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Surgical management of gallbladder cancer

Surgical management of gallbladder cancer
Literature review current through: Jan 2024.
This topic last updated: Oct 27, 2022.

INTRODUCTION — Gallbladder cancer is the most common biliary tract malignancy but accounts for only 4000 new cancer cases in the United States each year. Gallbladder cancer is one of the few cancers that are more common in women than men, with an annual incidence of 1.4 per 100,000 population [1].

For patients with early-stage disease, surgery alone can provide cure. Unfortunately, fewer than 10 percent of symptomatic patients and only 20 percent of patients diagnosed incidentally with cholecystectomy have early-stage gallbladder cancer.

The surgical management of gallbladder cancer is reviewed in this topic. Other related topics are discussed separately:

Clinical evaluation and diagnosis of gallbladder cancer – (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis".)

Management after surgical resection of gallbladder cancer – (See "Prognosis and adjuvant treatment for localized, resected gallbladder cancer".)

Palliative management of advanced-stage gallbladder cancer – (See "Treatment of advanced, unresectable gallbladder cancer".)

Management of cholangiocarcinoma – (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma".)

GALLBLADDER ANATOMY AND PHYSIOLOGY — The gallbladder is a small, pear-shaped organ that is located inferior to the margin of the right lobe of the liver (figure 1).

The gallbladder is divided into distinct segments: the fundus, body, infundibulum, and neck [2].

The fundus is the expanded end of the gallbladder that projects away from the margin of the liver. It is anatomically associated with the anterior abdominal wall and hepatic flexure of the colon.

The body of the gallbladder is attached to the liver by loose connective tissue superiorly. Inferiorly, the free margin abuts the duodenum and transverse colon. Superiorly, it is anatomically associated with segments IV and V of the liver (figure 2).

The neck of the gallbladder extends from the infundibulum to the cystic duct. Some authors use the terms neck and infundibulum synonymously.

The cystic duct joins the common bile duct along its course from the liver to the duodenum. The level of the juncture and course of the cystic duct can vary (figure 3).

The gallbladder is supplied by the cystic artery, which is a branch of the right hepatic artery. The cystic artery courses along the cystic duct and divides at the neck of the gallbladder into superficial and deep branches, which supply the anterior/inferior and posterior/superior aspects of the gallbladder, respectively. The cystic artery or an accessory cystic artery can arise from the right hepatic, left hepatic, or common hepatic artery (figure 4). The venous drainage of the gallbladder generally parallels the course of the arteries draining into the cystic vein, which drains into the gallbladder fossa directly into the middle hepatic vein (ie, it does not accompany the cystic artery).

The sympathetic nerves that supply the gallbladder are derived from the ninth thoracic segment and from the celiac plexus. The phrenic nerve on the right contributes a few somatic fibers.

The primary function of the gallbladder is the storage of bile, a fluid produced by the liver that aids with the digestion of fat. Bile is released into the duodenum in response to cholecystokinin (CCK), the major hormone responsible for gallbladder contraction and pancreatic enzyme secretion. CCK is produced in discrete endocrine cells that line the mucosa of the small intestine. (See "Physiology of cholecystokinin".)

Lymphatic drainage — The lymphatic drainage of the gallbladder is via several pathways and does not always follow a predictable drainage pattern [3-6]. In some cases, lymph nodes associated with gallbladder cancer can first be seen posterior to the pancreas or portal vein [3]. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'TNM staging system'.)

The cholecysto-retropancreatic pathway is the principal pathway and drains along the cystic duct (cystic nodes), common bile duct (pericholedochal nodes, station 12b), portal vein (portocaval node, station 12p), and posterior pancreas (superior retropancreatic node, station 13) to the paraaortic region (paraaortic nodes, station 16). In one study, this route was stained in 95 percent of patients [4].

The cholecysto-celiac pathway, the next most common pathway, drains along the cystic duct (cystic nodes) and medially along the hepatoduodenal ligament (station 12a) superior to the head of the pancreas to the portal vein (station 12), hepatic artery (station 8), and celiac axis (station 9). Among lymph nodes along this route, one study found that the posterior common hepatic node was most frequently stained (45 percent) [4].

The cholecysto-mesenteric pathway drains to the left in front of the portal vein (station 12) connecting with the nodes at the root of the mesentery (superior mesenteric nodes, station 14).

A hilar route that ascends directly toward the hepatic hilum has been described in an animal model [6].

The cystic duct, common bile duct, hepatic artery, and portal vein lymph nodes are considered locoregional according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual (2017) [7]. Tumor involvement of the paraaortic, paracaval, superior mesenteric artery, and celiac lymph nodes is considered distant metastasis. Thus, during potentially curative surgery for gallbladder cancer, lymphadenectomy is generally not performed beyond the porta hepatis and hepatoduodenal ligament. (See 'Lymph node dissection' below.)

STAGING — The American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) staging classification of gallbladder cancer is the preferred classification in the United States, and the latest (8th) edition is shown here (table 1). Other classification schemes and the distribution of disease by stage are discussed elsewhere. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'Staging'.)

The risk of distant metastases increases as the T stage increases. In one review, peritoneal and/or liver metastases were present in 16, 42, and 79 percent of patients with T2, T3, and T4 disease, respectively [8].

Lymphatic metastases are found in 35 to 80 percent of patients with ≥T2 disease at diagnosis [9-13]. Locoregional nodes, including those along the cystic duct, common bile duct, hepatic duct, and/or portal vein, can be removed by a lymph node dissection with or without excision of the extrahepatic bile duct. However, involvement of paraaortic, paracaval, superior mesenteric artery, and/or celiac artery nodes is considered distant metastatic disease and incurable with surgery, even with a lymph node dissection.

