Located deep within the surgical soul, and surrounded by a forest of critical structures, cancers of the distal biliary tract and periampullary region are difficult to diagnose, and even more difficult to treat. They demonstrate aggressive biology and they present late, features that often make them unmanageable, and even uniformly fatal. However, advances in our understanding of molecular genetics, diagnostic imaging, surgical technique, neoadjuvant and adjuvant therapies, and palliative care have opened new options for the care of patients with these malignancies. Scientific advances over the next few years will place us on an exciting new frontier in the journey to successfully address what has been one of surgery’s greatest challenges.

Each year 13,000 people in the United States are diagnosed with biliary tract cancer, and close to 4000 people die. While these numbers may be small, accounting for only 3% of all gastrointestinal malignancies, the rising incidence, advanced presentations, and high associated mortality of these cancers make their early detection and effective treatment an urgent priority.¹

Cholangiocarcinoma (CC) affects a critical and complex anatomic region, and diagnostic and therapeutic approaches must account for the specific anatomic location and context of each case. Indeed, the broad classification of CC reflects essential anatomic considerations. CC is often categorized as intrahepatic cholangiocarcinoma (iCCA) (6% of all CCs), perihilar cholangiocarcinoma (67% of all CCs), and distal cholangiocarcinoma (dCCA) (27% of all CCs). This chapter focuses on malignancies of the dCCAs and cancers of the ampulla (ACs) and adjacent structures. Successful curative and palliative approaches to cancers at this location require detailed insights about histopathology, molecular pathology, anatomy, and surgical technique. dCCAs and ampullary cancers are among the most difficult and most rewarding malignancies to treat.²  

Cholangiocarcinomas arise from the epithelium of the biliary tract and are therefore considered to be adenocarcinomas. Although most CCAs are sporadic with no identifiable risk factors, genetic studies and epidemiological associations suggest an interplay of host factors, inflammation, and the environment in the pathogenesis of CCAs. In the United States, the incidence of CCAs has been reported to range from 2.1 to 3.3 per 100,000, while in Southeast Asia, rates as high as 113 per 100,000 have been reported. This huge discrepancy in incidence has been attributed to differences between populations in risk factors such as hepatobiliary fluke infestation of the bile ducts (Opisthorchis viverrini, Clonorchis sinensis), bile duct cystic disorders, and hepatolithiasis (especially with calcium bilirubinate stones). CCAs have also been associated with inflammation and bile stasis caused by biliary enteric drainage. Thorotrast, an old radiocontrast dye used in the 1930s, and similar agents have been associated with a 300 times increase in the risk of CCA.³

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC), an autoimmune inflammatory condition of the bile ducts that is often accompanied by inflammatory bowel disease, has been associated with a 5% to 10% lifetime risk of CCA.³  

Tumors arising from the bile ducts are considered by pathologists in five groups:⁴

1. 
   

   Intrahepatic, which are often removed with a liver resection

   
   
2. 
   

   Perihilar, which can be resected segmentally or along with a segment of liver or with the gall bladder

   
   
3. 
   

   Cystic duct, which is resected with the gall bladder and often considered as a gall bladder neoplasm

   
   
4. 
   

   Distal (dCCA), which spans the common bile duct (CBD) between the cystic duct and ampulla, and which is usually resected using a pancreaticoduodenectomy (PD)

   
   
5. 
   

   Intra-ampullary, for which the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging is still somewhat unclear

This chapter focuses on groups 4 and 5 above.

Staging

The AJCC cancer staging for dCCAs is based on depth of invasion (T stage), nodal involvement, and distant metastasis. The T classification of the AJCC staging system for cholangiocarcinoma has been criticized for having poor correlation with survival. The T staging system, which classifies tumors as confined to the bile duct, invading beyond the wall of the bile duct, and invading adjacent organs and blood vessels, does not specifically quantify depth of invasion. This classification does not account for the variability in bile duct thickness and composition along its length, or for the markedly distinct geographic environments of the hilar and distal bile ducts. For example, a large, aggressive hilar CC may not invade the pancreas (T2), while a small distal CCA may invade the pancreas (T3)—but prognosis may have more to do with size and growth rather than invasion of the local microscopic environment. Hong et al⁵ proposed a specific and reproducible T staging system for distal CCAs, based on absolute depth of invasion. They found that depth of tumor invasion correlated well with other adverse pathological features of distal CCA (along with lymph node metastasis, and perineural and vascular invasion) was a better predictor of survival than AJCC T stage. 

