Xanthogranulomatous cholecystitis

INTRODUCTION — Xanthogranulomatous cholecystitis is a rare benign inflammatory disease of the gallbladder that may be misdiagnosed as carcinoma of the gallbladder on imaging [1-4]. Xanthogranulomatous cholecystitis is characterized by a focal or diffuse destructive inflammatory process, with accumulation of lipid laden macrophages, fibrous tissue, and acute and chronic inflammatory cells.

Xanthogranulomatous cholecystitis, previously known as fibro-xanthogranulomatous cholecystitis, was initially described as a variant of chronic cholecystitis. However, it is now recognized as a distinct clinical entity that can lead to significant morbidity as the inflammatory process usually extends into the gallbladder wall and adjacent structures. This topic will review the clinical features, diagnosis, and management of xanthogranulomatous cholecystitis. Other causes of acute cholecystitis are discussed in detail, separately. (See "Acute calculous cholecystitis: Clinical features and diagnosis" and "Treatment of acute calculous cholecystitis" and "Acalculous cholecystitis: Clinical manifestations, diagnosis, and management".)

EPIDEMIOLOGY — The prevalence of xanthogranulomatous cholecystitis varies by geographic region. The pooled prevalence of xanthogranulomatous cholecystitis in epidemiologic studies of European, Americas, or Far Eastern cohorts ranges from 1.3 to 1.9 percent in Europe and the Americas and up to 9 percent in India [5-10]. The mean age at presentation ranges from 44 to 63 years [5,11]. While some studies have reported a male predominance, others have found no sex predilection [3,5,8,11].

PATHOGENESIS — The pathogenesis of xanthogranulomatous cholecystitis may be related to extravasation of bile into the gallbladder wall from rupture of Rokitansky-Aschoff sinuses or by mucosal ulceration [3,12]. This event incites an inflammatory reaction in the interstitial tissue, whereby fibroblasts and macrophages phagocytose the biliary lipids in bile, such as cholesterol and phospholipids, leading to the formation of xanthoma cells.

Gallstones are present in the majority of patients and may have an important role in the pathogenesis [5,11,13]. It is hypothesized that xanthogranulomatous cholecystitis is analogous to xanthogranulomatous pyelonephritis, which results from obstruction and stasis due to renal calculi [14]. (See "Xanthogranulomatous pyelonephritis".)

CLINICAL FEATURES

Presentation — Presenting symptoms in patients with xanthogranulomatous cholecystitis include acute onset of right upper quadrant abdominal pain (85 percent), nausea (26 percent), and vomiting (22 percent). On physical examination, a positive Murphy's sign is present in approximately 53 percent of patients, and can mimic acute cholecystitis. (See "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Clinical manifestations' and 'Differential diagnosis' below.)

Other patients may have more chronic symptoms, including weight loss (9 percent) and anorexia (18 percent) [10]. A right hypochondrial mass is palpable in approximately 10 percent of patients, mimicking carcinoma of the gallbladder [15-17]. Approximately 20 percent of patients have jaundice at presentation due to obstructive complications of xanthogranulomatous cholecystitis [15]. (See 'Complications' below and 'Differential diagnosis' below.)

Imaging findings — Imaging may be suggestive of xanthogranulomatous cholecystitis but is not specific.

Ultrasonography — Features of xanthogranulomatous cholecystitis include hypoechoic nodules or bands in the gallbladder wall and a diffusely thickened gallbladder [15,18,19]. Other findings on ultrasonography include a gallbladder mass, subhepatic fluid collection, obscure border between the gallbladder and liver, and rarely, gas in the biliary tree in patients with a biliary fistula [15]. Concurrent gallstones are frequently present. Contrast-enhanced ultrasound may be more sensitive as compared with transabdominal ultrasound [20].

However, findings on ultrasonography are not specific for xanthogranulomatous cholecystitis. Intramural hypoechoic nodules can be seen in other conditions, including intramural abscesses, cholesterolosis, and adenomyomatosis [21-23]. (See "Gallbladder polyps".)

Computed tomography (CT) and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) — Features of xanthogranulomatous cholecystitis on CT and MRI include diffuse gallbladder wall thickening, intramural nodules, and a smooth gallbladder wall (image 1). After contrast enhancement features of xanthogranulomatous cholecystitis include continuous enhancement of the mucosal line, pericholecystic infiltration, transient hepatic attenuation difference at the gallbladder bed of the liver, and luminal surface enhancement [7,19,24,25].

CT and magnetic resonance findings in xanthogranulomatous cholecystitis correlate with pathologic findings [26]. Low-attenuation areas in the wall of the gallbladder correlate with foam and inflammatory cells or necrosis and/or abscess in xanthogranulomatous cholecystitis. Areas of iso- to slightly high signal intensity on T2-weighted images, showing slight enhancement at early phase and strong enhancement at last phase on dynamic study, correspond with areas of abundant xanthogranulomas. Areas with very high signal intensity on T2-weighted images without enhancement correspond with necrosis and/or abscesses.

