PERSPECTIVES, PATTERNS OF SPREAD, AND PATHOLOGY
The commonest site for cancers of the extrahepatic bile ducts is at the confluence of the right and left ducts—the Klatskin tumor or hilar cholangiocarcinoma.
PERSPECTIVE AND PATTERNS OF SPREAD
The onset of jaundice is the common provocative symptom that requires attention and may lead to an early diagnosis of an extrahepatic cholangiocarcinoma. An unusually high serum bilirubin (>10 to 20 mg) should suggest malignancy because bilirubin levels of 2 to 4 mg are normal for obstructive cholelithiasis. This uncommon malignant entity is a disease of elderly populations, peaking late in 80-year-olds. As with hepatocellular carcinoma, for which hepatitis B and C virus infections are predisposing factors, the presence of infection in the form of primary sclerosing cholangitis is most often associated with cholangiocarcinoma. Primary sclerosing cholangitis is an autoimmune process and produces multifocal strictures in both extrinsic and intrinsic hepatic bile ducts. Although the incidence of cancer is only detected in 10% of infected patients, it can be as high as 30% to 40% at autopsy. Another source of chronic infection, especially in the Far East, is biliary parasites, which can increase the risk of cholangiocarcinomas via hepatolithiasis. These parasites can lead to hepatic pigment stone formation to strictures, then to recurrent cholangitis and carcinogenesis. Another well-recognized risk factor is Canoli disease or congenital choledochal cysts. Canoli disease patients have a predisposition for harboring infection, which has been shown in adults and even when excised to have incidental rates of 15% to 20% bile duct cancers.
Patterns of spread depend on the site of origin in the biliary tree (Fig. 26.2; Table 26.2). Extrahepatic cholangiocarcinoma can arise anywhere along its length. By far the commonest site is at the confluence of the right and left hepatic ducts, which has an incidence of 40% to 60% and includes Klatskin tumor or hilar cholangiocarcinoma. Multifocality is rare, with ≤10% occurring throughout the biliary tree. The overwhelming majority are well-differentiated, mucin-producing adenocarcinomas (see Table 26.1).
Figure 26.1 | Cholangiocarcinoma. Well-differentiated neoplastic glands are embedded in a dense fibrous stroma.
Figure 26.2 | Patterns of spread for extrahepatic bile ducts. Color coded for T stage: Tis, yellow; T1, green; T2, blue; T3, purple; and T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern, i.e., SIMLAP Table 26.2.
Hilar or confluens cholangiocarcinomas can readily penetrate through the thin muscular walls of extrahepatic bile ducts and have immediate access to the major vessels of the porta hepatis, portal vein, and hepatic artery. Distal biliary duct cancers represent the other 20% to 30% of cholangiocarcinomas; midduct occurrence is rare. These cancers are discussed with periampullary cancers or cancers of the ampulla of Vater.
PATHOLOGY
There are numerous histopathologic types, but the overwhelming majority are well-differentiated, mucin-producing adenocarcinomas (Table 26.1; Figure 26.1).
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The TNM staging in the seventh edition of the American Joint Committee on Cancer (AJCC) AJCC Cancer Staging Manual has added perihilar bile ducts (PBD) (Klatskin tumor) as new and distinct from distal bile ducts (DBD). This division changes the descriptors for T but in so doing clarifies adjacent structures at risk for invasion, particularly for vascular invasion patterns. Thus DBD has been simplified but has major changes. A single classification is offered for both the clinical and pathologic staging. This site was added in the fourth edition (1992) of the AJCC Manual. The extrahepatic bile duct on cross section is lined by a single layer of columnar cells. In its collapsed state, the mucosa is pleated with longitudinal folds, and a thin subepithelial layer of fibrous and muscle cells is surrounded by serosal cells. For these reasons, T1 is confined to the bile duct, T2 is tumor beyond its confines, and both require histologic verification. T3 relates to the immediate surrounding anatomy in the porta hepatis being invaded as liver, gallbladder, and unilateral branches of the hepatic artery and portal vein, whereas T4 is further spread into the common portal vein or hepatic artery or into colon, stomach, or duodenum—essentially the other viscera.
For distal bile ducts, nodal involvement N1 refers to the hilar nodes near the gallbladder and around the portal vein, hepatic artery, cystic ducts.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
Distal Bile Duct
• Extrahepatic bile duct was a single chapter in the sixth edition. This has been divided into two chapters for the seventh edition [Distal Bile Duct (Fig. 26.3A) and Perihilar Bile Ducts (Fig. 26.3B)].
