In paraneoplastic muscle disease, the malignancy may remotely affect neuromuscular transmission or incite muscle inflammation or necrosis. In several of these diseases, an autoimmune basis for the muscle disease has been established and has become a defining feature. These paraneoplastic muscle diseases may be the first manifestation of a malignancy, and their diagnosis thus demands a vigilant search for an underlying tumor. This article is focused on inflammatory and necrotizing myopathies and disorders of neuromuscular transmission that may arise in the setting of malignancy and are considered paraneoplastic phenomena.
Skeletal muscle disease may arise in the setting of malignancy. The potential mechanisms are varied and may include direct invasion of the muscle by an adjacent tumor, the rare occurrence of a skeletal muscle metastasis, muscle injury from chemotherapy or infection, dysfunction from metabolic derangements, and wasting as a result of tumor-related cachexia. The term paraneoplastic is applied when none of these mechanisms are applicable. In paraneoplastic muscle disease, the malignancy may remotely affect neuromuscular transmission or incite muscle inflammation or necrosis. In several of these diseases, an autoimmune basis for the muscle disease has been established and has become a defining feature. These paraneoplastic muscle diseases may be the first manifestation of a malignancy, and their diagnosis thus demands a vigilant search for an underlying tumor. This article is focused on inflammatory and necrotizing myopathies and disorders of neuromuscular transmission that may arise in the setting of malignancy and are considered paraneoplastic phenomena.
Dermatomyositis and polymyositis
Dermatomyositis (DM) has been linked with underlying malignancy since the publication of 2 case reports of this association in 1916. A significantly increased risk of a malignancy among patients with DM has now been established from epidemiologic studies, with the risk of malignancy being highest at the time of or within 1 year of diagnosis. The risk of an underlying malignancy is much lower for polymyositis (PM) but remains statistically significant.
The criteria by Bohan and Peter for the diagnosis of PM and DM have been the standard since their publication in 1975, although new criteria are clearly needed. The author identified a total of 35 retrospective case series of inflammatory myopathy in the period between 1975 and 2009 that used these diagnostic criteria and reported the occurrence of malignancy in these patients ( Table 1 ). These series from diverse geographic areas include 2326 patients with DM, of whom 557 (24%) had an associated malignancy, and 941 patients with PM, of whom 97 (10%) had an associated malignancy. Carcinomas of the nasopharynx (23%), lung (15%), breast (15%), ovary (8%), colon (5%), stomach (3%), and liver (3%) were the most common malignancies associated with DM. There was no predominant tumor type among the limited number of cases associated with PM.
|References||Malignancy in DM||Malignancy in PM||Source of Patients|
|1/12 (8%)||1/15 (7%)||1 medical center (United States)|
|5/11 (45%)||2/11 (18%)||1 medical center (Canada), 73% fulfilled Bohan and Peter criteria|
|15/40 (38%)||2/35 (6%)||Cases referred to 3 electromyographic laboratories (Singapore)|
|30/103 (29%)||7/206 (3%)||1 medical center (Hungary)|
|10/28 (36%)||2/64 (3%)||1 medical center (Japan)|
|7/27 (26%)||1/31 (3%)||1 medical center (United States)|
|9/20 (45%)||4/15 (27%)||1 medical center (Israel)|
|8/53 (15%)||5/57 (9%)||1 medical center (United States)|
|10/39 (26%)||3/21 (14%)||All general hospitals in Israel, overlap myositis excluded|
|12/56 (21%)||12/84 (14%)||1 medical center (France)|
|16/91 (18%)||2/14 (14%)||1 medical center (Taiwan)|
|9/31 (29%)||8/40 (20%)||1 inpatient rheumatic disease unit (Canada)|
|11/50 (22%)||18/65 (28%)||1 medical center (United States)|
|7/36 (19%)||9/69 (13%)||1 medical center (Australia)|
|3/19 (16%)||4/51 (8%)||Multiple medical centers (Sweden)|
|4/10 (40%)||0/18||Muscle biopsy cases in 1 laboratory (Canada)|
|7/39 (18%)||2/20 (10%)||1 medical center (France)|
|5/16 (31%)||6/25 (24%)||1 medical center (Korea)|
|13/33 (39%)||3/7 (43%)||1 medical center (France)|
|3/24 (13%)||3/34 (9%)||1 inpatient rheumatic disease unit (United States)|
|25/62 (40%)||3/59 (5%)||1 medical center (United States)|
