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Gallbladder polyp From Wikipedia, the free encyclopedia Ultrasound image of gallbladder polyps measuring 3-7mm. Gallbladder polyps are growths or lesions resembling growths (polypoid lesions) in the wall of the gallbladder . True polyps are abnormal accumulations of mucous membrane tissue that would normally be shed by the body. The main types of polypoid growths of the gallbladder include cholesterol polyp/cholesterosis, cholesterosis with fibrous dysplasia of gallbladder, adenomyomatosis, hyperplastic cholecystosis, and adenocarcinoma . Contents 1 Epidemiology 2 Pathology 3 Symptoms and Diagnosis 4 Therapy 5 References Epidemiology Polypoid lesions of the gallbladder affect approximately 5% of the adult population. [1] The causes are uncertain, but there is a definite correlation with increasing age and the presence of gallstones (cholelithiasis ). Most affected individuals do not

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Page 1: Gallbladder Polyp

Gallbladder polypFrom Wikipedia, the free encyclopedia

Ultrasound image of gallbladder polyps measuring 3-7mm.

Gallbladder polyps are growths or lesions resembling growths (polypoid lesions) in the wall of the gallbladder. True polyps are abnormal accumulations of mucous membrane tissue that would normally be shed by the body. The main types of polypoid growths of the gallbladder include cholesterol polyp/cholesterosis, cholesterosis with fibrous dysplasia of gallbladder, adenomyomatosis, hyperplastic cholecystosis, and adenocarcinoma.

Contents

1 Epidemiology 2 Pathology 3 Symptoms and Diagnosis 4 Therapy 5 References

Epidemiology

Polypoid lesions of the gallbladder affect approximately 5% of the adult population.[1] The causes are uncertain, but there is a definite correlation with increasing age and the presence of gallstones (cholelithiasis). Most affected individuals do not have symptoms. The gallbladder polyps are detected during abdominal ultrasonography performed for other reasons.

The incidence of gallbladder polyps is higher among men than women. The overall prevalence among men of Chinese ancestry is 9.5%, higher than other ethnic types.[2]

http://www.mayoclinic.com/health/gallbladder-polyps/AN01044

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Pathology

Most small polyps (less than 1 cm) are not cancerous and may remain unchanged for years.[3] However, when small polyps occur with other conditions, such as primary sclerosing cholangitis, they are less likely to be benign.[4] Larger polyps are more likely to develop into adenocarcinomas.

Cholesterolosis is characterized by an outgrowth of the mucosal lining of the gallbladder into fingerlike projections due to the excessive accumulation of cholesterol and triglycerides within macrophages in the epithelial lining.[5] These cholesterol polyps account for most benign gallbladder polyps[citation needed].

Adenomyomatosis describes a diseased state of the gallbladder in which the gallbladder wall is excessively thick, due to proliferation of subsurface cellular layer. It is characterized by deep folds into the muscularis propria. Ultrasonography may reveal the thickened gallbladder wall with intramural diverticulae, called Rokitansky-Aschoff sinuses.[5]

Symptoms and Diagnosis

Most polyps do not cause noticeable symptoms. Gallbladder polyps are usually found incidentally when examining the abdomen by ultrasound for other conditions, usually abdominal pain.

Therapy

Most polyps are benign and do not need to be removed. Polyps larger than 1 cm with co-occurring gallstones occurring in people over the age of 50 may have the gallbladder removed (cholecystectomy), especially if the polyps are several or appear malignant. Laparoscopic surgery is an option for small or solitary polyps.

Abstract

Gallbladder cancer is a rather uncommon disease, when it gives symptoms it has usually reached an incurable stage. Therefore, every attempt must be made to find the asymptomatic stages and look for premalignant gallbladder polyps. Even if gallbladder cancer is a rare disease, gallbladder polyps are common, only a few polyps develop to cancer. This makes gallbladder polyps another problem: which are the polyps that must be surgically removed, which shall be followed-up, or for how long? The author used the keyword “gallbladder polypsn” in PubMed and reviewed the scientific literatures published from January 2000 to December 2011. The present review article has summarized almost all respects of gallbladder polyp, including the risk factors, clinical diagnosis and management, and comments made from the author, in which clinical treatments are recommended. It is author's purpose that the 11-year-knowledge about gallbladder polyps

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summarized from all worlds’ literatures is enough to know how clinicians will handle the next patient with gallbladder polyp.

Keywords: Cancer, clinical recommendations, diagnosis and management, gallbladder polyps, risk factors

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Introduction

Lesions that project from the gallbladder wall into the gallbladder interior are called gallbladder polyps (GPs). In the majority of patients, diagnosis is an incidental finding of a routine abdominal ultrasound or following cholecystectomy for gallstones or biliary colic. Even though most of the gallbladder polyps are benign in nature, malignant polyps are present in some cases, and early detection and appropriate early measure is important for curative treatment and long-term survival. The primary goal in the management of gallbladder polyps is to prevent the development of gallbladder carcinoma.

The term polypoid lesions of the gallbladder represents a wide spectrum of findings. Gallbladder polyps are classified as benign or malignant. Benign GPs are subdivided into: pseudotumors (cholesterol polyps, inflammatory polyps; cholesterolosis and hyperplasia), epithelial tumors (adenomas) and mesenchymatous tumors (fibroma, lipoma, and hemangioma). Malignant GPs are gallbladder carcinomas. The poor prognosis of gallbladder carcinoma patients means it is important to differentiate between benign polyps and malignant or premalignant polyps.[1]

The author reviewed, via PubMed, the literatures published between January 2000 and December 2011, and summarized respects of gallbladder polyp, in order for clinicians better to handle the next patient with gallbladder polyp.

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Incidence of gallbladder polyps

The prevalence of gallbladder polyps was reported as 4.3–6.9%. Polypoid gallbladder lesions include a variety of pathologic types.[2] Although there are some differences according to reports, the prevalence of polypoid lesions of the gall bladder are reported in 2–12% of cholecystectomy specimens, probably dependent on indications for cholecystectomy.[3]

Age and gender seem to be notable factors for incidence of gallbladder polyps. In a study of 1558 patients with gallbladder polyps, the age at the time of diagnosis was 49 years.[4] In the majority of publications in which the ratio is calculated, the incidence is more prevalent in men.[1,5] The sex ratio and age at the time of diagnosis of gallbladder polyps was 1.15 to 1 (male to female).[4,6]

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Risk factors for polyps

Polyps of gall bladder are tumor-like lesions of this organ. Little has been known about factors associated with the occurrence of gallbladder polyps. The formation of gallbladder polyps is however associated with fat metabolism. Relationship between gallbladder polyps and family history of some diseases suggests to perform some genetic studies.[7]

