Original Article
Genital Tumors among Men with Psoriasis Exposed to Psoralens and Ultraviolet A Radiation (PUVA) and Ultraviolet B Radiation
N Engl J Med 1990; 322:1093-1097April 19, 1990
- Abstract
- Abstract
Squamous-cell cancer occurs only rarely on the male genitalia. In a 12.3-year prospective study of 892 men in a cohort of patients with psoriasis who had been treated with oral methoxsalen (8-methoxypsoralen) and ultraviolet A photochemotherapy (PUVA), we identified 14 patients (1.6 percent) with 30 genital neoplasms.
The standard morbidity ratio (which was used as a measure of the risk of a genital neoplasm) comparing morbidity among patients treated with PUVA with that expected on the basis of population incidence data was 95.7 (95 percent confidence interval, 43.8 to 181.8) for invasive squamous-cell carcinoma of the penis and scrotum, and 58.8 (26.9 to 111.7) for invasive and in situ penile tumors. In patients exposed to high levels of PUVA, the incidence of invasive squamous-cell carcinoma was 286 times that in the general population and 16.3 times that in patients exposed to low levels (P<0.001 for both comparisons). After controlling for the level of exposure to PUVA, we found that patients exposed to high levels of ultraviolet B radiation had a risk of genital tumors 4.6 times higher than that in other patients (95 percent confidence interval, 1.4 to 15.1).
The strongly dose-dependent increase in the risk of genital tumors associated with exposure to PUVA and ultraviolet B radiation that we observed makes it prudent for men to use genital protection whenever they are exposed to PUVA or other forms of ultraviolet radiation for therapeutic, recreational, or cosmetic reasons. (N Engl J Med 1990; 322:1093–7.)
Media in This Article
Table 1
Classification of PUVA DoseTable 2
Levels of Exposure in 14 Patients in Whom Genital Tumors Developed.*Article Activity
- Article
IN the first clearly traced link between exposure to a carcinogen (tar pitch) and the development of cancer, Percival Pott in 1775 described the occurrence of squamous-cell cancer of the scrotum in chimney sweeps.1 Although these cancers of the male genitalia occur infrequently, their treatment may involve substantial morbidity. A case of fatal metastatic carcinoma of the penis in a 37-year-old man whose treatment for psoriasis included prolonged exposure to oral methoxsalen and ultraviolet A radiation (PUVA) prompted us to review the occurrence of genital tumors in our prospective cohort study of patients treated with PUVA (Henshaw CL Jr.: personal communication). Patients with psoriasis treated with PUVA have a dose-dependent increase in the risk of squamous-cell carcinoma on all parts of the body exposed to ultraviolet radiation during therapy.2 3 4 Because patients stand during therapy, male genitalia are exposed to this radiation, but female genitalia are not. In analyzing the study data, we found an even higher risk of squamous-cell carcinoma of the male genitalia.
Methods
The PUVA follow-up study has evaluated prospectively 1380 patients, including 892 men (97 percent white), who first began treatment with PUVA for psoriasis at 16 university centers in 1975 and 1976. Irrespective of their continued use of PUVA therapy, the patients are interviewed annually and examined periodically. The study methods have been described elsewhere.2 3 4
In this report we discuss 14 men in whom squamous-cell carcinoma, squamous-cell carcinoma in situ, or keratoacanthoma developed on the genitalia (penis or scrotum) before May 1, 1989. All final diagnoses were based on the examination of tissue specimens by pathologists or dermatopathologists who were unaware of the patients' levels of exposure to PUVA. To assess the magnitude of the problem, we used two methods. First, using traditional methods of prospective cohort studies, we compared the incidence of genital tumors in this cohort and in subgroups defined by the extent of their exposure to PUVA with the expected incidence in the general population. To control for confounding, we also performed a nested, matched, case–control analysis.5 For each case patient with a genital tumor, we selected four male patients from the same university center who were within five years of the case patient's age and whose dates of enrollment in the study were closest to that of the case patient. This matched analysis helped to control for confounding due to factors such as age, race and ethnicity, circumcision, and variations between centers in genital-shielding practices that influence susceptibility to these tumors, as well as to the patterns of use of PUVA and other therapies before PUVA, which also varied among treatment centers.
