Gallbladder cancer

The American Journal of Surgery (2008) 196, 252–264

Review

Gallbladder cancer Stavros Gourgiotis, M.D., Ph.D.a,*, Hemant M. Kocher, M.D., F.R.C.S.b, Leonardo Solaini, M.D.b, Arvin Yarollahi, M.D.b, Evangelos Tsiambas, M.D.c, Nikolaos S. Salemis, M.D., Ph.D.a a

Second Surgical Department, 401 General Army Hospital of Athens, Athens, Greece; bBarts and The London HPB Centre, The Royal London Hospital, London, UK; cCytopathology Department, 401 General Army Hospital of Athens, Athens, Greece KEYWORDS: Gallbladder cancer; Pathology; Diagnosis; Treatment; Prognosis

Abstract BACKGROUND: Gallbladder cancer (GC) is a relatively rare but highly lethal neoplasm. We review the epidemiology, etiology, pathology, symptoms, diagnosis, staging, treatment, and prognosis of GC. METHOD: A Pubmed database search between 1971 and February 2007 was performed. All abstracts were reviewed and articles with GC obtained; further references were extracted by handsearching the bibliography. The database search was done in the English language. RESULTS: The accurate etiology of GC remains unclear, while the symptoms associated with primary GC are not specific. Treatment with radical cholecystectomy is curative but possible in only 10% to 30% of patients. For patients whose cancer is an incidental finding on pathologic review, re-resection is indicated, where feasible, for all disease except T1a. Patients with advanced disease should receive palliative treatment. Laparoscopic cholecystectomy is contraindicated in the presence of GC. CONCLUSION: Prognosis generally is extremely poor. Improvements in the outcome of surgical resection have caused this approach to be re-evaluated, while the role of chemotherapy and radiotherapy remains controversial. © 2008 Elsevier Inc. All rights reserved.

Gallbladder cancer (GC), first described by Stoll in 1777,1 is a relatively rare neoplasm and has been considered to be a highly lethal disease. With an incidence of .8% to 1.2%, this is the most common biliary tract tumor and the fifth most common malignancy of the gastrointestinal tract.2 GC account for approximately 7,100 new cases and 3,500 new deaths per annum in the United States.3,4 There are no specific clinical symptoms or signs, and most patients have advanced disease at presentation. The minority of GCs are first diagnosed on microscopic examination after routine cholecystectomy for a benign disease.5 * Corresponding author. Tel./fax: ⫹30 2106525802. E-mail address: [email protected] Manuscript received July 16, 2007; revised manuscript November 2, 2007

0002-9610/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.11.011

The prognosis of GC generally is extremely poor due to the high proportion of tumor that is advanced at the time of presentation. The 5-year prognosis for all stages of GCs is about 5%,6 –9 while the median survival for patients with suspected cancers is 9.2 months, and for those with incidentally diagnosed cancers, 26.5 months.10 However, during the last few decades, important advances and sophistication of diagnostic methods in clinical practice have resulted in a significant changes in early diagnosis of GC, and the use of radical aggressive surgical approaches promises to improve survival. The aim of current review is to summarize currently available data regarding epidemiology, etiology, risk factors, pathology, clinical presentation, and prognosis of GC and to discuss diagnostic problems, staging, and management doubts that always affect clinicians and surgeons. The

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English-language studies on GC published between 1971 and 2007 were identified using Medline, and additional cited works not detected in the initial search were obtained. Articles reporting on prospective and retrospective comparisons and case reports were included. The results were tabulated to show outcomes of different studies and were compared.

Epidemiology GC represents 80% to 95% of the biliary tree tumors in autopsy studies worldwide and affects women 2 to 6 times more commonly than men.10 The incidence steadily increases with age (it is diagnosed more frequently in the sixth and seventh decades of life), although it varies greatly in different parts of the world.11,12 However, Kiran et al13 reported that there is a significant reduction in the incidence of GC over the last decade in patients older than 50 years, with a slight increase in the incidence in younger patients. The highest incidence rate was shown by women from Delhi, India (21.5 per 100,000), followed by the Andean area (15.5 per 100,000) and South Karachi, Pakistan (13.8 per 100,000).11 In North America, low rates predominate, with the exception of high rates reported among Indians in New Mexico (11.3 per 100,000) and intermediate rates among female immigrants from Latin America.11 In Europe, the highest incidence was found in the countries of Eastern Europe: Poland, the Czech Republic, and Slovakia. Population-based studies also indicate that the incidence of GC is elevated in Granada, Spain and is relatively high in Far East Asia: Korea and Japan. In males, the highest incidence rate of GC was reported in the Andean area (4.1–7.5 per 100,000) and in some areas of Asia and Eastern Europe (4.4 – 8.8 per 100,000). Low incidence rates (⬍3 per 100,000 women and 1.5 per 100,000 men) emerged for most registries from Northern Europe, United States, Canada, Singapore, and Nigeria. The incidence of GC varies among ethnic groups within countries; Hispanic women in California and New Mexico had higher incidence rates than any other ethic group in the United States. Marked geographic, ethnic, and cultural differences in the frequency of GC suggest that there are genetic and environmental risk factors for the development of GC.

Etiology/Risk Factors The accurate etiology of GC remains unclear. Many studies report that gallstone disease (cholelithiasis) is considered to be the primary risk factor for the tumor; these reports are derived through clinical association but lack experimental data to support them.14 –16 This clinical association has been described in patients with symptomatic cholelithiasis for at least 20 years prior to GC diagnosis.16,17

Figure 1 Histopathology of gallbladder carcinoma. Main image and upper inset show a well-differentiated gallbladder adenocarcinoma of the intestinal type composed of short or long cancerous tubular glands resembling colonic type epithelium (black arrow). Hematoxylin & eosin stain, original magnification 100x, 200x, respectively. Bottom inset image shows the corresponding tissue formalin-fixed and paraffin-embedded section. White to yellow area represents the expansion of adenocarcinoma (yellow arrow).

