Original Article
Risk of Cancer in Patients with Dermatomyositis or Polymyositis
N Engl J Med 1992; 326:363-367February 6, 1992
- Abstract
- Abstract
Background.
An association between polymyositis and cancer was first proposed in 1916, but the existence of the association has been disputed. An association between dermatomyositis and cancer is better accepted, but its magnitude is not known.
Methods.
We undertook a study to provide accurate estimates of the risk of cancer in patients with dermatomyositis or polymyositis. We studied the incidence of cancer and the rate of mortality from cancer in a population-based cohort of 788 patients with dermatomyositis or polymyositis in Sweden from 1963 through 1983. The results were compared with those for the general population.
Results.
Among the 396 patients with polymyositis, 42 cancers were diagnosed at the same time or after polymyositis was diagnosed in 37 patients (9 percent). The relative risk of cancer was 1.8 (95 percent confidence interval, 1.1 to 2.7) in the male patients and 1.7 (95 percent confidence interval, 1.0 to 2.5) in the female patients. Eighty-four males and 85 females died, and in 24 of these cases (14 percent) cancer was the principal cause of death. The mortality ratio (the rate of mortality from cancer in these patients as compared with that in the general population) was 0.90 (95 percent confidence interval, 0.6 to 1.4).
Among the 392 patients with dermatomyositis, 61 cancers were diagnosed at the same time or after dermatomyositis was diagnosed in 59 patients (15 percent). The relative risk of cancer was 2.4 (95 percent confidence interval, 1.6 to 3.6) in the male patients and 3.4 (95 percent confidence interval, 2.4 to 4.7) in the female patients. Fifty-seven males and 110 females died, and in 67 of these cases (40 percent) cancer was the principal cause of death (mortality ratio, 3.8; 95 percent confidence interval, 2.9 to 4.8).
Conclusions.
The risk of cancer is increased in patients with polymyositis or dermatomyositis. In patients with dermatomyositis there is also a higher rate of mortality from cancer. (N Engl J Med 1992;326:363–7.)
Media in This Article
Figure 1
Temporal Relation between the Diagnosis of Polymyositis and the Diagnosis of Cancer.Figure 2
Temporal Relation between the Diagnosis of Dermatomyositis and the Diagnosis of Cancer.Article Activity
- Article
AN increase in the incidence of cancer in patients with polymyositis, first noted in 1916,1 has been reported in many studies2 3 4 5 6 7 8 9 10 11 12 13 14 from different countries, but this relation is not uniform.15 Estimates of the associated risk vary widely (between 6 and 60 percent), probably because of the small size of the studies and the selected nature of the groups of patients studied at referral centers. The possible effects of the length of follow-up and age at diagnosis are also unclear. In addition, it is uncertain whether any particular sites of cancer are involved. To provide more accurate estimates of the risk, we studied a population-based cohort of 788 patients who received a diagnosis of dermatomyositis or polymyositis in Sweden between 1963 and 1983. Follow-up was complete through 1987, and observation time thus ranged from 5 to 25 years after a patient's first evaluation for dermatomyositis or polymyositis.
Methods
Patients
Beginning in 1964, the Swedish National Board of Health and Welfare collected information about people who were hospitalized. In 1964 the registry covered only 20 percent of the country's population of 8.3 million, but its coverage increased during the following years, so that by 1969 60 percent of the population was covered. Since 1970 the registry has been virtually nationwide. The information collected includes a unique identification number for each person, used in all population statistics in Sweden, the dates of admission and discharge, the diagnosis, and the nature and dates of any surgical procedures.
From this registry we selected the diagnoses of dermatomyositis and polymyositis, using codes 710.00, 710.01, and 726.30 from the Swedish adaptation of the International Classification of Diseases, 7th Revision (ICD-7) for the period 1964 through 1968, and codes 716.00 and 716.10 from the eighth revision (ICD-8) for the period 1969 through 1983. Patients seen only as outpatients were not included in the study, but in Sweden it is customary to hospitalize patients suspected of having dermatomyositis or polymyositis for evaluation. Patients given a diagnosis of polymyositis from 1964 through 1968 were excluded from the study, since the ICD-7 code did not cover that diagnosis alone during the period.
