Penile cancer: Importance of circumcision, human papillomavirus and smoking in in situ and invasive disease
Abstract
Few population‐based case‐control studies have assessed etiologic factors for penile cancer. Past infection with high‐risk human papillomavirus (HPV) is a known risk factor for penile cancer; however, few previous studies have related the HPV DNA status of the tumor to potential demographic and behavioral risk factors for the disease or evaluated whether in situ and invasive penile cancer share risk factors. Little information is available on the role and timing of circumcision in the etiology of penile cancer. We conducted a population‐based case‐control study in western Washington state that included 137 men diagnosed with in situ (n = 75) or invasive (n = 62) penile cancer between January 1, 1979, and December 31, 1998, and 671 control men identified through random digit dialing. Cases and controls were interviewed in person and provided peripheral blood samples. Case and control blood samples were tested for antibodies to HPV16 and HSV‐2, and tumor specimens from cases were tested for HPV DNA. Men not circumcised during childhood were at increased risk of invasive (OR = 2.3, 95% CI 1.3–4.1) but not in situ (OR = 1.1, 95% CI 0.6–1.8) penile cancer. Approximately 35% of men with penile cancer who had not been circumcised in childhood reported a history of phimosis compared to 7.6% of controls (OR = 7.4, 95% CI 3.7–15.0). Penile conditions such as tear, rash and injury were associated with increased risk of disease. Among men not circumcised in childhood, phimosis was strongly associated with development of invasive penile cancer (OR = 11.4, 95% CI 5.0–25.9). When we restricted our analysis to men who did not have phimosis, the risk of invasive penile cancer associated with not having been circumcised in childhood was not elevated (OR = 0.5, 95% CI 0.1–2.5). Cigarette smoking was associated with a 4.5‐fold risk (95% CI 2.0–10.1) of invasive penile cancer. HPV DNA was detected in 79.8% of tumor specimens, and 69.1% of tumors were HPV16‐positive. The proportion of HPV DNA‐positive tumors did not vary by any risk factors evaluated. Many risk factors were common for both in situ and invasive disease. However, 3 factors that did not increase the risk for in situ cancer proved significant risk factors for invasive penile cancer: lack of circumcision during childhood, phimosis and cigarette smoking. The high percentage of HPV DNA‐positive tumors in our study is consistent with a strong association between HPV infection and the development of penile cancer regardless of circumcision status. Circumcision in early childhood may help prevent penile cancer by eliminating phimosis, a significant risk factor for the disease. © 2005 Wiley‐Liss, Inc.
Penile cancer is a rare disease. The annual incidence is 1.5/100,000 in the United States, and approximately half of the tumors are in situ (45%) and half are invasive (55%).1 Few population‐based case‐control studies have assessed etiologic factors related to this disease. In 1993, we published the first case‐control study of penile cancer that included evaluation of tumor tissue for the presence of high‐risk human papillomavirus (HPV) DNA, which proved to be a significant risk factor for penile cancer.2 Once reliable methods for HPV16 antibody testing were developed, we extended our investigation by including these samples in a study comparing HPV antibodies across several HPV‐related anogenital cancer sites.3
We continued and expanded our study of penile cancer in the Pacific Northwest (our first study also included cases and controls from Vancouver, British Columbia) by adding additional years of diagnosis (1990–1998) (n = 81 cases, n = 363 controls). This report presents the final results from the western Washington portion of our population‐based case‐control study. To evaluate whether in situ and invasive penile cancer might not represent a continuum of the same disease,4 we present separate analyses for the 2 diagnoses. Potential risk factors are compared to biologic markers of HPV exposure through testing of pathologic specimens for HPV DNA in cases and testing for serum HPV16 antibodies in both cases and controls. Because circumcision status has been shown to modify the risk of penile cancer in previous studies,2, 5 circumcision status and the timing of the procedure are given special attention.
Material and methods
Cases
Eligible cases included all men 18–74 years old diagnosed with invasive or in situ penile cancer, regardless of histologic type, between January 1, 1979, and December 31, 1998, and whose primary residence was in one of the 13 counties of western Washington included in the Cancer Surveillance System. This population‐based registry is part of the National Cancer Institute's Surveillance, Epidemiology and End Results program.
Controls
A sample of men from the general population of the 13 counties was identified using unrestricted random digit dialing.6 Control subjects were selected so as to be frequency‐matched to case subjects based on age (5‐year groups), reference year (year of diagnosis for cases) and whether they resided in either the 3‐county Seattle area or the other 10 counties of western Washington covered by the registry. To be eligible as a control, potential participants needed to have a working telephone number, reside in a noninstitutional setting, have the ability to communicate in English and have no history of penile cancer.
Data collection
Interviews were conducted by trained interviewers in each subject's home or at another place of his choice. The information collected included demographic characteristics, sexual practices, history of sexually transmitted diseases, tobacco and drug use and medical history, including conditions associated with the penis, circumcision status, age at circumcision and hygienic practices. All interview information was collected by instructing participants to refer only to the period prior to his reference date (the diagnosis date of cancer for cases and a comparable time for controls).
At the time of interview, a peripheral blood sample was collected by routine venipuncture from both cases and controls, then processed into multiple aliquots and frozen for storage. Blood samples were collected from 92.7% of cases and 86.9% of controls. Cases were asked for permission to obtain paraffin‐embedded specimens containing their tumor tissue, and 83.9% signed a tissue release form. Tissue was available from the hospitals for 105 (76.6%) interviewed cases.
Laboratory analyses
Seropositivity to HPV16 capsid proteins was determined using an antigen capture ELISA. This assay detected HPV16‐specific antibodies to a conformational epitope to the L1 protein of a vaccinia virus–expressed construct, as described in Carter et al.7 Briefly, capsids were produced using HPV16 L1 and HPV18 L1 recombinant vaccinia viruses and purified on cesium chloride gradients. Capture antibodies were kindly provided by Dr. N. Christensen (University of Pennsylvania Hershey Medical Center, Hershey, PA). Human sera were tested in triplicate with and without capsids by researchers blinded to case‐control status. Bound human IgG was detected using a goat antihuman alkaline‐phosphatase–conjugated antibody (Roche Diagnostics, Indianapolis, IN) and developed with Sigma Alkaline‐Phosphatase Substrate 104 (St. Louis, MO). Positive controls (a pool of HPV16‐ or HPV18‐reactive sera) were included on each plate. For each sample, a value was calculated as follows: natural log of the average of the 3 wells containing antigen minus natural log of the average of 3 wells with no antigen.
Serologic response to herpes simplex virus type 2 (HSV‐2) was assessed using a specific Western blot assay that reliably discriminates between HSV‐1 and HSV‐2.8 Serology laboratories were blinded to the case‐control status of samples.
PCR methods were used to amplify HPV DNA extracted from paraffin‐embedded tumor tissue, to determine the presence or absence of specific HPV genotypes. Two different HPV‐typing protocols were used. For the earliest samples (33 of 105 cases), PCR products were amplified from the HPV L1 open reading frame using MY09/MY11 consensus primers9 and typed by Southern hybridization using oligonucleotides specific for HPV types 6/11, 16, 18/45 and 31/33/35.10 For more recent specimens (72 of 105 cases), HPV genotype was assigned by comparing the restriction patterns of amplified HPV L1 fragments from tumor tissue with those of HPV recombinant plasmids. When L1 products could not be assigned an HPV genotype based on restriction analysis, genotypes were determined by automated sequencing of the L1 consensus products. Positive controls consisted of recombinant plasmids containing HPV types 6, 16 and 18. HPV‐negative human genomic DNA served as the negative control. Under both protocols, additional primers were derived from the E6 open reading frames11 and the identity of the HPV16E6, HPV18E6 and HPV6E6 products was confirmed by Southern hybridization. HPV DNA‐negative results were tested by PCR to amplify 536 and 268 bp fragments of the β‐globin gene, to ensure that amplifiable DNA was present in the sample. Of the 105 tumor blocks retrieved, 11 (10.5%) were β‐globin‐negative. Of the 94 tumor samples evaluated for HPV DNA, 3 (3.2%) had restriction patterns that were not identifiable but inadequate material remained for sequencing; these results are referred to as “HPV DNA‐positive, type unknown”. There was no association between HPV DNA positivity and time from diagnosis to testing of the tissue blocks (p = 0.43).
