Chapter 47 Hepatobiliary Cancer
Hepatobiliary malignant diseases include hepatocellular carcinoma (HCC), gallbladder cancer, extrahepatic cholangiocarcinoma (EHCC), and intrahepatic cholangiocarcinoma (IHCC). In 2010, the expected incidence in the United States was 33,880 cases, with 22,230 deaths.1 HCC, already the fifth most common malignant tumor worldwide,2 is increasing in incidence in the United States as a result of the hepatitis C epidemic.3 A similar increase has been reported in the incidence of IHCC for reasons that are not known.4 The primary therapy for all hepatobiliary tumors is resection, but only a minority of patients present with resectable disease. A number of therapies have been in use for unresectable patients, including systemic and regional chemotherapy (using standard cytotoxic agents and, more recently, sorafenib), chemoembolization, immunotherapy, and various ablative techniques. The role of these modalities has not been defined, and there is currently no accepted standard for the management of unresectable hepatic malignant tumors. Historically, RT has not played a significant role in the treatment of liver malignant diseases because of the low tolerance of the whole liver to radiation.5,6 With the advent of three-dimensional conformal treatment planning and intensity-modulated radiation therapy (IMRT), interest in the use of irradiation for malignant diseases of the liver has increased. Modern-day techniques allow delivery of higher doses to the target lesions than had been previously possible, while minimizing the dose to the noninvolved liver. At the same time, our understanding of the relationships between radiation dose and volume and the risk of radiation-induced liver disease has improved considerably. These developments have led to a body of evidence that now exists in support of the use of RT for unresectable hepatobiliary cancer.
Epidemiology And Etiology
Epidemiology
Cancer of the hepatobiliary system is uncommon in the United States, accounting for only about 2% of new cancer cases.7 Hepatobiliary cancers occur primarily in the elderly; the incidence increases with age. The most common hepatobiliary cancer is HCC, followed by gallbladder cancer, EHCC, and IHCC. Approximately one quarter of the cholangiocarcinomas occur at the bifurcation of the common hepatic duct and are known as hilar tumors or Klatskin tumors. Other cancers of the liver, such as carcinoid tumors, hepatoblastoma, angiosarcoma, and leiomyosarcoma, are extremely rare. HCC and IHCC are three and two times more common in men than women, respectively, whereas gallbladder cancer is about three times more common in women and EHCC occurs with approximately equal frequency.5
There is considerable variation in the incidence of HCC worldwide. In Asia, southeast Asia, and sub-Saharan Africa, HCC is between 15 and 100 times more common than in North America,8 although the incidence is increasing in the United States and Europe.9 Carcinoma of the gallbladder also has shown a substantial geographic variation, and the incidence in some areas, such as northeastern Europe, is more than 20 times higher than in the United States.10 Although EHCC has a fairly uniform incidence, IHCC is also more common in southeast Asia than in other parts of the world, presumably because of the higher incidence of liver fluke infestation in this region.
Considerable variation in the incidence of HCC is also observed in the United States. For example, HCC is five times more common in black men than white women.11 Gallbladder cancer is 15 times more common among Native American women in New Mexico than white women in the same state.10 The other major types of hepatobiliary tumors are of approximately equal distribution or show a slight preponderance among whites.
Etiology
Hepatocellular Carcinoma
In Korea and Taiwan, approximately 90% of patients with HCC have positivity for hepatitis B surface antigen (HBsAg), and prospective studies have found that hepatitis B virus carriers have a 200-fold increase in the relative risk for HCC.8 Indeed, 90% of patients with HCC who are also HBsAg positive have viral DNA integrated into the host genome.12 The greatest evidence of a causal relationship between hepatitis B infection and HCC development, however, is the observation that the incidence of childhood HCC in Taiwan has declined significantly since a nationwide vaccination program was instituted.13
The hepatitis C virus has also been implicated in the pathogenesis of HCC but with a lower incidence of coexistent cirrhosis and without evidence of host genome integration of the viral DNA.8 These findings have suggested that an alternate mechanism may be in play that does not involve either cirrhosis or host DNA alterations.
