Keywords

Introduction

Gallbladder cancer (GBC) is an adenocarcinoma developing from the gallbladder mucosa. It is a relatively uncommon disease, with an incidence in North America from 1 to 2 cases per 100,000 population.

Incidence may significantly differ geographically, as in regions of East Asia, East Europe, and South America. Residents of the Indo-Gangetic belt, particularly females of northern India (21.5/100000) and south Karachi Pakistan (13.8/100000), have been reported as one of the highly affected population in the world. In southern Chile, the rate of GBC reaches 12.3/100000 for males and 27.3/100000 for females [1].

GBC is often found incidentally after an elective or emergent laparoscopic cholecystectomy for gallstone disease or cholecystitis. The main risk factors associated with the development of cancer include the following:

  • Female:male ratio (1.3–3.5:1) [2]

  • History of gallstones/cholecystitis [3,4,5,6,7,8]

  • Ethnic groups: Native American, Mexican, East Asian, Hispanic [9]

  • Obesity and a high carbohydrate diet [10, 11]

  • Anomalous pancreaticobiliary duct junction (APBDJ) [12, 13]

  • Chronic GB infection (S. typhi) [14]

  • Age (increased incidence) [15]

  • Previous gastric surgery [16]

Definitions/Terminology

  • Simple cholecystectomy (SC) : removal of the gall bladder and a portion of the cystic duct performed laparoscopically or open. Simple cholecystectomy is conducted in a subserosal plane.

  • Radical cholecystectomy (RC) : removal of the gallbladder including a subsegmental or segmental 4B/5 liver resection, removal of the portal/hepatoduodenal lymph nodes and possible common bile duct excision (depending upon cystic duct margin status) with appropriate reconstruction.

Incidental Gallbladder Cancer (IGBC)

Almost 50% of all patients who present with gallbladder cancer are detected incidentally during or after elective/emergent cholecystectomy. Cancers detected at the time of surgery are referred to as incidental gallbladder cancer (IGBC). In most cases, cancer is diagnosed by a pathologist after the initial cholecystectomy (index cholecystectomy, IC). Following this IC, patients undergo clinical staging to complete later an oncologic extended resection and ensure removal of any local residual cancer.

There is conflicting data whether non-oncologic index cholecystectomy leading to discovery of IGBC negatively impacts survival. Early studies showed that long-term survival was not worse for patients with IGBC who undergo oncologic extended resection after prior simple cholecystectomy than for patients with non-IGBC who undergo upfront radical cholecystectomy [17,18,19].

However, recent data suggests that tumor disruption, such as in patients with the tumor in the dissection plane of a routine cholecystectomy (T2b, hepatic- side tumors), has a negative survival impact from IC [20]. Therefore, in trying to favor a single-time oncologic operation, a high level of suspicion should be kept before index cholecystectomy in patients with thickened gallbladder/chronic inflammatory changes in the preoperative imaging. Surgeons may change their approach (laparoscopic to open) if there is a high preoperative level of suspicion and be prepared for frozen section to decide upon completion of radical surgery favoring a single-time operation.

Staging

Unfortunately, less than 25% of patients will present with disease amenable for curative intent surgery at the time of diagnosis [21,22,23,24]. The high incidence of patients presenting with advanced disease, spillage of bile and tumor cells during initial cholecystectomy, evidence of rapid progression, and dismal prognosis when important residual disease is left after the first operation highlight the role of accurate restaging before oncologic extended resection.

The role of routine staging laparoscopy and paraaortic lymph node biopsy is a matter of debate to prevent a futile radical (most commonly open) surgery.

CT and MRI

  • CT and MRI are the most common imaging techniques used to evaluate local and distant extension of disease and recognize the relationship between localized or residual tumor and nearby vascular structures and the biliary tree.

  • MRI has a higher yield in detecting smaller liver metastatic lesions and their relationship with intrahepatic ducts. However, it has well-recognized limitations for the detection of tumor recurrence mostly related to difficulty in differentiating residual/recurrent tumor from surgically induced scarring or inflammatory changes.

PET-CT

  • Limitations of cross-sectional imaging studies to restage patients with residual disease have prompted exploration of the added diagnostic value of FDG PET-CT. Functional imaging prior to attempted curative intervention could improve the pre-treatment selection of patients who might potentially benefit from such interventions.

  • FDG PET-CT has been reported to improve the sensitivity to detect non-clinically evident metastatic disease. FDG PET-CT may change management by identifying metastatic disease not seen in previous studies in 23–25% of cases [25, 26].

