A pilot study on the endoscopic surveillance of colorectal dysplasia and cancer in long-standing ulcerative colitis

S. Khorrami Mashhadi, M. Trapero, J. P. Gisbert, E. Gómez Domínguez and J. Maté-Jiménez

Service of Digestive Diseases. Hospital Universitario de La Princesa. Madrid, Spain

 

ABSTRACT

Introduction: patients with ulcerative colitis (UC) have a greater risk of developing colorectal cancer (CRC) when compared to the general population. Epithelial dysplasia comes before this neoplasm, and thus endoscopic surveillance is recommended to these patients. This pilot study aims at establishing the incidence of dysplasia and CRC in patients with long-standing UC in our hospital.
Material and methods: this is a prospective observational study performed in patients with a definite diagnosis of UC for more than 8 years. These patients were encouraged to enroll in an endoscopic surveillance program for CRC. All patients underwent colonoscopy and multiple biopsies every 18 to 24 months in order to detect epithelial dysplasia.
Results: thirty-nine patients were included from January 1994 to December 2003. Half of them were males. Mean age was 52 ± 13 years. Mean duration of UC was 15 ± 8 years. Thirteen (35%) patients had left colitis, and 26 (65%) had pancolitis or extensive colitis. The presence of mild dysplasia was detected in four patients, on two occasions in one of them (13%; 95% CI: 6.1-33.5); the incidence of mild dysplasia was 1.3% patients per surveillance year. No severe dysplasia or CRCs were identified.
Conclusion: the incidence of dysplasia in our area is lower than expected, and does not support surveillance programs for these patients. However, no definite conclusions may be drawn from such a small number of patients.

Key words: Dysplasia. Ulcerative colitis. Colorectal carcinoma. Inflammatory bowel disease.

---

Khorrami Mashhadi S, Trapero M, Gisbert JP, Gómez Domínguez E, Maté-Jiménez J. A pilot study on the endoscopic surveillance of colorectal dysplasia and cancer in long-standing ulcerative colitis. Rev Esp Enferm Dig 2005; 97: 16-23.

---

Recibido: 25-03-04.
Aceptado: 18-05-04.

Correspondencia: José Maté Jiménez. Pº Alameda de Osuna, 159. 28042 Madrid. Telf.: 915 202 254 - Fax: 914 022 299. e-mail: jmatej@mixmail.com; mtraperomarugan@terra.es

 

INTRODUCTION

Patients with ulcerative colitis (UC) have a greater risk of developing colorectal cancer (CRC) when compared with the general population, particularly those who suffer from extensive or long-standing disease (1). In a recent meta-analysis, the overall incidence of CRC in UC was estimated as 3 per 1000 patients/year (2). In extensive colitis and pancolitis, the cummulative risk of this complication is 2-5% per year during the first 10 years of disease, 5-10% per year during the second decade, and 12-20% per year over the third decade (2-5). Left colitis entails a similar increased risk of CRC a decade later than more extensive disease (6,7). It is currently admitted that dysplasia is a disease stage that heralds CRC, and its presence in colic mucosal biopsies predicts a concurrent carcinoma or a high-risk situation, particularly in case of a high-grade dysplasia or a dysplasia-associated lesion or mass (DALM) (5,8). In order to reduce CRC-related mortality in these patients, regular colonoscopies with multiple biopsy samples are recommended to detect dysplasia (9-11). The incidence of post-colitis CRC and dysplasia is unknown in our setting, and thus the cost-effectiveness of this strategy remains unproven.

This work attempts to be a pilot study to approach actuality and to allow the planning of a prospective research to establish the incidence of dysplasia and CRC in patients with long-standing UC in Spain.

MATERIAL AND METHODS

This is a pilot, prospective, observational study performed in patients definitely diagnosed with long-standing UC who were encouraged to enroll in an endoscopic surveillance program for CRC.