Due to advanced disease, only 15 to 60 percent of patients with gallbladder cancer are candidates for resection at time of diagnosis [14,15]. Thus, staging prior to considering resection is important and can be accomplished using a combination of cross-sectional imaging and diagnostic laparoscopy. (See 'Evaluation for resectability and staging' below.)

GALLBLADDER CANCER DIAGNOSED BEFORE SURGERY — Gallbladder cancer may be diagnosed preoperatively, intraoperatively at the time of surgical exploration for abdominal symptoms attributed to another disease process, or postoperatively upon examination of the gallbladder specimen, typically removed for symptomatic cholelithiasis. In contemporary series, only approximately 50 percent of gallbladder cancers are recognized before surgery [16,17].

Patients with right upper abdominal pain, and particularly those with jaundice or signs of duodenal obstruction, are more likely to have locally advanced disease and to be identified preoperatively. Unfortunately, only 10 to 25 percent of such patients are amenable to a curative resection [8,16]. As such, patients diagnosed or suspected of having gallbladder cancer must undergo an evaluation to determine if radical abdominal surgery is warranted (algorithm 1).

Evaluation for resectability and staging — The minimal staging evaluation of patients with suspected or proven gallbladder cancer includes cross-sectional imaging and diagnostic laparoscopy [18].

Cross-sectional imaging — For patients who present with an ultrasound-detected gallbladder mass, we recommend:

Abdominal computed tomography (CT) with dual-phase contrast to rule out involved extraregional lymph nodes, vascular invasion, liver spread (direct extension or metastases), or peritoneal implants (image 1). Multiphase CT also allows for accurate assessment of tumor extent and direct involvement of the hepatic arteries, portal veins, and adjacent organs (duodenum, colon, bile ducts).

Abdominal magnetic resonance imaging (MRI) with contrast to evaluate the liver parenchyma and bile duct.

Chest CT with or without contrast to rule out distant metastasis to the lung or pleura.

The routine use of integrated fluorodeoxyglucose positron emission tomography (PET)/CT scan for staging is controversial, but it may be considered when CT/MRI findings are equivocal for distant sites of metastases or lymphadenopathy beyond the portal area [19].

The sensitivity of these modalities in the diagnosis and staging of gallbladder cancer is discussed elsewhere. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'Diagnostic evaluation'.)

Staging laparoscopy — Gallbladder cancer frequently involves regional lymph nodes or extends directly to adjacent structures such as the liver, bile ducts, stomach, duodenum, pancreas, colon, omentum, or abdominal wall. Such findings may preclude curative resection but may not be detectable by preoperative imaging studies such as CT or MRI.

Diagnostic staging laparoscopy frequently identifies metastatic disease or other findings that contraindicate tumor resection [15,20-23]. As an example, in a large prospective study of 409 patients undergoing staging laparoscopy for gallbladder cancer, 23 percent of patients had disseminated disease (liver surface disease or peritoneal deposits) [15]. Based on the high incidence of positive findings, staging laparoscopy is recommended prior to laparotomy for all suspected or proven gallbladder cancers >pT1b.

If available, laparoscopic ultrasound should be employed as an adjunctive imaging method at the time of staging laparoscopy to look for satellite lesions in the liver and define the location of the gallbladder tumor, the relationship of the tumor to surrounding blood vessels, and the likelihood of attaining an adequate margin of liver [24]. (See "Diagnostic staging laparoscopy for digestive system cancers", section on 'Laparoscopic ultrasound'.)

The general principles of diagnostic staging laparoscopy for digestive malignancies are discussed elsewhere. (See "Diagnostic staging laparoscopy for digestive system cancers".)

Unresectable disease

Absolute contraindications to resection

Liver metastases.

Peritoneal metastases.

Malignant ascites.

Tumor involvement of paraaortic, paracaval, superior mesenteric artery, and/or celiac artery lymph nodes. Such involvement is considered distant rather than locoregional metastatic disease and therefore incurable [7]. (See 'Staging' above.)

Extensive involvement of the hepatoduodenal ligament by tumor either directly or through lymph node involvement.

Encasement or occlusion of major vessels (eg, common hepatic artery or main portal vein) by tumor.

Direct involvement of the colon, duodenum, or liver does not represent an absolute contraindication. Given that the majority of patients with gallbladder cancer who present with preoperative jaundice will have disseminated disease, such patients should undergo multidisciplinary evaluation before surgery is offered [25,26].

Relative contraindications to resection

Preoperative jaundice is considered a relative contraindication to radical resection of fundus-based gallbladder cancer [18].

Perihilar-type gallbladder cancer arising from the infundibulum or cystic duct typically presents with jaundice. In this situation, jaundice should not be considered a contraindication to operative resection.

Overall survival was shorter among patients who presented with jaundice (hazard ratio [HR] 2.21, 95% CI 1.64-2.97); patients with jaundice were less likely to have resectable disease due to extensive tumor involvement of the hepatoduodenal ligament (odds ratio 0.27, 95% CI 0.17-0.43), and jaundiced patients had higher odds of postoperative morbidity, bile leak, and postoperative liver failure versus nonjaundiced controls [27]. In at least one series, the few patients who underwent surgery because they appeared to have potentially resectable disease by radiographic staging had a median length of disease-free survival of only six months, and there were no disease-free survivors at two years [28].

