+Model
ARTICLE IN PRESS
JVS-398; No. of Pages 12
Journal of Visceral Surgery (2014) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
REVIEW
Gallbladder tumor and pseudotumor: Diagnosis and management J. Zemour a,∗, M. Marty b, B. Lapuyade c, D. Collet a, L. Chiche a a
Service de chirurgie digestive, hôpital Haut Levêque, CHU de Bordeaux, 1, avenue de Magellan, 33604 Pessac cedex, France b Service d’anatomopathologie, hôpital Haut Levêque, CHU de Bordeaux, 1, avenue de Magellan, 33604 Pessac cedex, France c Service d’imagerie médicale, hôpital Haut Levêque, CHU de Bordeaux, 1, avenue de Magellan, 33604 Pessac cedex, France
KEYWORDS Gallbladder cancer; Gallbladder polyp; Gallbladder pseudotumor; Atypical cholecystitis; Gallbladder imaging
Summary The most common gallbladder disease, by far, is cholecystolithiasis. Nevertheless, the discovery of abnormal thickening of the gallbladder wall or a tumorous lesion (with or without gallstones), is a frequent problem. The physician who confronts this finding must be aware of the various lesions to be considered in the differential diagnosis, whether neoplastic or pseudotumoral, epithelial or not, benign or malignant. Because of the particularly grim prognosis of gallbladder cancer, especially when discovered at a late stage, it is especially important to focus on the potential for malignant degeneration of any gallbladder lesion. Imaging plays an important role in distinguishing these lesions; ultrasound remains the key diagnostic tool for gallbladder disease, but other modalities including CT and MRI may help to characterize these lesions. The resulting treatment strategies vary widely depending on the risk of malignancy. A wide and extensive resection is recommended for malignant lesions; prophylactic cholecystectomy is recommended for lesions at risk for malignant degeneration while observation is indicated for purely benign lesions. © 2014 Elsevier Masson SAS. All rights reserved.
Introduction Gallbladder tumors are rare compared to gallstone disease which forms the bulk of gallbladder pathology. However, its prevalence varies from 3% to 7% in the general population [1], which makes it not infrequent in day-to-day surgical practice. On ultrasound exam, the presence of a tumorous lesion of the gallbladder, whether associated with gallstones or not, must be systematically sought. The main challenge of management of malignant or pre-malignant gallbladder tumors lies in early diagnosis; the diagnosis of gallbladder cancer is all too often delayed and the lesion is commonly at an incurable stage [1,2].
∗
Corresponding author. E-mail address: [email protected] (J. Zemour).
http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003 1878-7886/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
2
J. Zemour et al.
Gallbladder adenocarcinoma, the most feared, has a mean 5-year survival rate of 5%, all stages combined [3], and the prognosis depends mainly on tumor stage at the time of diagnosis. Clinical context is essential to the diagnostic process but in most cases, an isolated gallbladder lesion needs to be accurately characterized by modern imaging methods. Abdominal ultrasound remains the first-line examination for patients with symptoms of biliary disease, but CT and MRI have become essential to characterize any abnormal appearance of the gallbladder parenchyma. Other tests (Contrast-enhanced ultrasound [CEUS], Endoscopic ultrasound, endoscopic ultrasound [EUS], and Positron emission tomography [PET]) are currently being evaluated [4,5]. These modern imaging techniques are needed to help distinguish between benign lesions, those at risk of malignant degeneration, and malignant lesions, in order to select the most appropriate surgical management. The objective of this systematic review is to define the various neoplastic and pseudo-tumorous pathologies of the gallbladder, based on data from the literature and on our own experience, and thereafter to establish a diagnostic strategy using available imaging modalities, and finally to define an appropriate therapeutic strategy.
Different gallbladder pathologies Gallbladder lesions occur commonly; their prevalence on ultrasonography varies from 2% to 12% in the general population in different series [1,6]. Table 1 summarizes the various benign and malignant pathologies that can be seen. But signs of malignancy in lesions at risk for malignant degeneration must be sought in order to select an appropriate management strategy, particularly since the patient’s prognosis depends on diagnosis at an early stage.
Benign lesions Most gallbladder lesions are benign. In the study of Yang et al. [7] study, more than two-thirds of the 182 patients who underwent cholecystectomy performed were found to have benign lesions. These included both polypoid lesions and also atypical thickening of the gallbladder wall (inflammation or infection), which can be diagnostically misleading because they mimic cancerous lesions.
Polypoid lesions Cholesterolosis and cholesterol polyps Cholesterol polyps represent the majority of benign lesions, with a prevalence ranging from 60—90% in different studies [1,7]. These polyps arise from the accumulation of triglycerides and cholesterol esters within macrophages in the gallbladder wall, without any cellular proliferation. Polyps are small (usually 1—2 mm, always less than 10 mm) and multiple [7]. In gross appearance, they are yellow, relatively friable, carpeting the mucosal surface of the gallbladder lumen; they are often attached to the mucosa by a pedicle. Cholesterolosis involves the gallbladder diffusely and has a mean prevalence of 10% in autopsy series [8]. This lesion is clinically asymptomatic as a rule but may occasionally manifest itself as biliary pain or even by distal migration provoking cholecystitis. Ultrasound imaging allows diagnosis based on findings of a hyper-echoic intraluminal polyp without posterior shadowing that remains in a fixed mural
location with change in position; it is typically round or slightly lobulated (Fig. 1). Other imaging techniques are not particularly useful [4]. The diagnosis of cholesterol polyp requires no further surveillance or treatment as long as no biliary symptoms are present. In case of doubt, repeat ultrasound imaging at six-month interval is indicated.
Inflammatory or fibrous polyps These represent 10% of gallbladder polyps and result from secondary sequelae of fibrosis and chronic inflammation. They are small in size and ultrasound imaging is diagnostic of simple benign poly; the diagnosis of these non-cholesterol polyps is based on histologic exam [8,9].
Heterotopic polyps These consist of ectopic tissue such as liver, gastric, pancreatic, adrenal or thyroid tissue lining the bile duct [9]. Only ectopic gastric or pancreatic tissue causes symptoms. A literature review found fifty cases of ectopic gastric and thirty cases of ectopic pancreatic tissue [10]. No risk factors for malignant degeneration could be identified. Non-surgical observation can be proposed but the unusual lesion is usually diagnosed by postoperative histological analysis.
Mesenchymal lesions Rare benign tumors such as leiomyomas, lipomas and fibroids may develop from smooth muscle cells [11]. Macroscopically, these are solid, nodular and well-circumscribed lesions. Again, there is no specific indication for excision, but diagnostic uncertainty can lead to surgery.
Gallbladder wall thickening Gallbladder inflammation or cholecystitis usually results in a diffuse thickening of the wall. Its presentation can be acute or chronic, of more or less serious gravity, and the diagnosis is suggested by non-specific thickening of the gallbladder wall.
Acute cholecystitis Acute cholecystitis results from obstruction of the cystic duct or gallbladder by impaction of a gallstone in 95% of cases, with inflammation of the gallbladder wall, often associated with bacterial infection. Acute acalculous cholecystitis occurs in only 5% of cases, typically occurring in ICU patients or multiple trauma, where gallbladder inflammation is due to hemorrhagic or ischemic events or biliary stasis (parenteral nutrition) [12]. The diagnostic and therapeutic criteria of calculous cholecystitis are well described and codified with a set of recommendations (Tokyo Guidelines) published in 2007 and recently updated [13,14]. The diagnosis is suggested by the association of clinical signs (RUQ abdominal pain, guarding, mass, Murphy’s sign) and laboratory findings of inflammation (leukocytosis, elevated CRP). The diagnosis is confirmed by ultrasound imaging showing gallstones, wall thickening ≥4 mm, peri-cholecystic fluid, and the elicitation of a positive Murphy sign on ultrasound examination. Management and the interval before surgical intervention depend on the severity of cholecystitis, but the curative treatment remains cholecystectomy [14]. Management of certain forms of acute cholecystitis should be individualized because of their severity and specific aspects of imaging: • gangrenous cholecystitis is accompanied by ischemia and hemorrhagic necrosis of the gallbladder wall. CT scan shows an irregular wall, with thinning in places (necrosis), sometimes with air present within the wall or lumen of the gallbladder, a marked edema, and/or a peri-cholecystic
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management Table 1
3
Tumors and pseudo-tumors of the gallbladder.
Malignant tumors
Benign tumors
Epithelial tumors
Adenocarcinoma Undifferentiated carcinoma Adenosquamous carcinoma Squamous cell carcinoma Neuro-endocrine tumor
Epithelial tumors
Adenoma Adenomyomatosis Papillomatosis Heterotopic tissue
Non-epithelial tumors
Lymphomas Sarcomas
Non-epithelial tumors
Leiomyoma Lipoma Neural tumors
Metastatic tumors
Melanoma Kidney Breast
Pseudo-tumors
Cholecystitis Cholesterolosis Inflammatory polyp
abscess. Irregular or discontinuous enhancement of the wall is also a predictive sign of gangrenous cholecystitis [4.15]. This constitutes a true life-threatening emergency and requires urgent surgical intervention without delay; • emphysematous cholecystitis arises due to infection by anaerobic gas-producing bacteria. In more than half the cases, the patients are male and diabetic, and in 30% of cases, the cholecystitis is acalculous [15]. The mortality rate can reach 15%. Ultrasound reveals focal hyper-echoic images with posterior shadowing or ‘‘comet tail’’ artifact. If the mural gas is present in large quantities, one may see a hyper-echogenic crescent with posterior shadowing [4]. The presence of air in the gallbladder wall or lumen, or in the peri-cholecystic fat is a sign of perforation and requires emergency surgery; • less common non-bacterial forms of infection including cholecystitis due to Cytomegalovirus (CMV), Cryptococcus (in HIV patients) and IgG4 have been described [16,17]. Management of these entities is the same as for conventional acute cholecystitis except when IgG4 cholecystitis mimics a gallbladder cancer. Indeed, sclerosing IgG4 disease must be considered in the differential diagnosis of gallbladder malignancies, especially outside the context of autoimmune acute pancreatitis (the most common clinical context). The diagnosis is often aided by laboratory testing (white blood count with the ratio of eosinophils to polymorphonuclear cells, serology). It is important to make this diagnosis since the treatment is based on
Figure 1.
corticosteroid therapy, which often results in dramatic improvement in symptoms and histologic lesions.
Calculous chronic cholecystitis This is a late complication of gallstones, occurring mainly in the elderly, and often diagnosed incidentally in an asymptomatic patient. Ultrasound shows an irregular circumferential wall thickening associated with intraluminal calculi. CT scan shows a ‘‘halo’’ corresponding to a hypodense well-delineated peri-cholecystic band [5]. The sclero-atrophic form, which probably has a potential for malignant degeneration, is often associated with disappearance of the gallbladder lumen on imaging. Cholecystectomy is indicated in such cases.
Xanthogranulomatous cholecystitis This is probably the most misleading form [18]. Xanthogranulomatous cholecystitis is an inflammatory form of chronic cholecystitis with pseudotumor whose appearance, in association with gallstones, may mimic gallbladder cancer. Chronic inflammation is caused by extravasation of bile into the wall via mucosal ulcerations or the sinuses of Rokitansky. Macroscopically, there is a yellowish mass that often infiltrates the peri-cholecystic fat, with associated lymphadenopathy or biliary obstruction (Fig. 2). It represents 1—13% of gallbladder lesions, and is mostly seen in women over the age of 60. It presents clinically as acute cholecystitis, but some radiological criteria that help to guide diagnosis include nodules or hypo-echoic intramural bands
Cholesterolosis of the gallbladder. The ultrasound shows multiple small, hyper-echogenic polyps.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
4
J. Zemour et al.
Figure 2. Xanthogranulomatous cholecystitis: macroscopic view of cholecystectomy specimen.
and MRI images showing fluid in the gallbladder wall [5]. It is difficult to differentiate this from gallbladder cancer by imaging, and surgery should be performed with routine frozen section examination [18].
Figure 3. Adenomyomatosis: macroscopic view of cholecystectomy specimen.