Statistical analyses
Multiple logistic regression was used to obtain odds ratio (OR) estimates as measures of the relative risk of penile cancer associated with potential risk factors. Polytomous logistic regression was used to obtain ORs when comparing multiple case groups (i.e., in situ to invasive cases and HPV DNA‐positive to HPV DNA‐negative cases) and controls, allowing for a direct comparison of case group estimates. The following variables were evaluated as potential confounders and found not to substantially change the OR in any comparisons: reference year (continuous linear), annual income (≥$30,000, $15,000 to <$30,000, <$15,000), alcohol use (never, former, current), education (≥13 years, <13 years), marital status (married/living as married/widowed, never married, divorced/separated) and race (white, black, other). The following 3 variables were adjusted for in the analyses: age at reference date (continuous linear), smoking status (never, former, current) and lifetime number of sex partners (1, 2–4, 5–14, ≥15 or 1–4, 5–14, ≥15, as presented in tables). The risk associated with the presence of HSV‐2 antibodies was further adjusted for the presence of HPV16 antibodies (negative, positive).
Several tests of significance were used in this analysis. Two‐sample t‐test p values were calculated for between‐group means; χ2 p values were calculated for differences in the distribution of variables between cases and controls; likelihood ratio p values were used to evaluate multiplicative interaction between risk factors and to test equality of coefficients across 2 case groups in polytomous models; and Wald p values were used as tests for significance of ORs and for age‐adjusted differences.
Circumcision status was classified into the following 3 categories: (i) childhood, defined as circumcision either at birth (375 controls, 59 cases) or before age 10 (17 controls, 5 cases); (ii) later, defined as circumcision after age 9 but more than 5 years prior to diagnosis or reference date (31 controls, 11 cases); (iii) never, included men never circumcised (247 controls, 60 cases) and those circumcised in the 5 years prior to diagnosis or reference date (1 control, 10 cases).
Results
Of a total of 249 men with primary penile cancer identified from the Cancer Surveillance System, 137 (55.0%) were interviewed. Reasons for nonresponse included participant refusal (n = 39, 15.7%), death before recruitment (n = 33, 13.3%), physician refused to give permission to approach the patient (n = 22, 8.8%) and patient could not be located or had moved out of the area (n = 18, 7.2%). Nonrespondents were of similar age and county distribution as cases who participated in the interview but were less likely to be married at the time of diagnosis than participants (57% of nonrespondents compared to 77% of participants, p = 0.002). The majority of interviewed patients had been diagnosed with squamous cell carcinoma (133 of 137, 97.1%). The nonsquamous histologies of participants included the following: 1 basal cell carcinoma, 1 melanoma, 1 leiomyosarcoma and 1 Kaposi's sarcoma.
Of the 949 men identified as eligible for selection as controls through primary sampling, 671 (70.7%) were enrolled and successfully interviewed. The overall response rate for controls (i.e., proportion of screened residences, 93.9%, multiplied by proportion of eligible and successfully interviewed men) was 66.4%.
Men with penile cancer were more likely to have been single, with an adjusted OR of 2.5 [95% confidence interval (CI) 1.1–5.6, Table I], relative to married men. In contrast, there was no relationship to reported sexual orientation (OR = 1.0, 95% CI 0.3–3.1). A greater proportion of cases were current smokers at the reference date (35.0%) compared to controls (21.8%; OR = 2.3, 95% CI 1.4–4.0).
| Characteristic | Controls (n = 671) n (%) | Cases (n = 137) n (%) | Adjusted OR1 (95% CI) |
|---|---|---|---|
| Age at reference date (years) | |||
| <50 | 206 (30.7) | 36 (26.3) | |
| 50–64 | 290 (43.2) | 52 (38.0) | |
| 65+ | 175 (26.1) | 49 (35.8) | |
| Race | |||
| White | 636 (94.8) | 129 (94.2) | 1.0 |
| Black | 10 (1.5) | 4 (2.9) | 2.3 (0.7–7.7) |
| Other | 25 (3.7) | 4 (2.9) | 0.8 (0.3–2.3) |
| Education (years) | |||
| ≤ 12 | 222 (33.1) | 63 (46.0) | 1.0 |
| > 12 | 449 (66.9) | 74 (54.0) | 0.7 (0.5–1.0) |
| Marital status | |||
| Married/living as married /widowed | 559 (83.3) | 104 (75.9) | 1.0 |
| Never married | 34 (5.1) | 11 (8.0) | 2.5 (1.1–5.6) |
| Separated/divorced | 78 (11.6) | 22 (16.1) | 1.3 (0.7–2.2) |
| Sexual orientation | |||
| Heterosexual | 645 (96.9) | 132 (96.3) | 1.0 |
| Bisexual/homosexual | 21 (3.1) | 5 (3.7) | 1.0 (0.3–3.1) |
| Missing | 5 | 0 | |
| Lifetime number of female sex partners | |||
| 1 | 134 (20.3) | 14 (10.3) | 1.0 |
| 2–4 | 149 (22.6) | 33 (24.3) | 2.1 (1.0–4.0) |
| 5–14 | 196 (29.7) | 39 (28.7) | 1.8 (0.9–3.5) |
| 15+ | 180 (27.3) | 50 (36.8) | 2.4 (1.3–4.7) |
| Missing | 12 | 1 | |
| Cigarette smoking status | |||
| Never | 224 (33.4) | 28 (20.4) | 1.0 |
| Former | 301 (44.9) | 61 (44.5) | 1.4 (0.8–2.3) |
| Current | 146 (21.8) | 48 (35.0) | 2.3 (1.4–4.0) |
| Time from circumcision to diagnosis2 (years) | |||
| 0–5 | 1 (3.1) | 10 (47.6) | |
| 6–20 | 7 (21.9) | 5 (23.8) | |
| > 20 | 24 (75.0) | 6 (28.6) | |
| Circumcised in childhood3 | |||
| Yes | 392 (58.5) | 64 (47.4) | 1.0 |
| No | 278 (41.5) | 71 (52.6) | 1.5 (1.0–2.2) |
| Never circumcised | 247 (36.9) | 60 (44.4) | 1.4 (0.9–2.1) |
| Circumcised later | 31 (4.6) | 11 (8.2) | 2.1 (1.0–4.4) |
| Missing | 1 | 2 | |
- 1 Adjusted for age (linear), cigarette smoking and number of sex partners.
- 2 Among men circumcised after age 9; men circumcised in the 5 years prior to diagnosis are subsequently included in the “never circumcised” category.
- 3 Circumcision prior to age 10 is considered “in childhood”.
Timing of circumcision differed between men with penile cancer and controls (Fig. 1) as cases were more likely to have been circumcised after age 9. Twenty‐one cases were circumcised after age 9, and 11 of them were included in the circumcised later group in Table I. The other 10 cases were circumcised within 5 years of diagnosis and are included in the circumcised never group in all analyses (Table I). Late circumcision for these 10 cases was reported in the interview as attributable to cancer (n = 4), genital warts (n = 1), inflammation or infection (n = 3) or no reason given (n = 2). It is likely that the latter group received late circumcision for treatment of early disease; hence, their circumcision could not have an etiologic role in disease.

Age at circumcision for cases and controls.
A greater percentage of subjects with penile cancer had not been circumcised in childhood (52.6%) compared to controls (41.5%) (OR = 1.5, 95% CI 1.0–2.2), though this difference was within the limits of chance (p = 0.07). The circumcised in childhood category includes subjects circumcised neonatally (59 cases, 375 controls) and between ages 1 and 9 (5 cases, 17 controls). These categories were combined because the risk estimates were not elevated for subjects circumcised between ages 1 and 9 (OR = 1.4, 95% CI 0.4–4.1).
