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Background Benign anal lesions are often considered to cause a predisposition to anal cancer. To reexamine this association, we linked national data on hospital discharge and cancer in Denmark.
Methods After making certain exclusions, we used the Danish Central Hospital Discharge Register to identify 68,549 patients hospitalized with benign anal lesions between 1977 and 1989. Through computerized linkage to the Danish Cancer Registry, all incident cases of epidermoid anal cancer and colorectal cancer among these patients were identified. Follow-up for the occurrence of cancer started the month after the date of the first hospital discharge and continued until the patient died (10.6 percent of the sample), emigrated (0.7 percent), or was lost to follow-up (0.04 percent) or until December 31, 1989 (88.6 percent), whichever came first.
Results The median follow-up period was 6.2 years. There were 23 epidermoid anal cancers and 416 colorectal cancers. The overall relative risk of anal cancer (observed vs. expected cases) was 4.4 (95 percent confidence interval, 2.8 to 6.6). The relative risk was 12.0 (95 percent confidence interval, 5.2 to 23.6) within the first year after hospitalization for benign lesions, 4.6 (95 percent confidence interval, 2.3 to 8.3) from one to four years after hospitalization, and 1.8 (95 percent confidence interval, 0.5 to 4.7) five or more years after hospitalization. The risk of colorectal cancer was significantly increased only during the first year after hospitalization (relative risk, 2.6; 95 percent confidence interval, 2.1 to 3.1).
Conclusions There is a strong temporal association between the diagnosis of benign anal lesions and the diagnosis of anal cancer. Although we could not exclude the possibility of a moderate increase in the long-term risk of anal cancer, our data do not support the view that benign anal lesions cause anal cancer.
To reexamine the association between benign anal lesions and the risk of anal cancer, we linked national data on hospital discharge and cancer in Denmark. Since it has been reported that benign anal lesions may precede or coincide with the development of colorectal cancers,10,11 we also investigated the association with these cancers.
Methods
The Danish Central Hospital Discharge Register contains information on nearly all hospital admissions in Denmark since 197712. We included in our study four cohorts of patients with benign anal lesions who were listed in the register during the period from 1977 to 1989: patients who received a diagnosis of a fissure or underwent excision of a fissure, those who received a diagnosis of a fistula (whether transsphincteric or extrasphincteric) or underwent excision of a fistula, those with perianal or perirectal abscesses, and those who underwent surgery or sclerotherapy for hemorrhoids. Patients were followed from the date of their first hospital discharge. A history of hospital discharges during the period from 1977 to 1989 was obtained for each patient. Thus, anal lesions preceding the diagnosis of anal cancer could be evaluated for a possible relation to Crohn's disease or ulcerative colitis.
Each citizen in Denmark is assigned a unique 10-digit identification number, which permits accurate linkage of information from different registers. Permission was obtained in advance from the National Scientific Ethics Committee and the Data Protection Board to identify the patient cohorts in the Danish Central Hospital Discharge Register and to link this information to data from the Central Person Register and the Danish Cancer Registry, which was started in 1943. The Central Person Register keeps updated files on all residents of Denmark and documents such demographic variables as death and migration. Strict patient confidentiality was maintained as prescribed for the Danish Cancer Registry13.
Of the 69,739 people in the Danish Central Hospital Discharge Register who had benign anal lesions, 406 (0.6 percent) were excluded from the study because of incorrect personal identification numbers or because they were not Danish residents; another 784 (1.1 percent) were excluded because they had been followed for less than one month after discharge from the hospital. This left 68,549 patients for the study of subsequent anal and colorectal cancers. Through computerized linkage to the files of the Danish Cancer Registry,13 all incident cases of anal and colorectal cancer among patients with benign anal lesions were identified. In classifying cancers, we made a special effort to distinguish between epidermoid anal carcinoma and rectal adenocarcinoma. Only nonadenocarcinomas and nonmelanomas were included in the observed and expected numbers of anal cancers14.
Using information from the Central Person Register, we followed patients for the occurrence of cancer, starting the month after the date of the first hospital discharge. Thus, patients with simultaneous diagnoses of benign and cancerous anal lesions were excluded. Follow-up continued until death (accounting for 10.6 percent of the sample), emigration (0.7 percent), the last date at which a person lost to follow-up was known to be alive and residing in Denmark (0.04 percent), or December 31, 1989 (88.6 percent), whichever came first15. We calculated the expected numbers of cancers by multiplying age-, sex-, and period-specific national incidence rates by the person-years for each of the four cohorts. Ratios of observed to expected cases of cancer (i.e., standardized incidence ratios) served as measures of the relative risk. Assuming a Poisson distribution of the observed cancers, we calculated 95 percent confidence intervals for the estimates of relative risk, using Byar's limits16.
