Evidence of an association between non-Hodgkin's lymphoma and skin cancer

THE DANISH AND SWEDISH CANCER REGISTRIES

The Danish cancer registry was started in 1943 and the Swedish cancer registry in 1958. Since the initiation of these national registries, cancers have been coded in both countries according to the seventh edition of the International Classification of Diseases (ICD-7), with slight national modifications. In addition, registrations with specific histology and topography have been performed since 1978 according to the International Classification of Diseases for Oncology (ICD-O). Notification of newly diagnosed cancers is mandatory in both countries, and most cases are notified by more than one source (clinicians, pathologists, cytologists). The overall reporting is estimated to be close to 99% of all diagnosed cases.4 A unique 10 digit national registration number ascribed to every citizen ensures accurate identification in the registration of all notified cancers. These registries monitored a combined population of about 13.6 million in 1989.

SELECTION OF STUDY COHORT

We included all patients registered with non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, malignant melanoma, and squamous cell skin cancer according to the following criteria. The non-Hodgkin's lymphoma cohort comprised all cases registered under ICD-7 codes 200 and 202 in Denmark 1943-89 and in Sweden 1958-89. The chronic lymphocytic leukaemia cohort contained all cases under a Danish modification of ICD-7 code 204.0 diagnosed in Denmark 1943-89 and all cases under Swedish modifications of ICD-7 codes 204.0 or 204.1 diagnosed in Sweden 1958-89. The malignant melanoma cohort comprised all cases under ICD-7 code 190 in Denmark 1943-89 and in Sweden 1958-89. The squamous cell skin cancer cohort contained all cases in Sweden 1958-89 and in Denmark 1978-89 (short calendar period because squamous cell skin cancer were coded together with basal cell skin cancers before 1978) under the combined ICD-O topography codes 173.1-173.9 and histology codes 80513-80523, 80703-80763, 80943, and 85603.

Outcome in several non-Hodgkin's lymphoma subgroups can be leukaemic1 Whether the clinical presentation is predominantly leukaemic or lymphomatous, the process is identical morphologically and phenotypically, and the subgroups represent different clinical presentations of the same population of neoplastic cells. In epidemiological studies, the clinical entity chronic lymphocytic leukaemia should thus be referred to the group of non-Hodgkin's lymphoma, since it is more essential to identify individual disease entities than differences in clinical presentation.

ANALYSIS

We obtained information about date of death and migration status for every individual in the cohorts through linkage to the central population registries in the respective countries by using the unique national registration number. This provided us with accurate data to calculate person years at risk for subsequent malignancies. The patients with systemic malignancies (non-Hodgkin's lymphoma and chronic lymphocytic leukaemia cohorts) were followed for the occurrence of subsequent skin cancers (malignant melanoma and squamous cell skin cancer) and, conversely, the patients with initial skin cancers were followed for the occurrence of subsequent systemic malignancies.

To evaluate the extent to which the cohort members were at a generally increased risk of cancer, even cancers unlikely to be related to ultraviolet light, we also examined, in Denmark, the risk in all four patient cohorts of all types of malignancy except skin neoplasms and lymphomas and leukaemias. The period of follow up for occurrence of cancer started the month following the date of the cohort defining malignancy and continued until death, emigration, or 31 December 1989, whichever came first. Expected numbers of subsequent cancers were calculated by sex and by age and period specific (both in five year intervals) national incidence rates multiplied by the exact person years under observation in the cohorts. The ratios of observed to expected cancers (standardised incidence ratio) served as measures of the relative risk. Confidence limits for the relative risk estimates were calculated, assuming Poisson distribution of the observed cancers.28

SYSTEMIC MALIGNANCIES AND SUBSEQUENT SKIN CANCER

In general, we observed stronger associations between initial systemic malignancies (non-Hodgkin's lymphoma or chronic lymphocytic leukaemia) and the development of subsequent skin cancers (squamous cell skin cancer or malignant melanoma) than the reverse. These findings could be explained by differences in dose-response effects to ultraviolet light—more intense exposure to ultraviolet light may be required for the development of non-Hodgkin's lymphoma than for skin cancer. Ultraviolet light has been shown not only to affect the systemic immune system but also to cause local immunosuppression in the skin,18 23 29 30 Alternatively, the ease with which squamous cell skin cancers or malignant melanomas are diagnosed, compared with the efforts generally needed to establish a diagnosis of a systemic malignancy, raises the possibility that the time gained (lead time) in diagnosing skin cancer after non-Hodgkin's lymphoma or chronic lymphocytic leukaemia is greater than that in the reverse sequence. This may have contributed to the stronger associations observed between initial non-Hodgkin's lymphoma or chronic lymphocytic leukaemia and subsequent squamous cell skin cancer or malignant melanoma than in the opposite sequence. However, neither of the four analyses of initial non-Hodgkin's lymphoma or chronic lymphocytic leukaemia and subsequent squamous cell skin cancer or malignant melanoma revealed an excess risk of skin cancers in the first years of follow up, which suggests that this reservation is mostly theoretical.

