Cancer gallbladder; treatment of advance and unresectable disease.

Patients with locally advanced, unresectable gallbladder carcinoma may present with symptoms of jaundice, pain, and bowel obstruction. These patients have a limited life expectancy, on the order of months, especially in the setting of liver and/or peritoneal dissemination.

• The treatment of locally advanced, unresectable gallbladder carcinoma is palliation aimed at relief of pain, jaundice, and bowel obstruction, along with prolongation of life.

• Patients who have pain from local growth may benefit from radiation therapy with or without concomitant chemotherapy.
  
• Although biliary or intestinal bypass can be considered, a percutaneous or endoscopic approach may be preferred, given the limited median survival in patients with advanced disease (generally, less than six months).

Recurrence
In a recent retrospective review of the patterns of initial disease recurrence after potentially curative surgical resection, Jarnagin et al. followed 80 patients with gallbladder carcinoma and compared them to 76 patients with hilar cholangiocarcinoma.

• The median time to disease recurrence was shorter for gallbladder carcinoma patients (11.5 months) compared to patients with hilar cholangiocarcinoma (20.3 months).
• At a median follow-up of 24 months, 68% of patients with hilar cholangiocarcinoma and 66% of patients with gallbladder carcinoma suffered disease recurrence.
• The site of initial disease recurrence was locoregional in only 15% of patients with gallbladder carcinoma compared to 59% of patients with hilar cholangiocarcinoma.
• In contrast, 85% of patients with gallbladder carcinoma had a distant (+/−locoregional) site as their initial site of failure compared to 41% of patients with hilar cholangiocarcinoma.
• This study provides considerable insight into the clinical behavior of these malignancies and suggests that in the case of gallbladder carcinoma, improvements in survival are most likely to be achieved with more effective systemic therapies as opposed to adjuvant treatment such as radiation therapy designed to achieve better locoregional control.

Radiation therapy

External beam radiation(EBRT) may be considered for palliative management of patients with locally advanced disease, particularly if there is no evidence of metastatic disease, and patients are symptomatic. At the time of exploration, the margins of unresectable and/or residual disease are often marked with radiopaque clips to facilitate treatment planning.

• Hanna and Rider reported on 51 patients with gallbladder carcinoma from the Princess Margaret Hospital, 35 of whom underwent a potentially curative surgical resection and EBRT.
• There was a survival advantage for those patients who received adjuvant EBRT in addition to surgery compared with those who had surgery alone.
• Several other small, retrospective series consisting of heterogeneous groups of patients with diverse treatment schema and follow up criteria have been published, making definitive conclusions about the potential benefits of adjuvant EBRT difficult.
• Most recently, Kresl et al. published their retrospective analysis of adjuvant EBRT with concurrent 5-FU after curative surgical resection in 21 patients with gallbladder cancer treated at the Mayo Clinic from 1985 through 1997. Patients with a margin-negative (R0) resection followed by adjuvant EBRT plus 5-FU had a favorable 5-year survival rate of 64%.
• However, similar to the findings of Jarnagin et al. [58], 67% of the patients suffered distant failure, emphasizing the need for more effective adjuvant chemotherapy for this disease.

Intraoperative radiation therapy (IORT) has been advocated as a means to deliver high-dose, small-field therapy directly to the tumor bed without the dose limitations associated with EBRT. Todoroki et al. have reported the most substantial experience with IORT in 85 patients with AJCC stage IV gallbladder cancer who underwent aggressive surgical resection with or without IORT at a mean dose of 21 Gy.

• Fortyseven patients in total received some form of radiation therapy (EBRT and/or IORT).
• The local control rate was significantly higher after adjuvant radiotherapy (59%) than after resection alone (36%).
• Moreover, the 5-year survival rate was significantly higher after adjuvant radiotherapy (9%) than after resection alone (3%), with the most pronounced improvement in 5-year survival rate (17%) in patients with only microscopic residual disease (R1 resection).

The role of radiation therapy for the palliation of symptoms such as jaundice, pain, and pruritus in patients with unresectable disease is difficult to ascertain as published studies consist of small numbers of patients with the significant confounding variable that most patients also underwent a biliary drainage procedure.

Chemotherapy

Most published studies concerning the role of chemotherapy in patients with locally advanced or metastatic gallbladder carcinoma are limited by the small numbers of patients and by the inclusion of patients with biliary tract cancers.

• Unfortunately, no single chemotherapeutic agent or combination of agents has been identified to be effective in the treatment of this disease .
• Though overall response rates range as high as 64%, complete responses are rare and median overall survival rates range from only 20 weeks to 15 months.
• 5-fluoruracil (5-FU), administered either alone or in combination, is the most extensively studied chemotherapeutic agent for this disease.
• In a prospective, randomized study of 53 patients with advanced gallbladder cancer treated with oral 5-FU alone or in combinationwith either streptozocin or methyl-CCNU, objective response rates ranged from 5 to 12% in the three treatment arms.
• 5-FU administered in combination with doxorubicin and mitomycin C (FAM) or in combination with cisplatin and epirubicin (CEF) has yielded response rates of 8% and 33%, respectively.
• Better response rates have been published in patients treated with combinations of 5-FU with hydroxyurea (30%) or interferon alpha-2b (34%).

Other chemotherapeutic agents have exhibited variable success in the treatment of advanced gallbladder cancer. Cisplatin, mitomycin C, paclitaxel, and CPT-11 have produced response rates of 10% or less as single agents.

