Controversies regarding the proper surgical management

Currently, there are multiple controversies regarding the proper surgical management of gallbladder cancer: choice of initial procedure for preoperatively suspected gallbladder cancer, timing of re-resection, extent of resection for T1b or greater lesions (including number of lymph nodes needed, extent of parenchymal resection, and need for routine excision of the common bile duct), and the appropriateness of the minimally invasive approach. Although laparoscopic cholecystectomy was one of the first minimally invasive procedures of the gastrointestinal tract and still one of the most common, the suspicion or diagnosis of gallbladder cancer has been considered a contraindication to laparoscopy. Regardless, most gallbladder cancers are diagnosed after routine laparoscopic cholecystectomy; when found to be a T1a lesion, the therapeutic management is considered complete. When the postoperative pathologic examination, however, reveals a T1b to T3 lesion, most patients are referred to tertiary oncology centers and undergo open re-resection. Patients found to have T4 lesions or metastatic disease are considered inoperable and only offered palliative chemotherapy. Neoadjuvant chemoradiation is considered for large T2 lesions that would warrant a formal hepatectomy in an effort to decrease the tumor burden, for all T3 lesions, and when there are concerns for bile leakage during initial cholecystectomy.

Preoperatively suspected gallbladder cancer

When patients are found to have gallbladder polyps or mass greater than 1 cm or less than 1 cm with the presence of blood flow, porcelain gallbladder, or evidence of invasion into the gallbladder hepatic parenchymal bed, gallbladder cancer should be suspected. Currently, at most centers, when there is no evidence of metastatic disease or concerns for a T4 lesion, most patients undergo a laparoscopic cholecystectomy followed by either intraoperative frozen-section analysis and open completion radical cholecystectomy at the same operation or a second operation after final histopathologic review.

Advent of the laparoscopic approach

Surgeons have been reluctant to apply minimally invasive techniques to the surgical management of gallbladder cancer because of the perceived difficulty of laparoscopically dissecting tumors off the structures of the portal triad. As a result, laparoscopic radical cholecystectomy has been one of the last minimally invasive procedures performed. Gumbs and colleagues reported the first laparoscopic radical cholecystectomy in 2009 on a patient with the preoperative suspicion of gallbladder cancer due to a 4-cm mass seen on abdominal ultrasound and cross-sectional imaging. Despite a negative preoperative serum immunoglobulin G4 (IgG4) level, the postoperative diagnosis was consistent with autoimmune cholecystitis. Nonetheless, the patient was discharged home tolerating a regular diet on the second postoperative day.

The next patient with the preoperative suspicion of gallbladder cancer was found to have a 7.5-cm malignant mass in the dome of the gallbladder, with intraparenchymal invasion during the laparoscopic radical cholecystectomy; as a result, a formal resection of hepatic segments IVB and V was required to obtain an R₀ resection. In addition, the cystic duct stump at the confluence with the common bile duct was found to have disease. A laparoscopic common bile duct excision was then performed and the biliary tree reconstructed with a laparoscopic Roux-en-Y choledochojejunostomy. Because of the success with these patients, we began to approach patients who had undergone previous cholecystectomy and were found to have gallbladder cancers.

Postoperatively diagnosed gallbladder cancer

The need for re-resection following an incidentally diagnosed gallbladder cancer depends on the final pathologic stage of the tumor. By definition, T1a tumors only invade the lamina propria. A cholecystectomy with negative margins done laparoscopically or by open techniques is considered curative because re-resection of the gallbladder fossa with or without lymphadenectomy has never been proved to yield a survival benefit. Re-resection, however, is advised in patients with T1b to T3 tumors because of improved overall survival. Patients with incidentally diagnosed gallbladder cancer often have a better prognosis because most are early lesions (T1 to T2). Patients found to have incidental gallbladder carcinomas who undergo re-resection may actually have improved survival compared with those with nonincidentally diagnosed cancer. T2 lesions make up the majority (67%) of incidentally diagnosed gallbladder carcinomas and are associated with a 5-year survival rate of greater than 60%, compared with less than 20% for those treated with cholecystectomy alone. Patients with T3 disease, which is defined as a tumor that invades into the serosa and/or the liver and/or an adjacent organ, are at a higher risk for peritoneal carcinomatosis. Formal re-resection and hepatoduodenal lymphadenectomy may provide a survival benefit in patients without evidence of peritoneal disease. Patients with improperly treated T3 disease have a 5-year survival rate of 0 to 15% compared with 25% to 65% for T3 patients who undergo completion radical cholecystectomy re-resection. The extend of liver resection for gallbladder malignancy is still ill defined.