In contrast to the well-known risk factors for gallstones, attempts to identify risk factors for developing gallbladder polyps have not shown any consistent relationship between formation of polyps and age, gender, obesity, or medical conditions such as diabetes. There is some literature to suggest an inverse relationship between gallbladder polyps and stones. It is hypothesized that polyps either mechanically disrupt the formation of stones or that polyps are harder to diagnose radiographically when stones are present.[8]

Patients with congenital polyposis syndromes such as Peutz-Jeghers and Gardner syndrome can also develop gallbladder polyps. A large retrospective analysis of risk factors for gallbladder polyps in the Chinese population identified chronic hepatitis B as a risk factor.[8]

Proposed patient risk factors for malignant gallbladder polyps include age greater than 60, presence of gallstones, and primary sclerosing cholangitis. Polyp risk characteristics include a size greater than 6 mm, solitary, and sessile.[8]

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Symptomatology

The presenting symptoms of polypoid lesions of the gallbladder are nonspecific and vague, and in many cases asymptomatic. For such reason, polypoid lesions of the gallbladder are often detected incidentally.[3,9] However, there are some patients with gallbladder polyps which may suffer nausea, vomiting, and occasional pain in the right hypochondrium, due to intermittent obstructions caused by small fragments of cholesterol that become detached from the gallbladder mucosa. There are descriptions of polyps that protrude greatly obstructing the cystic canal or the primary biliary ducts, causing acute cholecystitis or obstructive jaundice, but these are very rare complications.[1]

Polyps are sometimes identified on transabdominal ultrasounds done for right upper quadrant pain. In the absence of other findings, the gallbladder polyp may be considered a source of biliary colic. If any symptoms are caused, most commonly right upper quadrant pain, nausea, dyspepsia, and jaundice are seen. However, most of the patients have gallstones; it is unclear whether the polyps were primarily driving the symptoms. There was no difference in presenting symptoms between patients with benign versus malignant polyps. In a large retrospective analysis found to have gallbladder polyps on abdominal ultrasound, 64% of these polyps were diagnosed during a work-up of unrelated illness. Twenty-three percent had abdominal symptoms, and 13% had elevated liver function tests. Cholesterol polyps may detach and behave clinically

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as a gallstone, causing biliary colic, obstruction, or even pancreatitis. There are also reports of gallbladder polyps causing acalculous cholecystitis or even massive hemobilia.[8]

Symptoms may be associated with pseudo-polyps such as a cholesterol polyp, inflammatory or hyperplastic polyp, which include indigestion, right upper quadrant pain, and discomfort, cholecystitis or gallbladder stone.[10] Metabolic syndrome has a close relationship with the development of cholesterol polyps.[10]

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Relation between gallbladder stones and gallbladder polyps

The purpose of one study was to determine the clinical characteristics of subjects with gallbladder polyps and cholelithiasis compared with those with gallbladder polyps only. No significant difference in the mean interval change of polyp size during the follow-up period between the study and control groups was noted. A significantly higher proportion of examinees in the study group had attacks of acute cholecystitis compared with the control group. By multivariate logistic regression analysis, gallbladder wall thickening on initial ultrasonography (US) and the interval increase in the size of the gallbladder polyps were significant independent risk factors for cholecystectomy. No gallbladder cancer occurred during the follow-up period. There was, therefore, no significant difference in delta polyp size between the examinees with gallbladder polyps and cholelithiasis and those with gallbladder polyps only.[11]

Some patients who are confirmed to have polypoid lesions of the gallbladder through cholecystectomy are associated with gallstone. Symptoms were significantly associated with malignant polyp compared with benign polyp. The association of symptom and presence of associated gallstone was separately analyzed. Significant association of symptom to associated gallstone was not found. However, symptomatic cases tended to increase with the increase in polyp size. Therefore, a speculation can be made that symptom may be associated with the size of the polyp rather than the association of gallstone.[3]

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Imaging of gallbladder polyps

The development and refinement of diagnostic imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and US and their widespread application have led to an increase in the coincidental diagnosis of gallbladder stones and gallbladder polyps. However, the appropriate management of these entities remains controversial.[12]

Ultrasonography

Abdominal ultrasound is looked upon as the best available exam for diagnosing gallbladder polyps, not only because of its accessibility and low cost, but also because of its good sensitivity and specificity. The polyps can be located, counted, and measured with ultrasound, and the three

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layers of the gallbladder wall and any abnormalities can be viewed.[1] The polyps appear as fixed, hyperechoic material protruding in to the lumen of the gallbladder, with or without an acoustic shadow. The sensitivity of abdominal ultrasound for diagnosis of gallbladder polyps is superior to both oral cholecystography and CT and good to distinguish a cholesterol polyp from an adenoma or an adenocarcinoma. A cholesterol polyp shows as a mass with similar echogenicity to the gallbladder wall and with no shadow cone. However, the distinction is difficult to make, and the status of polyps as benign or malignant cannot be determined with abdominal ultrasound alone.[1] Generally, polyps in the gallbladder are demonstrable on US, only when they are over 5 mm in diameter. Sonographic differentiation between benign and malignant polyps (and calculous disease) relies greatly on the size of a single nonmobile lesion within the gall bladder. A gallstone impacted within the gallbladder wall may be easily mistaken for a polyp on ultrasound scanning.[13]

However, abdominal ultrasound is often limited by the body habitus of the patient, and technical limitations can lead to intraobserver variability in interpretation. Abdominal ultrasound is generally considered the first of line study for making this diagnosis; it is by no means a definitive indicator of the presence of a gallbladder polyp or its malignant potential.[8] A retrospective study reported the symptoms probes were picking up small mucosal folds or misdiagnosing gallstones that did not have posterior shadowing or were immobile. Ultrasound can underestimate maximum diameter, and size assessments can be misleading. Ultrasound is therefore unable to reliably distinguish between nonneoplastic and neoplastic polyps.[9]

The measurement of lesion size by conventional US alone is inadequate for differentiating them. Cholesterol polyps of the gallbladder can readily be detected by abdominal ultrasound. They are composed of foamy histiocytes that contain cholesterol, are covered by a single layer of columnar cells similar to those lining the adjacent mucosa, and are considered benign.[14]

The discrepancy between US and CT scanning

The mean values for CT scanning tended to be smaller than for US. The discrepancies in maximum diameters between US and CT scanning were 6 ± 4 mm in the cholesterol polyp group and 2 ± 2 mm in the noncholesterol polyp group, and this difference was statistically significant.[10] In diagnosis of polypoid lesions of the gallbladder, the discovery rate of B-ultrasound is significantly higher than that of CT or cholecystography. Therefore, B-ultrasonography could be first used for the diagnosis of polypoid lesions of the gallbladder. However, CT could display local anatomic correlations of the liver, gallbladder, porta hepatis, and the other organs. Enhanced CT could improve the discovery rate of polypoid lesions of the gallbladder for CT.[15]

