Extrahepatic biliary tumors

Overview

Extrahepatic biliary tumors are rare. Patients classically present with painless jaundice secondary to biliary obstruction. Management of bile duct tumors is challenging and best approached with input from an experienced multidisciplinary team. This chapter focuses on the cause of most common of these tumors, cholangiocarcinoma. We describe its epidemiology, preoperative evaluation, management, surgical technique, and long-term outcomes.

Epidemiology and risk factors

Cholangiocarcinoma accounts for 3% of all digestive cancers and is classically divided into three subtypes: intrahepatic cholangiocarcinoma (ICC) (20% of all cholangiocarcinoma in the United States) (see Chapter 50 ) and extrahepatic cholangiocarcinoma (EHC), which includes both perihilar cholangiocarcinoma (HC) (50%–60%) and distal cholangiocarcinoma (DC) (20%–30%). Although derived from biliary epithelial cells, the subtypes of cholangiocarcinoma differ in epidemiology, prognosis, and treatment paradigms. The incidence of both ICC and EHC are increasing over time. The incidence of EHC increased 20% from 1973 to 2012, from 1.6 per 100,000 individuals in 1973 to 1975 to 2.3 per 100,000 in 2011 to 2012 ( Fig. 51A.1 ). In the United States, there are approximately 2500 new cases of EHC annually. The incidence of EHC is evenly distributed between sexes. Rates among blacks and whites appear to be increasing in contrast to those of Hispanics and people of non-Hispanic ethnicity. ^, Although most cases of EHC occur in older patients, approximately 20% of EHCs are diagnosed before the age of 60, with the largest rise in incidence seen in 18- to 44-year-olds.

Several risk factors are associated with an increased incidence of cholangiocarcinoma; however, it must be noted that most cholangiocarcinoma cases in Western countries are sporadic, with no obvious risk factors. Conditions associated with cholangiocarcinoma include primary sclerosing cholangitis (PSC) (see Chapter 41 ), choledochal cysts (see Chapter 46 ), recurrent pyogenic cholangiohepatitis (see Chapter 44 ), hepatolithiasis (see Chapter 39 ), and biliary parasites (see Chapters 45 and 71 ). Commonalities across these risk factors include the likelihood of these conditions to cause cholestasis and chronic inflammation.

Cholestatic liver diseases such as PSC, congenital hepatic fibrosis, Caroli disease, and choledochal cysts are well-recognized risk factors. Genetic disorders with an increased risk of EHC are rare and include Lynch syndrome and bile salt transporter protein gene defects (see Chapter 9E ).

More recently, metabolic conditions such as type 2 diabetes have been found to be associated with an increased risk of EHC . For example, in a meta-analysis, individuals with type 2 diabetes had an increased risk of cholangiocarcinoma (relative risk [RR], 1.60; 95% CI 1.38–1.87), EHC (RR, 1.63; 95% CI, 1.29–2.05) and ICC (RR, 1.97; 95% CI, 2.57–2.46). Nonalcoholic fatty liver disease, obesity, dyslipidemia, and hypertension are also associated with an increased risk of EHC. ^, These conditions are increasing worldwide and, in part, may explain the rising incidence of EHC.

Tumor location and histopathology

Extrahepatic cholangiocarcinoma can arise anywhere from first-order bile ducts within the liver down to the ampulla of Vater. Perihilar cholangiocarcinoma (HC or Klatskin tumors) was first described in 1965 by Klatskin and comprises 50% of all cholangiocarcinomas. HC arises in the right or left hepatic duct or at the confluence of the right and left ducts, whereas DC arises in the common bile duct distal to the takeoff of the cystic duct ( Fig. 51A.2 ). Any extrahepatic biliary strictures are highly suggestive of malignancy; however, histopathologic assessment with brushing or biopsy has limited sensitivity although are highly specific. Thus, in the absence of histologic findings indicating malignancy, preoperative differentiation between cholangiocarcinoma and benign strictures (also known as malignant masquerade) is difficult. ^, Benign strictures may arise from autoimmune cholangiopathy, autoimmune pancreatitis, stone-related disease, or primary sclerosing cholangiopathy and should be treated accordingly when recognized (see Chapter 42 ).