|12/50 (24%)||—||1 medical center (Bulgaria)|
|9/32 (28%)||—||1 medical center (France)|
|13/32 (41%)||—||1 medical center (France)|
|23/53 (43%)||—||2 medical centers (United Kingdom)|
|6/10 (60%)||—||1 medical center (Singapore)|
|12/38 (32%)||—||1 medical center (Singapore)|
|34/118 (28%)||—||All dermatologic university medical centers in France|
|12/28 (43%)||—||1 medical center (Singapore)|
|9/18 (50%)||—||1 medical center (Norway)|
|20/130 (15%)||—||All university hospitals of Tunisia|
|5/12 (41%)||—||1 medical center (Singapore)|
|9/18 (50%)||—||1 medical center (Denmark)|
|16/84 (19%)||—||1 medical center (Hungary)|
|10/29 (35%)||—||1 medical center (France)|
|5/43 (12%)||—||1 medical center (United States)|
|29/121||—||2 medical centers (France)|
|8/32||—||1 medical center (Bosnia)|
|115/678||—||1 medical center (China)|
These case series demonstrated that the association with malignancy was much stronger for DM than for PM. These series also highlighted the influence of ethnicity on the types of associated malignancy, the temporal association between the myositis and the malignancy, and the type of evaluation used to recognize the malignancy. These cases were also subject to several forms of bias and thus do not establish a casual link between malignancy and either DM or PM. Almost all cases had a referral bias, using patients seen in tertiary hospitals or specialty clinics. In addition, these cases were subject to Berkson bias; a patient with an occult malignancy who had an associated myopathy was more likely to be hospitalized than a similar patient without myopathy. The bias of increased suspicion and scrutiny for malignancy in patients with PM/DM also existed.
The association of malignancy with DM and PM has been scrutinized in 5 population-based retrospective cohort studies ( Table 2 ). In each study, the risk of malignancy in a population-based cohort of patients with PM and DM was compared with that in a normal population. This study design reduced the biases related to referral and diagnostic suspicion of malignancy. In 4 of the studies, all patients with PM and DM hospitalized during a defined period were identified from national hospital discharge databases. These studies analyzed cohorts from Sweden, Denmark, Finland, and Scotland, which were ethnically homogeneous. The fifth study identified all cases of biopsy-proven idiopathic inflammatory myopathies in the state of Victoria, Australia during a defined period, using the records of the state reference neuropathology laboratory in which all muscle biopsies results are reviewed. The occurrence of malignancy (excluding nonmelanoma skin cancers) in these patients was determined from national cancer registries and also, in 1 study, from death records for the same period. Malignancies that were identified at the same time or after the diagnosis of myositis were included in the calculation of risk. In some studies, malignancies that were identified during the first 3 to 12 months after the myositis diagnosis were excluded in separate analyses to eliminate diagnostic suspicion bias.
|References||Frequency of Malignancy in DM||DM SIR||Frequency of Malignancy in PM||PM SIR|
|36/85 (42%)||6.2 (3.9–10.0)||58/321 (18%)||2.0 (1.4–2.7)|
|19/71 (27%)||6.5 (3.9–10.0)||12/175 (7%)||1.0 (0.5–1.8)|
|77/286 (27%)||7.7 (5.7–10.1)||71/419 (17%)||2.1 (1.5–2.9)|
|31/203 (15%)||3.8 (2.6–5.4)||26/336 (8%)||1.7 (1.1–2.4)|
|59/392 (15%)||2.4 (1.6–3.6), men; 3.4 (2.4–4.7), women||37/396 (9%)||1.8 (1.1–2.7), men; 1.7 (1.0–2.5), women|
Each of these 5 studies identified an increased risk of malignancy in patients with DM compared with the general population (see Table 2 ). The overall standardized incidence ratios ranged from 3.8 to 7.7. In addition, 2 of the studies identified an increased but lesser risk in patients with PM, with overall standardized incidence ratios of 1.7 to 2.0. The cancer risk was increased approximately sixfold during the first year after myositis diagnosis but was lower during the second year, with no significant excess in subsequent years of follow-up. The increased risk of malignancy in DM remained evident when malignancies identified during the first 3 months or the first year after the diagnosis of myositis were excluded. Inclusion body myositis was also associated with an increased risk of malignancy in the one study that used muscle biopsy reports for case finding.