Cases (8.2%) were more likely to have been circumcised after age 9 but more than 5 years before the reference date than controls (4.6%; OR = 2.1, 95% CI 1.0–4.4, p = 0.06). Age at circumcision (Fig. 1) was greater for cases (mean = 37.8 years, median = 41.0 years) than controls (mean = 20.3 years, median = 18.0 years).
Table II presents the history of sexually transmitted diseases, urinary tract infections and pathologic conditions of the penis reported by cases and controls. Of men with penile cancer, 25.7% reported a history of genital warts compared to 4.8% of controls (OR = 7.6, 95% CI 4.3–13.5). Cases were more likely than controls to demonstrate serum antibodies to HSV‐2 (OR = 3.0, 95% CI 1.9–4.7) and to HPV16 (OR = 1.9, 95% CI 1.2–3.2). There was also an increased risk of penile cancer among subjects who reported a history of urinary tract infections (OR = 1.7, 95% CI 1.1–2.7). Although subjects with penile cancer were more likely to report a history of gonorrhea (OR = 1.5, 95% CI 0.9–2.7) and nongonococcal urethritis (OR = 1.5, 95% CI 0.8–3.0), but these increases were within the limits of chance.
| Characteristic | Controls (n = 671) n (%) | Cases (n = 137) n (%) | Adjusted OR1 (95% CI) |
|---|---|---|---|
| Genital warts | |||
| No | 638 (95.2) | 101 (74.3) | ref |
| Yes | 32 (4.8) | 35 (25.7) | 7.6 (4.3–13.5) |
| Missing | 1 | 1 | |
| HSV‐22 | |||
| Negative | 488 (85.3) | 77 (62.6) | ref |
| Positive | 84 (14.7) | 46 (37.4) | 3.0 (1.9–4.7) |
| Not tested | 99 | 14 | |
| HPV 16 serology | |||
| Negative | 509 (87.5) | 92 (76.0) | ref |
| Positive | 73 (12.5) | 29 (24.0) | 1.9 (1.2–3.2) |
| Not tested | 89 | 16 | |
| Gonorrhea | |||
| Never | 612 (91.2) | 114 (84.4) | ref |
| Ever | 59 (8.8) | 21 (15.6) | 1.5 (0.9–2.7) |
| Missing | 0 | 2 | |
| Nongonococcal urethritis | |||
| Never | 624 (93.7) | 122 (89.1) | ref |
| Ever | 42 (6.3) | 15 (10.9) | 1.5 (0.8–3.0) |
| Missing | 5 | 0 | |
| Urinary tract infections | |||
| Never | 554 (82.9) | 105 (76.6) | ref |
| Ever | 114 (17.1) | 32 (23.4) | 1.7 (1.1–2.7) |
| Missing | 3 | 0 | |
| Phimosis3 | |||
| No | 254 (92.4) | 46 (64.8) | ref |
| Yes | 21 (7.6) | 25 (35.2) | 7.4 (3.7–15.0) |
| Missing | 4 | 2 | |
| Smegma3 | |||
| Never/rarely | 264 (95.7) | 64 (91.4) | ref |
| Sometimes/usually | 12 (4.3) | 6 (8.6) | 1.9 (0.7–5.4) |
| Missing | 3 | 3 | |
| Penile tear | |||
| No | 624 (93.1) | 102 (74.5) | ref |
| Yes | 46 (6.9) | 35 (25.5) | 5.2 (3.1–8.7) |
| Missing | 1 | 0 | |
| Penile rash | |||
| No | 658 (98.2) | 107 (78.1) | ref |
| Yes | 12 (1.8) | 30 (21.9) | 14.9 (7.2–30.8) |
| Missing | 1 | 0 | |
| Penile injury | |||
| No | 650 (97.0) | 124 (90.5) | ref |
| Yes | 20 (3.0) | 13 (9.5) | 3.2 (1.5–6.8) |
| Missing | 1 | 0 | |
| Penile inflammation | |||
| Never | 655 (98.1) | 126 (92.7) | ref |
| Ever | 13 (1.9) | 10 (7.3) | 3.5 (1.5–8.5) |
| Missing | 3 | 1 | |
| Urethral stricture | |||
| No | 629 (94.3) | 120 (88.9) | ref |
| Yes | 38 (5.7) | 15 (11.1) | 2.0 (1.1–3.9) |
| Missing | 4 | 2 | |
- 1 Adjusted for age (linear), cigarette smoking status and lifetime number of sex partners.
- 2 OR also adjusted for HPV16 serology.
- 3 Among those who were not circumcised in childhood (prior to age 10).
A number of other penile conditions were associated with an increased risk of penile cancer. Phimosis, a pathology observed in uncircumcised or improperly circumcised males that is characterized by the inability to retract the foreskin over the glans, was more common in cases (35.2%) than controls (7.6%) among those men who were not circumcised in childhood (OR = 7.4, 95% CI 3.7–15.0). Penile tear (OR = 5.2, 95% CI 3.1–8.7), penile rash (defined as chronic dermatitis lasting at least 1 month; OR = 14.9, 95% CI 7.2–30.8), penile injury (OR = 3.2, 95% CI 1.5–6.8), penile inflammation (OR = 3.5, 95% CI 1.5–8.5) and urethral stricture (OR = 2.0, 95% CI 1.1–3.9) were associated with increased risk of penile cancer (Table II). In a multivariate model that included 5 penile conditions (i.e., penile tear, rash, injury, inflammation and stricture), only penile tear, rash and injury conferred an increased risk of penile cancer.
Because of the potential association between circumcision status and the penile conditions evaluated in the study, we stratified these variables as well as other risk factors by circumcision status (Table III). ORs were not calculated for men circumcised after age 9 due to the small number of cases in this group; however, the distributions among cases and controls are presented for completeness. There was a strong association between younger age at reference date and being circumcised among both cases and controls (t‐test p < 0.001 for each). Having had a greater number of sex partners conferred an increased risk of penile cancer only among men circumcised in childhood (OR = 3.2, 95% CI 1.5–6.4).
