The Bethesda Handbook of Clinical Oncology

Davendra P. S. Sohal and Alok A. Khorana

INTRODUCTION

Carcinomas of the biliary tract include cancers arising in either the gallbladder or the bile duct system—the latter usually referred to as cholangiocarcinomas and further categorized as intra- or extrahepatic. There will be an estimated 11,420 new cases of gallbladder and biliary tract cancers (excluding intrahepatic biliary tract cancer) in 2016 in the United States with 3,710 expected deaths. Worldwide, 186,000 cases and 140,000 deaths were reported in 2013. Gallbladder cancer is the most common biliary tract cancer, occurring nearly twice as often as cholangiocarcinomas. The epidemiology, clinical features, staging, and surgical treatment are distinct for carcinomas arising in the gallbladder and bile duct, therefore, these are described separately. The systemic therapy options are similar and are discussed together later in the chapter.

CARCINOMA OF THE GALLBLADDER

Epidemiology

Women have a 2- to 6-fold higher incidence of gallbladder cancer.

There is a prominent geographic variation in the incidence of gallbladder cancer. Higher rates are seen among Native Americans, in South American countries (particularly Chile), and in countries such as India, Pakistan, Japan, and Korea. These populations share a high prevalence of cholelithiasis, which is a common risk factor.

The United States is considered a low-incidence area. The age-adjusted incidence of carcinoma of the gallbladder is 1.2 per 100,000 population in the United States.

Etiology

Cholelithiasis (gallstones): A history of gallstones appears to be one of the strongest risk factors for gallbladder cancer. Most (70% to 90%) patients have gallstones. The risk increases with an increase in the size and duration of the stones.

Porcelain gallbladder: Extensive calcium deposition in the gallbladder wall was associated with cholecystitis in nearly all cases. Previously, the incidence of gallbladder cancer in patients with this condition was thought to range from 12.5% to 60%, although more recent data suggest the incidence is closer to 2% to 3%. Stippled, mucosal calcifications appear to be associated with a higher risk than diffuse intramural calcifications.

Chronic infection: Carriers or those colonized with Salmonella typhi and Helicobacter pylori may be at increased risk of developing gallbladder cancer.

Gallbladder polyps: Polyps >1 cm have the greatest malignant potential and therefore are an indication for cholecystectomy.

An anomalous pancreatobiliary duct junction may contribute to the development of gallbladder cancer.

Miscellaneous: Obesity, diabetes, medications (methyldopa, estrogens, isoniazid), and carcinogen exposure (radon, chemicals from the rubber industry, cigarettes) have also been associated with this disease.

Clinical Features

Early-stage disease may be asymptomatic or present with very nonspecific symptoms, including the following:

Often, it is noted as an incidental finding on cholecystectomy for cholelithiasis or cholecystitis

Pain

Weight loss

Anorexia

Nausea or vomiting

Mass in the right upper quadrant

Jaundice

Abdominal distension

Pruritus

Diagnosis

Three clinical scenarios exist in patients presenting with gallbladder cancer: final pathology after a routine laparoscopic cholecystectomy incidentally discovers gallbladder cancer; gallbladder cancer is suspected/diagnosed intraoperatively; or gallbladder cancer is suspected preoperatively.

An incidental surgical or pathologic finding is the most common clinical scenario. It is estimated that 1% to 2% of patients undergoing exploration for presumed benign disease will be found to have gallbladder cancer.

Ultrasound is a useful modality in the preoperative workup for gallbladder pathology. In the case of gallbladder cancer, the ultrasonographic findings may include a thickened or calcified wall, a protruding mass, or a loss of gallbladder to liver interface; however, these may not be specific for gallbladder cancer.

Triple-phase computed tomography (CT) scan (liver protocol), which includes a noncontrast phase, a hepatic arterial phase, and a portal venous phase, allows visualization of the extent of tumor growth, can aid in determining the nodal status as well as identifying distant metastases, and is particularly useful in determining the relationship of the tumor mass to the major hilar inflow structures, which is an important preoperative determinant. This modality is less helpful in distinguishing benign from malignant polyps.

