Gut Online First, published on November 18, 2005 as 10.1136/gut.2005.070201 Elevated anal squamous-cell carcinoma risk associated with G u benign inflammatory anal lesions t: firs t p Caroline Nordenvall,1 Olof Nyrén, M.D., Ph.D.,1 Weimin Ye, M.D., Ph.D.1 ub lis h e 1. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE 171 d a 77, Stockholm, Sweden s 1 0 .1 1 3 6 /g u t.2 0 Correspondence to: 0 5 Weimin Ye .0 7 0 Department of Medical Epidemiology and Biostatistics 2 0 Karolinska Institutet 1 o Box 281 n 1 SE 171 77, Stockholm 8 N Sweden o v e Email: [email protected] m b e Key words: benign anal lesions; anal cancer; cohort; risk r 20 0 5 . D Supported in part by KI fonder grant (to WY). o w n lo The Corresponding Author has the right to grant on behalf of all authors and does a d grant on behalf of all authors, an exclusive licence (or non exclusive for government ed employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this fro m article (if accepted) to be published in GUT and any other BMJPGL products and h sublicences such use and exploit all subsidiary rights, as set out in our licence ttp (http://gut.bmjjournals.com/misc/ifora/licenceform.shtml). ://g u t.b m Competing Interest: None declared. j.c o m o/ n J a n u a ry 1 6 , 2 0 2 3 b y g u e s t. P ro te c te d b y c o p y rig h t. 1 Copyright Article author (or their employer) 2005. Produced by BMJ Publishing Group Ltd (& BSG) under licence. ABSTRACT G u Bdaatcak fgrormou lnadrg: eT choeh aosrsto sctiuadtiieosn abreet waveaeinla bbelen.i gn anal lesions and anal cancer is still unclear. Few t: firs Methods: We conducted a register-based retrospective cohort study including 45,186 patients t p u b hospitalised for inflammatory anal lesions (anal fissures, fistulas, and perianal abscesses), as well as lis h 79,808 hemorrhoid patients from 1965 through 2002. Multiple record linkages identified all e d incident anal (squamous-cell carcinoma only) and colorectal cancers through 2002. Relative risk a s was estimated by standardised incidence ratio (SIR), the ratio of observed number of cases divided 1 0 by that expected in the age-, sex- and calendar-year-matched general Swedish population. .1 1 Results: There was a distinct incidence peak in the first 3 years of follow-up among patients with 36 /g inflammatory lesions. SIR then leveled off at around 3 and remained on this level throughout u follow-up (SIR during year 3-37 of follow-up was 3.3; 95% confidence interval, 1.8 to 5.7). A t.2 0 0 similar initial incidence peak was observed among hemorrhoid patients, but it was confined to the 5 .0 first year. SIR was 2.8 in the second year, and then it further dropped and was close to unity in the 7 0 following years (SIR during year 3-37 was 1.3; 95% confidence interval, 0.7 to 2.1). Among either 20 1 inflammatory lesion or hemorrhoid patients, significantly increased risk for colorectal cancer was o n observed only in the first year after hospitalization. 1 8 Conclusions: Inflammatory benign anal lesions are associated with a significantly increased long- N o term risk for anal cancer. By contrast, hemorrhoids appear not to be a risk factor for this v e m malignancy. b e r 2 0 0 5 . D o w n lo a d e d fro m h ttp ://g u t.b m j.c o m o/ n J a n u a ry 1 6 , 2 0 2 3 b y g u e s t. P ro te c te d b y c o p y rig h t. 2 BACKGROUND G u AHonwale cvaenrc, ethr eis i nacni duennccoem ims monu dchis ehaigseh eirn itnh em heent ewrohsoe xreugaul lpaorlpyu plaraticotnic we iatnha al-nr einccepidtievnec ein otef r1c opuerrs 1e,0 a0b,0o0u0t . t: firs 35 per 100,000.1 Besides a strong link to sexual promiscuity and human papillomavirus (HPV) t pu b infection, suspected risk factors include genital warts, herpes simplex virus type 2, and smoking.2-6 lis h e d In 1863 the first connection between inflammation and cancer was made by Rudolf Virchow.7 Since as 1 then several types of cancer have been associated with infection and inflammation,7 and different 0 .1 mechanisms have been hypothesized. Local inflammation may contribute to ovarian cancer;8 ulcerative 13 6 colitis