| Circumcised in childhood | Never circumcised | Circumcised later | ||||||
|---|---|---|---|---|---|---|---|---|
| Controls (n = 392) n (%) | Cases (n = 64) n (%) | OR2 (95% CI) | Controls (n = 247) n (%) | Cases (n = 60) n (%) | OR2 (95% CI) | Controls (n = 31) n (%) | Cases (n = 11) n (%) | |
| Age (years) | ||||||||
| <50 | 173 (44.1) | 28 (43.8) | 30 (12.1) | 7 (11.7) | 3 (9.7) | 1 (9.1) | ||
| 50–64 | 154 (39.3) | 23 (35.9) | 118 (47.8) | 24 (40.0) | 17 (54.8) | 5 (45.5) | ||
| 65+ | 65 (16.6) | 13 (20.3) | 99 (40.1) | 29 (48.3) | 11 (35.5) | 5 (45.5) | ||
| Lifetime number of female sex partners | ||||||||
| l–4 | 155 (40.2) | 13 (20.3) | ref | 118 (49.0) | 27 (45.8) | ref | 10 (32.3) | 5 (45.5) |
| 5–14 | 124 (32.1) | 20 (31.3) | 1.8 (0.9–3.9) | 59 (24.5) | 14 (23.7) | 0.9 (0.4–1.8) | 13 (41.9) | 5 (45.5) |
| 15+ | 107 (27.7) | 31 (48.4) | 3.2 (1.5–6.4) | 64 (26.6) | 18 (30.5) | 1.0 (0.5–2.0) | 8 (25.8) | 1 (9.1) |
| Smoking | ||||||||
| Never | 135 (34.4) | 16 (25.0) | ref | 79 (32.0) | 9 (15.0) | ref | 10 (32.3) | 2 (18.2) |
| Former | 174 (44.4) | 20 (31.3) | 0.8 (0.4–1.7) | 113 (45.7) | 34 (56.7) | 2.8 (1.2–6.5) | 7 (22.6) | 2 (18.2) |
| Current | 83 (21.2) | 28 (43.7) | 2.2 (1.1–4.5) | 55 (22.3) | 17 (28.3) | 3.1 (1.2–8.0) | 14 (45.2) | 7 (63.6) |
| Genital warts | ||||||||
| No | 367 (93.6) | 43 (68.3) | ref | 241 (98.0) | 47 (78.3) | ref | 30 (96.8) | 9 (81.8) |
| Yes | 25 (6.4) | 20 (31.7) | 6.7 (3.2–14.0) | 5 (2.0) | 13 (21.7) | 13.3 (4.3–41.3) | 1 (3.2) | 2 (18.2) |
| HSV‐2 serology3 | ||||||||
| Negative | 281 (84.9) | 33 (57.9) | ref | 184 (86.8) | 36 (64.3) | ref | 22 (78.6) | 6 (75.0) |
| Positive | 50 (15.1) | 24 (42.1) | 3.0 (1.5–4.8) | 28 (13.2) | 20 (35.7) | 3.4 (1.6–7.1) | 6 (21.4) | 2 (25.0) |
| HPV16 serology | ||||||||
| Negative | 295 (86.8) | 37 (66.1) | ref | 189 (88.7) | 46 (83.6) | ref | 24 (85.7) | 8 (100.0) |
| Positive | 45 (13.2) | 19 (33.9) | 2.6 (1.3–5.1) | 24 (11.3) | 9 (16.4) | 1.5 (0.6–3.5) | 4 (14.3) | 0 (0.0) |
| Gonorrhea | ||||||||
| Never | 358 (91.3) | 51 (79.7) | ref | 233 (94.3) | 52 (88.1) | ref | 20 (64.5) | 9 (90.0) |
| Ever | 34 (8.7) | 13 (20.3) | 1.7 (0.8–3.8) | 14 (5.7) | 7 (11.9) | 2.2 (0.8–6.3) | 11 (35.5) | 1 (10.0) |
| Nongonococcal urethritis | ||||||||
| Never | 360 (92.5) | 53 (82.8) | ref | 236 (95.9) | 56 (93.3) | ref | 27 (90.0) | 11 (100.0) |
| Ever | 29 (7.5) | 11 (17.2) | 1.9 (0.8–4.2) | 10 (4.1) | 4 (6.7) | 1.4 (0.4–4.9) | 3 (10.0) | 0 (0.0) |
| Urinary tract infection | ||||||||
| Never | 329 (84.1) | 51 (79.7) | ref | 199 (81.2) | 46 (76.7) | ref | 25 (80.7) | 7 (63.6) |
| Ever | 62 (15.9) | 13 (20.3) | 1.5 (0.8–3.1) | 46 (18.8) | 14 (23.3) | 1.5 (0.7–3.0) | 6 (19.4) | 4 (36.4) |
| Phimosis4 | ||||||||
| No | 237 (96.3) | 41 (68.3) | ref | 17 (58.6) | 4 (40.0) | |||
| Yes | 9 (3.7) | 19 (31.7) | 15.7 (6.0–41.1) | 12 (41.4) | 6 (60.0) | |||
| Smegma4 | ||||||||
| Never/rarely | 239 (97.1) | 54 (90.0) | ref | 24 (82.8) | 9 (100.0) | |||
| Sometimes/usually | 7 (2.9) | 6 (10.0) | 4.0 (1.2–13.0) | 5 (17.2) | 0 (0.0) | |||
| Penile tear | ||||||||
| No | 359 (91.6) | 53 (82.8) | ref | 236 (95.5) | 42 (70.0) | ref | 29 (93.5) | 5 (45.5) |
| Yes | 33 (8.4) | 11 (17.2) | 2.1 (1.0–4.7) | 11 (4.5) | 18 (30.0) | 12.5 (5.0–31.1) | 2 (6.5) | 6 (54.5) |
| Penile rash | ||||||||
| No | 384 (98.0) | 51 (79.7) | ref | 244 (98.8) | 47 (78.3) | ref | 30 (96.8) | 8 (72.7) |
| Yes | 8 (2.0) | 13 (20.3) | 9.5 (3.6–24.9) | 3 (1.2) | 13 (21.7) | 23.2 (5.9–90.4) | 1 (3.2) | 3 (27.3) |
| Penile injury | ||||||||
| No | 381 (97.2) | 58 (90.6) | ref | 238 (96.4) | 55 (91.7) | ref | 31 (100.0) | 9 (81.8) |
| Yes | 11 (2.8) | 6 (9.4) | 3.5 (1.2–10.6) | 9 (3.6) | 5 (8.3) | 2.3 (0.7–7.4) | 0 (0.0) | 2 (18.2) |
| Penile inflammation | ||||||||
| No | 387 (99.0) | 58 (90.6) | ref | 240 (97.2) | 55 (93.2) | ref | 29 (93.5) | 11 (100.0) |
| Yes | 4 (1.0) | 6 (9.4) | 7.9 (2.0–31.0) | 7 (2.8) | 4 (6.8) | 2.6 (0.7–9.7) | 2 (6.5) | 0 (0.0) |
| Urethral stricture | ||||||||
| No | 375 (95.7) | 57 (91.9) | ref | 227 (92.7) | 53 (88.3) | ref | 27 (90.0) | 8 (72.7) |
| Yes | 17 (4.3) | 5 (8.1) | 1.8 (0.6–5.2) | 18 (7.3) | 7 (11.7) | 1.5 (0.6–4.0) | 3 (10.0) | 3 (27.3) |
- 1 Circumcision prior to age 10 is considered “in childhood”, and circumcision in the 5 years prior to reference is considered “never circumcised” 2 cases have known circumcision status.
- 2 Adjusted for age (linear), cigarette smoking status and lifetime number of sexual partners.
- 3 OR also adjusted for HPV16 serology.
- 4 Among those not circumcised in childhood.
Among men circumcised in childhood, the risk of cancer associated with various penile conditions was not different from that observed among men who had never been circumcised, with the exception of the increased risk of cancer associated with penile tear. Men who had never been circumcised had a >12‐fold increased risk of penile cancer associated with penile tear (OR = 12.5, 95% CI 5.0–31.1); among men circumcised in childhood, the risk was only 2‐fold (2.1, 95% CI 1.0–4.7, p for interaction = 0.006). Over one‐half (54.5%, n = 6) of 11 cases circumcised later had suffered a penile tear compared to 6.5% of 31 controls (χ2 p for difference = 0.001). There was a suggestion that subjects circumcised after age 9 were more likely than other cases to be current smokers at the reference date and to report a history of penile injury and urethral stricture. Both cases and controls circumcised later in life tended to report phimosis more frequently compared to cases and controls who were never circumcised.
Among cases, we evaluated various tumor characteristics, including extent of disease (in situ vs. invasive), location of lesion on the penis and presence of HPV DNA by both circumcision status and extent of disease (Table IV). Cases circumcised in childhood were more likely to be diagnosed with in situ disease than cases never circumcised or circumcised later in life (χ2 p for difference = 0.01, Table IV). Among the 65% of cases for whom the specific location of the tumor on the penis was known, men who were never circumcised or were circumcised later in life were more likely to have tumors located on the glans than men who were circumcised in childhood. Extent of disease did not vary according to location on the penis.