• In contrast, four of eight patients with gallbladder carcinoma treated with single-agent oral capecitabine had either a complete (n =2) or partial (n =2) response.
• Several case reports have shown that gemcitabine is active in the treatment of patients with gallbladder carcinoma.
• Accordingly, several phase II studies of gemcitabine in combination with other agents have subsequently been reported.
• Gemcitabine in combination with cisplatin has yielded response rates of 36 to 64%; in combination with docetaxel yielded a response rate of only 9%; and in combination with 5-FU has produced response rates of 9 to 33%.
• Based on these studies, it appears that gemcitabine is an important component of the systemic therapy of gallbladder carcinoma, but additional studies of gemcitabine in combination with other agents are warranted, as the survival benefit with existing regimens is modest at best.

Hepatic arterial infusion chemotherapy has been studied in a few patients with locally unresectable gallbladder cancer.

• Partial response rates of up to 60% have been reported, but the median duration of response was only 3 months and all patients developed progressive disease.
• The median overall survival rates of 12 to 14 months in these studies is comparable to that achieved with intravenous chemotherapy, providing little impetus to recommend this more complicated mode of drug delivery.

Targeted therapy —

Early data suggest possible benefit from blockade of the epidermal growth factor receptor (EGFR) by the oral tyrosine kinase inhibitor erlotinib.

• In one study, 42 patients with advanced biliary cancer (not stratified according to primary site), 57 percent of whom had received prior chemotherapy, received erlotinib (150 mg daily).
• There were three partial responses (two with documented expression of EGFR) and seven additional patients remained progression-free at six months.
• All responding patients had mile (grade 1 or 2) skin toxicity.

• Further experience with this drug is needed, particularly combined with cytotoxic chemotherapy.

Palliative surgery

For patients with unresectable disease detected radiographically or laparoscopically, biliary drainage is best achieved by endoscopic or percutaneous means.

• If unresectable disease is discovered at the time of laparotomy, a biliary bypass (hepaticojejunostomy or segment III bypass) can be performed.
• However, in a prospective study of 21 consecutive patients with unresectable gallbladder cancer who underwent a segment III bypass, six (29%) suffered complications; three (14.3%) patients had bile leaks, and three patients died as a result of the procedure.
• The median survival of these 21 patients was only 20 weeks, and all but three patients died within 32 weeks of the surgery.
• Given this limited life expectancy, patients with unresectable gallbladder cancer and biliary obstruction are best palliated by percutaneous or endoscopic stenting.

Intestinal bypass offers durable relief of intestinal obstruction, though there are reports of excellent palliation of malignant duodenal obstruction by the endoscopic placement of expandable metal Wallstents.

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.

Gallbladder carcinoma

In the United States, Gallbladder Carcinoma (GBC) is the fifth most common gastrointestinal (GI) cancer, and the most common involving the biliary tract; fewer than 5000 new cases are diagnosed each year in the United States.

• The majority are found incidentally in patients undergoing exploration for cholelithiasis; a tumor will be found in 1 to 2 percent of such cases.
  
• The poor prognosis associated with GBC 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.

EPIDEMIOLOGY

• High rates of GBC are seen in South American countries, particularly Chile, Bolivia, and Ecuador, as well as some areas of India, Pakistan, Japan and Korea.
  • In Chile, mortality rates from GBC are the highest in the world.
    
  • These populations all share a high prevalence of gallstones and/or salmonella infection, both recognized risk factors for GBC.

• Worldwide, there is a prominent geographic variability in GBC incidence that correlates with the prevalence of cholelithiasis.

Gallbladder carcinoma affects women three times more often than men and its incidence increases steadily with age, with a steep rise beyond the age of sixty.

• The incidence of gallbladder cancer is higher in certain ethnic groups, mirroring the incidence of cholelithiasis in these groups.
  
• Alaskan and American Indian natives have a frequency of gallbladder cancer that is six times that of the rest of the country.
• GBC is more common in Caucasians than in blacks

In the United States, however, the incidence and mortality rates of gallbladder cancer have been decreasing since 1970, related at least in part to increasing numbers of cholecystectomies performed annually for gallbladder disease in the United States.

RISK FACTORS
Gallstone disease

• Gallstones are present in 70 to 90 percent of patients with GBC, and a history of gallstones appears to be one of the strongest risk factors for the development of GBC.
• Despite the increased risk of GBC in patients with gallstones, the overall incidence of GBC in patients with cholelithiasis is only 0.5 to 3 percent.
  
• The risk is higher with larger gallstones (in one study, patients with stones larger than 3 cm had a 10-fold higher risk of GBC compared to those with stones <1>

Cholecystoenteric fistula

• There is a 15% incidence of gallbladder cancer in patients with a history of a cholecystoenteric fistula and the presence of Mirizzi’s syndrome.

Porcelain gallbladder

• Porcelain gallbladder is an uncommon manifestation of chronic cholecystitis that is characterized by intramural calcification of the gallbladder wall.
  
• It is associated with cholelithiasis in more than 95 percent of cases.
  
• As with other gallstone-related conditions, these patients are at increased risk of GBC.
  
• The reported incidence of GBC in patients with a porcelain gallbladder ranges from 12.5 to 60 percent.