increases the risk of colorectal cancer;9, 10 infection of Helicobacter pylori increases the risk of /g u distal stomach cancer;11 HBV and HCV infection is a well-recognized risk factor for hepatocellular t.2 0 carcinoma;12 and tumor necrosis factor (TNF), a protein mediating inflammation, has been suggested to 0 5 be involved in the progression and spread of cancer.13 .07 0 20 1 The possible association of benign anal lesions, including fissures, fistulas, perianal abscesses, and o n hemorrhoids with anal cancer has long been under debate.2, 3, 14, 15 In a case-control study, a 1 8 significantly increased risk of anal cancer was found in patients treated for anal fissures, fistulas, or N o with more than 12 episodes of hemorrhoids.2 Constant irritation, chronic inflammatory changes, and ve m repeated epithelial regeneration was hypothesized to be the explanation of the association.2 This finding b e was supported by another case-control study, in which a significantly increased risk of anal cancer was r 2 0 reported in patients with severe hemorrhoids, and a weak association was also observed between anal 05 cancer and other infections and inflammations in the anogenital area.15 A third case-control study found . D o an association with hemorrhoids and nonspecific anal irritation among men but not among women.16 w n lo Case-control studies may be subject to recall bias, thus a cohort study design is favorable, although few a d cohort studies are available due to the rarity of anal cancer. In the only two cohort studies, a null ed association was reported.14, 17 fro m h Given contradictory results from case-control studies and rarity of cohort studies, we therefore aimed to ttp investigate the association between benign anal lesions and anal cancer using a large cohort with a long ://g u follow-up. t.b m j.c o m o/ METHODS n J Identification of the Cohort a n u The Swedish National Board of Health and Welfare established the Inpatient Register in 1964 to a ry document individual hospital discharges. Each Inpatient Register record corresponds to one in-hospital 1 6 episode, and contains (a) the patient’s national registration number – a unique identifier assigned to all , 2 0 Swedish residents, (b) the date for hospital admission and discharge, and (c) up to eight discharge 2 3 diagnoses coded according to the 7th version of International Classification of Diseases (ICD-7) until b y 1968, the 8th version (ICD-8) from 1969 through1986, the 9th version (ICD-9) from 1987 to 1996, and gu e the 10th version (ICD-10) thereafter. The national registration number permits unambiguous linkage st. P across all national registers in Sweden. ro te c All records in the Inpatient Register with a diagnosis of benign anal lesion, including fissure (ICD7: ted b 574.00, ICD8: 565.00, ICD9:565.A, ICD10:K60.1, K60.2, K60.3), fistula (ICD7: 574.10, ICD8: y c 565.10, ICD9:565.B, ICD10:K60.3, K60.4, K60.5), perianal abscess (ICD7: 575.00, ICD8:566.00, o p y ICD9:566, ICD10:K61.0), and hemorrhoid (ICD7: 461.99, ICD8: 455.99, ICD9: 455, ICD10:I84) from rig h t. 3 January 1965 to December 2002 were initially selected. We identified 135,276 unique national G u r egistration numbers with hospital admissions for benign anal lesions during the period studied. t: firs Follow-up/Record linkage t pu b In order to obtain correct dates for censoring, our dataset was first linked to the nationwide registers of lis h Total Population, Migration, and Causes of Death. National registration numbers which could not be e d found in any of these registers (N=316, 0.23% of the identified records) were deemed to be erroneous as 1 and the corresponding records were removed, since a correct national registration number is a 0 .1 prerequisite for record linkage and thus for follow-up. The National Cancer Register, founded in 1958 1 3 and estimated to be 98% complete,18 was used to ascertain all incident cancers diagnosed in the cohort 6/g u before and from the start of follow-up, until December 31, 2002. The Cancer Register has coded t.2 0 malignant neoplasm according