Cholangiography: Magnetic resonance cholangiopancreatography (MRCP) can provide further information regarding the extent of disease.

Laboratory studies are generally not diagnostic. Elevated serum bilirubin or alkaline phosphatase can indicate biliary obstruction. CA19.9, a tumor marker, is often checked, but is neither sensitive nor specific for a diagnosis.

Pathology

Adenocarcinoma accounts for close to 85% of cases. It is further classified into papillary, tubular, mucinous, or signet cell type. Other histologies include anaplastic, squamous cell, small-cell neuroendocrine tumors, sarcoma, and lymphoma.

Staging

There are several staging systems available for gallbladder cancer. The original staging system was developed by Nevin in 1976; the preferred classification scheme in the United States is the TNM staging system of the American Joint Committee on Cancer (AJCC) (Table 6.1).

TABLE 6.1 AJCC Staging System for Gallbladder Cancer

Primary Tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor invades lamina propria or muscular layer
T1a	Tumor invades lamina propria
T1b	Tumor invades muscular 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 two or more extrahepatic organs or structures
Regional Lymph Nodes (N)
NX	Regional lymph nodes cannot be assessed
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 mesenteric artery, and/or celiac artery lymph nodes
Distant Metastasis (M)
M0	No distant metastasis
M1	Distant metastasis
Anatomic Stage/Prognostic Groups
Stage 0	Tis	N0	M0
Stage I	T1	N0	M0
Stage II	T2	N0	M0
Stage IIIA	T3	N0	M0
Stage IIIB	T1-3	N1	M0
Stage IVA	T4	N0-1	M0
Stage IVB	Any T	N2	M0
Stage IVB	Any T	Any N	M1

The AJCC TNM staging classification was updated in 2010.

The updated stage groupings were realigned to better correlate with resectability and prognosis.

Treatment

Surgery

Surgical resection remains the only potentially curative therapy.

The lack of a peritoneal lining on the side of the gallbladder that is attached to the liver represents an important anatomic consideration in the surgical management of gallbladder cancer. In a simple cholecystectomy, the surgeon dissects the plane between the muscularis of the gallbladder and the cystic plate, which is a fibrous lining that occupies the space between the gallbladder and the liver. For this reason, simple cholecystectomy is considered inadequate surgical therapy for all but the earliest stages of the disease.

Factors determining resectability include the stage of the tumor as well as the location. T0-2 tumors are potentially resectable with curative intent. T3 tumors are difficult to resect.

For incidentally detected gallbladder cancer after simple cholecystectomy, careful clinical, laboratory, radiologic, and pathologic evaluation should be conducted to assess the extent of disease.

For completely resected (margin-negative) nonperforated T1a tumors with no evidence of nodal or metastatic disease, observation alone is usually sufficient as 5-year overall survival is over 90%.

Patients with T1b or greater lesions should undergo extended cholecystectomy after metastatic disease has been ruled out. Optimal resection (extended cholecystectomy) includes a cholecystectomy with en bloc hepatic resection and regional lymphadenectomy with or without bile duct excision. Achievement of R0 resection margins correlates strongly with long-term survival.

The type of resection that is ultimately required to achieve an R0 resection can at times depend on the location of the tumor within the gallbladder. Tumors of the body and fundus may be manageable with a localized segment IV/V resection while those of the infundibulum may require division of inflow structures and consequently major hepatic resection with or without bile duct resection/reconstruction.

Contraindications to surgery include distant metastases, extensive involvement of the porta hepatis causing jaundice, significant ascites, and encasement or occlusion of major vessels. Direct involvement of adjacent organs is not an absolute contraindication.

If cancer is suspected, perforation of the gallbladder (such as during percutaneous biopsy) during surgery should be avoided to prevent seeding of the peritoneal cavity.

