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Malignant Biliary Obstruction of the Hilum and Proximal Bile Ducts
Malignant biliary obstruction of the hilum and proximal intrahepatic bile ducts can result from primary pancreaticobiliary cancers, primary liver cancers, portal lymphadenopathy, or metastatic disease. Primary pancreaticobiliary cancers affecting the proximal bile ducts and hilum include cholangiocarcinoma (CCA) and gallbladder cancer. CCA can cause obstruction at any level of the biliary tract. Cancer of the gallbladder can present with hilar or right intrahepatic duct obstruction caused by local tumor extension, extrinsic compression from portal adenopathy, or Mirizzi's syndrome. This chapter will focus on the diagnosis and management of biliary obstruction from hilar and proximal bile duct cancers. Refer to Table 40.1 for a differential diagnosis of hilar strictures. This chapter also features a discussion of recent developments in local ablative therapy for CCA and a comparison of endoscopic to percutaneous drainage in the setting of malignant biliary obstruction. Malignant biliary obstruction of the distal bile ducts, including distal CCA, is discussed in Chapter 39 .
TABLE 40.1
Differential Diagnosis of Hilar Strictures
Data from Wetter LA, Ring EJ, Pellegrini CA, et al. Differential diagnosis of sclerosing cholangiocarcinomas of the common hepatic duct (Klatskin tumors). Am J Surg. 1991;161:57. Verbeek PC, van Leeuwen DJ, de Wit LT, et al. Benign fibrosing disease at the hepatic confluence mimicking Klatskin tumors. Surgery. 1992;112:866. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660. Zaydfudim VM, Wang AY, de Lange EE, et al. IgG4-associated cholangitis can mimic hilar cholangiocarcinoma. Gut Liver. 2015;9:556–560.
| Malignant | Benign |
|---|---|
| Cholangiocarcinoma Gallbladder cancer Nodal metastases at porta hepatis Hepatocellular carcinoma Hepatic metastases Metastases to biliary tree Lymphoma |
Primary sclerosing cholangitis Choledocholithiasis/hepatolithiasis Inflammatory stricture Postoperative stricture Extrinsic compression (Mirizzi syndrome) Benign fibrosing/sclerosing cholangitis Radiation-induced stricture Caroli disease Ischemic stricture Infectious associated IgG4-associated cholangitis |
Cholangiocarcinoma
CCA arises from cholangiocytes, the epithelial cells of the bile ducts. CCA accounts for approximately 3% of all gastrointestinal malignancies. CCA can be divided into three unique subtypes: proximal (intrahepatic), hilar, and distal (extrahepatic) cancers. Most CCA is located in the hilar region (60% to 70%), whereas 20% to 30% are distal tumors and CCA originating from the intrahepatic ducts accounts for only 5% to 10%. Cancers arising in the hilar region have been further classified according to the pattern of involvement of the hepatic ducts (see the section, “ Bismuth-Corlette Classification ”). There have been a number of studies reporting an increased incidence of intrahepatic CCA over the past few decades in several countries worldwide. Everhart and Ruhl reported that, between 1979 and 2004, the incidence of CCA increased by 22% in the United States, with increasing incidence of intrahepatic CCA responsible for all of this increase. Over this same period, the 5-year survival rate did not change, remaining near 10%. There is evidence supporting that misclassification of the location of CCA in SEER data and changes in the ICD coding practice may be responsible for a portion of the observed increase in intrahepatic CCA. Independent of the impact of classification errors, a real increase in the incidence of intrahepatic CCA has been reported in many nations worldwide, an issue that warrants further investigation. The majority of CCAs (>90%) are adenocarcinomas. Squamous cell carcinomas account for most of the remaining cases. Adenocarcinomas are divided into the sclerosing (>70%), nodular (20%), and papillary (5% to 10%) types. Both nodular and sclerosing (scirrhous) tumors have lower resection and cure rates.