| Characteristic | All cases (n=137) n (%) | Circumcision status1 | Extent of disease | |||
|---|---|---|---|---|---|---|
| Childhood (n=64) n (%) | Never (n=60) n (%) | Later (n=11) n (%) | In situ (n=75) n (%) | Invasive (n=62) n (%) | ||
| Extent of disease | ||||||
| In situ | 75 (54.7) | 41 (64.1) | 30 (50.0) | 2 (18.2) | ||
| Invasive | 62 (45.3) | 23 (35.9) | 30 (50.0) | 9 (81.8) | ||
| Site | ||||||
| Prepuce/foreskin2 | 20 (14.6) | 2 (3.1) | 15 (25.0) | 2 (18.2) | 9 (12.0) | 11 (17.7) |
| Glans3 | 47 (34.3) | 17 (26.6) | 23 (38.3) | 7 (63.6) | 25 (33.3) | 22 (35.5) |
| Corpus | 22 (16.1) | 19 (29.7) | 2 (3.3) | 1 (9.1) | 13 (17.3) | 9 (14.5) |
| Penis, not specicied | 48 (35.0) | 26 (40.6) | 20 (33.3) | 1 (9.1) | 28 (37.3) | 20 (32.3) |
| HPV DNA | ||||||
| Tested | 94 | 44 | 42 | 7 | 51 | 43 |
| Negative | 19 (20.2) | 6 (13.6) | 12 (28.6) | 1 (14.3) | 6 (11.8) | 13 (30.2) |
| Positive | 75 (79.8) | 38 (86.4) | 30 (71.4) | 6 (85.7) | 45 (88.2) | 30 (69.8) |
| HPV 16+ only | 56 (59.6) | 29 (65.9) | 21 (50.0) | 5 (71.4) | 35 (68.6) | 21 (48.8) |
| HPV 16/other+4 | 9 (9.6) | 4 (9.1) | 4 (9.5) | 1 (14.3) | 5 (9.8) | 4 (9.3) |
| HPV31/33/35+ | 4 (4.3) | 3 (6.8) | 1 (2.4) | 0 (0.0) | 2 (3.9) | 2 (4.7) |
| HPV6+ | 3 (3.2) | 0 (0.0) | 3 (7.1) | 0 (0.0) | 1 (2.0) | 2 (4.7) |
| Unknown type | 3 (3.2) | 2 (4.5) | 1 (2.4) | 0 (0.0) | 2 (3.9) | 1 (2.3) |
- 1 Circumcision prior to age 10 is considered in childhood.
- 2 Two men reported circumcision at birth but had a site of “foreskin” and had circumcision as part of their treatment.
- 3 Also includes corona and meatus.
- 4 Other HPV types among these 9 cases: 6, 18, 31, 33 (n = 2), 45, 53, 73‐IS223 and an unknown type.
Of the 94 (68.6%) tumor specimens tested for HPV DNA, 75 (79.8%) were HPV DNA‐positive (Table IV), with the most common genotype being HPV16 (86.7% of HPV‐positive tumors). All patients had a similar prevalence of HPV DNA in their tumors regardless of circumcision status. The prevalence of HPV DNA was lower for invasive cancers (69.8%) than for in situ cancers (88.2%, age‐adjusted p = 0.03). Of the 4 non‐squamous cell cancers, the melanoma was HPV16‐positive and the other 3 tumors were β‐globin‐negative.
We evaluated the various risk factors for penile cancer according to the extent of disease (Table V). Mean age at diagnosis of men with in situ disease was 56.4 years and did not differ from that of men with invasive disease, 58.1 years; likewise, median age at diagnosis was 60 for men with in situ disease and 59 for men with invasive disease. Interestingly, the risk of invasive, but not in situ, penile cancer was elevated among cases not circumcised in early childhood (OR = 2.3, 95% CI 1.3–4.1, p for equality of coefficients in a polytomous model = 0.05). A history of phimosis was also a stronger risk factor for invasive (OR = 11.4, 95% CI 5.0–25.9) than for in situ tumors (OR = 3.8, 95% CI 1.4–10.1, p for equality of coefficients in a polytomous model = 0.04). When we restricted our analysis to subjects with no history of phimosis, the risk of invasive penile cancer associated with not having been circumcised in childhood was no longer elevated (OR = 0.5, 95% CI 0.1–1.7; data not shown). Finally, current smoking was associated with an increased risk for invasive (OR = 4.5, 95% CI 2.0–10.1), but not in situ, (OR = 1.5, 95% CI 0.7–2.9, p for equality of coefficients in a disease polytomous model = 0.03). No other risk factor studied varied substantially by extent of disease.
| Characteristic | Controls (n = 671) n (%) | In situ cases (n = 75) | Invasive cases (n = 62) | ||
|---|---|---|---|---|---|
| n (%) | OR1 (95% CI) | n (%) | OR1 (95% CI) | ||
| Age at reference date (years) | |||||
| <50 | 205 (30.5) | 21 (28.0) | 15 (24.2) | ||
| 50–64 | 291 (43.4) | 25 (33.3) | 27 (43.5) | ||
| 65+ | 175 (26.1) | 29 (38.7) | 20 (32.3) | ||
| Smoking | |||||
| Never | 224 (33.4) | 19 (25.3) | ref | 9 (14.5) | ref |
| Former | 301 (44.9) | 36 (48.0) | 1.3 (0.7–2.4) | 25 (40.3) | 1.8 (0.8–3.9) |
| Current | 146 (21.8) | 20 (26.7) | 1.5 (0.7–2.9) | 28 (45.2) | 4.5 (2.0–10.1)* |
| Circumcised in childhood2 | |||||
| Yes | 392 (58.5) | 41 (56.2) | ref | 23 (37.1) | ref |
| No | 278 (41.5) | 32 (43.8) | 1.1 (0.6–1.8) | 39 (62.9) | 2.3 (1.3–4.1) |
| Never | 247 (36.9) | 30 (41.1) | 1.1 (0.7–2.0) | 30 (48.4) | 1.9 (1.0–3.6) |
| Later | 31 (4.6) | 2 (2.7) | 0.6 (0.1–2.6) | 9 (14.5) | 5.2 (2.1–12.9)* |
| Missing | 1 | 2 | 0 | ||
| Genital warts | |||||
| No | 638 (95.2) | 52 (69.3) | ref | 49 (80.3) | ref |
| Yes | 32 (4.8) | 23 (30.7) | 9.8 (5.1–18.7) | 12 (19.7) | 5.4 (2.5–11.9) |
| Missing | 1 | 0 | 1 | ||
| HSV‐2 serology3 | |||||
| Negative | 488 (85.3) | 45 (64.3) | ref | 32 (60.4) | ref |
| Positive | 84 (14.7) | 25 (35.7) | 2.9 (1.6–5.1) | 21 (39.6) | 3.4 (1.8–6.6) |
| Not tested | 99 | 5 | 9 | ||
| HPV16 serology | |||||
| Negative | 509 (87.5) | 55 (79.7) | ref | 37 (71.1) | ref |
| Positive | 73 (12.5) | 14 (20.3) | 1.7 (0.9–3.2) | 15 (28.9) | 2.3 (1.2–4.6) |
| Not tested | 89 | 6 | 10 | ||
| Gonorrhea | |||||
| Never | 612 (91.2) | 62 (83.8) | ref | 52 (85.3) | ref |
| Ever | 59 (8.8) | 12 (16.2) | 1.7 (0.8–3.6) | 9 (14.7) | 1.4 (0.6–3.2) |
| Missing | 0 | 1 | 1 | ||
| Nongonococcal urethritis | |||||
| Never | 624 (93.7) | 66 (88.0) | ref | 56 (90.3) | ref |
| Ever | 42 (6.3) | 9 (12.0) | 1.8 (0.8–3.9) | 6 (9.7) | 1.3 (0.5–3.5) |
| Missing | 5 | 0 | 0 | ||
| Urinary tract infection | |||||
| Never | 554 (82.9) | 55 (73.3) | ref | 50 (80.7) | ref |
| Ever | 114 (17.1) | 20 (26.7) | 1.9 (1.1–3.3) | 12 (19.3) | 1.4 (0.7–2.9) |
| Missing | 3 | 0 | 0 | ||
| Phimosis4 | |||||
| No | 254 (92.4) | 26 (78.8) | ref | 20 (52.6) | ref |
| Yes | 21 (7.6) | 7 (21.2) | 3.8 (1.4–10.1) | 18 (47.4) | 11.4 (5.0–25.9)* |
| Missing | 4 | 1 | 1 | ||
| Smegma4 | |||||
| Never/rarely | 264 (95.7) | 30 (93.7) | ref | 34 (89.5) | ref |
| Sometimes/usually | 12 (4.3) | 2 (6.3) | 1.4 (0.3–6.9) | 4 (10.5) | 2.4 (0.7–8.0) |
| Missing | 4 | 2 | 1 | ||
| Penile tear | |||||
| No | 624 (93.1) | 58 (77.3) | ref | 44 (71.0) | ref |
| Yes | 46 (6.9) | 17 (22.7) | 4.2 (2.2–8.0) | 18 (29.0) | 7.1 (3.6–14.0) |
| Missing | 1 | 0 | 0 | ||
| Penile rash | |||||
| No | 658 (98.2) | 59 (78.7) | ref | 48 (77.4) | ref |
| Yes | 12 (1.8) | 16 (21.3) | 13.3 (5.9–29.9) | 14 (22.6) | 14.0 (6.0–32.7) |
| Missing | 1 | 0 | 0 | ||
| Penile injury | |||||
| No | 650 (97.0) | 67 (89.3) | ref | 57 (91.9) | ref |
| Yes | 20 (3.0) | 8 (10.7) | 3.7 (1.6–8.9) | 5 (8.1) | 2.7 (0.9–7.6) |
| Missing | 1 | 0 | 0 | ||
| Penile inflammation | |||||
| No | 656 (98.1) | 69 (93.2) | ref | 57 (91.9) | ref |
| Yes | 13 (1.9) | 5 (6.8) | 3.5 (1.2–10.3) | 5 (8.1) | 3.9 (1.3–11.7) |
| Missing | 2 | 1 | 0 | ||
| Urethral stricture | |||||
| No | 629 (94.3) | 66 (89.2) | ref | 54 (88.5) | ref |
| Yes | 38 (5.7) | 8 (10.8) | 1.9 (0.8–4.4) | 7 (11.5) | 2.1 (0.8–5.0) |
| Missing | 4 | 1 | 1 | ||
- 1 Polytomous logistic regression used to obtain ORs adjusted for age (linear), smoking and number of partners.
