Carcinoma Gallbladder; curative surgery

The poor prognosis associated with Ca Gallbladder is thought related to advanced stage at diagnosis, which is due both to the anatomic position of the gallbladder, and the vagueness and nonspecificity of symptoms.

• Complete surgical resection offers the only chance for cure of gallbladder cancer.
  
• Unfortunately, only 10 to 30% of patients have surgically resectable disease.
  
• The extent of surgery is largely dictated by the T stage of the tumor, which in turn is proportional to the likelihood of lymph node metastases (N stage) and peritoneal and distant dissemination (M stage).

The most significant change in sixth edition of The American Joint Committee on Cancer (AJCC) TNM staging system for gallbladder carcinoma, is that there is no longer a distinction between T3 and T4 tumors based on the depth of liver invasion.

The management of patients with gallbladder carcinoma is dependent on the stage of disease at presentation. Patients present in one of three ways:

• (1) an incidental finding after cholecystectomy for suspected benign disease;
• (2) a suspected or confirmed lesion that appears resectable after preoperative studies;
• (3) advanced, unresectable disease.

Each of these presentations demands a unique treatment strategy, with surgical resection as the only curative option.

• Though high-quality cross-sectional imaging studies are increasingly capable of detecting metastatic disease that would preclude curative resection, all patients with potentially resectable gallbladder carcinoma should undergo staging laparoscopy prior to an attempt at curative resection.
  • Approximately 50% of patients with gallbladder carcinoma have metastatic disease detected at the time of laparoscopy and thus can be spared a laparotomy.
    
  • Should the staging laparoscopy prove negative, definitive curative resection should then be entertained.

Contraindications

Among the absolute contraindications to surgery are liver or peritoneal metastases, ascites, extensive involvement of the hepatoduodenal ligament, and encasement or occlusion of major vessels. Direct involvement of colon, duodenum, or liver is not an absolute contraindication.

Five-year survival rates are 5 to 12 percent in many large series. In data derived from the National Cancer Data Base, five-year survival rates stratified according to stage were:

Tis disease — 60 percent

T1 N0 — 39 percent

T2 N0 — 15 percent

T3 N0 or node-positive disease — 5 percent

Better outcomes have been noted in the last decade, and attributed to more aggressive surgery and the use of postoperative adjuvant therapy.
The impact of radical surgery can be illustrated by results of one Japanese series.

• The five-year survival rates following simple cholecystectomy among all patients with T2 tumors was 40 percent, but in a small group who underwent radical reoperation (resection of the gallbladder fossa, 2 cm of adjacent liver, extrahepatic bile duct, and regional lymph nodes), 90 percent survived five years.
  
• Unfortunately, T1 or T2 disease is an uncommon finding in incidentally diagnosed Ca Gallbladder, accounting only for 5 to 10 percent of cases.

• Even for patients with more locally advanced but potentially resectable disease, radical surgery that achieves negative margins can result in long-term survival in a minority of patients.

Spread of the Disease

• Lymphatic metastases can be found in 35 to 80 percent of patients with ≥T2 disease at diagnosis.
• The gallbladder lymphatics drain first to the cystic node and the common duct (pericholedochal) nodes (previously called N1 nodes in the 1997 TNM classification, now classified only as regional nodes) and
• then into the pancreaticoduodenal, celiac axis, and paraaortic nodes (previously referred to as N2 nodes in the 1997 classification; currently considered regional nodes,
• with the exception of peripancreatic nodes along the body and tail of the pancreas, which denote metastatic disease).
• However, the lymphatic drainage pattern does not always follow a predictable pattern.
• In some cases, lymph nodes posterior to the pancreas or portal vein are involved initially.

• Direct spread.
• GBC frequently extends directly to adjacent structures such as liver, stomach, duodenum, pancreas, colon, omentum, or the abdominal wall.
• Hematogenous spread.
• Fewer than 10 percent of cases present with hematogenous metastases.

• Peritoneal carcinomatosis involving the upper abdomen may complicate the disease in patients with transmural or serosal penetration.

For patients undergoing cholecystectomy for gallstone-related disease, the surgeon should maintain a high index of suspicion for cancer gallbladder, particularly in an older patient with a longstanding history of gallstones or a thick-walled or calcified (porcelain) gallbladder, both major risk factors for Ca gallbladder.

• If cancer is suspected during an open procedure, a small biopsy should be obtained before dissection of the gallbladder.
  
• Although intraoperative frozen section analysis can reliably indicate whether a lesion is benign or malignant, it cannot reliably predict the depth of tumor invasion.

• Current consensus is that patients should undergo a second curative procedure if an unexpected cancer gallbladder is diagnosed postoperatively after cholecystectomy, except for those who are found to have T1a disease.

The likelihood of finding an unsuspected GBC during a laparoscopic cholecystectomy is similar to that with open procedures.

• In two large series combined, incidental GBC was found in 14 of 2616 patients undergoing laparoscopic cholecystectomy (0.5 percent).
• If GBC is strongly suspected, an open rather than laparoscopic procedure is recommended
• If an obviously malignant lesion is encountered laparoscopically, it is best not to sample it laparoscopically to reduce the hazard of seeding, and the procedure should be converted to an open resection if surgical expertise with resection of gallbladder cancer is available.
  
