How can I be sure that the patient has gallbladder cancer?

Gallbladder cancer is most typically diagnosed in the seventh decade of life, with a median age of 62 to 66 years.

The symptoms of gallbladder cancer overlap with the symptoms of gallstones and biliary colic. Abdominal pain may be of a more diffuse and persistent nature than the classic right upper quadrant pain of gallstone disease. Jaundice, anorexia, and weight loss often indicate more advanced disease. Gallbladder cancer should be suspected in older patients (>70 years) with a history of persistent right upper quadrant pain and weight loss.

The most common clinical feature of gallbladder cancer would include right upper quadrant pain, making it difficult to distinguish from benign cholecystitis. Other clinical features of gallbladder cancer include jaundice, weight loss, and anorexia.

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A tabular or chart listing of features and signs and symptoms

There are no pathognomonic features of this disease.

  • Abdominal pain more diffuse and persistent than the classic right upper quadrant pain of gallstone disease

  • Jaundice

  • Anorexia

  • Weight loss

  • Jaundice

  • Ascites

  • Palpable mass in the right upper quadrant (Courvoisier sign, if this is due to a palpable gallbladder)

  • Periumbilical lymphadenopathy (Sister Mary Joseph nodes)

  • Left supraclavicular adenopathy (Virchow’s node)

  • Pelvic seeding: mass is palpated on digital rectal examination (Blumer shelf)

Differential diagnoses
  • Hilar and peripheral cholangiocarcinoma

  • Granulomatous cholecystitis

  • Acute cholecystitis

  • Choledocholithiasis

How can I confirm the diagnosis?

Right upper quadrant ultrasound is the initial radiologic study of choice. Typical features on ultrasound include gallstones and gallbladder wall thickening. However, the thickening is often discontinuous and there are more frequent findings of echogenic mucosa and submucosal echolucency, compared to benign gallbladder disease. A polypoid or invasive mass is frequently seen on ultrasound when gallbladder cancer is present.

CA 19-9 is the best serum tumor marker but is frequently not elevated in the presence of gallbladder cancer. Carcinoembryonic antigen (CEA) can be elevated in gallbladder cancer, but the sensitivity is only about 50%. Increased alkaline phosphatase and bilirubin levels are found in cases of advanced gallbladder cancer.

Abdominal triphasic CT scan or MRI with MRCP (magnetic resonance cholangiopancreatography) is utilized to confirm the diagnosis and demonstrates a mass partially obliterating the gallbladder lumen in about 50% of cases. A polypoid mass is identified in about 25% of cases. Diffuse wall thickening is present on CT or MRI in about 6% of cases.

Endoscopic ultrasound (EUS) may be helpful as an additional test to identify the presence of a gallbladder mass and to evaluate for periportal and peripancreatic adenopathy, as well as possible tissue diagnosis. Nevertheless, large inflammatory lymph nodes are difficult to differentiate from metastatic adenopathy without pathologic confirmation.

Endoscopic retrograde cholangiopancreatography (ERCP) and bile cytology can be useful in confirming the diagnosis of gallbladder cancer but cytologic positivity is found in approximately 50% of cases. Once a mass concerning for the presence of gallbladder cancer is identified, a biopsy is only rarely indicated to confirm the diagnosis. A biopsy should only be considered if surgical resection is not possible due to significant comorbidities. In addition, it is generally recognized that cholecystectomy as a diagnostic biopsy before definitive resection is not appropriate. The treating physician must be prepared for definitive surgical resection at the time of initial surgical exploration, even if it is a locally advanced tumor. If the ultrasound is suspicious then a CT scan or MRI and MRCP is warranted. If diagnosis is confirmed, surgical resection is indicated. If diagnosis remains in doubt, EUS or ERCP with bile cytology would be the next step. Biopsy of the gallbladder mass is indicated only in patients not medically fit for surgical resection.

Laboratory tests
  • Liver function tests. Elevated alkaline phosphatase and bilirubin levels are often found with more advanced disease due to bile duct obstruction.

  • Tumor markers including CA 19-9 may be significantly elevated in both cholangiocarcinoma and gallbladder cancer. It is more helpful if the clinical suspicion for gallbladder cancer is high. It can be useful in conjunction with CEA.