Radiation

A number of reports have documented improvements in survival rates in cases of intraoperative or postoperative adjuvant radiotherapy. No prospective randomized controlled trials have been performed to address this issue. In 2003, however, Jarnigan and colleagues found that only 15% of patients had locoregional recurrence as their only site of recurrent disease, which highlights the importance of effective, adjuvant systemic strategies.

Systemic Therapy and Palliation

The benefits and options available for systemic therapy and palliation of carcinoma of the gallbladder are the same as those for cholangiocarcinoma, which is discussed in the next section.

Survival

The various aspects of survival following treatment of gallbladder cancers according to stage are given in Table 6.2.

TABLE 6.2 Treatment and 5-Year Survival of Gallbladder Cancers According to Stage

TNM Stage	Treatment	Median Survival (mo)	-Y Survival (%)
I	Simple cholecystectomy	19	60–100
	Radical cholecystectomy
II	Radical cholecystectomy	7	10–20
	+/− Radiation therapy (not standard)
III	Radical cholecystectomy	4	5
	+/− Radiation therapy (not standard)
IV	Palliation with stent placement	2	0
	Surgery or radiation or chemotherapy or combination of these

Carcinoma of the Bile Ducts (Cholangiocarcinoma)

Epidemiology

Cholangiocarcinomas arise from the epithelial cells of either intrahepatic or extrahepatic bile ducts.

The reported incidence within the United States is 1 to 2 cases per 100,000 persons.

Median age at diagnosis is between 50 and 70 years. However patients with primary sclerosing cholangitis (PSC) and those with choledochal cysts tend to present at younger ages.

In contrast to gallbladder cancer, cholangiocarcinomas are more common in males.

Cholangiocarcinomas are categorized into proximal extrahepatic (perihilar or Klatskin tumor; 50% to 60%), distal extrahepatic (20% to 25%), intrahepatic (peripheral tumor; 20% to 25%), and multifocal (5%) tumors.

Extrahepatic cholangiocarcinomas are more common than intrahepatic cholangiocarcinomas, and perihilar cholangiocarcinoma is the most common type.

Etiology

A number of risk factors have been associated with the disease in some patients; however, no specific predisposing factors have been identified.

Inflammatory conditions: PSC is associated with an annual risk of 0.6% to 1.5% per year and a 10% to 15% lifetime risk of developing cholangiocarcinoma. Ulcerative colitis and chronic intraductal gallstone disease also increase risk. Nearly 30% of cholangiocarcinomas are diagnosed in patients with coexistent ulcerative colitis and PSC.

Bile duct abnormalities: Caroli disease (cystic dilatation of intrahepatic ducts), bile duct adenoma, biliary papillomatosis, and choledochal cysts increase risk. The overall incidence of cholangiocarcinoma in these patients can be as high as 28%.

Infection: In Southeast Asia, the risk can be increased 25- to 50-fold by parasitic infestation from Opisthorchis viverrini and Clonorchis sinensis. These parasitic infections are more commonly associated with intrahepatic cholangiocarcinoma. An association with viral hepatitis has also been seen. A higher than expected rate of hepatitis C-associated cirrhosis was noted in patients with cholangiocarcinoma. An association with hepatitis B has also been suggested.

Genetic: Lynch syndrome II and multiple biliary papillomatosis are associated with an increased risk of developing cholangiocarcinoma. Biliary papillomatosis should be considered a premalignant condition as one study noted that up to 83% will undergo malignant transformation. More recently, certain genetic polymorphisms (NKG2D) have been determined to be possible risk factors for developing cholangiocarcinoma.

Miscellaneous: Smoking, toxic exposures, such as thorotrast (a radiologic contrast agent used in the 1960s), asbestos, radon, and nitrosamines are also known to increase the risk. Recently, patients with diabetes or a metabolic syndrome have been noted to have an increased risk of developing a cholangiocarcinoma as well.

Clinical Features

Cholangiocarcinomas usually become symptomatic when the biliary system becomes obstructed.

Extrahepatic cholangiocarcinoma usually presents with symptoms and signs of cholestasis (icterus, pale stools, dark urine, pruritus, or cholangitis, which includes pain, icterus, and fever). Laboratory studies will typically suggest biliary obstruction with elevated direct bilirubin and alkaline phosphatase.

