Caputo et al. REFERENCES 1. Winkelmann RK. Adult histiocytic skin diseases. G Ital Derrnatcl Venereol1980;15:67-76. 2. Winkelmann RK. Cutaneous syndromes of non-X histiocytosis: a review of the macrophage-histiocyte diseases of the skin. Arch DermatoI1981;117:667-72. 3. Hu CH, Winkelmann RK. Unusual normolipemic cutaneousxanthomatosis: a comparison oftwo cases illustrating the differential diagnosis. Acta Derm Venereol (Stockh) 1977;57:421-9. 4. Sanchez RL, Raimer SS, Peltier F, et al. Papular xanthoma. Arch DcrmatoI1985;121:626-31.
Journal of the American Academy of Dermatology
5. Bundino S, Zina AM, Aloi F. Papular xanthoma: clinical, histological and ultrastructural study. Dermatologica 1988;177:382-5. 6. Gianotti F, Caputo R. Histiocytic syndromes: a review.J AM ACAD DERMATOL 1985;13:383-404. 7. Winkelmann RK, Kossard S, Fraga S. Eruptive histiocytoma of childhood. Arch Dermatol 1980;116:565-70. 8. Gianotti F, Caputo R, Ermacora E, et al. Benign cephalic histiocytosis. Arch Dermatol 1986;122:1038-43. 9. Caputo R, Gianotti F. Cytoplasmic markers: ultrastructural features in histiocytic proliferations of the skin. G Ital Dermatol Venereal 1980;115:107-20.
The prevalence of malignant tumors in patients with psoriasis B. Lindelof, MD,a G. Eklund, OD, PhD,b S. Liden, MD,a and R. S. Stern, MDC Stockholm, Sweden, and Boston, Massachusetts A possibleassociation between psoriasisand cancer was investigated by linking the Swedish Psoriasis Association's membership registry to the SwedishCancer Registry.The population studied was 20,328 livingpersons.Since 1958 a cancer was recorded in 520 of them. The expected number, based on the prevalenceof cancer in Sweden,was 540. Among 43 cancer sites for men and 46 for women selected primarily for analysis, a significantassociationwith psoriasis was found only in twotypes of cancer. For male breast cancer the observednumber was 4 and the expected number was 0.58, and for femalekidney cancers the observed number was 17 and the expected number was 6.1. The statistically significantexcess risk found for these two forms of cancer may be the result of multiple statistical testing rather than a phenomenon of true biologic significance. Thus psoriasis patients seem not to deviate from the general population with regard to cancer prevalence. (J AM ACAD DERMATOL 1990;22: 1056-60.)
Some authors have hypothesized that cancer is less likely to develop in patients with psoriasis. This hypothesis has been tested by several investigators"? (Table I). The data suggest that, independent of exposure to carcinogenic agents, patients with psoriasis have a risk of systemic and cutaneous cancer that is comparable to that of the general population. Many agents used in psoriasis therapy, including ultraviolet light, coal tar preparations, and From the Departments of Dermatology" and Cancer Epidemiology," Karollnska Hospital,Stockholm,and the Department of Dermatology,Beth Israel Hospital, Harvard Medical School, Boston," Accepted for publication Sept. 16, 1989. Reprint requests; Bernt Lindelof, MD, Department of Dermatology, Karolinska Hospital, S-104 01 Stockholm, Sweden. 16/1/16757
1056
ionizing radiation, are known to be carcinogenic. Some studies suggest that the risk of certain cancers in patients with psoriasis who have received substantial exposure to certain carcinogens is likely to be increased. Such an association has been most clearly demonstrated between nonme1anoma skin cancer and exposure to oral methoxsalen photochemotherapy (PUVA), UVB, ionizing radiation, and topical tar preparations. Data that suggest an association between psoriasis or psoriasis therapy and an increased risk of other types of cancer are less clear. A 10-year prospective study of 1380 patients treated with PUVA detected a significant increase in the risk of central nervous system (eNS) tumors. 10 Smaller but significant increases in risk were noted for colon and rectal can-
Volume 22 Number 6, Part 1 June 1990
Prevalance of malignant tumors in psoriasis 1057
Table I. Literature review of cancer risks reported in association with psoriasis Author (yr)
Reference No.
