Annals of the Royal College of Surgeons of England (1992) vol. 74, 222-224
Primary carcinoma of the gallbladder: a 10-year experience John A Paraskevopoulos MD FRCS
Bryan Ross MD FRCR
Surgical Registrar
Consultant Radiologist
Ashley R Dennison MD FRCS
Alan G Johnson MChir FRCS
Senior Surgical Registrar
Professor of Surgery
University Department of Surgery, Royal Hallamshire Hospital, Sheffield Key words: Gallbladder carcinoma; Gallstones
New developments in the management of galistone disease, and particularly percutaneous and extracorporeal treatments that leave the mucosa intact, have renewed interest in the relationship between cholelithiasis and carcinoma. These treatments are both available in our hospital and to examine this question we studied the patients presenting between 1980 and 1990 with gallbladder cancer. The study comprised 21 patients with histologically proven carcinoma. The M:F ratio was 1:4 with a mean age of 76 years. Galistones were present in 18 patients (85.7%). Ten patients remain alive today and in the 11 who died the median survival was 4 months. A preoperative diagnosis was made by ultrasound in only two patients. The lack of a preoperative diagnosis in the majority of patients is clearly a cause for concern and while our figures, like other series, do not establish a causal relationship with gallbladder carcinoma, it is vital to be diligent in the follow-up of high-risk patients (stones > 3 cm) with intact gallbladder mucosa after the treatment of stone disease.
Primary carcinoma of the gallbladder is the most common malignancy of the biliary tract (1), being found in approximately 1% of cholecystectomy operations in the United Kingdom (2). The disease has a poor prognosis mainly due to its non-specific clinical symptoms and a presentation which is almost invariably similar to gallstone disease. This generally produces a considerable delay before the definitive diagnosis becomes apparent, with a consequent worsening of the prognosis. Furthermore, although a wide range of investigations has been used in an attempt to identify these lesions at a treatable stage, none has yet emerged which is likely to be useful on a routine basis. Correspondence to: John A Paraskevopoulos MD FRCS, University Department of Surgery, Floor K, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF
These problems assume greater importance when an institution has free access to methods of gallstone treatment which leave the gallbladder mucosa intact, particularly after prolonged exposure to stones. Both extracorporeal shock wave lithotripsy (ESWL) and percutaneous gallstone extraction (PGSE) are used in our hospital and this served as the stimulus for this study. We hoped by reviewing our cases of gallbladder cancer to ascertain whether it was possible to develop a management policy which incorporated these new techniques but allowed a diligent approach to the detection and treatment of early gallbladder carcinoma in high-risk patients (stones > 3 cm).
Patients and methods All patients operated on at the Royal Hallamshire Hospital between 1980 and 1990 and found to have carcinoma of the gallbladder are included. Data was obtained from the hospital's diagnostic index, pathology laboratory reports, theatre records and hospital discharge reports. Patients' notes were then reviewed to establish details of presentation, preoperative assessment, provisional diagnosis and follow-up.
Results Between January 1980 and January 1990, 3197 patients had routine cholecystectomies. Among these, 21 were found to have carcinoma of the gallbladder at operation. The mean age was 76 years. A correct preoperative diagnosis was made in only two patients, despite the fact that all but one had ultrasound examination (which
Pnimaty carcinoma of the gallbladder Table I. Clinical features of gallbladder carcinoma at the Royal Hallamshire Hospital: 1980-1990 1. 2. 3.
4.
5.
6. 7. 8. 9. 10.
11.
12. 13.
