These include abdominal pain, weight loss, weakness, abdominal fullness and swelling, jaundice, and nausea (Table 92–3). Presenting signs and symptoms differ somewhat between high- and low-incidence areas. In high-risk areas, especially in South African blacks, the most common symptom is abdominal pain; by contrast, only 40–50% of Chinese and Japanese patients present with abdominal pain. Abdominal swelling may occur as a consequence of ascites due to the underlying chronic liver disease or may be due to a rapidly expanding tumor. Occasionally, central necrosis or acute hemorrhage into the peritoneal cavity leads to death. In countries with an active surveillance program, HCC tends to be identified at an earlier stage, when symptoms may be due only to the underlying disease. Jaundice is usually due to obstruction of the intrahepatic ducts from underlying liver disease. Hematemesis may occur due to esophageal varices from the underlying portal hypertension. Bone pain is seen in 3–12% of patients, but necropsies show pathologic bone metastases in ∼20% of patients. However, 25% of patients may be asymptomatic.
Table 92–3 Hepatocellular Carcinoma Clinical Presentation (n = 547) |Favorite Table|Download (.pdf)
Table 92–3 Hepatocellular Carcinoma Clinical Presentation (n = 547)
|Symptom||Patient # (%)|
|Other (workup of anemia and various diseases)||64(12)|
|Routine physical exam finding, elevated LFTs||129(24)|
|Appetite loss||59 (11)|
|Routine CT scan screening of known cirrhosis||92(17)|
|Cirrhosis symptoms (ankle swelling, abdominal bloating, increased girth, pruritus, GI bleed)||98(18)|
|Mean age (yr)||56 ± 13|
|Middle Eastern||10 %|
|African American||5 %|
|No cirrhosis||19 %|
|Hepatic tumor numbers|
|3 or more||65 %|
|Portal vein invasion||75 %|
Hepatomegaly is the most common physical sign, occurring in 50–90% of the patients. Abdominal bruits are noted in 6–25%, and ascites occurs in 30–60% of patients. Ascites should be examined by cytology. Splenomegaly is mainly due to portal hypertension. Weight loss and muscle wasting are common, particularly with rapidly growing or large tumors. Fever is found in 10–50% of patients, from unclear cause. The signs of chronic liver disease may often be present, including jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema. Budd-Chiari syndrome can occur due to HCC invasion of the hepatic veins, with tense ascites and a large tender liver (Chap. 308).
Most paraneoplastic syndromes in HCC are biochemical abnormalities without associated clinical consequences. They include hypoglycemia (also caused by end-stage liver failure), erythrocytosis, hypercalcemia, hypercholesterolemia, dysfibrinogenemia, carcinoid syndrome, increased thyroxin-binding globulin, changes in secondary sex characteristics (gynecomastia, testicular atrophy, and precocious puberty), and porphyria cutanea tarda. Mild hypoglycemia occurs in rapidly growing HCC as part of terminal illness, and profound hypoglycemia may occur, although the cause is unclear. Erythrocytosis occurs in 3–12% of patients and hypercholesterolemia in 10–40%. A high percent of patients have thrombocytopenia or leukopenia, resulting from portal hypertension, and not from cancer infiltration of bone marrow, as in other tumor types.
Multiple clinical staging systems for HCC have been described. A widely used one has been the American Joint Commission for Cancer (AJCC)/tumor-node-metastasis (TNM) classification. However, the Cancer of the Liver Italian Program (CLIP) system is now popular as it takes the cirrhosis into account, based on the Okuda system (Table 92–4). Other staging systems have been proposed, and a consensus is needed. They are all based on combining the prognostic features of liver damage with those of tumor aggressiveness and include systems from Spain (Barcelona Clinic Liver Cancer [BCLC]), Japan, Hong Kong, and others (Chinese University Prognostic Index [CUPI], Japan Integrated Staging [JIS], and SLiDe which stands for S, stage; Li, liver damage; De, des-γ-carboxy prothrombin). The best prognosis is for stage I, solitary tumors of less than 2-cm diameter without vascular invasion. Adverse prognostic features include ascites, jaundice, vascular invasion, and elevated α-fetoproteins (AFPs). Vascular invasion in particular has profound effects on prognosis and may be microscopic or macroscopic (visible on CT scans). Most large tumors have microscopic vascular invasion, so full staging can usually be made only after surgical resection. Stage III disease contains a mixture of lymph node–positive and -negative tumors. Stage III patients with positive lymph node disease have a poor prognosis, and few patients survive 1 year. The prognosis of stage IV is poor after either resection or transplantation and 1-year survival is rare. A working staging system based entirely on clinical grounds that incorporates the contribution of the underlying liver disease was originally developed by Okuda et al. (Table 92–4). Patients with Okuda stage III have a dire prognosis because they usually cannot be curatively resected, and the condition of their liver typically precludes chemotherapy.