• Two site-specific prognostic factors, preoperative or pre-treatment serum carcinoembryonic antigen and CA19.9, are recommended for collection.
The TNM Staging Matrix is color coded for identification of stage group once T and N stages are determined (Tables 26.3A and 26.3B).
DISTAL BILE DUCT
Figure 26.3A | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Note that stages I and II are divided into substages A/B. Resectability is possible with stage IA/B and stage IIA and decreases with stage IIB (purple) when nodes are involved and invasion of gallbladder occurs. Stage III is unresectable, and stage IV is metastatic and not treatable. Stage 0, yellow; I, green; II, blue; III, purple; IV, red; and stage IV (metastatic), black. Definitions of TN on left and stage grouping on right.
PERIHILAR CHOLANGIOCARCINOMA BILE DUCT
Perspective and Patterns of Spread
The Klatskin tumor is the most common cancer of the biliary tree and is at the bifurcation of the left and right hepatic ducts. The distal bile duct is the second-most-common cancer, and intrahepatic bile duct is the least common. Of all the bile duct cancers, this is regarded as the most challenging to treat because of the juxtaposition of vital vascular structures in the portahepatic. This is a rare cancer, occurring at a rate of 1 to 2 per 100,000 in the United States, but it comprises 50% to 70% of cholangiocarcinomas (Table 26.3B).
The pattern of spread predominantly is direct invasion of the liver and occurs in 85% of presentations. The next structure invaded commonly is the portal vein. Extension along the biliary tree, cystic duct, and gallbladder also can occur.
Histopathology
The staging system applies to a large variety of histopathologic types of carcinomas (98%), but sarcomas and carcinoids are excluded.
• Carcinomas in situ
• Adenocarcinoma
• Adenocarcinoma, intestinal type
• Clear cell adenocarcinoma
• Mucinous carcinoma
• Signet ring cell carcinoma
• Squamous cell carcinoma
• Adenosquamous carcinoma
• Small cell carcinoma (grade 4 by definition)
• Undifferentiated carcinoma (grade 4 by definition)
• Spindle and giant cell types
• Small cell types
• Papillomatosis
• Papillary carcinoma, noninvasive
• Papillary carcinoma, invasive
• Carcinoma, not otherwise specified*
Summary of Changes Seventh Edition AJCC
• Extrahepatic bile duct tumors have been separated into perihilar (proximal) and distal groups and separate staging classifications defined for each (Fig. 26.3B).
• T1 (confined to bile duct) and T2 (beyond the wall of the bile duct) have been specified histologically.
• T2 includes invasion of adjacent hepatic parenchyma.
• T3 is defined as unilateral vascular invasion.
• T4 is defined on the basis of bilateral biliary and/or vascular invasion.
• Lymph node metastasis has been reclassified as stage III (upstaged from stage II).
*Preceding passage from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, pp. 221–222.
The stage IV groupings define unresectability based on local invasion (IVA) or distant lymph nodes (N2) and metastatic disease (IVB).
T-oncoanatomy
The perihilar bile duct region is at the portahepatic and is surrounded by numerous vital structures. The right and left hepatic veins parallel the major right and left bile ducts, as does the right and left hepatic arteries. The juxtaposition to the quadrate lobe of the liver and gallbladder is evident. The anatomy of the portahepatic region is also highly variable.
N-oncoanatomy
The portahepatic lymph nodes are the sentinel lymph nodes; in addition, pericholodochal nodes in the hepatoduodenal ligament are involved.
Regional Lymph Nodes
In perihilar cholangiocarcinoma, the prevalence of lymphatic metastasis increases directly with T category and ranges from 30% to 53% overall. Hilar and pericholedochal nodes in the hepatoduodenal ligament are most often involved.†
M-oncoanatomy
The major spread pattern is to the juxtaposed liver via intrahepatic duct extension or invasion of portal vein. Extrahepatic metastases are uncommon, but lung, brain, and bone metastases have been noted.
RULES FOR STAGING
There are a variety of imaging methodologies. The most dramatic and clear visualization is by percutaneous transhepatic cholangiography outlining the biliary tree. However, computed tomography (CT) and magnetic resonance (MR) are required to determine cancer extensions. MR cholangiopancreatography is recommended. The most accurate staging is most often at surgery, and, if unresectable, biopsy of suspected extensions is advised.
