Relative frequency of primary liver masses. Adapted from: Goodman ZD. Neoplasms of the liver. Mod Pathol 2007 Feb;20 Suppl 1:S49–60
Annual incidence of hepatocellular carcinoma in cirrhosis by etiology of liver disease
Liver disease etiology
Annual incidence of hepatocellular carcinoma
Stage 4 primary biliary cirrhosis
Some conditions confer a risk for HCC without concurrent cirrhosis. These include chronic hepatitis B, with an annual incidence of HCC in noncirrhotic patients of approximately 0.5 % per year, and nonalcoholic fatty liver disease, with an annual incidence of HCC in noncirrhotic patients of approximately 1.5 % per year . Additionally, while most benign liver masses (focal nodular hyperplasia, hemangiomas, and simple cysts) do not harbor a risk of malignant transformation to hepatocellular carcinoma, hepatocellular adenomas are the exception. The overall risk of malignant transformation of hepatocellular adenomas is low (4.2 %). Risk factors for transformation of a hepatocellular adenoma include larger diameter (≥5-cm), anabolic steroid use, male sex, and glycogen storage diseases .
Chronic hepatitis C (HCV) infection is the most common cause of cirrhosis in the U.S. and the most common HCC risk factor . Other risk factors, concomitant with HCV infection, further increase HCC risk, including older age at the time of HCV infection, male sex, coinfection with human immunodeficiency virus (HIV) or hepatitis B (HBV), alcohol or tobacco abuse, and possibly diabetes and obesity [6, 9].
Chronic HBV infection is a strong promoter of hepatocarcinogenesis and the leading risk factor for HCC in Asia and Africa [7, 10]. Unlike most other HCC risk factors, HCC frequently occurs in HBV-infected patients without cirrhosis . As with HCV, several risk factors interact with HBV infection to increase HCC risk, including male sex, older age, duration of HBV infection, high HBV replication, family history of HCC, aflatoxin exposure, coinfection with HCV, HIV, or hepatitis D, alcohol or tobacco abuse, and infection with HBV genotype C [6, 9]. Predictive models are available to estimate the risk of developing HCC with chronic HBV infection [11, 12].
Factors that protect against the development of HCC have also been identified. Viral suppression of HBV and cure of HCV reduce but do not completely abrogate HCC risk . Smoking and alcohol cessation may reduce HCC risk, even after cirrhosis has already developed [13, 14]. Additionally, population-level studies have shown a lower HCC incidence with high coffee consumption in both cirrhotic and noncirrhotic patients .
The diagnosis of HCC is typically made using cross-sectional imaging studies, without the need for tumor biopsy. Dynamic computerized tomography (CT) or magnetic resonance imaging (MRI) with imaging acquisition in the arterial, portal venous, and delayed phases has a high sensitivity, specificity, and accuracy for HCC diagnosis [6, 7]. HCC enhances more than the background liver in the arterial phase and enhances less (washes out) in the portal venous and delayed phases because its principal blood supply derives from the hepatic artery, while blood supply to the background liver primarily derives from the portal vein . In tumors over 2-cm in diameter, the diagnosis of HCC can usually be made when a solid liver mass exhibits arterial enhancement and portal venous and delayed phase washout on dynamic CT or MRI (Fig. 6.2). The presence of an enhancing ring around the periphery of the mass, a pseudocapsule, also supports a HCC diagnosis, particularly when the mass is between 1 and 2 cm. However, imaging-based diagnosis is less accurate for tumors smaller than 2-cm in diameter or when cirrhosis is not present .
Multiphase contrast-enhanced magnetic resonance imaging demonstrating the typical radiographic features of hepatocellular carcinoma. The liver mass (arrow in all panels) prominently enhances in the arterial phase (panel a) and is hypoenhancing to the surrounding liver parenchyma (washes out) in the portal venous (panel b) and delayed phases (panel c). A ring of enhancement (pseudocapsule) encircles the periphery of the mass (arrowheads in panels b and c). Images provided by Alice Fung, MD
If a suspected HCC does not possess characteristic imaging findings or occurs in a noncirrhotic liver, a biopsy may be necessary to establish the diagnosis . The risk of tumor seeding the needle track with biopsy is low (2.7 %) and should not discourage its use when an imaging-based diagnosis is not possible . The serum alpha-fetoprotein (AFP) level may be elevated in HCC, but it may also be elevated in other liver conditions, including CCA, metastatic colon cancer, and chronic viral hepatitis, making the use of AFP in the diagnosis of HCC controversial . Additionally, the AFP level is normal in approximately 40 % of HCC patients, even when the cancer is advanced. However, the trajectory of the AFP level is useful as a marker of treatment response in patients with AFP-producing tumors .