Table 92–4 CLIP and Okuda Staging Systems for Hepatocellular Carcinoma |Favorite Table|Download (.pdf)
Table 92–4 CLIP and Okuda Staging Systems for Hepatocellular Carcinoma
|i. Tumor number||Single||Multiple||–|
|Hepatic replacement by tumor (%)||<50||<50||>50|
|ii. Child-Pugh score||A||B||C|
|iii. α Fetoprotein level (ng/mL)||<400||≥400||–|
|iv. Portal vein thrombosis (CT)||No||Yes||–|
|CLIP stages (score = sum of points): CLIP 0, 0 points; CLIP 1, 1 point; CLIP 2, 2 points; CLIP 3, 3 points.|
|Tumor extenta||Ascites||Albumin (g/L)||Bilirubin (mg/dL)|
|Okuda stages: stage 1, all (–); stage 2, 1 or 2 (+); stage 3, 3 or 4 (+)|
Consensus is needed on staging. These systems will soon be upended by proteomics.
Approach to the Patient: Hepatocellular Carcinoma
The history is important in evaluating putative predisposing factors, including a history of hepatitis or jaundice, blood transfusion, or use of intravenous drugs. A family history of HCC or hepatitis should be sought and a detailed social history taken to include job descriptions for industrial exposure to possible carcinogenic drugs as well as contraceptive hormones. Physical examination should include assessing stigmata of underlying liver disease such as jaundice, ascites, peripheral edema, spider nevi, palmar erythema, and weight loss. Evaluation of the abdomen for hepatic size, masses or ascites, hepatic nodularity and tenderness, and splenomegaly is needed, as is assessment of overall performance status and psychosocial evaluation.
AFP is a serum tumor marker for HCC; however, it is only increased in approximately one-half of U.S. patients. The lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) assay is thought to be more specific. The other widely used assay is that for des-γ-carboxy prothrombin (DCP), a protein induced by vitamin K absence (PIVKA-2). This protein is increased in as many as 80% of HCC patients but may also be elevated in patients with vitamin K deficiency; it is always elevated after Coumadin use. It may predict for portal vein invasion. Both AFP-L3 and DCP are FDA-approved. Many other assays have been developed, such as glypican-3, but none have greater aggregate sensitivity and specificity. In a patient presenting with either a new hepatic mass or other indications of recent hepatic decompensation, carcinoembryonic antigen (CEA), vitamin B12, AFP, ferritin, PIVKA-2, and anti-mitochondrial Ab should be measured, and standard liver function tests should be performed, including prothrombin time (PT), partial thromboplastin time (PTT), albumin, transaminases, γ-glutamyl transpeptidase, and alkaline phosphatase. Decreases in platelet count and white blood cell count may reflect portal hypertension and associated hypersplenism. Hepatitis A, B, and C serology should be measured. If HBV or HCV serology is positive, quantitative measurements of HBV DNA or HCV RNA are needed.
Newer biomarkers are being evaluated, especially tissue- and serum-based genomics profiling.
