Biliary tract malignancy (BTC) is a highly aggressive malignancy that originates in the biliary tract. It includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GC), which accounts for about 3% of gastrointestinal malignancies. Despite significant advances in oncology, the prognosis is generally poor because these tumors are often found to be advanced and highly aggressive. Tumor metastasis often occurs in the early stage of BTC, and its morbidity and mortality are on the rise. For those patients with resectable local lesions, surgery often provides the best outcome. However, even with radical surgery, the risk of recurrence is high. As a result, patients with BTC are increasingly adopting a multimodal treatment strategy, including surgical resection, systemic therapies (e.g., molecularly targeted drugs, intravenous chemotherapy, immunotherapy), and regimens in combination with local therapies. In view of the complexity of treatment and the continuous advancement of surgical diagnosis and treatment techniques, this article specifically interprets the key points of the latest practice guidelines regarding the surgical treatment of BTC (especially ECC and GC) and the considerations for perioperative management (Table 1).
1BTC Evaluation Points
1.1 Diagnosis and staging of ECC
ECC is anatomically classified as hilar cholangiocarcinoma (pCCA) or distal cholangiocarcinoma (dCCA), with pCCA originating in the common hepatic duct also known as Klatskin tumor and dCCA originating in the common bile duct below the confluence of the cystic duct. Given the differences in the biological properties of ICC and ECC, they should be treated as separate cancers. Patients with ECC typically present with abdominal pain and jaundice due to biliary obstruction. dCCA can be treated with pancreaticoduodenectomy, whereas pCCA usually requires more extensive hepatic resection and extrahepatic bile duct resection.
For patients with pCCA, preoperative biliary drainage can help restore liver function and reduce the incidence of postoperative complications. If biliary drainage is not treated prior to extensive hepatectomy, elevated preoperative bilirubin levels may increase postoperative morbidity and mortality. When considering extensive hepatectomy with pCCA, preoperative drainage is particularly important to ensure adequate FLR in the future. The European Society for Medical Oncology (ESMO) guidelines recommend that imaging should be done prior to drainage, as stents or drains may interfere with the determination of the extent of the lesion. National Comprehensive Cancer Network (NCCN) guidelines recommend that preoperative drainage should be performed when clinicians are concerned about inadequate FLR or when the patient requires portal vein embolization. The European Society for Gastrointestinal Endoscopy (ESGE) clinical guidelines state that although routine preoperative biliary drainage is not recommended in the setting of extrahepatic biliary obstruction, it should be considered in patients with cholangitis, symptomatic jaundice (e.g., pruritus), delayed surgery, or a neoadjuvant chemotherapy schedule. The American Association of Hepatobiliary and Pancreatic Surgery (AHPBA) consensus statement also states that preoperative biliary drainage should also be performed in the setting of malnutrition, hepatic insufficiency, or renal insufficiency due to elevated bilirubin, and in preparation for portal vein embolization. According to data from three retrospective studies, biliary drainage by endoscopic approach prolongs survival and reduces intrahepatic recurrence compared with percutaneous transbile duct drainage. Therefore, ESMO and ESGE guidelines agree that endoscopic drainage should be the first choice for preoperative biliary drainage. Endoscopic retrograde cholangiopancreatography (ERCP) allows biliary stents to be placed to drain and support the biliary tract. At the time of ERCP, endoscopic ultrasound (EUS) should be utilized to assess the nature of the mass and biopsy should be performed. However, if a biliary stent cannot be placed because the mass is difficult to penetrate, percutaneous transhepatic interventional radiology techniques may be used to drain the dilated intrahepatic bile duct.
In clinical practice, the diagnosis and anatomical scope of ECC are often difficult, especially in pCCA. Doctors can use ERCP to irrigate the biliary system and biopsy of enlarged lymph nodes with EUS-guided fine needle aspiration. In addition, SpyGlass choledoscopy is able to more accurately assess the extent of the lesion and provide critical information for surgical planning. The Organ Procurement and Transplantation Network (OPTN) guidelines state that patients should not undergo percutaneous or transperitoneal biopsy (including biopsy under EUS) if they are considering organ transplantation, given the high risk of tumor implantation. In cases where biopsy histopathology does not confirm the diagnosis, direct surgical treatment is appropriate.
