BACKGROUND.Early detection of hepatocellular carcinoma (HCC), one of the most common and deadly tumors worldwide, still is difficult due to the lack of adequate biomarkers that show high sensitivity and specificity. The authors recently demonstrated that squamous cell carcinoma antigen (SCCA) variants were overexpressed remarkably in all surgically resected HCCs. METHODS.For the current study, the authors assessed the presence of SCCA, as a free form and complexed with immunoglobulins, in serum from patients with HCC, cirrhosis, and chronic hepatitis and from healthy control participants and compared SCCA measurement with the measurement of ␣-fetoprotein (AFP) levels. RESULTS.Circulating immune complexes (ICs) composed by SCCA and immunoglobulin M (IgM) IC (SCCA-IgM IC) were undetectable (Ͻ 120 arbitrary units[AU]/mL) in serum from a healthy control population (0 of 73 controls); however, 35 of 50 patients with HCC (70%) were reactive for SCCA-IgM IC independent of etiology (mean Ϯ standard deviation [SD], 2568.5 Ϯ 6797.3 AU/mL). No correlation was found with AFP levels, which were elevated significantly in only 21 of 50 patients with HCC (42%). By using an AFP cut-off value of 20 ng/mL, 96% of patients with HCC were positive for at least 1 marker. Among cirrhotic patients, the presence of circulating SCCA-IgM IC was displayed in 13 of 50 patients (26%), but at lower levels compared with the patients who had HCC (mean Ϯ SD, 147.5 Ϯ 348.3 AU/mL; P Ͻ 0.01; Student t test), whereas 9 of 50 patients with chronic hepatitis (18%) were reactive (mean Ϯ SD, 39.5 Ϯ 89.7 AU/mL). No significant presence of free SCCA, free anti-SCCA variants IgG or IgM, or SCCA-IgG IC was found. CONCLUSIONS.The study results indicated that SCCA-IgM ICs represent novel serologic biomarkers, which, alone or in combination with AFP, can increase the sensitivity for diagnosing HCC significantly.

We assessed the presence of alpha-fetoprotein (AFP) complexed with IgM (AFP-IgM IC) in serum of patients affected by hepatocellular carcinoma (HCC), cirrhosis and chronic hepatitis as well as in healthy subjects by means of a dedicated ELISA assay. The amount of AFP-IgM IC was expressed in arbitrary units (AU) on a reference standard curve. Free AFP (FAFP) levels were determined in parallel in each sample by means of an automated immunoassay system. The mean serum concentration of AFP-IgM IC was significantly higher in HCC patients (mean +/- SD: 1378.3 +/- 2935.7 AU/mL) than in cirrhotic patients (129.8 +/- 261.4 AU/mL) and in patients with chronic hepatitis (80.9 +/- 168.9 AU/mL) (p < 0.01). HCC patients had FAFP values above the 20 ng/mL cutoff in 44% of cases (22/50) and AFP-IgM IC values above the 120 AU/mL cutoff in 60% of cases (30/50). The occurrence of the free and IgM-complexed form of circulating AFP did not overlap, and 82% of patients (41/50) were positive for at least one marker. The results indicate that AFP-IgM IC is a complementary serological marker to FAFP and that the combination of these biomarkers may be useful in the diagnosis of liver cancer.

We have recently shown that alpha fetoprotein (AFP) and squamous cell carcinoma antigen (SCCA), biomarkers associated with hepatocellular carcinoma, may be detected in patient sera as circulating immune complexes with IgM, and that assessment of serum levels of AFP-IgM and SCCA-IgM may be used for the detection of liver cancer. In this study we measured the levels of carcinoembryonic antigen (CEA) as free form (FCEA) and complexed to IgMs (CEA-IgM) in sera of patients affected by colorectal carcinoma (CRC) at different stages as well as in healthy subjects. FCEA levels were above the 5 ng/mL cutoff in 43% of CRC patients (31/72) and CEA-IgM levels were above the 200 AU/mL cutoff in 38% of CRC patients (27/72). Serum levels of CEA-IgM immune complexes (IC) and FCEA did not overlap and 64% of patients (46/72) were positive for at least one marker without compromising the detection specificity (94%). Early detection of CRC was significantly improved by CEA-IgM IC assay. CRC patients at an early stage (stage 1) had elevated CEA-IgM levels in 29% of cases (7/24), while FCEA levels were elevated in only 8% of cases (2/24). These results indicate that CEA-IgM is a complementary serological marker to FCEA which is much more sensitive for early stage CRC, and that the combination of these biomarkers may be useful in the early detection of colorectal cancer.

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