Statistical Analysis
In our cohort analysis, we calculated the expected number of genital tumors on the basis of the age-specific incidence rates from three population-based cancer registries. For invasive squamous-cell carcinomas in all exposed genital sites (i.e., penis and scrotum), we used age-specific incidence rates for white men from a federal study of nonmelanoma skin cancer in eight geographic areas6 (and Scotto J, National Cancer Institute: unpublished data). For squamous-cell carcinomas and squamous-cell carcinomas in situ of the penis, we used data for white men from the Surveillance, Epidemiology and End Results (SEER) Study.7 To calculate the expected number of scrotal squamous-cell carcinomas, we used incidence data (race not specified) from the Connecticut Tumor Registry.8 We calculated these expected numbers for all men in the cohort and for subgroups stratified according to the level of exposure to PUVA. Using methods described previously, we then calculated the standard morbidity ratio for each dose-specific stratum and determined the standard morbidity ratio for patients exposed to high doses as compared with those exposed to lower doses.3 We calculated confidence intervals for the standard morbidity ratios assuming a Poisson distribution. For standard morbidity ratios comparing morbidity in the patients with expected morbidity in the general population, we calculated Fisher's exact confidence intervals. For standard morbidity ratios comparing levels of exposure to PUVA, we calculated approximate limits.9 Since we know of no population incidence data for squamous-cell carcinomas in situ of the scrotum, the disorder was excluded from these calculations.
In our matched analysis, we used exact conditional logistic regression to calculate the relative risks (and confidence intervals) of genital tumors with increasing exposure to PUVA.10 To determine the independent effects of exposure to ultraviolet B radiation, which in the univariate analysis was the only other exposure significantly related to the risk of tumors, we performed a matched analysis for exposure to ultraviolet B radiation, controlling for the level of exposure to PUVA.9
Exposure Classification
In the cohort analysis, we classified the level of exposure to PUVA of case and control patients according to the total number of treatments recorded at each of six follow-up examinations that occurred from an average of 2.0 to 10.2 years after the first treatment (Table 1Table 1
Classification of PUVA Dose). This dose classification of PUVA extends the system of classification we used in an earlier analysis of cancer of other sites that spanned the first 5.3 years of our study.3 As described elsewhere, a high level of exposure to tar was defined as the use of topical tar products for more than 90 months, and a high level of exposure to ultraviolet B radiation was classified as more than 300 ultraviolet B treatments.11 Since the time to development of tumors varied among the case patients, in the matched analysis we used the intensity of treatment (defined as the annual number of treatments before the development of a first genital tumor) as the primary measure of the level of exposure to PUVA. To calculate the intensity of exposure to PUVA in the matched controls, we determined the number of treatments per year each control had received during a period equal to that before the detection of the genital tumor in the corresponding case patient. Case and matched control patients with an average of fewer than 20 treatments per year were considered to have a low level of exposure, patients with 20 to 39 treatments per year a medium level, and patients with 40 or more treatments per year a high level. Approximately 50 percent of the controls had a low level, 35 percent a medium level, and 15 percent a high level of exposure to PUVA.
Results
Eight hundred ninety-two men enrolled in the PUVA follow-up study. Their average (±SD) age at enrollment was 46± 15 years, and 35±23 percent of their body area was covered with psoriasis. One hundred sixty (18 percent) have died. Follow-up in our cohort has averaged 12.3 years. We interviewed 632 of the surviving 732 men (86 percent) at least 11 years after their first treatment with PUVA. Physical examinations had been completed in 89 and 77 percent of the surviving patients at least 6 and 10 years, respectively, after the first treatment.