Chapman et aL (1979)
1
Shuster et al. (1979)
2
Halprin et al. (1982) Stern et aL (1982)
4
No. of psoriasis patients
3
150 1367
Alderson and Clarke (1983) Champion (1983) Meffert et al. (1983) Stern et aL (1985)
5 6
8405
7 8
300
Lindegard (1986)
9
372
738
Conehsion
Decreased risk of skin cancer (hypothesis) Decreased risk of skin cancer (hypothesis) Increased risk of cancer No change in risk of systemic and cutaneous cancer No change in risk of cancer No change in risk of cancer No change in risk of cancer Increased risk of basal cell carcinomas No change in risk of squamous cell carcinomas Association between psoriasis in women and lung cancer
relatives with psoriasis; we estimate that these persons represent less than 5% of the study population.
cer in this cohort. Although no single exposure seemed to explain these increases, this cohort is representative of only the most severely affected patients who have received substantial therapy. Therefore the question remains as to whether the observed increases in cancer risk are due to these patients' exposures to treatment, special characteristics of patients with psoriasis, or chance. We undertook this investigation to determine whether the tumors noted to have increased incidence in the PUV A follow-up study'? had an increased prevalence in a more representative sample of patients with psoriasis.
Nationwide information on the cancer incidence in Sweden is available from 1958, when compulsory registration was begun. The overall reporting to the registry is estimated to be close to 100% of all diagnosed cases. 12 By using record linkage between the Swedish Psoriasis Registry and the Swedish Cancer Registry, we identified all persons in the Psoriasis Registry who had a history of any cancer, except basal cell carcinomas, from 1958 to 1984. 13
MATERIAL AND METHODS
Statistics
The Swedish Psoriasis Association An estimated 2% of the Swedish population have psoriasis (approximately 160,000 persons). About one fourth regularly treat their disease. 11 Outpatient centers play an important role in the treatment of psoriasis. These centers are usually sponsored by the government in cooperation with the Swedish Psoriasis Association. As of Jan. 1, 1987, this voluntary patient organization had 22,048 members. A special national authority in Sweden, The Data Inspection Board, the Swedish Psoriasis Association, and the local committee for medical ethics, gave their consent to this study. Nearly 2000 of the 22,048 members' files lacked complete personal identification data and were excluded. Therefore a total of 20,328 members with complete personal identification were used to determine the prevalence of cancer in this cohort. The population includes 11,292 female and 9036 male subjects, with a median age of 48 years (range 2 to 96 years). In the study population a few did not have psoriasis but acted as support members for
The Swedish Cancer Registry
The expected number for each type of cancer was estimated on the basis of prevalence data from the Swedish Cancer Registry after due consideration for age and sex. We obtained the 95% confidence interval (CI) of the prevalence by dividing the 95% limits of the observed numbers!" by the expected numbers. The two prior hypotheses about skin cancer and CNS tumors were tested by assuming that the observed numbers follow the Poisson distribution and that the error in the expected numbers are negligible. The level of significance was 5% (two-tailed test). Relative risks were obtained as the ratio between observed and expected numbers. The confidence limits were chosen so that they separate 2.5% of the Poisson distribution in each tail. All sites were tested in the same way. With respect to the presumption of excess risk of cancer types other than skin and eNS, the number of types of neoplasms, 43 for men and 46 for women, complicates the analysis. Because a multiple comparison problem arises, a correction was made to allow multiple hypothesis testing. The following steps were undertaken.
Journal of the American Academy of Dermatology
1058 Lindelof et al. The estimation wascarried out for different conventional significance levels. In the first step it was studied if the most significant ratio was significant at the level of 0.05 + 89 = 0.00056. If this level was passed, it was calculated if there was another ratio passing the level 0.05 + 44 = 0.0011, and so on. RESULTS
A total of 520 site-specific cases of cancer in the 20,328 members were registered. On the basis of Swedish cancer registry data, we expected 540 cases, a relative risk (RR) not statistically different (RR = 0.96; 95% CI :;: 0.88 to 1.05). Similarly, we failed to detect any difference in the prevalence of CNS tumors, with 15 observed and 20.3 expected (RR = 0.74; 95% CI = 0.4 to 1.2 (Table II). The prevalence of colon and rectal cancer among patients with psoriasis was also nearly identical to that in the general Swedish population (RR = 0.76; 95% CI =: 0.6 to 1.1). The prevalence of melanoma in the two populations was also comparable (RR = 1.1; 95% CI = 0.8 to 1.6). Although the prevalence of breast cancer among female psoriasis patients was nearly identical to that in the general population (RR = 1.03; 95% CI:;: 0.85 to 1.25), there was a significant and substantial difference in the prevalence of male breast cancer in these two populations. Among patients with psoriasis, the prevalence of male breast cancer was nearly seven times as high as that expected from general population rates (RR :;: 6.90; 95% CI = 1.9 to 17.7). Overall, the increase in the risk of renal cancer was small and not significant (RR = 1.4; 95% CI == 0.9 to 2.1). The prevalence of this tumor in men and women with psoriasis relative to that expected in members of the same sex in the general population, however, was very different. In men there was no apparent increase in risk of renal cancer (RR = 0.59; 95% CI = 0.2 to 1.3). In women there was a significant increase (RR = 2.79; 95% CI = 1.6 to 4.5). Cancers of the skin other than melanoma had a slightly increased prevalence in patients with psoriasis (RR = 1.48; 95% CI = 0.96 to 2.2). Although the overall prevalence did not reach significance at the p < 0.05 level,certain sites did have a significant increase in risk. The prevalence of tumors on the trunk and extremities was nearly four times higher in patients with psoriasis than in the general population (RR = 3.7; 95% CI = 2.2 to 5.9).
