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The characteristics and prognosis of cryptogenic hepatocellular carcinoma (HCC) remain unclear. The albumin-bilirubin (ALBI) grade and its updated version, the easy ALBI (EZ-ALBI) grade, are important prognostic predictors for HCC. We aimed to investigate the long-term survival of patients with cryptogenic HCC and the prognostic role of ALBI and EZ-ALBI grade in these patients. A prospective cohort of 2,937 HCC patients with viral or cryptogenic etiology were retrospectively analyzed. The multivariate Cox model was used to determine prognostic predictors. Cryptogenic HCC patients were often older and diabetic, had lower serum ɑ-fetoprotein (AFP) levels, larger tumor burden, poor performance status, advanced cancer stage, and received non-curative treatments compared with hepatitis B or C-related HCC. The Cox analysis showed that age &gt; 65 years, serum AFP &gt; 400 ng/mL, presence of vascular invasion or distant metastasis, presence of ascites, performance status 2–4, ALBI grade 2 and 3, EZ-ALBI grade 2 and 3, and non-curative treatment, were independent predictors of decreased survival in cryptogenic HCC ( p  &lt; .001). Significant survival differences were found across ALBI grade and EZ-ALBI grade in cryptogenic HCC and subgroup patients receiving curative or non-curative treatments. The Cancer of Liver Italian Program was the best staging system for patients with cryptogenic HCC. Patients with cryptogenic HCC have a larger tumor burden and advanced cancer stage at disease presentation compared with those with viral HCC. The ALBI and EZ-ALBI score are robust models to evaluate liver functional reserve for these patients independent of treatment modality.

Cryptogenic hepatocellular carcinoma: characteristics, outcome, and prognostic role of albumin-bilirubin (ALBI) grade vs easy ALBI grade