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ObjectiveTo investigate histologic features of immunological components in the primary tumor site of patients with cancer-associated myositis (CAM) by focusing on tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which play major roles in antitumor immunity.MethodsCancer-associated myositis patients were selected from the single-center idiopathic inflammatory myopathy cohort based on the availability of primary tumor specimens obtained before the introduction of immunomodulatory agents. Control cancer subjects without CAM were selected from the cancer tissue repository at a ratio of 1:2 matched for demographics and cancer characteristics of CAM cases. A series of immunohistochemical analyses was conducted using sequential tumor sections. TLS was defined as an ectopic lymphoid-like structure composed of DC-LAMP+ mature dendritic cells, CD23+ follicular dendritic cells (FDCs) and PNAd+ high endothelial venules. TLS distribution was classified into the tumor center, invasive margin, and peritumoral area.ResultsSix CAM patients and 12 matched non-CAM controls were eligible for the study. There was no apparent difference in the density or distribution of TILs between the groups. TLSs were found in 3 CAM patients (50%) and 4 non-CAM controls (33%). TLSs were exclusively located at the tumor center or invasive margin in CAM cases but were mainly found in the peritumoral area in non-CAM controls. FDCs and class-switched B cells colocalized with follicular helper T cells were abundantly found in the germinal center-like area of TLSs from CAM patients compared with those from non-CAM controls.ConclusionThe adaptive immune response within TLSs in the primary tumor site might contribute to the pathogenic process of CAM.

BackgroundConcomitant malignancy is one of the prognostic factors in patients with myositis,1 but clinical parameters for mortality still remain unknown in patients with cancer-associated myositis (CAM).ObjectivesInitial predictors for mortality were examined using a multicenter cohort of CAM patients.MethodsThis retrospective study enrolled 67 consecutive patients diagnosed as having CAM in 3 referral hospitals between 1995 and 2017. Clinical data at diagnosis of myositis as well as treatment regimens and outcomes of myositis and malignancy were collected by review of medical charts. Myositis-specific autoantibodies (MSAs) were comprehensively detected using RNA immunoprecipitation (IP), enzyme-linked immunosorbent assay, and IP-immunoblotting. We initially conducted a univariate analysis to select variables that were different between survivors and dead cases. In multivariate analysis, the Cox proportional hazard model with backward selection method (p>0.20) was employed to identify factors independently associated with mortality. Explanatory variables were chosen based on the following three models. The Model 1 included age at diagnosis of myositis, gender and candidate variables (p<0.1) selected by the univariate analysis. The Model 2 included age, gender, prognostic factors previously reported in myositis, such as dermatomyositis, dysphasia, interstitial lung disease (ILD), anti-ARS, and anti-MDA5, and malignancy type and staging, as explanatory variables. In the Model 3, age, gender, disease duration before diagnosis of myositis, period between diagnosis of myositis and tumour, myositis classification, MSAs, dysphasia, ILD, myositis disease activity after treatment, and malignancy type and staging were used as explanatory variables. Cumulative survivals calculated using the Kaplan-Meier method were compared between the patients with and without risk factors.ResultsThe median age at diagnosis of myositis was 63 years, and 62% were female. MSAs were detected in 47 patients: anti-TIF1-γ in 27, anti-ARS in 6, anti-MDA5 in 5, anti-Mi-2 in 3, anti-NXP2 in 3, anti-SAE in 2, and anti-SRP in 1. During the median observation period of 2 years, 19 (28%) of 67 CAM patients were dead due to tumour in 16, ILD in 1, and an unknown cause in 2. The univariate analysis identified significant poor prognostic factors (p<0.1) as follows: male (p=0.04), elder age at diagnosis of myositis (p=0.08), longer period between diagnosis of myositis and tumour (p=0.07), absence of breast cancer (p=0.001), malignancy stage III/IV (p=0.006). In multivariate analysis, male (HR 8.1, 95% CI 2.6–25.2; p<0.001) and malignancy stage III/IV (HR 12.1, 95% CI 3.3–44.9; p<0.001) were identified as independent risk factors for mortality in the Model 1, and identical variables were identified in the Models 2 and 3. Cumulative survival rates of patients with 0, 1, or 2 risk factors were 100%, 93%, and 69% at 1 year, and 100%, 82%, and 0% at 3 years, respectively. Cumulative survival rates were statistically different between the groups stratified by the...