Gallbladder Tumors Treatment & Management

Cholecystectomy is recommended for suspicious gallbladder polyps in order to facilitate early detection and treatment. Risk factors for malignancy include the following:

• Polyp larger than 1 cm
• Primary sclerosing cholangitis
• Presence of a single polyp
• Patient older than 50 years

Vascularity and invasion of the gallbladder wall seen on ultrasonography (US) are suspicious findings. One study demonstrated that 7.4% of gallbladder polyps that were 1 cm in size or smaller were neoplastic. ^[21] The report's authors recommended cholecystectomy for lesions that are 6 mm in size or larger.

Gallbladder cancer is commonly diagnosed incidentally following cholecystectomy or on the basis of preoperative imaging. The surgical indications are based on stage and margin status (see Staging). ^[22]

Incidentally discovered T1a gallbladder cancers (limited to the mucosa) can generally be treated with cholecystectomy alone. T1b tumors (invading the muscle layer) are typically treated with resection of liver segments IVb and V and portal lymph node dissection. Bile duct resection is sometimes required to achieve a negative margin, especially if the cystic duct margin was positive on the cholecystectomy specimen. T2 and T3 lesions are also treated with liver resection and portal lymph node dissection, but extended right hepatectomy may be necessary to achieve negative margins. ^[4]

Contraindications for surgery with curative intent include the following:

• Presence of distant metastatic disease (including biopsy-proven metastatic aortocaval lymphadenopathy)
• T4 lesion (local invasion of the hepatic artery, main portal vein, and multiple adjacent structures)
• Inability to obtain a negative margin

Most North American surgeons have considered the presence of celiac and retroperitoneal lymph node metastases a contraindication for resection because of the poor oncologic outcome of these patients with available treatments. For the same reason, there has been some controversy about the benefit of resecting patients with T3 lesions. Some patients may have lesions that are technically resectable but may be unable to tolerate the necessary procedure.

Small gallbladder tumors are common, and many can be safely followed with serial US examination. It is generally thought that polyps smaller than 1 cm are safe to follow, though one study recommended that polyps that are 6 mm in size or larger be considered for cholecystectomy. ^[21] The factors listed above should be considered when deciding between surgery and observation for gallbladder polyps.

Chemotherapy is used in the adjuvant and palliative treatment of gallbladder cancer. Because of the rarity of this cancer, the benefit of adjuvant treatment remains unproven, and no standard adjuvant treatment protocol has been defined.

Phase II studies have shown that the use of single-agent chemotherapy (with gemcitabine, capecitabine, or 5-fluorouracil [5-FU]) in the palliative setting can be beneficial. Combination chemotherapy also has been shown to be beneficial and is usually based on gemcitabine, ^[23] capecitabine, or 5-FU used in combination with cisplatin or oxaliplatin. Fluoropyrimidine-based chemoradiotherapy is commonly employed in the palliative and adjuvant setting as well. No regimen has been conclusively established as superior.

A 2008 study found that only 20% of patients with gallbladder cancer received adjuvant treatment. ^[24] In that report, no benefit from adjuvant therapy could be demonstrated, but only a small number of patients received this treatment.

Generally, fluoropyrimidine-based chemoradiotherapy or single-agent chemotherapy with fluoropyrimidines or gemcitabine is used. ^[25] Because of the high cure rate with surgery alone for T1N0 lesions, adjuvant therapy is not commonly offered to these patients.

A 2017 review by Mitin et al found that the use of adjuvant chemotherapy for resected gallbladder cancer did not increase appreciably between 2005 and 2013, even though statistically significant improvements in 3-year overall survival were reported in several studies (except in cases of T1N0 disease). ^[26]

A 2019 guideline from the American Society for Clinical Oncology (ASCO) recommended that patients with resected biliary tract cancer be offered adjuvant capecitabine chemotherapy for 6 months. ^[27] Patients with extrahepatic cholangiocarcinoma or gallbladder cancer and a microscopically positive surgical resection margin (R1 resection) may be offered chemoradiation therapy.

Although the application of molecular targeted drugs and immunotherapy to the treatment of gallbladder cancer appears promising, there remains a need for further research into the capacity of such approaches to yield significant improvements in prognosis. ^[28]

Operative resection offers the only chance for long-term survival. ^[29]  Laparoscopic, open, and robotic approaches are available. Specific indications for surgical treatment, choice of approach, and use of multidisciplinary treatment strategies remain subjects of discussion. ^[22]

Benign lesions

Cholecystectomy is recommended in patients with polyps larger than 1 cm or with polyps in the setting of primary sclerosing cholangitis, as well as in patients with a porcelain gallbladder. The decision between a laparoscopic and an open operation depends on the risk of the lesion being malignant. Preoperative imaging should be reviewed to exclude the presence of invasion before a laparoscopic approach is planned.

In these cases, the gallbladder is evaluated with frozen section. If a T1b or deeper cancer is identified, then more extensive surgery is performed as described below. The patient should be counseled about this possibility preoperatively.

Guidelines on the management and follow-up of gallbladder polyps have been jointly developed by the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the European Association for Endoscopic Surgery and Other Interventional Techniques (EAES), the International Society of Digestive Surgery–European Federation (EFISDS), and the European Society of Gastrointestinal Endoscopy (ESGE). ^[30]  (See Guidelines.)

