Basal-Cell Carcinoma of the Skin: A Harbinger of Cutaneous and Noncutaneous Multiple Primary Cancer

Epidemiologic studies of various incidence patterns of multiple primary cancer in patients with cancer have guided research about carcinogenic mechanisms that may apply to several organ sites [1, 2]. At issue is whether risk patterns exist that predict subsequent primary cancer in patients with an index primary cancer of a particular organ and type. Also at issue is whether apparent increases in risk result from 1) shared or common etiologic factors in the pathogenesis of the index and second primary cases of cancer; 2) adverse toxic effects of agents used in the treatment of the index cancer; 3) random or chance effects [for example, those occurring after multiple significance testing]; or 4) spurious associations that are the result of confounding by correlated lifestyle risk factors or by biased ascertainment of new primary cancer as a result of more careful medical surveillance in patients with a history of cancer. The application of criteria for judging the biological plausibility of a common pathogenesis would require mutually excessive occurrences of second primary cancer in patients with cancer and epidemiologic features that are common to the organ sites [2]. The identification of specific and predictive patterns of multiple primary cancer should facilitate the cost-effective targeting of long-term early detection methods or other preventive interventions.

Unlike the population-based cancer registries in the United States, the Danish Cancer Registry has codified the types of nonmelanoma skin cancer since 1978. In patients with squamous-cell skin cancer, Frisch and colleagues [3] reported elevated relative risk for subsequent primary cancer of the buccal cavity, lung, and larynx; cutaneous melanoma; lymphoma; and leukemia. The measure of relative risk was the standardized incidence ratio (SIR) of the actual to expected number of cases of cancer, where the expected number was determined from age-, sex-, and time-specific national cancer incidence rates for all types of cancer. This is an appropriate measure of relative risk because the actual and expected numbers are derived from the same reference population. The SIR is limited, however, because it obscures temporal patterns or latency intervals; these are better shown by using regression methods of survival analysis.

In this issue, Frisch and colleagues [4] report the results of a follow-up study of Danish men and women with basal-cell carcinoma of the skin. In the subgroup of patients younger than 60 years of age with basal-cell carcinoma (which represented one third of the total patient-years of follow-up), the incidence density for multiple primary cancer for all sites may be estimated to be 9.2 cases per 1000 persons per year (95% CI, 8.5 to 9.8 cases per 1000 persons per year). After excluding all cases of skin cancer, the incidence density is estimated to be 7.6 cases per 1000 persons per year (CI, 7.0 to 8.2 cases per 1000 persons per year). When we analyzed the subgroup of patients 60 years of age and older, the incidence density for all sites of multiple primary cancer in this subgroup was 24.1 cases per 1000 persons per year (CI, 23.6 to 24.7 cases per 1000 persons per year); after we excluded all skin cancer, the incidence density was 20.7 cases per 1000 persons per year (CI, 19.7 to 21.6 cases per 1000 persons per year). In the subgroup of patients who received a diagnosis when they were younger than 60 years of age, the SIRs showed significantly elevated relative risk for subsequent primary cancer of the lip, breast, and testis and for melanoma and non-Hodgkin lymphoma. For those who received a diagnosis at 60 years of age and older, significantly elevated relative risks were noted for melanoma; Hodgkin lymphoma; cancer of the lip; and, in women, cancer of the salivary glands.

These complex patterns must be interpreted with caution because of the absence of information on lifestyle risk factors (such as smoking, exposure to the sun, nutrition, and occupation), family history, exposure to ionizing radiation, or iatrogenic causes of immunosuppression. Tobacco smoking (a major confounding risk factor for respiratory tract cancer) may also interact with ultraviolet radiation, causing squamous-cell carcinoma of the lip. The predominant risk factor for nonmelanoma skin cancer is chronic cumulative exposure to solar ultraviolet radiation [5]. The incidence of squamous-cell carcinoma exhibits a steeper inverse latitudinal gradient (that is, the closer patients are to the equator and the higher the dose of radiation to which they are exposed, the higher the rate of cancer incidence) than does the incidence of basal-cell carcinoma [6]. Ultraviolet radiation induces structural alterations in DNA by causing covalent links between adjacent pyrimidine bases and results in local and systemic immunosuppression [7, 8].