It is possible that the chronic inflammation related to gallstones promotes epithelial dysplasia and adenocarcinoma formation (Figure 1). However, only .3% to 3% of patients with cholelithiasis develop GC and approximately 20% of GC patients show no evidence of previous cholelithiasis.18 It has been reported that in patients with gallstones larger that 3 cm in diameter, the risk of gallbladder cancer is 10 times greater than in patients with stones smaller than 1 cm in diameter, while the relative risk is 2.4 if the gallstones are 2.0 to 2.9 cm.19 Cancer is more likely to occur with a single large gallstone than with multiple smaller gallstones. On the other hand, Moerman et al20 did not find any variation in GC risk according to gallstone size. Although the cholesterol and mixed gallstones represent approximately 80% to 90% of all cholelithiasis cases in the Western world, the specific type of stones seems to have no strong positive correlation with the incidence rates of GC. Porcelain gallbladder and gallbladder polyps represent other predisposing risk factors for GC. Porcelain gallbladder, which is the pathological finding of a brittle gallbladder with bluish discolouration resulting from extensive calcification of gallbladder wall, has been associated with GC in 12.5% to 62% of patients.21 In 1 series of 150 patients with GC and 44 patients with calcified gallbladders, 2 types of calcified gallbladders were noted: those with complete intramural calcification and those with selective mucosal calcification.22 The authors reported that the incidence of cancer was dependent on the pattern of calcification; selective mucosal calcification posed a significant risk of cancer (⬃7%), whereas diffuse intramural calcification did not. Polyps larger than 10 mm in diameter need to be removed even in asymptomatic patients, while in patients with polyps less than 10 mm in diameter,

254 gallbladder removal is recommended only if they produce symptoms associated with gallstones.23 Furthermore, many authors have underlined the utility of color Doppler in the differential diagnosis of GC with other polypoid lesions and have reported that the measurement of the flow rate is also important, with a higher rate for malignant than benign lesions.24,25 Hayakawa et al26 reported a sensitivity of 96% for diagnosis of malignant tumors using a cutoff point of 30 cm/s, while Komatsuda et al24 obtained a sensitivity of 72% and specificity of 66% with a cutoff of 20 cm/s. Another risk factor for GC involves an anomalous pancreatobiliary duct junction (seen in about 17% of patients with cancer compared with less than 3% of patients with other hepatobiliary diseases), which results in regurgitation of pancreatic juice into the gallbladder and causes bile stasis that leads to an inflammation status and precancerous status in the gallbladder mucosa.17,27 Obesity, endogenous and exogenous estrogens, and pregnancy increase the risk of cholelithiasis and constitute less significant risk factors for GC.11,15 Segmental adenomyomatosis of gallbladder, chronic inflammatory bowel disease, polyposis coli, and Mirizzi syndrome may lead to gallbladder cancer and chronic infection, inflammation, and irritation may play a possible role in carcinomatous change.28,29 Many cohort and case-control studies also have shown a strong association of mixed bacterial and Salmonella infections in the carcinogenesis of GC, especially in areas with a high endemicity of typhoid, and bacterial degradation of bile and chronic inflammation may play some role in the carcinogenic process.15,30,31 Some studies have shown the possibility of carcinogen involvement in the pathway of GC. Increased risk for this tumor among workers in the oil, paper, chemical, shoe, and textile industries suggests a role of the chemicals involved in carcinogenesis.30,32 Moreover, nitrosamines, methylcholanthrene, and O-aminoazotoluence can cause GC in animals.33 Finally, there are some reports of familial tendencies toward GC; although they are based on a very small number of patients.34 Information about the genetic changes involved in GC is limited. However, Wistuba et al35 reported that chromosome 3p loss of heterozygocity (LOH), including the fragile histidine triad (FHIT) candidate tumor-suppressor gene locus at 3p14.2, is frequently detected in GC. They also identified a high frequency of discontinuous LOH and breakpoints in the FHIT locus in the dysplastic and invasive GC specimens. FHIT gene abnormalities, expressed by considerable reduction or loss of Fhit immunostaining and allele loss, are nearly universal in GC and these changes are detected early in the sequential development of this neoplasm.35 Table 1 summarizes the risk factors for GC.

Pathology GC represents a progression from dysplasia, to carcinoma in situ, to invasive carcinoma over about 15 years.36

The American Journal of Surgery, Vol 196, No 2, August 2008 Table 1

Risk factors for gallbladder cancer

Cholelithiasis Porcelain gallbladder Gallbladder polyps Anomalous pancreatobiliary duct junction Obesity Endogenous and exogenous estrogens Pregnancy Segmental adenomyomatosis of gallbladder Chronic inflammatory bowel disease Polyposis coli Mirizzi syndrome Bacterial and Salmonella infections Industrial exposure to carcinogens Familial tendency