DISCUSSION
Overall, the prevalence of cancer in this group of more than 20,000 living persons registered with the Swedish Psoriasis Association was not significantly or substantially different from the prevalence expected, based on age and sex prevalence data for Sweden. We estimate that in Sweden approximately 160,000 persons have psoriasis. Therefore our study includes about one eighth of them. Because membership in the Swedish Psoriasis Association is generally required for access to specialized psoriasis treatment centers, it is likely that our cohort of patients was most representative of patients with moderate or severe psoriasis. Still, this population is far less selective with respect to severity of disease and treatment received than that studied by most other investigators. For example, the PUVA cohort of 1380 represents patients who were generally the most severely affected at 16 university centers in the United States at the time PUVA was introduced. 10 These patients are likely to have had much greater exposure on average not only to PUVA but to other treatments that might affect the risk of cutaneous or noncutaneous cancer. An earlier Swedish study that compared hospitalization rates between persons with and without psoriasis living in one city noted an association between psoriasis and lung cancer in females.? A Scottish study of 8905 patients who had been hospitalized for psoriasis from 1968 to 1979 used record linkage to establish the incidence of treatment for cancer in this group. In an average of 11.5 years of observation, the incidence of cancer in these patients with psoriasis was comparable to that in the general Scottish population and in no sites was there significantly increased risk ' Recently, Harland 1S suggested that the slight increase in prevalence of colon and rectal cancer observed in the PUVA study cohort'? might be due to a possible association between ulcerative colitis and psoriasis and the increased risk of colonic cancer in ulcerative colitis. The data from the Swedish registry failed to indicate any increased risk of colon and rectal cancer among patients with psoriasis. This study was in part prompted by concern about the more than fivefold increase in the risk of CNS tumors noted in the PUVA cohort study. The heterogeneous group of Swedish patients with psoriasis studied here did not confirm this. This finding suggests that the increase
Volume 22 Number 6, Part I June 1990
Prevalance oj malignant tumors inpsoriasis 1059
Table II. Prevalence figures for cancer by site in patients with psoriasis Males Site of cancer
Observed
All sites Lip Tongue Salivary glands Floor of mouth Mouth, other parts Mesopharynx Nasopharynx Hypopharynx Pharynx, unspecified Esophagus Stomach Small intestine Colon Rectum Biliary passages, liver Liver, not primary Pancreas Peritoneum Nose and nasal sinuses Larynx Trachea, bronchus, lung, pleura; primary Lung, not primary Mediastinum Breast Cervix uteri Corpus uteri Chorionepithelioma of uterus tJterus, unspecified Ovary, tube and broad ligament Other female genital organ Prostate Testis Other male genital organ Kidney Urinary organs (except kidney) Malignant melanoma of skin Skin (except melanoma) Eye eNS Thyroid gland Endocrine glands (except thyroid) Bone Connective tissue, muscle Other unspecified sites Malignant lymphoma, non-Hodgkin's Hodgkin's disease Reticulosis and related forms Multiple myeloma, plasmocytoma Lymphatic leukemia, polycythemia
207 3 0 2 0 1 1 1 0 0 1 6 0 10 12 1 0 0 0 1 7 5 1 0 4
*p < 0.01, ordinary significance analysis.
tp < 0.001, ordinary significance analysis.
!
Females Expected
223.6 6.0
0.9 1.5
0.4 1.2 0.4 0.6 0.4 0.02 0.7 6.5 1.2 17.3 11.9 0.8 0.05 0.9 0.01 0.7 4.9 8.3 0.4 0.04 0.58*
Observed
313 0 0 3 1 0 1 0 0 0 0 1 1 14 7 1 0 0 0 1 0 3 0 0 107 31
28 0 6 18 3 41 6 4 6 21 16 19 1 9 5 3 1
0 0 5 2 2 0
7
J
Expected
316.1 0.5 0.5 1.5 0.07t 0.8 0.3 0.3 0.1 0.00 0.2 3.2 0.8 16.7 9.0 1.0 0.04 0.7 0.00 0.4 0.6 2.8 0.2
0.0 103.4 32.5 31.5 0.4 3.1 21.3 2.5
47.4 6.6 1.8
10.2 24.9 13.7 12.2 1.5 9.3 3.1 6.9 1.4 2.8 2.3
17 5 17 7 1 6 5 14 0 4
6.2
2 2 2 2 2
3.8 1.6 2.6 6.0
1
6.1t 6.6 15.7 5.4 1.3 11.0 9.1 12.8 0.8 2.4 2.1 3.9 2.2 1.0 1.9 4.1
1060
Journal of the American Academy of Dermatology
Lindelof et al.
