PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
Cancer of the gallbladder is insidious in onset and is associated with gallstones in 75% of presentations.
PERSPECTIVE AND PATTERNS OF SPREAD
An elaborate bile ductal system originates in the liver, which becomes extrahepatic at the porta hepatis. The gallbladder can be viewed as a bile reservoir that responds to fat in meals and is connected by a cystic duct to the common bile duct (CBD). The CBD joins the pancreatic duct and forms an ampulla within the head of the pancreas referred to as the ampulla of Vater, which terminates in a papilla that empties into the second part of the duodenum. This complex of branching bile ducts and fusion with the pancreatic duct is best appreciated diagrammatically. These sites give rise to a variety of cancers, but the most common are adenocarcinomas.
The gallbladder and the extrahepatic biliary ducts account for 960 new cancer cases annually, and approximately 50% of these patients survive. Cancer of the gallbladder is insidious in onset and is associated with gallstones in 75% of presentations. Many gallbladder cancers are unsuspected and found incidentally by the surgeon, who may be operating because of cholelithiasis. Although extrahepatic bile duct cancers can arise anywhere in its network, it is worth noting that 70% to 80% are found at the confluence of the right and the left hepatic ducts, and the other 20% to 30% arise more distally. Obstructive jaundice is a frequent consequence and can occur even with small tumors. The main reason for identifying the ampulla of Vater separately is that obstruction at the site induces severe pain and causes jaundice and a most disconcerting reflux pancreatitis. Patterns of spread are into bile ducts, liver, and adjacent viscera (Table 27.2; Fig. 27.2).
Gallbladder cancer (GBC) is the sixth-most-common cancer of the digestive system, but only accounts for 3% to 4% of all gastrointestinal (GIT) cancers. GBC occurs in the elderly and is three times more common in females. Gallstones lead to chronic inflammation; larger stones (>3 cm) are associated with 10 times higher risk of cancer. The calcified gallbladder, so-called porcelain wall, is associated with a very high risk, ranging from 20% to 50%, of leading to cancer. Thus, symptoms and signs are usually nonspecific initially; as the cancer advances, right upper quadrant pain becomes continuous and there is a palpable mass and eventually jaundice, pruritis, and weight loss. Hepatomegaly and ascites suggest liver invasion. Laboratory data include elevated alkaline phosphatase, bilirubin, and aminotransferase.
PATHOLOGY
Adenocarcinomas are the most common cancer type and can vary from differentiated to anaplastic cancer, often with a desmoplastic reaction.
The histopathology of gallbladder cancers are largely adenocarcinomas and the variety of cancers are listed in Table 27.1 and Fig. 27.1 illustrates the typical pathology with gallstones.
Figure 27.1 | Carcinoma of the gallbladder. The gallbladder wall is infiltrated by a moderately differentiated adenocarcinoma, which has stimulated a desmoplastic response.
Figure 27.2 | Patterns of spread for gallbladder. Color coded for T stage: Tis, yellow; T1, green; T2, blue; T3, purple; 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 27.2.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The gallbladder and the extrahepatic bile ducts terminating at the ampulla of Vater share a hollow structure with thin walls. With the exception of the gallbladder, most bile duct cancers can obstruct and still be small. Whereas cancer of the ampulla of Vater can be confused with primary duodenal and/or pancreatic cancer of the head of the gland, their relative infrequency suggests that this diagnosis may be made by exclusion.
Each of these staging systems has been revised and simplified. Each primary site is of hollow structure with muscular walls, and they share common staging criteria (Fig. 27.3). T1 is a tumor that invades the lamina propria muscle layer and is contained within the wall. In stage T2, the tumor penetrates to the serosa. T3 tumor invades and penetrates the wall through the serosa to a surrounding structure as liver or pancreas. T4 is an advanced cancer with invasion of multiple adjacent sites and into blood vessels. The staging criteria attempt to stage cancers of extrahepatic ducts as T3 to indicate resectability versus T4, which are nonresectable. Two of these three cancer sites are presented together to enable comparisons.
The malignant gradient of the gallbladder is highest at the surface in contact with the liver and decreases on the free side and the cystic duct. For the extrahepatic ducts, the malignant gradient is close to liver at the confluence of the right and left hepatic ducts and decreases peripherally.