  • However, other studies have proven that sensitivity and positive predictive values of FDG PET-CT for residual disease may be as low as 28.5% and 20%, respectively, particularly among those patients with small volume carcinomatosis and signet ring cell tumors [25].

  • These studies showed that the use of PET is definitively helpful in 5% and confirmatory in 15% of cases. However, in 3% of patients it may underestimate signs of unresectable disease. In the majority of patients, CT and PET were completely concordant and PET did not add any information [27].

  • With modern high-quality cross-sectional imaging, it is uncommon for PET findings to be the sole determinant of resectability [27]. FDG PET-CT is therefore not routinely recommended unless there is persistent imaging uncertainty.

Staging Laparoscopy

  • Staging laparoscopy identifies metastatic disease/locally advanced deemed unresectable in 27.6% of patients with suspected GBC [28].

  • The yield of staging laparoscopy for identifying metastatic disease is higher among poorly differentiated, T3 or positive-margin gallbladder tumors [29].

Routine Paraaortic (Station 16b1) Lymph Node Biopsy.

  • Involvement of paraaortic (16b1) lymph node in GBC is a sign of advanced disease with a prognosis equivalent to that of distant metastases [30].

  • The appearance (size >10 mm and heterogeneous internal architecture) of the 16b1 lymph nodes on CT of the abdomen has been reported to be useful in predicting metastatic involvement in some studies; however, others have not found these factors to be good predictors of metastatic disease [31, 32].

  • Routine 16b1 LN biopsy has proven to prevent non-therapeutic radical resection in 18.6% of patients deemed resectable on preoperative staging [33].

AJCC Eighth Edition

The recommended staging system is the International Union Against Cancer and American Joint Committee on Cancer (UICC/AJCC), eighth edition, with some changes introduced to the previous edition [34] (Tables 10.1, 10.2, 10.3, 10.4, 10.5).

Table 10.1 Primary tumor (T)
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Table 10.2 Regional lymph node (N)
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Table 10.3 Distant metastasis (M)
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Table 10.4 AJCC prognostic stage groups
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Table 10.5 Survival by AJCC stage group
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The main change of this classification was the novel definition of T2a and T2b which effectively stratified the prognosis of patients with T2 GBC. Furthermore, patients with stage IIa tumors also obtained significantly improved overall survival time compared with patients with stage IIb tumors (Table 10.1). Additionally, the new N category stratified the survival of patients effectively based on the number of positive lymph nodes and not on their anatomical distribution (Table 10.2).

Management

Table 10.6 General approach
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Special Notes: (See Tables 10.6, 10.7, 10.8)

  • In Ontario, all patients with known or suspected GBC should be referred for management at a high-volume hepatopancreatobiliary surgical oncology center.

  • Bile spillage is estimated to occur in up to 20–40% of elective laparoscopic cholecystectomy [37,38,39]. Bile spillage that has occurred during laparoscopic cholecystectomy in the setting of a high-grade tumor should not delay or act as a deterrent for definitive surgery. Patients should be evaluated and treated according to the pathology of the tumor, and fitness of the patient for surgery, although they are likely at higher risk of recurrence.

  • Further resection for T1b cancers has not been shown to improve overall survival but may decrease rate of recurrence [40, 41]. In reasonable operative candidates, recommendation is to proceed with segment 4B/5 resection and lymphadenectomy (Table 10.6).

  • A negative frozen section of the cystic duct margin is mandatory during all radical cholecystectomies if the extrahepatic bile duct is not being resected.

  • Jaundice is a poor prognostic marker (median disease-specific survival was 6 months vs 16 months in non-jaundiced patients; no jaundiced patients were alive at 3 years). Surgery exploration may not be warranted in this patient population [42].

  • The presence of residual cancer after incidental cholecystectomy (pT2b or higher, positive cystic duct margin or pN+) is associated with poor disease-specific survival even when R0 resection is achieved after oncologic extended resection. Median disease-free survival (DFS) is 11.2 vs. 93.4 months, (p < 0.0001) and disease-specific survival (DSS) 25.2 months vs. not reached, (p < 0.0001), when compared to no-residual cancer after IC [43,44,45].

  • Extended lymphadenectomy is required for IGBC, independent of cystic duct lymph node status. Cystic duct node positivity has been associated with positive perihilar nodes (odds ratio 5.2, p = 0.012), but not with common hepatic artery, pancreaticoduodenal nor paraaortic lymph nodes, which have an OS comparable to M1 disease [46].