Cirrhosis without hepatitis infection probably accounts for more cases of HCC in the United States than hepatitis infections.8,14 The development of HCC has been observed in a number of diseases, all of which share the endpoint of cirrhosis.15
Aflatoxin B is a toxic metabolite of fungi that can grow in stored grain and peanuts and has been linked with HCC development in some areas of Africa and Asia.12 A reactive intermediate metabolite of aflatoxin B has been shown to selectively bind to guanine, which is excised and preferentially replaced with thymidine. This guanine-to-thymidine mutation is commonly found in the TP53 tumor suppressor gene in cases of HCC occurring in areas of high aflatoxin ingestion but is not found where aflatoxin levels are low.
Gallbladder Cancer
Epidemiologic studies have found that gallbladder cancer is more common in regions or among populations with a high frequency of cholelithiasis.10,16 Whether the increased risk is related to a direct irritating effect of gallstones or to the presence of carcinogens in bile acids is unknown, however.10,17 Additionally, the incidence rate of cancer in patients with calcified gallbladders has implied that any chronic inflammatory condition could lead to carcinogenesis.18
Cholangiocarcinoma
The development of cholangiocarcinoma has been epidemiologically linked to liver fluke infestation, hepatolithiasis, pyogenic cholangitis, congenital bile duct cysts, past exposure to thorium dioxide, a typhoid carrier state, and ulcerative colitis.8,19 Patients with primary sclerosing cholangitis also have an increased risk, with an incidence of cholangiocarcinoma of about 10%.20 It is possible that EHCCs share a common pathway of carcinogenesis with gallbladder cancer because the risk is lessened 10 years after cholecystectomy.21
Prevention And Early Detection
The identification of patient groups at high risk for HCC and the poor results of therapy have made prevention and early detection strategies attractive.22 The prevention of HCC by vaccination for hepatitis B has been supported by a review of the childhood HCC rates in Taiwan after introduction of a nationwide vaccination program.13 Approximately 85% or more of infants in Taiwan have received hepatitis B vaccination since 1986 compared with none before 1984. On review, the incidence of HCC among 6- to 14-year-olds has significantly declined from 0.7 to 0.36 per 100,000, with corresponding reductions in mortality rates as well. Because the incidence of HCC peaks among people 50 to 60 years of age, it can be anticipated that reductions in HCC incidence will increase as the immunized population ages.
The early detection of HCC in endemic areas of hepatitis B has received considerable attention. One screening tool is serum alpha-fetoprotein (AFP), which has been used in extensive population surveys in China, Taiwan, and South Africa and among native Alaskans.23 Unfortunately, even when screening was limited to people at high risk, the number of HCC cases detected was low. For example, a screening study in South Africa obtained AFP levels in more than 11,000 HBsAg-positive patients but found only 10 with HCC.23 Similarly, in China, of about 2 million people who were screened with AFP, only 300 cases were found. Liver ultrasonography has also been pursued as a screening tool. In a Chinese trial, almost 19,000 people were randomized between screening AFP and ultrasound twice yearly or observation. Mortality rates from HCC were significantly lower in the screened group (83/100,000 vs. 132/100,000).24 Although ultrasonography may be superior to AFP screening,23 it is more expensive22 and its utility is dependent on the expected incidence in the screened population. Still, screening with AFP and ultrasound every 6 to 12 months is recommended by many, including the National Comprehensive Cancer Network (NCCN) in its practice guidelines.25
Given the increased risk of cholangiocarcinoma in patients with primary sclerosing cholangitis and ulcerative colitis, the difficulty in obtaining a diagnosis of malignancy, and the lethality of the cancer when diagnosed, the finding that serum CA19-9 may be useful for screening and early diagnosis is attractive.26 Its sensitivity of 63% and specificity of 50% make it difficult to recommend this test for routine use, however.27
There are no known preventive measures for the biliary tract cancers. Even though cholelithiasis is a risk factor for gallbladder cancer10,16 and may also be related to extrahepatic bile duct cancers, there is no evidence to justify cholecystectomy as a preventive measure.10,21