Gallbladder polyps

• Gallbladder polyps are outgrowths of the gallbladder mucosal wall that can be benign or malignant, and benign lesions are further classified as nonneoplastic (eg, cholesterol and inflammatory polyps, adenomyomas) or neoplastic (eg, adenomas, leiomyomas).

• The most common benign neoplastic lesion is an adenoma, a glandular tumor composed of cells resembling biliary tract epithelium.
  
• It is unclear whether adenomatous polyps represent a premalignant lesion, and if so, the frequency with which they progress to carcinoma.
  
• Unlike GBC, gallbladder polyps tend not to occur in patients with cholelithiasis, chronic inflammation is generally absent, and cancer-related molecular changes that are seen in GBCs have not been identified in adenomas.
  
• Nevertheless, larger polyps are more likely to contain foci of invasive cancer, and some studies suggest a correlation between the presence of gallbladder polyps and the risk of GBC.

Chronic infection

• Salmonella
  • In endemic settings, approximately 1 to 4 percent of acutely infected individuals become chronic asymptomatic carriers of salmonella typhi (S. typhi).
    
  • Several reports suggest an association between chronic S. typhi carriage and elevated risk of GBC.
    
  • A prospective case control study of patients with carcinoma of the gallbladder and gallstones (cases) or gallstones alone (controls) identified the S. typhi carrier state as an independent risk factor for carcinoma of the gallbladder (OR=14).
    
  • Because chronic carriage occurs more often in individuals with cholelithiasis, gallstones are thought to represent a potential nidus for ongoing infection.

• Helicobacter
  • Helicobacter colonization of the biliary epithelium (particularly H. bilis) has been implicated in the pathogenesis of gallbladder disease including gallbladder cancer based upon detection of Helicobacter-derived cytotoxins and surface proteins using sensitive molecular and immunohistochemical techniques.
    
  • The strength of this association requires further clarification.

Congenital biliary cysts

• Biliary cysts are associated with an increased risk of cancer, particularly cholangiocarcinoma.
  
• The incidence of malignancy varies with age.
  
• In a 1983 review of all published series of biliary cysts, the incidence of cancer was 0.7 percent in patients under 10 years of age, 6.8 percent in patients 11 to 20 years of age, and 14.3 percent in patients over 20 years of age.
  
• An incidence as high as 50 percent has been reported in older patients.
  
• At least one study suggests that the increased incidence of carcinoma in biliary cysts is confined to patients with an anomalous pancreaticobiliary duct junction.

Abnormal pancreaticobiliary duct junction

• Anomalous pancreaticobiliary duct junction is a rare anatomic variation in which the pancreatic duct drains into the common bile duct, resulting in a long common channel (usually over 2 cm in length).
  
• This condition may represent failure of the embryological ducts to migrate fully into the duodenum.
  
• This condition is most prevalent in Asians populations, mostly Japanese.

The long common channel may predispose to reflux of pancreatic juice into the biliary tree, since the ductal junction lies outside of the sphincter of Oddi.

• Elevated sphincter of Oddi pressures have been documented in anomalous pancreaticobiliary duct junction, and could also promote pancreaticobiliary reflux.
  
• The result is increased amylase levels in bile, intraductal activation of proteolytic enzymes, alterations in bile composition, and presumed biliary epithelial damage, inflammation, ductal distension, and cyst formation.

• Anomalous pancreaticobiliary duct junction appears to increase the risk of biliary and pancreatic malignancy even in patients without a biliary cyst or ductal dilation.
  
• Gallbladder cancer is the most common malignancy seen in patients with anomalous pancreaticobiliary duct junction and no bile duct cyst.
  
• As a result, prophylactic cholecystectomy is recommended in affected patients.

The molecular pathogenesis of GBC arising in patients with an anomalous pancreaticobiliary duct junction appears to be different from that underlying the development of GBC in the setting of gallstone disease.

Medications

Some drugs have also been implicated in biliary carcinogenesis, including

• methyledopa,
  
• oral contraceptives, and
  
• isoniazid.

Others have found no convincing evidence for an association between oral contraceptive use and GBC.

Carcinogen exposure

• Evidence is accumulating that carcinogen exposure may also be involved in the etiology of GBC. An increased risk of GBC has been described in workers in the oil, paper, chemical, shoe, textile, and cellulose acetate fiber manufacturing industries, and in miners exposed to radon.

MOLECULAR PATHOGENESIS

Differences in the demographics, clinical presentation, and gender distribution suggest that there are two key pathways to developing GBC in patients with cholelithiasis and anomalous pancreaticobiliary duct junction.

The main mechanism involves cholelithiasis and resultant cholecystitis, and seems to be the driving force in most regions of the world where GBC is strongly associated with gallstone disease, female gender bias, and age over 65.

• It is hypothesized that chronic irritation of the gallbladder mucosa over a period of years may predispose to malignant transformation, or act as a promoter for carcinogenic exposure or genetic predisposition.
  
• In keeping with this hypothesis, bile samples from patients in endemic areas are more mutagenic than those from patients from low incidence areas.
  
• Despite these data, there is no conclusive evidence linking bile composition to GBC.

A second mechanism involves anomalous pancreaticobiliary duct junction, which is associated with a relatively high proportion of cases of GBC in Japan.

• Cancers associated with this condition occur at a younger age, show less female gender bias, and have a lower incidence of associated cholelithiasis.