Diffuse wall thickening due to extra-vesicular causes There are numerous causes of gallbladder wall thickening other than acute cholecystitis. The most common are ascites, hepatitis (viral or drug-toxic) and hypoproteinemia [19]. Certain inflammatory or infectious processes such as acute pancreatitis, acute pyelonephritis, or peri-hepatitis (Fitz-Hugh-Curtis syndrome) may also result in wall thickening [4]. The clinical and laboratory findings along with imagery help to establish the etiology of this thickening and the treatment of the cause if necessary, but no specific treatment of the gallbladder is recommended, particularly since surgery is sometimes risky in this context (cirrhosis, malnutrition).
Benign lesions that have potential risk for malignant degeneration Adenoma Adenoma, a benign tumor with pseudo-glandular proliferation surrounded by fibrous stroma, is present in 0.4 to 0.5% of cholecystectomy specimens [20]. The adenoma can be sessile, pedunculated, or polypoid, and usually measures from 0.5—2.0 cm [2]. It is usually asymptomatic. The risk of malignant degeneration varies with polyp size (it is only observed in adenomas larger than 10 mm), and in patients older than 50 years, or with sessile lesions or polyps associated with gallstones. In Park et al.’s study, of a cohort of 1558 patients whose polyps were monitored by serial ultrasound examination [21], an increase in size was seen in 3.5% of these patients, a quarter of whom had a true neoplastic lesion. On imaging, the adenomatous polyp is characterized by an isoechoic appearance (as opposed to cholesterol polyps, which are hyper-echoic), with no posterior acoustic shadowing; the lesion is intraluminal, attached to the wall and fixed during positional maneuvers. Color Doppler imaging confirms
its solid tissue nature. Evaluation of the thickness of the adjacent wall and the size of the polyp(s) is essential [4]. It is generally agreed that surgery should be performed for any polyp larger than 1 cm; polyps smaller than 1 cm should be monitored with serial ultrasound examinations every six months for two years, to detect any evidence of rapid growth [22].
Adenomyomatosis Adenomyomatosis is a common lesion with a prevalence ranging from 3% to 5% [8,23]. It represents 25% of gallbladder wall thickening and localizes preferentially in the gallbladder fundus. The thickening is well limited and contains multiple coalescing cystic structures (Fig. 3). It consists of hyperplasia of the epithelial and smooth muscle layers causing a thickening of the gallbladder wall. The epithelium invaginates through the muscularis, forming pseudo-diverticula (Rokitansky-Aschoff sinuses), which are specific for the lesion. The risk of malignant degeneration is still uncertain despite its frequent association with gallbladder cancer in some studies, because the concomitant presence of gallstones makes interpretation difficult [8]. This lesion has no specific clinical presentation. Its appearance on imaging is typical and should be appreciated [4]. On ultrasound, the wall is thickened with anechoic foci corresponding to the dilated sinuses, associated with small hyper-echoic foci and ‘‘comet tail’’ images corresponding to trapping of the ultrasonic beam in dilated sinuses. MRCP shows an image described as a ‘‘string of pearls’’ image formed by fluid containing diverticula [24]. MRI seems to be the best investigation to confirm the diagnosis of adenomyomatosis (diagnostic accuracy of 93% versus 75% for CT and 66% for ultrasound) [4]. When this lesion is isolated, it is not considered to have a risk of malignant degeneration and no
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management treatment recommended. However, when adenomyomatosis is seen in association with cholelithiasis or abnormalities at the bilio-pancreatic junction (BPJ), prophylactic cholecystectomy is indicated [8].
Papillomatosis In this condition, multiple recurrent papillary adenomas may extend throughout the entire biliary tree. Florid papillomatosis corresponds to diffuse lesions of dysplastic biliary epithelium growing around a fibro-vascular axis. This condition has high potential for malignant degeneration [25]. The extent of this lesion is underestimated on standard imaging by ultrasound, CT, or MRI. Endoscopic ultrasound (EUS) can detect thickening with vegetations of the gallbladder wall, sometimes in association with similar lesions involving the intrahepatic or extrahepatic bile ducts that may result in ductal dilatation due to obstruction by a polyp; the lesions are iso- or hyper-echogenic with no posterior acoustic shadowing. Surgical treatment specifically adapted to the extent and topography of the lesions is indicated [25].
Porcelain gallbladder This term designates calcification of the gallbladder wall. This can be complete diffuse intramural calcification (Type I), limited to complete involvement of the mucosa (Type II), or incomplete (Type III). The presence of parietal calcification is associated with a risk of malignant degeneration ranging from 12 to 60% [26]. The incidence depends on the type of calcifications, being lower for Type I than for isolated mucosal involvement (Types II and III) [27]. In the study by Khan et al. [28], the rate of malignant transformation of 140 porcelain gallbladders was 15%. Ultrasound or CT imaging is used to make the diagnosis and to characterize the type. Discovery of a porcelain gallbladder by imaging warrants prophylactic cholecystectomy because of the risk of carcinogenesis.
Malignant lesions Primary gallbladder cancer Primary cancers of the gallbladder are the fifth most common gastrointestinal malignancy (4% of all GI cancers) [27].
Adenocarcinoma Adnocarcinoma represents more than 80% of cases of gallbladder cancer and preferentially affects women between 65 and 75 years. Its overall incidence is 2.5 per 100,000 persons [27,29], and ranges from 0.8 to 25 cases per 100,000 people according to geographical distribution in the world (in France, from 0.8 to 1.5/100,000) [30]. Diagnosis at an early clinical stage is the exception. Diagnosis is fortuitous in half the cases, based on histological examination of a cholecystectomy specimen; more typically, diagnosis is made at an advanced stage based on biliary symptoms associated with impaired general condition. The imaging assessment generally depends on abdominal ultrasound or CT scan with IV contrast to distinguish three types of presentations: focal or diffuse thickening of the gallbladder wall, a polypoid mass projecting intralumenally, or a solid tissue mass centered on the gallbladder fossa with hepatic invasion [4]. This last form, corresponding to advanced stage disease, is the most common presentation (45—70% of cases [31]). The prognosis is poor due to early invasion of the liver, lymph nodes of the hepatic pedicle and the rapid progression of distant metastases to the peritoneum and liver in particular [32].
5
The sensitivity and specificity of ultrasound for evaluation of T stage is greater than 85% [4]. CT is less sensitive than ultrasound for the diagnosis of wall thickening but it may be useful to explore the gallbladder wall when gallstones mask calcification or thickening. CT and biliary MRI are particularly useful in the assessment of local, regional, and distant spread and also for the assessment of resectability. PET scan, EUS and exploratory laparoscopy can also be considered [5]. Therapeutic management depends mainly on the histological stage at the time of discovery (AJCC TNM classification) [33]. Simple cholecystectomy is sufficient for the very early stages (Tis or T1a) [29]. For stage T1b lesions (extending into the muscularis) and beyond, more extensive surgery is necessary [34,35].
Other primary cancers Other gallbladder malignancies are extremely rare. Symptomatology is non-specific, often asymptomatic. The diagnosis is based on histologic examination after surgical treatment. The various types of cancer include: • undifferentiated carcinoma represents 2—7% of gallbladder cancers [36]. This is a very aggressive tumor with direct invasion of adjacent organs, lymph node involvement and peritoneal dissemination; • adenosquamous carcinoma, representing 1—12% of gallbladder cancers [37], is a mixed tumor with components of adenocarcinoma and squamous cell carcinoma. It is most commonly localized in the gallbadder fundus with direct invasion the hepatic parenchyma and adjacent organs (colon). Lymph node involvement and peritoneal dissemination are rare, in comparison to the incidence of liver metastases; • squamous cell carcinoma represents 0—3% of gallbladder cancers [38]. This tumor is not prone to lymphatic spread, but often shows rapid loco-regional extension. The prognosis of these tumors is worse than that of adenocarcinoma; the average survival after diagnosis is six months. Treatment depends mainly on the quality of the surgical excision but the possible benefits of adjuvant radiotherapy or chemo-radiotherapy should be considered [39]; • neuro-endocrine tumors represent less than 0.5% of gallbladder cancers [40]. These tumors have a slow rate of growth and are low-grade malignancies, but the long-term prognosis is poor, depending on the tumor grade. A literature review of 53 cases showed a 1-year survival rate of 28% and zero survival at 2 years [41]. Treatment is surgical but adjuvant chemotherapy may improve survival (with a median of 13 months)[42]; • non-epithelial primary tumors are exceptional and consist mainly of sarcomas (1—2% of gallbladder cancers) [8]), and lymphomas (only 28 cases reported in the literature), the majority of which are MALT lymphoma and diffuse large B-cell lymphoma [43,44].
Metastases Three primary cancers seem to have a particular tropism for spread to the gallbladder: melanoma, renal cancer and breast cancer [45]. All these cancers are hypervascular on imaging. Sometimes gallbladder metastasis is part of generalized systemic metastasis, but, on occasion, it can be an isolated metachronous lesion [46]. In order of frequency, distinguishing features include metastatic melanoma, metastatic renal cell carcinoma, metastatic breast cancer and other metastases.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
6
J. Zemour et al.
Metastatic melanoma Melanoma can metastasize to any organ. It represents 50—65% of gallbladder metastases [47]. In most cases, there are biliary symptoms, so when a patient with a past history of melanoma develops biliary symptoms, a search should be made for a hypervascular lesion on imaging to make the diagnosis. Histology is usually identical to that of the primary tumor. The prognosis of these patients is poor, with a median survival of less than 12 months [47].
Metastatic renal cell carcinoma Renal cancer can metastasize to many sites. The most common are pulmonary, hepatic, bone and brain metastases, but unusual sites are also described: pancreas, skin, heart, prostate or gallbladder (only 0.5% to the gallbladder) [48,49]. The study of 28 cases by Ishizawa et al. [48] showed that less than half were synchronous, while two-thirds of cases are solitary metastases. This most often appears as a solitary intraluminal polypoid mass on a stalk (Fig. 4) and generally progresses rapidly to death with a picture of widespread distant metastasis, but very good long-term results have been reported after cholecystectomy for a solitary metastasis [49].
Metastatic breast cancer Breast carcinoma preferentially metastasizes to the axillary lymph nodes, bones, lungs and liver. Only 4—7% of breast carcinomas are associated with gallbladder metastases. They may occur late (one month to fifteen years time interval)[50]. Dissemination throughout the biliary system is exceptional. It generally progresses by hematogenous spread or direct invasion of the hepatic hilum. The diagnosis is usually made by histological analysis, and occurs more frequently with lobular than ductal breast cancer. There are no specific recommendations for treatment, which typically consists of surgical resection combined with hormonal therapy or the addition of zoledronic acid [50].
Other metastases Exceptional cases of pulmonary, gastric, uterine-cervical and hepatocellular carcinoma with metastasis to the gallbladder have been described in the literature [51—53].
Diagnostic strategy Non-calculous gallbladder disease is often discovered incidentally by imaging. This allows characterization of wall thickening and gallbladder content, especially in complicated forms of benign disease, lesions with malignant potential, or cancer [4]. But gallbladder wall thickening can be due to a variety of pathologies, and accurate diagnosis must be determined based on the combination of clinical, laboratory, and radiological data. The objective of this section is to establish an optimal diagnostic strategy by combining the clinical context with the various imaging tests available.
Clinical context Clinical setting Diagnostic orientation depends on the general context. Thus, the initial thinking is different for an elderly patient in poor general condition than for a young patient with no previous history. Assessment should include risk factors for malignancy and take into account the particular clinical setting and associated pathologies:
• age is regarded as a risk factor of malignancy. Beyond the age of 60 years [1,54], the incidence of gallbladder cancer gradually increases with age [24]. In a young patient, even if calculous cholecystitis is considered the most likely diagnosis, the presence of immunodepression, diabetes or a particular context should help guide the diagnosis of rare forms of cholecystitis; • ethnic origin is of diagnostic importance because there is great disparity in the worldwide incidence of gallbladder adenocarcinoma (higher incidence in Chile, Israel, Poland, Mexico, Bolivia, Japan and in the northern region of India) [24]; • a past history of cancer must be sought in order to consider the possibility of metastasis; • the presence of risk factors for malignant degeneration, such as chronic inflammation of the gallbladder mucosa, must be systematically sought during diagnostic work-up. Chronic inflammation may be observed in different contexts: primary sclerosing cholangitis (PSC) is associated with an incidence of gallbladder cancer of 1% per year [24], so cholecystectomy is indicated for any polyp associated with PSC; if surgery is not possible, the frequency of ultrasound surveillance should be increased [55]. The presence of large gallstones has been described as a risk factor for malignant degeneration increasing the risk by a factor of 2.4 for medium size stones (3 cm) [26,27,29]. The risk of developing cancer after a 20-year period is estimated at 0.26 to 0.5% in this case [32]. Porcelain gallbladder is an important risk factor for malignancy with an association present in 12—60% of cases [26]. The incidence depends on the type of parietal calcification. Chronic infection of the bile by certain bacteria (Salmonella typhi or paratyphi and Helicobacter pylori) results in a six-fold increased rate of gallbladder cancer compared to patients without chronic infection [26]. Anomalous junction of the pancreatic and biliary ducts (AJPB) is characterized by an abnormal connection between the bile duct and the pancreatic duct forming a long common channel (>10-15 mm) without its own sphincter; this promotes malignant degeneration of the gallbladder mucosa due to chronic reflux of pancreatic juice into the bile ducts. These patients are often young and gallstones are not present [27,35].
