polyp, but could not prevent cancer development. The COX-2 positive polyp responded to sulindac, supporting involvement of COX-2 inhibition in polyp regression. However, whether the rectal cancer could have been prevented if sulindac treatment had been continued for a prolonged period remains unknown. At present, the exact relationship between sulindac administration and the development of rectal cancer is not clear. Further investigation will be necessary concerning not only the genetic and epigenetic characteristics of flat tumors, but also the ability of NSAIDs to prevent such tumors.
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ACKNOWLEDGMENTS This paper was supported in part by a Grant-in-Aid for Exploratory Research from the Ministry of Education, Science, Sports, and Culture of Japan. Reprint requests and correspondence: Nobuyuki Matsuhashi, M.D., The Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
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