Generally, there is no overarching principle or context design for the digestive system (gastrointestinal tract) or major digestive glands (MDGs). Stages are frequently expanded to six by subdividing stages into A and B. The T and N categories are assigned to a stage grouping, specifically for division of a stage into more (a) versus less (b) favorable groupings. This occurs at different stages for different sites.
Specifically, there is a direct relationship between T categories and stage progression; that is, T1 = IA, T2 = IIA, T3 = IIB, and T4 = IV.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• The cystic duct is now included in this classification scheme.
• The N classification now distinguishes hilar nodes (N1: lymph nodes adjacent to the cystic duct, bile duct, hepatic artery, and portal vein) from other regional nodes (N2: celiac, periduodenal, and peripancreatic lymph nodes and those along the superior mesenteric artery).
• Stage groupings have been changed to better correlate with surgical resectability and patient outcome; locally unresectable T4 tumors have been reclassified as Stage IV.
• Lymph node metastasis is now classified as Stage IIIB (N1) or Stage IVB (N2).
• The T categories are the same and N categories are divided N1, N2.
• The major change is the assignment to a stage group, although the T/N clusters are the same.
The TNM Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 27.3).
GALLBLADDER
Figure 27.3 | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Gallbladder cancers are discovered incidentally to gallstones, with stage IIA (blue) being most resectable; stage IIB (purple), borderline N1 nodes; and stage III (red), unresectable. Stage 0, yellow; I, green; II, blue; III, purple; IV, red; and 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 three-planar oncoanatomy for the gallbladder is to the right of the midline (pararectus plane) at the subcostal region anteriorly and T12/L1 posteriorly (Fig. 27.4). The bile ducts are in a similar locale but inferior at L1/L2.
T-oncoanatomy
Figure 27.5 provides the orientation of three-planar views of these interrelated sites, anatomically as well as functionally; A. Coronal, B. Sagittal, C. Transverse axial.
• Coronal: The gallbladder is a pearlike organ with four layers: a lining epithelium, which is simple columnar consisting of common clear cells and occasional brush cells; the lamina propria, a layer of smooth muscle with connective tissue and cone of a serosa on the free caudad tail side; and the adventitia on the cephalad head side juxtaposed to the liver. When empty, the gallbladder is folded into tall parallel ridges; when it is filled, the folds are reduced.
• Sagittal: The extrahepatic ducts unite with the cystic duct to become the CBD. Again, there are four layers or sphincter muscles of Oddi that control the flow of bile and move pancreatic secretions in the correct directions without reflux of bile into the pancreas. The ampulla of Vater opens at a duodenal papilla to always maintain a prograde flow into the small bowel.
• Transverse: The gallbladder is at the inferior margin of the right lobe of the liver to which it is juxtaposed on its superior surface and to the bowel on its inferior surface. The cystic duct drains to the left, toward the midline, where it coalesces with the extrahepatic bile ducts to form the CBD at the porta hepatis.
Figure 27.4 | Orientation and overview of oncoanatomy. The anatomic isocenter for the three-planar oncoanatomy for the gallbladder is the right of the midline (pararectus plane) at the subcostal region anteriorly and L1/L2 posteriorly. A. Coronal. B. Sagittal.
Figure 27.5 | 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. 27.3) and patterns of spread (Fig. 27.2) and SIMLAP tables (Table 27.2). Connecting the dots in similar colors will provide an appreciation for the 3D oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
Patients have increased incidence of nodes as a function of T advancement: T1 = 10%, T2 = 33%, T3 = 58%, and T4 = 69%. The region is abundant in lymphatics, with the cisterna chyli located posterior to the head of the pancreas. The gall-bladder drains toward the porta hepatis (Fig. 27.6A; Table 27.4), and the extrahepatic bile ducts drain into the pancreatic duodenal nodes.
Regional Lymph Nodes
For accurate staging, all nodes removed at operation should be assessed for metastasis. Sentinel lymph nodes are limited to the hepatic hilus (including nodes along the common bile duct, hepatic artery, portal vein, and cystic duct). Celiac, periduodenal, peripancreatic, and superior mesenteric artery node involvement is now considered regional nodes (Table 27.4).*
*Preceding passage from Edge SB, Byrd DR, and Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York. Springer, 2010, p. 212.
