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The Diagnosis and Management of Gallbladder Cancer

Oncology
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Introduction

Gallbladder cancer is a rare disease with a poor prognosis. The overall 5-year survival rate is 19%, ranging from 65% for localized cancers to 28% for regional and less than 2% for distant or metastatic disease [1]. Worldwide in 2020, an estimated 115,949 people were diagnosed with and 84,695 died from gallbladder cancer [2]. Particularly high incidence and mortality is seen in the countries of Chile, Japan, Northern India and among indigenous populations in South, Central and North America [3, 4]. The incidence of gallbladder cancer continues to rise, primarily due to increasing risk factors and incidental cancers discovered after cholecystectomy [5-7].
It is hypothesized that inflammation of the gallbladder wall mucosa may lead to dysplasia, and this dysplasia ultimately leads to carcinoma [8]. As such, risk factors are often those associated with chronic inflammation. These include gallstones, gallbladder polyps, primary sclerosing cholangitis, infections such as Salmonella Typhi, anomalous junction of the pancreaticobiliary ductal system and porcelain gallbladder [9]. Genetic links continue to be studied, with support for genetic predispositions, familial components and sex-linked genetic variants [10-14]. Environmental risks associated with specific occupations and chemical exposures may also be associated with gallbladder cancer, such as petroleum, and those found in chemical processing, textiles and paper mills [15]. Additional risk factors, such as cigarette smoking and autoimmune diseases may present potential for mucosal inflammation and dysplasia [16, 17]. 

Anatomy & Histology

The gallbladder is located in the right upper quadrant of the abdomen, underneath the liver (Figure 1A). It has four unique anatomic zones: fundus, body/infundibulum, neck and cystic duct (Figure 1B). The majority of cancers arise in the fundus (60%), body/infundibulum (30%) and neck and cystic duct (10%). The layers of the gallbladder wall, critical for staging, include the epithelium, lamina propria, muscularis, perimuscular connective tissue and serosa (Figure 1C) [18]. More than 80% of gallbladder cancers are adenocarcinomas [19].  
Figure 1.
A) Gallbladder beneath the liver, B) Anatomy of the gallbladder and biliary tree, C) Layers of gallbladder wall

Presentation & Diagnosis

The presentation and diagnosis of gallbladder cancer can be challenging, generally due to non-specific symptoms, low clinical suspicion and lack of reliable screening. As a result, many patients are found to have gallbladder cancer during the work-up or treatment of cholelithiasis, cholecystitis or choledocholithatisis, with as many as 20% being diagnosed at time of cholecystectomy [20]. Common presenting symptoms include abdominal pain, nausea and vomiting, jaundice, fatigue, anorexia and weight loss [21, 22]. Constitutional symptoms, hepatomegaly, a palpable abdominal mass and ascites often reflect more advanced stage disease [23].
Ultrasound is often the initial diagnostic study, particularly if the patient is being worked up for gallstone related pathologies. Findings that are suggestive of gallbladder cancer include mural thickening or calcification (particularly if asymmetric), a mass protruding into the lumen, a fixed mass in the gallbladder, loss of the interface between the gallbladder and liver, or infiltration of the liver [24, 25]. The wall thickening from cholecystitis and carcinoma can appear similar, particularly when there is inflammation or sludge, often making these etiologies difficult to differentiate [26]. In addition, as many as 23% of polyps over 1 cm in diameter contain an invasive cancer [27].
For patients with suspicious lesions or incidentally diagnosed gallbladder cancer, cross-sectional imaging is recommended, including CT or MRI/MRCP. These modalities allow for more accurate evaluation of involvement and extent of gallbladder cancer [28]. MRI/MRCP has particular strengths in distinguishing benign from malignant disease, while also visualizing liver and bile duct invasion, vascular and lymph node involvement [29, 30].
Endoscopic Ultrasound can be a useful tool, particularly to assess tumor depth into the wall of the gallbladder and for evaluating lymph node involvement in the porta hepatis and peripancreatic regions [31]. In addition, EUS-guided FNA is a safe tool for the evaluation of gallbladder masses [32, 33]. Of note, direct cholangiography such as ERCP is usually of little use in the diagnosis of gallbladder cancer, but may be helpful to delineate the extent of biliary involvement or for stent placement in the case of biliary obstruction [34, 35].
Laboratory testing, including complete blood count and comprehensive metabolic panel, with liver function tests and coagulation factors, should be drawn. Tumor markers such as cancer antigen (CA) 19-9 can be useful, with a sensitivity and specificity of 72% and 96% respectively [36].

Staging

There are multiple staging systems for gallbladder cancer, including the modified Nevin-Moran, the American Joint Committee on Cancer (AJCC) TNM system and the Japanese Biliary Surgical Society [37-40]. There is controversy regarding the superiority of each system in predicting survival, but the TNM system is most commonly used. The current 8th edition AJCC TNM staging, updated to improve prognostic precision, is noteworthy for division of T2 category into two sub-groups based on the anatomical location of the tumor: T2a (peritoneal side) and T2b (hepatic side). In addition, the N category is now divided based on the number of metastatic nodes, rather than anatomic location. Lastly, T3 or N1 disease are now considered stage III, while N2 disease is stage IV [41].
Along with cross-sectional imaging for all cancers, complete staging should include diagnostic laparoscopy for suspected or proven > T1b disease [42]. The value of staging laparoscopy is evident as 50% of patients present with unresectable disease at the time of staging [43-47]. Contraindications to resection may include liver metastases, peritoneal metastases, malignant ascites, tumor involvement of the paraaortic, paracaval, superior mesenteric artery and/or celiac artery lymph nodes, extensive involvement of the hepatoduodenal ligament and encasement or occlusion of major vessels.