• There are also histologic and molecular differences in GBCs associated with an anomalous pancreaticobiliary duct junction and those associated with gallstones, providing further evidence that two distinct pathogenetic pathways are involved.
  • GBCs arising in Japan in the setting of an anomalous pancreaticobiliary duct junction are characterized by K-ras mutations and relatively late onset of p53 mutations.
    
  • By contrast, in Chilean patients with cholelithiasis and chronic cholecystitis, K-ras mutations are rare, while p53 mutations arise early during multistage pathogenesis.

Multistage pathogenesis

Most epithelial cancers are preceded by a series of histologic and molecular changers that evolve over a period of several years or decades.

• Similar to other GI tract adenocarcinomas, adenocarcinomas involving the gallbladder progress from dysplasia, to carcinoma in situ (CIS), and then to invasive cancer.
  
• The molecular changes that characterize these sequential changes are less well characterized than those in colorectal cancer.

• Preneoplastic changes can be found in the mucosa adjacent to over 90 percent of GBCs, and they are relatively frequent in routine cholecystectomy specimens.
  
• The entire sequence appears to take approximately 15 years.
  
• metaplasia is a rare premalignant lesion found in association with invasive squamous cell GBC.

By contrast, in both adults and children with an anomalous pancreaticobiliary duct junction, epithelial hyperplasia with a papillary or villous appearance is present in 39 to 61 percent of cases, and is thought to represent a premalignant histologic change in the gallbladder mucosa. Hyperplasia then progresses to dysplasia, similar to the usual form of GBC.

CLINICAL FEATURES

The symptoms of gallbladder cancer are typically those of benign gallbladder disease. Common symptoms include right upper quadrant abdominal pain, nausea, and fatty food intolerance.
More advanced symptoms include jaundice, anorexia, and weight loss.

Rarely, patients present with extraabdominal metastases, hepatomegaly, a palpable mass, ascites, or paraneoplastic syndromes (eg, ectopic hormone secretion or acanthosis nigricans).

DIAGNOSTIC MODALITIES

• Given the nonspecific presentation of patients with gallbladder carcinoma, the disease is difficult to diagnose preoperatively.
  
• Accordingly, the disease is usually diagnosed either incidentally after cholecystectomy or at a very advanced stage.
  
• If a gallbladder cancer is suspected preoperatively, usually as a result of an abnormally thickened gallbladder wall or the presence of a gallbladder mass on ultrasound, then further investigation with contrast-enhanced computed tomography scan or magnetic resonance imaging is warranted.
  
• These imaging modalities are critical in the determination of resectability, providing information about the local extent of disease, including portal vascular invasion, as well as the presence of lymphadenopathy and liver metastases.
  
• At The University of Texas M. D. Anderson Cancer Center, we perform percutaneous fine needle aspiration preoperatively to confirmthe diagnosis of gallbladder carcinoma in order to determine the extent of the planned surgical resection and any associated treatment, including portal vein embolization and neoadjuvant chemoradiation.

Ultrasound

• Findings that are suggestive but not diagnostic of GBC include mural thickening or calcification, a mass protruding into the lumen, a fixed mass in the gallbladder, loss of the interface between the gallbladder and liver, or direct liver infiltration.

• Small polypoid lesions within the gallbladder may represent adenomas, papillomas, cholesterolosis, or carcinomas.
  • Polyps over 1 cm in diameter are more likely to contain an invasive cancer than smaller ones.

Endoscopic ultrasound

Endoscopic ultrasonography (EUS) is more accurate for imaging the gallbladder than is extracorporeal US. It is useful both in the differential diagnosis of gallbladder polyps, and in staging tumor extent.

CT and MRI

• On CT, GBC can appear as a polypoid mass protruding into the lumen or completely filling it, a focal or diffuse thickening of the gallbladder wall, or a mass in the gallbladder fossa with the gallbladder itself being indiscernible; liver invasion, suspected nodal involvement, or distant metastases may be shown.

• CT is less helpful in distinguishing benign from malignant polyps.
  
• In contrast, dynamic MRI and MR cholangiopancreatography (MRCP) can help to differentiate benign from malignant gallbladder lesions in equivocal cases, and provide information as to disease extent.
  
• MRI is particularly useful for visualizing invasion into the hepatoduodenal ligament, portal vein encasement, and lymph node involvement.

Cholangiography

These procedures may be helpful in planning the surgical procedure as they may indicate tumor growth in intrahepatic biliary ducts or in the common bile duct.

Laboratory studies

• Laboratory studies are typically unremarkable unless the patient has developed obstructive jaundice an elevated alkaline phosphatase or serum bilirubin may be related to bile duct obstruction.
• Unfortunately, there are no reliable tumor markers, including CEA and CA 19-9 levels which are often elevated, but not diagnostically useful because they lack specificity and sensitivity.

HISTOLOGY

• The majority are adenocarcinomas, although other histologic types are occasionally found, including small cell cancer, squamous cell carcinoma, lymphoma, and sarcoma.
  
• Grossly, GBC can appear infiltrative, nodular, papillary, or a combination of these morphologies.
  
• Papillary carcinomas, which can sometimes fill the entire gallbladder, have the most favorable prognosis.

• Adenocarcinomas originate as mucosal lesions, invading the gallbladder wall as they grow.
  
• The lack of a well-defined muscularis layer permits early vascular, lymphatic, and neural invasion.
  
