Incidence of Malignant Disease in Biopsy-Proven Inflammatory Myopathy: A Population-Based Cohort Study

Although an association between polymyositis and dermatomyositis and malignant disease was first suggested in 1916 (1, 2), the validity and the magnitude of this association continue to be questioned (3-11). Clinical and methodologic factors that have hindered resolution of this question have included diagnostic suspicion and referral bias; the legitimacy of the diagnosis of myositis and, in particular, the distinction between polymyositis and dermatomyositis; studies with small samples and short duration of follow-up; and lack of an appropriate control group. It is important to know for certain whether an increased risk for malignant disease exists, and the magnitude and duration of that risk. This knowledge may assist clinicians in making decisions about the need to follow patients for malignant disease, particularly conditions for which benefits of early treatment are proven. We performed a population-based retrospective cohort study to determine the risk for malignant disease in patients with biopsy-proven idiopathic inflammatory myopathies. Methods Identification of Biopsy-Positive Inflammatory Myopathy We used the Victorian Neuropathology Service (which has reviewed all muscle biopsies performed in the state of Victoria, Australia, since 1981) to identify all patients in whom biopsy-positive idiopathic inflammatory myopathies were first diagnosed from 1981 through 1995. All muscle biopsy reports generated since 1981 were searched for key words that would identify all potential biopsy-positive inflammatory myopathies; these included the specific diagnostic labels inflammatory myopathy, myositis, polymyositis, dermatomyositis, inclusion-body myositis, childhood myositis, focal necrotizing myositis, and connective tissue disease. Reports were also searched for key words that suggested the presence of an inflammatory myopathy; these included inflammation, inflammatory cells, lymphocytes, rimmed vacuoles, and myosinolysis. One pathologist who was blinded to the biopsy reports subsequently reviewed all biopsies that were identified as including one or more key words in their reports. Myopathies were categorized as polymyositis, dermatomyositis, myositis associated with connective tissue disease, childhood myositis, or inclusion-body myositis according to the pathologic criteria for inflammatory myopathies of Banker and Engel (12). In brief, in idiopathic polymyositis, normal sarcomere architecture is destroyed, with resultant loss of cross-striations in affected muscle fibers. Other changes include myophagia, segmental degeneration, and regeneration. The inflammatory cell infiltrate usually consists of lymphocytes with some reactive macrophages. The minimum criteria for classification as polymyositis were segmental degeneration with diffuse fascicular involvement and some inflammatory cells. Dermatomyositis is characterized by myosinolysis, floccular degeneration, and capillary loss in the perifascicular regions of the muscle fasciculi. Perifascicular atrophy and inflammatory cells may also be observed in these regions and in the adjacent interstitial connective tissue. Changes on electron microscopy include tubuloreticular inclusions in endothelial cells of blood vessels. The minimum criteria for classification as dermatomyositis were myosinolysis and perifascicular focus. Childhood dermatomyositis may also show a more focal ischemic lesion. The minimum criteria for classification as childhood dermatomyositis were those used for dermatomyositis or the presence of several contiguous degenerating fibers. The criteria for classification as inclusion-body myositis were partial myophagia and the presence of rimmed vacuoles, along with additional fiber atrophy and endomysial fibrosis. Patients younger than 16 years of age at diagnosis of myositis were considered to have childhood myositis. Our earlier study established the validity of our method for identifying all biopsy-positive cases of idiopathic inflammatory myopathies in the state of Victoria, Australia (13). In that study, we used a dual search strategy to identify all newly diagnosed cases from 1989 through 1991. Review of all 1024 muscle biopsies performed during this period identified 103 cases that satisfied the pathologic criteria of idiopathic inflammatory myopathies. Hospital discharge diagnoses from all major metropolitan and 12 minor metropolitan and rural Victorian hospitals in 1989 through 1991 were also reviewed, and identified cases of idiopathic inflammatory myopathies were verified by medical record review. No additional biopsy-positive cases were identified by hospital record search (13). Identification of Malignant Disease The demographic characteristics of all identified patients with biopsy-proven myositis were matched to the records of the Victorian State Cancer Registry. This registry includes details of all cases of malignant disease occurring in Victoria, apart from nonmelanocytic