Source and characteristics of patients

Patients included in the endoscopic surveillance program for post-colitis CRC came from a monographic inflammatory bowel disease clinic in our hospital, and provided their signed informed consent. Demographic data for patients are partially listed on table I. A total of 39 patients were consecutively included in the surveillance program from January 1994 to December 2003. The male:female ratio was 1, and mean age was 52 ± 13 years. Mean UC duration was 17.8 ± 8 years. Mean time within the program was 4.6 ± 5 years, and 2.5 ± 2 colonoscopies per patient were performed on average. Thirteen (35%) patients had left colitis, and 26 (65%) had pancolitis or extensive colitis.

Definitions

The diagnosis of UC was established based on suggestive endoscopic findings (erythematous, edematous, ulcerated mucosa with either spontaneous or contact-related vascular friability), consistent histological findings, and follow-up for more than 8 years.

The extension of UC was determined based on an endoscopic examination of the colon during a flare-up of disease.

1. Pancolitis: the lesion extends beyond the hepatic angle of the colon.

2. Extensive colitis: the lesion extends beyond the splenic angle of the colon but does not reach the hepatic flexure.

3. Left colitis: the lesion extends beyond the rectum without ever reaching the splenic flexure.

Long-standing UC: it was considered that of more than 8 years' standing for pancolitis and extensive colitis, and more than 10 years' standing for left colitis.

Dysplasia: this was defined as a neoplastic proliferation of epithelial cells at the colic mucosa during inflammatory remission and with no evidence of submucosal invasion. The diagnosis was confirmed by at least two staff pathologists.

Dysplasia grades: low-grade or mild dysplasia was defined as a dysplasia where most foci of neoplastic cells lay deep within glands, whereas high-grade or severe dysplasia was defined as a dysplasia sporting greater cell disruption.

Maintenance therapy using 5-ASA: patients on this medication were taking at least 1.2 g of 5-ASA indefinitely since diagnosis, with interruptions only during steroidal therapy periods.

Methods

All patients with a diagnosis of UC for more than 8 years and with an extension greater than 15 cm were encouraged to undergo surveillance regarding their involved colic mucosa. In order to rule out the presence of UC-associated colic dysplasia and/or colon carcinoma, patients who agreed to enroll in the study underwent colonoscopy during clinical remission periods and every 18-24 months, with multiple biopsy sampling. The total number of biopsies ranged between 25 and more than 30 for patients with extensive colitis or pancolitis, and from 10 to 15 for patients with left colitis. No samples from unaffected mucosal areas were collected. Samples were examined by two pathologists to establish the presence of dysplasia, grade of dysplasia, and presence of carcinoma. Figure 1 describes the management of patients according to endoscopic and histological findings. In the absence of dysplasia, patients underwent regular endoscopic surveillance with biopsy collection every 18-24 months. Should dysplasia be identified in a mucosal setting lacking endoscopic or histological evidence of inflammation, a new examination with biopsy sampling would be indicated following complete inflammatory remission. In the presence of mild dysplasia with no evidence of mucosal inflammation, a new endoscopy with biopsy sampling would be indicated after 3 months. For severe dysplasia without inflammation, a new exploration with biopsy collection would be indicated after 4 weeks. Finally, for severe dysplasia and no inflammation identified during two consecutive procedures, patients would be referred to a surgeon for prophylactic pancolectomy. The primary endpoint of the endoscopic surveillance program was dysplasia development. Other endpoints assessed included duration of disease, presence or absence of endoscopic activity when dysplasia was detected, and dysplasia regression following maintenance therapy with 5-ASA.

Statistical analysis

A descriptive statistical analysis was performed by estimating mean and standard deviation values for quantitative variables, and percentages and 95% confidence intervals (95% CIs) for qualitative variables. An SPSS 11.0 software pack was used.

RESULTS

The presence of mild dysplasia was identified in 4 patients, on two occasions separated by 5 years in one of them (13%; 95% CI: 6.1-33.5); the incidence of mild dysplasia was 1.3% patients per surveillance year. No severe dysplasias or CRCs were detected. Table I summarizes the characteristics of patients with and without mild dysplasia in colic mucosa biopsies. Of five mild dysplasias identified, four (80%) had developed on a mucosa with endoscopic evidence of acute inflammation despite the fact that patients lacked symptoms suggesting an acute flare-up. Table II shows the performance of a follow-up protocol for patients with long-standing UC. Table III shows the characteristics of the four patients in whom dysplastic lesions were seen. No significance levels are expressed since the small number of dysplasias encountered renders statistical results unreliable.

