Robert Fox, MD


August 30, 2002


In certain malignancies, patients may have positive antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), and dsDNA. Has this been investigated and if so, what does the literature say? Also, how common is positive dsDNA in multiple sclerosis?

Gamal Ibrahim, MRCP, MSc

Response from Robert Fox, MD

The frequency of ANA in association with malignancies has not been carefully ascertained in most cancers, although case reports with malignancy associated with ANA are common. Perhaps the most carefully studied associations are ANA and hepatocellular carcinomas, due to the relatively high frequency of ANA with this malignancy.[1,2,3] A recent study examined sera from 200 hepatocellular carcinoma patients, 68 chronic hepatitis C patients, 126 chronic hepatitis B patients, and 30 alcoholic liver cirrhosis patients. Hepatocellular carcinoma had a significantly higher frequency of ANA using HEp-2 cells as substrate (31%) than chronic hepatitis C (10%), chronic hepatitis B (9.5%), alcoholic liver cirrhosis (10%), or healthy donors (4.5%).

The specificity of the ANA in malignancy is more diverse than in autoimmune disorders, where a particular pattern of ANA is often correlated with a clinical autoimmune disorder. The ANA in the sera of patients with hepatocellular carcinoma often included antibodies that colocalized with non-snRNP splicing factor SC35, suggesting that the antigenic targets might be involved in mRNA splicing. In other hepatocellular carcinoma sera, antibodies to 2 known nuclear autoantigens were identified: fibrillarin and p330d/CENP-F. These autoantigens are involved in the 5' processing of precursor ribosomal RNA transcripts and in mitotic functions, respectively.[1] Also, antibodies to topoisomerase[4] and other antigens[2] have been reported in hepatocellular carcinoma.

Paraneoplastic syndromes may be associated with neurologic disorders and autoantibodies to the Hu antigen that is cross-reactive with Sjögren's SS-A antigen.[5] In addition to the anti-Hu antibodies, autoantibodies against various autoantigens, including oncoproteins (P185, 1-myc, c-myc, c-myb), tumor suppression genes (P53), proliferation-associated antigens (cyclin A, B1, D1, E; CENP-F; CDK; U3-RNP), other onconeural antigens (Yo, Ri, Tr), cancer/testis antigens (MAGE, GAGE, BAGE, SSX, ESO, SCP, CT7), and rheumatic disease-associated antigens (RNP, Sm) have been reported.[6] In addition, antineuronal nuclear antibodies (ANNA-1, ANNA-2, and ANNA-3) are markers of paraneoplastic neurologic autoimmunity related to small-cell carcinoma, and the frequency of these antigens is approximately 20 in 50,000 patients with carcinoma.[7,8]

The association of carcinoma with polymyositis and dermatomyositis has been well described and is associated with ANA.[4] A wide variety of cancer types have been associated with the autoimmune disorders, which raises a question about immune reactions to the tumor as a cause of the autoimmune disorder.[9,10] Autoantibodies are frequently (up to 25% of patients) found in non-Hodgkin's lymphoma.[11] In addition, these patients may have autoimmune symptoms, including hemolytic anemia and thrombocytopenia.[11]

Antineutrophil cytoplasmic antibodies also have been found in patients with malignancies, particularly lymphoid and renal.[12,13] Anti-dsDNA antibodies have been reported in the pleural fluid of patients with lung cancer,[14] as well as in patients with coexistent systemic lupus erythematosus.[10]

Although anti-dsDNA antibodies have not been frequently associated with multiple sclerosis, anticardiolipin antibodies have been found frequently but their significance remains unclear.[15] It is also worth pointing out that patients infected with HIV may exhibit antibodies to dsDNA as well as to cardiolipin in up to 10% of cases.[16] These patients frequently have coexisting hepatitis C infection and may develop lymphoproliferative disease or encephalomalacia that could mimic multiple sclerosis.[17]