PROGNOSIS AND SURVIVAL
The adverse effect of vascular invasion is shown and clearly demonstrates the superior survival of partial hepatectomy versus concomitant resection of portal vein. For localized disease, a 5-year survival rate of 20% to 40% can be achieved.
MANAGEMENT
Surgical resection is preferred for early stages; in advanced stages, neoadjuvant chemoradiation regimens and liver transplantation are the only options. There is significant perioperative morbidity (30% to 50%) and mortality (5% to 10%).
†Preceding passage from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 228.
PERIHILAR BILE DUCT
Figure 26.3B | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Note that stages I and II are divided into substages A/B. Resectability is possible with stage IA/B and stage IIA and decreases with stage IIB (purple) when nodes are involved and invasion of gallbladder occurs. Stage III is unresectable, and stage IV is metastatic and not treatable. Stage 0, yellow; I, green; II, blue; III, purple; IV, red; and stage IV (metastatic), black. Definitions of TN on left and stage grouping on right.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The anatomic isocenter for the extrahepatic biliary tree is at the hilar level, and (i) the bullet is to the right of the midsagittal plane, and (ii) in the midcoronal plane, the bullet is anterior to the 12th rib (Fig. 26.4).
T-oncoanatomy
The complexity in understanding the oncoanatomy of the extra-hepatic biliary tree relates to the precise details in each individual, given the potential variations in the arrangements of the gallbladder, cystic duct, and the confluens, which can be a low or high union or swerving in its course (Fig. 26.5). In addition, resectability relates to the arrangement of the hepatic artery and the portal vein, as well as to their branching. Optimally, a confluens carcinoma with a low-lying union and separation of the right and left hepatic artery would be more resectable than a high union with the main hepatic artery lying anterior to the confluens.
• Coronal: The extrahepatic bile ducts, pancreatic bile ducts, and pancreatic ducts are dissected free. The left and right hepatic ducts collect bile from the liver and unite with the cystic duct superior to the pancreas and the duodenum (Fig. 26.5A).
• Sagittal: The extrahepatic bile duct lies posterior to the gall-bladder and passes posterior to the first part of the duodenum at the porta hepatis. The portal triad of the common bile duct, hepatic artery, and portal vein lies in the hepatoduodenal ligament, at the entrance to the lesser omental sac.
• Transverse: The inferior surface of the liver exposes the intimate relationship at the porta hepatis of the cystic duct to the common bile duct and its confluens in addition to medially placed hepatic artery and portal vein (Fig. 26.5B).
Figure 26.4 | Orientation and overview of oncoanatomy. The anatomic isocenter for the three-planar oncoanatomy for the gall-bladder is the right of the midline (pararectus plane) at the subcostal region anteriorly and L1/L2 posteriorly. The bile ducts are in a similar locale but inferior at L1/L2. A. Coronal. B. Sagittal.
Figure 26.5 | T-oncoanatomy. Connecting the dots. Structures are color coded for cancer stage progression. The color code for the anatomic sites correlates with the color code for the stage group (Fig. 26.3) and patterns of spread (Fig. 26.2) and SIMLAP table (Table 26.2). Connecting the dots in similar colors will provide an appreciation for the 3D oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
DISTAL BILE DUCTS
N-oncoanatomy
The lymphatic drainage of the extrahepatic bile duct is via the lymph nodes at the porta hepatis and include hilar, celiac, periduodenal, and peripancreatic nodes as well as nodes around the gallbladder and the hepatic triad. The sentinel nodes are the porta hepatis nodes. Nodal metastases are common and occur in 30% of cases (Fig. 26.6A; see Table 26.4).
Regional Lymph Nodes
Accurate tumor staging requires that all removed lymph nodes be analyzed. Optimal histologic examination of a pacreaticoduodenectomy specimen should include analysis of a minimum of 12 lymph nodes. If the resected lymph node is negative but this number of examined nodes is not met, pN0 should still be assigned. The regional lymph nodes are the same as those resected for cancers of the head of the pancreas, that is, nodes along the common bile duct, hepatic artery, and back toward the celiac trunk, the posterior and anterior pancreaticoduodenal nodes, and the nodes along the superior mesenteric vein and the right lateral wall of the superior mesenteric artery. Anatomic division of regional lymph nodes is not necessary; however, separately submitted lymph nodes should be reported as submitted.*
M-oncoanatomy
The venous drainage of the extrahepatic bile ducts joins the cystic vein and drains into the right gastric vein and posterior superior pancreaticoduodenal vein and then into the portal vein, returning to the liver. In addition to hematogenous spread, perineural and neural invasion are common (see Fig. 26.6B).