M-ONCOANATOMY
The entire portal circulation should be considered as a unit with regard to the venous anatomy of the gastrointestinal tract below the diaphragm (see Fig. 27.6B). The two major trunks are the inferior mesenteric and superior mesenteric veins. The inferior mesenteric vein drains the left colon and sigmoid colon tributaries, which covers the vascular drainage to the left of the midline originating from the superior rectal veins. On the right side, the superior mesenteric vein originates from the tributaries draining the ileum, the jejunum, the ileocolic, and the right middle colic veins. The inferior mesenteric vein usually joins the splenic vein, which coalesces with the superior mesenteric vein and forms the portal vein. The splenic vein, which is a major tributary of the portal system, also drains much of the stomach along its greater curvature and includes the short gastric veins and left and right gastroepiploic veins. The right gastric epiploic vein also flows into the superior mesenteric vein. The entire drainage of the lesser curvature of the stomach, including the left and right gastric veins, drains directly into the portal vein. Because the portal vein then drains directly into the liver, the liver is the target metastatic organ and most commonly involved in hematogenous spread pattern from the venous system of the gastrointestinal tract as compared with other parts of the body, where the drainage is directly into the lung by way of the caval system. The most common metastatic organ is liver via segments IV/V via cystic vein or direct extension.
Figure 27.6 | A. N-oncoanatomy. Sentinel nodes of the gallbladder and bile ducts include the porta hepatis nodes. B. M-oncoanatomy. The venous drainage of the gallbladder into the cystic vein 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 American Joint Committee on Cancer to simplify the staging so that both clinical and surgical criteria are the same. Imaging procedures include abdominal ultrasound, which is surpassed by computed tomography (CT) in defining biliary obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography define biliary tree anatomy. Magnetic resonance imaging (MRI) with gadolinium is also useful (Table 27.5; Fig. 27.7).
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 gallbladder.” The completeness of resection depends on the clearing of the deepest point of invasion: R0, complete; R1, microscopic; and R2, macroscopic.
Oncoimaging Annotations
• Advanced hepatocellular carcinoma (HCC) is tumor >2 cm. Only 10% to 20% of patients with HCC are candidates for surgical resection. Adverse prognostic factors are tumor >5 cm, lack of capsule, multifocal disease, presence of metastases in more than one lobe, diffuse type, lymph node metastases, and venous tumor thrombus.
• Imaging is used for tumor detection and evaluation of tumor resectability: Ultrasonography (including Doppler and ultrasound angiography), contrast-enhanced CT (intravenous bolus injection), multiple (early arterial, portal, and delayed scanning), and MRI (including T1 weighted, T2 weighted, and dynamic contrast enhanced) are all used.
• MRI is considered to have higher sensitivity for detection of smaller lesions.
• From 10% to 20% of carcinomas of the gallbladder are found incidentally in resected gallbladder specimens.
• Imaging approaches: ultrasonography with color Doppler, CT with bolus intravenous, contrast material injection, and multiphase scanning. T1- or T2-weighted MRI and dynamic scanning with gadolinium and ERCP are all helpful.
• CT delineates gallbladder mass with sensitivity and specificity of 90%.
• CT-guided biopsy is essential.
• Staging is excellent with either CT or MRI.
Figure 27.7 | Axial CTs of L1 and L2 level correlate with the T-oncoanatomy transverse section (Figure 27.5C). 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. Duodenum. 3. Superior mesenteric artery. 4. Pancreas (head). 5. Left renal vein. 6. Left renal artery. 7. Pancreas (uncinate process). GB, gallbladder; J, jejunum; LK, left kidney; RK, right kidney.
PROGNOSIS AND CANCER SURVIVAL
PPROGNOSIS
The limited number of prognostic factors are listed in Table 27.6.
CANCER STATISTICS AND SURVIVAL
The gallbladder and bile ducts accounted for 9,760 new cancer cases and 3,320 cancer deaths (51%). Survival rates (5-year) as a function of stage following an extended cholecystectomy with or without extended lobectomy of liver are as follows: T1, 90% to 100%; T2, 30% to 80%; and T3/T4, 10% to 25% (Fig. 27.8).
Figure 27.8 | Five-year survival for gallbladder cancer. (Data from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 212.)