The Washington Manual of Oncology, 3 Ed.

Hepatobiliary Cancers

Steven Sorscher

HEPATOCELLULAR CARCINOMA

 I. PRESENTATION

1. Subjective. Common symptoms of hepatocellular carcinoma (HCC) include anorexia, weight loss, increasing abdominal girth, and jaundice. Up to 25% of patients may be asymptomatic at presentation. Patients may present with paraneoplastic syndromes, including hypoglycemia, erythrocytosis, hypercalcemia, and dysfibrinogenemia or progressive signs of liver failure.
2. Objective. Hepatomegaly, ascites, fever, bleeding, and splenomegaly can be seen.
3. WORKUP AND STAGING. High-risk patients (including those with cirrhosis—such as viral- or nonviral-induced—and hepatitis B carriers without cirrhosis) should have periodic screening with ultrasonography (USN) of the liver, alpha-fetoprotein (AFP), and albumin and alkaline phosphatase levels (Cancer 1996;78:977). There is some evidence from a study of screening in Chinese patients with hepatitis B infection or a history of chronic hepatitis that screening results in fewer patients dying from HCC (J Cancer Res Clin Oncol 2004;130:417). A rising AFP with negative liver imaging should result in more frequent radiographic follow-up.

 Tissue diagnosis can be obtained by fine needle aspiration (FNA), core biopsy, or laparoscopic biopsy. The potential for tumor “spillage” appears to be very small. Although occasionally patients may be treated for HCC based on the clinical, radiologic, and biochemical features, generally an attempt should be made to obtain a tissue diagnosis. For example, while a serum AFP >400 ng/mL is sometimes considered diagnostic of HCC, such high values are seen only in a small number of patients with HCC. The American Association for the Study of Liver Diseases (AASLD) no longer includes AFP tests as part of the diagnostic evaluation. Magnetic resonance imaging (MRI) or four-phase computed tomography (CT) should be used to better define tumor extent. MRI with arterial phase enhancement may also be used for the evaluation of tumor extension (Surg Oncol Clin N Am2007;16:343). Staging should also include chest imaging and complete blood count CBC and liver function tests.

 The fibrolamellar histology is noteworthy for its higher likelihood of resectability and the lack of association with cirrhosis. The current American Joint Committee on Cancer/Union Internationale Contre Cancer (AICC/UICC) staging includes the presence or absence of cirrhosis/fibrosis, which are histologic features that predict prognosis after surgery.

 III. MANAGEMENT. Surgical resection represents the only known curative therapy. Child–Pugh classification and other scoring systems, which help predict liver function and reserves with surgery, have been used to identify patients eligible for resection (J Hepatolbiliary Pancreat Surg 2002;9:469).

1. According to the United Network for Organ Sharing (UNOS), transplant should be considered in those not eligible for resection and who fulfill all of the three Milan criteria: (1) Single tumor ≤5 cm or up to three tumors <3 cm; (2) Absence of macrovascular invasion; (3) No extrahepatic spread. The model for end-stage liver disease (MELD) may be useful for assessing placement on the liver transplant wait list. Four-year relapse-free survival up to 80% has been observed with carefully selected patients. After transplant, the survival may be as high as 92% in selected patients meeting the Milan criteria, with vascular invasion predicting lower survival (Ann Surg Oncol 2008;15:1001). Patients with unresectable but small tumors may be considered for tumor ablation followed by liver transplantation.

Other “local” therapies such as radiofrequency ablation (RFA), alcohol injection, cryotherapy, and chemoembolization may improve symptoms and control local disease in selected patients. RFA appears to be superior to percutaneous alcohol injection (PEI) (Hepatology 2009;49:453; Am J Gastroenterol 2009;104:514; J Hepatol 2010;52:380), with 5-year survival rates of 70% in selected patients. The likelihood of success with these approaches may involve the expertise of the clinician, the number, size, and location of the tumors, as well as whether there is vascular involvement by the tumors. Several arterial-directed therapies are now widely available. All arterial-directed therapies are considered relatively contraindicated in patients who have bilirubin levels greater than 3 mg/dL, unless segmental therapy is used.

Stereotactic beam radiation therapy (SBRT) resulted in 2-year progression-free survival (PFS) of 33% in selected patients (Cancer 2012;118:5424). SBRT has also been used as bridging therapy for those with HCC and cirrhosis awaiting transplant (J Surg Oncol 2012;105:692; Int J Radiat Oncol Biol Phys 2012;83:895; Liver Transpl 2012;18:949).