Severe dysplasia and carcinoma in situ have been found in more than 90% of gallbladders that contain GC.37 In 1 series of 1,326 patients, the average age of patients with epithelial dysplasia not associated with cancer was 51.9 years (n ⫽ 198), early cancer 56.8 years (n ⫽ 206), advanced carcinoma 62.9 years (n ⫽ 884), and metastasis of GC 63.1 years (n ⫽ 38), which suggests the progression from intraepithelial lesions towards carcinoma.38 Adenoma in the gallbladder also has been previously reported to be a precancerous lesion,39 but molecular analysis of this lesion does not show the genetic changes associated with GC.40 On the other hand, papillary carcinomas of the gallbladder join the group of malignant papillary neoplasms with an indolent clinical course that arise in ductal structures or hollow viscera and which are characterized by a noninvasive component that after many years may lead to invasion. Patients with noninvasive tumors have a more favorable prognosis than those with invasive papillary carcinomas whose histologic features differ from those of the noninvasive component.41 On gross examination, approximately 10% to 37% of the GCs cannot be identified with certainty, and their macroscopic findings are similar to those of chronic cholecystitis: asymmetric thickening of the gallbladder wall, which infiltrates the surrounding structures.42 It is important that the surgeon palpates the gallbladder after cholecystectomy to identify any abnormal, thickened, or indurated regions. Samples of any suspicious areas should be sent for immediate frozen section in order to establish a diagnosis. If GC is confirmed, a radical cholecystectomy should be performed at the time of the initial operation. Most carcinomas (60%) originate in the fundus of the gallbladder, 30% in the body, and 10% in the neck.43 Macroscopically, GC can be categorized into papillary, tubular, and nodular forms.44 Nodular types can show early invasion through the gallbladder wall into the liver or neighboring structures and have a higher incidence of lymph node metastasis. More than 80% of GCs are adenocarcinomas; they can be categorized into papillary, tubular, mucinous, and signet cell types. Undifferentiated or anaplastic carcinoma, squamous cell carcinoma, and adenosquamous carcinoma represent less common types of GCs, while other types such as

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Types of gallbladder cancer44

Tumor type

Incidence (%)

Adenocarcinoma Undifferentiated or anaplastic carcinoma Squamous cell carcinoma Adenosquamous carcinoma Small cell carcinoma Malignant melanoma Lymphoma Sarcoma Neuroendocrine tumor

80–95 2–7 1–6 1–4 NA NA NA NA NA

NA ⫽ not available.

carcinoid tumors, small cell carcinomas, malignant melanomas, lymphomas, and sarcomas are rare. However, a variety of neuroendocrine tumors of the gallbladder have been described.45 The types of GCs according to the World Health Organization (WHO) histological classification are shown in Table 2.44

in advanced stages. Neural spread, which is reported in 25% to 35% of cases, is a poor prognostic sign, while intraductal spread along the lumen and wall of the ducts is rare and is usually seen in the papillary type of GC.50

Molecular pathology Recent studies describe the presence of K-ras mutations in 20% to 59% of GCs but not in dysplasias or adenomas.51,52 A greater frequency (50%– 83%) of K-ras gene mutations has been reported in GC from patients having anomalous pancreatobiliary duct junction, suggesting that the reflux of pancreatic juice might contribute to the carcinogenesis process.53 Abnormalities of the p53 tumor-suppressor gene are seen in 35% to 92% of GCs.11 Genetic alterations of p53 appear to arise mainly in the last stage of GC. Other early genetic changes include LOH at the 9p21 (CDKN2 gene) and 18q21 (DCC gene) regions.54

Clinical Presentation The mode of spread of GC The pattern of lymph node spread from GC has been described by many authors. Fahim et al46 initially reported 2 different pathways to the superior pancreaticoduodenal lymph node: one was the principal route directly toward the paraaortic lymph nodes situated around the origin of the celiac artery, and the other was a secondary route via the posterior pancreaticoduodenal lymph nodes toward the lymph nodes situated around the origin of the superior mesenteric artery. Ito and Mishima47 proposed 3 pathways of lymphatic drainage from the gallbladder: the cholecystoretroperitoneal, the cholecystoceliac, and the cholecystomesenteric routes. These reports suggest that lymphatic metastases from GC spread widely from some point in the hepatoduodenal ligament toward the area around the head of the pancreas. Tsukada et al48 confirmed this theory using the surgical specimens from radical resections. The overall rate of lymph node metastasis in GC ranges from 54% to 64% and is strongly collated with the depth of invasion.49 Invasion of the tumor into the liver and initial location of liver metastasis to the portion adjacent to the gallbladder is due to the fact that venous drainage from the gallbladder drains into segment IV of the liver by short, direct communicating veins (they directly enter into middle hepatic vein radicals) or by veins accompanying the extrahepatic ducts into the liver (a vein from the gallbladder rarely enters into a portal vein). Vascular invasion is reported in 15% of cases.50 Therefore, removal of a portion of liver is recommended as part of the treatment approach for GC. Macroscopically, the tumor can invade the liver by 2 routes: direct liver bed invasion or via hilum along Glisson’s sheath. Trans-peritoneal spread is common and involves liver, common bile duct, colon, duodenum, pancreas, omentum, and stomach and may manifest as peritoneal carcinomatosis

The vague symptoms associated with primary cancer of the gallbladder make the early diagnosis of the disease difficult.55 GC is largely asymptomatic until the advanced stages of the disease, with gallstones and chronic inflammation being the most commonly associated clinical manifestations.56 In patients with symptoms of acute cholecystitis, generally long-term survival is possible because such patients may be diagnosed at an early stage of the disease.57 Patients with chronic cholecystitis may present with chronic unspecified upper epigastric pain or tenderness, food intolerance, and a sense of fullness. Patients with symptoms of biliary tract disease and those with clinical features of malignancy have extensive disease. Once a patient develops symptoms related to GC, the disease has often progressed beyond the curable state. Oerti et al58 reported that among 18 patients with GC who presented with jaundice, the resectability of the tumor was 0%. In another study, 44% of patients with GC who initially presented with jaundice were associated with unresectable disease.59 The fifth category of symptoms includes a small group of patients with gastrointestinal bleeding or upper gastrointestinal obstruction due to benign manifestations of the tumor outside the biliary tract. Only one third of all GCs are known preoperatively to be malignant growths or are operated on because a tumor is at least suspected, while two thirds of these carcinomas are called “incidental” because they are not suspected before surgery.10

Diagnosis Despite the use of modern imaging techniques, a differential diagnosis between benign and malignant gallbladder lesions is often difficult, especially in patients with small lesions.