Results
For the 68,549 patients included in the study, there was a total of 427,922 person-years of follow-up. The median follow-up period was 6.2 years. Twenty-three patients (0.03 percent) had an epidermoid anal cancer within 13 years after hospitalization for a benign anal lesion (Table 1). The cancer was located at the anal margin in 6 of the patients and in the anal canal in 17. One of the patients with anal cancer had received a diagnosis of cystadenocarcinoma of the ovary 28 years before hospitalization for hemorrhoids, and another patient had received a diagnosis of cervical cancer 35 years before treatment for hemorrhoids, with basal-cell carcinoma of the skin diagnosed shortly before treatment. We considered all 23 cancers as primary anal cancers and concluded that none of the benign anal lesions in these people were the consequence of other cancers.
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A total of 651 patients (0.9 percent) had Crohn's disease, and 509 (0.7 percent) had ulcerative colitis. However, none of the 23 cohort members with anal cancer had either inflammatory bowel disease.
Discussion
Although our findings confirm previous observations of a close association between benign anal conditions and anal cancer, they do not support a causative role for any of the four types of benign anal lesions that we studied. A high relative risk of anal cancer during the first year after hospitalization for benign lesions, with a rapid waning in the relative risk in subsequent years, is not compatible with the concept of causality17,18. In many of the patients given a diagnosis of anal cancer soon after hospitalization for benign anal lesions, the cancer was probably already present at the time of hospitalization. Some of the people we studied had had rectal symptoms for several years before hospitalization. Thus, a benign lesion could reasonably be considered a complication of an early cancer rather than its cause or, in the case of hemorrhoids, a misdiagnosed clinical presentation of an underlying cancer. Alternatively, in some patients with hemorrhoids, an unrelated and simultaneous anal cancer may have been detected as a result of diagnostic efforts to locate the source of rectal bleeding. If such an underlying or simultaneous anal cancer is not recognized when a benign anal lesion is diagnosed, it is likely to come to clinical attention shortly thereafter.
Benign anal lesions are common in patients with inflammatory bowel disease -- notably, Crohn's disease19. It has been hypothesized that anal lesions related to Crohn's disease increase the risk of anal cancer20,21. We did not find an excess risk of anal cancer among the patients with Crohn's disease or ulcerative colitis; none of the patients with anal cancer had inflammatory bowel disease. Additional large-scale follow-up studies of patients with inflammatory bowel disease are needed to evaluate this potential association in more detail.
We studied only people who were hospitalized. Many people with benign anal lesions, particularly hemorrhoids, are treated in outpatient settings. If hemorrhoids caused a predisposition to anal cancer, we would expect that patients with hemorrhoids severe enough to require hospitalization might be at particular risk. Yet we found no increase in the long-term risk of anal cancer among such patients (relative risk 5 to 13 years after hemorrhoidectomy, 1.4; 95 percent confidence interval, 0.2 to 5.0).
We did not study the role of other suggested risk factors for anal cancer, including sexual behavior, cigarette smoking, and immunodeficiency8,22,23. We doubt that the lack of adjustment for these potential risk factors for anal cancer, which differ from those for colorectal cancers, would explain the temporal association between benign anal lesions and both anal and colorectal cancers.
Rectal bleeding can be a symptom of both colorectal cancers and benign anal lesions. The significantly increased risk of colorectal cancer, like that of anal cancer, soon after the diagnosis of a benign anal lesion may result from misdiagnosis and, to some extent, increased surveillance. Patients with rectal bleeding should undergo early and comprehensive diagnostic studies of the large intestine10,11. Such an investigation will identify any underlying colorectal cancers, as well as proximal colon cancers that may be unassociated with the rectal bleeding. This combined selection and surveillance bias probably explains the significant excess of colorectal cancers diagnosed during the first year after hospitalization for a benign anal condition.
Since anal cancer is rare, a large-scale study linking data from different registers allows information to be obtained that would not be feasible to gather in a prospective cohort study. Although our study cannot exclude a moderate increase in the long-term risk of anal cancer after identification of a benign anal lesion, the theory that anal inflammation causes a predisposition to epidermoid anal cancer should be viewed with skepticism. In most cases in which presumably benign lesions (hemorrhoids, fistulas, fissures, or abscesses) precede anal cancer, the lesions probably represent the initial symptoms of an undetected anal cancer.
Supported by a grant (90-7620) from the Danish Cancer Society and a contract (85639-04) from the National Cancer Institute.
Source Information
From the Epidemiology Research Unit, Danish Epidemiology Science Center, Statens Seruminstitut (M.F., M.M.), and the Danish Cancer Society, Research Center, Division for Cancer Epidemiology (M.F., J.H.O., A.B.) -- both in Copenhagen.
Address reprint requests to Dr. Frisch at the Epidemiology Research Unit, Danish Epidemiology Science Center, Statens Seruminstitut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark.
References
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Related Letters:
Benign Anal Lesions and Anal Cancer
Lin A. Y., Gridley G., Tucker M.
Extract |
Full Text
N Engl J Med 1995;
332:190-191, Jan 19, 1995.
Correspondence
This article has been cited by other articles:
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