in risk observed in the PUVA cohort might be the result of chance alone or the result of some exposure that was more frequent or of greater magnitude in the PUVA cohort than in this more representative sample of patients. Alternatively, a genetic predisposition to CNS cancer in patients with psoriasis might be present only in persons of certain genetic backgrounds who might be represented in the U.S. population but not in the more homogenous Swedish population. In contrast to the PUVA study, which suggested a small increase in risk of breast cancer in women, our" data indicate that the prevalence of female breast cancer is not elevated in patients with psoriasis. A more than sixfold increase in male breast cancer was observed. Given the extremely low incidence of this tumor, the PUVA study lacks the power to detect an increase in risk of this magnitude. A case-control study is being conducted to establish whether any treatments that these patients might have had might be associated with this rare tumor. Somewhat puzzling and contradictory are the results with respect to renal cancer. Although the .prevalence of renal cancer in males with and without psoriasis was comparable, there was a significant increase in the prevalence of this tumor among females with psoriasis. A ready explanation of this sex-specific difference is not apparent, and this finding may also be due to chance alone. Again, we plan a case-control study to determine whether cases of renal cancer are associated with any exposure. The melanoma experience of this cohort is reassuring. Overall, the prevalence of melanoma in patients with psoriasis was nearly identical to that expected. Overall, a small increase in prevalence of nonmelanoma skin cancer, which in the Swedish Cancer Registry is almost completely squamous cell carcinoma, was noted. A significant increase was noted on the trunk and extremities, sites likely to be exposed to carcinogenic psoriasis therapies such as PUVA and UVB. The modest increases in risk compared with those observed in the PUVA cohort!" may well reflect the far smaller exposures to cutaneous carcinogens that this less highly selected cohort is likely to have had. These data suggest that the treatments used in Sweden for psoriasis has not been accompanied by a substantial increase in cancer in this relatively un-
selected population. Of course, this does not mean that some cancers that occurred in this population were not due to psoriasis treatment, especially in patients who are either particularly susceptible to carcinogenic effects of these therapies or who had been exposed to high doses. An additional caution in interpretation is that we present data on prevalence among living persons. For a tumor with a short survival time, cumulative incidence rather than prevalence would provide a more appropriate basis for comparison. Unfortunately, our data do not permit us to compare cumulative incidence. For brain tumors that have a relativelyshort survival time a comparison ofthe cumulative incidence rather than the prevalence would have been especially desirable but was not technically feasible. REFERENCES 1. Chapman PH, Rawlins MD, Shuster S. Activity of aryl hydrocarbon hydroxylase in psoriatic skin. Lancet 1979;1:297-8. 2. Shuster S, Chapman PH, Rawlins MD . Psoriasis and cancer. Br Med J 1979;1:941-2. 3. Halprin KM , Comerford BA, Taylor JR. Cancer in patients with psoriasis. J AM ACAD DERMATOL 1982;7: 633-8. 4. Stern R, Zierler S, Parrish 1. Psoriasis and the risk of cancer. J Invest Dermatol 1982;78:147-9. 5. Alderson MR, Clarke JA. Cancer incidence in patients with psoriasis. Br J Cancer 1983;47:857-9. 6. Champion PD. Psoriasis and cancer. J R Coll Gen Pract 1983;33:293-5. 7. Meffert H, Tschuschke D, Metz D, et al. Psoriasis und Hautkrebs. Dermatol Monatsschr 1983;169:675-7. 8. Stern RS, Scotto J , Fears TR . Psoriasis and susceptibility tononmelanoma skin cancer. J AM ACADDERMATOL 1985; 12:67-73. 9. Lindega rd B. Diseasesassociat ed with psoriasis in a general population of 159,200 middle-aged, urban, native Swed es. Dermatologica 1986;172:298-304. 10. Stern RS, Lange R . Cardiovascular disease, cancer and cause of death in patients with psoriasis: 10 years prospective experience in a cohort of 1380 patients. J Invest Dermatol 1988;91:197-201. 11. Fischer T. Psoriasis outpatient care centers: the Swedish model. Semin Dermatol 1985;4:293-5. 12. Mattsson B. Cancer registration in Sweden: studies on completeness and validity of incidence and mortality registers [Thesis]. Stockholm: Karolinska Institute, 1984:1-33. 13. Adami HO, Gunn arsson T , Sparen , et al. The prevalence of cancer in Sweden 1984. Act a Oncol 1989;28:463-70. 14. Documento Geigy. Scientific tables. 6th ed. Basel: Geigy, 1962. 15. Harland CC. Morbidity and mortality with PUVA: colonic cancer [Letter]. J Invest Dermatol 1989;92:774.