Treatment for unresectable disease — Patients found to have contraindications to resection based upon preoperative imaging, laparoscopic staging, or intraoperative exploration because of major encasement of vascular structures should be referred for chemotherapy. There is no role for a palliative noncurative radical surgery, for the purpose of debulking.

Some patients with locally advanced but nonmetastatic gallbladder cancer may be rendered potentially resectable after initial chemotherapy or chemoradiotherapy, but the frequency with which this occurs is low. Few data are available on long-term outcomes after neoadjuvant chemotherapy for gallbladder cancer. A systematic review concluded that there was insufficient evidence to support the routine use of neoadjuvant therapy in advanced gallbladder cancer [29]. Importantly, subsequent attempts at resection following neoadjuvant therapy should be undertaken only if it is possible to achieve a complete, potentially curative resection. This subject is discussed in detail elsewhere. (See "Treatment of advanced, unresectable gallbladder cancer", section on 'Local treatment for locally advanced non-metastatic disease'.)

Resectable disease — Once peritoneal metastatic disease and other absolute contraindications to attempted resection have been ruled out with cross-sectional imaging and diagnostic laparoscopy, the surgeon can proceed with resection. Surgery is the only potentially curative therapy for gallbladder cancer [30,31].

Surgical treatment of gallbladder cancer involves removal of the gallbladder (cholecystectomy) typically with a rim of liver tissue (extended cholecystectomy), except in T1a disease, and may include bile duct resection, lymph node resection, more extensive liver resection, or resection of involved adjacent organs, depending upon the Tumor, Node, Metastasis (TNM) stage of the tumor (table 1) [32]. General surgical approaches by tumor stages are presented here; technical details are discussed in the subsequent sections. (See 'Resection techniques' below.)

Early T stage diseases — Gallbladder cancers that are confined to the wall of the gallbladder (ie, stage 0, I, or II; Tis, T1, or T2 (table 1)) are potentially resectable with curative intent. For patients with a gallbladder cancer that extends beyond the mucosa (ie, >T1a), some but not all studies link better outcomes with more radical surgery [11,30,33-42]. However, randomized trials comparing simple cholecystectomy with radical surgery for gallbladder cancer have not been performed; all available studies are retrospective reports.

T1a — Simple cholecystectomy alone is felt to be adequate for patients with tumors that are limited to the lamina propria (T1a). Cure rates following simple cholecystectomy range from 73 to 100 percent in case series [43-48]. (See 'Simple cholecystectomy' below.)

T1b — Patients with stage T1b disease benefit from a more radical approach, given that T1b tumors are associated with a higher incidence of lymph node metastases compared with T1a tumors (15 versus 2.5 percent) [33,34,44,45,47,49]. Some investigators have shown a median survival advantage of over three years for extended versus simple cholecystectomy for T1b cancers (9.85 versus 6.42 years, respectively) [50]. Thus, extended cholecystectomy (cholecystectomy including adjacent liver tissue from segments IVb and V) should be performed for medically fit patients who have tumors that invade the muscular layer (T1b). And yet, a retrospective study of 464 patients from the National Cancer Database (2004 to 2012) showed that fewer than 50 percent of patients with T1b gallbladder cancer received extended cholecystectomy, and among those who did, 15 percent had positive lymph nodes [51]. Failure to perform extended cholecystectomy risks incomplete staging and thus undertreatment (omission of adjuvant chemotherapy) of those with T1b gallbladder cancer. (See 'Extended cholecystectomy' below.)

T2 — Extended cholecystectomy should also be performed in patients with a T2 tumor [52,53]. T2 tumors invade the perimuscular connective tissue without involvement of the serosa. In the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging manual (2017) (table 1), T2 gallbladder cancers are subdivided into T2a (peritoneal) and T2b (hepatic) depending on the invasion site. T2b disease generally has worse prognosis than T2a disease. Some authors have suggested that extended cholecystectomy should be mandated in patients with T2b (hepatic) but not T2a (peritoneal) disease based on survival benefit [54]. This approach, however, is not universally accepted, and the standard of care remains extended cholecystectomy for all resectable T2 disease [55].

The need to perform a more aggressive resection is supported by the high rate of residual disease discovered on reresection for T2 disease discovered incidentally. In a retrospective study of six major hepatobiliary centers, upon reresection of T2 tumors found incidentally, residual disease was found in 57 percent of the patients at any site; lymph nodes were involved in 31 percent, and the liver was involved in 10 percent [56]. Lymph node metastases have been seen in up to 62 percent of patients with T2 disease [57]. Given the high rate of residual disease seen after reresection of T2 disease, it is not surprising that high rates of positive margins (11 out of 25 in one study [48]) and high rates of local recurrence (40 percent) are found in patients with T2 disease treated with simple cholecystectomy alone [58].

Whether T2 gallbladder cancer should be resected with a segmental resection of segments IVb and V or a wedge resection is debated [59,60]. A propensity score-matched retrospective study associated segmental resection with improved disease-free survival (hazard ratio 0.708, 95% CI 0.51-0.99), but not overall survival, compared with wedge resection [61]. However, patients undergoing segmental resection incurred more complications (29 versus 9 percent) and a longer hospital stay (17 versus 19 days).

Locally advanced or node-positive diseases — In the past, surgeons were reluctant to operate on patients with locally advanced (T3/4) gallbladder cancer because of an overall poor prognosis. Although some series document poor survival even with extended resection [62], support for radical surgery in patients with T3 and even T4 disease has increased with the publication of retrospective reports indicating long-term survival in 15 to 63 percent and 7 to 25 percent of patients, respectively [8,11,33,34,44,63-68].