Symptoms The initial clinical examination is essential, allowing rapid differentiation of the acute infectious presentation suggestive of acute cholecystitis in its different forms from subacute or chronic cholecystitis without signs of sepsis where diagnosis is more difficult. The clinical exam searches for signs of systemic illness, evidence of infection, abdominal pain, tenderness or an abdominal mass. But in some cases, when a gallbladder lesion is discovered fortuitously, the patient will have no clinical symptoms and diagnosis is based solely on patient history and imaging studies.
The contribution of ultrasound Ultrasound is the first examination performed and is standard test (investigation?) for the diagnosis of acute cholecystitis; it also has an 85% sensitivity and 80% specificity for the diagnosis gallbladder tumors [4]. It yields information about both the content and the container.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management
Figure 4.
7
Metastasis from a renal cancer: macroscopic view. The tumor is hemorrhagic, consistent with its hypervascularity.
Evaluation of gallbladder content Ultrasonography often describes an intravesicular lesion referred to as a ‘‘polyp’’. Polyps are distinguished from calculi by their immobility and their lack of acoustic shadowing. To enable optimal management of gallbladder polyps, the radiologist must describe: the shape of the polyp (pedunculated or sessile), its appearance (echogenicity and heterogeneity), whether the lesion is isolated or not, and a precise measurement of size. Size is a major risk factor for malignant degeneration; the rate of malignancy varies from 0 to 5% for polyps less than 10 mm, to 50—70% for polyps larger than 15 mm [26]. Surgery is indicated for all polyps ≥ 10 mm [56]. When multiple polyps are present, the number and size of the largest polyps must be precisely defined. The presence of associated gallstones must be determined; a large stone adherent to the wall may simulate gallbladder cancer by its pseudo- tumor appearance as a fixed mass (Fig. 5). For lesions larger than 1 cm, color Doppler ultrasound is used to assess hypervascularity [4]. But it does not have adequate specificity to be an effective criterion for a positive diagnosis. Ultrasound with contrast increases the detection of polypoid lesions and helps to differentiate carcinoma from other polypoid lesions [57]. It is not commonly used in practice despite a 75% sensitivity and 100% specificity for the diagnosis of cancer when tumor enhancement and the presence of tortuous tumor vessels are used as diagnostic criteria.
gangrenous or chronic cholecystitis). It is also useful for preoperative evaluation of gallbladder cancer (anatomical extension to blood vessels, lymph nodes, liver parenchyma and distant metastases) [4,5]. The sensitivity of CT for evaluating the gallbladder wall is excellent, but is less so for the assessment of the gallbladder contents.
Magnetic resonance imaging The diagnostic capabilities and limitations of MRI are similar to those of CT. MRI is the standard test for distinguishing adenomyomatosis from gallbladder neoplasm because the Aschoff-Rokitansky sinuses show clear-cut hyper-intensity of T2-weighted images (Fig. 6). MRCP can be a useful adjunct
Evaluation of the gallbladder wall Ultrasonography may describe irregular wall thickening or budding as one aspect of a vegetative lesion protruding into the lumen. The lesion may be solitary or multiple, isoor hypo-echoic, without acoustic shadowing, and having a pedunculated or sessile base. Any focal thickening of the gallbladder wall >5 mm is suspicious for malignancy [5].
Computed tomography Ultrasound no longer accounts for most incidental discovery of gallbladder masses; CT scans are performed more frequently as first-line imaging for patients with abdominal symptoms or for patients undergoing scheduled surveillance. CT is a useful adjunct to ultrasound in difficult or complicated forms of acute cholecystitis (emphysematous,
Figure 5. Gallstone adherent to the gallbladder wall mimicking a tumorous protrusion; macroscopic view.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model
ARTICLE IN PRESS
JVS-398; No. of Pages 12
8
J. Zemour et al. of some specific lesions: the cholesterol polyp has a typical picture of a pedunculated homogeneous hyper-echoic mass without acoustic shadowing. Adenomyomatosis presents an image of a thickened gallbladder wall containing multiple microcysts of a few millimeters. EUS is more effective than percutaneous ultrasound for differentiating adenocarcinoma from adenomyomatosis [58].
Positron emission tomography The role of PET scan is not yet defined. PET with fluorodeoxyglucose labelled with fluorine-18 has a sensitivity and specificity of about 80—90% for the diagnosis of gallbladder cancer [27]. Some studies have reported its usefulness, showing the accuracy of PET for the diagnosis of benign versus malignant gallbladder lesions, albeit with some false positive diagnoses of cancer [54]. Figure 6. Adenomyomatosis of the gallbladder fundus. MRI with hyper-intense signal on T2-weighted images and the appearance of a ‘‘string of pearls’’.
by demonstrating the classical ‘‘string of pearls’’ appearance within the gallbladder wall [21]. For adenocarcinoma, MRI allows a better assessment of tumor infiltration; CT has a sensitivity of 67% and a specificity of 89% for hepatic invasion while biliary MRI had a sensitivity of 100% and a specificity of 89% for invasion of the biliary ducts [5,21].
Contribution of second-intention imaging modalities Endoscopic ultrasound EUS is more discriminating for differentiating small malignant lesions under 1 cm, with a specificity of 91% for differentiating neoplastic versus non-neoplastic lesions [5]. Performance of EUS should be discussed during the staging of gallbladder cancer. It also allows improved visualization
Management strategy Management of gallbladder disease depends on clinical findings and imaging data leading to the more or less clear establishment of a diagnosis. In the setting of a febrile patient with symptoms of RUQ abdominal pain and a thickened gallbladder wall on imaging, the diagnosis of acute cholecystitis is usually obvious. In an elderly patient in poor general condition who presents with a gallbladder mass, the diagnosis of gallbladder cancer seems equally obvious. However, when the clinical picture is less typical (atypical pain, subacute presentation, gallbladder wall thickening without a mass) or when a gallbladder lesion is discovered incidentally, diagnosis can be more difficult to establish. Although most lesions are benign (given the rarity of gallbladder malignancy), the possibility of cancer should be systematically discussed because of its severe prognosis. In practice, management varies for four frequently encountered situations.
Gallbladder Polyp
Size > 10 mm
+ - CT Scanning
Size < 10 mm
Risk factors of malignancy Yes
No Characteristics Yes
Cholecystectomy Hyperechoic
Cholesterol polyp
Rokitansky sinuses
Adenomyomatosis
Therapeutic abstention +- Follow-up
Graph 1.
Decisional algorithm for management of a gallbladder polyp.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management
9
gallbladder cancer. In such cases, one should not hesitate to perform cholecystectomy via an open laparotomy.
Gallbladder polyp
Figure 7. Xanthogranulomatous cholecystitis: CT appearance that could be mistaken for a carcinoma. Also note the large calcified gallstone.
Typical cholecystitis When the patient presents with clinical symptoms, ultrasound is the critical examination, and is, in most cases, sufficient to establish the diagnosis. Urgent laparoscopic cholecystectomy is recommended [14]. But when symptoms are atypical or the ultrasound is inconclusive, a CT scan with IV contrast may be needed. The possible association between cholecystitis and a gallbladder cancer should be considered in this situation, as well as atypical cholecystitis presenting with a clinical picture of advanced-stage
Figure 8.
The management strategy will depend on the size of the polyp, its characteristics on imaging, and the presence or absence of risk factors for malignant degeneration (Graph 1 — Decisional algorithm): • for polyps 10 mm and larger, cholecystectomy should be routinely performed [56]. The procedure can be performed laparoscopically taking great care to avoid gallbladder rupture or spillage, but a laparotomy approach seems preferable for polyp size greater than 15 mm to reduce the risk of peritoneal seeding [59]. Frozen section pathology examination of the specimen is recommended to determine how extensive the resection should be [59], since an additional contiguous hepatic resection is a major prognostic factor for survival in early stage gallbladder cancer [60]; • for polyps less than 10 mm, ultrasound imaging, Doppler ultrasound or contrast-ultrasound is essential to characterize the polyp [57]. MRI can be used as a second line imaging modality. Non-surgical surveillance with ultrasound monitoring every 6 months for 2 years is indicated if there are no risk factors for malignant degeneration [24]. However the presence of a gallbladder polyp in a patient older than 60, or with gallstones or other risk factors such as CSP, AJBP or porcelain gallbladder is an indication for cholecystectomy [26]. This can be
Adenocarcinoma of the gallbladder. Macroscopic appearance (above) and CT appearance (below).
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
10
J. Zemour et al. performed laparoscopically, taking great care to avoid any gallbladder tear or spillage.
metastasis to the gallbladder, cholecystectomy allows definitive diagnosis but widespread dissemination is often present making surgery unwarranted.
Gallbladder wall thickening In the absence of clinical acute cholecystitis, thickening of the gallbladder wall must be further assessed by CT and MRI. This morphological assessment helps to sort out the common diagnoses such as adenomyomatosis, xanthogranulomatous cholecystitis, porcelain gallbladder as well as extra-vesicular causes of wall thickening that do not require specific treatment. The possibility of gallbladder cancer should also be considered because of its severe prognosis, especially in cases of focal wall thickening exceeding 5 mm. Management in such cases is the same as for a gallbladder mass (Fig. 7): • adenomyomatosis is diagnosed by its specific appearance on ultrasound and MRI imaging [3,4,21]. Some authors recommend cholecystectomy for lesions larger than 1 cm or with associated cholecystolithiasis or other risk factors for malignant degeneration, because, even though the risk of malignant degeneration is not clearly defined [8], these factors may increase the risk of cancer and justify prophylactic cholecystectomy [20]; • diagnosis of xanthogranulomatous cholecystitis depends mainly by MRI but remains difficult since this lesion closely mimics cancer on imaging (Fig. 7). Management should be non-surgical unless doubt persists as to the possibility of cancer; in such cases cholecystectomy is recommended with routine frozen section pathology to avoid unjustified extensive resection [18]; • for porcelain gallbladder, the type of wall calcification can be characterized by ultrasound or CT imaging. Prophylactic cholecystectomy is recommended because of the risk of gallbladder cancer; this can be performed laparoscopically for patients with low-risk Type I lesions, taking care to avoid any tear of the gallbladder or bile spillage and converting to open laparotomy if there are any suspicious findings suggesting cancer [27].