- 2 Circumcision prior to age 10 is considered “in childhood”.
- 3 OR also adjusted for HPV16 serology.
- 4 Among those not circumcised in childhood.
- * p for difference between risk of in situ and invasive penile cancer < 0.05.
Although the number of HPV DNA‐negative cases (n = 19) in our study was small, prohibiting definitive conclusions, we attempted to assess whether HPV‐negative penile cancers represent an alternative pathway to disease by evaluating the various risk factors by the HPV status of the tumor (Table VI). Subjects with HPV DNA‐negative tumors were less likely to have antibodies to HPV16 (5.9%) than subjects with HPV DNA‐positive tumors (29.4%, χ2 p for difference = 0.04). Subjects with HPV DNA‐negative tumors were only slightly more likely to have had phimosis (46.1%) than subjects with HPV‐positive tumors (29.7%, p = 0.28). Urethral stricture was more common among subjects with HPV DNA‐negative tumors (21.1%) than subjects with HPV DNA‐positive tumors (6.8%, p = 0.06).
| Characteristic | Controls (n=671) n (%) | HPV+ cases (n=75) | HPV−cases (n=19) | HPV+ cases | p‐value2 | ||
|---|---|---|---|---|---|---|---|
| n (%) | OR1 (95% CI) | n (%) | OR1 (95% CI) | ||||
| Age at reference (years) | 0.38 | ||||||
| <50 | 205 (30.5) | 23 (30.7) | 3 (15.8) | 88.5% | |||
| 50–64 | 291 (43.4) | 23 (30.7) | 6 (31.6) | 79.3% | |||
| 65+ | 175 (26.1) | 29 (38.7) | 10 (52.6) | 74.4% | |||
| Smoking | 0.97 | ||||||
| Never | 224 (33.4) | 14 (18.7) | ref | 4 (21.1) | ref | 77.8% | |
| Former | 301 (44.9) | 36 (48.0) | 1.9 (0.9–3.6) | 9 (47.4) | 1.4 (0.4–4.6) | 80.0% | |
| Current | 146 (21.8) | 25 (33.3) | 2.6 (1.3–5.4) | 6 (31.6) | 2.8 (0.7–10.8) | 80.7% | |
| Circumcised in childhood3 | 0.21 | ||||||
| Yes | 392 (58.5) | 38 (51.4) | ref | 6 (31.6) | ref | 86.4% | |
| No | 278 (41.5) | 36 (48.6) | 1.3 (0.8–2.2) | 13 (68.4) | 2.0 (0.7–5.8) | 73.5% | |
| Never | 247 (36.9) | 30 (40.5) | 1.2 (0.7–2.2) | 12 (63.2) | 2.1 (0.7–5.9) | 71.4% | |
| Later | 31 (4.6) | 6 (8.1) | 1.9 (0.7–5.0) | 1 (5.3) | 1.8 (0.2–15.8) | 85.7% | |
| Missing | 1 | 1 | 0 | ||||
| Genital warts | 0.60 | ||||||
| No | 638 (95.2) | 54 (73.0) | ref | 15 (78.9) | ref | 78.3% | |
| Yes | 32 (4.8) | 20 (27.0) | 8.6 (4.3–17.0) | 4 (21.1) | 10.1 (2.8–36.4) | 83.3% | |
| Missing | 1 | 1 | 0 | ||||
| Herpes serology4 | 0.32 | ||||||
| Negative | 488 (85.3) | 41 (59.4) | ref | 13 (72.2) | ref | 75.9% | |
| Positive | 84 (14.7) | 28 (40.6) | 3.6 (2.0–6.4) | 5 (27.8) | 2.8 (0.9–8.6) | 84.8% | |
| Not tested | 99 | 6 | 1 | ||||
| HPV16 serology | 0.04 | ||||||
| Negative | 509 (87.5) | 48 (70.6) | ref | 16 (94.1) | ref | 75.0% | |
| Positive | 73 (12.5) | 20 (29.4) | 2.6 (1.4–4.7) | 1 (5.9) | 0.4 (0.1–3.3) | 95.2% | |
| Not tested | 89 | 7 | 1 | ||||
| Gonorrhea | 0.23 | ||||||
| Never | 612 (91.2) | 63 (84.0) | ref | 18 (94.7) | ref | 77.8% | |
| Ever | 59 (8.8) | 12 (16.0) | 1.8 (0.9–3.7) | 1 (5.3) | 0.6 (0.1–4.6) | 92.3% | |
| Missing | 0 | 0 | 0 | ||||
| Nongonococcal urethritis | 0.42 | ||||||
| Never | 624 (93.7) | 68 (90.7) | ref | 16 (84.2) | ref | 81.0% | |
| Ever | 42 (6.3) | 7 (9.3) | 1.4 (0.6–3.3) | 3 (15.8) | 3.8 (0.9–15.3) | 70.0% | |
| Missing | 5 | 0 | 0 | ||||
| Urinary tract infection | 0.21 | ||||||
| Never | 554 (82.9) | 58 (77.3) | ref | 12 (63.2) | ref | 82.9% | |
| Ever | 114 (17.1) | 17 (22.7) | 1.6 (0.9–2.9) | 7 (36.8) | 3.7 (1.3–10.4) | 70.8% | |
| Missing | 3 | 0 | 0 | ||||
| Phimosis5 | 0.23 | ||||||
| No | 254 (92.4) | 26 (70.3) | ref | 7 (53.9) | ref | 78.8% | |
| Yes | 21 (7.6) | 11 (29.7) | 5.5 (2.3–13.5) | 6 (46.1) | 13.5 (3.7–49.2) | 64.7% | |
| Missing | 4 | 0 | 0 | ||||
| Smegma5 | 0.75 | ||||||
| Never/rarely | 264 (95.7) | 34 (94.4) | ref | 12 (92.3) | ref | 73.9% | |
| Sometimes/usually | 12 (4.3) | 2 (5.6) | 1.3 (0.3–6.4) | 1 (7.7) | 1.4 (0.2–12.1) | 66.7% | |
| Missing | 4 | 0 | 0 | ||||
| Penile tear | 0.83 | ||||||
| No | 624 (93.1) | 57 (76.0) | ref | 14 (73.7) | ref | 80.3% | |
| Yes | 46 (6.9) | 18 (24.0) | 4.5 (2.4–8.5) | 5 (26.3) | 8.2 (2.6–26.0) | 78.3% | |
| Missing | 1 | 0 | 0 | ||||
| Penile rash | 0.44 | ||||||
| No | 658 (98.2) | 57 (76.0) | ref | 16 (84.2) | ref | 78.1% | |
| Yes | 12 (1.8) | 18 (24.0) | 15.6 (7.0–34.6) | 3 (15.8) | 10.3 (2.5–41.7) | 85.7% | |
| Missing | 1 | 0 | 0 | ||||
| Penile injury | 0.88 | ||||||
| No | 650 (97.0) | 68 (90.7) | ref | 17 (89.5) | ref | 80.0% | |
| Yes | 20 (3.0) | 7 (9.3) | 3.3 (1.3–8.2) | 2 (10.5) | 3.8 (0.8–18.4) | 77.8% | |
| Missing | 1 | 0 | 0 | ||||
| Penile inflammation | 0.24 | ||||||
| No | 656 (98.1) | 69 (93.2) | ref | 19 (100.0) | — | 78.4% | |
| Yes | 13 (1.9) | 5 (6.8) | 3.5 (1.2–10.4) | 0 (0.0) | — | 100.0% | |
| Missing | 2 | 1 | 0 | ||||
| Urethral stricture | 0.06 | ||||||
| No | 629 (94.3) | 69 (93.2) | ref | 15 (78.9) | ref | 82.1% | |
| Yes | 38 (5.7) | 5 (6.8) | 1.2 (0.4–3.1) | 4 (21.1) | 3.2 (1.0–10.7) | 55.6% | |
| Missing | 4 | 1 | 0 | ||||
- 1 Polytomous logistic regression used to obtain ORs adjusted for age (linear), smoking and number of partners.