Small polypoid lesions of the gallbladder are easily detected by US, but accuracy based solely on US is controversial.[16] The accuracy of sonography for diagnosing polypoid lesions of the gallbladder was poor. Many of the small polyps seen on sonography most likely represented a stone embedded in the gallbladder wall or other abnormality.[17]

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Three-dimensional ultrasonography

Three-dimensional ultrasound (3DUS) diagnosis correlates well with two-dimensional ultrasound (2DUS) with regard to most gallbladder problems and could be sufficient as a stand-alone technique.[18]

High-resolution ultrasonography

Endoscopic ultrasonography (EUS) was considered the most sensitive diagnostic modality for gallbladder polypoid lesions. However, the diagnostic accuracies of high-resolution ultrasound (HRUS) and EUS for the differential diagnosis of gallbladder polypoid lesions were comparable. In view of patient comfort and no requirement for sedation, it was considered that HRUS is likely to become an important diagnostic modality for the differential diagnosis and staging of gallbladder polypoid lesions and early gallbladder cancer.[19]

Harmonic imaging

The quality of images in the harmonic mode is better, and the walls of the gall bladder are more distinct. The polyps were therefore more evident on harmonic images, which are more precise measurements of the polyps. In the harmonic mode, the level of artifacts generated by the body wall is reduced and contrast resolution is increased due to reduction in noise level. The visualization of gallbladder is improved in the harmonic mode.[20]

Contrast-enhanced ultrasonography

Advances in conventional US, such as high-resolution US, have contributed to improved detection of polypoid gallbladder lesions. A galactose-based contrast agent was used in the US for differential diagnosis of polypoid gallbladder lesions.[2] When diffuse and branched types were considered indicative of cancer, accuracy was 85%, sensitivity 100%, and specificity 77%. In gallbladder cancer, staining throughout the tumor was continuous, consistent with diffuse hypervascularity. In benign gallbladder polyps, staining was scattered with the flow image being uniform and small. Ultrasonographic contrast enhancement patterns therefore show characteristic associations with pathologic findings, serve as valuable adjuncts in the diagnosis of gallbladder diseases,[21] and differentiate gallbladder carcinoma from other polypoid gallbladder disease lesions.[22]

Endoscopic ultrasonography (EUS)

EUS is better than B-ultrasonography.[15] EUS has gained widespread use for the diagnosis of gastrointestinal malignancies, submucosal lesions of the gastrointestinal tract, and abnormalities seen on cross-sectional imaging.[8] EUS is also recommended for further examination after conventional US, because images obtained are more distinct than with conventional US. Such images appear promising for distinguishing cholesterol polyps from other polyps, and the overall accuracy for differentiating neoplastic from non-neoplastic masses was reported as 91%.[2,8]

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Whether EUS alone can be used to determine a treatment strategy for gallbladder polyps is not clear. EUS alone is not sufficient in determining the course of treatment in polyps less than 10 mm, but it may be more accurate than transabdominal ultrasound in determining whether gallbladder polyps are neoplastic.[8] Distinguishing between non-neoplastic, neoplastic, and potentially malignant lesions is a major diagnostic dilemma, and the therapeutic options for these lesions remain controversial. EUS is considered to be superior to conventional US for imaging gallbladder lesions, because EUS can provide high-resolution images of small lesions with higher ultrasound frequencies (7.5–12 MHz vs. 3.5–5 MHz).[8] Although EUS was more accurate than US, its accuracy for differentiating malignancy less than 1.0 cm was low.[23,24]

Comparison with transabdominal ultrasonography

Transabdominal ultrasonography (US) has made the detection of gallbladder polyps easier, but the differential diagnosis of polyps less than 20 mm remains difficult. EUS markedly improve the accuracy of the differential diagnosis of gallbladder polyps and is thought to play an important role in determining the treatment strategy for gallbladder polyps.[25,26]

EUS scoring system

A scoring system to predict neoplastic polyps of the gallbladder has been presented.[27] The total EUS score based on the coefficient of multivariate analysis was as follows: (maximum diameter in mm) + (internal echo pattern score; where heterogeneous = 4, homogeneous = 0) + (hyperechoic spot score; where presence = - 5, absence = 0). According to EUS scoring system, the sensitivity, specificity, and accuracy for the risk of neoplastic polyps with scores of 12 or higher were 78%, 83%, and 83%, respectively.[28]

Computed tomography

Abdominal CT is incapable of detecting low density lesions, and its sensitivity for diagnosis of gallbladder polyps is not such satisfied, especially when gallbladder polyps were smaller than 10 mm in diameter, but it is useful for studying gallbladder carcinoma, anatomic correlations, and for investigating metastases of the ganglia.[1,10] Advances in multidetector-row CT have increased its accuracy rate for the differential diagnosis of gallbladder polyps, and CT generally shows polypoid gallbladder carcinoma as an enhancing, intraluminal tissue mass denser than surrounding bile and can reliably identify neoplastic lesions.[2] In particular, helical CT may be helpful for evaluating small polypoid lesions of the gallbladder, and can differentiate neoplastic and nonneoplastic small polypoid lesions of the gallbladder and reliably identify the presence of neoplastic lesions that should be resected.[14] The size bigger than 1.5 cm, sessile shape, and perception on unenhanced images are the main factors that differentiate neoplastic from nonneoplastic gallbladder polyps 1 cm or bigger.[29]

Magnetic resonance imaging

Magnetic resonance imaging has not been widely used to evaluate gallbladder diseases, having the disadvantages of poor spatial and contrast resolution. Among polypoid masses, malignant lesions demonstrated early and prolonged enhancements, while benign lesions showed early

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enhancement with subsequent washout.[2] It has reported that various malignant tumors may show high signal intensity on diffusion-weighted MR imaging (DWI), reflecting their high cellularity and/or their long relaxation time. Therefore, high b-value DWI may be useful for differentiating between benign and malignant polypoid gallbladder lesions.[30]

Positron emission tomography

It was presented a small case series of patients with gallbladder polyps that were correctly diagnosed preoperatively as benign or malignant with the use of positron emission tomography scanning with 18F-labelled deoxyglucose.[8]

Intravenous cholecystography

Intravenous cholecystography is a safe technique, but gallbladder polyps do not become sufficiently opaque.[1]

Transpapillary approach

Percutaneous transhepatic fine-needle aspiration and percutaneous transhepatic cholecystoscopy have been reported as precise diagnostic techniques in the evaluation of gallbladder polyps, but it is time consuming and poorly tolerated by patients. In addition, the diagnostic accuracy of endoscopic retrograde cholangiopancreatography is not satisfactory, because this can only show a filling defect in the gallbladder without delineating the surface of polypoid lesions.[2]

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Histopathology

Histologic classification and identification of the nature of gallbladder polyps remain a dilemma. In fact, the classification of polyps was very confusing until the introduction made by Christensen and Ishak in 1970's. Subsequently, a comprehensive review by the Armed Forces Institute of Pathology provided in depth classification and detailed description of the radiological and clinicopathological features of each of these individual lesions. This by far is the most detailed study on the subject in the English literature with thorough descriptions of each specific entity.

