Centre for Rheumatology, Bloomsbury Rheumatology Unit, Department of Medicine, University College London, London W1P 9PG, UK
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Abstract |
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Method. The University College London Lupus Clinic Database was used to identify a cohort of 276 patients followed up prospectively between 1978 and 1999. Standardized incidence ratios and 95% confidence intervals for all cancers were calculated using age and sex-specific cancer incidence rates for the southeast of England.
Results. In total, 16 malignancies were diagnosed in 15 patients. However, five malignancies were diagnosed before the diagnosis of SLE and were therefore excluded from the final statistical analysis. One case of basal cell carcinoma was also identified, but this was also excluded from the final analysis as no comparable figures were available for the general population. Death as a direct consequence of the malignancy occurred in six (2.3%) patients, accounting for 22.6% of the deaths in our cohort of SLE patients. Compared with the general population, the overall estimated risk for all cancers was not increased in the lupus cohort (standardized incidence rate 1.16 (95% confidence interval 0.552.13). Hodgkin's lymphoma was the only individual cancer that was increased in our cohort of patients [standardized incidence rate 17.82 (95% confidence interval 0.4599.23)].
Conclusions. In our cohort of patients with SLE we did not show an overall increased risk of malignancy. However, SLE was associated with an increased risk of Hodgkin's lymphoma compared with the general population. From our cohort of 276 patients, none of those treated with cyclosporin (3%) developed malignancy, and out of 49 (18%) patients treated with cyclophosphamide only one patient developed malignancy. Out of the 10 patients in the final analysis who developed malignancy, six had treatment with prednisolone, four with azathioprine, five with hydroxychloroquine and only one with cyclophosphamide. No statistical difference in the above cytotoxic therapy was observed between those patients who developed malignancy and those who did not.
KEY WORDS: Systemic lupus erythematosus (SLE), Malignancy, Cytotoxic therapy, Hodgkin's lymphoma.
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Introduction |
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Patients and methods |
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Statistical analysis
Observed cancers.
All cancers were identified by review of the medical notes. In all cases neoplasia was diagnosed after the onset of clinical features suggestive of malignant disease and not through a screening programme (excluding the case of cervical carcinoma, which was found on routine screening appropriate to that age group, which is currently available to the general population). The diagnosis of cancer was ascertained by histological examination or autopsy report. A total of 16 malignancies were identified in 15 patients in our cohort. However, five malignancies predated the diagnosis of SLE and were therefore excluded from the study. A case of basal cell carcinoma was excluded, as no comparable data were available for the general population. The Thames Cancer Registry [13] excluded basal cell carcinoma from their database. This is because skin lesions are now often treated by general practitioners or in out-patients clinics, where data capture facilities are poor or non-existent. The Registry data for the basal cell carcinoma were substantially incomplete and therefore of limited value.
Expected number of malignancies.
Five-year annualized age and gender-specific cancer incidence rates per 100 000 population for the southeast of England were used. The expected number of malignancies (E) was calculated as the sum of all person-years at risk in age group i from the study cohort (ni) multiplied by the age- and sex-specific cancer rates for the southeast of England in age group i (Ri) using the expression E = (ni) x Ri [14].
The expected numbers of cancers for men and women were calculated separately and then the total expected number of malignancies was calculated. The expected number of malignancies for individual cancers was also calculated using the available age-standardized rates for the southeast of England for breast cancer, lung cancer, Hodgkin's lymphoma, cervix cancer and prostate cancer from the Thames Cancer Registry [13].
Standardized incidence rate.
The standardized incidence rate (SIR) was calculated to estimate the risks for the overall and age-specific cancers. It was calculated as the ratio of the observed number of cancers to the expected number of cancers. The 95% confidence intervals (CI) for the SIR were obtained by regarding the observed number of cancers as a Poisson variable and finding its related interval from tables based on the Poisson distribution [14].
Differences in therapy.
To study whether the incidence of cancer was influenced by treatment with cytotoxic drugs, a comparison was made between patients who developed malignancies and had been treated and those patients with SLE who did not develop malignancies but had also been treated with the same drugs. Statistical analysis was made using the exact method for the 2 x 2 contingency tables.
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Results |
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In total, 16 malignancies were diagnosed in 15 patients. There were five cases of breast carcinoma, two cases of non-Hodgkin's lymphoma, and one each of carcinoma of the prostate, cholangiocarcinoma, cervical carcinoma, vulval carcinoma, small cell carcinoma of the lung, squamous cell carcinoma of the anal canal, carcinoma of the colon, thymoma and basal cell carcinoma. However, five malignancies (one non-Hodgkin's lymphoma, two breast carcinomas, one thymoma and one carcinoma of the colon) were diagnosed before the diagnosis of SLE and were therefore excluded from the final statistical analysis. Basal cell carcinoma was also excluded from the final analysis, as no comparable figures were available for the general population. All patients were Caucasians, comprising one male and 15 females. Death as a direct result of malignancy occurred in six (2.3%) patients, accounting for 22.6% of deaths in our cohort of SLE patients. The mean age of diagnosis of SLE was 34.7 yr and the mean time between diagnosis of SLE and the occurrence of malignancy was 7.4 yr. Table 1 shows the observed number of cancers in patients with SLE, patient-years at risk for females and the overall sex- and age-specific estimated risks of cancer in female patients. There was only one male patient in our cohort who developed prostate cancer in the age group 7579 yr (a total of 147 male patient-years at risk was calculated to estimate the expected number of cancers). The SIR was 7.7 (0.1942.89) (the P value was not statistically significant). The overall estimated risk for developing a malignancy was SIR 1.16 (95% CI 0.562.13, P < 0.05).