With these methods we identified 788 patients in whom dermatomyositis or polymyositis was listed in the registry for the first time from 1964 through 1983. There were 392 patients with dermatomyositis (145 male and 247 female, with a mean age of 47 years [range, 11 months to 88 years]) and 396 patients with polymyositis (168 male and 228 female, with a mean age of 56 years [range, 6 months to 92 years]). There were 77 patients under the age of 16 years (20 percent) among those with dermatomyositis, and 12 (3 percent) among those with polymyositis. The average follow-up was 10.4 years for cancer and 11.4 years for death. The number of person-years of observation was 5990, after correction for deaths during the study period.
The Swedish Cancer Registry and Cause-of-Death Registry
Information from the Swedish Cancer Registry from 1958 through 1987 was correlated with the records of the 788 patients to identify those with cancer. Nationwide information on the incidence of cancer in Sweden is available for the years since 1958, when compulsory registration began.16 The cancers are classified according to the ICD-7, as recommended by the World Health Organization. The cancer registry collects information on diagnosed cancers from clinicians and pathologists. If a person has more than one cancer, each is registered separately. Basal-cell carcinomas are not registered. The completeness of registration is close to 100 percent for all cancers.17
The cause-of-death registry includes information on all deceased persons listed in the parish registers, whether they died in Sweden or abroad.18 The underlying cause of death is generally determined from data on medical death certificates, which were designed in accordance with the internationally established norm.
Original Medical Records
Over 90 percent of the 788 patients were hospitalized in university hospitals or large central hospitals. Since the number of patients was large, and some had been in different Swedish hospitals up to 50 times since 1963, we judged it impossible to review all the hospital records, although we did review every 10th record. Two dermatologists reviewed the records and classified the patients according to the criteria of Bohan and Peter (as described by Caro19). Of the 76 patients selected for this review, the records of 7 were not available at the local hospital; 50 of the remaining 69 (72 percent) were classified as definitely having dermatomyositis or polymyositis, 14 (20 percent) as probably having one of the conditions, and 5 (7 percent) as probably not having either condition. For the 14 patients classified as probably having dermatomyositis or polymyositis, information about the criteria of Bohan and Peter was often absent in the medical records. This was particularly true in old records and cases for which only summaries were available.
Statistical Analysis
We estimated the expected number of cancers in our study group using incidence data from the cancer registry and a specially developed computer program, CANEST (CANcer ESTimates).20 The program calculated the risk of cancer for each patient individually. The calculation was based on incidence data for the years between the first diagnosis of dermatomyositis or polymyositis and 1987 (or death, if earlier). Information about deaths in the cohort was obtained from the cause-of-death registry. Total risk was calculated as the sum of the individual risks. The relative risk of cancer, which is the ratio between the actual and the expected number of cancers, was used to assess the risk of cancer. The actual number of cancers in the cohort was obtained from the cancer registry. We calculated confidence intervals for the relative risk assuming a Poisson distribution.21 This method has been described in detail elsewhere.20 A standardized mortality ratio was calculated on the basis of data from the cause-of-death registry in order to assess the extent to which mortality from dermatomyositis or polymyositis mirrored morbidity from dermatomyositis or polymyositis. The expected number of deaths during the study period was calculated in a similar manner, the comparison group in both instances being the general population of Sweden. Owing to incomplete identification numbers, 38 patients (11 with polymyositis and 27 with dermatomyositis) could not be matched with information from the cause-of-death registry. A lower limit of the 95 percent confidence interval that exceeded 1.0 was taken to indicate statistical significance.
We analyzed the cohort according to disease (dermatomyositis or polymyositis), sex, and time of diagnosis. To determine the risk of cancer in patients with no signs of cancer, we excluded all patients with a cancer diagnosed during their first hospital stay or one month thereafter. To minimize the effects of treatment with cytostatic and immunosuppressive drugs on the development of cancer, we analyzed the first five years after the diagnosis of dermatomyositis or polymyositis separately.
All tabulations and all statistical analyses not performed with the CANEST program were performed with the SPSS statistical package.