According to the histology of polyp,[31] the two types are: (1) benign neoplastic polyps, which include epithelial, adenoma, papillary, adenoma, nonpapillary, supporting tissues, hemangioma, lipoma, leiomyoma, granular cell tumor, hyperplasia, adenomatous, adenomyomatous, heterotropia, gastric mucosa, intestinal mucosa, pancreas, liver, polyp, inflammatory, cholesterol, miscellaneous, fibroxanthogranulomatous inflammation, parasitic infection, others; and (2) malignant polyps, which include adenocarcinoma, miscellaneous, mucinous cystadenoma, squamous cell carcinoma, and adenoacanthoma.

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Most gallbladder polyps are benign nonneoplastic lesions that only rarely cause symptoms. The most common type of polyps in the gallbladders is the cholesterol polyp. Adenomas or adenomyomatous polyps are very rare and were discovered in only 0.4% patients who underwent cholecystectomy for gallbladder disease.[7]

Cholesterol polyps

Recent studies have shown that the majority of gallbladder polyps are benign, and 60–90% of them are cholesterol polyps. Cholesterol polyps are generally less than 10 mm. often multiple cholesterol polyps are present. They are often associated with vesicular cholesterolosis and are thought to have no malignant potential, even if three cases of carcinoma associated with cholesterolosis have been reported.[14]

Inflammatory polyps

Inflammatory polyps are uncommon. They account for about 10% of gallbladder polyps and result from granulation and fibrous tissue secondary to chronic inflammation. They are typically less than 10 mm in size and are not neoplastic.[8] They are local epithelial proliferation inflammatory reactions with infiltration of inflammatory cells and are often associated with chronic cholecystitis.[1,32]

Gallbladder adenomas

Although adenomas are benign polyps, they can exhibit premalignant behavior. These lesions are habitually pedunculated single lesions and may be associated with gallstones or chronic cholecystitis. Adenomas account for about four premalignant of gallbladder polyps and are considered neoplastic. They range in size from 5 to 20 mm and are generally solitary.[1]

Gallbladder adenomas are rare, but well-documented benign epithelial tumors. They are usually found incidentally in cholecystectomy specimens or during preoperative imaging studies. Although they are usually asymptomatic, they may present as a result of associated symptomatic gallstones, or from cystic duct obstruction due to large adenoma. Adenomas may be sessile, pedunculated, or just polypoid projections, and most are accompanied by gallstones. Histologically, they can be tubular, papillary, or tubulopapillary. The tubular type is most prevalent and is composed of pyloric or intestinal type glands. These adenomas often coexist with hyperplastic and metaplastic lesions, may contain heterogeneous cell populations, and may show a wide range of morphologic patterns that further complicate the histologic interpretation.[7]

Adenomyomatosis

Adenomyomatosis, a noninflammatory gallbladder alteration, occurs in middle age patients, and the incidence increases with age. Originally depicted as a benign finding, it is currently identified as a precancerous lesion, and cancer cases associated with areas of adenomyomatosis have been reported [014x-6].[6] Adenomyomatosis accounts for up to 25% of gallbladder polyps and usually localizes to the gallbladder fundus appearing as a solitary polyp.[8,33]

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Prediction of malignancy

Numerous studies have attempted to define characteristics which increase the likelihood that a given gallbladder polyp may be malignant.[8] Some studies have revealed that age, presence of diabetes mellitus,[34] size of polyp, gallstones, solitary polyp, and symptomatic polyp[35] are important factors for malignancy.

Many studies have demonstrated that malignant gallbladder polyps are significantly more common in patients aged over 50.[1,3,8,34,35] Polyp size has long been noted to be an important factor. Gallbladder polyps larger than 1.5 cm, especially in solitary sessile hypoechogenic polyps, are associated with a risk of malignancy.[1,3,4,8,34,36]

Generally, polyps that are smaller than 1 cm and are asymptomatic are monitored for 6–12 months with control ultrasound scans, in order to detect any rapid growth. However, some studies have demonstrated that the polyp's diameter alone is not a safe exclusion criteria for neoplasm,[2,32] and therefore, recommend strongly consideration for cholecystectomy for any polyp greater than 6 mm.[9,37]

Correlation between ultrasonography and histopathology

To analyze the ultrasonographic and histopathologic findings of patients operated due to gallbladder polyps, the records of patients with ultrasonographic diagnosis of gallbladder polyp and that underwent cholecystectomy in a 13 years period were reviewed, collecting their demographic, ultrasonographic, and histopathological data. One hundred and twenty three patients were operated. All were single and larger than 10 mm. It was found that there is a significant correlation between ultrasonographic and histopathological polyp size determination. Polyp size was also a predictor of the presence of adenoma. It was concluded that there is a good correlation between the size of the gallbladder polyp in US and the size in the histopathology report.[38]

Shape of polyps

Sessile morphology is one of the important factors that suggest malignancy.[3] The sessile morphology was more dominant in the malignant patients. One of the possible explanations for frequent sessile morphology in malignant polypoid lesions of the gallbladder may be that most gallbladder cancers arise in situ from flat, dysplastic epithelium.[3] The patients with sessile polyps have a higher prevalence of malignancy than do the patients with pedunculated polyps, and the sessile carcinomas are rare at a more advanced stage than the pedunculated carcinomas.[14]

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Number of polyps

The neoplastic polyps tended to be solitary, whereas cholesterol polyps were typically multiple. Single lesion was significantly more frequent in malignant.[3] However, a study includinig 1558 patients with gallbladder solitary polyps did not have a higher risk of neoplastic polyps than multiple polyps.[4]

Tumor with regard to follow-up in time

One study aimed to evaluate the malignant risk of gallbladder polyps, 1558 patients with gallbladder polyps were diagnosed and followed with US. It took 7 years to notice the growth of one of neoplastic polyps. Therefore, a long period of follow-up to detect changes in gallbladder polyps was recommended. Small polyps have a risk of malignancy, careful long-term follow-up of gallbladder polyps will help detect and treat early gallbladder cancer.[4]