DISCUSSION

No carcinoma or high-grade dysplasia was detected in our patients. Of note, all mild dysplasias except one were seen on inflamed mucosa, despite the fact that patients had no symptoms suggesting acute disease, which raises suspicion that lesions were reactive to the inflammation. Similarly, all lesions regressed in one to three months after high-dose 5-ASA administration. No association or progression from mild dysplasia to high-grade dysplasia or carcinoma was seen. These results are in accordance with the clinical impression that UC-associated CRC is uncommon in our patients, and consequently deviate from cumulative experience by other teams (1-8).

The reason for these surprising results may be difficult to explain, and may involve a bias resulting from the small number of patients included in the program, further complicated by a short follow-up period. Similarly, other factors such as the high percentage of patients on 5-ASA, which seems to exert a protective effect against CRC development (9-17), or the varying incidence of CRC in our area's general population, which is less than half of that observed in other Western countries, may play a role (18).

While we have no better diagnostic method available for clinical practice, the incidence of dysplasia among patients with ulcerative colitis may likely not be representative of the incidence of UC-associated carcinoma. The true predictive value of mild dysplasia in CRC identification is still controversial. Its usefulness seemed scarce in early studies, as only 16-29% of patients progressed to more aggressive lesions (5,8,12). Unified histological criteria have improved this marker's specificity for the detection of malignant lesions. Connell et al. reported an increased predictive value, from 16% at baseline to 54%, upon reviewing 128 biopsies consistent with low-grade dysplasia (12). After 32 months of follow-up, on reassessing the biopsies from 18 patients with long-standing UC and mild dysplasia, Ullman et al. reported lesion progression in 50% of cases, with a cumulative incidence of 33% at 5 years for high-grade dysplasia or carcinoma (14). In a more recent paper, this same author reported that low-grade dysplasia progressed in 30% of patients, with a progression rate of 53% at 5 years (19). In contrast, another paper identified mild dysplasia progression in only 10% of patients on reviewing biopsies from a cohort including 128 patients undergoing surveillance for 10 years (20).

Interobserver and intraobserver variability is high in the histological diagnosis of mild dysplasia, with only 50-60% of agreement between every two expert pathologists (21,22). Added to the inability to obtain biopsies from the whole colon, this would raise the number of false positive results and -what is more- false negative results. We believe that the number of biopsies collected and the extent of colon examined in our surveillance program suffice. Since dysplasia is a patchy lesion (20), the American Gastroenterological Association (AGA), American Society of Gastrointestinal Endoscopy (ASGE), and British Society of Gastroenterology (12,23) recommend that the colon be fully explored regardless of disease extension, and that 2-4 biopsy samples every 10 cm be collected. This translates in greater costs and greater patient discomfort. In addition, a great majority of tumors and premalignant lesions are found in the furthermost reaches of the colon, and up to 25% of post-colitis carcinomas are not associated with dysplasia (19,24-27). Hence, such recommendations were categorized as "grade C", that is, as having only moderate evidence supporting their efficacy, with benefits closely matching adverse effects, which advises against their widesprad application (28).

In view of all previous information, and given ours was a small pilot study, our results should be considered an approach to actuality. In order to establish the cost-benefit ratio of a screening program for post-colitis carcinoma, further extensive, prospective, and multicenter studies are called for to determine the true incidence of CRC in long-standing UC in our setting.

ACKNOWLEDGEMENT

Supported in part by a grant from the Instituto de Salud Carlos III (C03/02).