Because of the authors’ success with these patients and the ability to spare patients unnecessary laparotomy, all resectable patients with preoperatively suspected gallbladder cancer and patients found to have T1b to T3 disease after cholecystectomy are now approached laparoscopically.

Operative indications

Operability in gallbladder cancer relies heavily on preoperative staging and considerations of findings during the initial laparoscopy or as part of a preoperative staging workup. The American Joint Committee on Cancer (AJCC) in its seventh edition has established subcategories for stage IV gallbladder cancer. Stage IVA is defined by tumor invasion into the main portal vein, the hepatic artery, or two or more extrahepatic structures. The presence of metastases to the periaortic, pericaval, or superior mesenteric artery or celiac nodes or of distant metastases further defines stage IVB (Table 15-1). As mentioned previously, the extent of liver resection needs strong consideration and is controversial, with differing opinions regarding the suitability of nonanatomic resections of the gallbladder bed versus complete resection of segments IVB and V and even extended right hepatectomy (segments IV to VIII). We consider major hepatectomy or even extended hepatectomy only when this is necessary to achieve an R₀ resection because there has been no conclusive difference noted in overall survival between minor and major hepatectomy.

Table 15-1 TNM Staging of Gallbladder Cancer

Nodal disease stretching down the portal chain posterior to the pancreas or duodenum may present a challenge. For disease that is not invading vascular structures, dissection is often achieved satisfactorily; however, larger nodes may not be removed successfully without a pancreatoduodenectomy. This must be taken with due caution in terms of morbidity and mortality when performing such a procedure allied with a radical cholecystectomy.

Powered analysis suggests that involvement of the common bile duct is associated with advanced T stage and is an independent prognostic factor in survival. Positive margins at the cystic duct mandate further resection of the common bile duct to achieve R₀ resection, which, although a poor prognosticator, is associated with a better survival outcome than R₁ resection.

Preoperative evaluation

Routine preoperative workup includes chest radiography, electrocardiography (ECG), serum complete blood count, chemistries, liver function studies, and serum tumor markers consisting of carcinoembryonic antigen and CA 19-9 levels. In addition, serum IgG4 levels are measured routinely in all patients before surgery to rule out the presence of autoimmune cholecystitis. Unfortunately, as noted previously, this test has a significant false-positive rate. The indocyanine green test is routine in Asia because the high rate of hepatitis-related cirrhosis may influence the extent of hepatic resection. All formal hepatectomies must be assessed for residual liver volume and Child-Pugh classification and should be followed by pathologic examination for underlying liver cirrhosis grade, especially if the liver is not chemotherapy naïve.

Ultrasound is limited in the diagnosis of early lesions and as such is unreliable for staging. In some 20% to 30% of cases, gallbladder cancer may present as an asymmetrical wall thickening that has an expanded differential diagnosis ranging from cholecystitis, adenomyomatosis, acute hepatitis, or portal hypertension to congestive heart failure. Gallbladder cancer arising on a background of chronic inflammation certainly makes radiologic interpretation more difficult. Asymmetrical wall thickening with persistent arterial enhancement or isodensity during the hepatic venous phase should, however, heighten suspicion. In cases in which a mass-occupying lesion is noted, as occurs in some 40% of patients, ultrasound that shows a heterogenous and hypoechoic tumor is classic.

Although ultrasound is often the first imaging technique performed in those undergoing cholecystectomy for unsuspected gallbladder cancer, high-resolution imaging in the form of computed tomography (CT) or magnetic resonance imaging (MRI) is most often used to help identify residual tumor burden or metastatic disease. CT scan with intravenous contrast is used to delineate the hepatic vasculature and rule out evidence of vascular invasion, such as portal vein or hepatic arterial narrowing or frank invasion. Abdominal MRI with gadolinium is used in an effort to ascertain the extent of intraparenchymal involvement. In cases of recent cholecystectomy, it may be difficult or impossible to differentiate hepatic invasion from enhancement because of scarring from the recent surgery.

The role of [18]F-fluorodeoxyglucose positron emission tomography (FDG-PET) in gallbladder cancer is still in flux. Because gallbladder cancer is highly PET avid, studies have suggested that FDG-PET may change the operative decision in 25% of cases. In up to 50% of cases of incidentally found gallbladder cancer, metastatic spread was shown by FDG-PET. Although this is highly suggestive of a role for FDG-PET, false-positive results may be noted in areas of inflammation from recent laparoscopic cholecystectomy, with recent data also noting FDG-PET to have a negative predictive value of 65%, suggesting a greater extent of residual disease that might be missed. It may be that the role of FDG-PET is best served to rule out distant spread, whereas residual disease is best assessed by intraoperative laparoscopic ultrasound and reexploration.