Histopathology

Most dCCAs arise from precursor lesions (intraductal papillary neoplasm, biliary intraepithelial neoplasm), and most are well-differentiated adenocarcinomas. Although it is difficult to distinguish these lesions from pancreatic adenocarcinomas, the distinction may be clinically significant, as dCCAs are associated with a better prognosis and may warrant a more aggressive surgical approach.³

Molecular Pathology

Mutations in the p53 tumor suppressor gene, which activate the KRAS proto-oncogene, and mutations that result in alterations in cell cycle regulation (e.g., cyclin-dependent kinase inhibitor overexpression and inactivation), have all been associated with bile duct tumors. Some of these mutations have been associated with chronic biliary tract irritation and inflammation, such as that resulting from pancreatic juice reflux from anomalous pancreatic-biliary duct junction (KRAS) mutations in Japan.

Specific chromosomal copy number variations have also been observed in gall bladder and biliary tract tumors.

Distal biliary malignancies cause symptomatic biliary obstruction earlier than more proximal tumors, whose obstructive effects may initially be masked by collateral biliary drainage and segmental atrophy of hepatic parenchyma. dCCAs should be suspected in patients presenting with painless jaundice, pruritus, dark urine, and fat malabsorption with associated pale stools. Patients may also present with more nonspecific symptoms such as abdominal pain, early satiety, weight loss, fevers, and night sweats. More rarely, an incidental fining of biliary dilation or hepatic metastases during abdominal sonography for another indication may eventually prompt the diagnosis of a dCCA.⁶

Laboratory Investigations

In dCCA patients with biliary duct obstruction, routine serum chemistries will demonstrate direct hyperbilirubinemia and alkaline phosphatase elevation. High-grade or long-standing obstruction, or metastatic disease may also alter transaminase levels, coagulation function, and albumin levels. Alkaline phosphatase elevation in association with increased gamma-glutamyl transferase (GGT) levels may be more sensitive for biliary obstruction than alkaline phosphatase levels alone, and should prompt a workup for biliary tract pathology.⁶

Elevations of tumor markers may help to distinguish malignant from benign biliary obstructions. Their imperfect sensitivity and specificity for dCCA mean that clinicians should not rely on them in isolation, but use them to help shape decision making as part of a constellation of diagnostic findings. Carbohydrate antigen (CA) 19-9 is an antibody that targets circulating glycoproteins that are coated by sialylated blood group antigens. Its sensitivity and specificity for distal dCCA range from 53% to 89% and 80% to 91%, respectively. CA 19-9 is elevated in other malignancies and in other causes of obstruction and inflammation of the bile ducts. Carcinoembryonic antigen (CEA), an oncofetal glycoprotein that is useful in surveillance for colorectal cancer recurrence and metastasis, is also elevated in dCCA, although it is a less sensitive and specific tumor marker than CA 19-9. CEA and CA 19-9 levels have been combined in the Ramage Score with the hope of improvement in diagnostic accuracy. This composite tumor marker score has been shown to be moderately sensitive and specific for dCCA in patients with underlying PSC (71% and 91%). Both tumor markers can be used postoperatively to screen for dCCA recurrence.⁶

All patients with perihilar or distal bile duct strictures should have serum immunoglobulin (Ig) G4 levels drawn, as IgG4-related conditions can mimic malignant biliary strictures. Suspicion of IgG4-related biliary stricture can be confirmed with immunohistochemical staining of biopsy specimens of the CBD, obtained via endoscopic retrograde cholangiography (ERC) or percutaneous transhepatic cholangiography (PTC).³  

Diagnostic Imaging

Abdominal ultrasound is often the first diagnostic modality used in the evaluation of patients with jaundice or right upper quadrant pain. Ultrasound may demonstrate dilation of the biliary tract and gall bladder, or, less often, a mass in the distal CBD or head of the pancreas. Cross-sectional imaging of patients with dCCA demonstrates thickening or stricture of the distal bile duct in association with proximal dilation. Computed tomography (CT) angiography, magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP) are useful studies to delineate local invasion or hepatic metastases. MRCP often demonstrates a stricture or polypoid mass causing biliary obstruction. Local invasion into adjacent periductal tissues and lymph node involvement can be demonstrated on MRI, particularly in the T1-weighted fat-suppressed images. The diagnosis of dCCA is especially difficult in patients with sclerosing cholangitis, but may be suspected in patients with worsening strictures, marked ductal dilation, or the presence of a polypoid mass.