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Ultrasound Ultrasound (US) is the most widely used technique in the preoperative study of GC and the standard initial study in patients with upper quadrant pain. Early cancer can be identified as a hypo- or iso-echogenic irregularly shaped lesion, appearing as a subhepatic mass that usually masks the gallbladder.60 The presence of gallstones trapped within the tumor during its growth is a very useful sign of possible GC.61 The thickness of the vesicular wall does not normally exceed 3 mm, and the tumor may present as a partial thickening of more than 1 cm, usually irregular and often asymmetric.62 This finding requires a differential diagnosis with other diseases that may also produce this thickening, such as acute or chronic cholecystitis and hyperplastic cholecystoses. The presence of a mass or polyp with intraluminal growth appears as an intraluminal mass, usually with a diameter of greater than 10 mm, which is not displaced by patient’s movements and has a nodular or smooth shape.63 If the tumor is advanced, US shows a loss of the interface between the gallbladder and the liver. US has a sensitivity of 85% and accuracy of 80% for the diagnosis of GC.61 Colour Doppler ultrasonography is another approach to improve the specificity of US. Komatsuda et al24 suggested that benign tumors have a lower percentage of detectable blood flow compared with malignant tumors. Measurement of the flow rate is also important, with a higher rate for malignant tumors than for benign tumors. Many authors have reported an even higher sensitivity figure with the use of US-guided fine-needle aspiration,64 while endoscopic ultrasonography (EUS) also has been proposed for diagnostic evaluation. EUS may improve diagnosis of GC by predicting the depth of tumor involvement with accuracy, but its usefulness for making a differential diagnosis between benign and malignant lesions remains controversial.28

Computed tomography Computed tomography (CT) can detect gallbladder abnormalities (mass replacing gallbladder, wall thickening, intraluminal polyp), and the extent and stage of tumor. When in mass form, the cancer is usually heterogenous, containing hyperdense areas due to necrosis and unequal uptake, which is preferentially peripheral with necrotic areas.65 Dual-phase spiral CT can even show early uptake in the arterial phase, either peripheral or heterogenous, in the latter cases simulating a hepatic carcinoma.66 In the extension study by CT, special attention must be paid to the detection of infiltration of the liver, bile duct, and other neighboring organs. CT also can reveal the presence of hepatic and peritoneal metastases and lymphatic dissemination.67 Many authors have reported that the sensitivity of CT to detect the extension of GC is low-to-moderate, although its high positive predictive value means that it is useful for determining resectability and assisting treatment planning.68 The use of spiral CT has been proposed as an attempt to improve the diagnostic accuracy of conventional CT, study-

The American Journal of Surgery, Vol 196, No 2, August 2008 ing both local spread and in-depth invasion by the tumor, and for assessing respectability.66 The advantages of spiral CT are lower slice time, shorter inter-slice interval, and optimal utilization of contrast medium.69 The recently developed multidetector CT (MDCT) holds promise for increasing detection of small perivesicular tumor infiltration and minimizing partial volume artefacts and thus improving tumor staging.69 MDCT allows for faster examination with lower collimation thickness and more reliable volumetric reconstructions. CT is known to have limitations for the detection of peritoneal metastasis. MDCT has a sensitivity of 85% to 93% for the detection of peritoneal metastases, in contrast with reported values of 63% to 79% for conventional CT.70

Magnetic resonance imaging There have been reports in the literature describing the usefulness of magnetic resonance imaging (MRI) and fast MRI techniques, including dynamic gadolinium-enhanced MRI and magnetic resonance cholangiopancreatography (MRCP) images, in the evaluation of GC.71 On T1weighted images, the tumor appears as a hypo- or isointense mass, while on T2-weighted images, all the tumor masses are heterogeneously hyperintense. Following contrast administration, all of the tumors show enhancement. MRI is particularly useful for visualizing invasion of the hepatoduodenal ligament, portal vein encasement, and lymph node involvement. The use of MRCP in the evaluation of malignant biliary obstruction has also been reported, providing more detailed information than US or CT.72 Kim et al73 added magnetic resonance angiography (MRA) to MRI in T1-, T2-weighted sequences and MRCP, facilitating the diagnosis of vascular infiltration, which is crucial before attempting curative resection.

Positron emission tomography with fluorine-18 –labeled fluoro-deoxyglucose Positron emission tomography (PET) using fluorine-18 – labeled fluoro-deoxyglucose (FDG) has the potential to demonstrate malignant tumor as an area of tracer accumulation. Its usefulness as a modality in the preoperative diagnosis and management of patients with suspected GC remains unclear. Many authors have reported that FDGPET is useful (sensitivity 78%) in the evaluation of localized or metastatic GC,74 while Koh et al75 reported that this technique provided reliable differential diagnosis, identifying GC with 75% sensitivity, 87.5% specificity, and 81.3% accuracy. FDG-PET is useful for the diagnosis of unsuspected distant metastases and the establishment of node (N) and metastasis (M) staging as part of the treatment planning process.72 The detection of functional changes by FDG-PET can be achieved earlier than the detection of direct or indirect structural changes by CT, so it is reasonable to conclude that is should be performed prior to extended resections. The main shortcoming of FDG-PET is that it is not yet

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widely available for routine clinical use, leading to its incorrect consideration as an expensive examination only for use in relatively restricted clinical situations. For this reason, and because of the low prevalence of GC, there is little information to date on the possible contribution of these procedures to the functional imaging diagnosis of GC.

