Two most important predictors of survival of patients who present with hepatocellular carcinoma (HCC) and cirrhosis are severity of liver disease and tumor characteristics. The tumor characteristics that provide the most useful information are tumor size, number of tumor nodules, tumor differentiation, and vascular invasion. Tumor size and number of tumor nodules are good surrogate markers of vascular invasion.1,2 Vascular invasion has been shown to be significantly more common in patients with tumor diameter greater than 5 cm as compared to those with smaller tumors.1 Tumor differentiation is also an important predictor of outcome.3–8 This information is easy to obtain in the explants or resection specimens of patients who undergo transplantation or partial hepatectomy. Aspiration cytology specimens, however, do not provide adequate information on tumor differentiation, and core biopsies may carry additional risks in patients with advanced cirrhosis. Additionally, large tumors are known to be heterogeneous and this may cause significant sampling errors.8
In the absence of extrahepatic disease, microscopic or macroscopic vascular invasion is the best predictor of tumor recurrence after resection or transplantation as vascular infiltration is considered to be a prerequisite for systemic tumor dissemination. Presence of macroscopic vascular invasion of the portal or hepatic veins, as determined by imaging or histology, carries a high risk of tumor recurrence and a very poor prognosis after hepatectomy or transplantation.1–8 In this issue of the journal, Kikuchi et al9 from Brazil suggest that tumor size and vascular invasion are independent predictors of survival in patients with small HCC, defined as less than 3 nodules and all less than 3 cm. There are several limitations with this retrospective study.9 In this study, only 3 of 74 patients had vascular invasion, and all 3 had portal vein thrombosis. It is difficult to make a firm conclusion based on 3 patients, as admitted by the authors in their discussion, but nevertheless, these observations in Latin American patients corroborate previous observations from other parts of the world.1–8 Authors also conclude that treatment of small HCC, defined as tumors less than 2 cm in diameter, was associated with better patient survival as compared with tumors more than 2 cm, but less than 3 cm. Intuitively, this makes sense as small tumors are easy to treat by ablation techniques, and less likely to invade vessels, but the supportive data for this conclusion are very weak as only 9 of 74 patients were conservatively managed; 6 of these 9 patients were not treated because of advanced cirrhosis and 3 were lost for follow-up.
What have we learned from the last 2 decades of experience with imaging characteristics of HCC and survival? High-resolution, multidetector computed tomography scan or magnetic resonance imaging has increased our ability to detect macrovascular invasion to a level that is comparable with angiography.10 However, microscopic tumor invasion, as defined by the presence of tumor emboli within the central hepatic vein, the portal, or the large capsular vessel, cannot be detected with preoperative imaging.3 Biomarkers such as vascular endothelial growth factor have been reported to predict microscopic tumor invasion, but these observations require further validation before it could be used for clinical purposes.11,12 It has been shown that the tumor recurrence rates after liver transplantation could be as high as 35% with microscopic vascular invasion, independent of tumor size. Although vascular invasion has shown good correlation with tumor size, vascular invasion can be found in small tumors as shown by an autopsy study, where portal vein thrombi were found in 40% of individuals with tumors less than 5 cm.4 Although we have come a long way, our current techniques are inadequate to precisely predict survival of patients with HCC who undergo curative treatment. Better understanding of molecular signaling pathways that lead to HCC, and advances in genomic research may help us to develop molecular signatures that could be used to ascertain HCC recurrence risk, and more importantly, better individualized, treatment options.
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9. Kikuchi LO, Pranagua-Vezozoo DC, Chagas AL, et al. Nodules less than 20 mm and vascular invasion are predictors of survival in small hepatocellular carcinoma. J Clinical Gastroenterol. 2008.
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11. Poon RT, Ho JW, Tong CS, et al. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg. 2004;91:1354–1360.
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