Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-/and alcoholic fatty liver disease (N/AFLD), and tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, etc.), and dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute to the development of HCC. The multitude and complexity of different pathomechanisms also reflect the difficulties in tailored medical therapy of HCC. Treatment options for HCC are strictly dependent on tumor staging and liver function, which are structured by the updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, and liver transplantation are valid and curative therapeutic options for early tumor stages. For multifocal and metastatic diseases, systemic therapy is recommended. While Sorafenib had been the standalone HCC first-line therapy for decades, recent developments had led to the approval of new treatment options as first-line as well as second-line treatment. Anti-PD-L1 directed combination therapies either with anti-VEGF directed agents or with anti-CTLA-4 active substances have been implemented as the new treatment standard in the first-line setting. However, data from clinical trials indicate different responses on specific therapeutic regimens depending on the underlying pathogenesis of hepatocellular cancer. Therefore, histopathological examinations have been re-emphasized by current international clinical guidelines in addition to the standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. In this review, we emphasize the current knowledge on molecular pathogenesis of hepatocellular carcinoma. On this occasion, the treatment sequences for early and advanced tumor stages according to the recently updated Barcelona Clinic Liver Cancer classification system and the current algorithm of systemic therapy (first-, second-, and third-line treatment) are summarized. Furthermore, we discuss novel precautional and pre-therapeutic approaches including therapeutic vaccination, adoptive cell transfer, locoregional therapy enhancement, and non-coding RNA-based therapy as promising treatment options. These novel treatments may prolong overall survival rates in regard with quality of life and liver function as mainstay of HCC therapy.

Keywords: Barcelona Clinic Liver Cancer classification system (BCLC); CTLA4; HCC; NAFLD; NASH; P53; PDL1; TERT; Tyrosine kinase inhibition (TKI); atezolizumab; immune checkpoint inhibition; lenvatinib; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; pembrolizumab; trans-arterial chemoembolization (TACE).

Figure 1

The BCLC classification system offers treatment recommendations based on tumor stage and liver function of patients with HCC. Treatment options are adjusted to the 5 stages of HCC (from very early to terminal stage). The prognosis is based on the tumor burden, liver function and physical performance status of the patient. Besides the recommended treatments, the BCLC system also includes prognosis and the expected survival time. Updated classifications and treatment options are illustrated as red boxes and arrows. This updated BCLC system further contains new workflows during radiological progression within between the stages (BCLCp-B, BCLCp-C1, BCLCp-C2) [13,14].

Figure 2

Algorithm of systemic therapy in HCC (BCLC stage C) based on approval by EMA and FDA. Scientific data supporting a therapy algorithm after 1st line therapy with Atezolizumab/ Bevacizumab is missing. Sorafenib is approved in the therapy of HCC regardless any other / previous therapy. Cabozantinib, ramucirumab and regorafenib are approved after previous therapy with sorafenib; Regorafenib for patients that has previously responded to sorafenib; Ramucirumab in patients with AFP-overexpressing tumors (AFP > 400 ng/mL).

Figure 3

Etiology and risk factors promoting HCC carcinogenesis. Continuous chronic exposure to hepatic injuries caused by environmental factors (viral hepatitis, alcohol abuse, NASH, exposure to toxins, etc.) repeatedly damage the hepatocytes and induce inflammation eventually leading to liver cirrhosis. In this stage, the liver is susceptible to genomic instabilities. That is why it is more likely for the hepatocytes to accumulate somatic mutations, epigenetic changes, and gene rearrangements which can lead to metabolic changes and molecular pathway alterations. These dysregulations drive tumor progression and metastasis.

Figure 4

Most likely dysregulated key-signaling pathways are in HCC carcinogenesis. The occurrence of distinct somatic mutations and the influence of either inhibiting or activating factors all favor the constitutive activation of significant signaling pathways. Consequently, the cell evades any regulatory mechanism and strongly promotes tumor-typical properties including cell growth, cell proliferation, migration, and metastasis. Thus, smallest changes in the finely tuned signaling cascades result in hepatocarcinogenesis.