• Tumors frequently extend outside of the gallbladder, invading adjacent organs, particularly the liver, as they grow.

STAGING

Nevin staging system — Originally described in 1976, the Nevin staging system for GBC includes five stages that are defined as follows :

Stage I — Intramucosal only

Stage II — Involvement of mucosa and muscularis

Stage III — Involvement of all three layers

Stage IV — Involvement of all three layers and the cystic lymph node

Stage V — Involvement of liver by direct extension or metastases to any other organ.

TNM Staging

Primary tumor (T)

TX -Primary tumor cannot be assessed

T0 -No evidence of primary tumor

Tis -Carcinoma in situ

T1 -Tumor invades lamina propria or muscle layer

T1a -Tumor invades lamina propria

T1b -Tumor invades muscle layer

T2 -Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver

T3 -Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, or pancreas, omentum or extrahepatic bile ducts

T4 -Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures

Regional lymph nodes (N)

NX -Regional lymph nodes cannot be assessed

N0 -No regional lymph node metastasis

N1 -Regional lymph node metastasis

Distant metastasis (M)

MX -Distant metastasis cannot be assessed

M0 -No distant metastasis

M1 -Distant metastasis

Stage grouping

Stage 0 -Tis N0 M0

Stage IA -T1 N0 M0

Stage IB -T2 N0 M0

Stage IIA -T3 N0 M0

Stage IIB -T1 N1 M0, T2 N1 M0, T3 N1 M0

Stage III -T4 Any N M0

Stage IV -Any T Any N M1

Gallbladder Tumors; clinical features, diagnosis and management.

CHOLESTEROLOSIS AND CHOLESTEROL POLYPS

• Cholesterolosis has been recognized since 1857, when Virchow described it in a report on the role of the gallbladder in fat metabolism.
• It is a benign condition that is usually diagnosed incidentally during cholecystectomy or on ultrasonography

• Cholesterolosis or ‘strawberry’ gallbladder is a disordercharacterized by deposits of cholesterol esters and otherlipids in the macrophages of lamina propria.
• The same lipids are deposited to a lesser degree in the epithelium andstroma of the gallblader wall.
  
• The planar variety of cholesterolosisis diffuse, creating a carpet of fine yellow papulesover the mucosa surface.
  
• In more than one third of cases, these surface masses are less than 1 mm in diameter.
• The polypoid form of cholesterolosis are single or multiple, discrete cholesterol polypoid lesions (‘polyps’)

Cholesterol polyps are the most common pseudotumors of the gallbladder.

• The polyps can be single or multiple, usually less than 10 mm in size.
  
• They have no predilection for any particular gallbladder site, and usually are attached to the gallbladder wall by a delicate, narrow pedicle.
  
• Cholesterol polyps and cholesterolosis may occasionally occur in association.
  
• No malignant potential has been identified for this type of pseudotumor.

Epidemiology

• Cholesterolosis is common; its prevalence in surgical studies varies from 9 to 26 percent.
  
• A large autopsy series of 1300 cases found the prevalence to be 12 percent.
  
• Cholesterolosis in association with gallstones is by far the most common pathologic finding in the gallbladder.
  
• Most surgical series suggest risk factors that are similar to those for gallstone formation.
  
• However, as mentioned above, an ultrasound study showed no association with any of the known risk factors for gallstones.
  
• Similarly, while gallstone disease is known to be more common in women, an autopsy series found the prevalence of cholesterolosis to be equal between men and women.
  
• These contradictory observations may be explained by the observation that surgical series generally focus on gallbladders from patients who were symptomatic, which is not necessarily the case in autopsy or ultrasonographic studies.

Pathology —

• Cholesterolosis results from abnormal deposits of triglycerides, cholesterol precursors, and cholesterol esters into the gallbladder mucosa.
  
• The lipid accumulation creates yellow deposits that are generally visible to the naked eye.
  
• The appearance of the yellow deposits on a background of hyperemic mucosa led to the description of this finding as a "strawberry gallbladder".

The main microscopic feature is the presence of fat laden macrophages within elongated villi.

• Most of the lipid in the cytoplasm of the macrophages is in the form of liquid crystals, which leads to birefringence under polarized light and gives a characteristic foamy appearance under microscopy.
  
• The hyperplastic villus is filled and distended with these cells, creating the small yellow nodules under the epithelium.
  
• In about two-thirds of cases, these nodules are less than 1 mm in diameter, which gives the mucosa the coarse and granular appearance that is characteristic of the diffuse or planar type of cholesterolosis.
  
• The remaining one-third of cases are referred to as the polypoid form in which the nodules are larger and polypoid in appearance.
  
• In the polypoid form the deposits give rise to solitary or multiple cholesterol polyps that are attached to the underlying mucosa with a fragile epithelial pedicle, the core of which is composed of lipid filled macrophages.
  
• These polyps can break off, leading to complications similar to those caused by small gallstones, such as biliary pain, pancreatitis, or obstructive jaundice.

CLINICAL FEATURES —

• Polyps of the gallbladder are typically incidental findings detected during radiologic imaging of the abdomen.
  
• Their significance usually surrounds uncertainty regarding their potential for malignancy.
• In addition, regardless of their type or etiology, gallbladder polyps can be associated with biliary pain.
  