to the ICD-7 classification scheme during the entire period of the study, 0 5 and used a pathology code to identify histological type. To restrict our outcome to first primary tumors, .0 7 0 we further excluded all persons with a cancer diagnosis preceding index hospitalization (N=7090). We 2 0 1 excluded additional 2876 subjects because of observed inconsistencies among data from the registers. o n Hence, the final cohort consisted of 124,994 patients. Since we hypothesized that inflammatory lesions 1 8 (fissures, fistulas, and perianal abscesses) and hemorrhoids may be differentially associated with anal N o cancer risk, the total cohort was broken down into two sub-cohorts. Patients who had been hospitalised v e m for both were allocated to the inflammatory lesion sub-cohort. The hemorrhoid and inflammatory b e lesion sub-cohorts consisted of 79,808 and 45,186 patients, respectively. The latter was further divided r 2 0 into three non-overlapping sub-cohorts, i.e., anal fissure (N=11,696), fistula (N=13,847), and perianal 0 5 abscess (N=19,643), according to the diagnosis of their first hospitalization (index hospitalization). . D o w n Statistical analysis lo a d Individual person-time was calculated from the day of the index hospitalization until first cancer e d diagnosis, death, emigration, or December 31, 2002, whichever came first. In order to avoid possible fro m ascertainment bias due to differential autopsy rates in the study cohort and in the general population, h we did not count anal cancers found incidentally at autopsy. To minimize the possibility of ttp misclassification, we limited our analyses to only anal squamous-cell carcinomas. The standardised ://g u incidence ratio (SIR) – the observed number of anal cancer occurrences divided by the expected – t.b m expressed relative risk among the cohort members. The expected number of anal cancers was j.c o calculated by multiplying age-, sex-, and calendar year-specific incidence rates in the general m population by the corresponding stratum-specific person-time accrued in the cohort. In the calculation o/ n of expected rates, we counted only first primary cancer and excluded individuals in the general Ja n population with prevalent cancer in the calculation of person-time. We calculated 95% confidence u a intervals (CIs) for SIR under the assumption that the observed events follow a Poisson probability ry 1 distribution.19 Stratified analyses were performed by follow-up duration, sex, age at index 6, 2 hospitalization, or calendar periods of index hospitalization. To assess the effect of treatment, we also 02 3 performed stratified analyses by number of hospitalization for inflammatory benign anal lesions or b y hemorrhoids. Person-years accrued before second hospitalization was attributed to the only-one- g u e hospitalization stratum. All P values presented in this report are two-sided and the results were s considered to be statistically significant at P less than 0.05. t. P ro te c te d RESULTS b y c The cohort members were followed for a mean of 12.5 years, with more than 1.5 million person-years o p accumulated. The mean age at entry (the first – index – hospitalization for a benign anal lesion) was yrig h t. 4 close to 49 years (Table 1). The mean follow-up duration was similar in the inflammatory lesion and G u htheem loatrtrehro. iTdh seurbe- wcoehroe rntso, sbiugtn mifiecmanbte grse nind ethr ed ilfafteterer nwceerse w, oitnh arveegraargde t,o h mosepainta floislelodw a-tu apn douldraetri oang eo rth mane an t: firs age at entry. Patients with inflammatory anal lesions were more likely to be hospitalised more than t pu b once than those with hemorrhoids (22.2 vs 9.7%). Crohn’s disease was more common in patients with lis h inflammatory benign anal lesions (3.5%) than in patients with hemorrhoids (0.1%). In total, 53 e d incident anal cancer cases (squamous-cell carcinoma) were observed during follow-up (26 and 27 in as 1 the inflammatory lesion and hemorrhoid sub-cohorts, respectively). Mean age at anal cancer diagnosis 0 .1 was 62 years (Table 1). 