skin cancers. Notification of malignant diagnoses to the registry is mandatory by law, and almost complete ascertainment is achieved by notification from pathology laboratories and hospital medical record departments and by screening of death certificates. The International Classification of Diseases, ninth revision (ICD-9), is used to code the site of malignant disease (14), and the ICD-Oncology morphology rubrics are used to code histologic type (15, 16). At the time of the study, the registry was complete through 1997. We used the date of diagnosis of malignant disease as listed in the Victorian Cancer Registry in our analysis. Identification of Deaths The Australian Institute of Health and Welfare also matched the demographic details of all identified biopsy-proven cases of myositis to the National Death Index to identify all deaths up until the end of 1999. The study was approved by the Ethics Committees of Monash University and the Anti-Cancer Council of Victoria. Statistical Analysis To estimate the risk for malignant disease, the analysis included all patients whose malignant disease was diagnosed concurrently with (within 7 days) or after diagnosis of myositis. Patients whose diagnosis of malignant disease predated their diagnosis of myositis by more than 1 week were included in descriptive statistics only. For patients with more than one malignant disease, only time to first malignant disease was considered unless the first case occurred before diagnosis of myositis and a subsequent independent case occurred after diagnosis of myositis (3 participants). A second analysis was performed in which the first year of follow-up after diagnosis of myositis was excluded. Because data were complete only through 1997, any malignancies diagnosed after this time were excluded from the analysis. Standardized incidence ratios for malignant disease were calculated for each myositis category, sex, and time since diagnosis by using the rates of malignant disease in the population of Victoria, Australia (17), stratified by age, sex, and calendar period (18). The standardized incidence ratio compares the incidence of malignant disease observed in the myositis cohort (or subgroup) with that expected if the cohort developed malignant disease at the same rates as the population of Victoria. A standardized incidence ratio greater than 1 indicates elevated incidence of malignant disease in the study cohort with myositis relative to the population. Crude incidence curves were produced by using the KaplanMeier method. Internal comparisons of rates within myositis subgroups were made by performing Cox regression with age as the basic time scale and adjusting for time since diagnosis (<1, 1 to <3, 3 to <5, or >5 years after diagnosis of myositis). In addition, sex and calendar period were controlled for as stratification variables because of their nonproportionality of hazards. Interactions between terms were assessed by adding cross-product terms to the regression model and using the likelihood ratio test. No interactions were statistically significant at the 10% level. All analyses were performed by using Stata for Windows, version 6 (Stata Corp., College Station, Texas). Results Five hundred thirty-seven patients with biopsy-positive idiopathic inflammatory myopathy were identified. Demographic characteristics are shown in Table 1. A total of 116 cases of malignant disease were identified in 104 patients (9 patients had 2 malignant conditions and 2 patient had 3 malignant conditions). The prevalence of malignant disease in each myositis diagnosis category ranged from 4% for childhood myositis to 18% for polymyositis and 42% for dermatomyositis. Seventy-four cases of malignant disease in 69 patients were diagnosed concurrently with or after myositis diagnosis. Another 6 cases of malignant disease were diagnosed in the 3 months before diagnosis of myositis. Figure 1 shows the duration of time between diagnosis of polymyositis and dermatomyositis and diagnosis of malignant disease. Twenty-six percent (15 of 58) of cases of malignant disease in polymyositis occurred before diagnosis of polymyositis, compared with 53% (19 of 36) of cases of malignant disease in dermatomyositis. Table 1. Biopsy-Positive Myositis in Victoria, Australia, 19821991 Figure 1. Time between diagnosis of polymyositis ( top ) or dermatomyositis ( bottom ) and diagnosis of malignant disease. Follow-up beyond 7 days before diagnosis of myositis was complete for 502 patients. The median follow-up was 5.3 years (range, 0.1 days to 15.7 years). When data from the first year after myositis diagnosis were excluded, 445 patients had a median follow-up beyond 1 year of 5.0 years (range, 41 days to 14.7 years). The overall risk for malignant disease in idiopathic inflammatory myopathy was increased (standardized incidence ratio, 2.6 [95% CI, 2.1 to 3.3]) (Table 2). Risk for malignant disease was also increased within each subgroup of myositis. This risk was highest in dermatomyositis (standardized incidence ratio,