Increased Cancer Mortality Following a History of Nonmelanoma Skin Cancer FREE

EUROPEAN CANCER registries have demonstrated an increased incidence of melanoma and certain noncutaneous cancers following an initial diagnosis of squamous cell skin cancer,^{1 - 2} basal cell skin cancer,³ or nonmelanoma and non–basal cell skin cancer.⁴ Among the noncutaneous cancers repeatedly found to be at increased incidence after nonmelanoma skin cancer (NMSC) were those of the salivary glands, lung, and prostate as well as non-Hodgkin lymphoma and leukemia. These apparent associations between NMSC and subsequent cancer incidence may have been due to intensified medical surveillance in patients with a history of cancer, confounding by lifestyle risk factors or external carcinogenic exposures, a shared internal pathway of cancer induction, adverse effects of agents used in the treatment of NMSC, or chance effects.⁵ We examined the relationship between a history of NMSC and subsequent cancer mortality in a large cohort of Americans for whom baseline data were available on potential confounding variables.

Study participants were drawn from the Cancer Prevention Study II (CPS-II), a prospective mortality study of 508353 men and 676306 women who completed a 4-page questionnaire in 1982. Baseline data from CPS-II included personal identifiers, demographic characteristics, various behavioral and dietary exposures, and personal and family histories of cancer and other diseases. Participants were identified and enrolled by American Cancer Society volunteers throughout the United States and Puerto Rico.⁶ Enrollment was restricted to persons aged 30 years and older.

The vital status of study participants was determined through December 31, 1994, using 2 consecutive approaches. In the initial phase, volunteers made personal inquiries in 1984, 1986, and 1988 to determine whether the enrollees were alive or dead and to record the date of all deaths. Subsequent to 1988, we used automated linkage with the National Death Index to extend follow-up through 1994 and to identify deaths among the few participants lost to follow-up between 1982 and 1988. A validation study that compared volunteer follow-up with National Death Index linkage found that the volunteers identified virtually all participant deaths and linkage with the National Death Index identified 93% of participant deaths.⁷ At completion of mortality follow-up in December 1994, 21.1% of the men and 12.8% of the women had died, 78.7% of the men and 86.9% of the women were presumed to be alive, and 0.2% of the men and 0.3% of the women had follow-up truncated on September 1, 1988, because of insufficient data for National Death Index linkage. Death certificates were obtained for 98.3% of all participants known to have died.

A history of NMSC was established at baseline by a positive response to the question, "Have you ever had cancer?" and further specification that the cancer was skin cancer but not reported to be melanoma. We excluded from our analytic cohort participants with a baseline history of melanoma or any noncutaneous cancer (25242 men and 57107 women), those whose death after enrollment was attributed to NMSC (98 men and 34 women), and those who claimed a baseline history of NMSC but did not provide the year of treatment (2719 men and 2553 women). Participants remaining in the analytic cohort are described in Table 1. The 19102 men (4.0%) and 15960 women (2.6%) with a history of NMSC were slightly older, more likely to be white, more educated, and more likely to have stopped smoking than were participants without a history of NMSC.

We used Cox proportional hazards modeling⁸ to examine the association between a baseline history of NMSC and mortality due to various causes. Cox models were stratified on age at enrollment and controlled for race (white, including 1.5% undetermined, vs all others), education, smoking status (Table 1), body mass index (calculated as weight in kilograms divided by the square of height in meters [kg/m²]), alcohol use, exercise, vegetable and fat intake, aspirin use, marital status, prevalent diabetes, and (for women) menopausal status, parity, and use of oral contraceptives and estrogen replacement therapy. As appropriate to site-specific cancer outcomes, certain multivariate models were also adjusted for hysterectomy status or family history of colorectal, prostate, breast, or ovarian cancer.

After 12 years of follow-up, 26622 men and 21084 women in our analytic cohort had died of cancer. After adjusting for only age and race, a history of NMSC was associated with all-site (including melanoma) cancer mortality for men (relative risk [RR], 1.23; 95% confidence interval [CI], 1.17-1.30) and for women (RR, 1.23; 95% CI, 1.15-1.32). Additional multivariate adjustment (Table 2) did not attenuate the association between a history of NMSC and all-site cancer mortality (men's RR, 1.30; women's RR, 1.26). Excluding from the analyses 427 men and 221 women who died of melanoma produced minimal change in the association between NMSC and death from cancer (fully adjusted men's RR, 1.27; women's RR, 1.24; Table 2).