Results
From 1958 to 1987, a total of 58 cancers were diagnosed in the patients with polymyositis, and 94 in the patients with dermatomyositis. The temporal relation between the diagnosis of cancer and the diagnosis of dermatomyositis or polymyositis is shown in Figures 1Figure 1
Temporal Relation between the Diagnosis of Polymyositis and the Diagnosis of Cancer. and 2Figure 2Temporal Relation between the Diagnosis of Dermatomyositis and the Diagnosis of Cancer.. No cancers were diagnosed in patients under 16 years of age.Polymyositis
Among the 396 patients with polymyositis, 42 cancers were diagnosed in 37 patients (9 percent) at the same time or after polymyositis was diagnosed. The relative risk of cancer was 1.8 (95 percent confidence interval, 1.1 to 2.7) in the male patients and 1.7 (95 percent confidence interval, 1.0 to 2.5) in the female patients. When individual sites of cancer were analyzed, a significant increase was found only for cancer of the lung in males (relative risk, 5.6; 95 percent confidence interval, 2.2 to 11.4). These results are summarized in Table 1Table 1
Number of Cancers Diagnosed in Patients with Polymyositis at the Time of the Diagnosis of Polymyositis or Later.*.To minimize the effects of immunosuppressive and cytostatic treatment on the risk of developing cancer, the first five-year period after the diagnosis of polymyositis was considered separately. The relative risk of cancer for this period was 2.4 (95 percent confidence interval, 1.4 to 4.0) in the male patients and 1.8 (95 percent confidence interval, 0.9 to 3.1) in the female patients. The risk of cancer was not significantly increased in any particular site.
To examine the risk of cancer in patients who had no obvious signs of cancer when polymyositis was diagnosed, we excluded nine patients in whom cancer was diagnosed during the first hospitalization for polymyositis or within one month after discharge. The relative risk for the remaining patients was 1.5 (95 percent confidence interval, 0.7 to 2.8) in the males and 1.4 (95 percent confidence interval, 0.7 to 2.6) in the females.
During the study period, 169 of the 385 patients with polymyositis for whom data on death were available (44 percent; 84 males and 85 females) died. The respective mortality ratios were 1.3 (95 percent confidence interval, 1.0 to 1.6) for males and 1.1 (95 percent confidence interval, 0.9 to 1.3) for females.
The principal cause of death was cancer in 24 of these patients (14 percent) (mortality ratio, 0.9; 95 percent confidence interval, 0.6 to 1.4). Twenty-two (13 percent) died of polymyositis, and 77 (46 percent) of circulatory diseases (Table 2Table 2
Mortality among 365 Patients with Dermatomyositis and 385 Patients with Polymyositis, with Principal Causes of Death.*). The survival of these patients is shown in Figure 3Figure 3
Actual and Expected Survival of Patients 16 Years Old or Older with Dermatomyositis or Polymyositis..Dermatomyositis
Among the 392 patients with dermatomyositis, 61 cancers were diagnosed in 59 patients (15 percent) at the same time or after dermatomyositis was diagnosed. The relative risk of cancer was 2.4 (95 percent confidence interval, 1.6 to 3.6) in the male patients and 3.4 (95 percent confidence interval, 2.4 to 4.7) in the female patients. The risks for individual sites of cancer are shown in Table 3Table 3
Number of Cancers Diagnosed in Patients with Dermatomyositis at the Time of Diagnosis of Dermatomyositis or Later.*.The five-year period after the diagnosis of dermatomyositis was considered separately. The relative risk of cancer for male patients with dermatomyositis during this period was 4.4 (95 percent confidence interval, 3.0 to 7.5), and for female patients it was 4.8 (95 percent confidence interval, 4.3 to 9.0). The distribution and risk of individual cancers were similar to those shown in Table 3, but the individual risks were higher. For example, the risk for cancer of the ovary was 16.7 (95 percent confidence interval, 5.4 to 38.9) during this period.
Twenty-three patients were given a diagnosis of cancer during their first hospitalization for dermatomyositis or within one month after discharge. The relative risk of cancer in the remaining patients was 2.2 in the males (95 percent confidence interval, 1.0 to 4.3) and 3.9 in the females (95 percent confidence interval, 2.3 to 6.2).
During the study period, 167 of the 365 patients with dermatomyositis for whom data on death were available (46 percent; 57 males and 110 females) died. The respective mortality ratios were 1.5 (95 percent confidence interval, 1.2 to 2.0) for males and 2.1 (95 percent confidence interval, 1.7 to 2.5) for females.
The principal cause of death was cancer in 67 of these patients (40 percent) (mortality ratio, 3.8; 95 percent confidence interval, 2.9 to 4.8). Seventeen (10 percent) died of dermatomyositis, and 44 (26 percent) of circulatory diseases (Table 2). The survival of these patients is shown in Figure 3.
