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Xanthogranulomatous cholecystitis mimicking advanced gallbladder carcinoma – Analysis of 8 cases


1 Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
2 Department of Surgery, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India

Date of Submission28-Dec-2019
Date of Decision07-Apr-2020
Date of Acceptance06-May-2020
Date of Web Publication22-Oct-2020

Correspondence Address:
Sabina Khan,
Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi - 110 062
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1180_19

 > Abstract 


Background/Aim: Xanthogranulomatous cholecystitis (XGC) is a rare destructive inflammatory disease of the gallbladder. It is frequently misdiagnosed as gallbladder carcinoma (GBC) as it mimics latter with regard to clinical manifestations, imaging and intraoperative findings, often leading to extended surgical resection in these patients. The aim of this study was to evaluate the diagnostic dilemma of XGC cases clinico-radiologically diagnosed with GBC.
Materials and Methods: From January 2017 to June 2019, a total of eight cases histopathologically diagnosed as XGC, were misdiagnosed with GBC based on preoperative and intra-operative findings. The clinical characteristics, imaging, intra-operative findings, and surgical data of these patients were collected and analyzed.
Results: A total of 2154 cholecystectomy specimens were received in the histopathology section during the study period. Sixty-nine cases (3.2%) were histologically diagnosed as XGC, of which 8 cases (11.6%) were preoperatively diagnosed with GBC. These cases were predominantly seen in males in the age range of 24–62 years. The most common clinical presentation was chronic cholecystitis. Gallstones were present in all the 8 cases. Six cases presented with heterogeneous enhancement within thickened gallbladder walls on imaging. Intraoperatively, adhesions to adjacent organs were observed in seven cases. All these eight cases misdiagnosed with GBC underwent aggressive surgical treatment following which histopathology ultimately revealed XGC.
Conclusion: Neither clinical manifestations nor laboratory tests/radiological methods can provide an effective means of differentiating between XGC and GBC. Preoperative diagnosis is difficult, and histopathology remains the gold standard to differentiate the two entities.

Keywords: Carcinoma, gallbladder, xanthogranulomatous cholecystitis



How to cite this URL:
Khan S, Abeer I, Husain M, Hassan MJ, Jetley S. Xanthogranulomatous cholecystitis mimicking advanced gallbladder carcinoma – Analysis of 8 cases. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 2]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=298861




 > Introduction Top


Xanthogranulomatous cholecystitis (XGC) is a rare destructive inflammatory disease of the gallbladder. It was first described by Christensen and Ishak in 1970[1] as “fibroxanthogranulomatous inflammation” and later in 1976 as XGC by McCoy et al.[2] It is predominantly seen in the Japanese or South Asian population with the age of presentation between 44 and 63 years.[3] Its prevalence ranges from 0.7% in the USA to 10% in India, with no clear gender difference.[4]

XGC is characterized by proliferative fibrosis with infiltration of macrophages and foamy cells within the gallbladder wall and is benign in nature but often shows a destructive inflammatory process.[5],[6],[7] The inflammatory infiltration and fibrosis cause asymmetrical thickening of the gallbladder wall and formation of multiple yellowish-brown nodules, which often extend into the neighboring organs, such as the liver, omentum, and duodenum.[8] Due to the overlapping features between the two diseases, XGC is frequently misdiagnosed wih gallbladder carcinoma (GBC), and such patients usually undergo an extended radical surgery. Sometimes, XGC might even have a coexistent GBC.[5]

Imaging is helpful preoperatively, but the diagnosis is often a postoperative histological surprise.[9] Accurate diagnosis is important for the proper surgical management of these patients. Preoperatively, differentiating between XGC and GBC would help avert unnecessary morbidity, especially in the form of radical surgery.

In the present study, we analyzed the clinical, radiological, surgical, and morphological features of 8 cases of XGC preoperatively misdiagnosed with carcinoma gall bladder. In all of these cases, clinical, radiological, and intraoperative findings were highly suggestive for malignancy, thereby leading to radical resection. Histopathology was ultimately benign, much to the relief of patients and their families.