A gallbladder mass If the diagnosis of cancer is suspected, further morphological examination by CT or endoscopic ultrasound will help establish the TNM stage preoperatively (Fig. 8) [5]. CT evidence of liver metastases or carcinomatosis calls for percutaneous or laparoscopic tumor biopsy. If the lesion is localized, surgical resection should be discussed as the initial gesture, since biopsy of a gallbladder mass exposes the patient to the risk of bile peritonitis or tumor dissemination. A laparotomy approach for cholecystectomy is mandatory. Simple cholecystectomy is indicated for early Tis or T1a tumors. Extended cholecystectomy is performed with resection of a 2 cm thickness of the gallbladder bed for T1b or T2 tumors. Bi-segmentectomy including segments IVb and V is recommended for T3 and T4 tumors [29,34]. Radical cholecystectomy should include lymphadenectomy of the hepatic pedicle and the falx of the hepatic artery at a minimum, but can be extended to include the celiac region. A frozen section pathologic exam of the cystic duct margin is recommended; if the margin is not tumor-free, resection of a portion of the common bile duct may be necessary [35]. Some studies have reported parietal recurrence after laparoscopic cholecystectomy for unrecognized cancer but the usefulness of excision of trocar sites at re-operation has not been demonstrated [32,35]. In cases of isolated
Conclusion Gallbladder cancer is a rare but very serious condition; this reinforces the importance of performing prophylactic cholecystectomy for precancerous lesions and appropriate treatment of diagnosed cancers. The discovery of a pathological gallbladder demands thorough clinical and radiological investigation to precisely define the lesion. This investigation leads to either a decision for non-surgical management in rare cases, to prophylactic cholecystectomy for lesions at risk for malignant degeneration, for early stage cancers, or whenever there is diagnostic doubt, or to a more radical surgical resection for advanced stage cancers. KEY POINTS • The most frequent benign tumors and pseudotumors of the gallbladder are: cholesterol polyp, adenoma, adenomyomatosis and cholesterolosis. • Gallbladder polyps larger than 1 cm are associated with a high risk of malignant degeneration and are indications for cholecystectomy. • Age greater than 60 years, chronic presence of large gallstones, gallbladder wall calcification, the presence of primary sclerosing cholangitis or abnormal bilio-pancreatic junction are risk factors for malignant degeneration. • Gallbladder polyps smaller than 1 cm but in association with other risk factors for malignant degeneration are an indication for cholecystectomy. • Gallbladder polyps less than 1 cm without risk factors of malignant degeneration can be observed. • Advanced gallbladder cancer must be included in the differential diagnosis of atypical cholecystitis. • The most common malignant tumor of the gallbladder is adenocarcinoma. The prognosis is very poor; it depends on the T stage at the time of diagnosis, and requires rapid and appropriate management. • The three most common types of primary cancer that metastasize to the gallbladder are melanoma, kidney cancer and breast cancer.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Andrén-Sandberg A. Diagnosis and management of gallbladder polyps. North Am J Med Sci 2012;4:203—11. [2] Matos AS, Baptista HN, Pinheiro C, et al. Gallbladder polyps: how should they be treated and when? Rev Assoc Med Bras 2010;56:318—21.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management [3] Shukla HS. Gallbladder cancer. J Surg Oncol 2006;93:604—6. [4] Zins M, Boulay-Colette I, Molinié V, et al. Imagerie des épaississements de la paroi vésiculaire. J Radiol 2006;87:479—93. [5] Vialle R, Velascoa S, Milinb S, et al. Place de l’imagerie dans le diagnostic et le bilan des tumeurs de la vésicule biliaire. Gastroentérol Clin Biol 2008;32:931—41. [6] Inui K, Yoshino J, Miyoshi H. Diagnosis of gallbladder tumors. Intern Med 2011;50:1133—6. [7] Yang HL, Sun YG, Wang Z. Polypoid lesions of the gallbladder: diagnosis and indications for surgery. Br J Surg 1992;79: 227—9. [8] Owen CC, Bilhartz LE. Gallbladder polyps, cholesterolosis, adenomyomatosis, and acute acalculous cholecystitis. Sem Gastroint Dis 2003;14:178—88. [9] Lee KF, Wong J, Li JC, et al. Polypoid lesions of the gallbladder. Am J Surg 2004;188:186—90. [10] Hayama S, Suzuki Y, Takahashi M, et al. Heterotopic gastric mucosa in the gallbladder: report of two cases. Surg Today 2010;40:783—7. [11] Gerolami A. Tumeurs bénignes et formations pseudo tumorales des voies biliaires — foie-pancréas et voies biliaires. 5th ed. Paris: Flammarion; 1972. p. 166—8. [12] Boulay-Coletta I, Molinié V, Loriau J, et al. Cholécystites aiguës : pièges et formes graves. Imagerie Dig JFR 2009:27—36. [13] Yokoe M, Takada T, Strasberg SM, et al. New diagnostic criteria and severity assessment of acute cholecystitis in revised Tokyo guidelines. J Hepatobiliary Pancreat Sci 2012;19:578—85. [14] Hirota M, Takada T, Kawarada Y, et al. Diagnostic criteria and severity assessment of acute cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg 2007;14:78—82. [15] Bennet GL, Balthazar EJ. Ultrasound and CT evaluation of emergent gallbladder pathology. Radiol Clin N Am 2003;41:1203—16. [16] Adolph MD, Bass SN, Lee SK, et al. Cytomegaloviral acalculous cholecystitis in acquired immunodeficiency syndrome patients. Am Surg 1993;59:679—84. [17] Shin SW, Kim Y, Jeong WK, et al. Isolated IgG4-related cholecystitis mimicking gallbladder cancer: a case report. Clin Imaging 2013;37:969—71. [18] Hale MD, Roberts KJ, Hodson J, et al. Xanthogranulomatous cholecystitis: a European and global perspective. HPB (Oxford) 2014;16:448—58, http://dx.doi.org/10.1111/hpb.12152. [19] Ralls PW, Quinn MF, Juttner HU, et al. Gallbladder wall thickening: patients without intrinsic gallbladder disease. AJR Am J Roentgen 1981;137:65—8. [20] Gourgiotis S, Kocher HM, Solaini L, et al. Gallbladder cancer. Am J Surg 2008;196:252—64. [21] Park JY, Hong SP, Kim YJ, et al. Long-term follow-up of gallbladder polyps. J Gastroenterol Hepatol 2009;24:219—22. [22] Randi G, Fransceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006;118:1591—602. [23] Aldridge MC, Gruffaz F, Castaing D, et al. Adenomyomatosis of the gallbladder. A pre-malignant lesion? Surgery 1991;109:107—10. [24] Yoshimitsu K, Honda H, Aibe H, et al. Radiologic diagnosis of adenomyomatosis of the gallbladder: comparative study among MRI, helical CT, and transabdominal US. J Comput Assist Tomogr 2001;25:843—50. [25] Di Rienzo M, Annunziata A, Russo A, et al. Diagnostic and oncologic updating on gallbladder papilloma. Personal experience and review of the literature. Ann Ital Chir 1998;69:627—37. [26] Kianmanesh R, Scaringi S, Castel B, et al. Lésions précancéreuses de la vésicule biliaire. J Chir 2007;144:278—86. [27] Misra S, Chaturvedi A, Misra CM, et al. Carcinoma of the gallbladder. Lancet Oncol 2003;4:167—76. [28] Khan ZS, Livingston EH, Huerta S. Reassessing the need for prophylactic surgery in patients with porcelain gallbladder: case series and systematic review of the literature. Arch Surg 2011;146:1143—7. [29] Boutros C, Gary M, Baldwin K, et al. Gallbladder cancer: past, present and an uncertain future. Surg Oncol 2012;21:183—91.
11
[30] Randi G, Malvezzi M, Levi F, et al. Epidemiology of biliary tract cancers: an update. Ann Oncol 2009;20:146—59. [31] Orth K, Beger HG. Gallbladder carcinoma and surgical treatment. Langenbecks Arch Surg 2000;385:501—8. [32] Fuks D, Regimbeau JM, Pessaux P, et al. Is port-site resection necessary in the surgical management of gallbladder cancer? J Visc Surg 2013;150:277—84. [33] Edge SB, Burd DR, Compton CC, et al. Gallbladder cancer. AJCC Cancer staging manual. 7th ed. New York: Springer; 2010. p. 211—7. [34] Goetze TO, Paolucci V. Benefits of re-operation of T2 and more advanced incidental gallbladder carcinoma: analysis of the german registry. Ann Surg 2008;247:104—8. [35] Isambert M, Leux C, Métairie S, et al. Incidentally-discovered gallbladder cancer: when, why and which re-operation? J Visc Surg 2011;148:77—84. [36] Albores-Saavedra J, Scoazec JC, Wittekind C, et al. Tumours of the gallbladder and extrahepatic bile ducts. In: Hamilton SR, Aaltonen LA, editors. World Health Organization classification of tumours: pathology and genetics of tumours of the digestive system. Lyon, France: IARC Press; 2000. p. 203—18. [37] Waisberg J, Bromberg SH, Franco MI, et al. Squamous cell carcinoma of the gallbladder. Sao Paulo Med J 2001;119:43. [38] Rekik W, Ben Fadhel C, Boufaroua AL, et al. Primary squamous cell carcinoma of gallbladder. J Visc Surg 2011;148:149—51. [39] Bourmèche M, Ben Salah H, Kallel M, et al. Une longue survie après traitement d’un carcinome épidermoide de la vésicule biliaire. Cancer/Radiother 2013;17:58—61. [40] Machado MC, Penteado S, Montagnini AL, et al. Carcinoid tumor of the gallbladder. Sao Paulo Med J 1998;116:1741—3. [41] Fujii H, Aotake T, Horiuchi T, et al. Small cell carcinoma of the gallbladder: a case report and review of 53 cases in the literature. Hepatogastroenterology 2001;48:1588—93. [42] Elahi F, Ahmadzadeh A, Yadollahzadeh M, et al. Neuroendocrine tumor gallbladder. Arch Iran Med 2013;16: 123—5. [43] Ono A, Tanoue S, Yamada Y, et al. Primary malignant lymphoma of the gallbladder: a case report and literature review. Br J Radiol 2009;82:15—9. [44] Viswanathan SR, Khalpey Z, Ashley SW. Gallbladder lymphoma. Med Oncol 2011;28:810—2. [45] Kim MJ, Kim KW, Kim HC, et al. Unusual malignant tumors of the gallbladder. Am J Roentgenol 2006;187:473—80. [46] Brasseur P, Bissen L, Dupont H, et al. Métastase de la vésicule biliaire secondaire à une tumeur rénale à cellules claires. J Radiol 1999;80:739—40. [47] Katz SC, Bowne WB, Wolchok JD. Surgical management of melanoma of the gallbladder: a report of 13 cases and review of the literature. Am J Surg 2007;193:493—7. [48] Ishizawa T, Okuda J, Kawanishi T, et al. Metastatic renal cell carcinoma of the gallbladder. Asian J Surg 2006;29:145—8. [49] Sartelet H, Simon M, Alowanou A, et al. Une tumeur bourgeonnante de la vésicule biliaire : le carcinome à cellules claires. Ann Pathol 2004;24:58—61. [50] Essola B. Métastase vésiculaire d’un carcinome mammaire : une nouvelle observation. Rev Med Brux 2012;33:171—5. [51] Jeong YS, Han HS, Lim SN. Gallbladder metastasis of non-small cell lung cancer presenting as acute cholecystitis. Chin J Cancer Res 2012;24:249—52. [52] Bilici A, Seker M, Oven U. Gallbladder metastasis secondary to gastric cancer as a first site of recurrence presented with acute cholecystitis: case report and literature review. Turk J Gastroenterol 2012;23:764—8. [53] Disibio G, French SW. Metastatic pattern of cases: results from a large autopsy study. Arch Pathol Lab Med 2008;132: 931—9. [54] Gallahan WC, Conway JD. Diagnosis and management of gallbladder polyps. Gastroenterol Clin North Am 2010;39: 359—67. [55] Leung UC, Wong PY, Roberts RH, et al. Gallbladder polyps in sclerosing cholangitis: does the 1 cm rule apply? ANZ J Surg 2007;77:355—7.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
12 [56] Ito H, Hann LE, D’Angelica M, et al. Polypoid lesions of the gallbladder: diagnosis and follow-up. J Am Coll Surg 2009;208:570—5. [57] Numata K, Oka H, Morimoto M, et al. Diffferential diagnosis of gallbladder diseases with contrast-enhanced harmonic gray scale ultrasonography. J Ultrasound Med 2007;26:763—74. [58] Yoon JH, Cha SS, Han SS, et al. Gallbladder adenomyomatosis: imaging findings. Abdom Imaging 2006;31:555—63.
