Abstract

Patients treated with glucocorticoids may have an increased risk of skin cancer. Using data from the population-based North Jutland Prescription Database and the Danish Cancer Registry, we compared observed and expected numbers of cases of skin cancer and non-Hodgkin lymphoma among 59 043 individuals who received prescriptions for glucocorticoids, a common immunosuppressive therapy, during an 8-year period from January 1, 1989, through December 31, 1996. The overall risks for squamous cell carcinomas and basal cell carcinomas of the skin were increased, particularly among persons who had 15 or more prescriptions (standardized incidence ratio [SIR] for squamous cell carcinomas = 2.45, 95% confidence interval [CI] = 1.37 to 4.04; SIR for basal cell carcinomas = 1.52, 95% CI = 1.09 to 2.07). An elevated risk was also found for non-Hodgkin lymphoma among those with 10–14 prescriptions (SIR = 2.68, 95% CI = 1.16 to 5.29). Our data suggest that use of glucocorticoids may be a shared risk factor for certain skin cancers and lymphomas.

Immunosuppressive therapy appears to increase the risk of both skin cancer and non-Hodgkin lymphoma among patients with renal transplantation (16), but the effects of immunosuppressive therapy in other settings is less clear (79). Glucocorticoids, a group of immunosuppressive drugs, are widely used to treat acute and chronic inflammatory diseases (10), and any associated increase in cancer risk would have major public health implications. We therefore examined the risks of skin cancer and non-Hodgkin lymphoma in a large cohort of glucocorticoid users.

We used the population-based North Jutland Prescription Database (North Jutland County, Denmark; 500 000 inhabitants) (11) to identify the study cohort. This database is generated by a computerized pharmacy accounting system that sends data to the Danish National Health Service. In addition to providing free access to general practitioners and hospitals, the Health Service refunds part of the costs associated with prescribed drugs.

The North Jutland Prescription Database contains information on all refundable prescriptions filled in the county after January 1, 1989, including the patient’s personal identification number, the drug prescribed, and the prescription date. Medications dispensed during hospital stays are not included in the database. During the study period—from January 1, 1989, through December 31, 1996—data for the following drugs, taken either orally or by injection, were collected and analyzed: betamethasone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone. We also obtained data on all prescriptions for other cytostatic and immunosuppressive drugs (azathioprine, methotrexate, cyclosporin, mycophenolate, and tacrolimus) to take into account use of these agents (e.g., for cancer treatment or organ transplant).

During the study period, 59 685 persons older than 15 years received a glucocorticoid prescription. Of these, 642 (1%) were excluded because they received a prior prescription for cytostatic or immunosuppressive drugs. We linked the remaining 59 043 patients to the Danish Cancer Registry, which collects information on all individuals diagnosed with cancer, including non-melanoma skin cancers (12). Use of the personal identification number ensured a complete prescription history and unambiguous record linkage.

We followed patients for skin cancer and non-Hodgkin lymphoma from the first glucocorticoid prescription until death, for prescriptions for cytostatic or other immunosuppressive drugs, or until December 31, 1998, whichever came first. We censored 1226 persons because they received a prescription for cytostatic or other immunosuppressive drugs during follow-up. Person-years were stratified according to the number of reimbursed prescriptions (1, 2–4, 5–9, 10–14, or 15 or more prescriptions). The expected number of cancer cases was calculated by multiplying the county-specific cancer incidence rates obtained from the Danish Cancer Registry in sex, age (fifteen 5-year groups), and calendar year (1988–1992, 1993–1997, and 1998) groups with the corresponding person-years accumulated in each strata for the steroid users. The 95% confidence intervals (CIs) for the standardized incidence ratios (SIRs; i.e., the ratio of observed to expected cancers) were computed by use of Byar’s approximation (13).