Cholangiography Among the cholangiographic techniques, endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are the most useful for diagnosing GC and its spread into the biliary tree. In jaundiced patients, ERCP and PTC are useful in localizing the obstruction, facilitating stent placement through the obstruction, establishing a diagnosis via sampling, and planning surgical procedures because they can show tumor growth in adjacent intrahepatic ducts or in the common bile duct.76 ERCP is mainly useful for nonjaundiced patients with biliary symptoms, in the absence of dilated intrahepatic biliary ducts. ERCP also may demonstrate an anomalous pancreatobiliary duct junction, providing the opportunity of brush cytology and biopsy.77

nagin et al80 reported that staging laparoscopy identifies the majority of patients with unresectable hepatobiliary malignancies, significantly improves resectability, and reduces the number of days in the hospital and the total charges. The yield of laparoscopy is greatest for detecting peritoneal metastases, additional hepatic tumors, and unsuspected advanced cirrhosis, but it often fails to identify nonresectability because of lymph node metastases, vascular involvement, or extensive biliary involvement. Patients with unresectable disease that is not detected at laparoscopy most often have locally advanced tumors.78 The advantages of detecting unresectable disease at laparoscopy include a shortened recovery time, improvement of quality of life, and shorter time to initiation of non-operative therapy.

Tumor markers Carcinoembryonic antigen (CEA) and CA 19-9 are traditionally used tumor markers for GC. Their increased presence should raise suspicions of malignancy. CEA concentrations greater than 4 ␮g/L are 93% specific, but only 50% sensitive, while a CA 19-9 concentration higher than 20 U/mL has 79.4% sensitivity and 79.2% specificity.81 Chaube et al82 suggested that CA 125 is one of the important markers of GC: CA 125 concentrations higher than 11U/mL have 64% sensitivity and 90% specificity.

Laparoscopy Laparoscopy can detect small-volume peritoneal disease or liver secondary tumors missed on cross-sectional imaging, although it is less accurate for detecting vascular invasion, lymph node involvement, and extent of biliary spread. Patients with GC frequently have unresectable disease that is not apparent on preoperative imaging studies. Laparoscopy identifies unresectable disease and prevents unnecessary laparotomy in up to a third of patients with GC who have been deemed resectable radiologically.78 Tilleman et al79 reported that sensitivity and negative predictive value of diagnostic laparoscopy for detecting unresectable disease were 60% and 52%, respectively, while diagnostic laparoscopy avoided unnecessary laparotomy in 41% of patients with a malignant proximal bile duct obstruction considered resectable according to conventional imaging studies. Jar-

Table 3

The different staging systems used have been a source on confusion in the assessment of surgical outcomes. The currently used tumor-node-metastasis (TNM) staging system for GCs, developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC),83 is the most widely used and recommended system (Table 3). It is based on the depth of tumor invasion and correlates well with prognosis. Any therapeutic decision in GC must be based on its staging, based on knowledge of the involvement of different layers of the vesicular wall (mucosa, muscle, subserosa, and serosa), infiltration of the liver and/or other neighboring organs, and lymph node and distal dissemination. In this review, we use the version

UICC/AJCC TNM staging system of gallbladder cancer (5th ed)83

Stage 0 Stage I

Tis T1

N0 N0

M0 M0

Stage II Stage III

T2 T3 T1–3 T4 Any T Any T

N0 N0 N1 N0–1 N2 Any N

M0 M0 M0 M0 M0 M1

Stage IVA Stage IVB

Staging

Carcinoma in situ T1a: invades lamina propria or muscle layer T1b: invades the muscle layer T2: invades perimuscular connective tissue T3: perforates the serosa and/or directly invades one adjacent organ (⬍2 cm into liver) N1: metastases in cystic duct, pericholedochal, and/or hilar lymph nodes T4: extends ⬎2 cm into liver and/or into 2 or more adjacent organs N2: metastases in peripancreatic (head only), periduodenal, periportal, celiac, and/or superior mesenteric lymph nodes M1: distant metastases

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Table 4 Stage Stage Stage Stage Stage

0 IA IB IIA IIB

Stage III Stage IV

UICC/AJCC TNM staging system of gallbladder cancer (6th ed)84 Tis T1 T2 T3 T1–3

N0 N0 N0 N0 N1

M0 M0 M0 M0 M0

T4 Any T

Any N Any N

M0 M1

Carcinoma in situ T1: invades lamina propria or muscle layer T2: invades perimuscular connective tissue T3: perforates the serosa and/or directly invades the liver and/or one adjacent organ N1: regional lymph nodes metastases (cystic duct, pericholedochal, hilar, peripancreatic, head, periduodenal, periportal, celiac, and/or superior mesenteric lymph nodes) T4: invades main portal vein, common hepatic artery, or multiple extrahepatic organs M1: distant metastases, including metastases in lymph nodes at the pancreatic body and tail

from 1997 because nearly all published data are based on this classification, although the UICC/AJCC TNM classification has been revised more recently (Table 4).84 The staging system was revised to recognize that locally advanced tumors are potentially resectable for cure and to emphasize the worse prognosis of positive nodal involvement.85 It was also revised because patient outcomes have changed based on new information that was generated since the fifth edition. T2N0 lesions have been downstaged from stage II to stage Ib, T3N0 from stage III to stage IIa, and T1–3N1 to stage IIb from stage III.85 Furthermore, in the sixth edition, the adjacent liver is not considered a metastatic site, the depth of penetration into the liver is not used to determine the tumor (T) classification, and regional node involvement is not separated by site.85