Biologic Characteristics And Molecular Biology
Molecular techniques have led to significant advances in delineating the process of hepatocarcinogenesis. Frequently, fragments of hepatitis B viral DNA can be found within the genome of the HCC,8,12 leading to the hypothesis that viral integration activates oncogenes or interferes with tumor suppressor genes. In fact, the normal liver of patients with chronic hepatitis B infection will show viral DNA integration early in the course of the disease, suggesting that the HCC originated from clonal expansion of the affected hepatocytes.28 Against these arguments, however, is the finding that the sites of viral DNA integration are not consistent and do not occur near any known oncogenes or tumor suppressor genes. Nor does the viral DNA itself contain any known oncogenes. If, therefore, the integration of viral DNA is necessary for carcinogenesis, the mechanism may be caused by genomic instability from deletions and chromosomal rearrangement rather than specific oncogene activation or disruption of a tumor suppressor gene pathway.28
Hepatocarcinogenesis may not be the result of one particular molecular change but may be related to the ability of the liver to respond to damage by regeneration. The continuous liver damage seen with chronic hepatitis or cirrhosis leads to increased turnover of hepatocytes. During normal hepatocyte regeneration, both proto-oncogene activation and inactivation of suppressor genes occur. Chronic liver damage leads to a nearly continuous cellular reproduction, which may allow carcinogenic molecular changes to accumulate without repair.28 The observation of apparent stepwise progression of small HCCs from regenerating nodules of liver cirrhosis supports this hypothesis.29
Pathology And Pathways Of Spread
Hepatocellular Carcinoma
On gross examination, HCC can appear as expanding or spreading, depending on whether the margin is discrete or poorly defined, or as multifocal, with multiple tumors scattered throughout the liver without an obvious primary-to-secondary relationship.30 The microscopic appearance of HCC resembles that of normal liver tissue, both in its cytologic findings and in its characteristic platelike growth. Nuclear grading is typically judged using a four-grade system, but for prognostic purposes cells are either low grade (grade 1 or 2) or high grade (grade 3 or 4).31 Grade 1 tumors can be difficult to differentiate from adenomas or atypical hyperplastic nodules. Similarly, grade 4 tumors can resemble other anaplastic cancers and require special stains for further characterization.15
HCC may locally invade the portal vein, hepatic vein, or diaphragm. Approximately one-third of patients have regional disease at presentation, with metastases to the portahepatic and celiac axis lymph node chains.11 Intra-abdominal metastasis to the peritoneal lining or liver or extra-abdominal spread to the lungs and bone is found in about one third of patients.11 Metastasis to other sites, such as the brain or muscle, occurs infrequently.
Fibrolamellar carcinoma is a unique subtype of HCC that makes up about 5% of the cases in North America.31 It is associated with the longest survival times of any of the HCC subtypes and is typically found in young women. Grossly, fibrolamellar carcinoma is classified as an expanding, sclerosing tumor, characterized by septa of retracted collagenous structures radiating from a central region.30 On cytologic examination, the tumor cells are large and polygonal, with a granular cytoplasm resulting from numerous mitochondria. The abundant fibrous stroma is characteristic and is arranged in parallel lamellae around nests, cords, and sheets of tumor cells.15
Gallbladder Cancer
Most gallbladder cancers are adenocarcinomas.32 The gross appearance can vary from localized nodular growths to involvement of the entire organ.33 Histologically, both grade and vascular invasion are of prognostic value.32 Papillary adenocarcinoma is a variant histologic type that makes up about 6% of the total number of cases and has a much longer median survival time than the more common type. Mucinous carcinoma is another variant of adenocarcinoma, occurring in about 5% of cases and associated with perforation of the gallbladder.33