Accurate staging of HCC is a crucial determinant for treatment selection and prognostication. Multiple staging systems have been proposed, including the American Joint Committee on Cancer Tumor-Node-Metastasis system, the Okuda classification , the Barcelona Clinic Liver Cancer (BCLC) staging system , and others. The BCLC system is most frequently used because it unifies the cancer stage, liver function, and comorbid illnesses into a clinically practical approach that facilitates the selection of HCC treatment . BCLC staging incorporates tumor size, number, extent, liver function (represented by the Child–Pugh score), and comorbid illnesses (represented by the performance status) to stage patients as stage 0 (very early HCC), stage A (early HCC), stage B (intermediate HCC), stage C (invasive or metastatic HCC), and stage D (end-stage HCC) (Fig. 6.3). Each BCLC stage is linked to a suggested treatment and prognosis.
The Barcelona clinic liver cancer staging system for hepatocellular carcinoma. HCC hepatocellular carcinoma, PST performance status, TACE transarterial chemoembolization. Adapted from: Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet 2009;373: 614–616
Optimal management of HCC requires a multidisciplinary approach with the involvement of gastroenterologists/hepatologists, hepatobiliary and transplant surgeons, diagnostic and interventional radiologists, and medical and radiation oncologists. Patients with very early HCC (BCLC stage 0), who have single tumors less than 2-cm in diameter with excellent liver function and performance status, may be treated with surgical resection or percutaneous ablation . Resection is the treatment of choice, though only 5 % of patients in Western countries are candidates due to surgical contraindications such as portal hypertension, poor liver function, or non-liver-related comorbidities . In cirrhotic patients, resection may induce hepatic decompensation, and careful preoperative patient selection may prevent this potentially deadly complication. The 5-year overall survival after resection of very early HCC is theoretically over 90 %, but recurrence is common, occurring in approximately 70 % of patients within 5 years [6, 7].
Early stage HCC (BCLC stage A) may be treated with surgical resection if only 1 tumor is present with preserved liver function and good performance status. Therapeutic options for nonresectable BCLC stage A HCC include percutaneous ablation, transarterial chemoembolization , transarterial radioembolization , and radiation therapy , with liver transplantation available as an adjunctive treatment in selected patients. Percutaneous ablation includes percutaneous ethanol injection, radiofrequency ablation , cryoablation, microwave ablation, and irreversible electroporation . Percutaneous ethanol injection is an effective treatment for small tumors (<2-cm), achieving a necrosis rate of 90–100 %, but it is less effective for larger tumors (only 50 % tumor necrosis is achieved for tumors greater than 3-cm) and it requires multiple procedures [6, 7]. Radiofrequency ablation involves the insertion of electrodes into the tumor that deliver directed heat to induce tumor necrosis . The efficacy of radiofrequency ablation is similar to ethanol injection for tumors less than 2-cm, generally requires fewer repeat procedures, and is much more effective than ethanol injection for larger tumors up to 5-cm in diameter [17, 18]. Both ethanol injection and radiofrequency ablation are associated with a small risk of needle-track tumor seeding [19, 20].
Candidacy for liver transplantation depends on the extent of the tumor and the presence of medical and psychosocial comorbidities (including substance abuse). Most liver transplant centers in the U.S. employ the Milan criteria as the upper limit of cancer size and number to permit transplantation . These criteria require a single tumor less than 5-cm in diameter or up to 3 tumors, all less than 3-cm in diameter, and predict a 4-year posttransplant survival of over 70 %. A small number of U.S. transplant centers utilize less restrictive selection criteria for the transplantation of HCC, including the University of California San Francisco criteria, which allow tumors up to 6.5-cm in diameter, or transplantation only after cancer treatment has reduced the size and number of tumors to within the Milan criteria (“downstaging”) [22, 23].