10. Cytotoxic chemotherapy has traditionally been associated with low response rates and questionable disease control. An international Phase III placebo-controlled trial in which 602 patients with hepatocellular carcinoma were randomly assigned to receive sorafenib 400 mg twice daily or placebo demonstrated an overall survival (OS) benefit for those receiving sorafenib (10.7 vs. 7.9 months) (N Engl J Med 2008;359:378). Roughly 97% of patients in this study had Child–Pugh A liver function. Therefore, sorafenib should be used cautiously with Child–Pugh B liver function. Enrollment in clinical trials utilizing novel agents and approaches should be considered.

 IV. EPIDEMIOLOGY. HCC is among the most frequent causes of cancer death worldwide, more commonly affecting men than women. In the United States, HCC is relatively less common, but is increasing in frequency, in part due to hepatitis C infection (Am Intern Med 2003;139:817). Among patients with hepatitis C–induced cirrhosis, 1% to 2% per year develop HCC. Although HCC in patients with hepatitis C occurs almost exclusively in patients with advanced fibrosis or cirrhosis, hepatitis B–induced HCC may occur without cirrhosis in a minority of patients. Other risk factors for HCC include cirrhosis due to other causes (alcohol, aflatoxin B), primary biliary cirrhosis, hereditary hemochromatosis, and nonalcoholic steatohepatitis (NASH) in patients with diabetes (Hepatology 2003;37:917).

CANCER OF THE GALLBLADDER

 I. PRESENTATION

1. Subjective. Patients typically present with symptoms referable to the biliary tract, and often cholecystitis or biliary colic is suspected. Suspicion of malignancy should particularly be raised in older patients with weight loss and more continuous pain. In a retrospective study of 6,135 patients at a single institution and treated with curative resection, 47% of the gallbladder carcinomas were diagnosed incidentally during laparoscopic cholecystectomy (J Surg Oncol 2008;98:485).
2. Objective. Physical examination may reveal icterus, scratch marks from pruritis, and hepatomegaly.
3. WORKUP AND STAGING. A carbohydrate antigen 19-9 (CA19-9) greater than 20 µ/mL has a reported 79% sensitivity and 79% specificity. Approximately 93% of patients with gallbladder cancer where surgery is planned for benign disease will have carcinoembryonic antigen (CEA) greater than 4 ng/mL (Int J Cancer 1990;45:821).

 An abnormality on USN may imply the need for CT, MRI, or magnetic resonance cholangiopancreatography (MRCP) for a better characterization of the extent of the disease. PET scanning may help identify regional lymph nodes and distant metastases (J Am Coll Surg 2008;206:57; J Gastroenterol 2010;45:560). Endoscopic retrograde cholangiopancreaticography (ERCP) with endoscopic USN may identify patients with unresectable disease, or allow for a tissue diagnosis. There is no clear risk of dissemination in obtaining cytology using ERCP and endoscopic USN.

 Diagnosis is often made at the time of surgery, and definitive resection rather than cholecystectomy should be planned in suspicious, yet resectable cases. In addition to cytology specimens obtained with ERCP, percutaneous needle biopsy and core biopsy are used, although core biopsy, in particular, may carry significant “tracking” risk and should be reserved for unresectable cases (Acta Cytol 1995;39:494). Gallbladder cancer is typically adenocarcinoma, although other histologic subtypes occur infrequently. Higher grade tumors are associated with a worse prognosis, whereas the rare papillary tumors are associated with a better prognosis (Cancer1992;70:1493). If no distant metastases are identified radiographically, laparoscopy should be considered to complete preoperative staging.

 III. MANAGEMENT. Patients with incidentally found gallbladder tumors who are identified as having resectable disease should be considered for cholecystectomy, en bloc hepatic resection, lymphadenectomy, and possible bile duct resection. A similar approach is warranted for patients with preoperative radiographic staging, which reveals the possibility of resection of all radiographically evident tumors. If jaundice is present, the evaluation may include ERCP/percutaneous transhepatic cholangiography/MR cholangiography. If, at cholecystectomy, the gallbladder is removed intact, and a T1a tumor with negative margins is identified, no additional surgery is recommended. Lymph node involvement is very rare for T1. For T1b or greater disease, more extensive surgery has been recommended, although the evidence supporting radical resection for T1b tumors is not definitive (Arch Surg 2011;146:734; World J Gastroenterol 2012;18:4736).

 In combining retrospective reviews, 5-year survival for patients with T1 tumors generally approaches 100%; whereas for T2, 70% to 90% survival may be expected (Ann Surg 1992;215:326; Eur J Surg 1997;163:419; Surgery1994;115:751). Surgery remains the only curative therapy with 5-year survivals of 45% to 63% for patients with N1 disease.