• Otherwise, patients should be referred to a tertiary center for further exploration.
  
• Although available data suggests that laparoscopic manipulation does not diminish the survival of patients with incidentally found GBC, port site recurrences have been described.
  • Because of this, laparoscopic port sites should be removed at the time of reexploration.

Surgical options

• Simple cholecystectomy

• Radical or extended cholecystectomy, which includes removal of the gallbladder plus at least 2 cm of the gallbladder bed, and dissection of the regional lymph nodes from the hepatoduodenal ligament behind the second portion of the duodenum, head of the pancreas and the celiac axis

• Radical cholecystectomy with resection of liver (segmental or lobar), or bile duct/pancreaticoduodenectomy

• When it is deemed necessary, the extent of liver dissection is controversial, with recommendations ranging from nonanatomical wedge resection to removal of segments IV and V, segments IV, V, and VIII, right hepatic lobectomy, and right trisegmentectomy (segments IV, V, VI, VII, VIII). Right hepatic lobectomy alone is generally not recommended, since up to one-third of tumors invade the left lobe (segment IV), which remains untreated with this approach. A right hepatic lobectomy may make sense in selected patients because of clinical or anatomic considerations (eg, tumor of the gallbladder neck involving the right portal triad). For T3/T4 tumors, a formal segmental hepatic resection (segment IVb and V) is generally required.

For patients with gallbladder carcinoma in situ (Tis) or invasive carcinoma limited to the mucosa (T1a),

• most surgeons agree that simple cholecystectomy is adequate treatment provided that the cystic duct margin is negative.
• The incidence of lymph node metastases in patients with T1a tumors is only 2.5% and so an extended resection to include the regional lymph nodes, with its attendant increased morbidity and mortality, is not justified for the small potential survival benefit.

There is justification for an extended resection in patients with T1b (invasive of muscle) tumors, however, given a 15% incidence of nodal metastases with these lesions [36].

• Several investigators have shown an improvement in 5-year survival after extended cholecystectomy for T1b tumors.

As T2 (invasive of perimuscular connective tissue) tumors are associated with a 56% incidence of regional lymph node metastases, an extended cholecystectomy with regional lymphadenectomy is warranted.

• In addition, since a routine cholecystectomy employs a subserosal plane of dissection on the liver side that will result in a positive margin, an extended cholecystectomy including at least a wedge resection of the gallbladder fossa of the liver (segments IVb and V) must be performed.
• The benefit of extended resection in these patients is supported by data demonstrating improved survival. Shirai et al. reported a 5-year survival rate of 40% for T2 tumors after simple cholecystectomy compared with a rate of 90% after extended cholecystectomy. Chijiiwa et al. reviewed 28 patients with T2 gallbladder carcinomas who underwent surgical resection and found a significantly better 5-year survival rate in patients who underwent an extended cholecystectomy (59%) compared to those who had a simple cholecystectomy (17%).
• Radical second operations for T2 tumors are also associated with improved 5-year survival rates of 61 to 75%.
• Even patients with involved cystic, portal and portacaval lymph nodes may be curable by extended lymphadenectomy.
• In contrast, few if any patients with peripancreatic, celiac, and/or superior mesenteric nodal involvement are long-term survivors, and resection cannot be generally recommended.

In the medically high-risk patient for whom reresection is not feasible, observation could be considered for cancer limited to the mucosa or submucosa, while radiation therapy (RT) with concomitant chemotherapy should be strongly considered for more advanced lesions, if the patient can tolerate this treatment.

Locally advanced (T3/4) resectable disease

• In the past, surgeons were reluctant to operate on patients with locally advanced (T3/4) disease because of their overall poor prognosis.

• Some Japanese groups advocate even more extensive surgery involving hepatectomy, pancreaticoduodenectomy, colectomy, and even nephrectomy for patients with locally advanced but potentially resectable disease.
• Although long-term survivors are reported, morbidity and mortality rates are high (48 to 54, and 15 to 18 percent, respectively).

For patients with regional nodal (N1) disease (ie, limited to cystic, portal, and portocaval nodes), five-year survival rates from 28 to 60 percent are reported with radical resection.
Results with radical lymphadenectomy are less favorable with N2 disease, particularly if the extent of nodal disease is beyond the hepatoduodenal ligament, posteriosuperior pancreaticoduodenal area, and along the common hepatic artery.

Locally advanced, unresectable disease

• Patients who are locally unresectable (eg, because of major encasement of vascular structures) should be referred for chemotherapy alone or chemoradiotherapy.
• There is no indication for radical surgery for the purpose of debulking, and attempted resection should only be undertaken if it is possible to achieve a complete resection.

• Although the value of a debulking simple cholecystectomy has not been definitely proven in this situation, this approach is recommended by some to prevent future episodes of cholecystitis in patients with locally unresectable disease.
• The optimal way to manage these patients has not been established and treatment must be individualized based on extent and resectability of the disease and experience of the management team.