Journal of the American Academy of Dermatology
5. Bundino S, Zina AM, Aloi F. Papular xanthoma: clinical, histological and ultrastructural study. Dermatologica 1988;177:382-5. 6. Gianotti F, Caputo R. Histiocytic syndromes: a review.J AM ACAD DERMATOL 1985;13:383-404. 7. Winkelmann RK, Kossard S, Fraga S. Eruptive histiocytoma of childhood. Arch Dermatol 1980;116:565-70. 8. Gianotti F, Caputo R, Ermacora E, et al. Benign cephalic histiocytosis. Arch Dermatol 1986;122:1038-43. 9. Caputo R, Gianotti F. Cytoplasmic markers: ultrastructural features in histiocytic proliferations of the skin. G Ital Dermatol Venereal 1980;115:107-20.
The prevalence of malignant tumors in patients with psoriasis B. Lindelof, MD,a G. Eklund, OD, PhD,b S. Liden, MD,a and R. S. Stern, MDC Stockholm, Sweden, and Boston, Massachusetts A possibleassociation between psoriasisand cancer was investigated by linking the Swedish Psoriasis Association's membership registry to the SwedishCancer Registry.The population studied was 20,328 livingpersons.Since 1958 a cancer was recorded in 520 of them. The expected number, based on the prevalenceof cancer in Sweden,was 540. Among 43 cancer sites for men and 46 for women selected primarily for analysis, a significantassociationwith psoriasis was found only in twotypes of cancer. For male breast cancer the observednumber was 4 and the expected number was 0.58, and for femalekidney cancers the observed number was 17 and the expected number was 6.1. The statistically significantexcess risk found for these two forms of cancer may be the result of multiple statistical testing rather than a phenomenon of true biologic significance. Thus psoriasis patients seem not to deviate from the general population with regard to cancer prevalence. (J AM ACAD DERMATOL 1990;22: 1056-60.)
Some authors have hypothesized that cancer is less likely to develop in patients with psoriasis. This hypothesis has been tested by several investigators"? (Table I). The data suggest that, independent of exposure to carcinogenic agents, patients with psoriasis have a risk of systemic and cutaneous cancer that is comparable to that of the general population. Many agents used in psoriasis therapy, including ultraviolet light, coal tar preparations, and From the Departments of Dermatology" and Cancer Epidemiology," Karollnska Hospital,Stockholm,and the Department of Dermatology,Beth Israel Hospital, Harvard Medical School, Boston," Accepted for publication Sept. 16, 1989. Reprint requests; Bernt Lindelof, MD, Department of Dermatology, Karolinska Hospital, S-104 01 Stockholm, Sweden. 16/1/16757
1056
ionizing radiation, are known to be carcinogenic. Some studies suggest that the risk of certain cancers in patients with psoriasis who have received substantial exposure to certain carcinogens is likely to be increased. Such an association has been most clearly demonstrated between nonme1anoma skin cancer and exposure to oral methoxsalen photochemotherapy (PUVA), UVB, ionizing radiation, and topical tar preparations. Data that suggest an association between psoriasis or psoriasis therapy and an increased risk of other types of cancer are less clear. A 10-year prospective study of 1380 patients treated with PUVA detected a significant increase in the risk of central nervous system (eNS) tumors. 10 Smaller but significant increases in risk were noted for colon and rectal can-
Volume 22 Number 6, Part 1 June 1990
Prevalance of malignant tumors in psoriasis 1057
Table I. Literature review of cancer risks reported in association with psoriasis Author (yr)
Reference No.
Chapman et aL (1979)
1
Shuster et al. (1979)
2
Halprin et al. (1982) Stern et aL (1982)
4
No. of psoriasis patients
3
150 1367
Alderson and Clarke (1983) Champion (1983) Meffert et al. (1983) Stern et aL (1985)
5 6
8405
7 8
300
Lindegard (1986)
9
372
738
Conehsion
Decreased risk of skin cancer (hypothesis) Decreased risk of skin cancer (hypothesis) Increased risk of cancer No change in risk of systemic and cutaneous cancer No change in risk of cancer No change in risk of cancer No change in risk of cancer Increased risk of basal cell carcinomas No change in risk of squamous cell carcinomas Association between psoriasis in women and lung cancer
relatives with psoriasis; we estimate that these persons represent less than 5% of the study population.
cer in this cohort. Although no single exposure seemed to explain these increases, this cohort is representative of only the most severely affected patients who have received substantial therapy. Therefore the question remains as to whether the observed increases in cancer risk are due to these patients' exposures to treatment, special characteristics of patients with psoriasis, or chance. We undertook this investigation to determine whether the tumors noted to have increased incidence in the PUV A follow-up study'? had an increased prevalence in a more representative sample of patients with psoriasis.