Of the 217 891 total corticosteroid prescriptions, there were 133 847 (61%) for tablets, 83 989 (39%) for injections, and 55 (0.02%) unknown; 41% of the prescriptions were for prednisone, 18% for prednisolone, 13% for triamcinolone, 17% for betamethasone, 8% for methylprednisone, and 3% for other drugs.

There were 535 basal cell carcinomas, 111 squamous cell carcinomas, and 27 unspecified skin cancers diagnosed in the cohort during 333 733 person-years of follow-up. Overall SIRs were increased for both basal cell carcinomas and squamous cell carcinomas among those prescribed corticosteroids (Table 1). The highest SIRs were found for those with 15 or more prescriptions (SIR for basal cell carcinomas = 1.52, 95% CI = 1.09 to 2.07; SIR for squamous cell carcinomas = 2.45, 95% CI = 1.37 to 4.04) (Table 1). For melanoma, we detected an elevated overall SIR of borderline statistical significance. The highest SIR was for persons having 10–14 prescriptions (SIR = 1.59, 95% CI = 0.43 to 4.06).

A total of 105 non-Hodgkin lymphomas occurred during the study period; the overall SIR was 1.30 (95% CI = 1.06 to 1.58). As for melanoma, the highest SIR was for patients with 10–14 prescriptions (SIR = 2.68, 95% CI = 1.16 to 5.29).

For squamous cell carcinomas, basal cell carcinomas, and non-Hodgkin lymphoma, the tests for trend in SIRs over numbers of prescriptions had borderline statistical significance. The data may also suggest a threshold pattern.

Increased risks of squamous cell carcinomas, basal cell carcinomas, and non-Hodgkin lymphoma are well known among strongly immunosuppressed transplant patients (13,5,6,14,15). The data are less clear for melanoma, although several studies reported elevated risks in transplant recipients (14).

Data for other groups taking immunosuppressive drugs are more limited. As in our study, they suggest that, in these other groups, use of immunosuppressive drugs is associated with increased risks of non-melanoma skin cancers and non-Hodgkin lymphoma, although the increase is less than that for transplant recipients (1,5). For example, in several studies, patients with rheumatoid arthritis had an excess risk for non-Hodgkin lymphoma and skin cancers, primarily among those treated with azathioprine or cyclophosphamide (8). Fewer studies have evaluated the potential cancer risk associated with more commonly used immunosuppressive drugs such as glucocorticoids. Our results are consistent with a recent case–control study that reported increased risks of squamous cell carcinomas and basal cell carcinomas after oral glucocorticoid use for more than 1 month (16). To our knowledge, no prior studies have examined risk of melanomas or non-Hodgkin lymphoma in relation to glucocorticoid use.

Although our study was a large, population-based follow-up study with no losses to follow-up, we lacked clinical detail (e.g., regarding comorbid diseases, intensity of sun exposure, and compliance with the prescriptions). We did not have data regarding the reason for the prescriptions, and some diseases associated with glucocorticoid use (e.g., autoimmune disorders) may in themselves be associated with lymphoma risk.

As in earlier studies, we found elevated risks specifically for squamous cell carcinomas, basal cell carcinomas, and non-Hodgkin lymphoma; therefore, surveillance bias is unlikely to explain the observed associations. The incidence of skin cancers and non-Hodgkin lymphoma has increased worldwide (1623), suggesting that these malignancies may share a common etiology. Indeed, in a Scandinavian cohort study, the risk for squamous cell carcinoma of the skin was 5.5 times higher among patients with non-Hodgkin lymphoma than that in the general population (22). Exposure to ultraviolet radiation, an important risk factor for skin cancers, does not appear to contribute to the occurrence of non-Hodgkin lymphoma (24). Results of our cohort study indicate that immunosuppression by glucocorticoids may be a shared risk factor for these malignancies.

Table 1.