Presence of gallstones

The presence of stones or biliary sludge appears to be a risk factor. However, there are two concerns to consider before making gallbladder polyps with gallstones and indication for cholecystectomy. First, its associated risk is not as great as polyp size. When we consider both polyp size and gallstones, stones alone show only ambiguous significance, and the presence of stone is not very useful in predicting small neoplastic polyps. Second, there is a technical problem, as the presence of gallstones hinders the precise evaluation of gallbladder polyps with ultrasound. Thus, gallbladder polyp has to be evaluated more carefully in the presence of gallstones because gallstones are both a risk factor and cause for interference.[4]

Tumor markers

Serum CEA and CA 19-9 have little role in differentiating benign and malignancy. The impracticality of the tumor markers in differential diagnosis may be explained by the fact that most of the malignant polyps in polypoid lesions of the gallbladder are early gallbladder cancers.[3]

Primary sclerosing cholangitis

Primary sclerosing cholangitis is one of the risk factors for malignancy in a gallbladder polyp. Any gallbladder polyp, regardless of size, in a patient with primary sclerosing cholangitis should be considered for cholecystectomy. Solitary sessile polyps greater than 10 mm in patients over age 50 should be considered for cholecystectomy, particularly in patients with cholelithiasis and primary sclerosing cholangitis.[7–9,39] Although gallbladder polyps are common and are usually benign in the general population, they are often malignant in primary sclerosing cholangitis. Therefore, regardless of size, any gallbladder polyps in a patient with primary sclerosing cholangitis should be considered for cholecystectomy.[40] If a cholecystectomy is not performed, careful follow-up is warranted.[41]

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Clinical series, indications for surgery, and recommended follow-up

Any gallbladder polyp that is felt to be symptomatic should be removed. In patients at risk for malignancy, a polyp of 6 mm or greater should likely be resected. Patients without risk factors are good candidates for EUS for further evaluation. Those polyps that are considered high risk by EUS criteria should be considered for resection.

The cholecystectomy should only be undertaken in cases where there are clinical signs of gallbladder polyps, polyps with diameters greater than 10 mm, fast-growing polyps, sessile polyps or wide-based polyps, polyps with long pedicles, patient aged over 50, concurrent gallstones, polyps of the gallbladder in fundibulum or abnormal gallbladder wall ultrasound.[1] The surgery of choice is laparoscopic cholecystectomy. A gallbladder polyp greater than 18 mm in size has a high likelihood of being an advanced cancer; it should be removed with open cholecystectomy, partial liver resection, and possible lymph node dissection.[8]

Gallbladder polyps that are not resected should be followed-up with serial ultrasound examinations. Clear guidelines on a screening interval are so far not available, even though a screening interval of every 6–12 months has been documented.[8] It would be more efficient to make a flexible and tailored follow-up plan or treatment plan for gallbladder polyps based on scientifically found signs rather than fixed or inflexible guidelines.[10]

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The reviewers’ comments

In the majority of patients, diagnosis of gallbladder polyps is an incidental finding or following cholecystectomy for acute or chronic cholecystitis. Even though most of the gallbladder polyps are benign in nature, malignant polyps are found in some cases. Because advanced gallbladder cancer displays poor prognosis, early detection and appropriate early measure are important for curative treatment and long-term survival. The primary goal in the management of gallbladder polyps is to prevent the development of gallbladder carcinoma, even though it is a rare illness. Therefore, better understanding of clinicopathologic characteristics and further investigations into risk factors for gallbladder polyps are necessary for establishment of appropriate treatment strategies.

Clinical recommendations

If there are signs of malignancy, the patient should have a cholecystectomy in a hospital where a prompt liver resection could be performed. In doubtful cases, a laparoscopic approached may be tried, and a cholecystectomy performed if there are no signs of growth to the serosa at laparoscopy. If there are signs of growth in the serosa, an open approach must be recommended and – if a frozen section shows malignancy – a resection of the nearby liver segments and the tissue in the duodeno-hepatic ligament may be tried. Also if frozen section shows malignancy

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after laparoscopic cholecystectomy, an enlarged resection must be considered during the same surgical procedure.

In patients with age ≥60 years, sessile polyp morphology, and polyp size ≥10 mm, a generous approach to EUS or multislice CT (in the future maybe virtual gallbladder scopy?) for closer characterization should be the normal. In all cases where there are indications of malignancy, a cholecystectomy should be recommended.

If there are no signs of malignancy, a follow-up with the same modality is done after 6 months. If by 6 months there is no changes in size, contour, or vascualrity, the follow-up should be individualized – most often a follow-up after another 12 months could be recommended.

For polyps 6–9 mm in diameter without signs of malignancy, a new US is recommended after 6 months. If the does not show any significant changes a new US is recommended after another 12 months and if no changes is found than no further imaging studies are made. Gallbladder polyps smaller than 6 mm are not followed up, if there are no indications of malignancy.

Pathophysiology

Chronic inflammation from a variety of stimuli has been implicated in the pathogenesis of gallbladder cancer. Numerous studies have investigated genetic abnormalities in gallbladder cancer and have shown that approximately 39-59% of gallbladder cancers are associated with the K-ras mutation, while more than 90% of them are associated with a p53 mutation. Other studies have identified higher levels of microsatellite instability and loss of heterozygosity when gallbladder cancers develop in a background of chronic cholecystitis. A number of other genetic abnormalities have been associated with gallbladder cancer including overexpression of the c-erb-2 gene, upregulation of cyclin D1, p16, p27, and MSH2.[7]

An adenoma-carcinoma sequence is thought to be involved in many cases of gallbladder cancer. Gallbladder cancer spreads early via lymphatic, hematogenous, and transcoelomic dissemination. Local invasion into the liver and surrounding organs is common.

Relevant Anatomy

The gallbladder is a saccular structure located at the inferior surface of the liver, at the division of the right and left lobes, just below segments IV and V. The gallbladder is composed of 4 different areas: the fundus, body, infundibulum, and neck. The gallbladder is approximately 7-10 cm long and about 2.5-3.5 cm wide. It normally contains approximately 30-50 mL of fluid, but it can distend and hold up to 300 mL of fluid. Gallbladder cancer generally spreads via the lymphatic channels and venous drainage, and peritoneal metastasis is common. Since the gallbladder is immediately adjacent to the liver, bile duct, portal vein, hepatic artery, duodenum, and transverse colon, involvement of these structures is common.

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The cystic plate is the reflection of the visceral peritoneum between the liver and the gallbladder. The dissection between the gallbladder and the liver during cholecystectomy divides the plane between the cystic plate and the muscle layer of the gallbladder. This is the anatomic basis for the improved survival in patients undergoing liver resection for T1b gallbladder cancer.