Radiographic studies
  • Ultrasonography (US). A mass in the gallbladder area can be identified in 50% to 75% of patients with cancer. Metastatic lesions in the liver can be identified. Increased Doppler flow can be seen within the mass.

  • Computed tomography. CT scans can demonstrate tumor invasion outside of the gallbladder and identify metastatic disease elsewhere in the abdomen or pelvis The combination of CT scan and US provides details of disease extension, including liver invasion and possible adenopathy.

  • Magnetic resonance imaging (MRI with MRCP). Also helpful to evaluate disease extension into other tissues or metastatic disease in the liver. It can provide anatomic details.

Endoscopic evaluations
  • Endoscopic retrograde cholangiopancreatography (ERCP). It can demonstrate the site of the obstruction and exclude ampullary pathology. Brush and bile cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide tissue diagnosis. Palliative stenting can also be performed.

  • Endoscopic ultrasound (EUS). To assess regional lymphadenopathy and depth of tumor invasion into the wall of the gallbladder. It also can provide a means of obtaining tissue diagnosis.

Additional testing
  • Percutaneous transhepatic cholangiography (PTC) may allow access to the proximal biliary tree. Material for cytology can be obtained, drainage, and potentially palliative stenting as well.

  • Percutaneous biopsy with CT or US guidance for tissue diagnosis.

  • Chest x-ray to rule out metastatic disease.

What other diseases, conditions, or complications should I look for in patients with gallbladder cancer?

Cholelithiasis, especially large stones (>2 cm), can be found and has been reported in 75% to 98% of all cases of gallbladder cancer. In the United States, women are 2 to 3 times more likely than men to develop gallbladder cancer. Porcelain gallbladder (calcification of the gallbladder) is associated with gallbladder cancer in 10% of cases. Other differential diagnoses include cholangitis, malabsorption, and bowel obstruction.

  • Cholangitis due to ductal obstruction is a life-threatening situation.

  • Malabsorption with significant weight loss from lack of bile emptying and fat emulsification.

  • Bowel obstruction from adjacent organ involvement, specifically colon and duodenum.

What is the right therapy for the patient with gallbladder cancer?

Complete surgical resection with negative margins is the only therapy that offers a chance of cure in this disease. Definitive surgical resection depends on the stage and location of the tumor. For T1 tumors (stage 1A), simple cholecystectomy is adequate. For gallbladder carcinomas that are stage 1B, stage II, and stage III, en bloc resection of the gallbladder, segments 4B and 5 of the liver, and regional lymph node dissection are indicated.

The extent of the regional lymph node dissection typically should include, at a minimum, resection of the soft tissue anterior to the duodenum and pancreas and skeletonization of the portal vein and hepatic artery. It is also appropriate to perform a Kocher maneuver and resect lymph node tissue behind the pancreas and duodenum. Removal of lymph nodes between the aorta and inferior vena cava implies an extensive lymphadenectomy. If the tumor involves the cystic duct and a negative margin cannot be obtained without extrahepatic bile duct resection, this should be performed.

It is controversial whether the extrahepatic bile duct should be routinely resected during definitive treatment for all stage 1B-III gallbladder cancers. Proponents indicate that it allows for more extensive lymphadenectomy in the porta hepatis. However, there is no data to support its routine use. Extrahepatic bile duct resection is probably best performed on a selective basis, when there is obvious nodal disease in the porta hepatis or if inflammation or scarring compromise adequate lymphadenectomy. Sometimes after prior cholecystectomy the differentiation between scar and tumor in the porta hepatis is problematic. In these cases, depending on the area of concern, the best management may be an extended right hepatectomy and extrahepatic bile duct resection.

Many patients will have local or regional recurrence of gallbladder carcinoma following surgical resection. In addition, there is a high incidence of development of metastases involving the liver, peritoneal surfaces and distant sites.

Unfortunately, there are few randomized studies that guide the selection of appropriate adjuvant therapy in this disease. The role of adjuvant radiation therapy is to control microscopic residual deposits of carcinoma in the tumor bed and regional lymph nodes. Post-operative adjuvant radiotherapy can be administered by either external beam radiotherapy, brachytherapy, or intraoperative radiotherapy or a combination of these modalities.

