Selective histopathology in cholecystectomy for gallstone disease

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1 ORIGINAL ARTICLE Selective histopathology in cholecystectomy for gallstone disease Rohin Mittal Mark Ranjan Jesudason Sukria Nayak Abstract Background Incidental gallbladder cancer is found in upto 1% of cholecystectomy specimens for gallstone disease. Currently, in our institution, all gallbladder specimens are sent for routine histopathology, to rule out incidental gallbladder carcinoma. This study was aimed at assessing the need for routine histopathology of gallbladder specimens after cholecystectomy for gallstone disease. Methods Hospital records of all patients undergoing cholecystectomy for gallstone disease over a ten-year period, between 1998 and 2007, in a single surgical unit were reviewed. Results A total of 1312 patients underwent cholecystectomy for gallstone disease. Gallbladder carcinoma was detected in 13 patients. Macroscopic abnormalities of the gallbladder were found in all the 13 patients. In patients with a macroscopically normal gallbladder, there were no cases of gallbladder carcinoma. Conclusion Gallbladder carcinoma is associated with macroscopic abnormalities in all cases. Therefore histopathology should be restricted to only those specimens which reveal a macroscopic abnormality. This would identify all cases of incidental gallbladder carcinoma, at the same time decreasing cost and pathological work load. See Editorial on page 9 R. Mittal M. R. Jesudason S. Nayak Department of Surgery Unit 5, Christian Medical College and Hospital, Vellore Tamil Nadu , India Dr. Rohin Mittal ( ) rohinmittal@gmail.com Received: 12 June 2009 / Revised: 28 August 2009 / Accepted: 11 October 2009 Indian Society of Gastroenterology 2010 Keywords pathology Introduction Incidental gallbladder cancer routine surgical Gallstone disease affects 10-15% of the western population, 1,2 with an annual incidence of 1 in Indian studies have revealed a prevalence of 6.12%, 3 being more common in women (9.6%) than men (3.1%). 3 However, only 1-4% become symptomatic every year, 1,2 needing further treatment. Laparoscopic cholecystectomy is the current gold standard for treatment of symptomatic gallstone disease. Incidental gallbladder carcinoma is found in about % of cholecystectomies for gallstone disease. 4-8 On the other hand gallstones are found in 74-92% of patients with gallbladder carcinoma. 5,7 It is standard practice to submit all gallbladders removed for gallstone disease for routine histopathology, to exclude gallbladder malignancy. The Royal College of Pathologists in their report titled Histopathology and cytopathology of limited or no clinical value recommended that all gallbladder specimens should be examined, as significant pathology may be present with normal gross morphology. 9 It has, however, been argued that all patients with incidental gallbladder malignancy have suspicious features on pre-operative imaging or intra-operative findings A policy of routine histopathology of all gallbladders removed for gallstone disease may therefore not be necessary. A more selective approach may be able to identify all patients with incidental gallbladder malignancy, at the same time decreasing pathological work load and costs. The aim of this study was to assess the need for routine histopathology in cholecystectomy for gallstone disease. Methods A retrospective review of all patients undergoing cholecystectomy for gallstone disease, over a ten-year period, 1 Springer

2 Selective histopathology in cholecystectomy 33 between 1998 and 2007, in a single surgical unit, was conducted. The hospital records of these patients were reviewed and data on pre-operative imaging (ultrasound or CT scans), intraoperative findings, macroscopic appearance of the specimen and histopathology reports were collected. Details on macroscopic abnormalities were collected from operative notes (surgeon s impression of thickened gallbladder and other gross abnormalities) as well as from gross histopathology reports, after formalin fixation. All gallbladder specimens had been examined for macroscopic abnormalities after cutting open the specimen. The gallbladder wall was considered thickened if the surgeon reported a thickened gallbladder or if the wall thickness was 3 mm or more on the ultrasound or histopathology report. Wall thickness of 1-2 mm was taken as normal. 