- 2 Statistical significance as measured by a χ2 test of the difference in the proportion of HPV DNA positivity across the primary strata of each variable.
- 3 Circumcision prior to age 10 is considered “in childhood”.
- 4 OR also adjusted for HPV16 serology.
- 5 Among those not circumcised in childhood.
Discussion
In this study, we observed an increased risk for invasive (OR = 2.3), but not in situ, penile cancer (OR = 1.1) among men not circumcised in childhood, consistent with the findings of Tseng et al.5 Here and in other studies,2, 5, 12, 13 a history of phimosis was a strong risk factor for penile cancer. Interestingly, though it was a risk factor for both invasive and in situ disease, the proportions of subjects with invasive and in situ penile cancer who reported a history of phimosis (47% and 21%, respectively) were different (χ2 p for difference = 0.02). It is likely that much of the increased risk for invasive penile cancer observed in men not circumcised in childhood (OR = 2.3) can be attributed to the increased risk associated with phimosis in this group (OR = 11.4). Indeed, when we restricted our analysis to subjects with no history of phimosis, the risk of invasive penile cancer associated with not having been circumcised in childhood was no longer elevated (OR = 0.5). These findings suggest that childhood circumcision reduces penile cancer risk by eliminating the possibility of phimosis, a strong risk factor for invasive penile cancer. In adult men, phimosis may lead to repeated episodes of inflammation of the glans or foreskin that may predispose to cancer.
We posit that men who have never been circumcised may be at higher risk of HPV acquisition and persistence even though they appear to have engaged in lower‐risk sexual activity than men who are circumcised in childhood. As shown in Table III, having a greater number of sex partners confers increased risk of penile cancer only among those circumcised in childhood, and there is no increased risk with number of partners for men who were never circumcised. The lack of risk by number of partners in never‐circumcised men may be indicative of a non‐HPV route to penile cancer or that certain conditions, such as phimosis, increase the risk of HPV‐associated carcinogenesis. In the latter instance, trauma to the penis associated with phimosis may increase the access of HPV to the basal epithelium, thereby increasing the likelihood of HPV infection with fewer sexual partners; and inflammation may help sustain a persistent infection. Regardless of the role of number of partners, the proportion of HPV‐positive tumors observed among individuals circumcised in childhood was similar to that among those who were not circumcised (86.4% and 73.5%, respectively; p = 0.21), which suggests that HPV may be the central agent in a majority of penile tumors.
In addition to circumcision status and a history of phimosis, current smoking was a risk factor identified in our study that distinguished invasive from in situ penile cancer cases. Men diagnosed with invasive penile cancer were more likely to be smokers at the reference date than men diagnosed with in situ cancer (OR = 4.5 and 1.5, respectively; Table V). Our results are in contrast to those of Tseng et al.,5 who found risks of similar magnitude (>2‐fold) associated with being a current smoker at reference for both in situ and invasive cancers. The strong relationship of smoking to risk of penile cancer is also consistent with the data of Hellberg et al.13 and our studies of other HPV‐related anogenital cancers14 but in contrast to the case‐control data of Brinton et al.12 conducted in China. Other than this difference in risk for in situ and invasive disease, current smoking was consistently associated with penile cancer risk independent of sexual orientation, number of lifetime sexual partners, history of genital warts and HPV positivity as determined by either HPV DNA in the tumor or HPV16 serology. Although an association with smoking has been repeatedly observed in HPV‐related anogenital cancers (including in situ disease), the precise role that smoking plays in the etiology of these tumors remains undefined. Because smoking was most important in cases who were current smokers at diagnosis, it appears likely that smoking is most important in the later stages of disease progression.
The proportion of cases and controls reporting a history of genital warts was somewhat higher among subjects circumcised in childhood than among those who were not. This finding is consistent with that of Cook et al.,15 who found that circumcised men were more likely than uncircumcised men to have penile warts. Castellsague et al.16 reported that male circumcision was associated with reduced risk of penile HPV infection. In that study, current HPV infection was measured, whereas we measured past HPV exposure by HPV antibodies and genital warts in cases and controls and by HPV DNA in the tumors of cases.
In the present study, we found in situ tumors to be more likely than invasive tumors to be positive for any type of HPV DNA (88.2% vs. 69.8%, age‐adjusted p = 0.03); however, the proportion positive did not vary according to the other risk factors for penile cancer, possibly due to the limited number of HPV‐negative cases (n = 19). We would expect to observe a difference in the ages of subjects with in situ compared to invasive diagnoses, those with invasive disease being older at diagnosis. However, we did not see any age difference between subjects diagnosed with in situ and invasive penile disease (mean in situ = 56.4 years, mean invasive = 58.1 years, p = 0.4). This may support the theory that in situ and invasive penile carcinoma do not represent a continuum of disease4 and in situ penile cancer may actually represent multiple conditions with varying potential to progress to invasive disease.17
We collected and tested tumor tissues for the presence of high‐risk HPV DNA. In addition to extent of disease, we correlated the HPV DNA results with a variety of demographic, medical and behavioral risk factors. We found that 79.8% of the penile tumors contained HPV DNA, a higher proportion than the 10–74% reported in most recent series of penile cancers that were tested by PCR;18, 19, 20, 21 however, nearly 80% HPV positivity is close to the figure observed among the 618 other anogenital tumors (cervical, vulvar, vaginal and anal sites) tested in our previous studies.3 Our findings suggest that penile cancer shares a similar etiology with other anogenital cancers in which high‐risk HPV infection is thought to play a necessary but not sufficient role in the majority of tumors.