Nationwide information on the cancer incidence in Sweden is available from 1958, when compulsory registration was begun. The overall reporting to the registry is estimated to be close to 100% of all diagnosed cases. 12 By using record linkage between the Swedish Psoriasis Registry and the Swedish Cancer Registry, we identified all persons in the Psoriasis Registry who had a history of any cancer, except basal cell carcinomas, from 1958 to 1984. 13
MATERIAL AND METHODS
Statistics
The Swedish Psoriasis Association An estimated 2% of the Swedish population have psoriasis (approximately 160,000 persons). About one fourth regularly treat their disease. 11 Outpatient centers play an important role in the treatment of psoriasis. These centers are usually sponsored by the government in cooperation with the Swedish Psoriasis Association. As of Jan. 1, 1987, this voluntary patient organization had 22,048 members. A special national authority in Sweden, The Data Inspection Board, the Swedish Psoriasis Association, and the local committee for medical ethics, gave their consent to this study. Nearly 2000 of the 22,048 members' files lacked complete personal identification data and were excluded. Therefore a total of 20,328 members with complete personal identification were used to determine the prevalence of cancer in this cohort. The population includes 11,292 female and 9036 male subjects, with a median age of 48 years (range 2 to 96 years). In the study population a few did not have psoriasis but acted as support members for
The Swedish Cancer Registry
The expected number for each type of cancer was estimated on the basis of prevalence data from the Swedish Cancer Registry after due consideration for age and sex. We obtained the 95% confidence interval (CI) of the prevalence by dividing the 95% limits of the observed numbers!" by the expected numbers. The two prior hypotheses about skin cancer and CNS tumors were tested by assuming that the observed numbers follow the Poisson distribution and that the error in the expected numbers are negligible. The level of significance was 5% (two-tailed test). Relative risks were obtained as the ratio between observed and expected numbers. The confidence limits were chosen so that they separate 2.5% of the Poisson distribution in each tail. All sites were tested in the same way. With respect to the presumption of excess risk of cancer types other than skin and eNS, the number of types of neoplasms, 43 for men and 46 for women, complicates the analysis. Because a multiple comparison problem arises, a correction was made to allow multiple hypothesis testing. The following steps were undertaken.
Journal of the American Academy of Dermatology
1058 Lindelof et al. The estimation wascarried out for different conventional significance levels. In the first step it was studied if the most significant ratio was significant at the level of 0.05 + 89 = 0.00056. If this level was passed, it was calculated if there was another ratio passing the level 0.05 + 44 = 0.0011, and so on. RESULTS
A total of 520 site-specific cases of cancer in the 20,328 members were registered. On the basis of Swedish cancer registry data, we expected 540 cases, a relative risk (RR) not statistically different (RR = 0.96; 95% CI :;: 0.88 to 1.05). Similarly, we failed to detect any difference in the prevalence of CNS tumors, with 15 observed and 20.3 expected (RR = 0.74; 95% CI = 0.4 to 1.2 (Table II). The prevalence of colon and rectal cancer among patients with psoriasis was also nearly identical to that in the general Swedish population (RR = 0.76; 95% CI =: 0.6 to 1.1). The prevalence of melanoma in the two populations was also comparable (RR = 1.1; 95% CI = 0.8 to 1.6). Although the prevalence of breast cancer among female psoriasis patients was nearly identical to that in the general population (RR = 1.03; 95% CI:;: 0.85 to 1.25), there was a significant and substantial difference in the prevalence of male breast cancer in these two populations. Among patients with psoriasis, the prevalence of male breast cancer was nearly seven times as high as that expected from general population rates (RR :;: 6.90; 95% CI = 1.9 to 17.7). Overall, the increase in the risk of renal cancer was small and not significant (RR = 1.4; 95% CI == 0.9 to 2.1). The prevalence of this tumor in men and women with psoriasis relative to that expected in members of the same sex in the general population, however, was very different. In men there was no apparent increase in risk of renal cancer (RR = 0.59; 95% CI = 0.2 to 1.3). In women there was a significant increase (RR = 2.79; 95% CI = 1.6 to 4.5). Cancers of the skin other than melanoma had a slightly increased prevalence in patients with psoriasis (RR = 1.48; 95% CI = 0.96 to 2.2). Although the overall prevalence did not reach significance at the p < 0.05 level,certain sites did have a significant increase in risk. The prevalence of tumors on the trunk and extremities was nearly four times higher in patients with psoriasis than in the general population (RR = 3.7; 95% CI = 2.2 to 5.9).