An ultrasound examination of the liver is an excellent screening tool. The two characteristic vascular abnormalities are hypervascularity of the tumor mass (neovascularization or abnormal tumor-feeding arterial vessels) and thrombosis by tumor invasion of otherwise normal portal veins. To determine tumor size and extent and the presence of portal vein invasion accurately, a helical/triphasic CT scan of the abdomen and pelvis, with fast-contrast bolus technique should be performed to detect the vascular lesions typical of HCC. Portal vein invasion is normally detected as an obstruction and expansion of the vessel. A chest CT is used to exclude metastases. MRI can also provide detailed information, especially with the newer contrast agents. Ethiodol (Lipiodol) is an ethiodized oil emulsion retained by liver tumors that can be delivered by hepatic artery injection (5–15 mL) for CT imaging 1 week later. For small tumors, Ethiodol injection is very helpful before biopsy because the histological presence of the dye constitutes proof that the needle biopsied the mass under suspicion. A prospective comparison of triphasic CT, gadolinium-enhanced MRI, ultrasound, and fluorodeoxyglucose positron emission tomography (FDG-PET) showed similar results for CT, MRI, and ultrasound; PET imaging was unsuccessful.
The altered tumor vascularity that is a consequence of molecularly targeted therapies is the basis for newer imaging techniques including contrast-enhanced ultrasound (CEUS) and dynamic MRI.
Histologic proof of the presence of HCC is obtained through a core liver biopsy of the liver mass under ultrasound guidance, as well as random biopsy of the underlying liver. Bleeding risk is increased compared to other cancers because (1) the tumors are hypervascular, and (2) patients often have thrombocytopenia and decreased liver-dependent clotting factors. Bleeding risk is further increased in the presence of ascites. Tracking of tumor has an uncommon problem. Fine-needle aspirates can provide sufficient material for diagnosis of cancer, but core biopsies are preferred. Tissue architecture allows the distinction between HCC and adenocarcinoma. Laparoscopic approaches can also be used. For patients suspected of having portal vein involvement, a core biopsy of the portal vein may be performed safely. If positive, this is regarded as an exclusion criterion for transplantation for HCC.
Immunohistochemistry has become mainstream. Prognostic subgroupings are being defined based on growth signaling pathway proteins and genotyping strategies. Furthermore, molecular profiling of the underlying liver has provided evidence for a "field-effect" of cirrhosis in generating recurrent or new HCCs after primary resection.
Screening High-Risk Populations
Screening has not been shown to save lives. Prospective studies in high-risk populations showed that ultrasound was more sensitive than AFP elevations. An Italian study in patients with cirrhosis identified a yearly HCC incidence of 3% but showed no increase in the rate of detection of potentially curable tumors with aggressive screening. Prevention strategies including universal vaccination against hepatitis are more likely to be effective than screening efforts. Despite absence of formal guidelines, most practitioners obtain 6-monthly AFP and CT (or ultrasound) when following high-risk patients (HBV carriers, HCV cirrhosis, family history of HCC).
Cost-benefit analysis is not yet convincing, even though screening is intuitively sound. However, studies from areas of high HBV carrier rates have shown a survival benefit for screening as a result of earlier stage at diagnosis. Gamma-glutamyl transpeptidase appears useful for detecting small tumors.
Treatment: Hepatocellular Carcinoma
Most HCC patients have two liver diseases, cirrhosis and HCC, each of which is an independent cause of death. The presence of cirrhosis usually places constraints on resection surgery, ablative therapies, and chemotherapy. Thus patient assessment and treatment planning has to take the severity of the nonmalignant liver disease into account. The clinical management choices for HCC can be complex (Fig. 92-1, Table 92–5, and Table 92–6). The natural history of HCC is highly variable. Patients presenting with advanced tumors (vascular invasion, symptoms, extrahepatic spread) have a median survival of ∼4 months, with or without treatment. Treatment results from the literature are difficult to interpret. Survival is not always a measure of the efficacy of therapy because of the adverse effects on survival of the underlying liver disease. A multidisciplinary team, including a hepatologist, interventional radiologist, surgical oncologist, transplant surgeon, and medical oncologist, is important for the comprehensive management of HCC patients.
Hepatocellular carcinoma treatment algorithm. Treatment approach to patients with hepatocellular carcinoma. The initial clinical evaluation is aimed at assessing the extent of the tumor and the underlying functional compromise of the liver by cirrhosis. Patients are classified as having resectable disease, unresectable disease, or as transplantation candidates. LN, lymph node; OLTX, orthotopic liver transplantation; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; UNOS, United Network for Organ Sharing. Child's A/B/C refers to the Child-Pugh classification of liver failure.