Intrahepatic cholangiocarcinoma may present as a mass, be asymptomatic, or produce vague symptoms such as pain, anorexia, weight loss, night sweats, and malaise. These patients are less likely to be jaundiced.

Diagnosis

A cholestatic picture may be seen as described previously. Liver function tests may be elevated, particularly with intrahepatic cholangiocarcinoma. Tumor markers such as CEA and CA-19-9 by themselves are neither sensitive nor specific enough to make a diagnosis. Ultrasonography is the first-line investigation for suspected cholangiocarcinoma, usually to confirm biliary duct dilatation, localize the site of obstruction, and rule out cholelithiasis. This technique can often overlook masses and is poor at delineating anatomy.

CT/MRI is recommended as part of the diagnostic workup of cholangiocarcinoma, intrahepatic tumors in particular. These imaging modalities can help determine tumor resectability by evaluating the tumor and the surrounding structures (major vessels, lymph nodes, presence of metastases).

Cholangiography: MRCP is noninvasive and can provide excellent imaging of the intrahepatic and extrahepatic bile ducts. This provides valuable information about disease extent and surgical options. Due to their ability to obtain brushings from as well as stent across strictures within the biliary tree, ERCP, and/or PTC offer both diagnostic and therapeutic value in the workup and management of biliary obstruction; however, the diagnostic yield on cytology obtained from biliary brushings can be low.

EUS may be useful in visualizing the extent of tumor and lymph node involvement of distal bile duct lesions. Its role in proximal bile duct lesions is less clear.

Pathology

Adenocarcinomas account for 90% to 95% of tumors. The remainder are squamous cell carcinomas. Adenocarcinomas are graded as well, moderately and poorly differentiated, and are further classified as sclerosing, nodular, and papillary subtypes. Patients with papillary tumors present with earlier disease and have the highest resectability and cure rates; however, they are the least common subtype.

Staging

The AJCC TNM staging system is primarily based on the extent of ductal involvement by the tumor.

The seventh edition staging system for extrahepatic cholangiocarcinomas separates perihilar and distal bile duct tumors. These changes have improved the prognostic stratification of the TNM staging system. Please refer to the seventh edition AJCC Staging Manual for details.

Cancers arising in the perihilar region have been also further classified according to their patterns of involvement of the hepatic ducts, the Bismuth-Corlette classification.

Treatment

Surgery

Except in the case of distal common bile duct cancer, cholangiocarcinoma is a disease that, when managed surgically, often requires major hepatic resection (segmentectomy, anatomic lobectomy, and trisegmentectomy) with or without bile duct resection/reconstruction. Therefore, the general principles of such resection(s) should be reviewed.

From the standpoint of major hepatic resection, the surgical principles are simple and revolve primarily around leaving the patient with an adequate volume of a functioning liver remnant to sustain them postoperatively. This requires executing an operation that ensures both adequate inflow to (hepatic artery and portal vein) and outflow from (hepatic vein and bile duct) the remnant liver.

Generally speaking, roughly 75% of a patient’s liver volume can safely be resected; however, consideration must be given to the health of the background liver. Such consideration includes underlying chronic liver disease (hepatitis, prior alcohol use, and steatosis/steatohepatitis) as well as any acute insults, which in the case of cholangiocarcinoma often involves cholestasis. The former issues can limit the extent of resection that can safely be performed, while the latter often necessitates preoperative delays while the cholestatic picture resolves.

If there is any concern about the adequacy of the planned future liver remnant, portal vein embolization on the side of the liver that is anticipated to be resected can be performed in an attempt to allow the contralateral side to hypertrophy preoperatively.

Intrahepatic Cholangiocarcinoma

Surgery is the only potentially curative therapy for patients with intrahepatic cholangiocarcinoma; however, most patients present with advanced disease and are not surgical candidates.

Multiple hepatic tumors, regional lymph node involvement, large tumor size, and vascular invasion predict poor recurrence-free survival postresection.