Some groups advocate even more extensive resection involving hepatectomy, pancreaticoduodenectomy, colectomy, and even nephrectomy for patients with higher T stage but potentially resectable disease. A median survival time of 17 months with a 2 percent mortality rate has been reported [35]. Although long-term survivors are reported, morbidity and mortality rates are high (48 to 54 percent and 15 to 18 percent, respectively). A study of 79 major hepatectomies alone and 38 major hepatectomies combined with pancreaticoduodenectomy found longer survival associated with the former (32 versus 10 months) and higher morbidities and mortalities associated with the latter [69].

T3 — T3 tumors invade through the serosa of the gallbladder and directly invade the liver and/or one other adjacent organ that normally contacts the gallbladder (eg, stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile duct). For T3 tumors, an extended cholecystectomy en bloc with the involved adjacent organ may be performed but has not been associated with improved survival in Western reports [38]. Thus, radical surgery such as major hepatic resection is appropriate to clear disease when necessary but not mandatory in all cases. (See 'Hepatic resection' below.)

T4 — T4 tumors are generally locally unresectable due to vascular invasion of the main portal vein or hepatic artery or involvement of multiple adjacent extrahepatic organs or structures. Curative resection may be possible in selected patients with stage IVa disease (T4, N0-1, M0), though this approach is most commonly futile given the frequent coexistence of metastatic disease. N2 or M1 diseases are distant metastasis and not curable. (See 'Unresectable disease' above.)

Node-positive — For patients with tumor involvement of locoregional lymph nodes (cystic duct, common bile duct, hepatic artery, or portal, and portal vein), five-year survival rates from 28 to 60 percent are reported with radical resection [44,64,70].

Results with radical lymphadenectomy are less favorable if the extent of nodal disease is beyond that of the hepatoduodenal ligament, posterosuperior pancreaticoduodenal area, and along the common hepatic artery [34,70]. If preoperative fine needle aspiration confirms involvement of a lymph node beyond the locoregional nodes, the patient is not curable; thus, surgery should be performed only for palliation of specific problems. (See 'Unresectable disease' above and 'Palliative procedures' below.)

GALLBLADDER CANCER DIAGNOSED DURING GALLBLADDER SURGERY — Patients with early, invasive, potentially curable gallbladder cancer are often asymptomatic or may have nonspecific symptoms that mimic or are due to cholelithiasis or cholecystitis. Because the symptoms are nonspecific, gallbladder cancer may not be suspected preoperatively. Gallbladder cancer may be identified or strongly suspected at surgical exploration [15,16]. Therefore, it is important to have a plan for identifying and managing gallbladder cancer during the course of a routine laparoscopic or open cholecystectomy [16].

The surgeon should maintain a high index of suspicion for gallbladder cancer in patients with risk factors such as calcified (porcelain) gallbladder, gallbladder polyps, congenital biliary cysts, anomalous pancreaticobiliary junction, or longstanding chronic infection. A risk-score model has been proposed to predict incidental gallbladder cancer based on age, sex, previous cholecystitis, and either jaundice or acute cholecystitis [71]. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'Risk factors' and "Porcelain gallbladder".)

If an obviously malignant lesion is encountered intraoperatively during laparoscopic cholecystectomy, it is best not to sample the lesion laparoscopically, to reduce the hazard of peritoneal seeding. Intraoperative options for managing a suspected gallbladder cancer depend upon the experience of the operating surgeon with complex hepatobiliary surgery.

Surgeons experienced in hepatobiliary surgery — If the surgeon is experienced in complex hepatobiliary surgery, the cholecystectomy should proceed as usual, and the specimen should be sent for a frozen section of the suspicious area of the gallbladder. If the frozen section is positive for malignancy, the procedure should be converted to open, and an extended cholecystectomy is carried out. The indications for performing extrahepatic bile duct resection or lymph dissection are the same as for other gallbladder cancer surgeries. (See 'Bile duct resection' below and 'Lymph node dissection' below.)

Surgeons inexperienced in hepatobiliary surgery — For surgeons who are unfamiliar with complex hepatobiliary surgery, closing the incisions with or without simple cholecystectomy and referral to a more experienced surgeon or center is appropriate. In a small retrospective review, no significant differences in survival were found comparing six patients who underwent immediate open conversion and radical resection with 33 patients who were referred to another center for resection [20]. Patients will undergo further evaluation and treatment as outlined in the next section. (See 'Gallbladder cancer diagnosed after gallbladder surgery' below.)

GALLBLADDER CANCER DIAGNOSED AFTER GALLBLADDER SURGERY — A common scenario leading to a diagnosis of gallbladder cancer is the return of a final pathology report indicating gallbladder cancer in a resected gallbladder specimen [20,72,73]. Incidental gallbladder cancer is found in 0.25 to 1.5 percent of patients undergoing laparoscopic cholecystectomy [16,20,43,72,74-80]. In patients undergoing cholecystectomy for cholelithiasis, unsuspected gallbladder cancer may be diagnosed based upon intraoperative findings or the final pathologic analysis. In three large series combined, incidental gallbladder cancer was found in 31 of 9497 patients undergoing laparoscopic cholecystectomy (0.33 percent) [43,72,76].