Risk Factors
The single most important risk factor for the development of CCA is primary sclerosing cholangitis (PSC). Almost one-third of CCAs are diagnosed in patients with primary PSC, with or without associated chronic ulcerative colitis. Other notable risk factors associated with CCA include biliary tract disease (e.g., hepatolithiasis, choledochal cysts), non–PSC-related cirrhosis, hepatitis B viral infection, parasitic infection (e.g., with Clonorchis sinensis or Opisthorchis viverrini ), polycystic liver disease, toxic exposures (e.g., to thorotrast and rubber), and genetic disorders (e.g., Lynch syndrome and biliary papillomatosis). Each CCA subtype (proximal, hilar, or distal) is a unique pathologic entity and consequently each risk factor confers a different amount of risk for each of the CCA subtypes, although the subtypes share most known risk factors.
Conversely, there is evidence from case-control studies that aspirin use is associated with a roughly threefold decrease in the risk of developing CCA. Moreover, preclinical evidence in mice and correlative data from case-control studies indicate that metformin has a protective effect in CCA, which warrants further investigation.
Anatomy of the Bile Ducts
Understanding segmental liver anatomy and variations in the relationships of the major sectoral ducts is of paramount importance in performing safe and appropriate drainage and decreasing endoscopic retrograde cholangiopancreatography (ERCP)–related adverse events (see Chapter 8 ) in patients with hilar obstruction. It is a common misperception that the bile ducts are simply shaped like a “Y,” with the right and left ducts joining together to form the common hepatic duct. In reality, the anatomic pattern of the biliary tree can be quite variable and includes eight segments ( Fig. 40.1 ). Knowledge of this anatomy, as well as the common variations of the segmental intrahepatic ducts and biliary confluence ( Figs. 40.2 and 40.3 ), is essential for successful endoscopic management of complex proximal and hilar CCA. Segment I (caudate lobe) is typically drained by several small ducts into both the right and left ductal systems. These branches are generally not seen on ERCP. Segments II, III, and IV comprise the left lobe. Segment II/III is usually drained by the large left intrahepatic duct that is targeted on endoscopic therapy. Segment IV is further divided into two smaller segments, IVa and IVb, which are typically not targets of endoscopic drainage given the small portion of hepatic parenchyma they drain. The right hepatic ducts are divided into the right anterior sectoral duct, which drains segments V and VIII, and the right posterior sectoral duct, which drains segments VI and VII.
Bismuth-Corlette Classification
Cancers arising in the perihilar region have been classified according to their pattern of involvement of the hepatic ducts. The Bismuth classification for CCA is useful for determining and planning surgical resection and endoscopic stent placement. Bile duct tumors that involve the confluence of the major ducts are referred to as Klatskin tumors or hilar CCA ( Fig. 40.4 ).
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Type I: Tumors below the confluence of the left and right hepatic ducts
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Type II: Tumors reaching the confluence of the right and left hepatic ducts
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Type III: Tumors occluding the common hepatic duct and either the first radicals of the right ( IIIa ) or left ( IIIb ) intrahepatic system
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Type IV: Tumors that are multicentric or involve the confluence of the major ducts and radicals of both right and left intrahepatic ducts
Diagnostic Evaluation
The necessity of obtaining a definitive tissue diagnosis of malignancy preoperatively is debated. There is concern that preoperative tissue acquisition via endoscopic ultrasonography (EUS) or computed tomography (CT)–guided fine-needle aspiration (FNA) can result in peritoneal seeding of tumor cells and should be avoided in patients with potentially curable tumors. Acquisition of these biopsies can be challenging, and even after extensive diagnostic evaluation many patients will require surgical exploration to confirm the diagnosis and determine resectability of suspected malignant lesions.