The increased RR for all-site cancer mortality paralleled the increased RRs that we identified for death from the following cancers: melanoma, pharynx, lung, non-Hodgkin lymphoma; in men only, salivary glands, prostate, testis, bladder, and leukemia; and in women only, breast (Table 2). No sites demonstrated a significant decrease in cancer mortality associated with a history of NMSC.

The small increase in all-cause death rates among participants with a history of NMSC (fully adjusted men's RR, 1.03; 95% CI, 1.00-1.06; 94754 deaths and women's RR, 1.04; 95% CI, 1.00-1.09; 70401 deaths) was entirely attributable to cancer mortality. The fully adjusted RRs related to all circulatory diseases were 0.91 (95% CI, 0.87-0.95; 45210 deaths) for men and 0.96 (95% CI, 0.90-1.02; 31235 deaths) for women. The fully adjusted RRs related to all other causes were 0.98 (95% CI, 0.93-1.04; 22922 deaths) for men and 0.96 (95% CI, 0.89-1.05; 18082 deaths) for women.

The proportional hazards assumption was tested and found not to be violated for models predicting all-cancer mortality, mortality due to the major cancers, and all-cause mortality.

This large prospective study found death rates from all noncutaneous cancers to be 20% to 30% higher among participants who reported a history of NMSC than among participants who did not. Our finding is similar in direction and magnitude to the results of 3 previous studies based on incidence data from European cancer registries^{1 ,3 - 4} and the results of a fourth European incidence study when its analysis was restricted to persons whose initial squamous cell skin cancer was diagnosed at younger than 65 years.² Our findings (Table 2) also resemble those from the European cancer registries with respect to the specific cancers associated with NMSC. For each of the cancers for which higher death rates were associated with NMSC in our study, at least 1 of the European studies reported increased cancer incidence. Our prospective study, like the European incidence studies, found no increase in cancers of the esophagus, stomach, pancreas, ovary, or colorectum.

Intensified medical surveillance of persons with a history of NMSC is unlikely to explain the increased cancer mortality found in our study because we assessed deaths rather than incident cancers. Our participants were equally subject to ascertainment of death from cancer irrespective of their baseline histories. However, ascertainment of subsequent incident cancers may not have been equal in studies comparing persons with cancer history with those in the general population.

The observed association between NMSC and fatal cancers is unlikely to be explained by confounding from educational status, smoking, obesity, alcohol use, exercise, or any of the other measured risk factors for which we controlled. Although the European incidence studies were unable to control their analyses for these variables, we found no evidence that the associations with NMSC changed after multivariate adjustments. This reduces concern about residual confounding from these measured risk factors.

It is possible that the association between NMSC and subsequent cancers may reflect one or more unmeasured shared exposures or susceptibilities. For example, a high cumulative exposure to UV radiation leading to NMSC^{9 - 10} might also be associated with systemic T-lymphocyte–mediated immunosuppression¹¹ or with the acquisition of somatic mutations (eg, p53 tumor suppressor gene¹² ). Several studies have considered (but not resolved) the role played by solar UV exposure in the etiology of non-Hodgkin lymphoma.^{13 - 18} Diet in early life,^{19 - 20} ionizing radiation (including NMSC therapy),^{10 ,21} various chemicals (including topical anesthetics or treatments),¹⁰ or viruses^{22 - 26} might also contribute to the small increase in shared risk. Alternatively, an underlying susceptibility factor (inherited or acquired) such as DNA repair deficiency²⁷ could play a role in the observed associations.

The clinical and public health implications of these epidemiological findings are not yet clear. However, a history of NMSC should increase the clinician's alertness for selected neoplasms.²⁸

Since submission of our manuscript we have encountered 2 additional incidence studies reporting malignancies following basal cell skin cancer. One study²⁹ found an increased incidence of all-site, noncutaneous cancers and the other³⁰ did not.