 > Materials and Methods Top


A retrospective analysis of database collected from the histopathology section of our department, on patients operated n with a preoperative diagnosis of GBC between January 2017 and June 2019 was done. All those patients who underwent a radical cholecystectomy for GBC and ultimately were histopathologically diagnosed as XGC were included in the study. Out of a total of 9 such patients, 8 were finally recruited in the study; one patient had GBC associated with XGC and was excluded from the analysis. A total of eight cases were misdiagnosed as GBC based either on preoperative radiographs and/or intraoperative findings. The clinical characteristics, preoperative imaging, intraoperative findings, surgical data, and histopathological features of these patients were collected and analyzed with an attempt to identify features that could aid in the preoperative diagnosis of XGC.


 > Results Top


A total of 2154 cholecystectomy specimens were received in the histopathology section during the study period. Sixty-nine cases (3.2%) were histologically diagnosed as XGC, of which 8 cases (11.6%) were preoperatively diagnosed as GBC. A total of 9 patients who underwent radical resection due to preoperative diagnosis of GBC, were diagnosed with XGC on histopathology. One patient had GBC associated with XGC and was excluded from the study. These cases were predominantly seen in males in the age range of 24–62 years. Of these 8 cases, 3 were female and 5 males. The clinical records, radiologic findings and surgical data of these 8 patients with histologically confirmed XGC were studied retrospectively.

Most common clinical presentation was chronic cholecystitis. Five out of eight patients presented with features suggestive of chronic cholecystitis which included recurrent right upper quadrant (RUQ) pain (3 cases), abdominal distension (2 cases), and anorexia (4 cases). The second-most common presentation was acute cholecystitis, in which patients presented with acute RUQ pain (3 cases) high-grade fever (3 cases), elevated WBC count (2 cases), nausea, and vomiting (3 cases). Two patients had mild jaundice. On examination, RUQ mass was palpable in 3 patients. Increased CA19-9 level was observed in 6 patients, while carcinoembryonic antigen (CEA) was raised in 2 patients [Table 1].
Table 1: The clinicopathological profile of Xanthogranulomatous cholecystitis patients (8 cases)

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All of these eight patients underwent ultrasonography. Gallstones were present in all the 8 cases. Six cases presented with heterogeneous enhancement within thickened gallbladder walls on imaging. Intraoperatively, adhesions to adjacent organs were observed in 7 cases. Five patients showed diffuse thickening of the gallbladder wall. Choledocholithiasis was also seen in 2 cases. Computed tomography (CT) scan was done in only 5 patients. The presence of a thickened gallbladder wall was noted in all 5 patients, with 4 of the patients having a diffuse thickening. Three patients with markedly thickened gallbladder walls were associated with intramural hypoattenuated nodules. Blurred liver/gallbladder interface was observed in 5 patients, 4 of whom presented with an abnormal enhancement in the hepatic parenchyma neighboring the gallbladder, which indicated hepatic infiltration [Figure 1]. In addition, the infiltration of other adjacent structures could also be noted in 3 of the patients, including the omentum, colon, duodenum, and the stomach [Table 2].
Figure 1: Computed tomography image showing gallbladder mass with the loss of fat planes between liver and gallbladder

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Table 2: Abdominal computed tomography or magnetic resonance imaging findings

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Operative notes of all 8 cases were analyzed. Intra-operative findings such as presence of GB adhesions to adjacent tissues, thickened gallbladder wall, gallstones, mass lesions, gallbladder internal fistula, and enlarged regional lymph nodes were recorded.