Surgical Management Surgical resection is the only potentially curative therapy for GC. There are 4 groups of patients who warrant discussion: (1) patients with the incidental finding of a gallbladder polyp on imaging; (2) patients with GC that was found at the time of cholecystectomy (laparoscopic or open) for gallstone disease, or on subsequent histologic assessment of the gallbladder after cholecystectomy; (3) patients with GC that was suspected or diagnosed in a symptomatic patient after clinical or diagnostic investigation; and (4) patients with advanced GC (Table 4). Each of the 4 groups will be analyzed in terms of surgical approach or other palliative measures required. Surgical options for patients with GC are summarized in Table 5.

Incidental finding of gallbladder polyp on imaging Polyps that are sessile, solitary and 1 cm or greater in diameter or the finding of an enhancing lesion by contrast CT scan or Doppler showing high-velocity vessel inside a polyp should be deemed as highly suspicious. Polyps that have developed in patients older than 50 years of age, associated with stones or symptomatic, are at higher risk of being malignant or subsequently turning malignant.86,87 The treatment of choice in these patients is laparoscopic chole-

cystectomy. However, when the suspicion of malignancy is high, open exploration, intraoperative frozen section, and preparation for extended resection are required. Patients with fewer than 3 polyps, regardless of size, should be considered for laparoscopic cholecystectomy if the morbidity of resection is minimal, while patients with more than 3 polyps are likely to have pseudotumors and can be safety observed without surgery unless symptoms of biliary colic develop. For low-risk polyps, the common practice is to recommend 6-month follow-up with US, which can stop 2 years later if they remain unchanged.

Incidental finding at open or laparoscopic cholecystectomy or on histologic assessment of the gallbladder after cholecystectomy During the era of open cholecystectomy, the diagnosis of GC is incidentally made in about 27% to 41% of cases during or after cholecystectomy performed for benign biliary disease.88,89 In the age of laparoscopic cholecystectomy, GC is incidentally found in .3% to .5% of cases in Western countries,90,91 and in .8 to .9% in Japan.92 Most of these cases are stages T1 and T2.93 Table 5 cancer

Surgical options for patients with gallbladder

1. Simple cholecystectomy. No further treatment in cases Tis/T1a and in cases T1b with negative surgical resection margins 2. Radical or extended cholecystectomy: removal of gallbladder ⫹ at least 2 cm of the gallbladder bed ⫹ dissection of lymph nodes from the hepatoduodenal ligament behind the second part of the duodenum, head of the pancreas, and the coeliac axis 3. Radical cholecystectomy ⫹ liver resection (segmental or lobar) 4. Radical cholecystectomy ⫹ extensive lymph node (paraaortic) dissection 5. Radical cholecystectomy ⫹ resection of bile duct or pancreaticoduodenectomy 6. Any of the above procedures ⫹ resection of port sites in patients who initially underwent laparoscopic cholecystectomy

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Although laparoscopic cholecystectomy in patients who are at high risk for GC should not be performed, some investigators have stated that the possibility of tumor implantation to the abdominal wall did not increase after laparoscopic surgery.94 It has been reported that pneumoperitoneum with carbon dioxide may promote the dissemination of malignancy,95 while bile spillage may affect prognosis in patients with unsuspected GC.10 Thus it is mandatory to avoid perforation of the gallbladder and bile spillage in the surgical field during laparoscopic cholecystectomy.96 Furthermore, laparoscopic insufflation and manipulation lead to a higher risk of tumor dissemination in the peritoneal cavity and tumor implantation of the port sites compared to open cholecystectomy; it has been reported that the incidence of port-site recurrence increased from 9% in patients without intraoperative gallbladder perforation to 40% in patients with documented perforation.97 In a large international survey, port-site recurrence was seen in 70 of 409 (17.1%) cases with incidental GC over a median period of 6 months following laparoscopic cholecystectomy.90 It was also noted that the stage of the tumor (T1a or higher) or use of protective retrieval bag for the extraction of gallbladder did not prevent port-site metastasis in 8 patients. The presence of GC should be suspected if the cholecystectomy is difficult. All gallbladders must be opened and examined carefully for any suspicious lesions before the abdomen is closed. If a cancer is discovered in this way, it is reasonable for the surgeon to take tissue samples for histology and then terminate the operation. A radical cholecystectomy can be done, with histological confirmation of malignancy as the first step. The surgeon must carefully evaluate the extent of disease and determine if it is appropriate to proceed to a major operation for which the patient has not consented or been prepared. If GC is found on histologic assessment after cholecystectomy, disease management depends on the depth of tumor invasion through the gallbladder wall (T stage), and the involvement of the surgical margins (Figure 2), as these are the 2 major determinants of prognosis; the presence of lymph node metastasis and perineural invasion are also relevant, although information about nodal involvement (N stage) is usually not available. Patients with GC confined to lamina propria (T1a) have excellent prognostic features and can be cured by cholecystectomy alone.98,99 If the tumor invades but does not breaches the muscle layer (T1b), it is suggested that a simple cholecystectomy is adequate, especially if the surgical margins are clear, there is no evidence of lymph nodal spread, and the gallbladder was not perforated at the time of surgery.88,93,98,99 However, it remains a matter of discussion whether this approach is appropriate for T1b tumors because the possibility of lymph node metastasis is 16% (vs 2.5% for T1a tumors)100 and that for lymphatic, venous, and perineural infiltration is up to 50%.101 This is the reason some investigators recommend an extended cholecystectomy as offering better long-term survival.100 –102 Recently, Wakai et al99 found 10-year sur-

