The most important underlying factors in hepatocarcinogenesis are viral infections (HBV, HCV) and toxic injuries (aflatoxin, alcohol). Thus, where HBV and HCV are endemic, there is a very high incidence of HCC. Coinfection further increases risk. Aflatoxin is a mycotoxin produced by Aspergillus species that contaminates staple food crops in Africa and Asia. Aflatoxin metabolites are present in the urine of individuals who consume these foods, as are aflatoxin-albumin adducts in serum. These biomarkers identify populations at risk and have helped to confirm the importance of aflatoxin in hepatocarcinogenesis. As discussed earlier, aflatoxin synergizes with HBV (and perhaps also with HCV) to increase risk further.
Other HCC risk factors all share the ability to cause chronic liver injury associated with varying degrees of inflammation. These factors include:
Alcohol consumption, which synergistically increases risk with HBV, HCV, and possibly even cigarette smoking.
Inherited disorders, particularly hereditary hemochromatosis and α1AT deficiency, and to a lesser degree Wilson disease
Metabolic syndrome and its attendant obesity, diabetes mellitus, and NAFLD, all of which increase the risk for HCC.
Fig. 16.36 (A)HepatitisC–relatedcirrhosiswithadistinctivelylargedys-plasticnodule(arrows). Nodule-in-nodulegrowthsuggestsanevolvingcancer.
(B)HistologicallytheregionwithintheboxinA showsawell-differentiatedhepatocellularcarcinoma(right side) andasubnoduleofmoderatelydiffer-entiatedhepatocellularcarcinomawithinit(center, left). (Courtesy of Dr. Masamichi Kojiro, Kurume University, Kurume, Japan.)
As with all cancers, HCC is induced by acquired driver mutations in oncogenes and tumor suppressor genes. No single, universal sequence of molecular or genetic alterations leads to emergence of HCC. Gain of function mutations in beta-catenin and loss of function mutations in p53 are the two most common driver mutations. Beta-catenin mutations are identified in up to 40% of HCCs. These tumors are more likely to be unrelated to HBV and to demonstrate genomic instability. Inactivation of TP53 is present in up to 60% of HCCs. These tumors are strongly associated with exposure to aflatoxin, which appears in many cases to be directly responsible for the causative TP53 mutations.
HCC often appears to arise from premalignant precursors lesions. Hepatic adenoma has already been discussed, some of which carry beta-catenin–activating mutations. Chronic liver disease is associated with cellular dysplasias called large-cell change and small-cell change. These may be found at any stage of chronic liver disease, before or after development of cirrhosis, and serve to indicate which patients need more aggressive cancer surveillance. Dysplastic nodules are usually found in cirrhosis, either radiologically or in resected specimens (including explants). Low-grade dysplastic nodules may or may not undergo transformation to higher-grade lesions, but they indicate a higher risk for HCC. High-grade dysplastic nodules are probably the most important precursor of HCC in viral hepatitis and alcoholic liver disease. Overt HCC is often found in high-grade dysplastic nodules in biopsy or resection specimens.
MORPHOLOGYHCC may appear grossly as (1) a unifocal (usually large) mass (
Fig.16.37 );(2) multifocal,widely distributed nodules of variable size; or (3) a diffusely infiltrative cancer, permeatingwidelyandsometimesinvolvingtheentireliver.SometimesHCCsarisewithindysplasticnodules(