1 3 6 /g u Table 1. Characteristics of the 124,994 patients hospitalised for benign anal lesions and t.2 0 their follow-up 0 5 Benign anal lesions .0 7 0 Inflammatory Hemorrhoids Total 2 0 1 lesions* o n Number of subjects 45,186 79,808 124,994 1 8 Men 29,057 42,168 71,225 N o Women 16,129 37,640 53,769 ve m Total number of person-years 555,646 1,022,543 1,578,189 b e Men 350,194 537,228 887,422 r 2 0 Women 205,452 485,314 690,766 0 5 Mean follow-up duration 12.3 12.8 12.6 . D o (years) w n Men 12.0 12.7 12.5 loa d Women 12.7 12.9 12.8 e d Mean age at entry (years) 42.2 52.6 48.8 fro m Men 41.9 52.2 48.0 h Women 42.7 53.1 49.9 ttp No. of hospitalizations (%) ://g u 1 77.7 90.3 t.b m 2+ 22.2 9.7 j.c o Presence of Crohn’s disease (%) 3.5 0.1 1.3 m No. of anal cancer 26 27 53 on/ J Mean age at diagnosis of anal 59.5 ± 15.0 65.0 ± 14.6 62.3 ± 14.9 a n u cancer ± SD a ry * Including fissure, fistula, and perianal abscess 1 6 , 2 0 2 3 Table 2 shows SIRs by follow-up duration. Among patients with inflammatory lesions, we observed 6 b y g anal cancer cases, as compared with 0.25 expected, entailing a SIR of 24.0 (95% CI 8.8-52.3) in the first u e year of follow-up. Over 8-fold excess risk was still noted 1 to 4 years after hospitalization, which was st. P mainly attributed by highly significant excess risks in the second and third year of follow-up. The excess ro risks dropped somewhat, but still significant, in the following years (SIR=5.3, 95% CI 2.0-11.7 for 5 to 9 te c years after hospitalization; SIR=2.6, 95% CI 1.0-5.7 for 10 or more years after hospitalization, ted b respectively). The observed 6 cases of anal cancer after 10 years of follow-up were evenly distributed y c throughout the observation period (SIR=2.2, 2.9 and 2.8 for 10 to14, 15 to19 and 20 or more years after o p y hospitalization, respectively). After excluding the first 3 years of observation, SIR during year 3-37 was rig h t. 5 3.3 (95% CI 1.8-5.7), based on 13 observed anal cancer cases. We observed a similarly significant excess G u rdirsokp fpoerd a tnoa al pcpanrocxeirm ina ttehley f3ir isnt ytheea rs eocf ofnodll oywea-ru po fa fmololnowg -huepm, oarnrdh oiti dw paast icelnostse. tHo ouwneitvye trh, erreelaatfitveer (rSisIkR t: firs during year 3-37 was 1.3; 95%CI, 0.7-2.1). Significant excess risks for colorectal cancers (excluding anal t pu b cancer) were noted only in the first year of follow-up in both inflammatory lesion and hemorrhoid cohort. lis h During year 3-37 there was an around 30% excess risk for lung cancer among patients with inflammatory e d lesions (SIR=1.3, 95%CI 1.1-1.4). as 1 0 .1 Table 2. Standardised incidence ratios (SIRs) and their 95% confidence intervals (CIs) for anal and colorectal cancer 1 3 6 among patients with benign inflammatory anal lesions and hemorrhoids, by duration of follow-up /g Inflammatory lesions* Hemorrhoids ut.2 0 0 5 Anal cancer Colorectal cancer† Anal cancer Colorectal cancer† .0 7 0 2 0 1 Obs SIR (95%CI) Obs SIR (95%CI) Obs SIR (95%CI) Obs SIR (95%CI) o n <1 year 6 24.0 (8.8-52.3) 71 3.9 (3.0-4.9) 11 14.9 (7.5-26.7) 200 3.6 (3.1-4.1) 1 8 1-4 year 8 8.3 (3.6-16.3) 88 1.3 (1.0-1.6) 2 0.7 (0.1-2.5) 228 1.1 (0.9-1.2) N 1 year 4 16.3 (4.4-41.7) 21 1.2 (0.7-1.8) 2 2.8 (0.3-9.9) 68 1.3 (1.0-1.6) ov e 2 year 3 12.3 (2.6-36.1) 22 1.3 (0.8-1.9) 0 -- 55 1.0 (0.8-1.3) m b 3-4 year 1 2.1 (0.05-11.7) 45 1.4 (1.0-1.8) 0 -- 105 1.0 (0.8-1.2) e 5-9 year 6 5.4 (2.0-11.7) 97 1.3 (1.0-1.5) 6 1.8 (0.7-3.9) 243 1.0 (0.9-1.1) r 20 0 10+ year 6 2.6 (1.0-5.7) 180 1.1 (0.9-1.3) 8 1.3 (0.6-2.5) 509 1.1 (1.0-1.1) 5 . D 10-14 year 2 2.2 (0.3-7.9) 75 1.2 (0.9-1.5) 3 1.1 (0.2-3.3) 189 1.0 (0.8-1.1) o w 15-19 year 2 2.9 (0.4-10.6) 56 1.2 (0.9-1.5) 4 2.2 (0.6-5.6) 145 1.0 (0.9-1.2) n lo 20+ year 2 2.8 (0.3-10.2) 49 0.9 (0.7-1.2) 1 0.6 (0.01-3.0) 175 1.2 (1.0-1.4) a d 3-37 year 13 3.3 (1.8-5.7) 322 1.2 (1.1-1.3) 14 1.3 (0.7-2.1) 857 1.0 (1.0-1.1) e d * Benign inflammatory anal lesions included anal fissure, fistula and perianal abscess. fro † Excluding anal cancer. m h ttp ://g u Among patients with inflammatory lesions, stratified