259

Figure 2 Treatment algorithm for management approach for patients with GC incidentally discovered at cholecystectomy.

vival for T1b tumors after simple cholecystectomy was 87% and recommended that it should be performed as standard procedure. However, Chan et al103 suggested that these patients should be subjected to a repeat resection of the cystic duct stump or common bile duct resection and biliary reconstruction, if the cystic duct margin is positive. If the tumor has invaded the perimuscular connective tissue but there is no extension beyond the serosa or into the liver (T2), a radical cholecystectomy is necessary. The reasons for performing radical cholecystectomy are that positive margin status is reported to be 24% after simple cholecystectomy for this subgroup of patients104 and that many studies have reported that the incidence of lymph node metastasis may be as high as 39% to 54%,7,105 while the incidences of lymphatic, venous, and perineural invasion are also very high.102,106 Radical (extended) cholecystectomy involves wedge resection of the liver segments IVb and V at least 3 cm in depth from the gallbladder bed, together with regional lymphadenectomy, which includes the nodes of the cystic duct, portal vein, hepatoduodenal ligament, and the liver hilum (first level, N1) and the nodes around the pancreatic head, duodenum, and celiac artery (second level, N2), and excision of the extra-hepatic bile duct with biliary reconstruction.102,107 The laparoscopic port sites should also be excised.93,106 However, many authors suggest that radical operations are not indicated for GC with N2 nodal disease and sampling of nodes should be performed before starting radical resection.108 Kondo et al109 reported extremely poor postoperative survival (1-year survival rate 43% with a median survival of 5.8 months), while others found no 5-years survivors with N2 node metastases.109

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Preoperatively suspected or confirmed GC The correct preoperative diagnosis of GC remains difficult. GCs that have caused symptoms and then been identified on imaging are locoregionally quite advanced. However, more than one third of patients present with obstructive jaundice; many of them may be correctly diagnosed preoperatively. Preoperative investigations and patient parameters (age, clinical status) can determine whether or not the patient is a suitable candidate for radical surgery (Figure 3). The surgical management of T3 and T4 GC is a challenging problem. Survival for these patients is generally poor compared with patients who have early-stage tumors. Radical resection offers the only chance of cure or prolongation of survival. A diagnostic laparoscopy prior to laparotomy may be useful in further staging the extent of disease. Radical excision requires a liver resection involving at the very least segments IVb and V, but a wide central resection of segments IV, V, and VIII or in some instances even a trisegmentectomy may be necessary, depending on the extent of liver involvement.77 However, surgery should not be performed for the purpose of debulking alone; radical surgery should be attempted only if it is possible to achieve a complete resection. Furthermore, para-aortic lymph node metastasis is present in 19% to 25% of these patients. Para-aortic lymphadenectomy does not provide a survival advantage in patients undergoing radical cholecystectomy.109 Reported 5-year survival rates range from 15%– 63% to 7%–25% in patients with T3 and T4 disease treated by radical cholecystectomy, respectively.7,100,110 –112 By contrast, no patients who under-

Figure 3 Treatment algorithm for management approach for patients with GC preoperatively suspected or confirmed.

The American Journal of Surgery, Vol 196, No 2, August 2008 went simple cholecystectomy for T3 and T4 disease survived to 5 years. Direct involvement of colon, duodenum, or liver is not an absolute contraindication for surgery. Extended resections, including extended right hepatectomy (which can be performed when the right portal triad is involved by direct extension of the primary tumor) or combined major hepatic and pancreatic resections such as combined pancreatoduodenectomy with complete lymphadenectomy, have been suggested by several authors.109,113–117 Recent studies also reported that extended operations can improve long-term survival.88,118,119 Toyonaga et al88 reported that radical second resection lengthened the median survival time from 7 to 15 months in a small number of patients with T3 tumors. Frena et al118 reported a 1-year survival rate of 53.8% in a small number of patients with T3 and T4 tumors who were treated radically with major surgery. Finally, Miyazaki et al119 reported that the mean survival of patients with T3 and T4 tumors after curative resection was approximately 2 years, whereas after noncurative resection it was only 4 months. However, this surgical approach remains controversial with regard to the balance between risk and effect on survival and has not been adopted by the majority of surgeons. Furthermore, multiple metastases in the liver are a contraindication to radical cholecystectomy or extended hepatectomy since it is a manifestation of disseminated disease.

Advanced malignancy When there is clinical or radiologic evidence for advanced malignancy, laparotomy for biopsy alone is no longer justified, since percutaneous fine-needle cytology can yield a positive diagnosis in the majority of cases.107 Long-term survival is poor in patients with advanced-stage GC who are not candidates for surgical resection. The objective of palliation should be relief of pain, jaundice, or cholangitis, as well as gastric outlet obstruction and bowel obstruction. Palliative procedures commonly performed for jaundice include Roux-en-Y or jejunal loop anastomosis with common hepatic duct, left duct, segment III, or Longmire bilioenteric anastomosis, while gastrojejunostomy is the preferable procedure to relieve symptoms of gastric outlet obstruction.77 The segment III biliary by pass (the anastomosis stays clear of the hepatoduodenal ligament, where progression will ultimately cause repeat obstruction) has been reported on 41 patients by Kapoor et al120 with an 87% success rate and 12% 30-day mortality rate. Currently, a biliary stent has been proposed as the appropriate palliation.121 The goal of this management is to relieve symptoms related to obstructive jaundice, prevent cholangitis, and improve quality of life. In particular, the metallic stent is associated with a lower incidence of complications, remains patent longer, and is more cost-effective, although it is initially more expensive.121 It is also possible that a percutaneous transhepatic insertion of the metallic stent or an endoscopic approach provides better palliation.