• Proposed mechanisms of pain include prolapse of the polyp into Hartman's pouch, which, if occurring during gallbladder ejection, can lead to biliary type pain that subsides upon spontaneous reduction.
  • Another possible mechanism is that a detached portion of a polyp, when lying free in the gallbladder lumen, can obstruct the cystic duct in much the same way a gallstone would, leading to biliary colic or cholecystitis.
    
• The detached portion can also obstruct the common bile duct, leading to obstructive jaundice and pancreatitis.
  
• In a review of 3,797 cholecystectomies, 55 cases of gallbladder cholesterolosis without cholelithiasis were identified.
  
• Twenty-seven of these patients presented with recurrent attacks of acute pancreatitis, which disappeared after cholecystectomy.
  
• The gallbladders had frank cholesterolosis with a polypoid appearance.
  
• The authors postulated that the detached cholesterol polyps temporarily impact at the sphincter of Oddi, leading to pancreatitis.

• Chronic dyspeptic abdominal pain.
  • In a study of 269 patients who underwent cholecystectomy and were found to have cholesterolosis, 96 percent had abdominal pain that was described as severe and had persisted for more than two years in most patients.
    
• Other symptoms reported in the same study were nausea and vomiting (61 percent) and dyspepsia (60 percent).
  
• Most of these symptoms resolved after cholecystectomy.
  
• In another study, 35 of 55 patients with chronic abdominal pain underwent cholecystectomy; cholesterolosis was found in 20 patients, 19 of whom had improvement in symptoms.
  
• It has been suggested that these lesions can lead to poor gallbladder emptying and compartmentalization that may be responsible for these symptoms.
  
• However, the mechanism of these dyspeptic symptoms remains unclear since these observations have not been confirmed in other studies and the results of surgery are variable.
  
• Thus, it remains debatable whether polyps, cholesterolosis, or adenomyomatosis can lead to chronic dyspeptic pain.

DIAGNOSIS —

Although none of the available modalities can reliably and unequivocally predict the type, histology, or the presence of malignancy, a combination of features seen on ultrasound, CT scan, and endoscopic ultrasonography (EUS) can provide valuable information.

Ultrasonography —

• Polyps are easily identified on ultrasonography as single or multiple echogenic foci that can be easily differentiated from gallstones because they are fixed.
  
• They do not move when the patient is rolled from one side to another and they do not cast a shadow.
  
• As noted above, the most useful predictive feature for malignancy is the size of the polyp.
  
• Polyps larger than 2 cm are almost always malignant and in many cases the cancer is advanced.
  
• Polyps of 1 to 2 cm in size should be regarded as possibly malignant.
  
• As mentioned above, several pathologic studies support this with the incidence of carcinoma being 43 to 77 percent in polyps larger than 1 cm and 100 percent in polyps larger than 2 cm.
  
• Cholesterol polyps are usually smaller than 1 cm.

In addition to size and number, ultrasonography can delineate other useful distinguishing characteristics in the appearance of polyps. These may include

• echogenicity,
  
• surface architecture, and the
  
• presence of a pedicle.

Cholesterol polyps are usually

• multiple,
• homogeneous, and
  
• pedunculated polypoid lesions
  
• that are more echogenic than the liver parenchyma.
  
• They may or may not contain hyperechoic spots and have a mulberry-like surface.

Adenomas are also

• homogeneous, but are
  
• isoechogenic with the liver parenchyma, and
• have a smooth surface and no pedicle.

Adenocarcinomas are

• homogeneous, heterogeneous sessile, or mass-like polypoid structures that are usually
  
• isoechogenic with the liver parenchyma and
  
• exhibit a mulberry-like surface.

When located in the fundus, adenomyomatosis can produce a mucosal projection that can give the appearance of a polyp on ultrasonography.

• These polypoid lesions are about 10 to 20 mm in diameter.

In contrast to cholesterol polyps, diffuse cholesterolosis has no specific ultrasonographic finding. As a result, the diagnosis is usually made during surgery.

In patients with adenomyomatosis, ultrasonography shows

• non-specific focal thickening (>4 mm) of the gallbladder wall.
  
• Careful examination may predict the presence of adenomyomatosis by revealing diffuse or segmental thickening with round anechoic foci that represent the intramural diverticula.

Oral cholecystography —

• Oral cholecystography (OCG) has fallen out of favor since ultrasonography is much more sensitive and specific.
  
• The OCG requires a functioning gallbladder and a patent cystic duct to visualize the gallbladder.
  
• Polyps would appear as immobile filling defects which are usually difficult to differentiate from gallstones.
  
• Adenomyomatosis has a characteristic appearance of an invagination in the wall that may occasionally show Rokitansky-Aschoff sinuses.

Computed tomography —

• Computed tomography is generally most useful in patients with gallbladder cancer since it can stage the disease by revealing liver invasion or metastasis.
  
• There are only limited data regarding the use of the CT scan in the differential diagnosis of gallbladder polyps.
  
• One study noted a 100 percent sensitivity of contrast enhanced CT for detecting gallbladder polyps in 20 patients who underwent CT scans with and without contrast and subsequently had cholecystectomy.
  
• As in other studies, the size of the polyp was a useful predictor for malignancy.
  
• None of the six polyps less than 10 mm in diameter were neoplastic, while 5 of 14 polyps more than 10 mm in diameter were malignant and two were adenomas.
  