analyses (first 3 years excluded) showed no t.b m conspicuous variation in relative risks for anal or colorectal cancer by sex, age at index hospitalization, j.c calendar period of index hospitalization, or number of hospitalization for inflammatory anal lesions om (Table 3). The absence of any strong association with anal or colorectal cancer was evident across o/ n different strata in patients with hemorrhoids (Table 3). J a n u a Table 4 lists results for the 3 subtypes of inflammatory lesions. After the first 3 years of follow-up, we ry 1 observed 5 cases of anal cancer among fissure patients, corresponding to a close to 4-fold excess risk 6, 2 (95% CI 1.3-9.2). Excess risk was also noted for patients with perianal abscesses (number of cases, 6; 0 2 3 SIR=5.3), but less obvious for patients with anal fistulas (number of cases, 2; SIR=1.3). Stratified b y analyses by sex and follow-up duration showed similar results in most strata, except that for perianal g u abscess patients, excess risk was noted only among women (SIR=9.7 for women vs. 1.6 for men). es t. P ro For sensitivity analysis, after excluding patients with a history of Crohn’s disease, human te c immunodeficiency virus disease, condylomata acuminata, cervix cancer in situ, or organ te d transplantation, 42,857 inflammatory anal lesion patients remained. Overall SIR during year 3-37 was b y somewhat attenuated, but still statistically significant (number of cases, 10; SIR=2.7, 95% CI 1.3-5.0), co p and the excess risk persisted after 10 years of follow-up (number of cases, 5; SIR=2.3, 95% CI 0.7-5.3). y rig h t. 6 Table 3. Standardised incidence ratios (SIRs) and their 95% confidence intervals (CIs) for anal and colorectal G cenantrcye,r o arm nounmgb pear toiefn htos swpiitthal ibzeantiiognns i*n flammatory anal lesions and hemorrhoids, by sex, age at entry, periods at ut: firs Inflammatory lesions† Hemorrhoids t p u b lis Anal cancer Colorectal cancer‡ Anal cancer Colorectal cancer‡ he d a s Obs SIR (95%CI) Obs SIR (95%CI) Obs SIR (95%CI) Obs SIR (95%CI) 10 .1 Sex 1 3 Men 4 2.2 (0.6-5.7) 223 1.2 (1.0-1.4) 6 1.5 (0.5-3.2) 489 1.0 (0.9-1.1) 6 /g Women 9 4.3 (2.0-8.2) 99 1.1 (0.9-1.4) 8 1.1 (0.5-2.3) 368 1.1 (1.0-1.2) u Age at entry (years) t.20 0 <50 6 2.9 (1.1-6.3) 101 1.1 (0.9-1.3) 3 0.7 (0.2-2.1) 218 1.1 (0.9-1.2) 5 .0 50+ 7 3.8 (1.5-7.9) 221 1.2 (1.1-1.4) 11 1.6 (0.8-2.9) 639 1.0 (0.9-1.1) 7 0 Period at entry (year) 20 1 1965-1986 9 3.2 (1.5-6.1) 244 1.2 (1.0-1.3) 9 1.1 (0.5-2.1) 671 1.1 (1.0-1.2) o n 1987-2002 4 3.7 (1.0-9.4) 78 1.2 (0.9-1.4) 5 1.6 (0.5-3.8) 186 0.9 (0.8-1.1) 1 8 Number of hospitalizations N o 1 10 3.3 (1.6-6.1) 241 1.1 (1.0-1.3) 14 1.4 (0.8-2.4) 774 1.0 (1.0-1.1) v e m 2 or more 3 3.4 (0.7-9.9) 81 1.3 (1.1-1.6) 0 -- 83 1.0 (0.8-1.2) b * Person-years and anal cancer cases accrued during the first 3 years of follow-up were excluded. er 2 † Benign inflammatory anal lesions included anal fissure, fistula and perianal abscess. 0 0 ‡ Excluding anal cancer. 5. D o w nlo a d e d Tpaatbielen t4s. wStiathn daanradl ifsiesdsu irnec,i dfiesntuclea ,r aotri opse (rSiaInRasl )a abnsdce tshse*i r 95% confidence intervals (CIs) for anal cancer among from Fissure Fistula Perianal abscess h ttp ://g Obs SIR 95%CI Obs SIR 95%CI Obs SIR 95%CI u t.b m Overall 5 3.9 1.3-9.2 2 1.3 0.2-4.9 6 5.3 1.9-11.5 j.c o Sex m Men 2 4.7 0.6-16.9 1 1.3 0.03-7.4 1 1.6 0.04-9.0 o/ n Women 3 3.6 0.7-10.4 1 1.4 0.04-7.6 5 9.7 3.1-22.6 J a n Follow-up duration (years) u a 3-9 3 5.9 1.2-17.3 0 - -- 4 7.1 1.9-18.3 ry 1 10+ 2 2.6 0.3-9.4 2 2.1 0.3-7.5 2 3.5 0.4-12.5 6 * Person-years and anal cancer cases accrued during the first 3 years of follow-up were excluded. , 2 0 2 3 b y g ue s DISCUSSION t. P This retrospective cohort study showed an increased risk of anal cancer for both male and female ro te patients hospitalised for inflammatory benign anal lesions, including anal fissures, fistulas, and perianal c te abscesses. In contrast, hemorrhoids do not appear to be associated with any increased risk for anal d b y cancer. c o p y rig h t. 7 Although there were marked