Table 92–5 Treatment Options for Hepatocellular Carcinoma |Favorite Table|Download (.pdf)
Table 92–5 Treatment Options for Hepatocellular Carcinoma
|Local Ablative Therapies|
|Radiofrequency ablation (RFA)|
|Percutaneous ethanol injection (PEI)|
|Regional Therapies: Hepatic Artery Transcatheter Treatments|
|Transarterial drug-eluting beads|
|131Iodine - Ethiodol|
|Conformal External-Beam Radiation|
|Therapy systemic therapies|
|Molecularly targeted therapies (sorafenib, etc.)|
|Hormonal therapy + growth control|
Table 92–6 Some Randomized Clinical Trials Involving Transhepatic Artery Chemoembolization (TACE) for Hepatocellular Carcinoma
Early-stage tumors are successfully treated using various techniques, including surgical resection, local ablation (thermal or radiofrequency [RFA]), and local injection therapies (Table 92–6). Because the majority of patients with HCC suffer from a field defect in the cirrhotic liver, they are at risk for subsequent multiple primary liver tumors. Many will also have significant underlying liver disease and may not tolerate major surgical loss of hepatic parenchyma, and they may be eligible for orthotopic liver transplant (OLTX). Living related donor transplants have increased in popularity resulting in absence of waiting for a transplant. An important principle in treating early-stage HCC is to use liver-sparing treatments and to focus on treatment of both the tumor and the cirrhosis.
The risk of major hepatectomy is high (5–10% mortality rate) due to the underlying liver disease and the potential for liver failure, but acceptable in selected cases. Preoperative portal vein occlusion can sometimes be performed to cause atrophy of the HCC-involved lobe and compensatory hypertrophy of the noninvolved liver, permitting safer resection. Intraoperative ultrasound (US) is useful for planning the surgical approach. The US can image the proximity of major vascular structures that may be encountered during the dissection. In cirrhotic patients, any major liver surgery can result in liver failure. The Child-Pugh classification of liver failure is still a reliable prognosticator for tolerance of hepatic surgery and only Child A patients should be considered for surgical resection. Child B and C patients with stages I and II HCC should be referred for OLTX if appropriate, as well as patients with ascites or a recent history of variceal bleeding. Although open surgical excision is the most reliable, the patient may be better served with a laparoscopic approach to resection, using RFA or percutaneous ethanol injection (PEI). No adequate comparisons of these different techniques have been undertaken and the choice of treatment is usually based on physician skill.
Local Ablation Strategies
Radiofrequency ablation (RFA) uses heat to ablate tumors. The maximum size of the probe arrays allows for a 7-cm zone of necrosis, which would be adequate for a 3- to 4-cm tumor. The heat reliably kills cells within the zone of necrosis. Treatment of tumors close to the main portal pedicles can lead to bile duct injury and obstruction. This limits the location of tumors that are anatomically suited for this technique. RFA can be performed percutaneously with CT or ultrasound guidance, or at the time of laparoscopy with ultrasound guidance.
Numerous agents have been used for local injection into tumors, most commonly, ethanol (PEI). The relatively soft HCC within the hard background cirrhotic liver allows for injection of large volumes of ethanol into the tumor without diffusion into the hepatic parenchyma or leakage out of the liver. PEI causes direct destruction of cancer cells, but it is not selective for cancer and will destroy normal cells in the vicinity. However, it usually requires multiple injections (average three), in contrast to one for RFA. The maximum size of tumor reliably treated is 3 cm, even with multiple injections.
Resection and RFA each obtain similar results.