Serologic Testing
Although nonspecific, serum liver chemistry is usually consistent with a pattern suggestive of biliary obstruction; the degree of elevation depends on the location, severity, and chronicity of the obstruction. A proximal lesion can be associated with an isolated alkaline phosphatase elevation. A prolonged prothrombin time may be seen in patients with chronic biliary obstruction because of vitamin K malabsporption. Carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 are the two markers that have been most widely used, but neither is highly sensitive or specific to be used alone for diagnosis. CEA and CA 19-9 may be elevated in a wide array of conditions, both benign and malignant. The use of CA 19-9 and CEA in concert with a host of novel markers identified with ELISA has the potential to improve the specificity of serologic testing for CCA. One marker, IL-6, has been studied for several years and has been shown to have specificity of approximately 90% to 92% and sensitivity ranging from 71% to 100% for detecting CCA. IL-6 may also be elevated in benign biliary disease and hepatocellular carcinoma as well as metastatic disease. This is an active area of research, and it will be of the utmost importance to identify reliable, validated markers to facilitate more timely detection of CCA in at-risk groups and in the general population.
Cytology
Bile aspirated during ERCP will result in positive cytology in only 30% of CCAs. Brush cytology also has a limited sensitivity of 35% to 69% and a specificity of 90%. The yield is increased if the stricture is disturbed by performing brushings ( Fig. 40.6 ) or biopsies of the lesion. A plastic stent placed during a prior ERCP can be sent for cytologic evaluation at the time of removal or exchange. Combining brushings, biopsies, FNA, and stent cytology can result in a positive diagnosis in approximately 80% of patients.
Assessment of DNA proliferation by both fluorescence in situ hybridization (FISH) and digital image analysis may further improve the specificity of cytology (see Chapter 41 ). FISH uses fluorescence-labeled DNA probes to detect abnormal loss or gain of chromosomes or chromosomal loci on cytologic analysis. Digital image analysis quantifies cellular DNA by measuring the intensity of nuclei stained with a dye that binds to nuclear DNA. Although both tests show promise in improving diagnostic yield, further studies are needed. Patients with PSC may have benign strictures that yield abnormal FISH results (see Chapter 48 ). In the setting of PSC, the positivity of FISH for trisomy/tetrasomy on multiple samples of the biliary tree is more specific for CCA.
Pathology
During ERCP, two methods can be used to obtain biopsies: targeted biopsies using direct visualization during cholangioscopy (see Chapters 27 and 41 ) or biopsy forceps using fluoroscopy to target the site. The cumulative diagnostic yield for bile duct strictures is increased to 63% when biopsies are obtained in addition to brush cytology. It has been proposed that biopsies performed with direct visualization during cholangioscopy may have a higher yield than biopsies obtained using fluoroscopic guidance without cholangioscopy. Genotyping of CCA tumor cells has led to a number of prognostic and theranostic (individualized) markers currently under investigation, which will likely pave the way for effective and precise therapeutic options and prognostication.
Radiologic Evaluation
In a patient with painless jaundice, CT scan and magnetic resonance imaging (MRI) are the preferred imaging modalities (see Chapter 34 ). MRCP can create three-dimensional images of the biliary tree, which are very useful for anatomic mapping with the added advantage of not requiring biliary instrumentation; it is the modality of choice when CCA is suspected ( Fig. 40.5 ). MRI with intravenous gadolinium administration commonly demonstrates CCA as minimal enhancement in the tumor periphery in the early arterial phase, with subsequent increased central enhancement in the delayed phase as a result of the central fibrous composition. Contrast-enhanced CT scans are also an excellent imaging tool for intrahepatic CCA. On contrast-enhanced CT scans, intrahepatic CCA is most often hypoattenuating or isoattenuating in relationship to healthy hepatic parenchyma throughout all phases of the study, except for enhancement seen in the delayed phase of the study. Positron emission tomography (PET) scan has been shown to detect nodular CCA as small as 1 cm because of the high glucose uptake of bile duct epithelium. PET is less helpful for detection of infiltrating tumors, and its sensitivity is also dependent on local expertise . Difficulty in distinguishing benign from malignant lesions makes the utility of PET scans limited as an independent imaging modality. PET may help in identifying distant metastatic disease, which may lead to adjustment of surgical planning.
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