The clinical characteristics of the 14 patients among the original 892 (1.6 percent) in whom genital tumors developed are summarized in Table 2Table 2
Levels of Exposure in 14 Patients in Whom Genital Tumors Developed.*. In these patients a total of 30 genital tumors developed (Table 3Table 3
Number of Invasive and in Situ Squamous-Cell Carcinomas, According to Location.). The patients came from 9 of the 16 participating centers. In only one (Patient 1) has cancer metastasized to regional lymph nodes. Patient 2 (Table 2) has previously been reported on.12 Cohort Analysis
On the basis of our sources of incidence data, 892 men in the general white population with the age distribution of our cohort would be expected to have 0.094 invasive squamous-cell carcinoma of the scrotum and penis, 0.153 invasive and in situ penile tumor, and 0.038 invasive scrotal cancer. As compared with that in the general population of white men, the morbidity due to invasive squamous-cell carcinomas of the penis and scrotum in our cohort produced a standard morbidity ratio of 95.7 (95 percent confidence interval, 43.8 to 181.8). Similar increases were noted for penile tumors and invasive tumors of the scrotum (Table 4Table 4
Standard Morbidity Ratios for Genital Tumors in the PUVA Cohort, According to Type and Location.*). As detailed in Table 4, there was a marked dose-dependent increase in the standard morbidity ratio. Patients with high levels of exposure to PUVA were 16.3 times more likely than those with low levels to have an invasive squamous-cell cancer of the penis and scrotum (95 percent confidence interval, 9.4 to 26.4) and 7.1 times more likely to have penile neoplasms (95 percent confidence interval, 2.8 to 14.5). There were no cases of scrotal cancer within the group with a low level of exposure to PUVA, and patients who received a high dose had a risk of scrotal cancer 13 times that of all those who received low or medium doses combined (95 percent confidence interval, 24.1 to 48.3).Case–Control Analysis
To control for possible confounding factors that might affect the estimate of a dose-dependent increase in risk calculated from the relative incidence, we performed a matched case–control analysis. Table 5Table 5
Demographic and Clinical Characteristics of Case Patients and Matched Controls.* summarizes the characteristics at entry and the levels of exposure to PUVA in the period before a tumor developed (or an equivalent interval in the matched controls) of the 14 case patients with genital tumors and the 56 age-matched controls. At entry, the case and control patients had comparable clinical and demographic characteristics. Levels of exposure to PUVA and ultraviolet B radiation were significantly higher in the case patients than the matched controls, but the use of tar products did not vary significantly between the groups (Table 5).Because no case patients with low levels of exposure were matched to controls with medium or high levels, the point estimates for the relative risk of genital tumors associated with medium and high doses as compared with low doses of PUVA could not be calculated. On the basis of exact conditional logistic regression, the lower bound of the 95 percent confidence interval for the relative risk associated with medium as compared with low doses of PUVA was 2.3, and the corresponding figure for high as compared with low doses was 18.5. In the matched analyses, after control for the level of exposure to PUVA, the relative risk associated with high as compared with low doses of ultraviolet B therapy was 4.6 (95 percent confidence interval, 1.4 to 15.1).
Discussion
Our data demonstrate that men with prolonged exposure to PUVA have a greatly increased risk of penile and scrotal tumors as compared with the general population. The increase in risk is substantially higher for the genitalia than for other sites exposed to PUVA.2 3 4 For example, in a population-based study of men, the ratio of squamous-cell carcinoma of the face, head, or neck to squamous-cell carcinoma of the genitalia was 83 to l.6 In our patients, this ratio was 3 to 1. At each level of exposure to PUVA, the increase in the risk of squamous-cell carcinoma of the genitalia was about 5 to 15 times higher than the significant dose-related increase in the risk of squamous-cell carcinoma we have documented in other areas of the body exposed to PUVA.3 , 4 The risk increases significantly with increased exposure to PUVA and ultraviolet B radiation. The risk of invasive squamous-cell carcinoma of the genitalia among men exposed to high-intensity PUVA is nearly 300 times that in the general white population. After 12 years, the cumulative risk of a genital tumor in men is 1.6 percent, and it rises to 6 percent in men exposed to high doses of PUVA. Invasive and in situ tumors of the vulva are more common than penile tumors in the general population,7 yet only one squamous-cell carcinoma in situ of the vulva has been detected among the 488 women in our cohort. This is probably because, unless shielded, male genitalia are exposed to substantial doses of ultraviolet radiation during treatment, whereas female genitalia are not.