Open radical surgery was performed in 5 patients, laparoscopy was attempted in 3 patients and laparoscopy was converted to open procedure in all of these 3 patients due to difficult surgery as a result of adhesions [Figure 2]. Intraoperative findings confirmed the presence of a thickened gallbladder wall in all patients. Intraoperatively, adhesions to adjacent organs were observed in 7 cases (adhesions to the omentum in 3, duodenum in 2, colon in 1, and to the stomach in 1). Peroperatively, 5 patients had obscured Calot's triangle anatomy. Gallstones were observed in all 8 patients, including two cases of combined CBD stones. Mass lesions were found in 2 patients [Table 3].
Figure 2: Peroperative image showing thick walled gallbladder with surrounding adhesions

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Table 3: Intraoperative findings in the study patients (8 cases)

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The excised gallbladder was sent to the histopathology section of the Pathology Department, where gross as well as microscopic features of all cases were studied [Table 4]. The gallbladder was examined macroscopically for the appearance of the mucosa, wall thickness, any mass lesion and the presence of stones. The gallbladder wall thickness of 1–2 mm was considered as normal, and a wall thickness of 3 mm or more grossly was considered thickened. All cases showed a thickened gallbladder wall with the presence of a mass lesion in a few cases. Yellowish areas were seen in the gallbladder wall, gallbladder bed, and infiltrating into adjacent organs [Figure 3].
Table 4: Histopathological findings in study patients (8 cases)

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Figure 3: Gross specimen of the gallbladder showing yellow-gray mass completely occupying gallbladder lumen and infiltrating into adjacent organs

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Microscopically, hematoxylin and eosin slides were evaluated for various histopathological features and multiple sections studied for excluding the presence of malignancy. Histologically, 7 cases showed transmural inflammation comprising sheets of foamy histiocytes, and dense mixed inflammatory infiltrate namely lymphocytes, plasma cells, eosinophils, and few neutrophils [Figure 4]. In one case, xanthogranulomatous inflammation was limited to the mucosa. Five cases showed multinucleated giant cells, while 3 showed cholesterol clefts [Figure 4]. Microscopically, liver bed involvement by the xanthogranulomatous process was seen in 2 cases. Lymph nodes were received in all 8 cases as radical resection was performed for presumed preoperative diagnosis of gall bladder carcinoma. Lymph nodes number in each case ranged from two to six and all showed reactive change except for one case, which showed numerous coalescent epithelioid granulomas suggestive of tuberculosis. Ziehl-Neelsen stain was negative in this case and simultaneously received gallbladder did not show any evidence of granuloma or necrosis.
Figure 4: Photomicrograph showing transmural inflammation comprising sheets of foamy histiocytes, and dense mixed inflammatory infiltrate, namely lymphocytes, plasma cells, eosinophils, and few neutrophils

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 > Discussion Top


XGC is an uncommon form of chronic cholecystitis, representing between 0.7% and 13.2% of gallbladder disease.[10],[11],[12] Its importance lies in the fact that XGC can be confused preoperatively with the prognostically far more ominous Carcinoma gallbladder. Both share peak incidences in the sixth and seventh decades of life, arise more commonly in women, have been associated with cholelithiasis and chronic inflammation, and present vague clinical signs and symptoms suggestive of biliary colic or acute or chronic cholecystitis.

In our study, all the 8 cases misdiagnosed as GBC underwent aggressive surgical treatment following which histopathology ultimately revealed XGC. In a study by Kwon et al., 77 patients had a radical cholecystectomy, of which 16 were reported as XGC on histopathology.[13] In a similar study by Deng et al., a total of 142 cases of pathologically diagnosed XGC were reviewed, among which 42 were misdiagnosed as GBC based on preoperative radiographs and/or intra-operative findings.[5] Rates of co-existing carcinoma vary from 2% to 15% of patients with XGC, suggesting a causal association.[12] In our study also, we encountered 1 case of XGC associated with Carcinoma gallbladder.

In the 8 XGC cases misdiagnosed as GBC, the patients had a wide age range of 24–62 years, and males were more affected as compared to females (5:3). In a similar study on XGC by Deng et al., the male-to-female ratio was 4:3 with an age range of 38–86 years.[5] In another study by Rajaguru et al., age of the patients with XGC ranged from 20 to 68 years with an M:F ratio of 2.2:1.[14]

Although the mechanism leading to this condition remains unclear, extravasation of bile into the gallbladder wall, with the involvement of Rokitansky-Aschoff sinuses, or extravasation through small ulceration in the mucosa, appears to be a precipitating factor. The pathogenesis of XGC is not fully understood, although the presence of gallstones and biliary obstruction might play an important role. Similar to various studies in the literature, almost all our patients also had cholelithiasis.