Discussion
Since an association between polymyositis and cancer was first proposed in 1916,1 its validity has been in dispute. Although not confirmed by all studies, there appears to be an increased incidence of cancer in patients with polymyositis and an even greater risk of cancer in patients with dermatomyositis.11
In 1975 Bohan and Peter22 defined five criteria for the diagnosis of dermatomyositis and polymyositis. These criteria have been used in Sweden since then, so that each of our study groups should have been relatively homogeneous. Since the study was based on data from a registry, however, we cannot guarantee that no patients with overlapping syndromes were included, although the results from the sample of records that were reviewed make this unlikely.
We found a moderate but significant increase in the incidence of cancer in male and female patients with polymyositis. There was a clear increase in the number of cancers in patients with dermatomyositis, especially in the female patients. Patients with dermatomyositis and polymyositis are often treated with cytostatic and immunosuppressive agents. To minimize the effect of such treatment on our results, we considered the first five years after the diagnosis of dermatomyositis or polymyositis separately. The risk of cancer was high during this period in the patients with dermatomyositis, which strongly suggests an association between dermatomyositis and cancer. The risk of cancer of the ovary was increased nearly 17-fold. One must also bear in mind that because the incidence of cancer is generally considered to be increased in patients with polymyositis and dermatomyositis, such patients are likely to be more thoroughly evaluated for cancer than others. This factor may have been responsible for the moderate increase in risk we found in the patients with polymyositis during this five-year period.
In Sweden it is customary to search for cancer in patients with dermatomyositis and polymyositis. The subcohort of patients with polymyositis who had no signs of cancer when first admitted to a hospital for polymyositis had no excess risk of cancer, but there was an elevated risk in the comparable subcohort of patients with dermatomyositis. The risk was elevated twofold in males and fourfold in females. These results indicate a need for close surveillance in patients with dermatomyositis.
Mortality was slightly increased in male patients with polymyositis, but not in female patients. Mortality was clearly increased in patients with dermatomyositis, particularly in the females, in whom the risk was doubled. This increase in the patients with dermatomyositis was due mainly to deaths from cancer (Table 2). When we considered cancer mortality, only patients with dermatomyositis had an increased risk of dying from cancer. Since the incidence of cancer is always questionable because of increased surveillance among patients with dermatomyositis or polymyositis, the data on cancer mortality probably provide sounder evidence of the association between these diseases and cancer.
Both dermatomyositis and polymyositis are rare diseases, so it is difficult for individual centers to accumulate many patients. Most earlier studies were based on patients from referral centers. Because patients with dermatomyositis or polymyositis who also have cancer are more likely to be referred, bias is introduced by the use of this population. A second problem, that of withdrawal bias, occurs when the patients who remain in a study have a higher frequency of the associated disease. This bias does not apply to our study, since all the patients could be followed through the Swedish Cancer Registry, which has national coverage. The estimated number of cancers was also very reliable, because since 1958 the cancer registry has provided yearly incidence figures that allow the very accurate estimation of numbers. The weakness of many previous studies is that they stated the incidence of cancer among patients with dermatomyositis or polymyositis but failed to relate this incidence to the expected number of cancers in that group. The expected number can be reliably estimated only by applying time- and age-specific data on incidence. A third bias, the bias of diagnostic suspicion, occurs when patients included in a study are evaluated more thoroughly for the putative associated disease than they would otherwise have been. Because the association between dermatomyositis or polymyositis and cancer has been known for a long time, it is indeed probable that this bias obtains. Its effects are probably evident, at least in part, in the peak number of cancers diagnosed around the time of the diagnosis of dermatomyositis or polymyositis. Since the observation time in our study was at least 5 years (average, 10) after the first evaluation for polymyositis or dermatomyositis, the effect should have disappeared over time.
Our findings demonstrate that patients with polymyositis have a moderately higher risk of cancer than the general population. The mortality data make it questionable whether the higher risk is real or the result of increased surveillance among such patients. On the other hand, patients with dermatomyositis have a definite increase in the risk of cancer, a finding supported by the data on mortality from cancer. In patients with dermatomyositis, a search for cancer at regular intervals is therefore warranted.
We are indebted to Ms. Lotti Barlow, Mr. Curt-Lennart Spetz, and Mr. Lars-Gunnar Hörte for data processing.
Source Information
From the Department of Dermatology, Karolinska Hospital, Stockholm (B.S., B.L.), the Department of Social Medicine, Huddinge Hospital, Huddinge (B.S., E.A.), and the National Board of Health and Welfare, Stockholm (O.E.), all in Sweden. Address reprint requests to Dr. Sigurgeirsson at the Department of Dermatology, Karolinska Hospital, S-104 01 Stockholm, Sweden.
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