 In a small trial, adjuvant 5-fluorouracil (FU) and radiation demonstrated an improved 5-year survival compared with surgery alone (64% vs. 33%) (Int J radiat Oncol Biol Phys 2002;52:167) and, as a result, has been recommended for those with greater than T1 disease. However, studies of adjuvant therapy for biliary cancer often involved both bile duct and gallbladder cancers. In a meta-analysis of 6,712 patients, there was a trend toward OS improvement with adjuvant therapy that was greater for those with gallbladder compared with other biliary cancers (J Clin Oncol 2012;30:1934).

 Patients with unresectable but not metastatic disease may benefit from combined chemotherapy and radiation therapy (RT), although this approach has not been extensively studied. Gemcitabine or capecitabine alone or in combination have been used in patients with metastatic disease. The overall prognosis from metastatic gallbladder cancer remains poor, with average survival of approximately 6 months for untreated patients and only approximately 5% of patients surviving 5 years. Biliary decompression may be necessary before initiation of chemotherapy and may also relieve obstructive symptoms. ABC-02 was a Phase III-controlled trial in which 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder, or ampullary cancer received gemcitabine alone or in combination with cisplatin. OS was 11.7 months for the combination versus 8 months for gemcitabine alone (N Engl J Med 2010;362:1273).

 IV. EPIDEMIOLOGY. Marked regional and ethnic differences are seen in the incidence of gallbladder cancer. For example, gallbladder cancer has been reported as the leading cause of cancer death in Chilean women. High rates are seen in other South American countries as well as in Central Europe, Israel, and in Native Americans, Japanese men, and others. In the United States, gallbladder cancer is the most common biliary tract cancer, and is more common in women than in men. There are approximately 2,800 deaths per year from gallbladder cancer.

 Chronic inflammation, often due to gallstones, is associated with gallbladder cancer. In fact, 75% to 98% of gallbladder cancer patients will have had gallstones (Cancer Treat Res 1994;69:97). The so-called “porcelain gallbladder” will be associated with cancer in up to 25% of patients. Gallbladder polyps, particularly those greater than 1 cm and those in older patients, warrant special attention (Br J Surg 1992;79:227). There are associations between gallbladder cancers and anomalous biliary ductal malformations as well as with typhoid.

CHOLANGIOCARCINOMA

 I. PRESENTATION

1. Subjective. Patients typically present with weight loss or symptoms related to biliary obstruction such as jaundice, pruritis, or fever from infection.
2. Objective. Physical examination may reveal icterus, a palpable gallbladder (Courvoisier’s sign), and an enlarged liver.
3. WORKUP AND STAGING. Cholangiocarcinomas arise in the biliary tree and are classified as intrahepatic or extrahepatic tumors. Extrahepatic cholangiocarcinomas account for 90% of all cholangiocarcinomas and include hilar cholangiocarcinomas, which are commonly called Klatskin’s tumors (Ann Surg 1996;224:463). Laboratory findings often reveal elevated liver function tests, CEA, and CA19-9. A variety of radiographic studies, such as USN and delayed contrast CT or MRI scanning, are used to define disease extent as well as chest imaging. Retrograde cholangiopancreatography with ERCP is used for stent placement and to obtain cytology for diagnosis. Cytology sampling has demonstrated 62% sensitivity. For hilar tumors, percutaneous transhepatic cholangiography may be used to define proximal bile duct involvement. MRI cholangiography, angiography, and endoscopic USN (which also define a mass for biopsy) have potential roles in defining disease extent and vascular involvement. Molecular testing has been shown to increase the sensitivity for diagnosis (Gastroenterology2006;131(4):1064).

 Adenocarcinoma is the most common histology. Subtypes include sclerosing, nodular, and papillary variants. Revised staging systems for intra- and extrahepatic cholangiocarcinomas incorporate features predictive of prognosis.

 III. MANAGEMENT. Surgery offers the best chances of cure for those with disease confined to a localized portion of the liver. Involvement of both hepatic lobes indicates generally unresectable disease. Nodal involvement or more distant metastases are usually considered contraindications to curative surgery. In summarizing multiple series, the median and 5-year survival rates after surgery have ranged from 15 to 29 months and 13% to 42%, respectively. Either stents or surgery can be used to improve biliary drainage and reduce symptoms and potentially delay hepatic function deterioration. Silastic stents are changed regularly as metal stents do not require changing, but cannot be removed once obstructed.

 For intrahepatic potentially resectable cholangiocarcinoma, a laparoscopy appears to improve detection of liver and peritoneal metastasis, and should be considered before resection. For intrahepatic cholangiocarcinomas, negative margin resection has been associated with an improved 5-year survival (39.8% vs. 4.7% for those with a positive margin) and lower recurrence rates (53.9% vs. 73.6%) (Arch Surg 2012;147:1107).