For gallbladder carcinoma, external beam radiotherapy is most frequently utilized due to its widespread availability and the capacity to deliver a homogeneous high dose to a large volume of tissue. Typically, adjuvant radiotherapy will be combined with chemotherapy since retrospective small phase 2 studies have suggested better outcomes for patients receiving adjuvant chemoradiotherapy. However, due to the small numbers of patients in clinical trials, possible selection bias and lack of randomized data showing a benefit, routine adjuvant chemoradiotherapy is not recommended for all patients. The most common practice is to deliver adjuvant radiotherapy with concurrent 5-FU, 5-FU plus leucovorin, or gemcitabine to high-risk patients such as those with positive resection margins or local lymph node involvement.

For advanced disease, palliative procedures for gallbladder carcinoma include drainage of the biliary system in the presence of jaundice. Drainage of the bile ducts can be performed with ERCP-placed stents, PTC-placed stents, or surgical bypass techniques. Metal expandable stents can be placed via these techniques so that biliary drainage is maintained for longer duration than that achieved with Silastic stents. Palliative surgical bypass should only be considered in patients who are being explored for attempted resection of disease and are found to be unresectable due to locally advanced disease. A hepaticojejunostomy to segment 3 of the liver can provide relief of jaundice.

For patients with unresectable disease, the median duration of survival is less than 6 months. The rationale for radiation therapy with or without concurrent chemotherapy in patients with unresectable disease is to provide palliation of symptoms. Rarely, it may increase survival but, typically, only for a limited time period.

What is the most effective initial therapy?

When gallbladder cancer is suspected, patients should undergo a careful resection of their gallbladder, together with the surrounding liver bed (segments 4B and 5). Care should be taken not to cut through the tumor. Removal of the porta hepatis and retroduodenal lymph nodes is also standard therapy.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

If a patient undergoes operative attempt at resection of gallbladder carcinoma and a positive surgical margin(s) is encountered, the treatment of choice is chemoradiation.

For external beam radiotherapy, the gallbladder fossa and adjacent liver plus the regional nodal areas should be irradiated. Following complete resection of gallbladder carcinoma, post-operative adjuvant chemoradiotherapy is reserved for those patients at high risk for recurrence.

If recurrence is identified following complete surgical resection of gallbladder carcinoma, typically the extent of disease is not considered curable. Therefore, the primary goal of therapy is to provide palliation. For this, chemotherapy or chemoradiotherapy may be indicated. If the recurrence is distant (in the liver or peritoneal cavity), chemotherapy alone may be indicated. If the recurrence is regional such as disease in the porta hepatis or nearby lymph nodes, chemoradiotherapy (if radiotherapy has not been previously given) may be indicated.

In a randomized, controlled single-institution study from India, Sharma et al. (2010) compared best supportive care versus 5FU/leucovorin or gemcitabine/oxaliplatin in 81 patients with unresectable gallbladder cancer. The gemcitabine/oxaliplatin treatment arm was statistically superior in terms of overall response rate, median overall survival, and progression-free survival.

Selected patients with unresectable disease may be considered for surgical resection after response to chemotherapy. This is based on a retrospective study showing markedly improved survival in a small number of patients who received gemcitabine and cisplatin followed by surgery. See Figure 1, algorithm for management of gallbladder cancer found incidentally on pathologic examination of a cholecystectomy specimen.

Figure 1.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Second-line therapies for gallbladder carcinoma following failure of fluoropyrimidine-based chemotherapy include the utilization of gemcitabine. The combination of gemcitabine and cisplatin or the combination of gemcitabine and capecitabine or gemcitabine and oxaliplatin may be more effective than gemcitabine alone.

Because EGFR is overexpressed in most biliary tract cancers, trials using EGFR-targeting agents have been performed. The BINGO trial, a phase II clinical trial of 101 patients (24% with gallbladder cancer), compared gemcitabine with oxaliplatin (GEMOX), alone or in combination with cetuximab; an interim analysis demonstrated a benefit for the GEMOX plus cetuximab arm, with a progression-free survival of 5 months compared with 7 months in the other arm.