  • Port/Trocar site metastases, the implantation of disease at any of the port sites (not limited to the extraction site), was originally estimated to occur in 10–18% cases after laparoscopic cholecystectomy [47]. More recent data suggests, however, that the incidence of abdominal wall recurrence after laparoscopic procedure is low (7%) and comparable to open technique (5.1%) [48].

Table 10.7 Management of advanced GB tumors
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Table 10.8 Unresectable/metastatic disease
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Port-site excision during re-resection for IGBC has been proven in more recent data not to be associated with improved overall survival and has the same distant disease recurrence compared to no port-site excision; therefore, it is no longer recommended routinely [49].

  • Patients without residual cancer at oncologic extended resection and positive incidental cystic duct node may have similar DSS to patients with negative nodes, 70 vs 60% (p = 0.337) [46].

  • Quality Indicators:

    • Pathologic review should include location and size of tumor, depth of invasion, presence of perineural/vascular/lymphatic invasion, cystic duct node involvement, surgical margin status (particularly cystic duct margin), and evidence of perforation of gall bladder.

    • Operative note should include whether gallbladder was removed intact, evidence of perforation or spillage of bile, excision of cystic node, removal of gallbladder using a bag with identification of the port site used, and use of wound protector.

Special Notes:

  • Early re-exploration for patients with incidentally found T2 lesions [51] (Table 10.7).

  • Adequacy of tumor resection (R0 status), rather than the extent of resection, predicts survival. Therefore, surgical resection should be tailored to obtaining complete oncologic clearance of the tumor and adequate lymphadenectomy [52].

  • Extent of surgery for formal resection is determined by the location and stage of the tumor, as well as the intrahepatic anatomy and cystic duct margin.

  • Right trisectionectomy is necessary for cancers involving the right hepatic artery and advanced lesions. PVE may be useful in these cases (Table 10.7).

  • Pancreaticoduodenectomy has been reported for distal lesions, although 5-year survival is reported at 9–10% in two small series and median survival of 21 months (one alive at 42 months) in another [53,54,55] series. The main limitation of a local (segment 4b/5) resection is the distance between the GB and the segment 8 portal pedicle, which can be as little as 2 mm away. Limited 4b/5 resections should only be considered in T2 lesions located in the fundus where an adequate (2 cm) margin can be obtained by ligation of the segment 5 portal pedicle with preservation of the segment 8 portal branches.

  • Routine bile duct resection does not improve overall survival [56, 57]. Resection of the extrahepatic biliary duct (EHBD), however, is indicated in cases where the cystic duct margin is positive for cancer or high-grade dysplasia [58].

  • Extrahepatic bile duct resection may be indicated in cases of cystic duct and Hartman’s pouch cancers, as well as cases where resection of the EHBD is required to achieve adequate oncologic clearance due to proximity of GB or tumor infiltration of the EHBD.

  • The presence of metastatic disease during exploration is considered unresectable (Table 10.8).

Landmark Publications

Prospective randomized control trials (RCTs) regarding surgical management of this disease are few due to the relative rarity of the disease. Surgical management is largely dictated by consensus statements formed by high-volume centers. Most data have been developed from retrospective series with limited number of patients. Any reference to staging refers to the eighth edition of UICC staging (Table 10.9).

Table 10.9 Restropective reviews and RCTs in GBC
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Referring to Medical Oncology

  1. 1.

    All patients who are stage 2 or higher for adjuvant chemotherapy [65].

  2. 2.

    All metastatic patients considered for palliative therapy.

Referring to Radiation Oncology

  1. 1.

    All patients who are T2 or higher and considered for adjuvant therapy (though there is limited evidence for this). Adjuvant treatment can be considered for R1 resection.

  2. 2.

    Palliative patients for consideration of symptomatic control.

Referring to MCC

  1. 1.

    All patients with T1b disease or higher.

Toronto Pearls

  • All incidental T1b and higher cancers should be considered for re-resection. Aggressive surgery in early-stage disease is associated with potential for cure.

  • Laparoscopic radical cholecystectomy has been reported with reasonable oncologic outcomes, but the data is not robust enough for it to be routinely recommended [67, 68].

  • Formal resection should be tailored to achieve complete oncologic (R0) clearance of the tumor.

  • Limited resection (seg4b/5) should be used selectively in T1b/T2 and T3 tumors located in the fundus where adequate tumor clearance can be achieved at the bifurcation of the right portal structures.

  • Bile duct resection may be performed selectively based on cystic duct margin or oncologic clearance of the tumor.

  • Portal lymphadenectomy should be performed for all cases with T1b and higher tumors.

  • Adjuvant therapy should be considered for stage 2 disease and higher.