However, imaging features of xanthogranulomatous cholecystitis and carcinoma of the gallbladder are similar, and both conditions can co-exist [24]. In a retrospective study that compared the CT features of 18 patients with xanthogranulomatous cholecystitis and 17 patients with gallbladder cancer, the following imaging features were useful in diagnosing xanthogranulomatous cholecystitis:

●Diffuse gallbladder wall thickening: sensitivity 89 percent, specificity 65 percent

●Continuous mucosal line: sensitivity 67 percent, specificity 82 percent

●Intramural hypoattenuated nodules: sensitivity 61 percent, specificity 71 percent

●Absence of macroscopic hepatic invasion: sensitivity 72 percent, specificity 77 percent

●Absence of intrahepatic bile duct dilatation: sensitivity 67 percent, specificity 71 percent

When at least three of these five CT findings were observed, the sensitivity, specificity, and accuracy were 83, 100, and 91 percent, respectively. However, these results have not been validated and these features are not uniformly reported in clinical practice.

MRI may have higher accuracy as compared with CT and ultrasound in differentiating between xanthogranulomatous cholecystitis and carcinoma of the gallbladder, and MRCP has the advantage of delineating abnormal dilated ducts and can evaluate the level of obstruction.

Laboratory findings — Laboratory studies are usually normal, but approximately 20 percent of patients have obstructive jaundice with elevated liver enzymes in a primarily cholestatic pattern (disproportionate elevation of the alkaline phosphatase, gamma-glutamyl transferase, and bilirubin) [15].

Complications — Approximately 30 percent of patients with xanthogranulomatous cholecystitis have complications at presentation [15]. Local complications include gallbladder perforation and bile duct obstruction. Bile duct obstruction may be due to development of strictures of the bile duct (xanthogranulomatous choledochitis) or choledocholithiasis, and rarely, is due to extrinsic compression of the bile duct (Mirizzi syndrome) [9]. Prolonged cystic duct obstruction and gallbladder distension under pressure during the acute inflammatory phase can lead to extension of the xanthogranulomatous inflammation beyond the gallbladder with formation of hepatic abscesses and fistulas into adjacent structures, such as the liver, duodenum, stomach, colon, and skin [11]. (See "Mirizzi syndrome".)

It is unclear if there is any association between gallbladder cancer and xanthogranulomatous cholecystitis. In rare cases, gallbladder carcinoma may be present concurrently [11,27]. In a larger series of 460 cholecystectomies performed for various gallbladder diseases, xanthogranuloma and carcinoma of the gallbladder were noted in only one case (0.2 percent) [5].

DIFFERENTIAL DIAGNOSIS — Xanthogranulomatous cholecystitis may be confused for gallbladder cancer in its clinical presentation and radiographic appearance [28,29]. Histopathological evaluation of the gallbladder usually facilitates differentiation of these disorders, although rarely the two can occur together. The clinical presentation of xanthogranulomatous cholecystitis can be similar to that of acute cholecystitis, however, the imaging findings are distinct. (See "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Diagnostic imaging'.)

DIAGNOSTIC EVALUATION

Clinical suspicion and diagnosis — The diagnosis of xanthogranulomatous cholecystitis is often made incidentally on histological examination of the resected gallbladder in a patient with suspected acute cholecystitis. However, a diagnosis of xanthogranulomatous cholecystitis should also be considered in the following clinical scenarios:

●Right upper quadrant mass and/or pneumobilia suggestive of an enterobiliary fistula on abdominal imaging. In such cases, we perform a magnetic resonance imaging/magnetic resonance cholangiopancreatography to delineate the biliary tree prior to surgery. (See 'Imaging findings' above.)

●In patients undergoing cholecystectomy, a markedly thick-walled gallbladder with extensive, dense, fibrous adhesions to neighboring structures should raise the suspicion for xanthogranulomatous cholecystitis. Intraoperative findings cannot reliably differentiate between gallbladder cancer and xanthogranulomatous cholecystitis. The presence of enlarged lymph nodes and the loss of interface between the gallbladder and liver bed intra-operatively can be seen in both xanthogranulomatous cholecystitis and gallbladder cancer. Intraoperative frozen section analysis should be performed to diagnose gallbladder cancer as this impacts surgical decision-making [11,30]. In a study of 142 patients with xanthogranulomatous cholecystitis, 42 were misdiagnosed as gallbladder cancer based on preoperative radiographs and/or intraoperative findings [31]. The accuracy rate of frozen section analysis and that of the surgeon's macroscopic diagnosis were 93 and 50 percent, respectively.

We do not perform fine needle aspiration cytology either pre-operatively or intra-operatively in patients with suspected xanthogranulomatous cholecystitis. Fine needle aspiration cytology can diagnose xanthogranulomatous cholecystitis [16,31-33]. However, cytology may be falsely negative for a concurrent gallbladder cancer and the procedure can create a fistula and can lead to seeding of the track with tumour. (See "Endoscopic ultrasound-guided fine needle aspiration in the gastrointestinal tract".)

Surgical pathology — On gross examination, the gallbladder is thickened and the serosa is covered with dense fibrous adhesions (picture 1). The mucosal surface may be ulcerated and cross sections through the wall reveal xanthogranulomatous foci, which appear as yellow nodules or plaques. These yellowish foci may extend into adjacent structures, such as the liver, duodenum, transverse colon, and omentum [5,11].