Adenocarcinoma is the dominant histologic group, comprising more than 75% of extrahepatic biliary tumors. Precancerous lesions include biliary intraepithelial neoplasia, intraductal papillary neoplasm of the biliary tract, intraductal tubular papillary neoplasm, and mucinous cystic neoplasm. Common immunohistochemical markers of EHC include mucin, MUC5AC, MUC6, S100P, SMAD4 loss, and BAP1. Adenocarcinomas are subdivided into three subtypes: sclerosing, nodular, and papillary ( Figs. 51A.3 and 51A.4 ). Papillary tumors are seen in up to 25% of EHCs and are associated with improved survival compared with nodular sclerosing lesions (see Fig. 51A.4 ). ^,

Molecular profiling of cholangiocarcinoma is distinct, depending on the subtype. KRAS (55%) and TP53 (40%) mutations in HC are common. ^, IDH , EPHA2, and BAP1 mutations and FGFR2 fusions are more common in ICC, whereas EHCs contain PRKACA and PRKACB fusions and mutations in ELF3, ERBB2, and ARID1B. ^{, ,} In contrast to ICC, targetable mutations in extrahepatic cholangiocarcinoma are rare.

Clinical presentation

Clinical presentation depends on tumor size and location. HC presents with jaundice in 90% of patients. Nonspecific symptoms such as abdominal pain, weight loss, nausea, and pruritus are also common. In general, tumors become clinically apparent as a result of jaundice and jaundice-related symptoms such as pruritus, acholic stools, choluria, or abnormal liver function tests. Cholangitis is rare at the time of initial presentation because of a lack of bactibilia in an uninstrumented biliary tree. Laboratory evaluations are consistent with biliary obstruction and includes elevated total bilirubin, direct bilirubin, alkaline phosphatase and gamma-glutamyl transferase. Tumor markers such as carbonic anhydrase 19-9 (CA19-9) and carcinoembryonic antigen (CEA) are elevated; however, the former is often markedly elevated in the setting of jaundice.

The presentation of DC is similar to those of other periampullary tumors in which painless jaundice is classically described. HC presenting with jaundice can be indicative of a late finding in the disease course because early on, incomplete obstruction of the biliary tree or unilateral obstruction does not cause jaundice and may manifest with nearly normal liver function tests. A common finding in these scenarios is an isolated elevation in alkaline phosphatase (even minimal changes) which ultimately leads to the diagnosis. Additionally, papillary hilar tumors may manifest with intermittent jaundice as a result of small fragments of tumor detaching from a friable papillary tumor of the right or left hepatic duct or a mobile main tumor causing a ball valve effect at the hepatic duct confluence.

The level of bilirubin elevation may help determine the cause of obstruction. Significantly elevated bilirubin levels (>10 mg/dL) suggests malignant obstruction, whereas obstruction from choledocholithiasis is often associated with lower bilirubin levels typically ranging from 2 to 4 mg/dL, although there is significant overlap. Cholangitis at presentation in patients without a history of biliary manipulation is rare; however, the incidence of bactibilia is 100% after biliary instrumentation that compromises the sphincter of Oddi. Although common bile duct stones or gallstones may coexist with bile duct cancer, it is rare for choledocholithiasis to cause obstruction at the hepatic confluence in the absence of predisposing conditions such as PSC, choledochal cyst, or hepatolithiasis. A thorough and complete evaluation outlining the level of obstruction and nature of obstructing lesion is critical to avoid missing a diagnosis of carcinoma.

The physical examination, other than the presence of jaundice, is generally unremarkable. Evidence of liver dysfunction, enlarged liver, and portal hypertension may be noted in cases of long-standing biliary obstruction and portal vein involvement. An enlarged gallbladder on examination prompts consideration of biliary obstruction distal to or involving the cystic duct. With proximal biliary obstruction the gallbladder is typically collapsed.

Diagnostic studies (see Chapter 16 )

Patients are usually referred after undergoing initial evaluation Imaging for staging and assessing resectability should be performed before biliary decompression. Abdominal ultrasound is commonly performed as a first method of evaluation. Although noninvasive and cost effective, ultrasound findings are typically nonspecific and consist of biliary dilatation. The level of biliary obstruction is sometimes noted; however, ultrasound has low sensitivity in this regard. Duplex ultrasonography in experienced hands can accurately predict vascular involvement ( Fig. 51A.5 ). Duplex ultrasound can be particularly useful for assessing portal venous invasion. In a series of 63 consecutive patients from Memorial Sloan Kettering Cancer Center (MSKCC), duplex US predicted portal vein involvement in 93% of cases, with a specificity of 99% and a positive predictive value of 97%. With the now more widespread availability of liver-specific multiphasic contrast enhanced imaging with CT and MRI/MRCP, ultrasound is less used in preoperative assessment; however, it can be a valuable adjunct when there is questionable vascular involvement.

