Progressive increase of SCCA‐IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma

Abstract

About 3-4% of cirrhotic patients develop primary liver cancer every year. Specific serologic markers have not yet been identified for screening of high risk patients. The serpin squamous cell carcinoma antigen (SCCA) is overexpressed in liver cancer and circulating SCCA-IgM complexes have been described in patients with hepatocellular carcinoma (HCC). The aim of the present study was to assess the behavior of SCCA-IgM in relation to HCC development in patients with cirrhosis. A retrospective, longitudinal study was conducted in a cohort of prospectively followed cirrhotic patients. Two groups with similar clinical profile at presentation were studied : group A included 16 patients who developed HCC during a median follow up of 4 years; group B included 17 patients who did not develop HCC during the same time interval. Circulating SCCA-IgM immune complexes were determined using a recently standardized ELISA assay. At presentation similar levels of SCCA-IgM complexes [mean 6 SD: 267.40 6 382.25 U/ml vs. 249.10 6 446.90 U/ml, p 5 0.9006] and of alpha-fetoprotein [AFP; 24.11 6 59.04 IU/ml vs. 10.91 6 23.34 IU/ml, p 5 0.3995] were detected in group A and in group B. The increase over time (/) of SCCA-IgM, assessed within at least one year before clinical diagnosis of HCC, was remarkably higher in group A than in group B (mean 6 SD 5 280.05 6 606.71 (U/ml)/year vs. 237.92 6 95.94 (U/ml)/year, p 5 0.0408), while AFP increase was not significantly different (11.89 6 23.27 (IU/ml)/year vs. 3.67 6 11.46 (IU/ ml)/year, p 5 0.2179). Receiver operating characteristic (ROC) curves were plotted for the rate of change in the levels of both markers and the diagnostic accuracy measured as AUROC was higher for SCCA-IgM / (0.821) than for AFP / (0.654). In conclusion, the progressive increase of SCCA-IgM over time was associated with liver tumor development, suggesting that monitoring the behavior of SCCA-IgM might become useful to identify cirrhotic patients at higher risk of HCC development. ' 2006 Wiley-Liss, Inc.Key words: SCCA-IgM; hepatocellular carcinoma; serologic prognostic marker; cirrhosis Hepatocellular carcinoma (HCC) is one of the major health problems worldwide, due to its high incidence and severe prognosis. Figures depicting half a million new cases per year have been reported, and projection studies have estimated an increase of tumor development within the next decade in developed countries. 1The reasons advocated to explain this phenomenon are the increased rate of HCV infection and an improvement in clinical management of liver cirrhosis, identified as the major risk factor for HCC development.2 About 3-4% of cirrhotic patients develop primary liver cancer every year and this justifies surveillance programs to detect HCC at an early stage. 3 The prognosis of the patients depends mainly on the evolutionary stage of the neoplasm, ranging from 5-years survival higher than 70% in surgical patients to less than 3 months in very advanced tumors. 4 Tumor size is one of the main factors influencing the possibility of b...

Experimental validation of specificity of the squamous cell carcinoma antigen-immunoglobulin M (SCCA-IgM) assay in patients with cirrhosis

“…been proposed in a prospective study of two groups of cirrhotic patients with or without HCC evolution. In this study, an increase in circulating SCCA-IgM was associated with the development of HCC (11). While conventional serum biomarkers failed in the screening of cirrhotic patients in HCC surveillance programmes, SCCA-IgM has shown promise (12).…”

“…This has been reported for a-fetoprotein (AFP) and des-gcarboxy-prothrombin (DCP), which are conventional serological biomarkers of HCC, and also for the newly described HCC biomarker squamous cell carcinoma antigen (SCCA) (7,8). In addition, the clinical value of SCCA-IgM as a predictive biomarker of evolution of HCC in patients with cirrhosis has been also reported, demonstrating that the increase in serum concentrations over time of SCCA-IgM in patients with cirrhosis was associated to higher risk of development of HCC (11). The behaviour of serum concentrations of SCCA-IgM was studied in two groups of cirrhotic patients with similar clinical profiles at presentation and followed prospectively.…”

Clinical applications of squamous cell carcinoma antigen-immunoglobulins M to monitor chronic hepatitis C

“…The increase of AFP, measured in parallel in the same serum samples, was not significantly different in patients who developed HCC and in those without liver tumor progression. Accordingly, the predictive value of SCCAIgM variation was found to be significantly better than that of AFP for predicting the progression to HCC (AUC: 0.821 vs 0.654) [51] . These data were in line with another retrospective study performed by Buccione et al [52] .…”

“…The first evidence of the behavior of SCCA-IgM during antiviral treatment with PEG-IFN and ribavirin was obtained from a longitudinal study in 2010 [48] . Giannini et al [48] demonstrated that in patients with HCVrelated cirrhosis who achieved sustained virological [44] Significant increase of SCCA-IgM levels over time in 75% of untreated patients with chronic hepatitis and with histologically proven liver disease progression (fibrosis score increase ≥ 2) after six years of follow-up Martini et al [46] In patients with chronic hepatitis C, SCCA-IgM was found an independent predictor of histologically proven non alcoholic steatohepatitis SCCA-IgM and antiviral treatment Giannini et al [48] In chronic hepatitis C treatment with standard therapy, only patients who achieved sustained viral response showed a significant decrease in median values of SCCA-IgM up to one year of follow-up Fransvea et al [49] Reduction of SCCA-IgM levels during the first month of standard antiviral therapy was an independent predictor of sustained viral response Martini et al [46] Significant reduction of SCCA-IgM, lasting up to 6 mo of follow-up, was observed only in HCV-positive patients with sustained response to standard therapy SCCA-IgM in diagnosis and prognosis of HCC Pontisso et al [51] Significant increase over time of SCCA-IgM only in patients with early cirrhosis (histologically proven) who developed HCC within four years of follow up Buccione et al [52] In HCV-positive patients with overt cirrhosis, SCCA-IgM negativity (cut off ≤ 200 AU/mL) accurately identified patients at low risk of liver cancer development in the subsequent year Beneduce et al [24] SCCA-IgM showed higher sensitivity for the diagnosis of HCC, compared to AFP Pozzan et al [53] In patients with HCC, SCCA-IgM levels were found an independent predictor of survival. A reduction in SCCA-IgM levels was correlated with response to HCC treatment HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; AFP: Alpha-fetoprotein; SCCA-IgM: Squamous cell carcinoma antigen-immunoglobulins M.…”

“…In liver cirrhosis the rate of HCC progression is 3%-4% every year [50] ; the identification of the subgroup of patients with possible HCC development within the next few years would allow the development of a personalized clinical management characterized by more effective early therapeutic interventions. In order to explore this possibility, SCCAIgM was analyzed in a retrospective, longitudinal study that was preliminary conducted in a cohort of HCVinfected patients with early stage of cirrhosis, defined on the basis of histological findings [51] . This population was divided in two groups with similar clinical characteristics and no significant difference in the absolute value of the immunecomplex at baseline.…”