Clinical findings and laboratory investigations do not appear to be of use in differentiating XGC from gall bladder In a study by Deng et al., 42 patients who were misdiagnosed as GBC, no specific symptoms were observed.[5] The most common presenting syndrome was of chronic cholecystitis. Patients with this clinical syndrome had chronic RUQ pain (62.5%), abdominal distension (48%), and anorexia (45%). Seven had mild jaundice without choledocholithiasis. In our study, abdominal pain (62.5%) was the most common symptom. Mild jaundice was seen in only 2 cases (25%).

Tumor markers are not very helpful in differentiating XGC from GBC as it can be high in both the conditions but may help in postoperative follow-up. CA 19.9 normalizes early after surgery for XGC, whereas it remains high for a longer duration in GBC. Increased CA19-9 level was observed in 32 (76%) patients, and increased CEA level was found only in 6 (14%) patients in a study by Deng et al.[5] In the present study, increased CA19-9 and CEA levels were seen in 6 and 2 patients, respectively.

ssRadiological investigations in XGC reveal the presence of gallstones and gallbladder wall thickening (diffuse 80%–90%, focal 10%–20%), intramural hypoattenuated nodules, and continuous mucosal line enhancement. Though typically considered characteristic of XGC, intramural nodules may also be seen in well­differentiated GBC with abundant mucin production[14] On radiology, the presence of a thickened gallbladder wall was noted in all our patients with 75% of the patients having a diffuse thickening. Features more commonly associated with malignant pathology include mass lesion, hepatic invasion, and enlarged lymph nodes, which may also be seen in florid XGC. There is too much overlap of the imaging findings between XGC and GBC to reliably differentiate between these two entities. On CT or MRI, intramural hypo-attenuated nodules occupying >60% of the GB wall thickness has significant specificity for the differentiation of XGC from GB cancer.[15] In a study by Denget al. on 42 cases of XGC mimicking GBC, 83% of cases presented with heterogeneous enhancement and thickened gallbladder walls on imaging, 69% of cases presented with abnormal enhancement in hepatic parenchyma showing hepatic infiltration.[5] On imaging, the cases in our study group were highly suggestive of GBC rather than XGC. Findings in our study that were indicative of potentially malignant processes included mass lesions, hepatic invasion, contiguous organ involvement, and lymph node enlargement. Furthermore, the rarity of XGC and the possibility of the coexisting GBC also contribute to the difficulty in the differential diagnosis.

In addition to sonography and CT, fine-needle aspiration cytology has been used in several cases with good results Preoperative FNAC in XGC is a distinct entity characterized by a spectrum of cytomorphologic features that can help in differentiating XGC from malignancy.[16],[17] It is less preferred as disadvantages of this procedure include seeding of the track with tumor and fistula formation. In the study, FNAC was performed in only one case, which showed scant cellularity with few atypical epithelial cells. Although the clinico-radiological features with preoperative FNAC or biopsy may help to differentiate between GBC and XGC; however, histopathology remains the final resort for an accurate diagnosis.

Intraoperative frozen section examination is another very valuable tool for differentiating XGC from malignancy. However, in cases showing extensive invasion of extra-gallbladder organs, the surgical strategy is not influenced by frozen section examination. None of the cases underwent a frozen section in our study.

A simple cholecystectomy is often enough for XGC. In general, the laparoscopic approach is not indicated for XGC (associated with conversion rates of up to 80%), and open approaches are often used initially due to suspicion of cancer and/or the anticipation of technical difficulty.[6] Contiguous organ involvement may necessitate extensive resection, in spite of knowing preoperatively that the underlying disease process is entirely benign. Therefore radical resection done in all our cases is justifiable, although the final diagnosis was benign. Nearly all our study group who underwent laparoscopic cholecystectomy (3 patients) presented with some difficulty during the surgical procedure and required conversion to open surgery. In a retrospective study by Rajaguru et al., out of the 22 misdiagnosed cases of XGC, 19 underwent a simple cholecystectomy (14 open, 3-laparoscopic converted to open, 2 laparoscopic), while 3 underwent radical cholecystectomy.[18] Peroperatively infiltration of other adjacent structures and enlarged lymph nodes were also noted in 7 out of the 8 cases of in our study, which is similar to the study by Deng et al. in which adhesion were seen in 95.2% of the cases.[5]