Preoperative imaging should be performed with multidetector multiphasic CT or MRI of the abdomen and pelvis. Contrast-enhanced cross-sectional imaging such as liver angiogram CT with chest and pelvis is a highly sensitive diagnostic modality to delineate the level of biliary obstruction, vascular involvement, relevant anatomy, hepatic lobar atrophy as well as assess for evidence of metastatic disease. Appropriate CT protocols consist of thin (1 mm) cuts in the arterial and portal venous phases of intravenous contrast. These can then be used to create high-quality three-dimensional images such as CT arteriography in a single session. The anatomy of the biliary tree, portal vein, and hepatic arteries, along with their relationship to the tumor, are specifically assessed ( Fig. 51A.6 ).

MRI with MRCP, including biliary tree reconstruction, has been increasingly utilized to evaluate biliary tree abnormalities. MRCP accurately depicts the level of biliary obstruction, biliary anatomy as well as obstructed or isolated ducts not always appreciated on percutaneous or endoscopic evaluations ( Fig. 51A.7 ) Vascular involvement, lobar atrophy, and regional nodal and distant metastases are also assessed ( Fig. 51A.8 ). MRCP has now replaced direct cholangiography in the initial assessment of biliary malignancy. Direct cholangiography with ERCP (see Chapters 20 and 30 ) and/or PTC (see Chapters 20 , 31 , 51B , and 52 ) should be used for therapeutic intervention. Specifically protocoled MRI with MRCP and contrast-enhanced CT have comparable outcomes in assessing tumor resectability.

The role of PET/CT in EHC is limited (see Chapter 18 ). In a systematic review and meta-analysis of 2125 patients from 47 eligible studies exploring the diagnostic test accuracy of [ ¹⁸ F]fluoro-2-deoxy-D-glucose ( ¹⁸ FDG-PET) as a diagnostic tool for diagnosis of primary tumor, lymph node invasion, distant metastases, and relapsed disease, the sensitivity and specificity of ¹⁸ FDG-PET for the diagnosis of primary tumor were 91.7% (95% CI, 89.8–93.2) and 51.3% (95% CI, 46.4-56.2), respectively. For lymph node involvement, sensitivity was 88.4% (95% CI, 82.6–92.8) and specificity was 69.1% (95% CI, 63.8–74.1). For distant metastases, sensitivity was 85.4% (95% CI, 79.5–90.2) and specificity was 89.7% (95% CI, 86.0–92.7). In identifying relapse after resection, sensitivity was 90.1% (95% CI, 84.4–94.3) and specificity was 83.5% (95% CI, 74.4–90.4). Routine use of PET/CT in the preoperative setting remains unproven although unstudied in prospective trials. PET/CT is best used as a problem-solving tool when there is an equivocal finding on cross-sectional imaging.

Direct cholangiography via ERCP or PTC encompasses highly sensitive, invasive techniques which delineate the biliary tree, tumor or stricture location and extent of biliary disease. Moreover, these studies allow for biopsy to establish a diagnosis and biliary drainage can be performed when necessary ( Fig. 51A.9 ). Both ERCP and PTC have a sensitivity and specificity of approximately 70% to 75% for obtaining a tissue diagnosis. ^, However, a tissue diagnosis is not mandatory before proceeding with attempted resection for cholangiocarcinoma, and a negative biopsy sample in the setting of a high clinical suspicion for malignancy does not provide helpful data. Noninvasive imaging has replaced direct cholangiography for the staging of EHC, and direct cholangiography is limited to biliary decompression and tissue sampling.