Microscopically, the xanthogranulomatous foci are composed of abundant lipid laden macrophages, fibroblasts, and inflammatory cells (picture 2). The lipid laden macrophages are of two morphological types: rounded foamy macrophages and spindle-shaped cells with more granular cytoplasm and elongated nuclei. Other findings include the presence of cholesterol clefts, lipid droplets, hemosiderin deposits, and extravasated bile [11].

MANAGEMENT — The only definitive treatment for xanthogranulomatous cholecystitis is cholecystectomy. Due to the inflammatory and invasive nature of xanthogranulomatous cholecystitis, complete resection of the xanthogranulomatous tissue adjacent to the gallbladder should be attempted, even if this includes resection into the hepatic bed [15,34]. An intraoperative frozen section should be performed to exclude gallbladder cancer [11,30]. (See "Treatment of acute calculous cholecystitis", section on 'Surgical approach' and "Surgical management of gallbladder cancer", section on 'Resection techniques'.)

In most patients requiring surgery for xanthogranulomatous cholecystitis, open cholecystectomy is required due to dense fibrosis and extensive local inflammation [35,36]. Laparoscopic cholecystectomy may be attempted, but conversion to open surgery is often required. The conversion rate ranged from 16 to 80 percent in reported case series [8,35-38]. Given the clinical presentation of biliary obstruction, patients frequently require preoperative biliary drainage via endoscopic or percutaneous methods [38]. Higher complication rates (including bile duct injury) have also been reported with laparoscopic cholecystectomy for xanthogranulomatous cholecystitis [37]. When the hepatocystic triangle has been obscured by the inflammatory process, subtotal cholecystectomy is an option to avoid major complications, as long as gallbladder cancer has been excluded by intraoperative frozen section [39]. (See "Managing the difficult gallbladder", section on 'Subtotal cholecystectomy'.)

PROGNOSIS — Morbidity following resection of xanthogranulomatous cholecystitis is largely related to postoperative complications. The postoperative morbidity rates were 30 and 32 percent in two series and were mainly related to wound infections, particularly in patients with fistulae [11,15].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cholecystitis and other gallbladder disorders".)

SUMMARY AND RECOMMENDATIONS

●Xanthogranulomatous cholecystitis is a rare inflammatory disease of the gallbladder characterized by a focal or diffuse destructive inflammatory process, with accumulation of lipid laden macrophages, fibrous tissue, and acute and chronic inflammatory cells. (See 'Epidemiology' above and 'Pathogenesis' above.)

●The mean age at presentation ranges from 44 to 63 years. Presenting symptoms in patients with xanthogranulomatous cholecystitis include acute onset of right upper quadrant abdominal pain, nausea, and vomiting. On physical examination, a positive Murphy's sign may be present and can mimic acute cholecystitis. Other patients may have more chronic symptoms, including weight loss and anorexia. A right hypochondrial mass is palpable in approximately 10 percent of patients, mimicking carcinoma of the gallbladder. (See 'Clinical features' above.)

●Features of xanthogranulomatous cholecystitis on abdominal imaging include hypoechoic nodules or bands in the gallbladder wall and a diffusely thickened gallbladder. However, imaging features of xanthogranulomatous cholecystitis are not specific. In addition, imaging cannot reliably distinguish between xanthogranulomatous cholecystitis and carcinoma of the gallbladder, and both conditions can co-exist. (See 'Imaging findings' above.)

●Approximately 30 percent of patients with xanthogranulomatous cholecystitis have complications at presentation. Local complications include gallbladder perforation and bile duct obstruction. Prolonged cystic duct obstruction and gallbladder distension under pressure during the acute inflammatory phase can lead to extension of the xanthogranulomatous inflammation beyond the gallbladder with formation of hepatic abscesses and fistulas into adjacent structures, such as the liver, duodenum, stomach, colon, and skin. (See 'Complications' above.)

●The diagnosis of xanthogranulomatous cholecystitis is often made incidentally on histological examination of the resected gallbladder in a patient with suspected acute cholecystitis. However, a diagnosis of xanthogranulomatous cholecystitis should also be considered in patients with right upper quadrant mass and/or pneumobilia suggestive of a enterobiliary fistula. In patients undergoing cholecystectomy, a markedly thick-walled gallbladder with extensive, dense, fibrous adhesions to neighboring structures should raise the suspicion for xanthogranulomatous cholecystitis. (See 'Diagnostic evaluation' above.)

●In patients in whom xanthogranulomatous cholecystitis is suspected pre-operatively, we perform an magnetic resonance cholangiopancreatography to delineate the biliary tree prior to surgery. Patients presenting with symptomatic biliary obstruction such as cholangitis may require preoperative biliary ductal decompression. The only definitive treatment for xanthogranulomatous cholecystitis is cholecystectomy. Intraoperative frozen section analysis should be performed to diagnose or exclude gallbladder cancer. A complete resection of adjacent xanthogranulomatous tissue should be attempted, even if this includes resection into the hepatic bed. (See 'Management' above.)