Patients who are diagnosed with gallbladder cancer previously unsuspected at the time of cholecystectomy should undergo staging evaluation with cross-sectional imaging as described above (see 'Cross-sectional imaging' above). As with patients with gallbladder cancer that is diagnosed preoperatively, the management of incidental gallbladder cancer depends upon disease extent (T stage) (table 1). If the T stage of the resected, incidental gallbladder cancer is T1b, T2, or T3, we recommend surgical re-exploration and reresection (algorithm 2), ideally within two months of the initial surgery.

The rationale is based on the observation that patients with T1b, T2, or T3 disease for whom a diagnosis of gallbladder cancer is made incidentally on postoperative gallbladder pathology have a high rate of residual disease, and those who undergo reresection have better survival than those who do not [8,9,20,56,81-84].

Investigators have developed models to better predict locoregional residual and distant disease in patients with incidentally diagnosed gallbladder cancer based on T stage, tumor grade, and additional information from pathology (eg, lymphovascular or perineural invasion) [85,86]; one such model is outlined in the table (table 2). However, independent validation of models such as these is needed before they can be considered for clinical use.

Although reresection is associated with additional risk, improvements in perioperative care and operative technique have decreased perioperative morbidity and mortality associated with major liver surgery in high-volume centers [24,87]. Prior to performing reresection, patients should be staged with cross-sectional imaging. A staging laparoscopy may be performed to rule out peritoneal metastases, especially in those with T3 disease, poorly differentiated histology, or positive margins [22]. However, staging laparoscopy is of less value in these cases, given the absence of peritoneal metastases at the recent laparoscopic cholecystectomy. (See 'Evaluation for resectability and staging' above.)

The optimal timing of the reoperation is not clear. In a retrospective study, those who underwent reoperations between four and eight weeks from the date of the original cholecystectomy had better overall survival (median 40.4, 95% CI 16.4 to 64.4 months) than those who underwent reoperations either before four weeks (median 17.4, 95% CI 11.1 to 23.7 months) or after eight weeks (median 22.4, 95% CI 18.2 to 26.6 months) [88]. However, these data are retrospective, and the timing of reoperation is often influenced by nonclinical factors such as patient access to a qualified surgeon or center.

T1a — Patients found to have incidental T1a tumors with negative margins are generally felt to be cured by the cholecystectomy that has already been performed [24,47,89-93]. Reresection for T1a tumors does not appear to provide an overall survival benefit [52,81,94,95].

The National Comprehensive Cancer Network (NCCN) guidelines recommend that these patients be observed without specifying details; we perform cross-sectional imaging at diagnosis and again in six to 12 months.

T1b — The optimal approach to incidental T1b disease is more controversial. If there is no contraindication to surgery, extended resection is reasonable for T1b gallbladder cancer. At least two retrospective studies comparing cholecystectomy alone versus extended cholecystectomy for T1b tumors found no significant difference in overall survival (with up to 87 percent 10 year survival), while other studies have reported improved survival with reresection [96].

A number of studies describe high rates of residual disease upon reresection, with lymph node metastases in 12 to 20 percent and liver involvement in up to 13 percent [12,56]. Furthermore, two reports described up to a 50 to 60 percent locoregional recurrence rate after cholecystectomy alone for T1b disease [97]. The authors of both reports concluded that gallbladder cancer is a locally aggressive disease and even early-stage disease warrants extended resection. Finally, as noted above, decision analysis showed a median survival advantage of over three years for extended versus simple cholecystectomy (9.85 versus 6.42 years) [50].

T2 — For patients with an incidentally detected T2 tumor on histologic review of the cholecystectomy specimen, re-exploration and extended cholecystectomy are also indicated. Re-exploration identifies residual tumor in 40 to 76 percent of cases [9,11,16,44,45], a high likelihood of liver involvement [63,98], and nodal metastases with T2 disease. Reresection significantly increases the likelihood of long-term disease-free survival in patients with T2 disease. In many series, five-year survival rates increased from 24 to 40 percent to 80 to 100 percent with aggressive surgery [8,9,11,33,34,44,45,48,99-104].

As an example, in an analysis of 3209 patients with early-stage gallbladder cancer (12 percent Tis, 30 percent T1, 58 percent T2) derived from the Surveillance, Epidemiology, and End Results (SEER) database, extended resection with lymph node excision was associated with increased survival compared with cholecystectomy alone [105]. However, a significant survival advantage for extended resection was seen only in patients with T2 lesions (hazard ratio [HR] 0.49, 95% CI 0.35-0.68). Lymph node excision was also associated with improved survival in patients with T2 lesions in a way that is related to the number of lymph nodes removed (HR 0.42, 95% CI 0.33-0.53 for one to four lymph nodes excised; HR 0.26, 95% CI 0.16-0.42 for five or more lymph nodes excised). Based upon these survival differences, one report suggests that for gallbladder cancer to be considered truly node negative, at least six lymph nodes should have been removed [106]. (See 'Lymph node dissection' below.)

T3 — Patients with T3 gallbladder cancer have very high rates of residual disease at re-exploration. In a retrospective study of 115 patients with incidentally discovered gallbladder cancer, 77 percent with T3 disease who underwent reresection had residual disease found in any site, 46 percent had lymph node metastases, and 36 percent had disease involvement in the liver bed [56]. Thus, patients with T3 tumors clearly warrant aggressive reresection.

In a retrospective study of 463 patients with incidental gallbladder cancer, 24 percent underwent reresection [104]. The median overall survival of reresected and unresected T3 disease was 23 and 12 months, respectively.

By definition, T4 disease should be clinically apparent at the initial gallbladder surgery and therefore should not be "incidentally" found on gallbladder pathology.