Observed numbers (Obs) and standardized incidence ratios (SIRs) of basal cell carcinoma, squamous cell carcinoma, melanoma, and non-Hodgkin lymphoma in 59 043 users of systemic glucocorticoids*

No. of prescriptions No. of person-years Basal cell carcinoma
 
 Squamous cell carcinoma
 
 Melanoma
 
 Non-Hodgkin lymphoma
 
 
  Obs SIR (95% CI) Obs SIR (95% CI) Obs SIR (95% CI) Obs SIR (95% CI) 
All 333 733 535 1.16 (1.06 to 1.26) 111 1.32 (1.09 to 1.59) 96 1.17 (0.95 to 1.43) 105 1.30 (1.06 to 1.58) 
178 977 233 1.06 (0.93 to 1.21) 48 1.29 (0.95 to 1.71) 47 1.13 (0.83 to 1.50) 39 1.00 (0.71 to 1.37) 
2–4 107 617 190 1.27 (1.09 to 1.46) 27 1.00 (0.66 to 1.46) 32 1.20 (0.82 to 1.70) 40 1.53 (1.09 to 2.09) 
5–9 27 992 53 1.09 (0.82 to 1.43) 16 1.61 (0.92 to 2.61) 1.05 (0.45 to 2.07) 11 1.32 (0.66 to 2.36) 
10–14 8162 19 1.09 (0.66 to 1.71) 1.30 (0.42 to 3.04) 1.59 (0.43 to 4.06) 2.68 (1.16 to 5.29) 
≥15 10 985 40 1.52 (1.09 to 2.07) 15 2.45 (1.37 to 4.04) 1.37 (0.44 to 3.19) 1.62 (0.65 to 3.33) 
    Ptrend   .09  .06  .63  .04 
No. of prescriptions No. of person-years Basal cell carcinoma
 
 Squamous cell carcinoma
 
 Melanoma
 
 Non-Hodgkin lymphoma
 
 
  Obs SIR (95% CI) Obs SIR (95% CI) Obs SIR (95% CI) Obs SIR (95% CI) 
All 333 733 535 1.16 (1.06 to 1.26) 111 1.32 (1.09 to 1.59) 96 1.17 (0.95 to 1.43) 105 1.30 (1.06 to 1.58) 
178 977 233 1.06 (0.93 to 1.21) 48 1.29 (0.95 to 1.71) 47 1.13 (0.83 to 1.50) 39 1.00 (0.71 to 1.37) 
2–4 107 617 190 1.27 (1.09 to 1.46) 27 1.00 (0.66 to 1.46) 32 1.20 (0.82 to 1.70) 40 1.53 (1.09 to 2.09) 
5–9 27 992 53 1.09 (0.82 to 1.43) 16 1.61 (0.92 to 2.61) 1.05 (0.45 to 2.07) 11 1.32 (0.66 to 2.36) 
10–14 8162 19 1.09 (0.66 to 1.71) 1.30 (0.42 to 3.04) 1.59 (0.43 to 4.06) 2.68 (1.16 to 5.29) 
≥15 10 985 40 1.52 (1.09 to 2.07) 15 2.45 (1.37 to 4.04) 1.37 (0.44 to 3.19) 1.62 (0.65 to 3.33) 
    Ptrend   .09  .06  .63  .04 
*

CI = confidence interval.

Funded in part by the Western Danish Research Forum for Health Sciences (Vestdansk Forskningsforum) and by Public Health Service grant CA 57494 (M. R. Karagas) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
We thank programmer Andrea Bautz from the Institute of Cancer Epidemiology for computer assistance.
Authors’ contributions: H. T. Sørensen, J. A. Baron, and M. R. Karagas jointly formulated the study hypothesis. The study protocol was finalized by H. T. Sørensen in collaboration with J. H. Olsen, L. Mellemkjær, and G. L. Nielsen. Analyses were conducted under the supervision of L. Mellemkjær and H. T. Sørensen. H. T. Sørensen drafted the first manuscript and all authors subsequently participated in revising it.

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