On gross examination, XGC shows a yellow-brown lesion, well-demarcated foci of mural thickening with or without surface ulceration. Gallstones are present in most cases. On microscopy, all the 8 cases preoperatively diagnosed as GBC showed characteristic features of XGC with no evidence of malignancy. Sections showed a large number of foamy histiocytes and inflammatory infiltrates, including lymphocytes, neutrophils, and plasma cells. Few cases showed cholesterol clefts and giant cell reaction. The xanthogranulomatous foci can infiltrate adjacent organs. In this study, microscopically 2 cases showed an extension of xanthogranulomatous inflammation into adjacent organs.

In conclusion, there is a significant overlap between XGC and GBC. Neither clinical presentation nor laboratory tests/radiological investigations/peroperative examination could provide an effective standard in the diagnosis. The definitive diagnosis by all means is dependent on the pathological examination. The preoperative identification of XGC can aid in the proper surgical management of these patients and in the differential diagnosis with other gallbladder diseases.


 > Conclusion Top


To conclude, differentiating XGC from GBC is a diagnostic dilemma as there is a significant overlap between the two entities. Neither clinical presentation nor laboratory tests/radiological investigations/peroperative examination could provide an effective means of diagnosing these two lesions, thus necessitating a histopathological examination for definitive diagnosis.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Christensen AH, Ishak KG. Benign tumors and pseudotumors of the gallbladder. Report of 180 cases. Arch Pathol 1970;90:423-32.  Back to cited text no. 1
    
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McCoy JJ Jr, Vila R, Petrossian G, McCall RA, Reddy KS. Xanthogranulomatous cholecystitis. Report of two cases. J S C Med Assoc 1976;72:78-9.  Back to cited text no. 2
    
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Zhang LF, Hou CS, Liu JY, Xiu DR, Xu Z, Wang LX, et al. Strategies for diagnosis of xanthogranulomatous cholecystitis masquerading as gallbladder cancer. Chin Med J (Engl) 2012;125:109-13.  Back to cited text no. 7
    
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Kwon AH, Matsui Y, Uemura Y. Surgical procedures and histopathologic findings for patients with xanthogranulomatous cholecystitis. J Am Coll Surg 2004;199:204-10.  Back to cited text no. 13
    
14.
Rajaguru K, Mehrotra S, Lalwani S, Mangla V, Mehta N, Nundy S. New scoring system for differentiating xanthogranulomatous cholecystitis from gall bladder carcinoma: A tertiary care centre experience. ANZ J Surg 2018;88:34-9.  Back to cited text no. 14
    
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Singh VP, Rajesh S, Bihari C, Desai SN, Pargewar SS, Arora A. Xanthogranulomatous cholecystitis: What every radiologist should know. World J Radiol 2016;8:183-91.  Back to cited text no. 15
    
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Shukla S, Krishnani N, Jain M, Pandey R, Gupta RK. Xanthogranulomatous cholecystitis. Fine needle aspiration cytology in 17 cases. Acta Cytol 1997;41:413-8.  Back to cited text no. 16
    
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Krishnani N, Dhingra S, Kapoor S, Pandey R. Cytopathologic diagnosis of xanthogranulomatous cholecystitis and coexistent lesions. A prospective study of 31 cases. Acta Cytol 2007;51:37-41.  Back to cited text no. 17
    
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Zimmitti G, Manzoni A, Guerini F, Ramera M, Bertocchi P, Aroldi F, et al. Current role of minimally invasive radical cholecystectomy for gallbladder cancer. Gastroenterol Res Pract 2016;2016:7684915.  Back to cited text no. 18
    


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