Author Affiliations: Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China (You Z, Ma WJ, Deng YL, Xiong XZ, Shrestha A, Li FY and Cheng NS)

Corresponding Author: Nan-Sheng Cheng, MD, PhD, Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China (Tel: +86-28-85422465; Fax: +86-28-85422468; Email: nanshengcheng2000@yeah.net)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60375-7

Published online May 21, 2015.

 

 

Acknowledgments: The authors acknowledge the support from the Department of Pathology of West China Hospital.

Contributors: CNS proposed the study. YZ, MWJ and DYL performed the research and wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts. YZ and MWJ contributed equally to this work. CNS is the guarantor.

Funding: This work was supported by grants from the Science & Technology Support Project of Sichuan Province (2011FZ0009 and 2014SZ0002-10).

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Unexpected gallbladder cancer may present with acute cholecystitis-like manifestations. Some authors recommended that frozen section analysis should be performed during laparoscopic cholecystectomy for all cases of acute cholecystitis. Others advocate selective use of frozen section analysis based on gross examination of the specimen by the surgeon. The aim of the present study was to evaluate whether surgeons could effectively identify suspected gallbladder with macroscopic examination alone. If not, is routine frozen section analysis worth advocating?

 

METHODS: A total of 1162 patients with acute cholecystitis who had undergone simple cholecystectomy in our hospital from February 2009 to February 2014 were enrolled in the study. The data of patients with acute cholecystitis especially those with concurrent gallbladder cancer in terms of clinical characteristics, operative records, frozen section diagnosis and histopathology reports were analyzed.

 

RESULTS: Thirteen patients with acute cholecystitis were found to have concurrent gallbladder cancer, with an incidence of 1.1% in acute cholecystitis. Forty patients with acute cholecystitis were suspected to have gallbladder cancer by macroscopic examination and specimens were taken for frozen section analysis. Six patients with gallbladder cancer were correctly identified by macroscopic examination alone but 7 patients with gallbladder cancer missed, including 3 patients with advanced cancer (2 T3 and 1 T2). Meanwhile, in 6 gallbladder cancer specimens sent for frozen section analysis, 3 early gallbladder cancers (2 Tis and 1 T1a) were missed by frozen section analysis. However, the remaining 3 patients with advanced gallbladder cancers (2 T3 and 1 T2) were correctly diagnosed.

 

CONCLUSIONS: The incidence of comorbidity of gallbladder cancer and acute cholecystitis is higher than that of non-acute cholecystitis. The accurate diagnosis of gallbladder cancer by surgeons is poor and frozen section analysis is necessary.

 

(Hepatobiliary Pancreat Dis Int 2015;14:300-304)

 

KEY WORDS: unexpected gallbladder cancer; acute cholecystitis; cholecystectomy; frozen section analysis

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with a late diagnosis and dismal prognosis. The only chance of long-term survival or potentially curative therapy for GBC is the early diagnosis and subsequently surgical resection.^[1-3] Even with the numerous diagnostic tests available, early diagnosis of GBC is still rarely achieved, and is frequently diagnosed incidentally during cholecystectomy for benign gallbladder disease as unexpected GBC.^{[4, 5]} Unexpected GBC can be asymptomatic or present with nonspecific symptoms. GBC might manifest as acute cholecystitis (AC) with fever, abdominal pain and enlarged gallbladder, due to sudden obstruction of the cystic duct with mass or concurrent gallstones.^[6-9] More than one percent of AC patients undergoing cholecystectomy have unexpected GBC, which shows a higher incidence of unexpected GBC than that in the patients undergoing elective cholecystectomy for non-AC.^[6-9] Preoperative distinguishment of GBC from AC is significant in guiding the treatment. Unfortunately, for GBC with AC presenting with atypical symptoms, computed tomography (CT) or ultrasound (US) demonstrates thickened gallbladder walls only, thus making it almost impossible to differentiate from simple AC preoperatively.^{[10, 11]}

 

During surgery, especially for the suspected cases, careful examination of the resected gallbladder mucosa and its frozen section (FS) analysis are required.^{[12, 13]} Generally, experienced surgeons usually prefer selective rather than the routine use of FS in gallbladder surgery, probably because FS analysis is time-consuming and costly. However, whether this practice is equally suitable in AC patients may be worth considering, because severe inflammation and adhesions due to AC may cause the normal structure of the gallbladder wall unrecognizable, especially in the multiple inflammations with a scarred and fibrosed gallbladder.^[14] In view of this, this retrospective study was to determine whether surgeons could effectively identify suspected gallbladder with macroscopic examination in AC patients. If not, is routine FS worth advocating?