J. Zemour et al. [59] Kim EK, Lee SK, Kim WW. Does laparoscopic surgery have a role in the treatment of gallbladder cancer? J Hepatobiliary Pancreat Surg 2002;9:559—63. [60] D’Hondt M, Lapointe R, Benamira Z, et al. Carcinoma of the gallbladder: patterns of presentation, prognostic factors and survival rate. An 11-year single centre experience. Eur J Surg Oncol 2013;39:548—53.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
ARTICLE IN PRESS
JVS-398; No. of Pages 12
Journal of Visceral Surgery (2014) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
REVIEW
Gallbladder tumor and pseudotumor: Diagnosis and management J. Zemour a,∗, M. Marty b, B. Lapuyade c, D. Collet a, L. Chiche a a
Service de chirurgie digestive, hôpital Haut Levêque, CHU de Bordeaux, 1, avenue de Magellan, 33604 Pessac cedex, France b Service d’anatomopathologie, hôpital Haut Levêque, CHU de Bordeaux, 1, avenue de Magellan, 33604 Pessac cedex, France c Service d’imagerie médicale, hôpital Haut Levêque, CHU de Bordeaux, 1, avenue de Magellan, 33604 Pessac cedex, France
KEYWORDS Gallbladder cancer; Gallbladder polyp; Gallbladder pseudotumor; Atypical cholecystitis; Gallbladder imaging
Summary The most common gallbladder disease, by far, is cholecystolithiasis. Nevertheless, the discovery of abnormal thickening of the gallbladder wall or a tumorous lesion (with or without gallstones), is a frequent problem. The physician who confronts this finding must be aware of the various lesions to be considered in the differential diagnosis, whether neoplastic or pseudotumoral, epithelial or not, benign or malignant. Because of the particularly grim prognosis of gallbladder cancer, especially when discovered at a late stage, it is especially important to focus on the potential for malignant degeneration of any gallbladder lesion. Imaging plays an important role in distinguishing these lesions; ultrasound remains the key diagnostic tool for gallbladder disease, but other modalities including CT and MRI may help to characterize these lesions. The resulting treatment strategies vary widely depending on the risk of malignancy. A wide and extensive resection is recommended for malignant lesions; prophylactic cholecystectomy is recommended for lesions at risk for malignant degeneration while observation is indicated for purely benign lesions. © 2014 Elsevier Masson SAS. All rights reserved.
Introduction Gallbladder tumors are rare compared to gallstone disease which forms the bulk of gallbladder pathology. However, its prevalence varies from 3% to 7% in the general population [1], which makes it not infrequent in day-to-day surgical practice. On ultrasound exam, the presence of a tumorous lesion of the gallbladder, whether associated with gallstones or not, must be systematically sought. The main challenge of management of malignant or pre-malignant gallbladder tumors lies in early diagnosis; the diagnosis of gallbladder cancer is all too often delayed and the lesion is commonly at an incurable stage [1,2].
∗
Corresponding author. E-mail address: [email protected] (J. Zemour).
http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003 1878-7886/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
2
J. Zemour et al.
Gallbladder adenocarcinoma, the most feared, has a mean 5-year survival rate of 5%, all stages combined [3], and the prognosis depends mainly on tumor stage at the time of diagnosis. Clinical context is essential to the diagnostic process but in most cases, an isolated gallbladder lesion needs to be accurately characterized by modern imaging methods. Abdominal ultrasound remains the first-line examination for patients with symptoms of biliary disease, but CT and MRI have become essential to characterize any abnormal appearance of the gallbladder parenchyma. Other tests (Contrast-enhanced ultrasound [CEUS], Endoscopic ultrasound, endoscopic ultrasound [EUS], and Positron emission tomography [PET]) are currently being evaluated [4,5]. These modern imaging techniques are needed to help distinguish between benign lesions, those at risk of malignant degeneration, and malignant lesions, in order to select the most appropriate surgical management. The objective of this systematic review is to define the various neoplastic and pseudo-tumorous pathologies of the gallbladder, based on data from the literature and on our own experience, and thereafter to establish a diagnostic strategy using available imaging modalities, and finally to define an appropriate therapeutic strategy.
Different gallbladder pathologies Gallbladder lesions occur commonly; their prevalence on ultrasonography varies from 2% to 12% in the general population in different series [1,6]. Table 1 summarizes the various benign and malignant pathologies that can be seen. But signs of malignancy in lesions at risk for malignant degeneration must be sought in order to select an appropriate management strategy, particularly since the patient’s prognosis depends on diagnosis at an early stage.
Benign lesions Most gallbladder lesions are benign. In the study of Yang et al. [7] study, more than two-thirds of the 182 patients who underwent cholecystectomy performed were found to have benign lesions. These included both polypoid lesions and also atypical thickening of the gallbladder wall (inflammation or infection), which can be diagnostically misleading because they mimic cancerous lesions.
Polypoid lesions Cholesterolosis and cholesterol polyps Cholesterol polyps represent the majority of benign lesions, with a prevalence ranging from 60—90% in different studies [1,7]. These polyps arise from the accumulation of triglycerides and cholesterol esters within macrophages in the gallbladder wall, without any cellular proliferation. Polyps are small (usually 1—2 mm, always less than 10 mm) and multiple [7]. In gross appearance, they are yellow, relatively friable, carpeting the mucosal surface of the gallbladder lumen; they are often attached to the mucosa by a pedicle. Cholesterolosis involves the gallbladder diffusely and has a mean prevalence of 10% in autopsy series [8]. This lesion is clinically asymptomatic as a rule but may occasionally manifest itself as biliary pain or even by distal migration provoking cholecystitis. Ultrasound imaging allows diagnosis based on findings of a hyper-echoic intraluminal polyp without posterior shadowing that remains in a fixed mural
location with change in position; it is typically round or slightly lobulated (Fig. 1). Other imaging techniques are not particularly useful [4]. The diagnosis of cholesterol polyp requires no further surveillance or treatment as long as no biliary symptoms are present. In case of doubt, repeat ultrasound imaging at six-month interval is indicated.
Inflammatory or fibrous polyps These represent 10% of gallbladder polyps and result from secondary sequelae of fibrosis and chronic inflammation. They are small in size and ultrasound imaging is diagnostic of simple benign poly; the diagnosis of these non-cholesterol polyps is based on histologic exam [8,9].
Heterotopic polyps These consist of ectopic tissue such as liver, gastric, pancreatic, adrenal or thyroid tissue lining the bile duct [9]. Only ectopic gastric or pancreatic tissue causes symptoms. A literature review found fifty cases of ectopic gastric and thirty cases of ectopic pancreatic tissue [10]. No risk factors for malignant degeneration could be identified. Non-surgical observation can be proposed but the unusual lesion is usually diagnosed by postoperative histological analysis.
Mesenchymal lesions Rare benign tumors such as leiomyomas, lipomas and fibroids may develop from smooth muscle cells [11]. Macroscopically, these are solid, nodular and well-circumscribed lesions. Again, there is no specific indication for excision, but diagnostic uncertainty can lead to surgery.
Gallbladder wall thickening Gallbladder inflammation or cholecystitis usually results in a diffuse thickening of the wall. Its presentation can be acute or chronic, of more or less serious gravity, and the diagnosis is suggested by non-specific thickening of the gallbladder wall.
Acute cholecystitis Acute cholecystitis results from obstruction of the cystic duct or gallbladder by impaction of a gallstone in 95% of cases, with inflammation of the gallbladder wall, often associated with bacterial infection. Acute acalculous cholecystitis occurs in only 5% of cases, typically occurring in ICU patients or multiple trauma, where gallbladder inflammation is due to hemorrhagic or ischemic events or biliary stasis (parenteral nutrition) [12]. The diagnostic and therapeutic criteria of calculous cholecystitis are well described and codified with a set of recommendations (Tokyo Guidelines) published in 2007 and recently updated [13,14]. The diagnosis is suggested by the association of clinical signs (RUQ abdominal pain, guarding, mass, Murphy’s sign) and laboratory findings of inflammation (leukocytosis, elevated CRP). The diagnosis is confirmed by ultrasound imaging showing gallstones, wall thickening ≥4 mm, peri-cholecystic fluid, and the elicitation of a positive Murphy sign on ultrasound examination. Management and the interval before surgical intervention depend on the severity of cholecystitis, but the curative treatment remains cholecystectomy [14]. Management of certain forms of acute cholecystitis should be individualized because of their severity and specific aspects of imaging: • gangrenous cholecystitis is accompanied by ischemia and hemorrhagic necrosis of the gallbladder wall. CT scan shows an irregular wall, with thinning in places (necrosis), sometimes with air present within the wall or lumen of the gallbladder, a marked edema, and/or a peri-cholecystic
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management Table 1
3
Tumors and pseudo-tumors of the gallbladder.
Malignant tumors
Benign tumors
Epithelial tumors
Adenocarcinoma Undifferentiated carcinoma Adenosquamous carcinoma Squamous cell carcinoma Neuro-endocrine tumor
Epithelial tumors
Adenoma Adenomyomatosis Papillomatosis Heterotopic tissue
Non-epithelial tumors
Lymphomas Sarcomas
Non-epithelial tumors
Leiomyoma Lipoma Neural tumors
Metastatic tumors
Melanoma Kidney Breast
Pseudo-tumors
Cholecystitis Cholesterolosis Inflammatory polyp
abscess. Irregular or discontinuous enhancement of the wall is also a predictive sign of gangrenous cholecystitis [4.15]. This constitutes a true life-threatening emergency and requires urgent surgical intervention without delay; • emphysematous cholecystitis arises due to infection by anaerobic gas-producing bacteria. In more than half the cases, the patients are male and diabetic, and in 30% of cases, the cholecystitis is acalculous [15]. The mortality rate can reach 15%. Ultrasound reveals focal hyper-echoic images with posterior shadowing or ‘‘comet tail’’ artifact. If the mural gas is present in large quantities, one may see a hyper-echogenic crescent with posterior shadowing [4]. The presence of air in the gallbladder wall or lumen, or in the peri-cholecystic fat is a sign of perforation and requires emergency surgery; • less common non-bacterial forms of infection including cholecystitis due to Cytomegalovirus (CMV), Cryptococcus (in HIV patients) and IgG4 have been described [16,17]. Management of these entities is the same as for conventional acute cholecystitis except when IgG4 cholecystitis mimics a gallbladder cancer. Indeed, sclerosing IgG4 disease must be considered in the differential diagnosis of gallbladder malignancies, especially outside the context of autoimmune acute pancreatitis (the most common clinical context). The diagnosis is often aided by laboratory testing (white blood count with the ratio of eosinophils to polymorphonuclear cells, serology). It is important to make this diagnosis since the treatment is based on
Figure 1.
corticosteroid therapy, which often results in dramatic improvement in symptoms and histologic lesions.
Calculous chronic cholecystitis This is a late complication of gallstones, occurring mainly in the elderly, and often diagnosed incidentally in an asymptomatic patient. Ultrasound shows an irregular circumferential wall thickening associated with intraluminal calculi. CT scan shows a ‘‘halo’’ corresponding to a hypodense well-delineated peri-cholecystic band [5]. The sclero-atrophic form, which probably has a potential for malignant degeneration, is often associated with disappearance of the gallbladder lumen on imaging. Cholecystectomy is indicated in such cases.
Xanthogranulomatous cholecystitis This is probably the most misleading form [18]. Xanthogranulomatous cholecystitis is an inflammatory form of chronic cholecystitis with pseudotumor whose appearance, in association with gallstones, may mimic gallbladder cancer. Chronic inflammation is caused by extravasation of bile into the wall via mucosal ulcerations or the sinuses of Rokitansky. Macroscopically, there is a yellowish mass that often infiltrates the peri-cholecystic fat, with associated lymphadenopathy or biliary obstruction (Fig. 2). It represents 1—13% of gallbladder lesions, and is mostly seen in women over the age of 60. It presents clinically as acute cholecystitis, but some radiological criteria that help to guide diagnosis include nodules or hypo-echoic intramural bands
Cholesterolosis of the gallbladder. The ultrasound shows multiple small, hyper-echogenic polyps.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
4
J. Zemour et al.
Figure 2. Xanthogranulomatous cholecystitis: macroscopic view of cholecystectomy specimen.
and MRI images showing fluid in the gallbladder wall [5]. It is difficult to differentiate this from gallbladder cancer by imaging, and surgery should be performed with routine frozen section examination [18].
Figure 3. Adenomyomatosis: macroscopic view of cholecystectomy specimen.
Diffuse wall thickening due to extra-vesicular causes There are numerous causes of gallbladder wall thickening other than acute cholecystitis. The most common are ascites, hepatitis (viral or drug-toxic) and hypoproteinemia [19]. Certain inflammatory or infectious processes such as acute pancreatitis, acute pyelonephritis, or peri-hepatitis (Fitz-Hugh-Curtis syndrome) may also result in wall thickening [4]. The clinical and laboratory findings along with imagery help to establish the etiology of this thickening and the treatment of the cause if necessary, but no specific treatment of the gallbladder is recommended, particularly since surgery is sometimes risky in this context (cirrhosis, malnutrition).