*Preceding passage from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.
Figure 26.6 | A. N-oncoanatomy. Sentinel nodes of the bile ducts include the porta hepatis nodes. B. M-oncoanatomy. The venous drainage of the extrahepatic bile ducts joins the cystic vein and drains into the right gastric vein and posterior superior pancreaticoduodenal vein and then into the portal vein, returning to the liver, resulting in liver metastases.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
The inability to evaluate the gallbladder, its ducts, and the ampulla of Vater has led the AJCC to simplify the staging so that both clinical and surgical criteria are the same. Imaging procedures include abdominal ultrasound, which is surpassed by CT in defining biliary obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography define biliary tree anatomy. Magnetic resonance imaging with gadolinium is also useful (see Table 26.5; Fig. 26.7).
Pathologic Staging
The surgically resected gallbladder and/or bile ducts with associated lymph nodes removed are assessed. Tumor extension and location of both primary and nodes should be documented. Accurate radial margins should be marked and recorded and are defined “as the surgically dissected surface adjacent to the deepest point of tumor invasion beyond the wall of the extrahepatic bile duct.” The completeness of resection depends on the clearing of the deepest point of invasion: R0, complete; R1, microscopic; and R2, macroscopic.
Oncoimaging Annotations
• Ultrasound initially reveals a dilated extrahepatic duct and intrahepatic duct system.
• Helical multiplanar CT with five 1- to 2-mm cuts best shows the mass. ERCP is an optional procedure that may show the common bile duct cancer without involvement of the pancreatic duct, but surgical evaluation followed by resection and microscopy is critical to both diagnosis and staging.
• When direct cholangiograms are needed, a percutaneous transhepatic cholangiogram identifies the common bile duct cancer site and is preferred over ERCP diagnosis and staging.
Figure 26.7 | Axial CTs of L1 and L2 level correlate with the T-oncoanatomy transverse section (Figure 26.5B). Oncoimaging with CT is commonly applied to staging cancers, often combined with PET to determine true extent of primary cancer and involved lymph nodes. 1. superior mesenteric vein. 2. superior mesenteric art. 3. crus of diaphragm. 4. pancreas (head). 5. common bile duct. 6. duodenum. 7. gallbladder. 8. colon: splenic flexure. A, abdominal aorta; J, jejunum; LK, left kidney; RK, right kidney; Stom, stomach.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS
The limited number of prognostic factors are listed in Table 26.6.
CANCER STATISTICS AND SURVIVAL
Complete resection is critical for survival. Node-negative patients do better, as anticipated; low recurrence is seven times more common without positive nodes. Survival for periampullary cancers is highly dependent on true anatomic site of origin. Liver resections with negative margins are the key to survival for hilar and confluens bile duct cancer (Fig. 26.8).
The majority of digestive systems neoplasms are successfully treated with multimodal treatment. The number of new patients with cancers are 275,000 of which 50% (140,000) survive. The incidence is slightly greater in males than females 54% vs. 46% i.e. 150,000 vs. 1260,000. The death rates over the past five decades have most dramatically decreased in stomach and colon rectum cancers and are unchanged for pancreas and liver. The deaths are also greater in males than females: 56% vs. 44% i.e. 80,000 vs. 60,000.
An overview of digestive system cancers and their incidence of new patients and their death rates are tabulated according to ACS Cancer Facts and Figures 2010 (Tables 22.6 and 22.7).
The largest gains in survival are in colon and rectum, followed by stomach. The poorest results are those in pancreas and liver. The gains other sites vary depending on early detection of cancer in a localized stage in esophago-gastric junction or where chemoradiation is very effective i.e. anal cancers.
Figure 26.8 | A. Five-year survival for distal bile duct cancer. (Data from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.)
Figure 26.8 | B. Perihilar survival. Adverse effect of vascular invasion on survival. In a study by Ebata, et al (2003), patients who underwent hepatectomy alone had a better outcome than patients who required concomitant portal vein resection, with 5-year overall survival of 37% vs. 10%, respectively. (Used with the permission of the American Joint Committee on Cancer (AJCC) Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh edition (2010) published by Springer SBM, LLC, p 220).