The normal liver lobule contains liver parenchymal cells (hepatocytes), cholangiocytes, which line the biliary tree, and other nonparenchymal cells including hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells. The sinusoidal lumen and perisinusoidal space of Disse contain intrahepatic lymphocytes and liver-specific natural killer cells [14]. Chronic exposure to etiologic factors results in repeated cycles of injury, regeneration, and repair, eventually leading to cellular senescence. Some cells escape senescence by activating the telomerase reverse transcriptase gene or alternate mechanisms of telomere maintenance and become immortalized. In the genotoxic milieu of inflammation with enhanced free oxygen radical concentrations, immortalized cells acquire the critical number of mutations needed to transform first into dysplastic, and then neoplastic cells. This process is aided by changes in the cellular microenvironment, as exhaustion of the regenerative capacity of the liver is associated with proliferation and activation of hepatic stellate cells, leading to fibrosis, abnormal remodeling of liver tissue, and the development of cirrhosis.

There is accumulating evidence that chronic HBV and HCV infection both suppress the intrahepatic immune system and create an environment that is more permissive for carcinogenesis [15, 16]. Furthermore, patients with chronic HBV infection almost all acquire integrations of HBV into the host genome, which can induce carcinogenesis through a number of mechanisms, including activation of the telomerase reverse transcriptase (TERT) gene and other oncogenic molecules, the generation of novel oncogenic viral-host fusion proteins, and the generation of novel oncogenic viral-host long noncoding RNAs [17, 18].

The advent of next generation sequencing and other advanced genetic and genomic technologies has led to an improved understanding of the genetic events and cell signaling pathways that are most important in liver tumorigenesis. Key genes include TP53 (p53), TERT, CTNNBI (β-catenin), AXIN1, ARID1A, ARID2, CDKN2A (p16), DMXL1, NFE2L2, NLRP1, PIK3CA, and RPS6KA3. The signaling pathways corresponding to these genes include the mitogen-activated protein kinase, PI3K/Akt/mTOR, Wnt/β-catenin, TGFβ, integrin, antioxidant, and chromatin remodeling cell signaling pathways. These pathways target both cell proliferation and cell cycle regulation, as well as tumor cell apoptosis, invasion, migration, and the epithelial–mesenchymal transition; they also modulate interactions with microenvironmental factors that affect angiogenesis, inflammation, and antitumor immunity.

The clinical features of HCC are varied and depend on the degree of hepatic reserve. In cirrhotic patients, HCC may present with hepatic decompensation manifesting as jaundice, ascites, spontaneous bacterial peritonitis, or encephalopathy. In noncirrhotic patients, typical symptoms include anorexia, weight loss, weakness, abdominal pain, or a palpable mass. Although rare, paraneoplastic syndromes including erythrocytosis, hypercalcemia, hypercholesterolemia, thrombocytopenia, and hypoglycemia can occur early in patients with HCC. Such syndromes have been reported in up to 40 % of patients with large tumors and high alpha fetoprotein (AFP) levels. Patients with metastatic disease may present with symptoms related to the location of the metastasis.

Early diagnosis of HCC is crucial due to the rapidly progressive nature of the disease as well as the high morbidity and mortality associated with advanced disease. Several organizations provide guidelines for HCC screening. Table 22.2 summarizes screening recommendations from the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver—European Organization for Research and Treatment of Cancer (EASL-EORTC) and the Asia Pacific Association for the Study of the Liver (APASL). Screening of the general population is not recommended. Since there are no experimental data to suggest the degree of risk that warrants surveillance, the decision to screen is based on cost-effectiveness models. In patients requiring surveillance, liver ultrasound and serum AFP every 6 months are the de facto standard for screening, although some experts discourage the use of AFP because of its low sensitivity for early stage disease [19]. In clinical practice, the sensitivity of liver ultrasound alone for detecting early stage HCC in cirrhotic patients was found to be as low as 32 %, although most studies report better performance [20]. The combination of biannual ultrasound and AFP testing increased the sensitivity of early stage HCC detection to 63.4 %. Recent studies suggest that trends or variations in AFP levels are also predictive of HCC development [21, 22]. Other biomarkers including the AFP-L3 % and the des gamma carboxyprothrombin are also used in some countries for surveillance or risk stratification.

Detection of a liver nodule on ultrasound during surveillance warrants further investigation depending on the size of the nodule (Fig. 22.2). If the nodule is less than 1 cm, repeat ultrasound in 3 months is recommended. For nodules greater than 1 cm on initial ultrasound screening or on follow-up ultrasound examination, imaging with four-phase multidetector computed tomography (CT) or dynamic contrast-enhanced magnetic resonance imaging (MRI) is recommended. In these larger sized lesions, a diagnosis of HCC is made when the hallmark features of arterial hypervascularity and portal venous or delayed phase washout are observed on either imaging modality (Fig. 22.3). Further characterization of HCC can be observed as T2 hyperintensity, intensity on diffusion-weighted imaging, and lack of uptake on delayed hepatobiliary phase sequences with gadoxetate disodium (Eovist) or gadobenate dimeglumine (MultiHance) contrast MRI [23].

When the characteristic features of HCC are not demonstrated on either CT or MRI, the other imaging modality should be utilized. If both CT and MRI fail to show the expected hallmark features in a liver lesion greater than 1 cm, biopsy with pathologic examination is recommended. In practice, the US United Network for Organ Sharing (UNOS) does not assign priority points in the allocation of organs for LT to patients with tumors less than 2 cm in size. Therefore, in transplant eligible patients, most hepatologists will follow these lesions by performing cross-sectional imaging every 3 months until the 2-cm size cutoff is reached. By the time such lesions grow to 2 cm, they will often have acquired typical imaging features of HCC. Consequently, it is reasonable to defer biopsy in this group of patients, so minimizing the small but real risk of needle track seeding, which is a greater concern in patients undergoing LT who will require long-term immunosuppression . Another important consideration when biopsying small lesions is the 10 % or greater risk of a false negative result.

The most widely accepted staging method for HCC is the Barcelona Clinic Liver Cancer (BCLC) staging system, which associates each stage with a treatment recommendation. Based on performance status (PS), tumor characteristics, and liver function as classified by the Child-Pugh (CP) score, BCLC stratifies patients into very early (0), early (A), intermediate (B), advanced (C), and terminal (D) stages (Table 22.3). Patients with very early stage 0 disease have well-preserved liver function (CP A), are asymptomatic (PS 0), with one nodule of less than 2 cm, without satellites or vascular invasion. Patients classified as having early, intermediate, or advanced-stage disease have CP A or B liver function. Those with early stage A disease have PS 0, with a single nodule or up to three nodules less than 3 cm. Patients with intermediate stage B disease have PS 0 and multinodular disease, while those with advanced stage C disease are symptomatic with PS 1-2, and have extensive disease characterized by portal invasion or extrahepatic spread. Patients with terminal stage D disease are symptomatic with PS > 2, CP C or advanced CP B.

The goal of treatment for patients with very early and early stage HCC is to cure the disease. Intermediate- and advanced-stage HCC should be treated with noncurative (palliative) therapies while symptomatic management is appropriate for patients with terminal stage HCC.