Direct liver invasion is frequent18 and may be related to the thin wall and single muscular layer of the gallbladder, the presence of Rokitansky-Aschoff sinuses (which themselves can penetrate the muscle layer in cases of chronic cholecystitis), and the fact that the perimuscular connective tissue of the gallbladder is directly contiguous with the interlobular connective tissue of the liver.32 Historically, approximately 40% to 50% of patients will have distant metastases at presentation, usually to the liver or peritoneum.18,32 Despite an increase in the number of cholecystectomies in recent years, driven mostly by the widespread adoption of laparoscopic techniques, the proportion of patients presenting with advanced disease has not declined.34,35 Lymphatic spread to the cystic, pericholedochal, hilar, and celiac lymph nodes is found in 45% of patients,18 but only 5% of patients will have positive regional lymph nodes with tumor confined to the gallbladder.32
Cholangiocarcinoma
Biliary cancer is typically divided according to the site of origin into intrahepatic tumors, extrahepatic tumors, or hilar (Klatskin) tumors. Grossly, biliary cancers are sclerotic, with a diffuse, firm gray-white annular thickening of the duct.36 Nearly all carcinomas of the biliary tree are mucin-producing adenocarcinomas with cell variation from cuboidal to columnar with prominent nucleoli. As with gallbladder cancer, the variant histologic type of papillary adenocarcinoma has a better prognosis.37
Cholangiocarcinoma typically spreads by direct extension along the biliary tree, although separate tumor nodules may represent either multifocal tumor development or metastatic deposits.38 Direct invasion of adjacent organs is more common for intrahepatic and hilar tumors than for extrahepatic tumors.11,37,39 Tumor involvement of the cystic, hilar, or celiac lymph nodes is found in 30% to 50% of patients.11,18,39 The incidence of distant metastases is about 30%, with a lower incidence of peritoneal disease than for gallbladder cancer.39
Clinical Manifestations, Patient Evaluation, And Staging
Symptoms and Signs
The typical presentation of a patient with hepatobiliary cancer depends on the site of origin. Patients with primary liver tumors, whether HCC or IHCC, frequently will complain of right upper abdominal or epigastric pain at presentation.8,39–41 The pain is usually dull but may be sharp and severe with end-stage disease. Rarely, patients with HCC will complain of a sudden, sharp, severe pain related to acute bleeding into the tumor or rupture of the tumor with intra-abdominal bleeding. The patient may also be aware of an abdominal mass or increased girth related to ascites.
Cirrhosis is present in approximately 70% of patients with HCC.14 Occasionally, patients with known cirrhosis will be evaluated because of an unexplained clinical deterioration. Jaundice is unusual with primary liver tumors and may be obstructive because of tumor compression of the biliary system or hepatocellular because of end-stage hepatic replacement with tumor.
In contrast to the primary liver tumors, patients with cholangiocarcinomas of the biliary hilum or distal biliary tree almost invariably present with jaundice.39,40 Abdominal pain and the nonspecific complaints of weight loss, anorexia, fatigue, fever, and night sweats are common in patients with either biliary or hepatic tumors. Patients with gallbladder cancer commonly complain of both abdominal pain and jaundice and may also have weight loss, anorexia, and fatigue but are usually undiagnosed before an attempted cholecystectomy.18,42,43
The most common physical finding in patients with primary hepatic tumors is hepatomegaly,40,41 which is frequently tender. The liver is often smooth but may be nodular as a result of tumor or cirrhosis. Occasionally, patients with HCC may have a hepatic bruit because of the highly vascular nature of the tumor. Ascites is a particularly ominous finding because it represents either hepatic dysfunction resulting from cirrhosis or tumor replacement, Budd-Chiari syndrome from malignant invasion of the hepatic veins, or peritoneal spread of cancer.
Laboratory Studies
The goals of the workup of patients with hepatobiliary malignant tumors are to define the extent of the tumor and to carefully assess liver function. Laboratory testing includes a complete blood count, routine biochemistry panel, and coagulation studies (Table 47-1). In addition, serum CA19-9 may have value as a tumor marker for cholangiocarcinoma.26
TABLE 47-1 Diagnostic Evaluation and Algorithm for Hepatobiliary Cancers
| General |
AFP, alpha-fetoprotein; anti-HCV, antibody to hepatitis C virus; CEA, carcinoembryonic antigen; CT, computed tomography; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; MRI, magnetic resonance imaging; PT, prothrombin time; PTT, partial thromboplastin time.