The three sources of population incidence data we used to calculate expected numbers of tumors provide consistent estimates of risk.6 7 8 Surveillance and case ascertainment are likely to be more complete in our cohort than in population-based studies. This fact would tend to bias our estimates of risk relative to the population upward, but it is likely that it accounts for only a small fraction of the increase in risk we detected, and it would not alter the strong dose-dependent increase in risk we noted.
Uncircumcised men are believed to have a higher risk of penile tumors.13 Although we lack data on circumcision in our group, circumcision is probably more common in our urban and largely middle-class cohort than in the general population. Circumcision rates vary with age, region, and social class, but our matched analysis should have helped to control for confounding due to this factor. The SEER study counted multiple independent primary tumors in a single patient as separate cases.7 We counted each person with a primary tumor of a given type only once. Had we used the SEER method of counting incident cases, the standard morbidity ratio for penile tumors in our cohort relative to penile tumors in the general population would have been more than twice as high. In the general population, the risk of scrotal cancer is strongly associated with certain occupational exposures. A majority of Connecticut men with scrotal carcinoma had been employed as metal workers.14 None of our cases reported such employment. If metal workers are excluded from our calculations of the expected number of cases, the standard morbidity ratio for scrotal squamous-cell carcinoma in our cohort would be about twice as high as we report.
Ascertainment bias is unlikely to account for the dose-dependent increases in risk we detected. Patients exposed to more treatments with PUVA are examined more often, but we attempted to interview and examine every patient, using a uniform protocol. In the case–control analysis, matching according to center should have helped to control for bias due to differences in the completeness of examinations at different follow-up sites. If undetected cases exist among patients in our cohort with low levels of exposure to PUVA, the dose-related increase in risk we report would be smaller but the risk relative to that in the general population and the absolute risk would be even higher. The high relative risk of squamous-cell carcinoma observed in all exposure groups raises the question of whether our observations reflect an innately greater susceptibility to squamous-cell carcinoma among persons with psoriasis. A general population-based study determined that the risk of squamous-cell carcinoma of the skin was not significantly or substantially different for people with a history of psoriasis.15
Additional evidence of the high susceptibility of the male genitalia to the carcinogenic effect of PUVA comes from a retrospective case series.16 A number of factors may account for the far larger increase in the risk of genital tumors than in the risk of those observed at other body sites in our cohort. Genital skin may be particularly susceptible to the carcinogenic effects of PUVA, as it is to certain other carcinogens.1 , 14 Since the skin of the scrotum, foreskin, and glans is thin and tans poorly, a far higher proportion of incident ultraviolet radiation may reach the germinative layer there than at other sites. These areas may also be more susceptible to the effects of other potential carcinogens, including ultraviolet B radiation and tar, to which many of these patients were exposed. Therefore, the high risk of tumors may reflect the combined carcinogenic effects of these agents and PUVA.