Malignant lesions

Gallbladder cancer can be diagnosed either incidentally in a surgical specimen excised for other reasons or on the basis of imaging studies. When it is diagnosed incidentally, simple cholecystectomy alone is recommended for T1a lesions (limited to the mucosa), and further surgery is considered for deeper lesions. Patients may also present with jaundice. The benefit of preoperative drainage is debatable.

Patients with localized gallbladder cancer are evaluated for surgical resection. Surgery is contraindicated in the presence of distant metastases. If the tumor was diagnosed incidentally in a surgical specimen, reresection is indicated for T1b or deeper lesions.

Malignant lesions are commonly staged laparoscopically in order to exclude the presence of undetected intra-abdominal metastases prior to curative laparotomy. Staging laparoscopy is also shown to be effective when the cancer was diagnosed following laparoscopic cholecystectomy.

T1a gallbladder cancer can be treated with simple cholecystectomy. Patients with T1b or deeper gallbladder cancer are typically treated with hepatic resection and lymph node dissection that includes the portal, gastrohepatic ligament, and retroduodenal nodes. Resection of liver segments IVb and V is frequently adequate to achieve negative margins. (See the images below.) Some have suggested that simple cholecystectomy may be sufficient for T1b lesions smaller than 1 cm. ^[31]

In some cases, extended liver resection or bile duct resection or both may be necessary to achieve negative margins. A study by He et al found that simple cholecystectomy was the optimal surgical procedure for stages 0 and I, whereas radical cholecystectomy was preferable for stages II and III. ^[32]

Adjuvant treatment with either fluoropyrimidine-based chemoradiotherapy or chemotherapy alone is recommended.

When patients have unresectable tumors, tissue diagnosis and relief of jaundice (if present) are required prior to initiation of palliative treatment.

Percutaneous biopsy is avoided in cases where the tumor is resectable.

Preparation for surgery

As outlined above, the preoperative evaluation of the patient with gallbladder cancer is similar whether the tumor is diagnosed incidentally after cholecystectomy or on the basis of imaging studies.

The history and physical examination determine the suitability of the patient for curative surgery. When the tumor is diagnosed incidentally following cholecystectomy, the pathology report and preoperative imaging are reviewed to note the margin status, location of the tumor, and depth of invasion. If the cystic duct margin is close or positive, bile duct resection may be considered, for example.

Laboratory evaluation determines the extent of hepatic reserve and the presence of biliary obstruction. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) values may be helpful as baseline studies that inform treatment decisions in the future. Computed tomography (CT) scans of the chest, abdomen, and pelvis are carefully reviewed to determine the presence of distant metastatic disease, the extent of local invasion, and the presence of vascular or biliary involvement.

The operative plan can usually be determined preoperatively. The need for biliary drainage in patients with preoperative jaundice is individualized, but some surgeons believe that the increased risk of infection with preoperative biliary drainage outweighs the risk of hepatectomy in the setting of biliary obstruction.

Operative details

Staging laparoscopy discovers undetected metastatic disease in a high percentage of patients and can be used to avoid a nontherapeutic laparotomy. The yield is reasonably high in patients that had a prior noncurative cholecystectomy as well. Many surgeons will plan staging laparoscopy for all patients prior to laparotomy with curative intent.

The initial exploration focuses on the presence of metastatic disease that was not detected by preoperative imaging and staging laparoscopy. As many as 15% of patients may be found to have metastatic disease that was not detected by these methods. In the view of most North American surgeons, biopsy-proven metastases in the celiac nodes preclude resection. Aortocaval nodal metastases are considered distant metastatic disease. Biopsy-proven metastases in the portal nodes may affect the risk-benefit analysis for individual patients as well.

Intraoperative US (IOUS) is used to evaluate the extent of involvement of the liver, as well as the portal and intrahepatic vasculature. The intrahepatic vascular anatomy is evaluated as a guide to liver resection techniques. This information is especially useful in ligating the pedicle to segment V and avoiding injury to the right anterior portal pedicle or segment VIII pedicle. Extended right hepatectomy may be necessary to achieve tumor clearance if the tumor involves the right portal pedicle.

Surgical exploration will determine the need to resect other organs that may be involved (eg, stomach, duodenum, or colon). It may be difficult to distinguish scar from malignancy. In these cases, suspicious tissue should be treated as malignancy in order to improve the chances of a margin-negative resection.

If tumor is suspected in the bile duct on the basis of a previous pathology report or operative exploration, the presence of tumor on the right hepatic duct must be evaluated. Suspicion of tumorous involvement of the right hepatic duct will necessitate an extended right hepatectomy, excision of the extrahepatic biliary tree, and Roux-en-Y hepaticojejunostomy to the left hepatic duct.

A lymph node dissection to include the portal lymph nodes, peripancreatic lymph nodes, and retroduodenal lymph nodes is performed. A study by Ito et al indicated that accurate staging requires examination of at least six lymph nodes. ^[33]  A study by Tsilimigras et al suggested that examination of four to seven nodes may be optimal in terms of staging and survival. ^[34]

The overall rate of complications and morbidity is approximately 25%. Complications are similar to those experienced with cholecystectomy and include infection, hematoma, and bile leaks. Complication rates are higher in patients undergoing more extensive resections. Liver failure can occur after extended hepatectomy, especially if jaundice is present preoperatively.

There are no data to support aggressive surveillance after resection of gallbladder cancer, because treatment of recurrences generally is not effective. However, many clinicians and patients prefer follow-up imaging every 6 months.