A number of penile conditions were related to risk of penile cancer. As has been found in previous case‐control studies of penile cancer,2, 5, 12, 13 a history of phimosis represented one of the strongest risk factors for penile cancer, with a 7‐fold increase in risk (OR = 7.4, 95 % CI 3.7–15.0). A history of penile tear, which we found to be related to phimosis in controls (χ2 p for difference < 0.001), was associated with a >5‐fold risk of penile cancer. In accordance with prior studies,2, 5 both penile inflammation (OR = 3.5) and previous injury to the penis (OR = 3.2) were associated with increased risk of cancer. In contrast to the findings of Tseng et al.,5 we found penile rash to be strongly related to cancer risk (OR = 14.9, 95% CI 7.2–30.8). Finally, a history of urethral stricture was reported by 11.1% of cases and 5.7% of controls (OR = 2.0, 95% CI 1.1–3.9). No previous studies have reported an association between urethral stricture and penile cancer; however, an earlier report from our group2 found a modest relationship between the 2 conditions that was within the limits of chance. It is possible that many penile conditions increase the risk for cancer via a similar mechanism, such as inflammation, as previously discussed with respect to phimosis. Perhaps inflammation represents a critical component of tumor development or progression since many cancers arise from sites of infection, chronic irritation or injury.22
Our study confirms the finding, observed in previous epidemiologic studies and in the clinic, that lack of circumcision in childhood represents a risk factor for the development of penile cancer.2, 5, 12 We found that men who were not circumcised in early childhood had a 1.5‐fold increase in the risk of penile cancer (95% CI 1.0–2.2, p = 0.07). However, the risk for penile cancer associated with circumcision later in life was increased 2‐fold (OR = 2.1, 95% CI 1.0–4.4). There was also an increased risk of invasive penile cancer associated with not being circumcised in childhood (OR = 2.3, 95% CI 1.3–4.1). This risk was further elevated among men who were circumcised later in life but more than 5 years prior to diagnosis or reference (OR = 5.2, 95% CI 2.1–12.9).
Our study confirms the reported association between a history of genital warts and the development of penile cancer,2, 5 with 25.7% of cases reporting a history of genital warts compared to only 4.8% of controls. When we stratified our data by extent of disease, we noted that a history of genital warts was more common among individuals diagnosed with in situ penile cancer (30.7%) than among those diagnosed with invasive cancer (19.7%). It is possible that some of the cases listed as in situ in the cancer registry represented misdiagnosed penile intraepithelial neoplasia (PIN)1 or PIN2 lesions; unfortunately, we were not able to do an independent pathology review. However, subjects with in situ diagnoses and a history of genital warts were as likely to harbor high‐risk HPV types in tumor tissue as were in situ diagnoses without a history of genital warts (χ2 p for difference = 0.96). Lastly, a history of one or more urinary tract infections was associated with an increased risk of penile cancer (OR = 1.7, 95% CI 1.1–2.7), in agreement with the findings of Tseng et al.5
The presence of antibodies to HSV‐2 was related to the development of penile cancer, even after adjustment for the presence of antibodies to HPV16. The etiologic significance of this finding is unclear; however, some of the observed increased risk in penile cancer risk might be attributed to residual confounding due to sexual factors leading to exposure to both HSV‐2 and HPV16. No previous case‐control study of penile cancer has included HSV‐2 serologic testing; the single study that tested tumor tissue for the presence of HSV‐2 DNA did not detect the virus in any penile tumors.23
Our ability to accurately assess factors and characteristics important in the etiology of penile cancer is strengthened by several aspects of our study. The population‐based design, in which all cases in a geographic area are ascertained and controls are drawn from the underlying population, increases the likelihood that controls are representative of the population giving rise to the cases and therefore the generalizability of our results. Our ability to test the tumor tissues for HPV DNA and to test sera for HPV16 and HSV‐2 antibodies allowed us to further explore the important role of high‐risk HPV and to identify the potential role of past exposure to HSV‐2 in the development of penile cancer.
In interpreting our results, it is important to consider several potential limitations of the study. We interviewed only 55.0% of the men with penile cancer in the cancer registry and 66.4% of the eligible controls. If participants differed from nonparticipants in a systematic fashion our results might be biased, though it is difficult to assess the direction of such potential bias. The possibility of bias is especially important in this study due to the sensitive nature of the disease and the questions asked. Additionally, the relatively low response rate affected our sample size, limiting our ability to precisely determine the risks associated with some exposures.
Although we tested a high percentage of tumor specimens from the cases, our study had limited power to evaluate exposures that might represent pathways to disease independent of HPV infection. HPV DNA was present in a large proportion of cases (79.8%), which left only 19 cases whose tumors tested negative for HPV DNA. Furthermore, HPV DNA results could possibly be impacted by some false‐negative or false‐positive results due to technical issues with the test sensitivity, specificity, tissue sampling or tissue handling. Such issues may have led to an underestimate or overestimate of the prevalence of HPV exposure and limited our ability to determine whether other risk factors might represent important alternative pathways to disease or if non HPV pathways exist.
Finally, circumcision status was ascertained at interview but not verified by medical examination of the penis. However, Castellsague et al.16 assessed the reliability of self‐reported circumcision status by medical examination and found that 95% of those examined had reported their status accurately. We were also not able to do a medical chart review to determine the circumstances leading to circumcision later in life, though we did collect self‐reported data regarding the reason for circumcision.
In summary, the high percentage of HPV DNA‐positive tumors in this study is consistent with an association between HPV infection and the development of most penile cancers. The role of circumcision in penile cancer prevention is unclear: it could possibly be ascribed to a lower baseline risk of disease due to a decrease in the amount of susceptible tissue, prevention of potential cofactors with HPV (such as phimosis) from promoting disease or another mechanism. Many demographic, behavioral and biologic characteristics, including HPV infection, were common in both in situ and invasive forms of the disease. However, 3 risk factors were more important in the development of invasive than in situ penile cancer: lack of circumcision in childhood, a history of phimosis and cigarette smoking. These observations raise questions about whether all in situ cancers have the potential to progress to invasive disease. They also bring into question why so many penile cancers are invasive at diagnosis and suggest that early detection efforts among men with certain risk factors identified in this report (lack of circumcision during childhood, phimosis, current smoking, genital warts and certain penile conditions) might lead to improved clinical outcomes.
Acknowledgements
This research was supported by PO1 CA 42792 from the National Cancer Institute. Support was also received for the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by contracts NO1‐CN‐05230 and NO1‐PC‐67009 from the Surveillance, Epidemiology and End Results Program of the National Cancer Institute, with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington Department of Health.
Notes :
- 1 Fax: +206‐667‐5948
- 1 Adjusted for age (linear), cigarette smoking and number of sex partners.
- 2 Among men circumcised after age 9; men circumcised in the 5 years prior to diagnosis are subsequently included in the “never circumcised” category.
- 3 Circumcision prior to age 10 is considered “in childhood”.
- 1 Adjusted for age (linear), cigarette smoking status and lifetime number of sex partners.
- 2 OR also adjusted for HPV16 serology.
- 3 Among those who were not circumcised in childhood (prior to age 10).
- 1 Circumcision prior to age 10 is considered “in childhood”, and circumcision in the 5 years prior to reference is considered “never circumcised” 2 cases have known circumcision status.
- 2 Adjusted for age (linear), cigarette smoking status and lifetime number of sexual partners.
- 3 OR also adjusted for HPV16 serology.
- 4 Among those not circumcised in childhood.
- 1 Circumcision prior to age 10 is considered in childhood.
- 2 Two men reported circumcision at birth but had a site of “foreskin” and had circumcision as part of their treatment.
- 3 Also includes corona and meatus.
- 4 Other HPV types among these 9 cases: 6, 18, 31, 33 (n = 2), 45, 53, 73‐IS223 and an unknown type.
- 1 Polytomous logistic regression used to obtain ORs adjusted for age (linear), smoking and number of partners.
- 2 Circumcision prior to age 10 is considered “in childhood”.
- 3 OR also adjusted for HPV16 serology.
- 4 Among those not circumcised in childhood.
- * p for difference between risk of in situ and invasive penile cancer < 0.05.
- 1 Polytomous logistic regression used to obtain ORs adjusted for age (linear), smoking and number of partners.
- 2 Statistical significance as measured by a χ2 test of the difference in the proportion of HPV DNA positivity across the primary strata of each variable.
- 3 Circumcision prior to age 10 is considered “in childhood”.
- 4 OR also adjusted for HPV16 serology.
- 5 Among those not circumcised in childhood.
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