incidence peaks for anal cancer in all sub-cohorts during the first 2-3 G u ymeiasrcsl aosfs iffoilclaotwio-nu pc,a nsungogt eesxtpinlagi nso tmhee oibnsiteiarvl emdi slocnlags-stiefrimca teixocne osfs arinsakl ocfa nacnearl acsa nbceenri ganm aonnagl pleastiieonntss, such t: firs hospitalised for anal fissures, fistulas, or perianal abscesses, as the excess risk persisted after 10 years t pu b or more of follow-up. Confounding by smoking is another potential explanation, as smoking has been lis h suggested as one risk factor for anal cancer.20 However, the incidence of lung cancer – a marker of the e d smoking prevalence in our cohort – was increased by no more than 30%. Accordingly, smoking cannot as 1 explain the observed 3-fold excess risk for anal cancer. Further, confounding by HPV and HIV 0 .1 infection may also partly explain the observed excess anal cancer risk. Previous organ transplantation 1 3 6 can lead to perianal abscess, and organ transplantation has been found to increase the risk of anal /g u cancer. 21 However, sensitivity analyses by excluding subjects with these comorbid diseases or organ t.2 0 transplantation revealed essentially unchanged results. 0 5 .0 7 0 Our finding of an increased risk associated with benign inflammatory anal lesions was consistent with 2 0 the results from two previous case-control studies,2, 15 which asked about any past medical history of 1 o n anal fissures, fistulas, infection, inflammation or itching in or around the anus. The association with 1 8 previous anorectal disease was less clear in another case-control study among women.4 Somewhat N o conflicting results among men and women emerged in a fourth case-control study; an increased risk of v e m anal cancer was observed among women with a previous history of anal abscesses, but risk in men was b e linked to hemorrhoids and unspecific irritation.16 In the above-mentioned two case-control studies,2, 15 r 2 0 an increased risk of anal cancer has been found among subjects who self-reported severe hemorrhoids, 0 5 which was in conflict with our finding. All these case-control studies had to rely on self-reports, and . D o misclassification of the lesion or recall bias may be quantitatively important. A previous cohort study w n from Denmark, of a similar design as ours, but with fewer observed cancer cases, found a comparable lo a d incidence peak shortly after index hospitalization, but did not observe any anal cancer cases in patients e d with anal fissures or fistulas, and a statistically non-significant excess risk among perianal abscess fro patients based on 2 observed cases, after 5 years or more of follow-up.14 The authors concluded that m h their data did not support a causal link between benign anal lesions and anal cancer, but the study was ttp clearly under-powered. A considerably larger American cohort study among male veterans showed a ://g u four-fold increased risk after 5-9 years among African Americans but no clear corresponding excess t.b m among Caucasians.17 As inflammatory lesions and hemorrhoids were lumped together, it is impossible j.c o to tell whether the racial differences reflected differences in case mix. m o/ n Strengths of our study include the essentially population-based cohort, the virtually complete and thus Ja n practically bias-free follow-up, and the restriction to first and squamous-cell carcinomas only. u a However, the relatively small observed number of anal cancers limited our ability for detailed stratified ry 1 6 analyses by sex or specific type of inflammatory benign anal lesions, and made estimates in some strata , 2 unstable. Moreover, the possibility of ascertainment or detection bias cannot be completely ruled out, 02 3 and the limited availability of information on potential confounding factors, notably smoking and HPV b y infection, is an important caveat. At last, patients with benign anal lesions are usually treated in the g u e outpatient setting. Thus hospitalised patients may represent a subgroup of more severe lesions. If s severity of disease is associated with