Clinicopathologic features and treatment outcomes in Cronkhite-Canada syndrome: Support for autoimmunity

Background and Aims: Cronkhite-Canada syndrome (CCS) is a noninherited condition, associated with high morbidity, and characterized by gastrointestinal hamartomatous polyposis, alopecia, onychodystrophy, hyperpigmentation, and diarrhea. All features may respond to immunosuppressive therapy, but little is known about the etiology. An autoimmune origin has been suggested but not proved. From a retrospectively selected cohort, we evaluated clinicopathologic features, including immunostaining for IgG4 (an antibody associated with autoimmunity), and therapeutic outcomes in a cohort of CCS patients to provide further insights into this disease. Methods: Cases included 14 consecutive CCS patients seen at the Mayo Clinic on whom tissue and follow-up were available. All histology was reviewed by an expert gastrointestinal pathologist. Immunostaining for IgG4 was performed on 42 polyps from CCS cases and on control tissues, including 46 histologically similar hamartomas [from juvenile polyposis syndrome (JPS)] and 20 normal mucosae (six stomach, three small bowel, and 11 colon). Clinical features and treatment outcomes were descriptive. Results: All CCS cases had both upper and lower gastrointestinal polyps; most had typical dermatologic features of alopecia, hyperpigmentation, and onychodystrophy; and most had evidence of protein-losing enteropathy. Ten patients (71%) had adenomatous polyps and 2 (14%) had colorectal cancer. IgG4 immunostaining was positive (>5 cells/HPF) in 52% of CCS polyps compared to 12% of JPS polyps (P = 0.001); IgG4 staining was negative in all other control tissues. Of 11 CCS patients treated with oral corticosteroids, 91% achieved remission. Relapse was common with steroid tapering. Five patients who initially responded to corticosteroids were maintained in remission on azathioprine (2 mg/kg/day) with no relapse after a median of 4.5 years. Conclusions: Immunostaining for the autoimmune-related IgG4 antibody is significantly increased in CCS polyps compared to disease and normal control tissues. Furthermore, immunosuppression by corticosteroids or long-term azathioprine may eradicate or lessen manifestations of CCS. These histologic findings and treatment responses are consistent with an autoimmune mechanism underlying CCS.