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.