anal cancer risk, our results may overestimate the true relative t. P ro risk. On the other hand, patients hospitalised for benign anal lesions usually have their lesions cured te c before discharge, especially for hemorrhoids. Thus, our results may underestimate the true association, te d especially for hemorrhoid patients. However, the fact that no obvious excess anal cancer risk was b y c observed among patient with recurrent hemorrhoids may somewhat allay such a concern. o p yrig h t. 8 Anal fissures and fistulas are typically infected and chronic inflammation is common. Perianal G u aisb tshcuess sreesa saoren,a pbeler dtoe fpionsittiuolna,t ei nthfeactt tehde. Oasns otchiea toitohne rb ehtawnede, nh eamnaolr frihsosiudr eiss, nfoistt uanla isn, fplaemriamnaatlo arbys dceissesaesse . It t: firs and anal cancer can be explained by prolonged inflammation. This conclusion is also supported by our t pu b findings. Almost one fourth of the patients treated for benign inflammatory anal lesions were lis h hospitalised more than once for their lesion, suggesting that surgical treatment was not able to eradicate e d all inflammatory tissue. Patients with relapsing infections had an increased risk of anal cancer as 1 compared to patients treated only once. The similarly elevated risk of anal cancer was not seen among 0 .1 patients with recurrent hemorrhoids. Inflammation and chronic activation of the immune system have 1 3 6 been proposed to cause cancer. In chronic inflammation macrophages, lymphocytes and plasma cells /g u infiltrate the damaged tissue, and persistent pathological activation of macrophages can result in t.2 continuous tissue damage.22 Macrophages release a number of powerful substances, among them nitric 00 5 oxide (NO). NO seems to directly damage DNA, inhibit DNA-repair enzymes, inhibit caspase activity .0 7 leading to inhibited apoptosis, and stimulate angiogenesis, which may promote tumor growth.23 The 02 0 1 inflammatory process also generates inflammatory cytokines and prostaglandins which repress cell o mediated immune responses and favor angiogenesis.24 Moreover, carcinogenic substances, as reactive n 1 8 oxygen species and metabolites, may be produced in sites with chronic inflammation. Ulcerative colitis N o is a well established risk factor for colon cancer.9, 10, 25 v e m b e Human papillomavirus is considered to play a central role in the aetiology of anal cancer.20 r 2 0 Epidemiological studies have also found that presence of genital warts (condylomata acuminata) is 0 5 linked to an elevated risk of anal cancer.2, 3, 6, 15 Thus, it is conceivable that benign inflammatory anal . D o lesions might either act as a cofactor to promote HPV-initiated carcinogenesis or facilitate access of w n HPV to the epithelium, or serve just as a marker of infection of high risk human papillomavirus.16 lo a d e d We conclude that benign inflammatory anal lesions are associated with a moderately increased long- fro m term risk for anal cancer. Whether this association is due to inflammation or to facilitated infection h with HPV warrants further investigation. Clinicians who are responsible for treatment of benign anal ttp lesions should be aware of the high possibility of misdiagnosis of anal cancer. Given the relative rarity ://g u of anal cancer and the only moderate excess long-term risk, however, regular surveillance for anal t.b m cancer among patients with benign inflammatory anal lesions is not justifiable. j.c o m o/ n J a n u a ry 1 6 , 2 0 2 3 b y g u e s t. P ro te c te d b y c o p y rig h t. 9 REFERENCES G u 1. Clark MA, Hartley A, Geh JI. Cancer of the anal canal. Lancet Oncol 2004;5:149-57. t: firs 2. Holly EA, Whittemore AS, Aston DA, Ahn DK, Nickoloff BJ, Kristiansen JJ. Anal cancer t pu b incidence: genital warts, anal fissure or fistula, hemorrhoids, and smoking. J Natl Cancer Inst lis h 1989;81:1726-31. e d 3. Frisch M, Glimelius B, van den Brule AJ, Wohlfahrt J, Meijer CJ, Walboomers JM, Goldman as 1 S, Svensson C, Adami HO, Melbye M. 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