RESECTION TECHNIQUES — Surgical treatment of gallbladder cancer involves removal of the gallbladder with a margin of liver (except in T1a disease) with or without regional lymph node or common bile duct resection. If frozen section analysis of the cystic duct stump is negative, a regional lymph node dissection is performed; if it is positive, then regional lymphadenectomy is undertaken along with extrahepatic bile duct resection. Resection of adherent involved adjacent organs may be necessary [30].

The optimal surgical approaches for patients diagnosed before, during, and after surgery have been discussed in the preceding sections. The surgical techniques used to resect gallbladder cancer are the focus of this section.

Simple cholecystectomy — Gallbladder removal is a common and generally straightforward operation. Techniques for simple cholecystectomy (open or laparoscopic) are discussed in detail elsewhere. (See "Open cholecystectomy" and "Laparoscopic cholecystectomy".)

Very early stage (Tis, T1a (table 1)) gallbladder cancers are cured with simple cholecystectomy alone (see 'T1a' above). Simple cholecystectomy may also be indicated in patients with more advanced disease as a palliative procedure to prevent future episodes of cholecystitis, although the value of this approach has not been definitely proven. (See 'Palliative procedures' below.)

Extended cholecystectomy — Extended cholecystectomy involves en bloc removal of the gallbladder with a rim of liver of at least 2 cm adjacent to the gallbladder bed. A formal central liver resection (segments IVb and V (figure 5)) may be appropriate depending upon the location of the tumor (fundus, body, neck).

An open rather than minimally invasive procedure generally has been recommended [107-111], although data from Hepato-Pancreato-Biliary specialized centers suggest the feasibility of a planned laparoscopic or robotic approach for an early-stage (T1b or T2) gallbladder cancer, the only group for which the risk of nodal metastases is sufficiently low that more radical resection can be avoided [112,113]. However, preoperative staging is not entirely reliable at identifying patients with T1a disease, and improperly staged tumors are at risk for inadequate resection and subsequent recurrence regardless of the operative technique [15].

Open gallbladder surgery is usually performed through a right subcostal incision. Additional exposure can be obtained with extension to the upper midline or to the left subcostal region as a chevron incision. (See "Open cholecystectomy", section on 'Incision'.)

Once the abdomen is entered and retractors are placed, the margin of liver to be resected can be scored superficially (around the gallbladder and gallbladder mass) with electrocautery to a depth of a couple of millimeters, or sutures can be placed at each side of the margin of resection with absorbable sutures on a blunt needle to mark the margin of resection. The gallbladder, tumor, and margin of liver are resected as a single en bloc specimen. Most studies demonstrate the importance of achieving negative margins (R0 resection) [12,56,63,114-116]. Intraoperative bile spillage should be avoided to minimize risk of cancer cell dissemination. Standard techniques for liver resection are used with bleeding minimized by lowering central venous pressure during liver dissection and the use of surgical hemostatic devices. (See "Open hepatic resection techniques", section on 'Specific resections'.)

The cystic duct and cystic artery are identified by gentle retraction on the infundibulum of the gallbladder, and once it is clearly identified and dissected, each is ligated and divided. A sample of the cystic duct margin should be sent for frozen section [56]. If the cystic duct margin is negative, portal lymphadenectomy should be performed. If the cystic duct margin is positive, bile duct resection (including portal and hepatoduodenal lymphadenectomy) and reconstruction are performed. Additional frozen sections will decide the need for further resection. Intraoperative frozen sections can reliably indicate whether tumor is present, but they cannot reliably predict the depth of tumor invasion (T stage of the tumor) [117]. (See 'Lymph node dissection' below and 'Bile duct resection' below.)

At specialized centers, laparoscopic and robotic reresection has been carried out for incidental gallbladder cancer with oncologic outcomes comparable to those of open reresection [118]. However, these studies are observational and small [119].

Bile duct resection — When gross tumor extends into the common bile duct, or a negative cystic duct margin (as determined by frozen section) cannot be obtained, extrahepatic bile duct resection should be performed [8,13,30,63,120]. In a study of 115 patients who underwent surgery for gallbladder cancer, 42 percent of patients had residual disease in the common bile duct when the cystic duct stump had a positive margin on frozen section [56]. Once a negative common hepatic duct margin is confirmed by frozen section, reconstruction is carried out with a Roux-en-Y hepaticojejunostomy (figure 6).

Some have advocated routine resection of the extrahepatic bile ducts, regardless of the result of the cystic duct stump frozen section, as a means for achieving a more complete lymphadenectomy [121]. However, several retrospective series have not shown a survival benefit for this approach in the management of gallbladder cancer [20,56,122,123]. Opponents of routine bile duct resection also cite the risk of potential serious complications of hepaticojejunostomy, such as bile leak and anastomotic stricture [39,122]. Further supporting this view, a retrospective study found that common bile duct resection did not yield a greater lymph node count [56].

Although the bile ducts do not need to be resected when the cystic duct margin is negative, the ducts may be compromised during skeletonization of the porta hepatis. If the ducts appear ischemic or otherwise injured, resection and reconstruction will become necessary.

Techniques of bile duction resection and reconstruction are discussed in another topic. (See "Bile duct resection and reconstruction".)

Lymph node dissection — Lymph node dissection is indicated whether or not bile duct resection is performed if the gallbladder cancer is >T1a. In many cases, lymph node involvement is not obvious intraoperatively, and thus, even normal-appearing nodes should be removed. Lymphatic metastases are found in 35 to 80 percent of patients with gallbladder tumors that invade the perimuscular connective tissue (≥T2) [2,9-13,36,124] and are one of the most reliable predictors of a poor outcome after surgery (five-year survival of 57 percent without versus 12 percent with lymph node metastases) [125].