Serum AFP is a widely used tumor marker for HCC; normal values are in the range of 20 µg/L or less, and levels greater than 400 µg/L (4000 µg/L in patients with hepatitis) are considered diagnostic of HCC. There is some evidence that AFP levels are prognostic for patients with tumors 5 cm or smaller as well as those with more than 50% involvement of the liver.44 The major difficulty in using AFP is that elevations to levels between 20 and 400 µg/L may represent either an exacerbation of hepatitis or the presence of a small, curable HCC.22,23 This observation has led to the recommendation that patients with known cirrhosis and/or hepatitis and a rise in AFP levels undergo retesting in 1 to 3 months, after an exacerbation of hepatitis would be expected to have improved. Another difficulty is the false-negative rate, which occurs in 10% to 15% of patients with HCC, presumably because the tumor is either too anaplastic or too well differentiated to produce the protein.22
Patients with HCC also frequently have a history of hepatitis. Although the hepatitis status does not appear to be prognostic,14 response rates to chemotherapy were higher and toxicity was lower in patients who were negative for hepatitis B or C in a trial of hepatic arterial chemotherapy.45 Approximately 5% of patients with HCC have a paraneoplastic syndrome,14 such as hypoglycemia, erythrocytosis, hypercalcemia, or hypercholesterolemia.41
Radiographic Studies
The primary imaging modalities currently being used for characterizing the extent of liver tumors include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Patients suspected of hepatic disease, whether IHCC or HCC, are typically first evaluated with ultrasonography. Although findings of focal liver lesions are often nonspecific, recent advances such as the use of Doppler ultrasound, contrast agents, and harmonic imaging have improved the usefulness of this area of examination.46,47 Still, ultrasound may be limited by patient characteristics such as obesity, intestinal distention, or scars, and it is very operator dependent. In evaluation for potential resection, MRI and CT are the dominant imaging modalities because of their ability to display hepatic segmental anatomy and the extent of hepatic disease and evaluate extrahepatic spread. The advent of spiral CT and, more recently, multislice spiral CT has improved hepatic imaging considerably. Now, with faster acquisition times, liver imaging can be accomplished during a single breath hold to improve spatial resolution. With thinner slices, multiplanar reformatting can be used to better assess resectability. State-of-the-art CT scanning involves acquisition of three contrast phases (arterial hepatic, portal venous, and equilibrium) that are very important for assessing lesion vascularity.46 For instance, HCC is hypervascular and typically displays intense enhancement during the arterial-hepatic phase with postcontrast washout, whereas cholangiocarcinoma may demonstrate delayed enhancement.
CT scanning can also be performed after administration of contrast via an angiographically placed superior mesenteric artery catheter (CT arterial portography) or a hepatic artery catheter (CT hepatic arteriography). With the former, the bolus of contrast passes through the intestinal vasculature and collects in the portal vein, providing excellent contrast between normal liver tissue and tumor tissue (Fig. 47-1). CT arterial portography and CT hepatic arteriography are considered the most sensitive methods of detecting small liver cancers,48,49 detecting lesions as small as 0.2 cm in diameter.50 However, a high false-positive rate has limited their usefulness.51
MRI plays an important role in detection and characterization of liver tumors. Modern MRI protocols usually include parenchymal imaging with one or more types of contrast agents, MR angiography, and MR cholangiopancreatography (MRCP). The superior contrast resolution and inherent capability of multiplanar evaluation have made MRI the examination of choice for characterization of lesions in cirrhotic patients.46,52
In patients with biliary obstruction, MRCP has limited the role of transhepatic or endoscopic cholangiopancreatography to instances when drainage and decompression of the biliary system are required.47 In addition to being noninvasive, the advantage of MRCP is its ability to define the extent of tumor not only within the intrahepatic and extrahepatic bile ducts but also to provide information on the status of the portal vein and lymph nodes.
The usual appearance of an EHCC is a stricture at the site of involvement with dilatation of the biliary tract proximal to the stricture (Fig. 47-2). The tumor itself may extend for some distance along the biliary tract. One area of particular difficulty is distinguishing bile duct cancer from primary sclerosing cholangitis, with the latter typically showing diffuse rather than focal biliary narrowing.20 Ultrasonography, CT, and MRI of the abdomen frequently show only intrahepatic biliary dilatation (with or without hepatic atrophy) but no identifiable mass.19
Although ultrasonographic examination is frequently obtained in patients suspected of having gallbladder disease, the study is rarely diagnostic of gallbladder cancer.42 Postoperative evaluation using CT scanning can be helpful in defining both residual disease and possible metastases.
