Cancer and scleroderma: A paraneoplastic disease with implications for malignancy screening

Purpose of review. Recent data suggest a paraneoplastic mechanism of scleroderma pathogenesis in unique subsets of scleroderma patients. In this article, we review these data, explore potential links between cancer and scleroderma, and propose an approach to malignancy screening in scleroderma. Recent findings. Emerging data have demonstrated that patients with scleroderma and RNA polymerase III autoantibodies have a significantly increased risk of cancer within a few years of scleroderma onset. Genetic alterations in the gene encoding RNA polymerase III (POLR3A) have been identified, and patients with somatic mutations in POLR3A have evidence of mutation specific T-cell immune responses with generation of cross-reactive RNA polymerase III autoantibodies. These data strongly suggest that scleroderma is a by-product of antitumor immune responses in some patients. Additional epidemiologic data demonstrate that patients developing scleroderma at older ages may also have a short cancer-scleroderma interval, suggestive of paraneoplastic disease. Summary. Scleroderma may be a paraneoplastic disease in unique patient subsets. Aggressive malignancy screening in these patients may aid in early cancer detection. Further study is required to determine whether cancer therapy could improve scleroderma outcomes in this patient population.