 

 

From February 2009 to February 2014, 13?029 patients underwent elective cholecystectomy for benign gallbladder disease in our hospital. Based on the case notes and histopathology reports, 1162 AC patients and 46 GBC patients were screened. We further collected and analyzed data of AC patients with particular emphasis on concurrent GBC, including clinical characteristics, operative records, frozen section diagnosis and histopathology reports. All cholecystectomies for AC were performed by experienced surgeons using laparoscopy or laparotomy. The resected gallbladders were routinely examined by a full dissection along its longitudinal axis. GBC was suspected by five distinct circumstances: (1) The unrecognized normal structure of the gallbladder wall, that can be replaced by connective tissue in all wall layers; (2) the existence of polypoid, nodule or mass lesions; (3) severe adhesions to the surrounding tissue (liver, stomach, duodenum or colon), and/or enlarged regional lymph nodes; (4) macroscopic mucosal color change; and (5) contracted or sclerotic mucosa. Suspicious areas would be labeled by a silk suture, and frozen section examination of this site was performed. If the mucosa was macroscopically intact, the gallbladder was cut along its long axis, and frozen sections were then obtained from four locations: the cystic duct and the neck, body, and fundus of the gallbladder. Simultaneously, the direct contact between surgeons and pathologists should be well established. Ultimately, combined with FS analysis reports and opinions of patients' families, only cholecystectomy was performed for benign, Tis or T1a lesions, whereas radical surgery was performed for T1b or greater lesions.

 

AC was diagnosed according to the Tokyo Guidelines^[14] and pathology reports such as: patients presenting with fever, elevated white blood cell (WBC) count, right upper quadrant abdominal pain and characteristic CT or US findings including enlarged gallbladder, thickened gallbladder walls and/or pericholecystic fluid collection. GBCs were classified according to the Tumor Node Metastasis (TNM) system as proposed by the American Joint Committee on Cancer (AJCC). Statistical significance was determined using a two-tailed Chi-square analysis and significance was defined as P value <0.05.

 

 

Of the 1162 AC patients, 397 (34.2%) underwent laparotomy and 765 (65.8%) underwent laparoscopic cholecystectomy. Thirteen patients (9 women and 4 men) were found to have concurrent GBC, which accounted for 1.1% of the total AC patients, whereas in patients with non-AC, the incidence of unexpected GBC was 0.3%. The mean age of AC patients with GBC was 73.8 years (range 55-88). There were 11 patients with adenocarcinoma, 1 with adenosquamous carcinoma, and 1 with mucinous adenocarcinoma. TNM staging revealed 5 patients with stage Tis, 2 with stage T1a, 2 with stage T2, and 4 with stage T3 (Table 1).

 

During surgery, 40 of the 1162 AC patients were diagnosed with GBC via gross examination by the experienced surgeon, and specimens were taken for FS analysis. The most common macroscopic abnormality suggestive of malignancy was the normal structure of the gallbladder wall replaced by connective tissue in all wall layers. However, definitive histopathological examinations detected GBC in 6 patients only. In addition, 7 GBCs were missed with gross examination, and 34 were incorrectly diagnosed. In these patients, xanthogranulomatous cholecystitis (XGC) (14 cases) was the most frequently misidentified as malignancy on gross examination, followed by inflammatory cell infiltration and/or proliferation of fibrous tissue and/or reactive lymphoid hyperplasia (10 patients) (Table 2). These results indicated that the sensitivity of surgeon's macroscopic diagnosis was 46% and the specificity was 97% (Table 3).

 

FS analysis revealed GBC in 3 patients (confirmed histopathologically) and other benign disease in 37. According to the TNM classification, all three GBCs were diagnosed at advanced stages including 2 T3 (patients 1 and 6) lesions and 1 T2 (patient 4) lesion, and the depth of invasion determined by FS matched the pathological findings postoperatively. But among the 37 patients with benign lesions, 2 with Tis cancer (patients 2 and 3) and 1 with T1a cancer (patient 5) were confirmed by histopathologic examination (Table 1). No false-positive diagnosis of GBC was made in FS analysis. The sensitivity of FS diagnosis was 50% and the specificity was 100% (Table 4).

 

Among the 13 AC patients with GBC, 5 patients with Tis cancer (patients 2, 3, 9, 12 and 13) and 2 with T1a cancer (patients 5 and 8), simple cholecystectomy was performed. In the remaining 6 patients with T2 or greater cancer requiring radical surgery, immediate reoperation was performed in 3 patients (patients 1, 4 and 6); whereas patients 7 and 10 underwent reoperation 2 weeks later and patient 11 refused reoperation. Unfortunately, direct liver invasion was discovered in patient 10 (T2 lesion) at the time of reoperation, suggesting that T2 GBC has progressed to T3 lesion 2 weeks after cholecystectomy.