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Discussion |
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Table 3 outlines the major published series to date. We selected large cohort studies rather than reviewing individual case reports. In summary, four large studies have indicated an overall increased risk when compared with the general population [5, 6, 8, 9.
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Petterson et al. [8] suggested that there was an increased risk for all malignancies but found a dramatically increased risk (RR 44, 95% CI 11.9111) based on four cases of non-Hodgkin's lymphoma. Lewis et al. [9] also suggested an increased risk. He also used hospital admission records to identify the patients with SLE. Again, this may have exaggerated the risk as they may have included patients with more severe SLE. Canoso and Cohen [10] suggested that there was perhaps an increased frequency, 11.4% of their cohort of 70 patients with SLE developing a malignancy. However, they had an excess of superficial epithelial lesions (three cervical intraepithelial neoplasias and one Bowen's carcinoma of the skin).
Abu-Shakra et al. [2] noted that the overall risk of cancer was not increased in their cohort of SLE patients, but there was a 4.1-fold increased risk for haematological malignancies, and only non-Hodgkin's lymphoma (three cases) was significantly associated with an increased risk (SIR 5.4). This association is far smaller than that reported by Pettersson et al. [8] (SIR 44) (based on four cases). The general impression from these studies remains that there may be an increased risk, particularly from haematological malignancies and breast and lung carcinomas.
Series looking into the cause of death in cohorts of patients with lupus do not give a true incidence of malignancy, as they do not mention whether any tumours had been treated successfully (as not all malignancies cause death) [1518]. Therefore these series may underestimate the incidence of malignancies.
There are numerous anecdotal reports of haematological malignancies in patients with SLE; in the majority of patients SLE precedes the diagnosis of lymphoproliferative disease. Patients with lymphoma may present with clinical and laboratory features suggestive of autoimmunity, including fever, rashes, arthralgias and autoantibodies. Our patients certainly fulfilled the revised ARA criteria for the classification of SLE [12], and several years had lapsed between the diagnosis of SLE and malignancy.
It has been shown previously that patients with RA are at increased risk of haematological malignancies [1]. Abu-Shakra [2] compared the risk of cancer in their cohort of SLE patients with RA and SSc. It was found that the overall risk of cancer was not increased in RA compared with the general population, but a twofold increased risk was observed in patients with SSc compared with the general population. The overall SIR in the SLE cohort was significantly lower compared with that in patients with RA (SIR 0.65, 95% CI 0.410.96) and patients with SSc (SIR 0.4, 95% CI 0.260.60). None of the 248 patients in the SSc cohort developed haematological malignancies. Of the 1426 RA patients, four had lymphoma, two had leukaemia and one developed a myeloma. The prevalences reported in two studies for patients with rheumatoid arthritis in the absence of immunosuppressive treatment were 0.08 and 1.56% respectively [20, 21].
Interestingly, both the patients who developed lymphoma in our study had both SLE and Sjögren's syndrome. The relative risk for primary Sjögren's syndrome patients developing non-Hodgkin's lymphoma has been estimated to be approximately 40-fold higher than that for age- and sex-matched control subjects in investigations at the National Institute of Health [19]. However, this may be a slight overestimate. We have also found that patients with Sjögren's syndrome have an increased risk of developing non-Hodgkin's lymphoma [4]. The prevalence of malignant non-Hodgkin's lymphoma in Sjögren's syndrome patients was estimated to be 4.3%, whereas the prevalence in two studies for patients with RA in the absence of immunosuppressive treatment was 0.08 and 1.56% respectively [22, 23].
The reason lymphoma occurs more commonly in patients with SLE than in the general population is unknown. A side-effect of immunosuppression is a possibility, as is intercurrent viral infection due to, for example, EpsteinBarr, herpes simplex, herpes zoster and polyoma viruses, which are potentially oncogenic. Patients who have had a renal transplant are known to have an increased risk of cancer [22]. They are, however, treated with much higher doses of immunosuppressive agents than patients with lupus. In the studies of Pettersson et al. [8] and Abu-Shakra [2] and in our study, the use of cytotoxic agents was not related to the occurrence of malignancy. It may be that the disease itself confers an increased risk. Patients with SLE have defects in both their cellular and humoral immune systems. Prolonged stimulation of B lymphocytes together with defective immune surveillance could result in the formation of autonomous B-cell clones. It is possible that malignant lymphoma, RA and SLE are manifestations of the same underlying disturbance, and may be ascribed to chronic antigenic stimulation [23].
Two studies have found an increased risk of breast carcinoma [4, 7]. Oestrogenic hormones have been suggested as a possible causal factor in the development of SLE. Risk factors such as low parity or nulliparity and large body size with truncal obesity are well-known risk factors for the development of breast cancer [24, 25].
However, large multicentre studies are required to address adequately the risk of developing malignancies in large cohorts of patients with SLE and to address issues such as associated risk factors and additional confounding factors, such as deprivation and exposure to therapy. The chance of detection of a malignancy may vary due to factors such as access to health services, which vary widely and are not uniformly available (cf. the USA), and may therefore underestimate the risk of malignancy.
In conclusion, we did not observe an overall increased risk for the development of malignancies in our cohort of patients when compared with the population of the southeast of England. However, we found that SLE was associated with an increased risk of Hodgkin's lymphoma. There was no statistically significant difference in therapy with cytotoxic agents between those patients who developed a malignancy and those that did not. We recommend vigilance in dealing with patients with SLE during long-term follow-up, checking in particular for persistent lymphadenopathy, splenomegaly and breast lumps.
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Notes |
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References |
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