• Unenhanced CT missed all cholesterol and hyperplastic polyps, while all adenomas and carcinomas (except for one) were seen before and after administration of contrast. Furthermore, all cholesterol polyps were pedunculated while most of the carcinomas were sessile.

Endoscopic ultrasonography —

• Endoscopic ultrasonography has the advantage of being able to image the gallbladder through the gastric wall without the deleterious attenuation by subcutaneous fat and interference from intestinal gas, which limit the usefulness of conventional extracorporeal ultrasonography.
  
• These benefits potentially make endoscopic ultrasonography a much more accurate imaging modality for the gallbladder compared to extracorporeal ultrasonography.
  
• However, EUS is not widely available and the data for its use in the differential diagnosis of gallbladder polyps are sparse.

One retrospective study defined certain criteria for diagnosing cholesterol polyps, adenomyomatosis, and adenocarcinoma on EUS.

• The presence of internal echo patterns characterized as tiny echogenic spots or an aggregation of multiple highly echogenic 1 to 3 mm spots with or without echogenic areas was considered diagnostic for cholesterol polyps.
  
• Adenomyomatosis (localized type) was diagnosed when there was a sessile echogenic mass containing multiple microcysts (corresponding to the dilated Rokitansky-Aschoff sinuses) or a comet tail artifact.
  
• In the absence of echogenic spots, multiple microcysts or a comet tail artifact, the lesion was diagnosed as neoplastic (adenoma or adenocarcinoma).

In a more recent follow-up study by the same group using the same EUS criteria, a total of 194 patients with small (<20>

• Fifty-eight of these patients underwent surgery either because of symptoms or a suspicion of a neoplastic lesion on EUS.
  
• Using these criteria, EUS correctly predicted the histology in 97 percent of the cases compared to 76 percent for transabdominal ultrasonography.
  

MANAGEMENT —

The only effective treatment for gallbladder polyps or cholesterolosis is cholecystectomy, which should be considered in symptomatic patients or as prophylaxis to prevent malignant transformation. Optimal follow-up of patients who do not undergo cholecystectomy is unclear.

• Although most gallbladder polyps are benign, the main objective is to exclude the presence of malignancy because advanced gallbladder cancer carries a poor prognosis and resection at an early stage offers the only hope for cure.
  
• What complicates matters is that none of the available imaging modalities can unequivocally distinguish neoplastic from non-neoplastic polyps.
  
• This can be achieved only by microscopic examination after surgery.
  
• Nevertheless, as discussed above, extracorporeal ultrasonography and endoscopic ultrasonography can give valuable information in the differential diagnosis of gallbladder polyps.

Patients who have gallbladder polyps and concomitant gallstones should undergo cholecystectomy regardless of the polyp size or the presence of symptoms since gallstones are a risk factor for gallbladder cancer in patients with gallbladder polyp.

Gallbladder polyps arising in the setting of primary sclerosing cholangitis are frequently malignant and thus warrant cholecystectomy.
Cholecystectomy should also be recommended for patients who have biliary colic or pancreatitis since an appreciable proportion of such patients who have cholesterolosis or adenomyomatosis improve after cholecystectomy.
On the other hand, patients with non-specific dyspeptic symptoms but without symptoms consistent with biliary colic should be managed conservatively (unless they have gallstones) since the pathogenesis of these symptoms is unclear and cholecystectomy may not relieve the symptoms. Such patients should be treated symptomatically as in other patients with chronic functional dyspepsia.

Recommendations for patients who do not fit in these categories can be made based upon the size of the polyps.

Lesions larger than 18 to 20 mm —

• Lesions larger than 18 to 20 mm are usually malignant and should be resected.
  
• Because these lesions may represent advanced cancer, patients should undergo preoperative staging with a CT scan and EUS.
  
• An extended cholecystectomy with lymph node dissection and partial hepatic resection in the gallbladder bed is required when performing cholecystectomy for malignancy.

Lesions from 10 to 20 mm —

• Polyps 10 to 20 mm in diameter should be regarded as possibly malignant (incidence of gallbladder cancer of 25 to 77 percent).
  
• Cancer of this size is usually an early stage cancer and laparoscopic cholecystectomy with full thickness dissection (removal of the entire connective tissue layers of the gallbladder bed to expose the liver surface) is recommended.

Lesions from 5 to 10 mm —

• Lesions 5 to 10 mm in diameter may represent cholesterol polyps, adenomas, or carcinomas.
  
• Multiple polyps, pedunculated polyps, and those that are hyperechoic as compared to the liver are usually cholesterol polyps, while solitary and sessile polyps that are isoechogenic with the liver are more likely to be neoplastic.
  
• However, the most reassuring finding is the stability of a polyp on repeated follow-up examinations.
  
• There is no consensus regarding the frequency of ultrasonographic examinations that need to be performed for these lesions.
  
• One group recommends that polyps of 5 to 10 mm in diameter should be followed in three months, six months, and then yearly.
  
• An increase in polyp size is an absolute indication for surgery.

Lesions smaller than 5 mm —

• Polyps smaller than 5 mm are usually benign and most frequently represent cholesterolosis.
  
• Asymptomatic patients with cholesterol polyps do not need treatment.
  
• However, a repeat ultrasound examination in 6 and 12 months may be appropriate.
  
• Follow-up examination are not necessary if the polyp is stable.
  
• Medical management aimed at increasing the solubility of cholesterol in bile by administering UDCA is without benefit in patients with cholesterolosis.
  