Laboratory tests should include liver function, coagulation, and routine blood tests to assess for potential hepatic impairment. Tumor marker testing should include CEA and CA19-9. NCCN guidelines also recommend that serum IgG4 levels should be measured if autoimmune cholangitis or bile duct disease is suspected. CT or MRI of the abdomen/pelvis with contrast, as well as CT of the chest, can be used to assess the extent of disease and distant metastases. ESMO guidelines recommend MRI with magnetic resonance cholangiopancreatography as the diagnostic tool of choice. In the setting of unresectable tumors or the presence of distant metastases, molecular testing should be performed according to NCCN guidelines to identify potential therapeutic targets.
1.2 Diagnosis and staging of GC
GC usually presents with symptoms of biliary colic or chronic cholecystitis, sometimes with jaundice. GC is predominantly manifested as a gallbladder mass on imaging or incidental findings on pathological examination. In most cases, GC is found on pathologic examination after laparoscopic cholecystectomy. Guidelines from the NCCN, ESMO, and the Spanish Society of Medical Oncology recommend testing for the staging of patients with GC, including chest CT scans, abdominal/pelvic CT or MRI scans, and laboratory tests including liver function tests and tumor markers CEA and CA19-9. If a mass is found on imaging, NCCN guidelines recommend laparoscopic exploration prior to final surgical resection. In the setting of unresectable or metastatic disease, biopsy tissue should be taken for molecular testing to identify gene mutation sites that can be targeted for therapy.
2. Clinical treatment recommendations
2.1 Surgical treatment of ECC
Surgical resection is recommended in patients with resectable ECC if there are no distant metastases. NCCN and European Network for Cholangiocarcinoma Research (ENS-CCA) guidelines state that laparoscopy is not usually required for ECC, but laparoscopic exploration should be considered prior to resection surgery in the setting of a high suspicion of disseminated disease. According to the AHPBA consensus statement, patients with non-metastatic pCCA are not candidates for surgery if they have bilateral segmental bile duct lesions, unilateral liver atrophy with contralateral segmental bile duct or vascular involvement, or unilateral segmental bile duct dilation with contralateral vascular involvement. Current guidelines generally consider the presence of distant liver metastases, peritoneal metastases, and extrahilar lymph node metastases to be contraindications to surgery, regardless of the location of the ECC.
The way the ECC is removed depends on its anatomical location. dCCA requires the Whipple procedure. ESMO, NCCN, and AHPBA guidelines recommend the use of the Bismuth-Corlette staging system and classification of pCCA according to the degree of biliary involvement (Figure 1). The current Bismuth-Corlette classification of pCCA is as follows: type I tumors are located distal to the confluence of the hepatic duct (HDC), type II tumors extend to and involve HDC, type III tumors involve HDC and proximal to the right (type III.A) or left (type III.B) hepatic ducts, and type IV tumors extend to bilateral proximal hepatic ducts up to the segmental bile ducts. Resection of the liver on the affected side and biliary remodeling are key to the management of tumors at the biliary confluence. Type I., II, and III.A tumors usually require expanded right hepatectomy, while type III.B lesions require left hepatectomy. In addition, the NCCN guidelines and the AHPBA consensus statement recommend that caudate lobes should be excised at the same time as pCCA to increase the chance of marginal negative resection, thereby reducing the rate of postoperative recurrence. Rarely, some patients with type I ECC or mid-bile duct tumors may require only cholangioresection and regional lymphadenectomy, but this practice is uncommon.
Note: Type I tumors are located distal to the confluence of the hepatic duct (HDC). Type II tumors extend to and involve HDC. Type III tumors involve HDC and the proximal end of the right (type III.A) or left (type III.B) hepatic duct. Type IV tumors extend into bilateral proximal hepatic canals up to the segmental bile ducts. RHD represents the right hepatic duct, LHD represents the left hepatic duct, and HDC is the confluence of the hepatic duct.