HCC that initially meets criteria for transplantation may later grow to exceed transplant criteria, leading to deactivation on the liver transplant wait-list. The rate of wait-list exclusion secondary to cancer progression is up to 25 % when the waiting time is greater than 1 year . To reduce waiting time for transplantation, patients with HCC are given additional priority for liver transplantation (termed “MELD exceptions”) . Enactment of MELD exceptions for HCC greatly increased the proportion of HCC patients receiving liver transplantation .
Patients with intermediate stage HCC (BCLC stage B) are primarily treated with transarterial chemoembolization or radioembolization, and are not candidates for surgical resection or liver transplantation. Transarterial chemoembolization involves catheterization of the femoral artery, followed by injection of chemotherapeutic agents and embolization of the branch of the hepatic artery feeding the tumor . Careful patient selection is necessary because transarterial chemoembolization may induce liver failure in patients with decompensated liver disease (Child–Pugh class B or C) . A self-limited postembolization syndrome characterized by fever, abdominal pain, nausea, and/or ileus occurs in 50 % of patients. Transarterial chemoembolization is not curative, but it has been shown to delay tumor progression and prolong survival (20–60 % at 2 years) [26, 27]. Transarterial radioembolization is a newer approach that is best suited for the treatment of larger, infiltrative tumors and involves the catheter-based delivery of a radioactive isotope (yttrium-90) bound to glass microspheres into the hepatic artery branch feeding the tumor . No randomized trials comparing transarterial chemoembolization with radioembolization have been performed, although observational studies suggest similar efficacy. Radioembolization has been associated with shorter hospitalization after treatment and better short-term quality of life [29, 30].
In patients with advanced HCC with preserved liver function and performance status (BCLC stage C) or in patients who failed liver-directed treatments, chemotherapy with sorafenib, an oral multikinase inhibitor, improves survival. In two randomized controlled trials, the median survival with sorafenib ranged from 6.5 to 10.7 months, compared to 4.2–7.9 months with placebo [31, 32]. Sorafenib may cause adverse effects including diarrhea, nausea, fatigue, weight loss, and a rash involving the palms and soles of the hands and feet (hand-foot syndrome) .
Patients with end-stage HCC (BCLC stage D) are not candidates for HCC therapy due to severe comorbidities, advanced liver disease, or poor performance status, regardless of the extent of their HCC. The prognosis of BCLC stage D HCC is poor (3-month median survival), and none of the therapies discussed earlier improve survival or quality of life . The primary treatment for BCLC stage D HCC includes symptomatic/palliative care approaches, and early referral to hospice is advised.
Fibrolamellar carcinoma is a rare variant of HCC, making up 0.85 % of primary liver cancers . Unlike typical HCC, fibrolamellar carcinoma generally occurs in noncirrhotic patients without a male predominance and is also more frequent in younger patients of white race [33, 34]. Like HCC, the diagnosis can usually be made solely with dynamic CT or MRI, and only rarely requires tumor biopsy . Compared to typical HCC, fibrolamellar carcinoma is more often amenable to surgical resection. Despite this advantage, fibrolamellar carcinoma has a prognosis similar to that of HCC in noncirrhotic patients [34, 35]. When resection is not an option, liver transplantation is sometimes possible . Because fibrolamellar carcinoma is rare, scant data are available for the use of liver-directed treatments and systemic chemotherapy .
Accounting for 8 % of primary liver cancers, cholangiocarcinoma (CCA) is the second most common primary liver cancer after HCC . CCA is classified according to its location within the biliary tree: intrahepatic (5–10 %), perihilar (60–70 %), or extrahepatic (20–30 %) . CCA treatment varies by the location of involvement.
The strongest risk factor for CCA is primary sclerosing cholangitis . Cirrhosis is also a strong risk factor for intrahepatic CCA. Other , weaker risk factors for CCA largely involve inflammatory disorders, toxic exposures, and congenital malformations of the biliary tract. These include tobacco or alcohol abuse, older age, liver fluke infection, Caroli’s disease, choledochal cysts, bile duct adenomas, chronic intrahepatic biliary stones, vinyl chloride exposure (an intermediate product in plastics manufacturing), and Thorotrast exposure (a commonly used radiocontrast agent in the 1930–1940s) [39, 40]. However, a large proportion of CCA occurs in patients without known risk factors .
