Liver transplantation for hepatocellular carcinoma

Biology of hepatocellular carcinoma (see Chapters 9B and 9C )

An understanding of the biology of HCC is critical to assist in clinical decision making about surveillance and treatment. Although the molecular biology of HCC remains to be fully elucidated, the close association between cirrhosis and the development of HCC is clear. Viral hepatitis, chronic alcohol use, and NAFLD (see Chapter 105 ) are the most common causes of cirrhosis in the Western world. NAFLD, an unfamiliar diagnosis as recently as the early 1980s, is now present in 17% to 30% of Americans, progressing to nonalcoholic steatohepatitis (NASH) in 32% to 37% and then to cirrhosis in 5% to 24%. ^, The development of cirrhosis in patients with NAFLD is driven by repetitive liver injury from lipid peroxidation, fatty acid toxicity, mitochondrial impairment, and oxidative stress, and 2.6% of patients with NASH cirrhosis develop HCC per year. A rough calculation, on the conservative side (330,000,000 Americans × 17% × 32% × 5% × 2.6%) yields 23,337 people developing HCC from NASH cirrhosis every year. This is to be compared with the prevalence of HCV in the US population of 0.9% (or 2.3 million people), and an expected rate of HCC development in this population over 30 years is about 1% to 3%.

Viral infection with HBV and HCV lead to cirrhosis by different mechanisms (see Chapters 9B ). HBV induces transgene activation, oncogene transcription, and loss of tumor suppressor genes as a result of viral DNA integration into the host genome. HCC will develop in as many as 30% of patients with chronic HBV without cirrhosis. HCV does not integrate into the host genome but rather leads to chronic inflammation through continued viral replication. This rapid hepatocyte turnover in the presence of oxidative stress drives the development of multiple dysplastic nodules.

Unlike what has been found in some other cancers, no sequential progression of genetic defects has been identified that leads to the development of HCC. Instead, a variety of genetic alterations are usually seen, broadly grouped into events that occur either early or late in the development of a tumor. Genetic alterations that lead to inhibition of the insulin-like growth factor II receptors are considered early mutations. Loss of heterozygosity of a variety of genes, often of tumor suppressor genes such as TP53, is a late event in the development of neoplasia ^, (see Chapters 9B and 9C ).

Clinically relevant aspects of hepatocellular carcinoma pathogenesis

The clinician must understand three aspects of HCC pathogenesis: (1) the influence of cirrhosis on HCC development, (2) arterial recruitment of the tumor, and the tendency for HCC to invade portal vein (PV) branches (see Chapters 14 and 89 ).

First, HCC most often develops in the context of cirrhosis, and the biology of HCC is related directly to the environment found in the cirrhotic liver (see Chapters 9B , 9C , and 74 ). Repeated insult causes chronic inflammation driven by tumor necrosis factor (TNF)-α; transforming growth factor (TGF)-β; and interleukin (IL)-1 from Kupffer cells, endothelial cells, and hepatocytes (see Chapters 9B and 9C ). This inflammation stimulates nodular regeneration with bridging fibrosis. Rapid cellular turnover in this regenerative environment leads to low-grade dysplastic nodules that contain only mild atypia and then to high-grade dysplastic nodules with at least moderate atypia. Eventually, a small percentage of these high-grade dysplastic nodules will go on to develop microscopic foci of HCC before becoming frank carcinoma. Evidence suggests that tumor cells may even secrete IL-6 and TNF-α, directly contributing to the inflammatory microenvironment by activating Toll-like receptors.

Because of the diffuse nature of the liver injury, multiple tumors can develop at the same time. If a focus of HCC is removed, recurrence is most often at a distant site ( Fig. 108A.1 ). This second tumor at the distant site is most likely a second primary tumor. Because most of the second lesions are found within a few years of treatment of the primary lesion, the tumor was most likely present when the first tumor was treated but was too small to be detected. The occurrence of synchronous and metachronous lesions in the same organ suggests the entire cirrhotic organ has the potential for neoplastic conversion, similar to the genetic defect in the colon in familial adenomatous polyposis, which leads to multiple cancers; this situation is referred to as a field defect.

Second, there is a clinically relevant difference in blood supply between foci of HCC and low-grade dysplastic nodules, which derive most of their blood supply from the PV. Histopathologic evaluation of high-grade dysplasia and HCC demonstrates the tumor being fed by branches of the hepatic artery that are not paired with the other structures of the portal tract, a process called arterial recruitment or neoangiogenesis. The resulting hepatic artery dominance in blood supply produces the characteristically hyperdense appearance of HCC that is used to identify tumors during the arterial phase of contrast imaging ^, and it allows for treatment by selective hepatic artery embolization.

Lastly, HCC is known to invade vascular structures, typically the PV but also hepatic veins (HVs) and, less frequently, the biliary tree (see Chapters 14 and 89 ). The development of vascular invasion appears to be a key step in the metastatic potential of the tumor, and the risk of PV invasion seems to be directly related to size and differentiation status of the tumor. Venous invasion is such a strong predictor of metastatic disease that tumor size and tumor number can be thought of as surrogate markers for vascular invasion.

The likelihood of microvascular and macrovascular PV invasion has implications for treatment decisions; for example, evidence of venous invasion on imaging or biopsy rules out transplantation because the probability of recurrence is unacceptably high. It is this risk of recurrence with large or multiple tumors that resulted in the poor outcomes with early attempts at LT for HCC, and it is the reason why patients with small tumors are selected for transplantation.

Hepatocellular carcinoma screening

Patients with HCC presenting as symptomatic disease have a 0% to 10% 5-year survival rate, so a screening program that identifies early disease can have a major impact on treatment outcomes (see Chapter 89 ). HCC meets the World Health Organization (WHO) criteria for performing screening, and an RCT showed that screening for HCC reduces mortality. An effective screening program evaluates patients at risk for disease, using a highly standardized and relatively inexpensive test with a high sensitivity. A screening program is used if the cost of screening a large population is less than the benefit of early detection of the disease in a small number of individuals in that population. Several decision-analysis and cost-efficiency models for HCC screening suggest that the ability of a screening program to decrease mortality while remaining cost-effective depends on the inclusion of patients with an incidence of HCC of at least 1.4% to 1.5%. Box 108A.1 lists patients who should be included in a screening program. Screening for HCC in patients with cirrhosis from NASH, α ₁ -antitrypsin deficiency, and autoimmune hepatitis is not considered mandatory, but most centers include these patients in their screening population. Consensus on screening patients with NASH that do not have cirrhosis is lacking.