Diagnosis
The NCCN guidelines recommend a biopsy for patients suspected of having HCC when the AFP level is 400 µg/L or less (≤4000 µg/L in patients with hepatitis). Fine-needle aspiration can also be used in patients with hepatic tumors to arrive at a diagnosis.15 Cytologic efforts have found an improved ability to confidently diagnose HCC on fine-needle aspiration by examining the nuclear-cytoplasmic ratio, trabecular pattern, and atypical naked hepatocytic nuclei.53
Establishing the diagnosis of cholangiocarcinoma can be difficult without exploration, presumably because of the large amount of sclerosis present. Performing an incisional biopsy or curettage at the time of surgery should be avoided, however, in view of an increased risk of peritoneal failure or wound implant with these procedures.54 When cytologic study only is used, cancer can be confirmed in 50% to 90% of cases.19,55
Staging
The American Joint Committee on Cancer staging manual, seventh edition, has defined separate TNM staging systems for hepatic tumors, IHCCs, gallbladder tumors, and EHCCs, divided into perihilar and distal bile duct lesions56 (Table 47-2). The staging for both gallbladder cancers and EHCC tumors is primarily surgical, reflecting the role of resection.
| Primary Tumor: Liver | |
| T0 | No evidence of primary tumor |
| T1 | Solitary tumor without vascular invasion |
| T2 | Solitary tumor with vascular invasion, or multiple tumors, none more than 5 cm |
| T3a | Multiple tumors more than 5 cm |
| T3b | Single or multiple tumors of any size involving a major branch of the portal or hepatic vein(s) |
| T4 | Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
| Primary Tumor: Intrahepatic Bile Duct | |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ (intraductal tumor) |
| T1 | Solitary tumor without vascular invasion |
| T2a | Solitary tumor with vascular invasion |
| T2b | Multiple tumors, with or without vascular invasion |
| T3 | Tumor perforating the visceral peritoneum or involving the local extrahepatic structures by direct invasion |
| T4 | Tumor with periductal invasion |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis present |
| Primary Tumor: Gallbladder | |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ |
| T1 | Tumor invades lamina propria or muscle layer |
| T1a | Tumor invades lamina propria |
| T1b | Tumor invades muscle layer |
| T2 | Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver |
| T3 | Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts |
| T4 | Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures |
| N0 | No regional lymph node metastasis |
| N1 | Metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein |
| N2 | Metastases to periaortic, pericaval, superior mesentery artery, and/or celiac artery lymph nodes |
| Primary Tumor: Perihilar Bile Ducts/Proximal Extrahepatic Cholangiocarcinoma | |
| Tis | Carcinoma in situ |
| T1 | Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue |
| T2a | Tumor invades beyond the wall of the bile duct to surrounding adipose tissue |
| T2b | Tumor invades adjacent hepatic parenchyma |
| T3 | Tumor invades unilateral branches of the portal vein or hepatic artery |
| T4 | Tumor invades main portal vein or its branches bilaterally, common hepatic artery, or the second-order biliary radicals bilaterally, or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis (including nodes along the cystic duct, common bile duct, hepatic artery, and portal vein) |
| N2 | Metastasis to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes |
| Primary Tumor: Extrahepatic Cholangiocarcinoma, Distal Bile Duct | |
| Tis | Carcinoma in situ |
| T1 | Tumor confined to the bile duct histologically |
| T2 | Tumor invades beyond the wall of the bile duct |
| T3 | Tumor invades the gallbladder, pancreas, duodenum, or other adjacent organs without involvement of the celiac axis or the superior mesenteric artery |
| T4 | Tumor involves the celiac axis or the superior mesenteric artery |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
| Distant Metastasis | |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
From Edge SB, Byrd DR, Compton C, et al, editors: AJCC Cancer Staging Manual, ed 7, New York, 2010, Springer.