Listing of these, including any guidelines for monitoring side effects.

Fluoropyrimidine- or gemcitabine-based chemotherapies represent first-line therapies. Although no standard second-line therapy exists, if the patient has failed fluoropyrimidines, gemcitabine-based therapy is indicated. If the patient has failed gemcitabine-based therapy, fluoropyrimidines are indicated. Rarely, doublet therapy of gemcitabine with oxaliplatin, gemcitabine with cisplatin, or gemcitabine with capecitabine may result in improved response rates compared to gemcitabine alone.

How should I monitor the patient with gallbladder cancer?

Gallbladder carcinoma can recur regionally as local spread of tumor or nodal disease and/or metastasize to the liver, intra-abdominal cavity, or distant parts of the body. Complications of the disease include recurrence of tumor, resulting in visceral pain from intra-abdominal involvement. Regional recurrence can lead to obstructive jaundice. Recurrent disease should be suspected in patients who are having unexplained weight loss, obstructive jaundice, or increasing intra-abdominal pain.

Following therapy, disease burden is best monitored through the utilization of CT scan of the chest/abdomen/pelvis. Rising serum CA19-9 and/or CEA may also be indicative of recurrent gallbladder cancer. PET/CT may also provide additional information not visualized on CT alone.

Gallbladder cancer is associated with a high recurrence rate and a 5-year overall survival of 5%. There are no data supporting the utilization of aggressive surveillance programs. There should be a patient/physician discussion regarding appropriate follow-up and imaging. Following definitive therapy, one approach includes follow-up serum CA19-9 levels and radiologic imaging of the abdomen/pelvis every 6 months for 2 years. If abnormalities are identified in serum CA19-9 values without definitive evidence of recurrence on CT scan, alternative imaging such as MRI should be considered. CT/PET may also reveal disease not identified on CT or MRI alone.

What's the evidence?

“SEER surveillance, epidemiology, and end results”.

“Staging Resources”. AJCC Staging Resources.

Sharma, A, Dwary, AD, Mohanti, BK. “Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study”. J Clin Oncol. vol. 28. 2010. pp. 4581-4586.

Valle, JS, Wasan, HS, Palmer, DD. “Gemcitabine with or without cisplatin in patients (pts) with advanced or metastatic biliary tract cancer (ABC): results of a multicenter, randomized phase III trial (the UK ABC-02 trial)”. J Clin Oncol. vol. 27. 2009. pp. 15s

Malka, D, Trarbach, T, Fartoux, L. “A multicenter, randomized phase II trial of gemcitabine and oxaliplatin (GEMOX) alone or in combination with biweekly cetuximab in the first-line treatment of advanced biliary cancer: interim analysis of the BINGO trial”. J Clin Oncol. vol. 27. 2009. pp. 4520

Gruenberger, B, Schueller, J, Heubrandtner, U. “Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study”. Lancet Oncol. vol. 11. 2010. pp. 1142-1148.

Gallardo, J, Rubio, B, Ahumada, M. “Therapy for advanced gallbladder cancer: Improving survival”. J Clin Oncol. 2008. -26.

Jensen, EH, Abraham, A, Jarosek, S. “Lymph node evaluation is associated with improved survival after surgery for early stage gallbladder cancer”. Surgery. vol. 146. 2009. pp. 706-711.

Bartlett, DL, Ramanathan, RK, Ben-Josef, E, DeVita, VT, Lawrence, TS, Rosenberg, SA. “Cancer of the biliary tree”. 2008. pp. 1156-1186.

Dingle, BH, Rumble, RB, Brouwers, MC. “The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: a systematic review”. Can J Gastroenterol. vol. 19. 2005. pp. 711-716.

Ito, H. “Accurate staging for gallbladder cancer: implications for surgical therapy and pathological assessment”. Ann Surg. 2011. pp. 24-1.

Belli, G. “Revision surgery for incidentally detected early gallbladder cancer in laparoscopic era”. J Laparoendosc Adv Surg Tech A. vol. 21. 2011. pp. 531-535.

Jai Young Cho. “Laparoscopic approach for suspected early-stage gallbladder carcinoma”. Arch Surg. vol. 145. 2010. pp. 128-133.