Fig.1 Bismuth-Corlette classification of hilar cholangiocarcinoma
NCCN and ESMO guidelines agree that the goal of surgical resection of hilar and distal ECC is to achieve margin-negative resection. According to NCCN guidelines: Intraoperative frozen margins may need to be evaluated during surgery to determine negative margins of the proximal and distal bile ducts. If margins are positive and conditions permit, further excision should be made to achieve negative margins. In addition, the guidelines state that standard treatment for pCCA should include dissection of the periportal lymph nodes. For dCCA, dissection including peripancreatic lymph nodes is also required.
Also according to NCCN guidelines: combined liver and pancreatic resection may be considered for patients who can tolerate surgery to remove a wider primary tumor. However, distally dissected lymph nodes is not recommended due to the difficulty of this procedure and the low survival benefit after surgery. NCCN guidelines report: For pCCA, resection and reconstruction of major vascular systems (eg, portal vein, hepatic artery) may be required to obtain marginal negative resection. However, the AHPBA consensus guidelines do not recommend routine vascurectomy. Conversely, whether or not to perform vascularization may need to be decided on a case-by-case basis during surgery. The ENS-CCA guidelines state that the base of the tumor exceeds 180° of the portal vein trunk or the common hepatic artery, which is associated with a poor prognosis. Even if there is extensive vascular involvement and there may be benefits to resection as much as possible, the risks and benefits of surgery should be weighed against each other prior to surgery.
For patients with unresectable pCCA (locally progressed but node-negative in the region), liver transplantation after completion of neoadjuvant chemoradiotherapy may be an option. The ENS-CCA, NCCN, and ESMO guidelines all recommend neoadjuvant chemoradiotherapy and transplantation evaluation in patients with unresectable HCC who meet selection criteria. According to the OPDN guidelines: patients with unresectable HCC must undergo neoadjuvant therapy and surgical staging evaluation to determine whether there are regional lymph node metastases, intrahepatic or extrahepatic metastases. Patients undergoing transplantation must meet the following diagnostic criteria, including a positive biopsy of malignant stricture and a CA19-9 level greater than 100 units/mL in the absence of cholangitis or a hilar mass <3 cm in diameter, without transperitoneal puncture or primary tumor biopsy. In addition, liver transplantation is only available for patients with early-stage pCCA (tumor < 3 cm, node-negative).
2.2 Perioperative treatment of ECC
Based on data from the BILCAP study, NCCN guidelines recommend capecitabine as an adjuvant chemotherapy agent for different types of patients with BTC. In contrast, data on adjuvant therapy for patients with ECC are limited. Retrospective studies have shown that adjuvant chemoradiotherapy in ECC patients can effectively improve local control and survival, especially in patients with T3/T4 tumors, R1 resection, or lymph node metastasis. In the Phase II S0809 trial conducted by the Southwest Oncology Group (SWOG), a combination of gemcitabine and capecitabine was administered to patients with T2~4 tumors or positive resecting margins, including ECC and GC patients, followed by radiation therapy (capecitabine as a sensitizer). This regimen was well tolerated, with a two-year survival rate of 65% and a median overall survival of 35 months. However, the data from the third phase still need to be further validated.
2.3 Surgical treatment of GC
NCCN and ESMO guidelines recommend early surgery for resectable GC. The NCCN and AHPBA consensus statements state that jaundice is a relative contraindication to surgery because these patients often have a higher rate of lymph node metastasis, tumor dissemination, or both, and have a poor prognosis. Guidelines from the NCCN, ESMO, and AHPBA all recommend that surgery should only be performed if negative margins can be achieved. Surgery usually involves a radical cholecystectomy and removal of 4b/5 segments of the liver. If a gallbladder removal has been performed before, then surgery is limited to segment 4b/5 of the liver. More advanced GC may require more extensive resection, such as right hemihepatectomy. The AHPBA guidelines also recommend intraoperative evaluation of cystic duct invasion. The AHPBA and NCCN guidelines suggest that routine removal of the bile duct is not recommended if the cryosection of the cystic duct is negative.