DISCUSSION
Overall, the prevalence of cancer in this group of more than 20,000 living persons registered with the Swedish Psoriasis Association was not significantly or substantially different from the prevalence expected, based on age and sex prevalence data for Sweden. We estimate that in Sweden approximately 160,000 persons have psoriasis. Therefore our study includes about one eighth of them. Because membership in the Swedish Psoriasis Association is generally required for access to specialized psoriasis treatment centers, it is likely that our cohort of patients was most representative of patients with moderate or severe psoriasis. Still, this population is far less selective with respect to severity of disease and treatment received than that studied by most other investigators. For example, the PUVA cohort of 1380 represents patients who were generally the most severely affected at 16 university centers in the United States at the time PUVA was introduced. 10 These patients are likely to have had much greater exposure on average not only to PUVA but to other treatments that might affect the risk of cutaneous or noncutaneous cancer. An earlier Swedish study that compared hospitalization rates between persons with and without psoriasis living in one city noted an association between psoriasis and lung cancer in females.? A Scottish study of 8905 patients who had been hospitalized for psoriasis from 1968 to 1979 used record linkage to establish the incidence of treatment for cancer in this group. In an average of 11.5 years of observation, the incidence of cancer in these patients with psoriasis was comparable to that in the general Scottish population and in no sites was there significantly increased risk ' Recently, Harland 1S suggested that the slight increase in prevalence of colon and rectal cancer observed in the PUVA study cohort'? might be due to a possible association between ulcerative colitis and psoriasis and the increased risk of colonic cancer in ulcerative colitis. The data from the Swedish registry failed to indicate any increased risk of colon and rectal cancer among patients with psoriasis. This study was in part prompted by concern about the more than fivefold increase in the risk of CNS tumors noted in the PUVA cohort study. The heterogeneous group of Swedish patients with psoriasis studied here did not confirm this. This finding suggests that the increase
Volume 22 Number 6, Part I June 1990
Prevalance oj malignant tumors inpsoriasis 1059
Table II. Prevalence figures for cancer by site in patients with psoriasis Males Site of cancer
Observed
All sites Lip Tongue Salivary glands Floor of mouth Mouth, other parts Mesopharynx Nasopharynx Hypopharynx Pharynx, unspecified Esophagus Stomach Small intestine Colon Rectum Biliary passages, liver Liver, not primary Pancreas Peritoneum Nose and nasal sinuses Larynx Trachea, bronchus, lung, pleura; primary Lung, not primary Mediastinum Breast Cervix uteri Corpus uteri Chorionepithelioma of uterus tJterus, unspecified Ovary, tube and broad ligament Other female genital organ Prostate Testis Other male genital organ Kidney Urinary organs (except kidney) Malignant melanoma of skin Skin (except melanoma) Eye eNS Thyroid gland Endocrine glands (except thyroid) Bone Connective tissue, muscle Other unspecified sites Malignant lymphoma, non-Hodgkin's Hodgkin's disease Reticulosis and related forms Multiple myeloma, plasmocytoma Lymphatic leukemia, polycythemia
207 3 0 2 0 1 1 1 0 0 1 6 0 10 12 1 0 0 0 1 7 5 1 0 4
*p < 0.01, ordinary significance analysis.
tp < 0.001, ordinary significance analysis.
!
Females Expected
223.6 6.0
0.9 1.5
0.4 1.2 0.4 0.6 0.4 0.02 0.7 6.5 1.2 17.3 11.9 0.8 0.05 0.9 0.01 0.7 4.9 8.3 0.4 0.04 0.58*
Observed
313 0 0 3 1 0 1 0 0 0 0 1 1 14 7 1 0 0 0 1 0 3 0 0 107 31
28 0 6 18 3 41 6 4 6 21 16 19 1 9 5 3 1
0 0 5 2 2 0
7
J
Expected
316.1 0.5 0.5 1.5 0.07t 0.8 0.3 0.3 0.1 0.00 0.2 3.2 0.8 16.7 9.0 1.0 0.04 0.7 0.00 0.4 0.6 2.8 0.2
0.0 103.4 32.5 31.5 0.4 3.1 21.3 2.5
47.4 6.6 1.8
10.2 24.9 13.7 12.2 1.5 9.3 3.1 6.9 1.4 2.8 2.3
17 5 17 7 1 6 5 14 0 4
6.2
2 2 2 2 2
3.8 1.6 2.6 6.0
1
6.1t 6.6 15.7 5.4 1.3 11.0 9.1 12.8 0.8 2.4 2.1 3.9 2.2 1.0 1.9 4.1
1060
Journal of the American Academy of Dermatology
Lindelof et al.