 Optimal adjuvant postoperative therapy has not been determined, but for intrahepatic cholangiocarcinoma (particularly with positive tumor margins [R1] or residual local disease [R2] after resection), reasonable options include fluoropyrimidine-based chemoradiation or chemotherapy alone with fluoropyrimidine or gemcitabine-based combinations.

 Local regional therapies for intrahepatic cholangiocarcinomas include RFA, transhepatic chemoembolization (TACE), drug-eluting spheres with TACE (DEB-TACE), and transarterial radioactive embolization with yttrium microspheres (TACE). Each of these approaches has been shown to be potentially effective in small series. For example, in a small series of patients with unresectable intrahepatic cholangiocarcinomas, OS was 38.5 months with RFA (AJR Am J Roentgeno 2011;196:W205).

 For extrahepatic cholangiocarcinomas, radical surgery appears to result in 5-year survival rates of 20% to 42% for resected hilar tumors and 16% to 52% for resected distal cholangiocarcinoma (World J Clin Oncol2011;2:94).

 Retrospective series together do appear to support adjuvant chemotherapy or chemoradiation therapy, particularly for higher risk biliary cancers after resection.

 Liver transplantation is a consideration for cholangiocarcinomas without distant spread. Five-year OS rates range from 25% to 42%. Neoadjuvant chemoradiation or adjuvant chemoradiation appear to be associated with an improved relapse-free survival compared with curative resection in select patients (Ann Surg 2005;242:451; Arch Surg 2011;146:683).

 IV. EPIDEMIOLOGY. Cholangiocarcinomas are associated with conditions causing chronic inflammation such as primary sclerosing cholangitis, chronic bile duct calculi, choledochal cysts, and liver flukes. Viral hepatitis also appears to be a risk factor for intrahepatic cholangiocarcinomas.

 Cholangiocarcinomas are more common in Southeast Asia and China, and the incidence and mortality from cholangiocarcinomas is rising (J Gastroenterol Hepatol 2002;17:1049).

SUGGESTED READINGS

Hepatocellular Carcinoma

Goudolesi GE, Roayaie S, Munoz L, et al. Adult living donor transplantation for patients with hepatocellular carcinoma: extending UNOS priority criteria. Ann Surg 2004;239:142–149.

Greten TF, Papendorf F, Bleck JS, et al. Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients. Br J Cancer 2005;92:1862–1868.

Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. A comparison of lipidol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med 1995;332:1256–1261.

Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002;359:1734–1939.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390.

Mazzaferro V, Ragalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N Eng J Med 1996;334:693–699.

Cancer of the Gallbladder

de Aretexaba XA, Roa IS, Burgos LA, et al. Curative resection in potentially resectable tumors of the gallbladder. Eur J Surg 1997;163:419.

Daines WP, Rajagopalan V, Groosbard ML, et al. Gallbladder and biliary tract carcinoma: a comprehensive update, part 2. Oncology (Huntington) 2004;18:1049.

Lazcano-Ponce EC, Miquel JF, Munoz N, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 2001;51:349.

Matsumoto Y, Fugii H, Aoyama H, et al. Surgical treatment of primary carcinoma of the gallbladder based on histologic analysis of 48 surgical specimens. Am J Surg 1992;162:239.

Shirai Y, Yoshida K, Tsukaka K, et al. Inapparent carcinoma of the gallbladder: an appraisal of a radical second operation after simple cholecystectomy. Ann Surg 1992;215:326.

Tsukaka K, Kurosaki I, Uchida K, et al. Lymph node spread from carcinoma of the gallbladder. Cancer 1997:80:661.

Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273–1281.

Cholangiocarcinoma

Heimbach JK, Haddock MG, Alberts SR, et al. Transplantation for hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study. Gastrointest Endosc 2004;60:68–75.

Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging resectability and outcome in 255 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507–517; discussion 517–519.

Klatskin G, Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatic: an unusual tumor with distinctive clinical and pathologic features. Am J Med 1965;38:241.

Lee CC, Wy CY, Chen JT, et al. Comparing combined hepatocellular-cholangiocarcinoma and cholangiocarcinoma: a clinicopatholigic study. Hepatogastroenterology 2002;49:1487.

Rajagopalan V, Daines WP, Grossbard ML, et al. Gallbladder and biliary tract carcinoma: a comprehensive update, part 1. Oncology 2004;18:889–896.

Sudan D, DeRoober A, Chinnakotla S, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant 2002;2:774–779.