11 The AJCC TNM system was used as reference for staging of carcinoma gallbladder. Results One thousand three hundred and twelve patients (749 [57.4%] women) underwent cholecystectomy for gallstone disease during the study period. The records of 7 patients were found to be incomplete and these were excluded from analysis. Their mean age was 45.3 years (range years). All 1305 specimens had been sent for histopathological examination. Chronic calculus cholecystitis was seen in 1010, cholesterosis in 153, xanthogranulomatous cholecystitis in 42, acute cholecystitis in 48 and metaplasia/adenoma in 10. Dysplasia was found in 1 patient and 28 had other miscellaneous diagnosis (Table 1). Gallbladder carcinoma was detected in 13 patients. Table 1 Histology in gallstone disease Diagnosis Number Chronic calculus cholecystitis 1010 (77.4%) Cholesterosis 153 (11.7%) Xanthogranulomatous cholecystitis 42 (3.2%) Acute cholecystitis 48 (3.7%) Metaplasia / Adenoma 10 (0.8%) Dysplasia 1 (0.08%) Carcinoma 13 (1%) Miscellaneous 28 (2.2%) One hundred and six (8.1%) patients were found to have a thickened gallbladder on preoperative ultrasound screening. Six hundred and ten (46.7%) of all patients were detected to have macroscopic abnormalities on gross examination of the gallbladder specimen. This included thickening, mucosal ulceration and polypoidal lesions. Of the 13 cases of gallbladder carcinoma 2 were male and 11 females. The mean age of diagnosis was 56.2 years (range years). Eight of these patients underwent laparoscopic cholecystectomy with 2 being converted to open, and 5 underwent open cholecystectomy. Conversions were due to presence of dense adhesions and inability to define Callot s triangle anatomy. A thickened gallbladder was detected on pre-operative ultrasound in 4 (30.8%) of these patients. Macroscopic abnormalities were found in all 13 patients with gallbladder carcinoma (Table 2). Nine (69.2%) patients had a thickened gallbladder, 2 (15.4%) had mucosal ulcerations and 2 (15.4%) had nodularity of the mucosa with polypoid projections. One patient was found to have carcinoma in situ, 9 patients had T2 lesions and 3 had T3 lesions. Table 2 Details of patients with a histopathological diagnosis of gall bladder carcinoma No. Age / Sex GB ultrasound* Surgery Macroscopic appearance* Pathology TNM Stage F Thick wall (4 mm) Laparoscopic Thickened GB (5 mm) Moderately differentiated T M Normal (2.6 mm) Open Thickened GB (3.6 mm) Poorly differentiated T F Normal (1.7 mm) Laparoscopic Polypoid projections (3 mm) Moderately differentiated T F Normal Laparoscopic Thickened GB (4 mm) Well differentiated T M Thick wall (5 mm) Open Thickened GB (6 mm) Moderately differentiated T F Thick wall (3.7 mm) Open Thickened GB (6 mm) Moderately differentiated T F Normal Laparoscopic Mucosal ulcer Moderately differentiated T F Normal Laparoscopic Nodular mucosa Moderately differentiated T F Normal Laparoscopic Mucosal ulcer Carcinoma in situ CIS converted to open F Normal Open Thickened GB (6 mm) Moderately differentiated T F Thick wall (6 mm) Laparoscopic Thickened GB (20 mm) Moderately differentiated T3 converted to open F Normal Open Thickened GB (5 mm) Well differentiated T F Normal Laparoscopic Thickened GB (4 mm) Well differentiated T2 GB: gallbladder *Values in parenthesis indicate wall thickness 1 Springer

3 34 Mittal, et al. There were no cases of carcinoma gallbladder in specimens which were normal on macroscopic examination. Discussion Carcinoma of the gallbladder is the most common malignancy of the extra hepatic biliary tree. 14 It usually presents at an advanced stage and carries a dismal prognosis. Treatment of gallbladder carcinoma is dependent on the stage of the disease. Simple cholecystectomy is considered adequate for Tis and T1a tumors. 6,7,15,16 Treatment of T1b tumors is controversial with advocates for both simple cholecystectomy 17,18 and more radical resection. 6,7,15,16 T2 tumors are treated with radical cholecystectomy, 6,7,16 More advanced tumors may be treated with radical resection if an R0 resection can be achieved or by palliation alone. 16 Adjuvant therapy has not found to be useful, and does not influence survival. 16,19 In cholecystectomy for gallstone disease, the current practice is to send all specimens for routine histopathology. The rationale behind this approach is that incidental gallbladder carcinoma is found in about % of these patients, 4-8 which is not detected on preoperative workup or intra-operatively. Also early stage gallbladder carcinoma may be difficult to distinguish from chronic cholecystitis, as they both present as a thickened gallbladder. 