Local immunosuppression from PUVA and infection with human papillomavirus may have played a part in causing these tumors.17 , 18 In our cohort an additional patient had bowenoid papulosis, a clinically distinctive disease caused by human papillomavirus infection. Bowenoid papulosis has a histologic appearance similar to that of squamous-cell carcinoma in situ and may occur more frequently in immunosuppressed patients.19 Exposure to PUVA decreases immunoreactivity.18
Policies concerning genital protection varied among treatment centers and over time for our cohort. During the first eight years of the study, genital shielding was not often used. To our knowledge, none of the case patients who had a tumor during these eight years regularly shielded their genitals before the tumor developed. Because a squamous-cell cancer developed in a patient enrolled at our center in 1983, it is now standard practice here (and at many other university centers) to recommend shielding the genitalia that are not affected by psoriasis and to limit exposure of the involved genitalia. Current labeling for PUVA still recommends shielding the genitals for just one third of the initial exposure time and only if the genitals are not affected by psoriasis.20 Therefore, shielding may not be common in other treatment settings or in patients exposed to other forms of ultraviolet radiation for the treatment of cutaneous disease or in tanning salons.
After the level of exposure to PUVA was controlled for, high levels of exposure to ultraviolet B radiation were associated with an approximately fourfold increase in the risk of genital tumors. This suggests that the genitalia may be sensitive to the carcinogenic effects of ultraviolet radiation independently of the use of psoralens. Many more persons expose their genitalia to other forms of ultraviolet radiation than to PUVA. In addition to the tens of thousands who receive ultraviolet B or PUVA therapy for the treatment of cutaneous disease, every day more than 1 million people in the United States are exposed to ultraviolet radiation from tanning devices.21 Both natural sunlight and the ultraviolet radiation emitted by tanning-salon lights are carcinogenic.22 The apparent high susceptibility of the male genitalia to these carcinogenic effects suggests that genital protection is prudent whenever a person is exposed to PUVA or other forms of ultraviolet radiation for therapeutic, recreational, or cosmetic reasons.
Supported by a contract (NOl-AM-3–2252) with the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.
*Cooperating centers and investigators: Stanford University School of Medicine: E. Abel, M.D.; University of California Medical School, San Francisco: B. Wintroub, M.D., and J.H. Epstein, M.D.; Baylor College of Medicine: J. Tschen, M.D., and J. Wolf, M.D.; Washington Hospital Center: T.P. Nigra, M.D.; University of Michigan Medical School: J. Voorhees, M.D., and T.F. Anderson, M.D.; Columbia University College of Physicians and Surgeons: R. Armstrong, M.D., and L. Harber, M.D.; Mayo Graduate School of Medicine: S. Muller, M.D.; University of Miami: J.R. Taylor, M.D.; Mt. Sinai Medical Center: P. Frost, M.D., and S. Horwitz, M.D.; Temple University School of Medicine: F. Urbach, M.D.; Beth Israel Hospital: K.A. Arndt, M.D.; Dartmouth Medical School: R.D. Baughman, M.D.; Yale University School of Medicine: I.M. Braverman, M.D.; Duke University Medical Center: J. Murray, M.D.; University of Pennsylvania Hospitals: J. Petrozzi, M.D.; and Massachusetts General Hospital: E. Gonzalez, M.D.
Coordinating center: J.A. Parrish, M.D., T.B. Fitzpatrick, M.D., and Rudee Lange, B.F.A.; Center for Clinical Computing, Beth Israel Hospital: H.L. Bleich, M.D.
We are indebted to the study coordinators, whose diligence made the study possible; to Nancy Mueller, Sc.D., and Alexander M. Walker, M.D., Ph.D., for their epidemiologic and statistical advice; to Joseph Scotto, M.S., for providing special tabulations of incidence data; and to Gail A. Howrigan, Ed.D., for editorial assistance.
Source Information
From the Departments of Dermatology, Beth Israel Hospital, Massachusetts General Hospital, and Harvard Medical School; the Charles A. Dana Research Institute, Beth Israel Hospital; and the Center for Analysis of Health Practices, Harvard School of Public Health, all in Boston. Address reprint requests to Dr. Stern at the Department of Dermatology, Beth Israel Hospital, 330 Brookline Ave., Boston, MA 02215.
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Citing Articles
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