The pattern for subsequent skin cancers showed differences between squamous cell skin cancer and malignant melanoma. There was an appreciable increase in the risk of squamous cell skin cancer in the years immediately following the diagnosis of non-Hodgkin's lymphoma or chronic lymphocytic leukaemia. This risk remained high and was significantly raised for 15 or more years after the diagnosis. Although significantly increased, the risk of malignant melanoma was lower than of squamous cell skin cancer and did not increase with time. Total exposure to ultraviolet light seems more important in squamous cell skin cancer than in malignant melanoma, for which the association with ultraviolet light may depend on more specific exposures, such as sunburns during early childhood.27 Therefore, the differences in relative risk observed between squamous cell skin cancer and malignant melanoma could be explained by differences in the mechanisms that link ultraviolet light to squamous cell skin cancer rather than malignant melanoma.

Therapeutic immunosuppression has been linked with increased risks of skin cancer and is another likely contributor to increased risk of squamous cell skin cancer after non-Hodgkin's lymphoma or chronic lymphocytic leukaemia.6 7 10 The non-Hodgkin's lymphoma cohort is made up of patients treated initially with radiotherapy or chemotherapy, or both (those with stage I, high grade non-Hodgkin's lymphoma) and then living without disease for various time periods, together with patients with low grade non-Hodgkin's lymphoma (including chronic lymphocytic leukaemia), for whom periods of treatment are mixed with a “wait and see” policy.33 Since the low grade is more common than the high grade,1 34 and since more intensive chemotherapy programmes with curative potential were not introduced until around 1970,35 most patients within the cohorts had active lymphoma intermingled with treatment periods. Many of the patients were probably intermittently immunocompromised, in particular during the first period after their malignancy was diagnosed.

There is no evidence that malignant melanoma is triggered by immunosuppression or radiation, and indeed the lack of an increasing trend in our data argues against such an association. There is no obvious explanation for the significantly raised risk of malignant melanoma after non-Hodgkin's lymphoma or chronic lymphocytic leukaemia. A common risk factor for skin cancers and non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, such as exposure to ultraviolet light, is yet to be determined

SKIN CANCERS AND SUBSEQUENT SYSTEMIC CANCERS

Squamous cell skin cancer was more closely linked to non-Hodgkin's lymphoma or chronic lymphocytic leukaemia than was malignant melanoma. For both skin cancer cohorts, the risk of developing non-Hodgkin's lymphoma or chronic lymphocytic leukaemia decreased with the time since the diagnosis of squamous cell skin cancer or malignant melanoma. Transient iatrogenic immunosuppression after radiotherapy for skin cancers may be partly responsible for this association, but as squamous cell skin cancer is usually treated with curettage rather than radiotherapy an alternative explanation is needed to link skin cancers to non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Ultraviolet light acting as a common risk factor for all the malignancies studied would explain the negative trend of non-Hodgkin's lymphoma or chronic lymphocytic leukaemia with time since the diagnosis of squamous cell skin cancer or malignant melanoma. Patients diagnosed as having skin cancers are advised to avoid extensive exposure to sun and are instructed to use lotions that filter ultraviolet light; they are likely to stop accumulating ultraviolet exposure. Non-Hodgkin's lymphoma or chronic lymphocytic leukaemia will occur predominantly in patients with heavy exposure to ultraviolet light before their diagnosis of skin cancer, and these systemic malignancies will occur soon after the skin cancer diagnosis. The increased risk of malignant melanoma observed in the years after non-Hodgkin's lymphoma or chronic lymphocytic leukaemia would comply with this hypothesis, as patients with non-Hodgkin's lymphoma or chronic lymphocytic leukaemia were not advised to avoid exposure to ultraviolet light.

A methodological explanation that should be considered is surveillance or ascertainment bias. Patients with a diagnosis of either non-Hodgkin's lymphoma or chronic lymphocytic leukaemia are usually under medical observation for long periods, during which minor skin lesions may be more easily observed and biopsied. Patients operated for either a malignant melanoma or squamous cell skin cancer may see a doctor for regular check ups, or they may be more aware of lymph node enlargements. Our data do not suggest, however, that such bias would explain the observed findings. For each of the four cohorts under study, the relative risk of developing new cancers at places other than skin and lymphatic or haematopoietic organs was close to what was expected from population data. The relative risk for these other cancers varied from 1.0 in the malignant melanoma cohort up to 1.3 in the chronic lymphocytic leukaemia cohort. Furthermore, data arguing against an excess of skin cancers due to increased surveillance in patients with internal malignancies have recently been provided: in a follow up of 955 patients with anal cancer, nine subsequent cases of skin cancer were observed when 8.9 were expected (relative risk=1.0; 0.5 to 1.9).36 Therefore, surveillance bias is likely to explain only a small part of the strong associations between skin cancers and systemic cancers found in this study.

CONCLUSIONS

These data provide evidence of a close association between non-Hodgkin's lymphoma or chronic lymphocytic leukaemia and squamous cell skin cancer or malignant melanoma. This supports the hypothesis of a role for ultraviolet light in the increasing incidence of non-Hodgkin's lymphoma.

We thank Dr Nancy E Mueller, Harvard School of Public Health, for valuable advice and Andrea Meersohn, Danish Cancer Society, for computer assistance with the Danish material. This study was supported by grants from the Swedish Cancer Society and by grant No 90-7620 from the Danish Cancer Society