20 In our series of 1305 patients, incidental gallbladder malignancy was found in 13 patients. In all these 13 patients, there was macroscopic evidence of disease in the form of thickening, nodularity, papillary projections and ulceration. There were no cases of gallbladder carcinoma in patients who had a macroscopically normal gallbladder. Though the Royal College of Pathologists recommends routine histopathological examination of all gallbladder specimens ( as significant pathology may be present with normal gross morphology ), 9 they quote only one paper to the contrary. However, now there is an increasing body of literature to the contrary Dix et al 12 found gallbladder malignancy in 5 out of 1308 patients (0.38%). All of these cases had a demonstrable macroscopic abnormality on gross examination. Three of these also had suspicious ultrasound features. The authors concluded that a more selective approach to histopathology of the gallbladder would be more evidence based. Bazoua et al 11 found 5 cases of gallbladder malignancy in 2890 consecutive cases (0.17%). Again all of these patients had visible macroscopic abnormal findings in the gallbladder. Darmas et al 10 have also concluded that a more selective policy to gallbladder histology would not miss any malignancy, but would be cost effective and reduce work load of the pathologist. A similar approach has been advocated by Taylor et al. 13 A review of the pathology of gallbladder malignancy reveals that gross descriptions of gallbladder cancer can be grouped into infiltrative, papillary, nodular and combined forms. 21,22 Infiltrative forms present with gallbladder wall thickening, papillary forms with polypoidal lesions with frond like projections and nodular forms present with more circumscribed masses. 20,22 Most tumors however, have an infiltrative pattern as at least a part of their presentation, causing thickening and induration of the gallbladder wall. 21 Thus by excluding macroscopically normal specimens we limit histopathology only to specimens likely to contribute to the clinical management of the patient. Concern has been raised about the presence of dysplasia and early mucosal gallbladder carcinoma in macroscopically normal gallbladders. In these cases, however a simple cholecystectomy is considered curative 6,7,15,16 and more radical resections do not improve survival. Hence this group of patients would have received appropriate treatment by a simple cholecystectomy, and do not require further intervention. Xanthogranulomatous cholecystitis and Mirrizi syndrome have been shown to have an increased association with carcinoma of the gallbladder. Rao et al 23 have reported a 6% association between xanthogranulomatous cholecystitis and gallbladder cancer whereas Kwon et al 24 have reported a 10% association. In people with Mirrizi syndrome, association with gallbladder cancer has been reported to be 5.3% by Prasad et al. 25 Histopathological examination should be done in these specimens where there are intra-operative or gross examination findings to suggest these diagnosis. The incidence of gallbladder cancer is reported to be higher in certain geographic areas, like the Karachi to Kolkata belt in the Indian subcontinent The use of selective histopathology in these areas needs further study. The patients in our group were dispersed over a wide geographic area, thus precluding such an analysis. There has been a significant increase in the pathological workload in recent times. Studies have shown that up to 25-40% of all laboratory tests may be unnecessary 29 and that in the absence of macroscopic abnormalities, routine histological examinations of certain specimens may be omitted. 29 Routine histopathology tends to be expensive and adds on to the pathological workload. 29 The average cost of processing one gallbladder specimen in our institute is INR 600 (approximately 12 USD; 1 USD = INR 50) and the average pathologist time spent per specimen is 15 minutes. Six hundred and ninety-five (53.3%) of our patients had macroscopically normal gallbladders. Thus by selective histopathology, there would have been a saving of INR 417,000 (USD 8340) during the study period. Also selective histopathology would have reduced pathological work load and resulted in saving of pathologist working hours. 1 Springer