Benign lesions that have potential risk for malignant degeneration Adenoma Adenoma, a benign tumor with pseudo-glandular proliferation surrounded by fibrous stroma, is present in 0.4 to 0.5% of cholecystectomy specimens [20]. The adenoma can be sessile, pedunculated, or polypoid, and usually measures from 0.5—2.0 cm [2]. It is usually asymptomatic. The risk of malignant degeneration varies with polyp size (it is only observed in adenomas larger than 10 mm), and in patients older than 50 years, or with sessile lesions or polyps associated with gallstones. In Park et al.’s study, of a cohort of 1558 patients whose polyps were monitored by serial ultrasound examination [21], an increase in size was seen in 3.5% of these patients, a quarter of whom had a true neoplastic lesion. On imaging, the adenomatous polyp is characterized by an isoechoic appearance (as opposed to cholesterol polyps, which are hyper-echoic), with no posterior acoustic shadowing; the lesion is intraluminal, attached to the wall and fixed during positional maneuvers. Color Doppler imaging confirms
its solid tissue nature. Evaluation of the thickness of the adjacent wall and the size of the polyp(s) is essential [4]. It is generally agreed that surgery should be performed for any polyp larger than 1 cm; polyps smaller than 1 cm should be monitored with serial ultrasound examinations every six months for two years, to detect any evidence of rapid growth [22].
Adenomyomatosis Adenomyomatosis is a common lesion with a prevalence ranging from 3% to 5% [8,23]. It represents 25% of gallbladder wall thickening and localizes preferentially in the gallbladder fundus. The thickening is well limited and contains multiple coalescing cystic structures (Fig. 3). It consists of hyperplasia of the epithelial and smooth muscle layers causing a thickening of the gallbladder wall. The epithelium invaginates through the muscularis, forming pseudo-diverticula (Rokitansky-Aschoff sinuses), which are specific for the lesion. The risk of malignant degeneration is still uncertain despite its frequent association with gallbladder cancer in some studies, because the concomitant presence of gallstones makes interpretation difficult [8]. This lesion has no specific clinical presentation. Its appearance on imaging is typical and should be appreciated [4]. On ultrasound, the wall is thickened with anechoic foci corresponding to the dilated sinuses, associated with small hyper-echoic foci and ‘‘comet tail’’ images corresponding to trapping of the ultrasonic beam in dilated sinuses. MRCP shows an image described as a ‘‘string of pearls’’ image formed by fluid containing diverticula [24]. MRI seems to be the best investigation to confirm the diagnosis of adenomyomatosis (diagnostic accuracy of 93% versus 75% for CT and 66% for ultrasound) [4]. When this lesion is isolated, it is not considered to have a risk of malignant degeneration and no
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management treatment recommended. However, when adenomyomatosis is seen in association with cholelithiasis or abnormalities at the bilio-pancreatic junction (BPJ), prophylactic cholecystectomy is indicated [8].
Papillomatosis In this condition, multiple recurrent papillary adenomas may extend throughout the entire biliary tree. Florid papillomatosis corresponds to diffuse lesions of dysplastic biliary epithelium growing around a fibro-vascular axis. This condition has high potential for malignant degeneration [25]. The extent of this lesion is underestimated on standard imaging by ultrasound, CT, or MRI. Endoscopic ultrasound (EUS) can detect thickening with vegetations of the gallbladder wall, sometimes in association with similar lesions involving the intrahepatic or extrahepatic bile ducts that may result in ductal dilatation due to obstruction by a polyp; the lesions are iso- or hyper-echogenic with no posterior acoustic shadowing. Surgical treatment specifically adapted to the extent and topography of the lesions is indicated [25].
Porcelain gallbladder This term designates calcification of the gallbladder wall. This can be complete diffuse intramural calcification (Type I), limited to complete involvement of the mucosa (Type II), or incomplete (Type III). The presence of parietal calcification is associated with a risk of malignant degeneration ranging from 12 to 60% [26]. The incidence depends on the type of calcifications, being lower for Type I than for isolated mucosal involvement (Types II and III) [27]. In the study by Khan et al. [28], the rate of malignant transformation of 140 porcelain gallbladders was 15%. Ultrasound or CT imaging is used to make the diagnosis and to characterize the type. Discovery of a porcelain gallbladder by imaging warrants prophylactic cholecystectomy because of the risk of carcinogenesis.
Malignant lesions Primary gallbladder cancer Primary cancers of the gallbladder are the fifth most common gastrointestinal malignancy (4% of all GI cancers) [27].
Adenocarcinoma Adnocarcinoma represents more than 80% of cases of gallbladder cancer and preferentially affects women between 65 and 75 years. Its overall incidence is 2.5 per 100,000 persons [27,29], and ranges from 0.8 to 25 cases per 100,000 people according to geographical distribution in the world (in France, from 0.8 to 1.5/100,000) [30]. Diagnosis at an early clinical stage is the exception. Diagnosis is fortuitous in half the cases, based on histological examination of a cholecystectomy specimen; more typically, diagnosis is made at an advanced stage based on biliary symptoms associated with impaired general condition. The imaging assessment generally depends on abdominal ultrasound or CT scan with IV contrast to distinguish three types of presentations: focal or diffuse thickening of the gallbladder wall, a polypoid mass projecting intralumenally, or a solid tissue mass centered on the gallbladder fossa with hepatic invasion [4]. This last form, corresponding to advanced stage disease, is the most common presentation (45—70% of cases [31]). The prognosis is poor due to early invasion of the liver, lymph nodes of the hepatic pedicle and the rapid progression of distant metastases to the peritoneum and liver in particular [32].
5
The sensitivity and specificity of ultrasound for evaluation of T stage is greater than 85% [4]. CT is less sensitive than ultrasound for the diagnosis of wall thickening but it may be useful to explore the gallbladder wall when gallstones mask calcification or thickening. CT and biliary MRI are particularly useful in the assessment of local, regional, and distant spread and also for the assessment of resectability. PET scan, EUS and exploratory laparoscopy can also be considered [5]. Therapeutic management depends mainly on the histological stage at the time of discovery (AJCC TNM classification) [33]. Simple cholecystectomy is sufficient for the very early stages (Tis or T1a) [29]. For stage T1b lesions (extending into the muscularis) and beyond, more extensive surgery is necessary [34,35].
Other primary cancers Other gallbladder malignancies are extremely rare. Symptomatology is non-specific, often asymptomatic. The diagnosis is based on histologic examination after surgical treatment. The various types of cancer include: • undifferentiated carcinoma represents 2—7% of gallbladder cancers [36]. This is a very aggressive tumor with direct invasion of adjacent organs, lymph node involvement and peritoneal dissemination; • adenosquamous carcinoma, representing 1—12% of gallbladder cancers [37], is a mixed tumor with components of adenocarcinoma and squamous cell carcinoma. It is most commonly localized in the gallbadder fundus with direct invasion the hepatic parenchyma and adjacent organs (colon). Lymph node involvement and peritoneal dissemination are rare, in comparison to the incidence of liver metastases; • squamous cell carcinoma represents 0—3% of gallbladder cancers [38]. This tumor is not prone to lymphatic spread, but often shows rapid loco-regional extension. The prognosis of these tumors is worse than that of adenocarcinoma; the average survival after diagnosis is six months. Treatment depends mainly on the quality of the surgical excision but the possible benefits of adjuvant radiotherapy or chemo-radiotherapy should be considered [39]; • neuro-endocrine tumors represent less than 0.5% of gallbladder cancers [40]. These tumors have a slow rate of growth and are low-grade malignancies, but the long-term prognosis is poor, depending on the tumor grade. A literature review of 53 cases showed a 1-year survival rate of 28% and zero survival at 2 years [41]. Treatment is surgical but adjuvant chemotherapy may improve survival (with a median of 13 months)[42]; • non-epithelial primary tumors are exceptional and consist mainly of sarcomas (1—2% of gallbladder cancers) [8]), and lymphomas (only 28 cases reported in the literature), the majority of which are MALT lymphoma and diffuse large B-cell lymphoma [43,44].
Metastases Three primary cancers seem to have a particular tropism for spread to the gallbladder: melanoma, renal cancer and breast cancer [45]. All these cancers are hypervascular on imaging. Sometimes gallbladder metastasis is part of generalized systemic metastasis, but, on occasion, it can be an isolated metachronous lesion [46]. In order of frequency, distinguishing features include metastatic melanoma, metastatic renal cell carcinoma, metastatic breast cancer and other metastases.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
6
J. Zemour et al.
Metastatic melanoma Melanoma can metastasize to any organ. It represents 50—65% of gallbladder metastases [47]. In most cases, there are biliary symptoms, so when a patient with a past history of melanoma develops biliary symptoms, a search should be made for a hypervascular lesion on imaging to make the diagnosis. Histology is usually identical to that of the primary tumor. The prognosis of these patients is poor, with a median survival of less than 12 months [47].
Metastatic renal cell carcinoma Renal cancer can metastasize to many sites. The most common are pulmonary, hepatic, bone and brain metastases, but unusual sites are also described: pancreas, skin, heart, prostate or gallbladder (only 0.5% to the gallbladder) [48,49]. The study of 28 cases by Ishizawa et al. [48] showed that less than half were synchronous, while two-thirds of cases are solitary metastases. This most often appears as a solitary intraluminal polypoid mass on a stalk (Fig. 4) and generally progresses rapidly to death with a picture of widespread distant metastasis, but very good long-term results have been reported after cholecystectomy for a solitary metastasis [49].
Metastatic breast cancer Breast carcinoma preferentially metastasizes to the axillary lymph nodes, bones, lungs and liver. Only 4—7% of breast carcinomas are associated with gallbladder metastases. They may occur late (one month to fifteen years time interval)[50]. Dissemination throughout the biliary system is exceptional. It generally progresses by hematogenous spread or direct invasion of the hepatic hilum. The diagnosis is usually made by histological analysis, and occurs more frequently with lobular than ductal breast cancer. There are no specific recommendations for treatment, which typically consists of surgical resection combined with hormonal therapy or the addition of zoledronic acid [50].
Other metastases Exceptional cases of pulmonary, gastric, uterine-cervical and hepatocellular carcinoma with metastasis to the gallbladder have been described in the literature [51—53].
Diagnostic strategy Non-calculous gallbladder disease is often discovered incidentally by imaging. This allows characterization of wall thickening and gallbladder content, especially in complicated forms of benign disease, lesions with malignant potential, or cancer [4]. But gallbladder wall thickening can be due to a variety of pathologies, and accurate diagnosis must be determined based on the combination of clinical, laboratory, and radiological data. The objective of this section is to establish an optimal diagnostic strategy by combining the clinical context with the various imaging tests available.
Clinical context Clinical setting Diagnostic orientation depends on the general context. Thus, the initial thinking is different for an elderly patient in poor general condition than for a young patient with no previous history. Assessment should include risk factors for malignancy and take into account the particular clinical setting and associated pathologies:
• age is regarded as a risk factor of malignancy. Beyond the age of 60 years [1,54], the incidence of gallbladder cancer gradually increases with age [24]. In a young patient, even if calculous cholecystitis is considered the most likely diagnosis, the presence of immunodepression, diabetes or a particular context should help guide the diagnosis of rare forms of cholecystitis; • ethnic origin is of diagnostic importance because there is great disparity in the worldwide incidence of gallbladder adenocarcinoma (higher incidence in Chile, Israel, Poland, Mexico, Bolivia, Japan and in the northern region of India) [24]; • a past history of cancer must be sought in order to consider the possibility of metastasis; • the presence of risk factors for malignant degeneration, such as chronic inflammation of the gallbladder mucosa, must be systematically sought during diagnostic work-up. Chronic inflammation may be observed in different contexts: primary sclerosing cholangitis (PSC) is associated with an incidence of gallbladder cancer of 1% per year [24], so cholecystectomy is indicated for any polyp associated with PSC; if surgery is not possible, the frequency of ultrasound surveillance should be increased [55]. The presence of large gallstones has been described as a risk factor for malignant degeneration increasing the risk by a factor of 2.4 for medium size stones (3 cm) [26,27,29]. The risk of developing cancer after a 20-year period is estimated at 0.26 to 0.5% in this case [32]. Porcelain gallbladder is an important risk factor for malignancy with an association present in 12—60% of cases [26]. The incidence depends on the type of parietal calcification. Chronic infection of the bile by certain bacteria (Salmonella typhi or paratyphi and Helicobacter pylori) results in a six-fold increased rate of gallbladder cancer compared to patients without chronic infection [26]. Anomalous junction of the pancreatic and biliary ducts (AJPB) is characterized by an abnormal connection between the bile duct and the pancreatic duct forming a long common channel (>10-15 mm) without its own sphincter; this promotes malignant degeneration of the gallbladder mucosa due to chronic reflux of pancreatic juice into the bile ducts. These patients are often young and gallstones are not present [27,35].
