Case Report: Coexisting antisynthetase syndrome and malignancy - a focused discussion of possible immunological links

Antisynthetase syndrome (ASSD) is an autoimmune disorder classified within the spectrum of idiopathic inflammatory myopathies (IIMs), characterized by specific autoantibodies directed against aminoacyl-tRNA synthetases and variable combinations of interstitial lung disease (ILD), myositis, arthritis, and other systemic features. Current risk-stratification frameworks classify ASSD as a comparatively low-risk phenotype for occult malignancy relative to dermatomyositis. However, this “low-risk” label is derived from population averages and may not adequately capture the risk borne by specific ASSD subsets, particularly older patients with systemic inflammatory features and low creatine phosphokinase (CPK) levels, in whom recent multicenter cohorts report a several-fold increase in cancer incidence. We report two patients with ASSD diagnosed in temporal association with malignancy: a 36-year-old woman with anti-Jo-1-positive inflammatory myopathy and arthritis concurrent with grade 2 infiltrating ductal breast carcinoma (T1c N0 M0), and a 61-year-old man with anti-PL-12-positive ILD, arthritis, mechanic’s hands and fever diagnosed in the setting of a poorly differentiated gastroesophageal junction adenocarcinoma (T4N3M0). In the first patient, autoimmune manifestations improved alongside oncological control and relapsed synchronously with metastatic recurrence, only to remit again after oncological retreatment without escalation of immunosuppression — a pattern compatible with a paraneoplastic phenomenon. In the second patient, advanced malignancy and diagnostic complexity culminated in a fatal outcome. These observations do not, in isolation, establish a causal or pathogenic relationship between ASSD and cancer. However, taken together with recent cohort data suggesting that cancer-associated myositis (CAM) may be more prevalent in ASSD than previously appreciated, they argue against an overly reassuring interpretation of ASSD´s malignancy risk. We further discuss, as an explicitly hypothesis-generating avenue, how oncogenic dysregulation of aminoacyl-tRNA synthetase expression, transcriptional control, and non-canonical signaling functions in tumor cells could theoretically create a substrate for immune cross-reactivity — a mechanistic hypothesis that remains open and should be the subject of translational investigation.