For those patients who have been diagnosed with accidental GC during a prior cholecystectomy, the ESMO guidelines recommend that the cystic duct should be removed from the site of confluence of the cystic duct with the bile duct if the gallbladder is not completely removed during the first surgery, or if the gallbladder is perforated during surgery. In contrast, the AHPBA and NCCN guidelines do not recommend routine resection of the tissue surrounding the puncture hole, as puncture-hole-related recurrence is often associated with spread of disease, and resection may not improve survival outcomes. At the time of hepatic resection, dissection of at least 6 regional lymph nodes should be routinely performed. Surgery can be performed with minimally invasive or open surgery. The NCCN guidelines clarify the surgical management of GC according to the stage, and GC accidentally found during cholecystectomy should be re-examined by a hepatobiliary pathologist.
T1a (invasion of lamina propria) GC does not require additional surgical treatment. Additional staging evaluation should be performed in patients with T1b or higher stage tumors, GC with cystic duct marginal positive or metastatic lymph nodes, and T1a tumors with surgical margin positivity to determine the need for additional surgical intervention. As the stage of the tumor increases, the risk of residual lesions in the liver and lymph nodes increases, so a second radical tumor resection should be considered. The extent of hepatic resection (i.e., formal anatomical type 4b/5 segment versus 2 cm non-anatomical partial hepatectomy) remains controversial. Currently, NCCN, ESMO, and AHPBA recommend a combination of liver 4b/5 segment resection and periportal lymph node dissection. According to the American Society of Extrahepatic Biliary Malignancies, the best time for resection is within 4 to 8 weeks after the first cholecystectomy.
The management of accidental findings of GC during surgery should vary depending on the availability of a skilled hepatobiliary surgeon. NCCN guidelines state that laparoscopy should be done without the involvement of a hepatobiliary surgeon, but biopsy should not be performed given the risk of abdominal transmission. If a hepatobiliary surgeon is involved and there is sufficient clinical evidence that the mass is GC, definitive surgical resection should be performed. The above comparison of the diagnosis and treatment strategies for GC in different settings is shown in Figure 2.
Fig.2 Clinical manifestations based on NCCN guidelines to guide the treatment of GC
2.4 Perioperative treatment of GC
Similar to the treatment of ECC, for patients with GC who do not have distant metastases, surgeons can use capecitabine for postoperative adjuvant therapy after upfront resection. The ongoing OPT-IN trial is a Phase II./II clinical trial to evaluate the efficacy of gemcitabine and cisplatin in neoadjuvant therapy in patients with histologically confirmed stage T2 or T3 GC. In this trial, patients were randomly assigned to receive neoadjuvant gemcitabine/cisplatin followed by re-surgical resection and continued adjuvant gemcitabine/cisplatin (NCT04559139).
3. Summary and outlook
ECC and GC in BTC, once diagnosed early, can usually benefit from radical surgical treatment. To develop the best treatment plan, patients should be consulted by a multidisciplinary team and discuss the treatment plan based on tumor characteristics and patient condition, while following clinical guidelines. Some patients with advanced tumors that were initially thought to be unresectable may be treated with systemic or local therapy to reduce the stage of the disease. Prior to surgery, it is critical to assess the patient's overall condition and planned postoperative FLR. When evaluating patients with liver and biliary tract cancer, correct patient selection, negative surgical margins, and appropriate systemic chemotherapy are essential to ensure long-term survival. Although current practice guidelines provide important guidance for treatment, the diagnosis and treatment of patients with BTC still needs to be individualized, and there is an increasing trend towards individualized and precise comprehensive diagnosis and treatment strategies.
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引证本文 Citation
Guo Wei, Li Xin, Wang Mingda, et al. Recommendations of the Yearbook of Oncological Surgery: Guidelines for the Clinical Diagnosis and Treatment of Extrahepatic Cholangiocarcinoma and Gallbladder Cancer[J]. Journal of Clinical Hepatobiliary Diseases, 2024, 40(4): 682-687
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