These 5 population-based cohort studies have limitations. Of these, 4 studies relied on the accuracy of discharge coding to identify patients with myositis. Airio and colleagues sought to review the medical records of all identified patients and subsequently excluded 226 of 627 patients. Sigurgeirsson and colleagues reviewed every tenth record and found that 7% probably had neither DM nor PM. There was no medical record review in the other 3 studies. With the exception of the study by Buchbinder and colleagues, the diagnoses of PM and DM were based on the criteria by Bohan and Peter in 1975 and thus did not require histopathologic confirmation, which may have led to the misclassification of myositis types and failure to exclude cases of inclusion body myositis from the PM subtype.
Types of Malignancies Associated with DM and PM
The types of malignancies associated with DM and PM in Western countries was best determined by Hill and colleagues with a pooled analysis of the original and more recent follow-up data from the 3 population-based cohort studies performed in Sweden, Denmark, and Finland. Among a total of 618 patients with DM, 115 developed cancer after the diagnosis of myositis. The overall standardized incidence ratio was 3.0 (95% confidence interval [CI], 2.5–3.6). The types of cancer with the greatest increased relative risk were ovary (10.5; 95% CI, 6.1–18.1), lung (5.9; 95% CI, 3.7–9.2), pancreatic (3.8; 95% CI, 1.6–9.0), stomach (3.5; 95% CI, 1.7–7.3), and colorectal (2.5; 95% CI, 1.4–4.4.) cancers and non-Hodgkin lymphoma (3.6; 95% CI, 1.2–11.1). Among 914 patients with PM, 95 developed cancer after the diagnosis of myositis. The relative risks were increased for non-Hodgkin lymphoma (3.7; 95% CI, 1.7–8.2), lung cancer (2.8; 95% CI, 1.8–4.4), and bladder cancer (2.4; 95% CI, 1.3–4.7). The most common cancer type was adenocarcinoma, accounting for 70% of all tumors associated with patients with DM and PM.
Among Asian populations, nasopharyngeal and hepatocellular carcinomas have been strongly associated with DM. Among 143 patients with probable or definite DM/PM in Taiwan, 18 (13%) had an identified malignancy, the most common being nasopharyngeal carcinoma. Similarly, gastric carcinoma may be the most common associated cancer in Japanese populations.
The histologic type and stage of certain cancers that are associated with DM have been characterized in case reports and series. Ovarian cancer was most often diagnosed during the first year after the diagnosis of DM, almost always epithelial in origin (adenocarcinoma or cystadenocarcinoma) and in Stage III or IV when recognized in the context of DM. In a review of the literature, Fujita and colleagues identified 24 patients (5 women and 19 men) with primary lung cancer associated with DM or PM. The most common cell types were small cell carcinoma (29%), squamous cell carcinoma (21%), and adenocarcinoma (8%). In 5 of these patients, the onset of myositis preceded the diagnosis of cancer by more than a year.
Clinical Course of Malignancy and Myositis
Isolated case reports have highlighted patients with DM with an associated malignancy in whom the DM improved after successful treatment of the tumor or worsened with evidence of tumor recurrence. Such a parallel course between the DM and the malignancy is supportive of a paraneoplastic phenomenon but was observed in only 8 of 45 patients reported by Bonnetblanc and colleagues In contrast, Andras and colleagues reported remission of the myositis in 16 of 22 patients with cancer-associated DM who received effective antitumor therapy. The failure to demonstrate this parallel course may reflect the advanced stage of the malignancy when it is ultimately diagnosed. The excess risk of malignancy that remains as long as 5 years after the diagnosis of myositis needs further study because it challenges the concept of a paraneoplastic phenomenon.
Risk Factors for Malignancy in DM and PM
A variety of factors influence the risk of an associated malignancy in DM/PM ( Box 1 ). The risk of malignancy is higher in older patients with DM or PM. In the population-based cohort studies by Airio and colleagues and Chow and colleagues, an increased risk of malignancy was only evident in patients older than 45 to 50 years at the time of myositis diagnosis. An increased risk was evident for patients with DM aged 45 to 74 years and patients with PM aged 15 to 44 years in the study by Stockton and colleagues. This increased risk of malignancy in older patients with DM was also evident in other cohort analyses but not in 2 others.
Older age at onset
More severe skin disease
Cutaneous necrosis and ulceration
Resistance to therapy
More severe muscle disease
Distal muscle weakness
Respiratory muscle involvement
Refractory to treatment
Elevated erythrocyte sedimentation ratio and C-reactive protein level
Low C4 level
Lower serum albumin level
Elevated levels of tumor markers
Interstitial lung disease
Positive test results for antinuclear antibodies and extractable nuclear antigens