The lymphatic drainage of the gallbladder proceeds from the cystic node to the pericholedochal nodes and then to the regional nodal basins, including the superior mesenteric, retropancreatic, retroportal, and celiac. Interestingly, direct drainage from the gallbladder to the aortocaval nodes has been demonstrated. For this reason, exposure of this region is a necessary step in the operative staging of gallbladder cancer.[10]

From Medscape

Background

Gallbladder tumors are recognized with increasing frequency due to improvements in imaging techniques and increased utilization of these studies. Approximately 5% of patients evaluated with ultrasonography for abdominal pain will have a gallbladder polyp. Cancer of the gallbladder is uncommon, although it is the fifth most common gastrointestinal malignancy. The size of a gallbladder polyp is generally the strongest predictor of malignant transformation.[1] (See image below.)

A schematic drawing of the extent of lymphadenectomy for gallbladder cancer, especially when the extrahepatic biliary tree is resected.

Benign lesions

Benign lesions of the gallbladder are relatively common, but only adenomatous polyps are considered to have malignant potential. Although ultrasonography can be useful in evaluating these lesions, considerable difficulty may be encountered in establishing the diagnosis preoperatively.

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Cholesterol polyps

Cholesterol polyps account for approximately 50% of all polypoid lesions of the gallbladder.

These lesions are thought to originate from a defect in cholesterol metabolism. They appear as yellow spots on the mucosal surface of the gallbladder and are identified histologically as epithelial-covered macrophages laden with triglycerides and esterified sterols in the lamina propria of the mucosal layer of the gallbladder.

As a rule, cholesterol polyps exist as multiple lesions and are usually less than 10 mm. Cholesterol polyps are generally asymptomatic.

Inflammatory polyps

These lesions result from chronic inflammation. They extend into the gallbladder lumen by a narrow vascularized stalk.

Adenomyomatosis

Adenomyomatosis is characterized by extensions of Rokitansky-Aschoff sinuses through the muscular wall of the gallbladder. Ultrasonography reveals a thickened gallbladder wall with intramural diverticula. Although adenomyomatosis is generally considered a benign condition, serial evaluation with ultrasonography is indicated to rule out enlarging adenomatous polyps and gallbladder cancer. Some authors have reported gallbladder cancer occurring in localized adenomyomatosis and have suggested a more aggressive approach to the benign lesions.

Adenomatous polyps

Adenomatous polyps are benign epithelial neoplasms with malignant potential. Papillary adenomas grow as pedunculated, complex, branching tumors projecting into the gallbladder lumen. Tubular adenomas arise as a flat, sessile neoplasm. Consequently, it can be difficult to distinguish some adenomas from other gallbladder polyps by ultrasonography. Like many gastrointestinal tumors, an adenoma-carcinoma sequence is generally thought to occur in these lesions.

Other lesions

Other rare, benign lesions found in the gallbladder include fibromas, leiomyomas, lipomas, hemangiomata, granular cell tumors, and heterotropic tissue, including gastric, pancreatic, and intestinal epithelium.

Malignant lesions

The incidence of gallbladder cancer is 1.2 cases 100,000 persons in the United States; the frequency is much higher in Mexican Americans and Native Americans, although the greatest incidence is found in the indigenous peoples of the Andes Mountains, in northeastern Europeans,

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and in Israelis. The female-to-male ratio for gallbladder cancer is about 3:1; incidence of the disease peaks in the seventh decade of life.[2]

The most common risk factor for gallbladder cancer is gallstones, which are present in 75%-90% of gallbladder cancer cases. The size of the gallstones plays a role in the risk of developing of gallbladder cancer. Gallbladders containing gallstones that are greater than 3 cm in diameter have a 10-fold greater risk for developing malignancy than do those containing gallstones that are 1 cm in diameter. Causality is difficult to establish, but other chronic inflammatory conditions, such as cholecystoenteric fistula, primary sclerosing cholangitis, pancreaticobiliary maljunction, and chronic infection with Salmonella typhi, have also been associated with an increased risk of gallbladder cancer.

Modern series report about a 10% incidence of gallbladder cancer in porcelain gallbladders (in which the gallbladder wall is calcified), a much lower rate than that reported in older series. Stippled calcification of the mucosa is thought to carry a higher risk of gallbladder cancer than does generalized calcification of the gallbladder wall.[3, 4] Based on these associations, chronic inflammation is postulated to be involved in the pathogenesis of gallbladder cancer.

Gallbladder cancer is often discovered incidentally during a workup for gallstone disease, and about 50% of gallbladder cancer cases are diagnosed incidentally in cholecystectomy specimens. Unfortunately, about 35% of patients have distant metastases at the time of diagnosis.

Histologically, adenocarcinoma is found in 90% of gallbladder cancer cases, and squamous cell carcinoma is found in 2% of cases. Rare types of gallbladder cancer include sarcoma, adenosquamous carcinoma, oat cell carcinoma, carcinoid, lymphoma, melanoma, and metastatic tumors. A number of histologic subtypes of adenocarcinoma have been described, but papillary adenocarcinoma represents about 5% of gallbladder cancers; it tends to be well-differentiated and carries a more favorable prognosis. (See images below.)

Sagittal ultrasonogram in a 71-year-old woman. This image demonstrates heterogeneous thickening of the gallbladder wall (arrows). The diagnosis was primary

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papillary adenocarcinoma of the gallbladder. A transaxial enhanced computed tomography (CT) scan of a 60-year-old man with right upper quadrant pain shows a partially calcified gallbladder (arrow). At laparotomy and histology, an infiltrating adenocarcinoma of the gallbladder was confirmed.

History of the Procedure

In 1924, Blalock suggested avoiding surgery on patients with gallbladder cancer if the diagnosis could be made preoperatively.[5] Therapeutic nihilism continued to define the approach to gallbladder cancer through most of the 20th century. Although most patients with gallbladder cancer continue to present with advanced disease, advances in imaging and hepatobiliary surgical techniques have made curative surgery possible in a greater number of cases.

Problem

It is possible to cure gallbladder cancer when tumors are treated surgically at an early stage. Since gallbladder polyps are common, it is important to identify those that carry a high risk of malignancy. The surgical approach to gallbladder cancer includes prevention, early detection, appropriate staging, and curative resection.