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However, endoprosthesis insertion carries a significant morbidity and mortality rate due to tube blockage or displacement.107

Adjuvant Chemoradiotherapy The high incidence of locoregional spread and recurrence in patients with GC makes adjuvant chemotheraphy and/or radiotherapy a very rational and attractive therapeutic option. Many studies include attempts at therapy with intraoperative or external-beam radiotherapy and chemotheraphy including 5-fluorouracil (5-FU) and/or mitomycin C. However, GC is generally considered relatively radioresistant, although the studies are too few and too small to allow any effective judgement of the value of various types of radiotherapy. Adjuvant chemotheraphy and/or radiotherapy has not altered the dismal prognosis of patients with GC but may marginally improve survival. Chao et al122 reported no survival benefit between 2 groups of patients who received and denied adjuvant chemotheraphy and/or radiotherapy, respectively. Todoroki et al123 used intraoperative radiation therapy after complete resection for stage IV GC; a 10% 3-year survival for patients who were treated with adjuvant radiotherapy was reported compared with 0% for those underwent resection only. On the other hand, Oswalt and Cruz124 and Morrow et al125 showed an improved median survival among patients who received postoperative chemotheraphy and/or radiotherapy. Similarly, in a study by Memon et al,4 patients who received adjuvant chemotheraphy for stage IV disease had a significantly longer mean survival compared with patients who did not receive this treatment, while Makela and Kairaluoma126 demonstrated that superselective intra-arterial chemotheraphy with mitomycin for GC had a 48% response rate and the responder had a significantly better survival (34 months) compared to the non-responders (8 months). In addition, Bode et al127 and Misra et al128 reported that the median survival of GC patients treated with surgery and intra-arterial chemotherapy with mitomycin C alone or mitomycin C and fluorouracil was better compared to the results of surgical treatment alone. However, the drugs toxicity limits the use of intraarterial chemotherapy and requires careful monitoring to prevent toxic reactions. Goldberg and Neifeld129 suggested that cryotherapy to the gallbladder fossa concomitantly with portal lymph node dissection may represent a safe and effective alternative to hepatic resection in the treatment of GC, while oncolytic adenoviral therapy and chemotherapy with gemcitabine and cisplatin have also been proposed.130,131 In particular, oncolytic therapy through the use of replicative viral agents offers new hope for a better outcome in GC treatment, although only a few studies have addressed using these agents.132,133 No follow-up is an appropriate recommendation for the patients with GC because most of them are incurable due to

261 their recurrent disease. The exception to this is to identify early recurrence only if patients with GC are included in a clinical trial to investigate the value of new therapy.

Prognosis At present, the therapeutic outcome of treatment for GC is poor. The prognosis depends on the stage of the tumor, but generally the prognosis remains extremely poor, because it is a highly malignant tumor, with fast, clinically recognizable disease indications. The 5-year survival for all stages of GC is about 5%.6,7 The incidental GCs show a minimally better prognosis, because they are often detected earlier, without severe clinical signs. The median survival for suspected carcinomas is 9.2 months, and for incidental carcinomas is 26.5 months.10 The data from the international medical literature for patients with T1 tumors show survival between 60% and nearly 100% following a simple and extended cholecystectomy.134 The survival of patients with T2 tumors varies, depending on whether the lymph nodes are positive or not, whether there was a re-operation (second radical procedure), and whether the patients had a negative margin or even the subserosal invasion was deeper than 2 mm. Patients with T2N0M0 who did not undergo a second radical operation have a survival between 10% and 22%, while after a radical resection, survival rates of 60% to 80% are described.105 The survival for patients with T3 tumors is 15%,135 while the outcome for stage T4 patients remains disappointing. For example, Lai et al136 reported that in their series all patients died within a few months with the exception of 1 patient who survived for 16 months. T3 and T4 are mostly systemic disease, because, for example, accidental intraoperative opening of the gallbladder and the resulting loss of bile liquid is very common and therefore the prognosis of both stages is fatal.

Conclusions GCs remain difficult tumors to diagnose and to treat effectively. GC is a highly lethal and aggressive disease with dismal prognosis in advanced stages. Early diagnosis is important in patients with cholelithiasis or other forms of chronic inflammatory conditions of the gallbladder. In patients with nonspecific upper abdominal symptoms, an US screening for abnormalities in the gallbladder wall may result in early detection, and CA 19-9 serum determination may heighten awareness of cancer in these patients. GC also should be suspected in patients with difficult cholecystectomy. Recent surgical results for cancers of the gallbladder provide some optimism for the possibility of cure, although the surgery involved is technically demanding and should be performed in specialist centers. Increased awareness of the presence of cancer and the understanding of appropriate management are important for improved outcome. Unfor-

262 tunately, most patients present with advanced disease and should be considered for palliative treatment. The use of interventional radiology and endoscopy has considerably improved our ability to obtain successful biliary drainage in patients with unresectable tumors. Modern chemotherapy regimens may have an increasing role, and need to be tested in clinical trial settings, while the value of radiotherapy remains unproven.

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