Management

The only curative treatment for gallbladder cancer is surgical resection. This includes simple cholecystectomy for T1a disease and requires more extensive resection for T1b disease or greater. An extended resection includes liver resection of the gallbladder bed (Couinaud sections IVb and V), portocaval lymph node dissection and – if involved – common bile duct resection, to ensure negative margins. Lymphadenectomy should evaluate six or more nodes at the time of resection [48]. The necessity of this resection is due to the anatomy of the gallbladder and the pattern of spread, as full thickness invasion of the muscular layer is into the perimuscular connective tissue. This more extensive resection, ensuring R0 resections, has been associated with improved survival [49-52]. Care must be taken during cholecystectomy to avoid spillage as it has the potential for carcinomatosis [53]. There is no role for port site excision, as it has demonstrated no benefit with regard to overall or recurrence free survival [54-56].
At this time, there is insufficient evidence to support the use of neoadjuvant therapy in gallbladder cancer [57]. In contrast, adjuvant chemotherapy has been associated with a survival benefit [58]. Although there are limited clinical trial data to define a standard regimen, including dosages, current National Comprehensive Cancer Network (NCCN) guidelines recommend capecitabine monotherapy for most patients. This is primarily based on the phase III BILCAP trial, a randomized, controlled, multicenter trial. Patients 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection with curative intent were randomly assigned to receive 1250 mg/m2 oral capecitabine twice daily or observation. Of the 447 patients enrolled, 223 received capecitabine which was associated with improved overall survival and an adequate safety profile [59, 60].
The work of BILCAP built on that of SWOG S0809, a phase II trial which evaluated the outcomes of 79 patients with extrahepatic cholangiocarcinoma or gallbladder carcinoma after radical resection. Patients received four cycles of gemcitabine and capecitabine, followed by capecitabine and radiotherapy. The findings were encouraging regarding efficacy and tolerance [61].
Patients with unresectable and metastatic disease should be treated with gemcitabine and cisplatin, based upon a phase II randomized, controlled trial evaluating 510 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer or ampullary cancer. Patients that received gemcitabine and cisplatin, versus gemcitabine alone, had a significant survival advantage [62]. Based on disease progression, the addition of FOLFOX as a second line therapy may provide additional survival benefit. The ABC-06 trial, a phase III randomized, controlled trial evaluated 162 patients with locally advanced or metastatic biliary tract cancer with documented radiological disease progression to first-line cisplatin and gemcitabine. These patients were assigned to active symptom control versus active symptom control and FOLFOX. Those who received FOLFOX had longer median overall survival [63]. There is no role for surgical intervention in these patients, aside from symptom management with palliative intent, for example, biliary drainage via endoscopic or percutaneous routes for jaundice) [42]. In addition, the inclusion of palliative care should be considered and when possible, clinical trials should be offered.

Surveillance

Few studies have published on the optimal timing of surveillance and recurrence after gallbladder cancer resection, but up to 50% of patients recur within 2 years of surgery [64]. Therefore, NCCN guidelines recommend imaging every 3-6 months for 2 years then 6-12 months for up to 5 years or as clinically indicated [65].

Controversies & Limitations

Despite published guidelines for surgical management of gallbladder cancer, few patients undergo the recommended surgery and adjuvant therapies. As previously mentioned, patients with stage T1b disease and greater should be managed with an extended radical resection. For many patients, this can happen upon initial diagnosis or at a second operation if gallbladder cancer is found incidentally or ultimately upstaged after surgery. It has been demonstrated that fewer than 10% of patients eligible for extended resection, undergo surgery, but those that do benefit from a significant survival advantage [66-70]. This is critical to understand as it has been demonstrated that more than 40% of patients who underwent re-resection for gallbladder cancer after cholecystectomy alone were found to have residual disease [71]. Similarly, the use of adjuvant chemotherapy in resectable gallbladder cancer is under-utilized, and associated with a significant survival advantage [72]. This is thought to be multifactorial, including patient-specific (i.e. insurance status) and institutional (i.e. guideline adherence and facility characteristics).
Similarly, as previously mentioned, despite guidelines recommending at least six nodes be evaluated at time of resection, fewer than 20% of patients undergo sufficient lymphadenectomy, which was associated with a significant survival benefit [73]. More so, fewer than 60% of patients undergo any form of lymph node dissection [74]. This survival benefit may be in part due to accurate staging and local tumor recurrence, demonstrating the value of lymphadenectomy as diagnostic, prognostic and therapeutic. This again is thought to be multifactorial, as differences based on age, insurance status and facility type have been demonstrated [73, 74]. In addition, guideline based care can be best achieved in multidisciplinary settings [75]. Therefore, patients with gallbladder cancer may benefit from referral to a specialized center.

Summary

Gallbladder cancer represents a terrible disease with poor survival. This is due largely in part to presentation with advanced disease. For these patients, diagnosis is best made with cross-sectional imaging and pathologic confirmation. Patients with stage T1b and greater disease require an extended surgical resection and should be paired with adjuvant chemotherapy. Despite these recommendations, the majority of patients do not receive the appropriate treatment and further concentrated efforts are necessary to ensure patients receive stage appropriate care. These efforts, in combination with clinical trials and future targeted therapies, offer the best chance for improved survival.

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