A proper regional lymph node dissection for gallbladder cancer involves removing all lymph nodes in the porta hepatis and along the hepatoduodenal ligaments, including those of the cystic duct, common bile duct, hepatic artery, and portal vein.

The 8th edition of the American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) staging system (2017) for gallbladder cancer distinguishes N1 versus N2 disease by the number of involved nodes (N1, 1 to 3; N2, >3) rather than by the location of involved nodes (table 1). It recommends that at least six lymph nodes be removed for proper staging [7]. This change from the 7th edition (location-based designation) was based upon studies that demonstrated that the number of metastatic lymph nodes and the lymph node ratio are more prognostic than the location of the metastatic lymph nodes.

Hepatic resection — For patients with tumors of the fundus or body of the gallbladder, the tumor is generally far enough from the inflow structures to the liver to allow a margin-negative resection with an at least 2 cm nonanatomic wedge resection of the gallbladder fossa or anatomic resection of segments IVb and V (figure 5) [126]. Various resection margins have been proposed, ranging from 1 to 5 cm, and none are solidly based on carefully collected data [127]. There are no data from randomized trials showing a benefit for anatomic resection of segments IVb and V in patients with localized disease where a negative margin has otherwise been obtained [128]. Although a nonanatomic resection may provide a sufficient margin, an anatomic approach reduces the risk for bleeding or bile leakage [129]. The pattern of drainage of the gallbladder veins may provide support for anatomic IVb/V resection over nonanatomic resection. Veins from the gallbladder rarely enter the portal vein; rather, they drain into the middle hepatic vein via the cholecysto-hepatic veins [97,130]. Direct lymphatic drainage into the liver has also been demonstrated. (See 'Lymphatic drainage' above.)

While a minimal parenchymal resection necessary for clear margins is appropriate in most cases, more aggressive surgical management may occasionally be necessary, which includes resection of other segments of the liver beyond that included in extended cholecystectomy [131,132]. As an example, extended right hepatectomy may be necessary for tumor infiltration into segments IV, V, and VIII or the right portal hilum.

However, in a series of 104 patients treated at Memorial Sloan-Kettering over a 12 year period, major hepatectomy, resection of adjacent organs other than the liver, and common bile duct excision increased perioperative morbidity but were not associated with better survival [38]. The authors concluded that major hepatic resection (including excision of the common bile duct) was appropriate, when necessary, to clear disease, but not mandatory in all cases.

Techniques for hepatic resection are discussed elsewhere. (See "Overview of hepatic resection" and "Open hepatic resection techniques", section on 'Specific resections'.)

Laparoscopic port site resection — Although available data suggest that laparoscopic manipulation does not diminish the survival of patients with incidentally found gallbladder cancer, port site recurrences have been described [89,133-136]. Although some have recommended port site excision at the time of re-exploration after laparoscopic cholecystectomy [43,78], radical resection does not require resection of the previous laparoscopy port sites [30,136]. If tumor is found in the port sites, this is a marker for disseminated peritoneal disease, and removal of the port sites will not be curative or beneficial [137].

In a study of 113 patients with gallbladder cancer detected incidentally at laparoscopic cholecystectomy, 69 had port site resection at the time of re-exploration and 44 did not [136]. Port site disease was seen only in patients with T2 or T3 disease and correlated with the development of peritoneal metastases. Port site resection was not associated with overall survival or recurrence-free survival. Therefore, we do not recommend routine port site resections.

PALLIATIVE PROCEDURES — Patients with unresectable gallbladder cancer may develop jaundice, upper abdominal pain, and symptoms of biliary obstruction. The optimal palliative therapy provides relief of symptoms with minimal perioperative morbidity and mortality [100]. The choice of palliative procedure depends upon the nature of obstructive symptoms and an assessment of medical risk associated with the procedure in the context of predicted patient longevity. Available options include:

Simple cholecystectomy. However, careful judgment must be exercised, recognizing that upper abdominal pain in these instances is rarely a result of cholecystitis.

Endoscopic or percutaneous biliary drainage – (See "Endoscopic stenting for malignant biliary obstruction".)

Endoscopic stenting or intestinal bypass – (See "Enteral stents for the palliation of malignant gastroduodenal obstruction" and "Management of small bowel obstruction in adults".)

Biliary bypass – Another option in patients who can tolerate surgery is biliary bypass, but many patients fail these procedures with recurrent obstruction as the disease progresses. In one study, intrahepatic segment III cholangiojejunostomy and staying away from the hepatoduodenal ligament, the most common site of disease progression, successfully palliated the majority of patients [36].

OUTCOMES

Survival — The overall five-year survival for all patients with gallbladder cancer is 20 percent, whereas for patients with localized cancer who are amenable to surgical resection, overall survival reaches 65 percent at five years.

The nonspecific symptoms and advanced stage of disease at presentation are reflected in the poor outcomes reported in most series for gallbladder cancer. Five-year survival rates are 5 to 12 percent in many large series [62,138,139]. Long-term outcomes are relatively poor for any stage of disease beyond T1N0 (table 1). Unfortunately, fewer than 10 percent of patients who present with symptoms have T1 tumors [140,141], whereas approximately 20 percent of patients with incidentally diagnosed gallbladder have T1 tumors (table 3) [9].