in risk observed in the PUVA cohort might be the result of chance alone or the result of some exposure that was more frequent or of greater magnitude in the PUVA cohort than in this more representative sample of patients. Alternatively, a genetic predisposition to CNS cancer in patients with psoriasis might be present only in persons of certain genetic backgrounds who might be represented in the U.S. population but not in the more homogenous Swedish population. In contrast to the PUVA study, which suggested a small increase in risk of breast cancer in women, our" data indicate that the prevalence of female breast cancer is not elevated in patients with psoriasis. A more than sixfold increase in male breast cancer was observed. Given the extremely low incidence of this tumor, the PUVA study lacks the power to detect an increase in risk of this magnitude. A case-control study is being conducted to establish whether any treatments that these patients might have had might be associated with this rare tumor. Somewhat puzzling and contradictory are the results with respect to renal cancer. Although the .prevalence of renal cancer in males with and without psoriasis was comparable, there was a significant increase in the prevalence of this tumor among females with psoriasis. A ready explanation of this sex-specific difference is not apparent, and this finding may also be due to chance alone. Again, we plan a case-control study to determine whether cases of renal cancer are associated with any exposure. The melanoma experience of this cohort is reassuring. Overall, the prevalence of melanoma in patients with psoriasis was nearly identical to that expected. Overall, a small increase in prevalence of nonmelanoma skin cancer, which in the Swedish Cancer Registry is almost completely squamous cell carcinoma, was noted. A significant increase was noted on the trunk and extremities, sites likely to be exposed to carcinogenic psoriasis therapies such as PUVA and UVB. The modest increases in risk compared with those observed in the PUVA cohort!" may well reflect the far smaller exposures to cutaneous carcinogens that this less highly selected cohort is likely to have had. These data suggest that the treatments used in Sweden for psoriasis has not been accompanied by a substantial increase in cancer in this relatively un-
selected population. Of course, this does not mean that some cancers that occurred in this population were not due to psoriasis treatment, especially in patients who are either particularly susceptible to carcinogenic effects of these therapies or who had been exposed to high doses. An additional caution in interpretation is that we present data on prevalence among living persons. For a tumor with a short survival time, cumulative incidence rather than prevalence would provide a more appropriate basis for comparison. Unfortunately, our data do not permit us to compare cumulative incidence. For brain tumors that have a relativelyshort survival time a comparison ofthe cumulative incidence rather than the prevalence would have been especially desirable but was not technically feasible. REFERENCES 1. Chapman PH, Rawlins MD, Shuster S. Activity of aryl hydrocarbon hydroxylase in psoriatic skin. Lancet 1979;1:297-8. 2. Shuster S, Chapman PH, Rawlins MD . Psoriasis and cancer. Br Med J 1979;1:941-2. 3. Halprin KM , Comerford BA, Taylor JR. Cancer in patients with psoriasis. J AM ACAD DERMATOL 1982;7: 633-8. 4. Stern R, Zierler S, Parrish 1. Psoriasis and the risk of cancer. J Invest Dermatol 1982;78:147-9. 5. Alderson MR, Clarke JA. Cancer incidence in patients with psoriasis. Br J Cancer 1983;47:857-9. 6. Champion PD. Psoriasis and cancer. J R Coll Gen Pract 1983;33:293-5. 7. Meffert H, Tschuschke D, Metz D, et al. Psoriasis und Hautkrebs. Dermatol Monatsschr 1983;169:675-7. 8. Stern RS, Scotto J , Fears TR . Psoriasis and susceptibility tononmelanoma skin cancer. J AM ACADDERMATOL 1985; 12:67-73. 9. Lindega rd B. Diseasesassociat ed with psoriasis in a general population of 159,200 middle-aged, urban, native Swed es. Dermatologica 1986;172:298-304. 10. Stern RS, Lange R . Cardiovascular disease, cancer and cause of death in patients with psoriasis: 10 years prospective experience in a cohort of 1380 patients. J Invest Dermatol 1988;91:197-201. 11. Fischer T. Psoriasis outpatient care centers: the Swedish model. Semin Dermatol 1985;4:293-5. 12. Mattsson B. Cancer registration in Sweden: studies on completeness and validity of incidence and mortality registers [Thesis]. Stockholm: Karolinska Institute, 1984:1-33. 13. Adami HO, Gunn arsson T , Sparen , et al. The prevalence of cancer in Sweden 1984. Act a Oncol 1989;28:463-70. 14. Documento Geigy. Scientific tables. 6th ed. Basel: Geigy, 1962. 15. Harland CC. Morbidity and mortality with PUVA: colonic cancer [Letter]. J Invest Dermatol 1989;92:774.