Liver Transplantation (OLTX)
A viable option for stages I and II tumors in the setting of cirrhosis is OLTX, with survival approaching that for noncancer cases. OLTX for patients with a single lesion ≤5 cm or three or fewer nodules, each ≤3 cm (Milan criteria), resulted in excellent tumor-free survival (≥70% at 5 years). For advanced HCC, OLTX has been abandoned due to high tumor recurrence rates. Priority scoring for OLTX previously led to HCC patients waiting too long for their OLTX, resulting in some tumors becoming too advanced during the patient's wait for a donated liver. A variety of therapies were used as a "bridge" to OLTX, including RFA, polyethylenimine, and transcatheter arterial chemoembolization (TACE). It seems clear that these pretransplant treatments allow patients to remain on the waiting list longer, giving them greater opportunities to be transplanted. What remains unclear, however, is whether this translates into prolonged survival after transplant. Further, it is not known whether patients who have had their tumor(s) treated preoperatively follow the recurrence pattern predicted by their tumor status at the time of transplant (i.e., post–local ablative therapy), or if they follow the course set by their tumor parameters present before such treatment. The United Network for Organ Sharing (UNOS) point system for priority scoring of OLTX recipients now includes additional points for patients with HCC. The success of living related donor liver transplantation programs has also led to patients receiving transplantation earlier for HCC and often with greater than minimal tumors.
Expanded criteria for larger HCCs beyond the Milan criteria (one lesion <5 cm or three lesions, each less than 3 cm) are being increasingly accepted by various UNOS areas for OLTX with satisfactory longer-term survival. Furthermore, downstaging HCCs by medical therapy (TACE) is increasingly recognized as acceptable treatment before OLTX.
The role of adjuvant chemotherapy for patients after resection or OLTX remains unclear. Both adjuvant and neoadjuvant approaches have been studied, but no clear advantage in disease-free or overall survival has been found. However, a meta-analysis of several trials revealed a significant improvement in disease-free and overall survival. Although analysis of postoperative adjuvant systemic chemotherapy trials demonstrated no disease-free or overall survival advantage, single studies of TACE and neoadjuvant 131I-Ethiodol showed enhanced survival post-resection.
A large adjuvant trial examining resection with or without sorafenib (see below) is in progress.
Fewer surgical options exist for stage III tumors involving major vascular structures. In patients without cirrhosis, a major hepatectomy is feasible, although prognosis is poor. Patients with Child's A cirrhosis may be resected, but a lobectomy is associated with significant morbidity and mortality rates, and long-term prognosis is poor. Nevertheless, a small percentage of patients will achieve long-term survival, justifying an attempt at resection when feasible. Because of the advanced nature of these tumors, even successful resection can be followed by rapid recurrence. These patients are not considered candidates for transplantation because of the high tumor recurrence rates, unless their tumors can first be down-staged with neoadjuvant therapy. Decreasing the size of the primary tumor allows for less surgery, and the delay in surgery allows for extrahepatic disease to manifest on imaging studies and avoid unhelpful OLTX. The prognosis is poor for stage IV tumors, and no surgical treatment is recommended.
A large number of controlled and uncontrolled clinical studies have been performed with most of the major classes of cancer chemotherapy. No single agent or combination of agents given systemically reproducibly leads to even a 25% response rate or has any effect on survival.
In contrast to the dismal results of systemic chemotherapy, a variety of agents given via the hepatic artery have activity for HCC confined to the liver (Table 92–6). Two randomized controlled trials have shown a survival advantage for TACE in a selected subset of patients. One used doxorubicin and the other used cisplatin. Despite the fact that increased hepatic extraction of chemotherapy has been shown for very few drugs, some drugs such as cisplatin, doxorubicin, mitomycin C, and possibly neocarzinostatin, produce substantial objective responses when administered regionally. Few data are available on continuous hepatic arterial infusion for HCC, although pilot studies with cisplatin have shown encouraging responses. Because the reports have not usually stratified responses or survival based on TNM staging, it is difficult to know long-term prognosis in relation to tumor extent. Most of the studies on regional hepatic arterial chemotherapy also use an embolizing agent such as Ethiodol, gelatin sponge particles (Gelfoam), starch (Spherex), or microspheres. Two products are composed of microspheres of defined size ranges—Embospheres (Biospheres) and Contour SE—using particles of 40–120, 100–300, 300–500, and 500–1000 μm in size. The optimal diameter of the particles for TACE has yet to be defined. Consistently higher objective response rates are reported for arterial administration of drugs together with some form of hepatic artery occlusion compared with any form of systemic chemotherapy to date. The widespread use of some form of embolization in addition to chemotherapy has added to its toxicities. These include a frequent, but transient fever, abdominal pain, and anorexia (all in >60% of patients). In addition, >20% of patients have increased ascites or transient elevation of transaminases. Cystic artery spasm and cholecystitis are also not uncommon. However, higher responses have also been obtained. The hepatic toxicities associated with embolization may be ameliorated by the use of degradable starch microspheres, with 50–60% response rates. Two randomized studies of TACE vs. placebo showed a survival advantage for treatment (Table 92–6). In addition, it is not clear that formal oncologic CT response criteria are adequate for HCC. A loss of vascularity on CT without size change may be an index of loss of viability and thus of response to TACE. A major problem that TACE trials have had in showing a survival advantage is that many HCC patients die of their underlying cirrhosis, not the tumor. However, improving quality of life is a legitimate goal of regional therapy.