Symptoms The initial clinical examination is essential, allowing rapid differentiation of the acute infectious presentation suggestive of acute cholecystitis in its different forms from subacute or chronic cholecystitis without signs of sepsis where diagnosis is more difficult. The clinical exam searches for signs of systemic illness, evidence of infection, abdominal pain, tenderness or an abdominal mass. But in some cases, when a gallbladder lesion is discovered fortuitously, the patient will have no clinical symptoms and diagnosis is based solely on patient history and imaging studies.
The contribution of ultrasound Ultrasound is the first examination performed and is standard test (investigation?) for the diagnosis of acute cholecystitis; it also has an 85% sensitivity and 80% specificity for the diagnosis gallbladder tumors [4]. It yields information about both the content and the container.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management
Figure 4.
7
Metastasis from a renal cancer: macroscopic view. The tumor is hemorrhagic, consistent with its hypervascularity.
Evaluation of gallbladder content Ultrasonography often describes an intravesicular lesion referred to as a ‘‘polyp’’. Polyps are distinguished from calculi by their immobility and their lack of acoustic shadowing. To enable optimal management of gallbladder polyps, the radiologist must describe: the shape of the polyp (pedunculated or sessile), its appearance (echogenicity and heterogeneity), whether the lesion is isolated or not, and a precise measurement of size. Size is a major risk factor for malignant degeneration; the rate of malignancy varies from 0 to 5% for polyps less than 10 mm, to 50—70% for polyps larger than 15 mm [26]. Surgery is indicated for all polyps ≥ 10 mm [56]. When multiple polyps are present, the number and size of the largest polyps must be precisely defined. The presence of associated gallstones must be determined; a large stone adherent to the wall may simulate gallbladder cancer by its pseudo- tumor appearance as a fixed mass (Fig. 5). For lesions larger than 1 cm, color Doppler ultrasound is used to assess hypervascularity [4]. But it does not have adequate specificity to be an effective criterion for a positive diagnosis. Ultrasound with contrast increases the detection of polypoid lesions and helps to differentiate carcinoma from other polypoid lesions [57]. It is not commonly used in practice despite a 75% sensitivity and 100% specificity for the diagnosis of cancer when tumor enhancement and the presence of tortuous tumor vessels are used as diagnostic criteria.
gangrenous or chronic cholecystitis). It is also useful for preoperative evaluation of gallbladder cancer (anatomical extension to blood vessels, lymph nodes, liver parenchyma and distant metastases) [4,5]. The sensitivity of CT for evaluating the gallbladder wall is excellent, but is less so for the assessment of the gallbladder contents.
Magnetic resonance imaging The diagnostic capabilities and limitations of MRI are similar to those of CT. MRI is the standard test for distinguishing adenomyomatosis from gallbladder neoplasm because the Aschoff-Rokitansky sinuses show clear-cut hyper-intensity of T2-weighted images (Fig. 6). MRCP can be a useful adjunct
Evaluation of the gallbladder wall Ultrasonography may describe irregular wall thickening or budding as one aspect of a vegetative lesion protruding into the lumen. The lesion may be solitary or multiple, isoor hypo-echoic, without acoustic shadowing, and having a pedunculated or sessile base. Any focal thickening of the gallbladder wall >5 mm is suspicious for malignancy [5].
Computed tomography Ultrasound no longer accounts for most incidental discovery of gallbladder masses; CT scans are performed more frequently as first-line imaging for patients with abdominal symptoms or for patients undergoing scheduled surveillance. CT is a useful adjunct to ultrasound in difficult or complicated forms of acute cholecystitis (emphysematous,
Figure 5. Gallstone adherent to the gallbladder wall mimicking a tumorous protrusion; macroscopic view.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model
ARTICLE IN PRESS
JVS-398; No. of Pages 12
8
J. Zemour et al. of some specific lesions: the cholesterol polyp has a typical picture of a pedunculated homogeneous hyper-echoic mass without acoustic shadowing. Adenomyomatosis presents an image of a thickened gallbladder wall containing multiple microcysts of a few millimeters. EUS is more effective than percutaneous ultrasound for differentiating adenocarcinoma from adenomyomatosis [58].
Positron emission tomography The role of PET scan is not yet defined. PET with fluorodeoxyglucose labelled with fluorine-18 has a sensitivity and specificity of about 80—90% for the diagnosis of gallbladder cancer [27]. Some studies have reported its usefulness, showing the accuracy of PET for the diagnosis of benign versus malignant gallbladder lesions, albeit with some false positive diagnoses of cancer [54]. Figure 6. Adenomyomatosis of the gallbladder fundus. MRI with hyper-intense signal on T2-weighted images and the appearance of a ‘‘string of pearls’’.
by demonstrating the classical ‘‘string of pearls’’ appearance within the gallbladder wall [21]. For adenocarcinoma, MRI allows a better assessment of tumor infiltration; CT has a sensitivity of 67% and a specificity of 89% for hepatic invasion while biliary MRI had a sensitivity of 100% and a specificity of 89% for invasion of the biliary ducts [5,21].
Contribution of second-intention imaging modalities Endoscopic ultrasound EUS is more discriminating for differentiating small malignant lesions under 1 cm, with a specificity of 91% for differentiating neoplastic versus non-neoplastic lesions [5]. Performance of EUS should be discussed during the staging of gallbladder cancer. It also allows improved visualization
Management strategy Management of gallbladder disease depends on clinical findings and imaging data leading to the more or less clear establishment of a diagnosis. In the setting of a febrile patient with symptoms of RUQ abdominal pain and a thickened gallbladder wall on imaging, the diagnosis of acute cholecystitis is usually obvious. In an elderly patient in poor general condition who presents with a gallbladder mass, the diagnosis of gallbladder cancer seems equally obvious. However, when the clinical picture is less typical (atypical pain, subacute presentation, gallbladder wall thickening without a mass) or when a gallbladder lesion is discovered incidentally, diagnosis can be more difficult to establish. Although most lesions are benign (given the rarity of gallbladder malignancy), the possibility of cancer should be systematically discussed because of its severe prognosis. In practice, management varies for four frequently encountered situations.
Gallbladder Polyp
Size > 10 mm
+ - CT Scanning
Size < 10 mm
Risk factors of malignancy Yes
No Characteristics Yes
Cholecystectomy Hyperechoic
Cholesterol polyp
Rokitansky sinuses
Adenomyomatosis
Therapeutic abstention +- Follow-up
Graph 1.
Decisional algorithm for management of a gallbladder polyp.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management
9
gallbladder cancer. In such cases, one should not hesitate to perform cholecystectomy via an open laparotomy.
Gallbladder polyp
Figure 7. Xanthogranulomatous cholecystitis: CT appearance that could be mistaken for a carcinoma. Also note the large calcified gallstone.
Typical cholecystitis When the patient presents with clinical symptoms, ultrasound is the critical examination, and is, in most cases, sufficient to establish the diagnosis. Urgent laparoscopic cholecystectomy is recommended [14]. But when symptoms are atypical or the ultrasound is inconclusive, a CT scan with IV contrast may be needed. The possible association between cholecystitis and a gallbladder cancer should be considered in this situation, as well as atypical cholecystitis presenting with a clinical picture of advanced-stage
Figure 8.
The management strategy will depend on the size of the polyp, its characteristics on imaging, and the presence or absence of risk factors for malignant degeneration (Graph 1 — Decisional algorithm): • for polyps 10 mm and larger, cholecystectomy should be routinely performed [56]. The procedure can be performed laparoscopically taking great care to avoid gallbladder rupture or spillage, but a laparotomy approach seems preferable for polyp size greater than 15 mm to reduce the risk of peritoneal seeding [59]. Frozen section pathology examination of the specimen is recommended to determine how extensive the resection should be [59], since an additional contiguous hepatic resection is a major prognostic factor for survival in early stage gallbladder cancer [60]; • for polyps less than 10 mm, ultrasound imaging, Doppler ultrasound or contrast-ultrasound is essential to characterize the polyp [57]. MRI can be used as a second line imaging modality. Non-surgical surveillance with ultrasound monitoring every 6 months for 2 years is indicated if there are no risk factors for malignant degeneration [24]. However the presence of a gallbladder polyp in a patient older than 60, or with gallstones or other risk factors such as CSP, AJBP or porcelain gallbladder is an indication for cholecystectomy [26]. This can be
Adenocarcinoma of the gallbladder. Macroscopic appearance (above) and CT appearance (below).
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
10
J. Zemour et al. performed laparoscopically, taking great care to avoid any gallbladder tear or spillage.
metastasis to the gallbladder, cholecystectomy allows definitive diagnosis but widespread dissemination is often present making surgery unwarranted.
Gallbladder wall thickening In the absence of clinical acute cholecystitis, thickening of the gallbladder wall must be further assessed by CT and MRI. This morphological assessment helps to sort out the common diagnoses such as adenomyomatosis, xanthogranulomatous cholecystitis, porcelain gallbladder as well as extra-vesicular causes of wall thickening that do not require specific treatment. The possibility of gallbladder cancer should also be considered because of its severe prognosis, especially in cases of focal wall thickening exceeding 5 mm. Management in such cases is the same as for a gallbladder mass (Fig. 7): • adenomyomatosis is diagnosed by its specific appearance on ultrasound and MRI imaging [3,4,21]. Some authors recommend cholecystectomy for lesions larger than 1 cm or with associated cholecystolithiasis or other risk factors for malignant degeneration, because, even though the risk of malignant degeneration is not clearly defined [8], these factors may increase the risk of cancer and justify prophylactic cholecystectomy [20]; • diagnosis of xanthogranulomatous cholecystitis depends mainly by MRI but remains difficult since this lesion closely mimics cancer on imaging (Fig. 7). Management should be non-surgical unless doubt persists as to the possibility of cancer; in such cases cholecystectomy is recommended with routine frozen section pathology to avoid unjustified extensive resection [18]; • for porcelain gallbladder, the type of wall calcification can be characterized by ultrasound or CT imaging. Prophylactic cholecystectomy is recommended because of the risk of gallbladder cancer; this can be performed laparoscopically for patients with low-risk Type I lesions, taking care to avoid any tear of the gallbladder or bile spillage and converting to open laparotomy if there are any suspicious findings suggesting cancer [27].