Although most patients with hilar strictures and jaundice have cholangiocarcinoma, alternative diagnoses are possible in 10% to 15% of patients. The most common of these are gallbladder carcinoma, Mirizzi syndrome, and benign focal strictures, such as autoimmune cholangitis, lymphoplasmacytic sclerosing pancreatitis/cholangitis, granulomatous disease, and PSC. A thickened, irregular gallbladder wall with infiltration into segments IV and V of the liver, selective involvement of the right portal pedicle, and obstruction of the mid–bile duct with occlusion of the cystic duct on endoscopic cholangiography all suggest gallbladder carcinoma ( Figs. 51A.10 and 51A.11 ).

Distal bile duct tumors frequently are mistaken for adenocarcinoma of the pancreatic head, the most common periampullary malignancy (see Chapter 17 ). Cross-sectional imaging and direct cholangiography can provide valuable information regarding the level of obstruction and may show clearly that the obstruction is arising from the bile duct and does not involve the pancreatic duct. MRCP is noninvasive and evaluates for choledocholithiasis as well as visualizes the distal bile duct. ERCP is therapeutic for patients with choledocholithiasis and can clearly show the level of obstruction of the distal bile duct. A dilated extrahepatic bile duct terminating abruptly at its distal aspect without a concomitantly dilated pancreatic duct suggests a distal bile duct carcinoma.

Benign strictures such as inflammatory strictures, sclerosing cholangitis or immunoglobulin G4 (IgG4)-related cholangiopathy account for 10% to 15% of resected strictures ^, (see Chapter 42 ). These can be difficult to differentiate from malignant strictures without resection. Biopsy approaches such as endoscopic brushings of the bile duct, endoscopic ultrasound–fine needle aspiration (EUS-FNA) and PTC endobiliary forceps biopsy have a high false-negative rate, and repeat attempts at biopsy can delay resection and increase procedure-related complications. ^, In patients with a stricture of the bile duct and a clinical presentation consistent with cholangiocarcinoma, histologic confirmation of malignancy is generally unnecessary, unless nonoperative therapy is planned. ^, Serum IgG4 levels can be helpful in diagnosing benign autoimmune strictures treatable with steroids.

Preoperative evaluation and management

When extrahepatic cholangiocarcinoma is suspected, evaluation should focus on determining resectability, hepatic reserve and overall performance status (see Chapters 51B and 52 ). Significant baseline comorbidities such as portal hypertension, cirrhosis, and poor performance status can preclude surgical resection. Patients with metastatic disease do not benefit from resection and should be offered palliative systemic chemotherapy. In unresectable or metastatic cases, biliary decompression in jaundiced patients and confirmation of the diagnosis with tissue sampling are warranted to move forward with palliative systemic chemotherapy.

Resectability is determined by assessing four criteria: (1) extent of biliary tree involvement, (2) lobar atrophy, (3) vascular involvement, and (4) the presence of metastatic disease ^, ( Table 51A.1 ). High-quality cross-sectional imaging, ideally performed before biliary decompression, provides an assessment of potential portal vein and hepatic artery involvement and the extent of biliary involvement. Obstructed bile ducts appear dilated up to the level of the tumor. A dilated gallbladder on examination or cross-sectional imaging should alert the physician to the possibility of distal cholangiocarcinoma, pancreatic cancer, or gallbladder cancer rather than hilar cholangiocarcinoma. Portal vein involvement is suggested by a change in contour of the vein or occlusion.

Assessment of hepatic atrophy is a critical component of assessing resectability because this may indicate extent of tumor involvement, which has implications in treatment decisions. Long-standing biliary obstruction may cause moderate atrophy, whereas concomitant ipsilateral portal venous compromise induces rapid and severe atrophy of the involved segments. Atrophy is noted on cross sectional imaging by a shrunken, hypoperfused liver with crowding of dilated bile ducts along with concomitant hypertrophy of the contralateral lobe ( Fig. 51A.12 ).

The right hepatic artery generally courses posterior to the common hepatic duct. Involvement of the right hepatic artery in left-sided biliary tumors requiring a left-sided liver resection precludes resection or requires arterial reconstruction in highly selected cases. Lymph node–positive disease has an adverse effect on long-term survival and significantly decreases the likelihood of cure; however, lymphadenopathy on cross-sectional imaging is neither sensitive nor specific for metastatic disease. Enlarged regional nodes on preoperative imaging are often reactive and nonneoplastic, particularly after biliary instrumentation; therefore surgical exploration can still be considered in these instances.