Endoscopic Retrograde Cholangiography

Endoscopic retrograde cholangiography (ERC) has become a mainstay in the workup of CCA. ERC findings such as dominant stricture, marked biliary tract dilation, or polypoid lesions are strongly suggestive of CCA. Cytologic analyses of biliary tract brushings may help to distinguish benign from malignant strictures. The emergence of endoscopic ultrasound (EUS), intraductal ultrasound with high-frequency microprobes, and contrast ultrasound has further extended our diagnostic capabilities to include assessments of resectability (depth of invasion, local spread to surrounding vascular structures, and lymph node involvement), and has opened up new opportunities for biopsy and tissue analysis. CCAs tend to elicit a strong desmoplastic reaction, and biopsy sampling error has been a difficult diagnostic challenge. The sensitivities of endoscopic retrograde cholangiopancreatography (ERCP) and EUS-directed biliary brushings or biopsies have remained low, and a negative test in no way excludes the possibility of malignancy in the stricture under investigation. In recent years, fluorescent in situ hybridization (FISH) has shown promise in improving the sensitivity and diagnostic accuracy of ERCP by detecting specific chromosomal abnormalities in patients with suspicious biliary strictures. The other issue with endoscopic biopsy is the possibility of needle tract seeding of malignant cells, and the risk of peritoneal spread. EUS-directed transperitoneal biopsies should therefore be limited in instances where needle tract seeding would change management.³

In patients with unresectable disease, ERCP can be used as a palliative strategy for diagnostic confirmation and to relieve biliary obstruction.¹

Staging Laparoscopy

Staging laparoscopy (SL) and laparoscopic ultrasound (LUS) have been promoted as strategies to determine the resectability of CCAs. Laparoscopic confirmation of peritoneal spread, hepatic metastases, locally advanced disease, or extensive nodal involvement may suggest that the primary tumor will be unresectable and may allow patients to avoid futile open explorations. The role of SL was evaluated in a recent study of 100 consecutive hilar CCA patients without radiological evidence of unresectability. SL detected evidence of radiologically unsuspected advanced disease in 45% of patients, thereby preventing a substantial number of unnecessary laparotomies.⁷ However, some investigators believe that steady advances in imaging technologies and techniques, and resulting improvements in preoperative staging, may be making SL obsolete. There is general consensus that better imaging is reducing the role of SL as a routine diagnostic adjunct, limiting it to circumstances where its yield will be greatest. These circumstances include T2/3 lesions, suspicion of metastases, and patients with potentially resectable disease who are undergoing invasive procedures for unrelated indications.⁸

Preoperative Biliary Drainage

Obstructive jaundice leads to a spectrum of issues that may adversely affect liver function and patient outcomes. Obstruction-related mitochondrial dysfunction can alter hepatocyte activity, leading to deterioration of synthetic and clearance functions, and even liver failure, hepatorenal syndrome, and multiorgan failure. Failure of bile to reach the duodenum can cause malabsorption with resulting hypoalbuminemia and other nutritional deficiencies. Prolonged biliary obstruction can also compromise gut barrier function, leaving patients susceptible to infection complications. Relief of biliary obstruction is known to result in improved mitochondrial function, better liver function, resolution of jaundice, and improved nutrition status after about 46 weeks. These findings provided a powerful physiological rationale for preoperative drainage of an obstructed biliary tree. However, instrumentation of the biliary tree can also lead to bacterial colonization or cholangitis (88% in drained patients), bleeding, inflammation and fibrosis of the biliary tract, loss of biliary tree dilation with greater technical difficulty in biliary anastomosis, surgical site infections, and even drain tract spread of malignancy. Early observational studies and small trials produced conflicting results regarding the potential of biliary drainage to reduce preoperative complications.⁹