A gallbladder mass If the diagnosis of cancer is suspected, further morphological examination by CT or endoscopic ultrasound will help establish the TNM stage preoperatively (Fig. 8) [5]. CT evidence of liver metastases or carcinomatosis calls for percutaneous or laparoscopic tumor biopsy. If the lesion is localized, surgical resection should be discussed as the initial gesture, since biopsy of a gallbladder mass exposes the patient to the risk of bile peritonitis or tumor dissemination. A laparotomy approach for cholecystectomy is mandatory. Simple cholecystectomy is indicated for early Tis or T1a tumors. Extended cholecystectomy is performed with resection of a 2 cm thickness of the gallbladder bed for T1b or T2 tumors. Bi-segmentectomy including segments IVb and V is recommended for T3 and T4 tumors [29,34]. Radical cholecystectomy should include lymphadenectomy of the hepatic pedicle and the falx of the hepatic artery at a minimum, but can be extended to include the celiac region. A frozen section pathologic exam of the cystic duct margin is recommended; if the margin is not tumor-free, resection of a portion of the common bile duct may be necessary [35]. Some studies have reported parietal recurrence after laparoscopic cholecystectomy for unrecognized cancer but the usefulness of excision of trocar sites at re-operation has not been demonstrated [32,35]. In cases of isolated
Conclusion Gallbladder cancer is a rare but very serious condition; this reinforces the importance of performing prophylactic cholecystectomy for precancerous lesions and appropriate treatment of diagnosed cancers. The discovery of a pathological gallbladder demands thorough clinical and radiological investigation to precisely define the lesion. This investigation leads to either a decision for non-surgical management in rare cases, to prophylactic cholecystectomy for lesions at risk for malignant degeneration, for early stage cancers, or whenever there is diagnostic doubt, or to a more radical surgical resection for advanced stage cancers. KEY POINTS • The most frequent benign tumors and pseudotumors of the gallbladder are: cholesterol polyp, adenoma, adenomyomatosis and cholesterolosis. • Gallbladder polyps larger than 1 cm are associated with a high risk of malignant degeneration and are indications for cholecystectomy. • Age greater than 60 years, chronic presence of large gallstones, gallbladder wall calcification, the presence of primary sclerosing cholangitis or abnormal bilio-pancreatic junction are risk factors for malignant degeneration. • Gallbladder polyps smaller than 1 cm but in association with other risk factors for malignant degeneration are an indication for cholecystectomy. • Gallbladder polyps less than 1 cm without risk factors of malignant degeneration can be observed. • Advanced gallbladder cancer must be included in the differential diagnosis of atypical cholecystitis. • The most common malignant tumor of the gallbladder is adenocarcinoma. The prognosis is very poor; it depends on the T stage at the time of diagnosis, and requires rapid and appropriate management. • The three most common types of primary cancer that metastasize to the gallbladder are melanoma, kidney cancer and breast cancer.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Andrén-Sandberg A. Diagnosis and management of gallbladder polyps. North Am J Med Sci 2012;4:203—11. [2] Matos AS, Baptista HN, Pinheiro C, et al. Gallbladder polyps: how should they be treated and when? Rev Assoc Med Bras 2010;56:318—21.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
Gallbladder tumor and pseudotumor: Diagnosis and management [3] Shukla HS. Gallbladder cancer. J Surg Oncol 2006;93:604—6. [4] Zins M, Boulay-Colette I, Molinié V, et al. Imagerie des épaississements de la paroi vésiculaire. J Radiol 2006;87:479—93. [5] Vialle R, Velascoa S, Milinb S, et al. Place de l’imagerie dans le diagnostic et le bilan des tumeurs de la vésicule biliaire. Gastroentérol Clin Biol 2008;32:931—41. [6] Inui K, Yoshino J, Miyoshi H. Diagnosis of gallbladder tumors. Intern Med 2011;50:1133—6. [7] Yang HL, Sun YG, Wang Z. Polypoid lesions of the gallbladder: diagnosis and indications for surgery. Br J Surg 1992;79: 227—9. [8] Owen CC, Bilhartz LE. Gallbladder polyps, cholesterolosis, adenomyomatosis, and acute acalculous cholecystitis. Sem Gastroint Dis 2003;14:178—88. [9] Lee KF, Wong J, Li JC, et al. Polypoid lesions of the gallbladder. Am J Surg 2004;188:186—90. [10] Hayama S, Suzuki Y, Takahashi M, et al. Heterotopic gastric mucosa in the gallbladder: report of two cases. Surg Today 2010;40:783—7. [11] Gerolami A. Tumeurs bénignes et formations pseudo tumorales des voies biliaires — foie-pancréas et voies biliaires. 5th ed. Paris: Flammarion; 1972. p. 166—8. [12] Boulay-Coletta I, Molinié V, Loriau J, et al. Cholécystites aiguës : pièges et formes graves. Imagerie Dig JFR 2009:27—36. [13] Yokoe M, Takada T, Strasberg SM, et al. New diagnostic criteria and severity assessment of acute cholecystitis in revised Tokyo guidelines. J Hepatobiliary Pancreat Sci 2012;19:578—85. [14] Hirota M, Takada T, Kawarada Y, et al. Diagnostic criteria and severity assessment of acute cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg 2007;14:78—82. [15] Bennet GL, Balthazar EJ. Ultrasound and CT evaluation of emergent gallbladder pathology. Radiol Clin N Am 2003;41:1203—16. [16] Adolph MD, Bass SN, Lee SK, et al. Cytomegaloviral acalculous cholecystitis in acquired immunodeficiency syndrome patients. Am Surg 1993;59:679—84. [17] Shin SW, Kim Y, Jeong WK, et al. Isolated IgG4-related cholecystitis mimicking gallbladder cancer: a case report. Clin Imaging 2013;37:969—71. [18] Hale MD, Roberts KJ, Hodson J, et al. Xanthogranulomatous cholecystitis: a European and global perspective. HPB (Oxford) 2014;16:448—58, http://dx.doi.org/10.1111/hpb.12152. [19] Ralls PW, Quinn MF, Juttner HU, et al. Gallbladder wall thickening: patients without intrinsic gallbladder disease. AJR Am J Roentgen 1981;137:65—8. [20] Gourgiotis S, Kocher HM, Solaini L, et al. Gallbladder cancer. Am J Surg 2008;196:252—64. [21] Park JY, Hong SP, Kim YJ, et al. Long-term follow-up of gallbladder polyps. J Gastroenterol Hepatol 2009;24:219—22. [22] Randi G, Fransceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006;118:1591—602. [23] Aldridge MC, Gruffaz F, Castaing D, et al. Adenomyomatosis of the gallbladder. A pre-malignant lesion? Surgery 1991;109:107—10. [24] Yoshimitsu K, Honda H, Aibe H, et al. Radiologic diagnosis of adenomyomatosis of the gallbladder: comparative study among MRI, helical CT, and transabdominal US. J Comput Assist Tomogr 2001;25:843—50. [25] Di Rienzo M, Annunziata A, Russo A, et al. Diagnostic and oncologic updating on gallbladder papilloma. Personal experience and review of the literature. Ann Ital Chir 1998;69:627—37. [26] Kianmanesh R, Scaringi S, Castel B, et al. Lésions précancéreuses de la vésicule biliaire. J Chir 2007;144:278—86. [27] Misra S, Chaturvedi A, Misra CM, et al. Carcinoma of the gallbladder. Lancet Oncol 2003;4:167—76. [28] Khan ZS, Livingston EH, Huerta S. Reassessing the need for prophylactic surgery in patients with porcelain gallbladder: case series and systematic review of the literature. Arch Surg 2011;146:1143—7. [29] Boutros C, Gary M, Baldwin K, et al. Gallbladder cancer: past, present and an uncertain future. Surg Oncol 2012;21:183—91.
11
[30] Randi G, Malvezzi M, Levi F, et al. Epidemiology of biliary tract cancers: an update. Ann Oncol 2009;20:146—59. [31] Orth K, Beger HG. Gallbladder carcinoma and surgical treatment. Langenbecks Arch Surg 2000;385:501—8. [32] Fuks D, Regimbeau JM, Pessaux P, et al. Is port-site resection necessary in the surgical management of gallbladder cancer? J Visc Surg 2013;150:277—84. [33] Edge SB, Burd DR, Compton CC, et al. Gallbladder cancer. AJCC Cancer staging manual. 7th ed. New York: Springer; 2010. p. 211—7. [34] Goetze TO, Paolucci V. Benefits of re-operation of T2 and more advanced incidental gallbladder carcinoma: analysis of the german registry. Ann Surg 2008;247:104—8. [35] Isambert M, Leux C, Métairie S, et al. Incidentally-discovered gallbladder cancer: when, why and which re-operation? J Visc Surg 2011;148:77—84. [36] Albores-Saavedra J, Scoazec JC, Wittekind C, et al. Tumours of the gallbladder and extrahepatic bile ducts. In: Hamilton SR, Aaltonen LA, editors. World Health Organization classification of tumours: pathology and genetics of tumours of the digestive system. Lyon, France: IARC Press; 2000. p. 203—18. [37] Waisberg J, Bromberg SH, Franco MI, et al. Squamous cell carcinoma of the gallbladder. Sao Paulo Med J 2001;119:43. [38] Rekik W, Ben Fadhel C, Boufaroua AL, et al. Primary squamous cell carcinoma of gallbladder. J Visc Surg 2011;148:149—51. [39] Bourmèche M, Ben Salah H, Kallel M, et al. Une longue survie après traitement d’un carcinome épidermoide de la vésicule biliaire. Cancer/Radiother 2013;17:58—61. [40] Machado MC, Penteado S, Montagnini AL, et al. Carcinoid tumor of the gallbladder. Sao Paulo Med J 1998;116:1741—3. [41] Fujii H, Aotake T, Horiuchi T, et al. Small cell carcinoma of the gallbladder: a case report and review of 53 cases in the literature. Hepatogastroenterology 2001;48:1588—93. [42] Elahi F, Ahmadzadeh A, Yadollahzadeh M, et al. Neuroendocrine tumor gallbladder. Arch Iran Med 2013;16: 123—5. [43] Ono A, Tanoue S, Yamada Y, et al. Primary malignant lymphoma of the gallbladder: a case report and literature review. Br J Radiol 2009;82:15—9. [44] Viswanathan SR, Khalpey Z, Ashley SW. Gallbladder lymphoma. Med Oncol 2011;28:810—2. [45] Kim MJ, Kim KW, Kim HC, et al. Unusual malignant tumors of the gallbladder. Am J Roentgenol 2006;187:473—80. [46] Brasseur P, Bissen L, Dupont H, et al. Métastase de la vésicule biliaire secondaire à une tumeur rénale à cellules claires. J Radiol 1999;80:739—40. [47] Katz SC, Bowne WB, Wolchok JD. Surgical management of melanoma of the gallbladder: a report of 13 cases and review of the literature. Am J Surg 2007;193:493—7. [48] Ishizawa T, Okuda J, Kawanishi T, et al. Metastatic renal cell carcinoma of the gallbladder. Asian J Surg 2006;29:145—8. [49] Sartelet H, Simon M, Alowanou A, et al. Une tumeur bourgeonnante de la vésicule biliaire : le carcinome à cellules claires. Ann Pathol 2004;24:58—61. [50] Essola B. Métastase vésiculaire d’un carcinome mammaire : une nouvelle observation. Rev Med Brux 2012;33:171—5. [51] Jeong YS, Han HS, Lim SN. Gallbladder metastasis of non-small cell lung cancer presenting as acute cholecystitis. Chin J Cancer Res 2012;24:249—52. [52] Bilici A, Seker M, Oven U. Gallbladder metastasis secondary to gastric cancer as a first site of recurrence presented with acute cholecystitis: case report and literature review. Turk J Gastroenterol 2012;23:764—8. [53] Disibio G, French SW. Metastatic pattern of cases: results from a large autopsy study. Arch Pathol Lab Med 2008;132: 931—9. [54] Gallahan WC, Conway JD. Diagnosis and management of gallbladder polyps. Gastroenterol Clin North Am 2010;39: 359—67. [55] Leung UC, Wong PY, Roberts RH, et al. Gallbladder polyps in sclerosing cholangitis: does the 1 cm rule apply? ANZ J Surg 2007;77:355—7.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
+Model JVS-398; No. of Pages 12
ARTICLE IN PRESS
12 [56] Ito H, Hann LE, D’Angelica M, et al. Polypoid lesions of the gallbladder: diagnosis and follow-up. J Am Coll Surg 2009;208:570—5. [57] Numata K, Oka H, Morimoto M, et al. Diffferential diagnosis of gallbladder diseases with contrast-enhanced harmonic gray scale ultrasonography. J Ultrasound Med 2007;26:763—74. [58] Yoon JH, Cha SS, Han SS, et al. Gallbladder adenomyomatosis: imaging findings. Abdom Imaging 2006;31:555—63.
J. Zemour et al. [59] Kim EK, Lee SK, Kim WW. Does laparoscopic surgery have a role in the treatment of gallbladder cancer? J Hepatobiliary Pancreat Surg 2002;9:559—63. [60] D’Hondt M, Lapointe R, Benamira Z, et al. Carcinoma of the gallbladder: patterns of presentation, prognostic factors and survival rate. An 11-year single centre experience. Eur J Surg Oncol 2013;39:548—53.
Please cite this article in press as: Zemour J, et al. Gallbladder tumor and pseudotumor: Diagnosis and management. Journal of Visceral Surgery (2014), http://dx.doi.org/10.1016/j.jviscsurg.2014.05.003