REFERENCES

1. Langholz E, Munkholm P, Davidsen M, Binder V. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 1992; 103: 1444-51.        [ Links ]

2. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001; 48: 526-35.        [ Links ]

3. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990; 323: 1228-33.        [ Links ]

4. Gyde SN, Prior P, Allan RN, Stevens A, Jewell DP, Truelove SC, et al. Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres. Gut 1988; 29: 206-17.        [ Links ]

5. Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990; 31: 800-6.        [ Links ]

6. Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994; 107: 934-44.        [ Links ]

7. Lindberg B, Persson B, Veress B, Ingelman-Sundberg H, Granqvist S. Twenty years' colonoscopic surveillance of patients with ulcerative colitis. Detection of dysplastic and malignant transformation. Scand J Gastroenterol 1996; 31: 1195-204.        [ Links ]

8. Ullman TA, Loftus EV Jr., Kakar S, Burgart LJ, Sandborn WJ, Tremaine WJ. The fate of low grade dysplasia in ulcerative colitis. Am J Gastroenterol 2002; 97: 922-7.        [ Links ]

9. Levin B. Risk of cancer in ulcerative colitis. Gastrointest Endosc 1999; 49: S60-2.        [ Links ]

10. Nugent FW, Haggitt RC, Gilpin PA. Cancer surveillance in ulcerative colitis. Gastroenterology 1991; 100: 1241-8.        [ Links ]

11. Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994; 343: 71-4.        [ Links ]

12. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 1997; 92: 204-11.        [ Links ]

13. Eaden JA, Mayberry JF. Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease. Gut 2002; 51 (Supl. 5): V10-2.        [ Links ]

14. Provenzale D, Onken J. Surveillance issues in inflammatory bowel disease: ulcerative colitis. J Clin Gastroenterol 2001; 32: 99-105.        [ Links ]

15. Pinczowski D, Ekbom A, Baron J, Yuen J, Adami HO. Risk factors for colorectal cancer in patients with ulcerative colitis: a case-control study. Gastroenterology 1994; 107: 117-20.        [ Links ]

16. Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000; 14: 145-53.        [ Links ]

17. Ryan BM, Russel MG, Langholz E, Stockbrugger RW. Aminosalicylates and colorectal cancer in IBD: a not-so bitter pill to swallow. Am J Gastroenterol 2003; 98: 1682-7.        [ Links ]

18. Registro de Cáncer de Navarra. Sección de enfermedades no transmisibles y estadísticas vitales. Incidence and mortality of cancer in Navarra, 1993-1997. Tendencies in the last 25 years. An Sist Sanit Navar 2001; 24: 339-62.        [ Links ]

19. Ullman TA, Croog V, Harpaz N, Sachar DB, Itzkowitz S. Progresion of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003; 125: 1311-9.        [ Links ]

20. Rubin CE, Haggitt RC, Burmer GC, Brentnall TA, Stevens AC, Levine DS, et al. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 1992; 103: 1611-20.        [ Links ]

21. Eaden J, Abrams K, McKay H, Denley H, Mayberry J. Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis. J Pathol 2001; 194: 152-7.        [ Links ]

22. Lim CH, Dixon MF, Vail A, Forman D, Lynch DA, Axon AT. Ten year follow up of ulcerative colitis patients with and without low grade dysplasia. Gut 2003; 52: 1127.        [ Links ]

23. The role of colonoscopy in the management of patients with inflammatory bowel disease. Gastrointest Endosc 1998; 48: 689-90.        [ Links ]

24. Prior P, Gyde SN, Macartney JC, Thompson H, Waterhouse JA, Allan RN. Cancer morbidity in ulcerative colitis. Gut 1982; 23: 490-7.        [ Links ]

25. Slater G, Greenstein AJ, Gelernt I, Kreel I, Bauer J, Aufses AH Jr. Distribution of colorectal cancer in patients with and without ulcerative colitis. Am J Surg 1985; 149: 780-802.        [ Links ]

26. Choi PM. Predominance of rectosigmoid neoplasia in ulcerative colitis and its implication on cancer surveillance. Gastroenterology 1993; 104: 666-7.        [ Links ]

27. Connell WR, Talbot IC, Harpaz N, Britto N, Wilkinson KH, Kamm MA, et al. Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis. Gut 1994; 35: 1419-23.        [ Links ]

28. Harris R, Helfand M, Woolf S, Lohr K, Mulrow C, Teutsch S, et al. for the Methods Work Group, Third U.S. Preventive Services Task Force. Current methods of the U.S. Preventive Services Task Force: a review of the process. Am J Prev Med 2001; 20: 21-35.        [ Links ]