Epidemiology

Frequency

Approximately 5% of patients evaluated with ultrasonography for abdominal pain will have a gallbladder polyp. Adenomatous polyps are found in about 1% of cholecystectomy specimens. The American Cancer Society estimated that 9,520 new cases of gallbladder cancer would be diagnosed in 2008 and that there would be 3,340 deaths from the disease.[2] The incidence of gallbladder cancer is 1.2 per 100,000 persons in the United States.[6] Mexican Americans and Native Americans have a greater incidence of gallbladder cancer than do other North American populations, while the highest incidences worldwide are found in the native peoples of the Andes Mountains, in northeastern Europeans, and in Israelis. The female-to-male ratio for gallbladder cancer is about 3:1; incidence of the disease peaks in the seventh decade of life.[7]

Etiology

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Gallstones are present in 75-90% of gallbladder cancer cases, but an etiologic influence remains unproven. Risk factors for developing gallbladder cancer include the inflammatory conditions listed above, advanced age, and the presence of a gallstone larger than 3 cm. Anomalous pancreatobiliary junction also may be a risk factor for the development of gallbladder cancer. Some authors have implicated bile acid composition, methyldopa, oral contraceptives, and occupational exposure to rubber, but these associations remain unproven. A 2008 study found evidence that excess body weight in women, specifically a 5 kg/m 2 increase in the body-mass index, is strongly associated with an increased risk of gallbladder cancer.[8]

Pathophysiology

Chronic inflammation from a variety of stimuli has been implicated in the pathogenesis of gallbladder cancer. Numerous studies have investigated genetic abnormalities in gallbladder cancer and have shown that approximately 39-59% of gallbladder cancers are associated with the K-ras mutation, while more than 90% of them are associated with a p53 mutation. Other studies have identified higher levels of microsatellite instability and loss of heterozygosity when gallbladder cancers develop in a background of chronic cholecystitis. A number of other genetic abnormalities have been associated with gallbladder cancer including overexpression of the c-erb-2 gene, upregulation of cyclin D1, p16, p27, and MSH2.[7]

An adenoma-carcinoma sequence is thought to be involved in many cases of gallbladder cancer. Gallbladder cancer spreads early via lymphatic, hematogenous, and transcoelomic dissemination. Local invasion into the liver and surrounding organs is common.

Presentation

As with most gallbladder lesions, early stage adenocarcinoma tends to present with symptoms similar to cholelithiasis or biliary dyskinesia. Advanced gallbladder cancer presents with more significant symptoms, such as weight loss, jaundice, anorexia, ascites, and right upper quadrant mass.

Given this presentation, less than 50% of gallbladder cancers are diagnosed preoperatively. Many are diagnosed incidentally in gallbladders removed for biliary colic or cholecystitis. Unfortunately, most gallbladder cancers are diagnosed in the later stages, and the overall 5 year survival rate is less than 5%.

Indications

Cholecystectomy is recommended for suspicious gallbladder polyps in order to facilitate early detection and treatment. Risk factors for malignancy include a polyp greater than 1 cm in size, primary sclerosing cholangitis, the presence of a single polyp, and a patient age of greater than 50 years. Ultrasonographic findings of vascularity and invasion of the gallbladder wall are suspicious findings. One study demonstrated that 7.4% of gallbladder polyps that were less than or equal to 1 cm were neoplastic.[9] The report's authors recommended cholecystectomy for lesions that are greater than or equal to 6 mm.

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Gallbladder cancer is diagnosed incidentally following cholecystectomy or based on preoperative imaging. The surgical indications are based on stage and margin status. Incidentally discovered T1a gallbladder cancers (which are limited to the mucosa) can be treated with cholecystectomy alone. T1b tumors (which invade the muscle layer) are 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.[7] (See images below.)

A schematic drawing of the extent of lymphadenectomy for gallbladder cancer, especially when the extrahepatic biliary tree is resected.

Gallbladder tumors. A schematic drawing of the extent of resection of liver segments IV-b and V for gallbladder cancer.

Relevant Anatomy

The gallbladder is a saccular structure located at the inferior surface of the liver, at the division of the right and left lobes, just below segments IV and V. The gallbladder is composed of 4 different areas: the fundus, body, infundibulum, and neck. The gallbladder is approximately 7-10 cm long and about 2.5-3.5 cm wide. It normally contains approximately 30-50 mL of fluid, but it can distend and hold up to 300 mL of fluid. Gallbladder cancer generally spreads via the lymphatic channels and venous drainage, and peritoneal metastasis is common. Since the gallbladder is immediately adjacent to the liver, bile duct, portal vein, hepatic artery, duodenum, and transverse colon, involvement of these structures is common.

The cystic plate is the reflection of the visceral peritoneum between the liver and the gallbladder. The dissection between the gallbladder and the liver during cholecystectomy divides the plane between the cystic plate and the muscle layer of the gallbladder. This is the anatomic basis for the improved survival in patients undergoing liver resection for T1b gallbladder cancer.

The lymphatic drainage of the gallbladder proceeds from the cystic node to the pericholedochal nodes and then to the regional nodal basins, including the superior mesenteric, retropancreatic,

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retroportal, and celiac. Interestingly, direct drainage from the gallbladder to the aortocaval nodes has been demonstrated. For this reason, exposure of this region is a necessary step in the operative staging of gallbladder cancer.[10]

Contraindications

Contraindications to surgery with curative intent include the 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), and inability to obtain a negative margin. Most North American surgeons consider the presence of celiac and retroperitoneal lymph node metastases a contraindication to resection because of the poor oncologic outcome of these patients with currently available treatment. For the same reason, some controversy exists about the benefit of resecting patients with T3 lesions. Some patients may be technically resectable but unable to tolerate the necessary procedure.

Laboratory Studies

Laboratory studies are generally not very nonspecific for gallbladder cancer.

In the later stages, liver function enzyme levels may be slightly elevated. These levels are generally not elevated in stages I and II.

An elevated bilirubin or alkaline phosphate level generally indicates advanced or obstructive disease.

Elevated carbohydrate antigen 19-9 (CA19-9) is 79.4% sensitive and 79.5% specific for gallbladder cancer. Elevated carcinoembryonic antigen (CEA) is also associated with gallbladder cancer and is 93% specific and 50% sensitive.

Imaging Studies

Ultrasonography is a very useful tool in the workup of gallbladder cancer. Polypoid lesions need to be at least 5 mm in size to be detected by ultrasonography. Cholesterol polyps generally appear as pedunculated lesions attached to the gallbladder wall.

Ultrasonographic findings that indicate possible malignancy or the need for further workup are a thick gallbladder wall, vascular polyp, a mass projecting into the lumen or invading the wall, multiple masses or a fixed mass in the gallbladder, a porcelain gallbladder, and an extracholecystic mass. Invasion of the liver can also be seen on ultrasonograms. (See image below.)

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Sagittal ultrasonogram in a 71-year-old woman. This image demonstrates heterogeneous thickening of the gallbladder wall (arrows). The diagnosis was primary papillary adenocarcinoma of the gallbladder.

Displacement of a stone to one side of the gallbladder is also suggestive of possible malignancy.

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) are useful in evaluating the extent of invasion and resectability of gall bladder tumors. CT scan results suggestive of gallbladder cancer include asymmetrical wall thickening or gallbladder mass with or without invasion into the liver. CT scanning of the chest, abdomen, and pelvis is a common staging modality that can determine the presence of distant metastases and give reliable information about involvement of other organs and vascular structures.

