Cancer and systemic sclerosis: novel insights into pathogenesis and clinical implications

Abstract

Purpose of review: Most epidemiologic studies have demonstrated an increased risk of cancer in scleroderma patients. Reasons for this risk increase have been poorly understood and often attributed to cytotoxic therapies or damage from scleroderma. Recognition that some patients have a close temporal relationship between cancer diagnosis and scleroderma clinical onset has focused attention on the possibility that scleroderma may be a paraneoplastic syndrome in a subset of patients. This review will discuss the latest epidemiologic data linking cancer and scleroderma and explore a model for the development of paraneoplastic scleroderma.

Recent findings: New investigations have demonstrated an association between RNA polymerase III autoantibodies and a close temporal relationship between cancer diagnosis and the development of clinical scleroderma. A unique nucleolar RNA polymerase III expression pattern has been identified in malignant tissue from these scleroderma patients suggesting that autoantigen expression in the cancer and the autoantibody response are associated. Similar data in inflammatory myositis have illustrated that disease-specific autoantigens may be expressed in cancers and damaged target tissues (muscle) undergoing regeneration.

Summary: These data suggest a model of paraneoplastic autoimmunity in which cross-reactive immune responses may target autoantigens that are expressed in both cancers and diseased autoimmune target tissues.

Figure 1. Scleroderma duration at cancer diagnosis by autoantibody status

Scleroderma patients with cancer and RNA polymerase III autoantibodies (anti-RNA pol I/III) had a close temporal relationship between cancer diagnosis and systemic sclerosis clinical onset compared to patients with other antibody types. Reproduced with permission from [24•].

Figure 2. RNA polymerase III staining is prominent in cancerous tissue from scleroderma patients as compared with normal tissues

Paraffin sections from cancerous breast tissue from a scleroderma patient (a) and from normal breast tissue (b) stained with antibodies against RNA polymerase III. Brown shows RNA polymerase III staining; blue shows nuclei (Mayer’s hematoxylin counterstain). Original magnification ×40. Reproduced with permission from [24•].

Figure 3. Conceptual framework for the paraneoplastic model – tumors and distant tissues may share antigens that are targets of the immune response

Transformed cells may expose self-antigen through varied mechanisms and trigger an antitumor immune response. This primes the immune system. Injured distant tissues may expose these same self-antigens during repair and regeneration mechanisms (e.g. differentiation of cell types involved in repair) and be a target of the immune response. Thus, the immune response initiated against tumor antigens may be propagated against the same antigens in target tissues.