Long-term prognosis, recurrence, and adjuvant therapy for the treatment of gallbladder cancer are discussed elsewhere. (See "Prognosis and adjuvant treatment for localized, resected gallbladder cancer", section on 'Prognosis and patterns of spread' and "Prognosis and adjuvant treatment for localized, resected gallbladder cancer", section on 'Adjuvant therapy'.)

Perioperative mortality and morbidities — Perioperative mortality rates of gallbladder cancer resection range from 0 to 21 percent [11,33,49,62,63,65,142-146]. Mortality is significantly higher for patients having extensive hepatectomy (right or left hepatectomy, or extended hepatectomy) compared with those having partial hepatectomy (wedge resection) or cholecystectomy (16 versus 2 and 7 percent, respectively) [147].

Major morbidity rates of gallbladder cancer resection range from 5 to 54 percent [11,33,34,142]. The most common complications are the same as for other hepatobiliary surgeries, such as postoperative bleeding, bile leak, and perihepatic abscess. (See "Overview of hepatic resection", section on 'Complications' and "Overview of hepatic resection", section on 'Mortality'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Gallbladder cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

Staging of gallbladder cancer – Staging prior to considering resection or reresection is important and can be accomplished using a combination of cross-sectional imaging (abdominal CT and MRI with contrast, and chest CT with or without contrast) and diagnostic laparoscopy (for >pT1b patients) to rule out locally unresectable or metastatic disease. The routine use of positron emission tomography (PET) scan or PET/CT in the preoperative setting is controversial, but it may be considered when CT/MRI findings are equivocal. (See 'Staging' above and 'Evaluation for resectability and staging' above.)

Evaluation for resectability – Gallbladder cancers with liver or peritoneal metastases, malignant ascites, metastases to lymph nodes beyond locoregional nodes (cystic, common bile duct, hepatic artery, or portal vein), extensive involvement of the hepatoduodenal ligament, or encasement or occlusion of major vessels are not resectable. Such patients should receive palliative chemotherapy and/or radiation therapy. Preoperative jaundice is considered a relative contraindication to radical resection of fundus- but not perihilar-based gallbladder cancer; such patients should undergo multidisciplinary evaluation before surgery is offered. Biliary obstructions can be treated with endoscopic or surgical drainage procedures. Routine use of neoadjuvant therapy to treat locally advanced but nonmetastatic gallbladder cancer is not yet supported by data. (See 'Unresectable disease' above and 'Palliative procedures' above and "Treatment of advanced, unresectable gallbladder cancer".)

Surgical resection of gallbladder cancer – Patients with a preoperative diagnosis of potentially resectable, localized gallbladder cancer should be offered definitive resection, which involves en bloc resection of the gallbladder with at least a 2 cm margin of underlying liver bed (nonanatomic resection or anatomic resection of segments IVb and V), portal and hepatoduodenal lymphadenectomy, and possibly extrahepatic bile duct resection. For locally advanced tumors (T3/4), en bloc resection of adjacent organ(s) (eg, duodenum, colon, pancreas) may be required (algorithm 1). (See 'Resectable disease' above and 'Extended cholecystectomy' above.)

Gallbladder cancer diagnosed during cholecystectomy – If an obviously malignant lesion is encountered intraoperatively during laparoscopic cholecystectomy, it is best not to sample the lesion laparoscopically, to reduce the hazard of seeding. Surgeons experienced in complex hepatobiliary surgery may proceed with resection in the same fashion as for a preoperatively diagnosed gallbladder cancer; surgeons less experienced in complex hepatobiliary surgery should close the incision with or without a simple cholecystectomy and refer the patient to an experienced center. (See 'Gallbladder cancer diagnosed during gallbladder surgery' above.)

Gallbladder cancer diagnosed after cholecystectomy – For patients with a final diagnosis of T1b, T2, or T3 gallbladder cancer previously unsuspected at the time of cholecystectomy, we suggest surgical reresection rather than other treatments (Grade 2C). For such patients, reresection entails removing at least a 2 cm margin of the underlying liver bed (nonanatomic resection or anatomic resection of segments IVb and V), portal and hepatoduodenal lymphadenectomy, and possibly extrahepatic bile duct resection (algorithm 2 and table 1). T1aN0M0 disease is presumed cured by simple cholecystectomy alone and does not require reresection. We do not routinely excise previous laparoscopic port sites at re-exploration. (See 'Gallbladder cancer diagnosed after gallbladder surgery' above.)

Role of bile duct resection – Extrahepatic bile duct resection should be performed if gross tumor extends into the common bile duct or if frozen section analysis of the cystic duct margin shows tumor involvement. However, we do not advocate routine bile duct resection for the purpose of increasing lymph node yield. (See 'Bile duct resection' above.)

Role of lymphadenectomy – Lymph node dissection is indicated for gallbladder cancers that are >T1a. A proper regional lymph node dissection for gallbladder cancer involves removing all lymph nodes in the porta hepatis and along the hepatoduodenal ligament, including those of the cystic duct, common bile duct, hepatic artery, and portal vein. If an extrahepatic bile duct resection is performed, a regional lymphadenectomy is usually performed with it. In patients who do not require bile duct resection, a portal and hepatoduodenal lymphadenectomy should be performed separately. A minimum of six lymph nodes should be removed for proper staging of gallbladder cancer; involvement of lymph nodes beyond the hepatoduodenal ligament is considered distant metastases (M1). (See 'Lymph node dissection' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Swanson, MD, who contributed to an earlier version of this topic review.

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Topic 15097 Version 22.0

References

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