A porcelain gallbladder has been commonly associated with gallbladder cancer; however, studies have shown that the type of calcification is more important in determining the risk for malignancy. Selective mucosal calcifications have an increased risk when compared to diffuse intramural wall calcification. (See image below.)

A transaxial enhanced computed tomography (CT) scan of a 60-year-old man with right upper quadrant pain shows a partially calcified gallbladder (arrow). At laparotomy and histology, an infiltrating adenocarcinoma of the gallbladder was confirmed.

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Computed tomography (CT) scan in a 65-year-old man. This image depicts squamous cell carcinoma of the gallbladder and invasion of the liver.

Positron emission tomography (PET) scanning has a sensitivity of 75% and a specificity of 88% in gallbladder cancer but is not used routinely in the preoperative staging or postoperative surveillance of the disease.[11, 12]

Diagnostic Procedures

Percutaneous CT scan – guided biopsy is avoided in patients considered resectable based on preoperative imaging. Because of the substantial risk of peritoneal seeding, percutaneous biopsy and diagnostic cholecystectomy are not necessary in the patient suspected of having gallbladder cancer. In these patients, exploration with curative intent is planned based on preoperative imaging alone.

Percutaneous CT scan – guided biopsy is a useful diagnostic tool in patients who appear to have a nonresectable tumor. Tissue diagnosis is necessary for palliative treatment.

Endoscopic ultrasonography with fine-needle aspiration can be used to evaluate for peripancreatic and periportal lymphadenopathy.

Histologic Findings

The vast majority of gallbladder cancers are adenocarcinomas. Papillary adenocarcinomas have a better prognosis, because they tend to be well-differentiated and less invasive. A number of other histologic subtypes have been described, but the prognostic implications are unknown. Some authors have described metaplastic and nonmetaplastic subtypes and have suggested that metaplastic tumors have a more favorable prognosis. Unfortunately, most gallbladder cancers are poorly differentiated and present at an advanced stage, limiting the prognostic importance of histologic subtypes.

Staging

The American Joint Committee on Cancer (AJCC) has designated staging by the TNM (primary t umor, regional lymph n odes, distant m etastasis) classification as follows[13] :

TNM Definitions

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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

o T1a - Tumor invades lamina propriao T1b - Tumor invades the muscularis

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

T3 - Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or 1 other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts

T4 - Tumor invades the 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 - Portal lymph node metastasis N2 - Distant lymph node metastasis such as periaortic, pericaval, superior mesenteric artery, or

celiac artery

Distant metastasis (M)

MX - Distant metastasis cannot be assessed M0 - No distant metastasis M1 - Distant metastasis

AJCC Stage Groupings

Stage 0: Tis, N0, M0 Stage I: T1 (a or b), N0, M0 Stage II: T2, N0, M0 Stage IIIA: T3, N0, M0 Stage IIIB: T1 to T3, N1, M0 Stage IVA: T4, N0 or N1, M0 Stage IVB: Any T, N2, M0, OR Any T, any N, M1

Medical Therapy

Small gallbladder tumors are common and many can be safely followed with serial ultrasonographic examination. It is generally thought that polyps of less than 1 cm are safe to follow, although a study[9] has recommended that polyps that are greater than or equal to 6 mm be

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considered for cholecystectomy. 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 the disease, the benefit of adjuvant treatment remains unproven. Phase II studies have shown that the use of single-agent chemotherapy (with gemcitabine, capecitabine, or 5-fluorouracil) in the palliative setting can be beneficial. Combination chemotherapy also has been shown to be beneficial and is usually based on gemcitabine, capecitabine, and 5-fluorouracil used in combination with cis-platinum or oxaliplatinum. Fluoropyrimidine-based chemoradiotherapy is commonly employed in the palliative and adjuvant setting as well. Since no regimen has shown superiority, participation in clinical trials is encouraged.

Surgical Therapy

Operative resection offers the only chance for long-term survival. The details are described below.[14]

Management of 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 about performing the operation laparoscopically or open depends on the risk of the lesion being malignant. Preoperative imaging should be reviewed to exclude the presence of invasion before planning a laparoscopic approach.

In these cases, the gall bladder 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.

Management of malignant lesions

Gall bladder cancer can be diagnosed incidentally in a surgical specimen excised for other reasons or based on imaging studies. When 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.

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

Percutaneous biopsy is avoided in resectable patients.

Treatment of benign lesions

The approach to treatment of benign lesions is described above.

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Treatment of malignant lesions

Patients with localized gall bladder 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 gall bladder cancer can be treated with simple cholecystectomy.

Patients with T1b or deeper gall bladder cancer are treated with hepatic resection and lymph node dissection that includes the portal, gastrohepatic ligament, and retroduodenal nodes. Resection of liver segments IVb and V are frequently adequate to achieve negative margins. In some cases, extended liver resection and/or bile duct resection may be necessary to achieve negative margins. (See images below.)

A schematic drawing of the extent of lymphadenectomy for gallbladder cancer, especially when the extrahepatic biliary tree is resected.

Gallbladder tumors. A schematic drawing of the extent of resection of liver segments IV-b and V for gallbladder cancer.

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

Preoperative Details

As outlined above, the preoperative evaluation of the patient with gall bladder cancer is similar whether the tumor is diagnosed incidentally following cholecystectomy or based on imaging studies. History and physical exam determine the suitability of the patient to undergo 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,

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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. CEA and CA19-9 may be helpful as baseline studies that inform treatment decisions in the future. 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.

Intraoperative 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 ultrasonography (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 when 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, such as the stomach, duodenum, and 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 on the bile duct based on 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 require 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 recent study indicates that accurate staging requires examination of at least 6 lymph nodes.[15]

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Postoperative Details

No standard adjuvant treatment protocol has been defined for gall bladder cancer. A 2008 study found that only 20% of patients with gall bladder cancer received adjuvant treatment.[16] In the 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.[17] Because of the high cure rate with surgery alone for T1N0 lesions, adjuvant therapy is not commonly offered to these patients.

Follow-up

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

Complications

The overall complication and morbidity rate 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 following extended hepatectomy, especially if jaundice is present preoperatively.

Outcome and Prognosis

The overall survival rate for adenocarcinoma of the gall bladder depends on the stage at presentation. For T1 lesions, many studies report 5-year survival rates of 100%, especially when hepatectomy is used routinely for T1b or deeper lesions. Five-year survival following extended cholecystectomy for T2 lesions varies in the literature from 38% to 77%. Extended resection is necessary for stage III and IV tumors and results in 5-year survival of about 25%. Patients with unresectable disease have a median survival of 2-4 months and a 1-year survival rate of less than 5%.[7, 18]

Future and Controversies

Improvements in the treatment of gallbladder cancer will rely on more effective chemotherapy to more effectively treat patients with systemic disease.