 

 

Early GBC does not have any specific signs and symptoms. It is possible that GBC may present with AC-like manifestations, probably due to concurrent gallstones obstruction in the cystic duct. Some studies^{[6, 8, 9]} have shown that more than 1% AC patients have concurrent GBC. Similarly, the present study also showed a high incidence (1.1%) of GBC among AC patients, which is higher than that in patients with non-AC(1.1% vs 0.3%, P<0.05), but not the rate of 2.3% documented in a previous population-based study.^[8]

 

For AC patients with GBC merely presenting with pain, fever and CT or US demonstration of thickened gallbladder walls, it is impossible to differentiate from simple AC preoperatively. In order to find unexpected GBC, the most appropriate way seems to be macroscopic examination of the gallbladder mucosa intraoperatively and to perform FS analysis of the suspected lesions. This process is more often used selectively, rather than routinely. But which gallbladder needs FS analysis? Kijima et al^[15] stated that surgeons can identify 85% of cases of early GBC using macroscopic examination alone, and subsequent studies by Aoki et al^[12] and Akyürek et al^[16] also suggested that a high rate of macroscopic diagnosis of early GBC is possible. In contrast, our study showed that the sensitivity of surgeon's macroscopic diagnosis was only 46% and the specificity was 97%. Surgeons using macroscopic examination alone correctly identified 6 GBC patients but recognized 34 false-negative specimens as malignant. Of them, XGC was most commonly misidentified as malignancy on gross examination. In addition, 7 GBCs were missed in this process. Three of the 7 missed tumors, including two T3 lesions and one T2 lesion, had to undergo immediate radical surgery if the patient's medical condition permitted. Unfortunately, 2 of them underwent radical reoperation 2 weeks later (1 patient refused reoperation), increasing patient suffering and medical expenses. In addition, direct liver invasion was discovered in one patient (patient 10) during the radical reoperation. The above results indicated that in acute inflammation the normal structure of the gallbladder wall is frequently replaced by diffuse inflammatory and/or connective tissue, and is easily obscure the diagnosis of GBC. Therefore, distinguishing early GBC from AC via macroscopic examination alone by surgeons is difficult and unreliable.

 

During intraoperative evaluation, gallbladder wall replaced by connective tissue in all the layers is the most common macroscopic abnormality suggestive of malignancy, followed by polypoid, nodule or other mass lesions. When these macroscopic abnormalities are found, FS analysis should be obtained. Reports on the efficacy of FS analysis are very rare. Our study suggested that the sensitivity of FS diagnosis was 50% and the specificity was 100%. In 3 patients with regenerative epithelial severe atypia diagnosed by FS, definitive pathological diagnosis showed 2 patients with carcinoma in situ and 1 with T1a lesion, which suggested the limits of FS analysis in diagnosis of early GBC especially carcinoma in situ may be due to difficulty in distinguishing carcinoma in situ from regenerative epithelial severe atypia histologically.^[17] But the clinical management and outcome of the patients was not compromised because early GBC can receive the appropriate treatment by cholecystectomy alone.^[18-20] The remaining 3 patients were diagnosed with T2 or T3 lesions pathologically since FS results was consistent with pathological results. We believed that immediate radical surgery is appropriate for these 3 patients based on the FS analysis. These results showed that the rate of successful diagnosis by FS analysis was satisfactory for advanced GBC.

 

From the above results, we conclude that in AC patients, the macroscopic abnormalities recognized by surgeons may not be used for determining gallbladders suspected of malignancy, and even some nonspecific macroscopic changes may harbor malignancy. And there was no relationship between types of abnormalities and the stages of GBC. Surgeons are not able to accurately determine whether the gallbladder in AC patients is appropriate for FS analysis via macroscopic examination alone. Of course, the sensitivity of FS diagnosis was only 50%, but it must be noted that the decreased sensitivity was mainly due to the limits of FS analysis in early GBC, and the ability of FS analysis to correctly diagnose T3 GBC is high. Fortunately, these early GBCs can be successfully treated by simple cholecystectomy only. In view of this, we therefore advocate routine FS analysis of every cholecystectomy specimen in AC. In this era of cost containment, more "cost-effectiveness" use of laboratory tests have been widely accepted and routine FS analysis in cholecystectomy for AC seems to challenge such value. But we should always keep in mind that the sole purpose of FS analysis of the gallbladder in cholecystectomy is to identify occult carcinoma.

 

To prevent stone and bile spillage and to decrease the risk of port site and peritoneal seeding with unexpected GBC in laparoscopic cholecystectomy,^{[21, 22]} specimen retrieval bag has been routinely used in our hepatobiliary surgery unit. No case of port site/wound recurrence occurred in 46 unexpected GBC patients over the past five years. Considering that some nonspecific macroscopic changes in the gallbladder may harbor malignancy even including advanced GBC in laparoscopic cholecystectomy for AC patients, we propose a reasonable algorithm to recommend the routine use of the retrieval bag for all gallbladders. The use of the retrieval bag to avoid port site seeding has not been proven beneficial,^[23] but at least it is harmless and not "wasteful" (the retrieval bag could be made by surgical gloves).

 

In summary, the incidence of unexpected GBC in AC patients is higher than that in non-AC patients. Concurrent AC is easier to obscure the diagnosis of GBC. In cholecystectomy for AC patients, the surgeon's macroscopic diagnosis of unexpected GBC is poor, and macroscopic abnormalities recognized by surgeons alone cannot be used to determine whether the gallbladder is appropriate for FS analysis. Despite the limits of FS analysis in the diagnosis of early GBC, the ability to correctly diagnose advanced GBC is high. Therefore, we advocate routine FS analysis of every cholecystectomy specimen in AC. However, a precise pre-operative diagnostic evaluation is essential before operation.

 

 

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