The major finding has been a survival advantage for oral sorafenib (Nexavar) vs. placebo controls in two randomized trials, leading to its approval by the FDA. However, tumor responses were negligible, and the survival in the treatment arm in Asians was below the placebo arm in the Western trial (Table 92–7). Furthermore, prolonged survival has been reported in phase II trials using newer agents, such as bevacizumab plus erlotinib. Several forms of radiation therapy have been used in the treatment of HCC, including external beam radiation and conformal radiation therapy. Radiation hepatitis remains a dose-limiting problem. The pure beta emitter 90Yttrium attached to either glass or resin microspheres has been assessed in phase II trials of HCC and has encouraging survival effects with minimal toxicities. Randomized trials have yet to be performed. Vitamin K has been assessed in clinical trials at high dosage for its HCC-inhibitory actions. This idea is based on the characteristic biochemical defect in HCC of elevated plasma levels of immature prothrombin (DCP or PIVKA-2), due to a defect in the activity of prothrombin carboxylase, a vitamin K-dependent enzyme. Two vitamin K randomized controlled trials from Japan show decreased tumor occurrence.
Table 92–7 Targeted Therapies in HCC: Trials |Favorite Table|Download (.pdf)
Table 92–7 Targeted Therapies in HCC: Trials
|Phase III||Target||Survival (mo)|
|Sorafenib vs placebo||Raf, VEGFR, PDGFR||10.7 vs. 7.9|
|Sorafenib vs placebo (Asians)||Raf, WGFR, PDGFR||6.5 vs. 4.2|
|Sunitinib||9.8, 8 (2 trials)|
|Bevacizumab plus erlotinib||VEGF plus EGFR||15.6|
|Bevacizumab plus capecitabine||8|
|Erlotinib||EGFR||13, 10.7 (2 trials)|
A number of new treatments are being evaluated for HCC (Table 92–8). These include the biologicals, such as Raf kinase and vascular endothelial growth factor (VEGF) inhibitors, 90Yttrium looks promising without chemotherapy toxicities, and vitamin K2 appears to prevent recurrences post-resection. The bottleneck of liver donors for OLTX is at last widening with increasing use of living donors, and criteria for OLTX for larger HCCs are slowly expanding. Patient participation in clinical trials assessing new therapies is encouraged (www.clinicaltrials.gov).
Table 92–8 Some Novel Medical Treatments for Hepatocellular Carcinoma |Favorite Table|Download (.pdf)
Table 92–8 Some Novel Medical Treatments for Hepatocellular Carcinoma
|EGF receptor antagonists: Erlotinib, gefitinib, lapatinib, cetuximab, brivanib|
|Multi-kinase antagonists: sorafenib, sunitinib|
|VEGF antagonist: bevacizumab|
|VEGFR antagonist: ABT-869 (linifanib)|
|mTOR antagonists: sirolimus, temsirolimus, everolimus|
|Proteasome inhibitors: bortezomib|
|131I – Ethiodol (lipiodol)|
|131I – Ferritin|
|90Yttrium microspheres (TheraSphere, SIR-spheres)|
|Three-dimensional conformal radiation|
|Proton beam high-dose radiotherapy|
|Gamma knife, CyberKnife|
|New targets: inhibitors of cyclin dependent kinases (Cdk) and caspases|