The carcinogenicity of ultraviolet B radiation (radiation that is in the 285 nm to 320 nm wavelength spectrum) has been linked to basal- and squamous-cell carcinoma and malignant melanoma. In places in temperate zones, such as the United States and northern Europe, basal-cell carcinoma is diagnosed 4 to 10 times more frequently than squamous-cell carcinoma. The trend in the United States has been correlated with depleting levels of stratospheric ozone; such depletion has resulted from the release of chlorofluorocarbons, which are used as propellants in aerosol spray cans and as refrigerants in air-conditioning units. Ozone, which is formed photochemically by the action of solar ultraviolet radiation on oxygen molecules, is a component of the earth's atmosphere that provides a protective shield from ultraviolet B radiation. For every 1% reduction of the average thickness of the ozone layer, the annual incidence of basal-cell carcinoma is expected to increase by 3% and the annual incidence of squamous-cell carcinoma is expected to increase by 5% [9, 10].

Squamous-cell carcinoma of the skin often results from chronic cumulative exposure to solar ultraviolet radiation, whereas basal-cell carcinoma is more often caused by a history of sun exposure that has resulted in burns during childhood and intermittent intense exposure during young adulthood. In contrast to squamous-cell carcinoma, which has actinic keratosis and Bowen disease as precursor lesions, basal-cell carcinoma has no apparent precursor lesion.

Rare hereditary diseases that predispose persons to basal-cell carcinoma and squamous-cell carcinoma are characterized by increased susceptibility to the effects of ultraviolet radiation. These conditions may serve to further our understanding of the mechanisms of skin carcinogenesis that are applicable to the general population. For example, the basal-cell nevus syndrome is an autosomal dominant disorder characterized by multiple cases of basal-cell carcinoma and developmental defects, including jaw cysts, skeletal anomalies, cutaneous pitting on the palms and soles, soft tissue calcifications, and hypertelorism; an increased risk for ovarian fibroma and medulloblastoma also exists. The basal-cell carcinoma in the syndrome usually manifests before the patient is 30 years of age. The early age at onset of basal-cell carcinoma in the basal-cell nevus syndrome is an expression of heightened “mutagen sensitivity,” particularly that due to exposure to sunlight and ionizing radiation [11]. The gene responsible for the syndrome has recently been localized to bands q22.3 to q31 of chromosome 9 by linkage analysis of affected kindred. Loss of heterozygosity for genetic markers in this region has been documented in one half of sporadic basal-cell carcinomas [12, 13].

The same 9q chromosomal region is being assigned to the xeroderma pigmentosum complementing group A. Xeroderma pigmentosum is an autosomal recessive disease in which patients exposed to sunlight have a 1000-fold increase in risk for basal-cell carcinoma, squamous-cell carcinoma, and melanoma by 20 years of age. Although considerable clinical and genetic heterogeneity exists in persons with xeroderma pigmentosum, a fundamental biological mechanism is a reduced ability to repair DNA [14, 15].

An intriguing association noted by Frisch and colleagues [3, 4] was the increased risk for non-Hodgkin lymphoma in patients with basal-cell carcinoma and squamous-cell carcinoma. The cause of the increase in incidence of non-Hodgkin lymphoma in the United States and Denmark has been only partially identified [16]. Immunodeficiency syndromes, either inherited or acquired, are accompanied by an increased risk for non-Hodgkin lymphoma. Infection with the human immunodeficiency virus, in association with high-grade B-cell lymphoma, may account for 15% to 20% of the increase since 1985, particularly that in men who received a diagnosis when they were between 20 and 50 years of age [17]. It has been hypothesized that a person's risk for non-Hodgkin lymphoma may be influenced by exposure to ultraviolet radiation and by immune dysfunction [18]. This hypothesis is based on correlational studies of population-based levels of exposure to ultraviolet radiation and concurrent incidence rates of malignant melanoma and non-Hodgkin lymphoma [19]. In the Swedish Cancer Register, more than 20 000 patients with cutaneous malignant melanoma were followed and elevated risks were reported for lymphoma and leukemia [20]. Further epidemiologic research to clarify this potential causal association should include case–control studies of non-Hodgkin lymphoma in relation to lifetime exposure to ultraviolet radiation, replication of population-based incidence studies of multiple primary cancer in patients with nonmelanoma and melanoma skin cancer, and continued monitoring of geographic patterns of incidence of non-Hodgkin lymphoma in relation to measurements of ultraviolet exposure on the earth's surface.

• Copyright ©2004 by the American College of Physicians