Unlike HCC, the diagnosis of CCA cannot be established with imaging alone and requires tumor biopsy. In patients with tumors that are considered to be technically resectable based on the extent of liver and bile duct involvement and the absence of medical comorbidities or major liver dysfunction, surgical resection is the initial diagnostic and treatment modality of choice . In patients who are not candidates for liver resection , needle core biopsy is required . Dynamic CT and MRI supplement biopsy for cancer staging and treatment planning, allowing the evaluation of vascular invasion, metastatic spread, and in surgical candidates, the size of the potential liver remnant [2, 40]. The tumor marker CA 19-9 is elevated in some CCA patients but has a sensitivity and specificity of only 62 and 63 % for CCA diagnosis . AFP and carcinoembryonic antigen (CEA) levels may also be elevated in CCA but are nonspecific [7, 41].
The 1-year mortality of untreated CCA is high (50–70 %), and aggressive treatment is warranted when possible . Surgical resection is the only curative treatment for CCA. Unfortunately, recurrence following resection occurs in most patients within 2 years, and the median survival after resection is 36 months . Surgical candidacy requires the absence of nodal or distant metastases or vascular invasion . Patients who are not candidates for surgical resection are treated with chemotherapy (gemcitabine and cisplatin), which achieves a median survival of 11.7 months, compared to 8.1 months for gemcitabine alone .
Historically, cholangiocarcinoma has been a contraindication for liver transplantation . However, recent studies have shown that carefully selected patients with early stage perihilar CCA may be treated with liver transplantation with good posttransplant survival (53 % at 5 years) . The restrictive protocol for transplantation of perihilar HCC requires an unresectable early stage perihilar CCA with a good tumor response to external beam radiation therapy and chemotherapy, followed by diagnostic laparoscopy showing no metastatic disease. A quarter of patients with potentially transplantable CCA drop off the transplant waiting list due to tumor progression or inability to complete pretransplant chemoradiation .
Rare Primary Liver Tumors
Epithelioid hemangioendothelioma (EHE) is an uncommon vascular tumor with moderate malignant potential. According to the most recent World Health Organization classification, EHE is considered a malignant vascular tumor similar to angiosarcoma, though with a better prognosis . The incidence of EHE is less than 1/1,000,000 . EHE risk factors are largely unknown given its low incidence, but it is most commonly diagnosed in young to middle-aged women . Oral contraceptive pills, vinyl chloride, and Thorotrast exposures have also been implicated as potential EHE risk factors . EHE is usually multifocal (81 %) and mimics metastatic disease on imaging studies, necessitating tumor biopsy for diagnosis . Because of its multifocality, resection is frequently not possible and liver transplantation is required for cure . The 1-year and 5-year survival rates of EHE without treatment are 39.3 and 4.5 %, respectively, but improve to 96 and 54.5 % with liver transplantation, and 100 and 75 % with surgical resection . In patients who are not candidates for resection or transplantation, chemotherapy and radiation regimens similar to those for angiosarcoma are recommended, typically including celecoxib, paclitaxel, and antiangiogenic drugs. The 1-year and 5-year survival rates with combination chemotherapy and radiation are 73.3 and 30 %, respectively .
Hepatic angiosarcoma is a rare primary liver cancer, representing 0.5–2 % of primary liver cancers. Less than 5 % of all angiosarcomas arise from the liver . Angiosarcoma risk factors are largely environmental, with exposure to vinyl chloride the most common (25 % of cases) [53, 54]. Arsenic and Thorotrast exposures have also been implicated in hepatic angiosarcoma . Finally, sparse data suggest that long-term anabolic steroid exposure may also increase hepatic angiosarcoma risk . Hepatic angiosarcoma can mimic HCC, EHE, and hepatic adenomas on imaging, mandating tissue evaluation for diagnosis . The utility of needle core biopsy is compromised by frequent false negative results, and surgical biopsy or resection is often necessary. Treatment for angiosarcoma includes a combination of surgical resection, chemotherapy , and/or radiation therapy . Without treatment, the median survival for hepatic angiosarcoma is 5 months, but the median survival increases to 17 months when these treatments are employed . Hepatic angiosarcoma may be complicated by spontaneous or biopsy-related tumor hemorrhage, and transarterial embolization may be used to effectively prevent or treat this complication . Hepatic angiosarcoma is a contraindication to liver transplantation due to frequent posttransplant cancer recurrence [56, 57].