Primary Therapy
Hepatocellular Carcinoma
Potentially curative treatments include partial hepatectomy, total hepatectomy with a liver transplant, and nonsurgical ablative therapies. Because there are no controlled trials comparing these treatments, recommendations are based on nonrandomized cohort studies rather than on firm evidence. Resection and transplantation appear to result in the best outcomes in well-selected candidates (5-year survival rate of 60% to 70%).* Percutaneous treatments provide good outcomes (5-year survival rate of 40% to 50%),67,68–70 but they are generally inferior to those achieved with surgery. Exceptions to the latter might be patients with carcinoma in situ or single small tumors.
Resection
Hepatic resection is the treatment of choice for HCC in noncirrhotic patients in whom major resections can be accomplished with low rates of complications.71 In contrast, among patients who have cirrhosis, strict selection criteria are required to avoid liver failure. State-of-the-art surgery is associated with operative mortality rates of 1% to 3% and 5-year survival rates of approximately 50%.58 Approximately 70% of patients suffer tumor relapse.71 Positive resection margins, microvascular invasion, poorly differentiated histologic characteristics, and satellite lesions predict for relapse.61,72
Adjuvant therapies have been attempted, but their efficacy has not yet been established. A 2002 review73 of randomized controlled trials identified 13 trials with relapse or survival endpoints reported at 3 years or longer. Three studies involved predominantly systemic adjuvant chemotherapy; four involved predominantly hepatic artery-based chemotherapy or embolization; and six used other therapeutic modalities, including immunotherapy, differentiation agents, and hepatic artery infusion of Lipiodol labeled with iodine-131 (131I). Improved disease-free survival (DFS) or overall survival (OS) rates were noted in six trials, five of which involved modalities other than systemic or hepatic artery chemotherapy or embolization. The authors concluded that systemic and hepatic artery chemotherapy or chemoembolization has not been shown to improve OS or DFS rates after resection of HCC. The other adjuvant modalities appeared more promising. A 2009 Cochrane systematic review of 12 randomized studies concluded that there is limited evidence that adjuvant Lipiodol therapy or immunotherapy may potentially improve DFS rates after resection of HCC.74 A separate meta-analysis of adjuvant interferon found a risk of mortality of 0.65 and of recurrence of 0.86 compared with curative local therapy alone in patients with viral hepatitis.75
Liver Transplantation
The advantage of a total hepatectomy with orthotopic liver transplantation for patients with cirrhosis is that the entire organ is removed, therefore taking all gross and microscopic tumor and premalignant disease. In addition, transplantation simultaneously addresses the underlying cirrhosis. The widespread use of liver transplantation, however, has been limited by the shortage of donor organs, the high cost of the procedure, and the high perioperative mortality rates, initially reported in the range of 10% to 25%.8 The use of stricter selection criteria (one lesion <5 cm in diameter or up to three lesions <3 cm in diameter) has improved outcomes dramatically. Today, 5-year OS of 70% and relapse rates lower than 15% can be expected.57,60,61,62,66 Most centers advocate the use of chemotherapy, chemoembolization, percutaneous ablation, or a combination of these treatments while patients are on the waiting list. The value of these therapies is unknown.
Percutaneous Ablation
Only 30% of patients present with resectable HCC. For those with small unresectable lesions, percutaneous ablation is the most common option and may offer a chance for long-term survival.68–7076 Ablation can be accomplished by the use of chemicals such as alcohol or acetic acid or by techniques using extreme temperatures, such as radiofrequency ablation, microwave, or laser coagulation or cryoablation. Radiofrequency ablation is the most common method used in the United States. A needle electrode is placed in the tumor, and a high-frequency alternating current heats the surrounding tissue to produce necrosis. The best results are produced with tumors less than 4 cm.77 A recent prospective randomized trial demonstrated reduced rates of local progression (2% vs. 11%) and overall recurrence (70% vs. 85%) and improved OS (74% vs. 57%) with radiofrequency ablation as compared with percutaneous ethanol injection.78 In a review of 3670 patients treated by radiofrequency ablation, the mortality rate was 0.5% and the complication rate was 8.9%.79 Subcapsular location and poorly differentiated histologic characteristics have been implicated in needle-track seeding. Cryoablation has fallen out of favor due to a high complication rate and recent data indicating inferior outcomes. Microwave and laser coagulation are still experimental techniques.76