4 Selective histopathology in cholecystectomy 35 Table 3 Macroscopic abnormalities associated with gallbladder malignancy Gallbladder wall thickening (3 mm or more) Mucosal ulceration Polypoidal lesions Nodularity of the mucosa All our 13 cases had sonological or macroscopic evidence to suspect malignancy. If selective histopathology was used, the estimated cost of diagnosing one carcinoma gallbladder would have been INR 28,154, which is less than half of the present cost incurred (INR 60,231). The major limitation of our study was its retrospective nature. Further prospective studies may be more appropriate to conclusively recommend the use of selective histopathology in cholecystectomy for gallstone disease. Conclusions In all cases of cholecystectomy for gallstone disease, the gallbladder should be opened and examined in detail for macroscopic abnormalities. Histopathology may be selectively recommended for those specimens with visible macroscopic abnormalities (Table 3) or pre-operative suspicion of malignancy. Such a selective policy will result in reduction of cost and pathological workload; at the same time not compromise patient management. Acknowledgement The authors thank the Department of Pathology, for their help with the study. References 1. Gallstones and Laparoscopic Cholecystectomy, NIH Consens Statement Online 1992 Sep [cited 2009 /08 /28];10(3): Halldestam I, Enell EL, Kullman E, Borch K. Development of symptoms and complications in individuals with asymptomatic gallstones. Br J Surg 2004;91: Khuroo MS, Mahajan R, Zargar SA, Javid G, Sapru S. Prevalence of biliary tract disease in India: a sonographic study in adult population in Kashmir. Gut 1989;30: Yamamoto H, Hayakawa N, Kitagawa Y, et al. Unsuspected gallbladder carcinoma after laparoscopic cholecystectomy. J Hepatobiliary Pancreat Surg 2005;12: Tantia O, Jain M, Khanna S, Sen B. Incidental carcinoma gallbladder during laparoscopic cholecystectomy for symptomatic gallstone disease. Surg Endosc 2009;23: Shimizu T, Arima Y, Yokomuro S, et al. Incidental gallbladder cancer diagnosed during and after laparoscopic cholecystectomy. J Nippon Med Sch 2006;73: Kraas E, Frauenschuh D, Farke S. Intraoperative suspicion of gallbladder carcinoma in laparoscopic surgery: what to do? Dig Surg 2002;19: Samad A. Gallbladder carcinoma in patients undergoing cholecystectomy for cholelithiasis. J Pak Med Assoc 2005;55: Royal College of Pathologists. Histopathology and cytopathology of limited or no clinical value. Report of working group of The Royal College of Pathologists, 2nd edition London:Royal College of Pathologists, Darmas B, Mahmud S, Abbas A, Baker AL. Is there any justification for the routine histological examination of straightforward cholecystectomy specimens? Ann R Coll Surg Engl 2007;89: Bazoua G, Hamza N, Lazim T. Do we need histology for a normal-looking gallbladder? J Hepatobiliary Pancreat Surg 2007;14: Dix FP, Bruce IA, Krypcyzk A, Ravi S. A selective approach to histopathology of the gallbladder is justifiable. Surgeon 2003;1: Taylor HW, Huang JK. Routine pathological examination of the gallbladder is a futile exercise. Br J Surg 1998;85: Berger D MR. Carcinoma of the Gallbladder. In: The Oxford Textbook of Surgery. Oxford University Press 1994: p You DD, Lee HG, Paik KY, Heo JS, Choi SH, Choi DW. What is an adequate extent of resection for T1 gallbladder cancers? Ann Surg 2008;247: Lai CH, Lau WY. Gallbladder cancer - a comprehensive review. Surgeon 2008;6: Wakai T, Shirai Y, Hatakeyama K. Radical second resection provides survival benefit for patients with T2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy. World J Surg 2002;26: Toyonaga T, Chijiiwa K, Nakano K, et al. Completion radical surgery after cholecystectomy for accidentally undiagnosed gallbladder carcinoma. World J Surg 2003;27: Itoh H, Nishijima K, Kurosaka Y, et al. Magnitude of combination therapy of radical resection and external beam radiotherapy for patients with carcinomas of the extrahepatic bile duct and gallbladder. Dig Dis Sci 2005;50: D Angelica M, Jarnagin WR. Tumors of the Gallbladder. In: Blumgart LH (ed) Surgery of the Liver, Biliary Tract, and Pancreas. Fourth Edition. Philadelphia, Saunders 2007; p Sumiyoshi K, Nagai E, Chijiiwa K, Nakayama F. Pathology of carcinoma of the gallbladder. World J Surg 1991;15: Crawford JM. The Liver and the Biliary Tract. In: Cotran RS, Kumar V, Collins T (ed) Pathological basis of disease. Sixth edition; Philadelphia, Saunders 1999; p Rao RV, Kumar A, Sikora SS, Saxena R, Kapoor VK. Xanthogranulomatous cholecystitis: differentiation from associated gallbladder carcinoma. Trop Gastroenterol 2005;26: Kwon AH, Sakaida N. Simultaneous presence of xanthogranulomatous cholecystitis and gallbladder cancer. J Gastroenterol 2007;42: Prasad TL, Kumar A, Sikora SS, Saxena R, Kapoor VK. Mirizzi syndrome and gallbladder cancer. J Hepatobiliary Pancreat Surg 2006;13: Springer

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