The extent of surgery is dictated by what is necessary to obtain clear margins. R0 resection with adequate margins is the aim and is ultimately associated with significantly longer survival rates that can range from 30% to 67%.

If microscopic positive tumor margins (R1) or residual local disease (R2) is noted after resection, patients should be evaluated for possible re-resection versus chemoradiation options.

The role of routine nodal dissection in the management of intrahepatic cholangiocarcinoma is controversial.

During laparotomy, thorough assessment of the intra-abdominal lymph node basins should be undertaken prior to hepatic resection, suspicious nodes should be biopsied, and attempts at resection should be aborted if nodal metastases are confirmed intraoperatively.

Distal Cholangiocarcinoma

Primarily treated with a Whipple procedure (pancreaticoduodenectomy).

Perihilar Cholangiocarcinoma

The main curative therapy for patients with extrahepatic perihilar cholangiocarcinoma is complete surgical resection.

Surgery for extrahepatic hilar cholangiocarcinomas is based on the stage of disease, and the goal of surgical intervention is to obtain a tumor-free margin (Table 6.3).

For patients with hilar cholangiocarcinoma, bile duct resection leads to high local recurrence rates. Hilar resection with lymphadenectomy and en bloc liver resection and biliary reconstruction are recommended for lesions in the extrahepatic biliary tree. Caudate resection is often required to achieve an R0 resection, particularly for tumors involving the left hepatic duct.

Five-year survival rates range from 20% to 40% in patients treated with surgical resection for hilar cholangiocarcinoma.

TABLE 6.3 Treatment and Survival of Cholangiocarcinomas According to Location

Location	Treatment	Median Survival (mo)	5-Y Survival (%)
Extrahepatic (hilar)	Type I + II: en bloc resection of extrahepatic bile ducts, gallbladder, regional lymphadenectomy, and roux-en-Y hepaticojejunostomy	12–24	9–18
	Type III: as above plus right/left hepatectomy
	Type IV: as above plus extended right/left hepatectomy
Extrahepatic (distal)	Pancreaticoduodenectomy	12–24	20–30
Intrahepatic	Resect involved segments or lobe of liver	18–30	10–45

Adjuvant Chemotherapy and Chemoradiation

Adjuvant chemotherapy with capecitabine is being recognized as a new standard of care for resected biliary tract cancers. This is based on presentation of results from the BILCAP study, which showed that adjuvant capecitabine for 6 months improved median overall survival from 36 months with placebo to 51 months (HR 0.80; P = 0.097). While not statistically significantly different, the results were encouraging, and parsing further, most improvement was seen for patients with positive nodes and higher grade of disease.

Chemotherapy in Advanced-Stage Disease

For metastatic biliary tract cancer, the standard of care is combination chemotherapy with gemcitabine and cisplatin, based on a large randomized controlled trial (ABC-02 study) that showed improved overall survival with the combination, compared with gemcitabine alone (11.7 vs. 8.1 months; HR 0.64; 95% CI, 0.52 to 0.80).

Oxaliplatin can be considered instead of cisplatin, in combination with gemcitabine, to minimize toxicities from therapy, based on extrapolation of data from phase II studies.

Targeted Therapy

Several targeted agents (cetuximab, panitumumab, erlotinib, bevacizumab, etc.) have been tested in advanced biliary tract cancers but have failed to show improvement in survival. Currently, therefore, there are no data to support the use of targeted therapies in this setting.

Palliation

Patients with unresectable or metastatic disease may benefit from palliative surgery, radiation, chemotherapy, or a combination of these.

Biliary drainage can be achieved by Roux-en-Y choledojejunostomy, bypass of the site of obstruction to left or right hepatic duct, or endoscopic or percutaneously placed stents (metal-wall stents have a larger diameter and are less prone to occlusion or migration and are preferably used in patients with a life expectancy of greater than 6 months and/or in those who have unresectable disease).

Celiac plexus blockade may also ameliorate symptoms of pain in the patient with inoperable disease.