Tumors of the Gallbladder

Benign and pseudotumors of the gallbladder

• Most benign tumors of the gallbladder are detected as polypoid lesions.
  
• In 1970, Christensen and Ishak proposed a simplified classification scheme of benign gallbladder lesions, which are classified as either tumors or pseudotumors.
  
• Benign tumors are further classified into
  • epithelial (adenoma) and
    
  • mesenchymal (hemangioma, lipoma, etc.) variants.
• Pseudotumors include such lesions as
  • cholesterol and inflammatory polyps,
    
  • adenomatous hyperplasia, and
    
  • heterotopic tissues.

The prevalence of polypoid lesions of the gallbladder (PLG) in healthy subjects varies from 3 to 7% on ultrasound in up to 10% in cholecystectomy specimens.

The most common type of PLG is the cholesterol polyp, comprising 63% of 172 cases in the largest series of PLG reported in the literature.

• Cholesterol polyps are characteristically small (10 mm), multiple, and appear as yellow spots on the surface of the gallbladder mucosa, giving rise to the term “strawberry gallbladder.”
  
• They are formed by the proliferation of lipid-laden macrophages in the lamina propria and have no malignant potential.
  

Inflammatory polyps of the gallbladder are reactive lesions without malignant potential that are usually discovered at the time of cholecystectomy performed for chronic cholecystitis.

• Microscopically, there is evidence of focal epithelial hyperplasia associated with a marked infiltration of chronic inflammatory cells.
  

Adenomyomatous hyperplasia of the gallbladder is characterized by extensions of the mucosa into and through a thickened muscular wall, typically in the fundus of the gallbladder.

• These lesions have long been thought to have no malignant potential, though there are case reports of gallbladder carcinoma developing in areas of adenomyomatosis.
  

Simplified classification of benign tumors and pseudotumors of the gallbladder.

Benign tumors

• Epithelial
  • Adenoma, papillary
  • Adenoma, nonpapillary

• Supporting tissue
  • Hemangioma
  • Lipoma
  • Leiomyoma
  • Granular cell tumor
    

Benign pseudotumors

• Hyperplasia
  • Adenomatous
  • Adenomyomatous (adenomyoma)
    

• Heterotopia
  • Gastric mucosa
  • Intestinal mucosa
  • Pancreas
  • Liver
• Polyp
  • Inflammatory
  • Cholesterol
    

• Miscellaneous
  • Fibroxanthogranulomatous inflammation
  • Parasitic infection
  • Other
    

The incidence of adenoma of the gallbladder is approximately 1% in cholecystectomy specimens, and these lesions can be papillary or sessile.

• It is unclear whether a gallbladder adenoma represents a premalignant lesion.
  
• Evidence in support of the adenoma to adenocarcinoma sequence comes from a study by Kozuka et al., in which the histology of 1605 gallbladders was reviewed.
  
• Adenomatous components were identified in all of the in situ carcinomas and in 19% of the invasive carcinomas.
  
• There was a distinct correlation between the size of the lesion and malignant change, with all benign adenomas measuring less than 12 mm in diameter, all adenomas with malignant change measuring greater than 12 mm in diameter, and most of the invasive cancers measuring greater than 30 mm in diameter.
  
• Similarly, Koga et al. performed a comparative analysis between benign and malignant gallbladder lesions and found that 94% of benign lesions were smaller than 10 mm, whereas 88% of malignant lesions were greater than 10 mm.
  
• Yang et al. provided further evidence in support of the malignant potential of large PLG in a clinicopathologic review of 182 patients with PLG. All 138 PLG less than 10 mm in diameter were benign, whereas all 13 malignant PLG measured greater than 10 mm in diameter, and most of these (11/13) were greater than 15 mm.

Others refute the polyp-to-cancer sequence and believe that gallbladder carcinomas arise in situ from flat, dysplastic epithelium.

Wistuba et al. extracted DNA from gallbladder adenomas and screened for mutations in the p53, Kras, and N-ras genes and five different chromosomal regions that had previously been shown to be frequently deleted in dysplasia, carcinoma in situ, and gallbladder carcinoma.

• They found no mutations of the p53 gene in 16 gallbladder adenomas but did identify K-ras mutations in 25% of the adenomas.
  
• K-ras mutations are rare in gallbladder carcinomas.
  
• They concluded that gallbladder adenomas lack the molecular changes frequently seen in gallbladder cancers, arguing against a proposed adenoma–carcinoma pathway.
  
• Other investigators have followed the natural history of PLG.
  

Moriguchi et al. followed 109 asymptomatic patients with PLG (94% <1>

• Only one gallbladder carcinoma was identified, at a site distinct from that of the pre-existing polyp, and 88% of the PLG were unchanged in size.
  
• The authors concluded that most PLG detected by ultrasound are benign.
  

Csendes et al. followed 111 patients with PLG smaller than 10 mm by clinical examination and ultrasound for a mean time of 71 months.

• No patient developed symptoms of biliary disease, gallstones, or gallbladder carcinoma.
  

Collectively, these studies confirm that the most significant risk factor for malignancy in a PLG is a diameter greater than 10 mm.

Other risk factors include solitary PLG, symptomatic PLG, concurrent gallstones, and patient age greater than 50 years.

• These factors then allow for the proper selection of patients with PLG who would most likely benefit from cholecystectomy.