No. 21 M:F ratio, 1:4 Duration of presenting symptoms (weeks) Median, 11 Range, 0.5-1040 Age (years) Mean, 75.9 Range, 49-90 Presenting symptoms and signs RUQ pain, 15 Jaundice, 6 Weight loss, 5 Vomiting, 5 Acute cholecystitis, 4 Palpable gallbladder, 3 Acute pancreatitis, 2 Previous biliary surgery, 0 Preoperative ultrasound performed, 20 Preoperative diagnosis of gallstones, 18 (85.7%) Correct preoperative diagnosis, 2 Operative treatment Cholecystectomy, 13 Cholecystectomy + bypass procedure, 2 Cholecystectomy + hepatic resection, 2 Bypass procedure, 1 Biopsy, 3 Follow-up (months) Alive (n = 10) Median, 9 Range, 1-108 Survival (months) Died (n = 11) Median, 4 Range, 0-56 Cause of death Myocardial infarction, 2 Carcinomatosis, 9
revealed gallstones in 18). No patient had previous
biliary surgery. The clinical features, surgical procedures performed and ultimate outcome are reviewed in detail in Table I. Gallbladder carcinoma was much more common in women (17) than men (4) with a ratio of over 4: 1, the same as gallstone disease in our hospital. Presenting symptoms were invariably those that would be consistent with benign biliary disease (with a mean duration of 11 weeks). There was no correlation between age and duration of symptoms (r = 0.179). The ultrasound appearances correlated with the findings at surgery rather than the subsequent histopathology and fall broadly into three groups. In the first group where the ultrasound findings were abnormal in respect of the gallbladder, carcinoma was only suggested by the radiologist on two occasions and in both these patients tumour was obvious at operation. In the remainder of this group (four patients where carcinoma was not mentioned in the definitive report) features such as a thickened wall or frankly very abnormal appearances
223
were noted and were present on review; the usual comment in these cases was that appearances were
compatible with cholecystitis (probably in view of the ubiquitous gallstone(s) identified in all patients). In one patient the radiologist commented on the lack of tenderness over the abnormal gallbladder yet labelled it cholecystitis, carcinoma being found at laparotomy. Also in this group must be included two cases in which a solid solitary tumour of the liver was identified on ultrasound contiguous to the gallbladder. Carcinoma was confirmed by biopsy or laparotomy although the gallbladder looked relatively normal. The second group (six patients) were those presenting with obstructive jaundice. In all these patients the fact of and site of the obstruction was correctly identified as was the presence of the gallstones. Thereafter, the investigation centred on delineating details about the site. In all these cases the only surgical option was palliation. The third group (17 patients) were in situ tumours where the radiologist reported no more than gallbladder wall thickening plus stones, a very common finding in biliary ultrasound. There were no discernible features which would suggest the diagnosis of carcinoma, and indeed in none of these cases was the diagnosis even suggested at surgery (only at subsequent histopathology examination). This group was the only one in which long-term survival was seen. Cholecystectomy was performed in 13 of the patients as the only surgical treatment. Ten patients are still alive but the median survival (in the 11 who died) was only 4 months (Table I).
Discussion Primary carcinoma of the gallbladder is the most common malignancy of the biliary tract, yet despite the tremendous advances in diagnostic methods (particularly ultrasonography, computed tomography and endoscopic retrograde cholangiopancreatography) the prognosis remains dismal. Results in our series are in accord with others where a F: M ratio of 4.5 to 5.1 has been reported (3-5) and where a clinical picture of gallbladder disease is usual. Correct preoperative diagnosis is also the exception rather than the rule in these series and ultrasound (the most commonly used diagnostic method) which is often used alone, has a very low diagnostic rate (3-5). While invasive diagnostic techniques such as coeliac or selective hepatic angiography will improve the rate of diagnosis (6), these can only be employed when a more routine method of investigation has questioned the diagnosis. In our patients there was an 85.7% incidence of gallstones consistent with but towards the upper end of other reported series (45-100%) (7). Simple cholecystectomy was the most commonly performed operative procedure, either because it was all that was possible or because even at operation the diagnosis of malignancy was not entertained. While this undoubtedly contributed to the dismal survival in our series (only one
224
J A Paraskevopoulos et al.
patient survived 5 years), it is nevertheless in keeping with other series, emphasising the diagnostic difficulties in these patients (8). Furthermore, the finding of an improved survival in patients with localised disease and short histories (9), suggests that the situation will only improve significantly when a diagnosis can be reached earlier. It is worth noting in respect of the ultrasound findings that all the cases in this series occurred over a 10-year period which saw a remarkable development in ultrasound equipment and its use. The equipment used in diagnosis ranged from grey scale B-scope to the latest realtime imaging equipment, and was accompanied by a concomitant increase in the experience of the operators. It is also now standard practice in our hospital for radiologists to scan the whole abdomen whatever the organ of interest originally indicated by the clinician, which will result in an increase of the 'incidental' finding of gallstones. While the latest equipment has the best chance of making an early diagnosis of gallbladder carcinoma, this study suggests that the findings of such patients may not only be difficult but at the expense of a gross overdiagnosis, which may not be in the patients' best interests, since many asymptomatic gallstones are discovered as a result of routine scanning. For the sonographer to make the diagnosis (differential) it would be necessary to bring to the attention of the referring clinician the possibility of in situ carcinoma in every case of gallstones where the wall shows any thickening. The surgical yield will be small but this approach would appear to be the only one to alter the outlook in a lethal condition significantly. The challenge is to be able to treat all cases of gallstones (with the ever-increasing number of methods available) leaving no patients with undiagnosed malignancy or with a significantly increased risk of developing it. Reviewing our hospital series and the world literature we suggest the following treatment policies: 1 Symptomatic patients with large stones (>3 cm) who, after treatment, have an intact gallbladder mucosa need regular follow-up. 2 In patients over 65 years of age, a preoperative diagnosis of 'a thickened gallbladder wall' when large stones are present should be treated with suspicion and intra-operative frozen sections may be necessary to determine the most appropriate procedure. 3 If stones recur after minimal invasive methods that leave the mucosa intact (percutaneous stone extrac-
tion and ESWL), then the gallbladder should be removed, especially in young patients. Carcinoma of the gallbladder is fortunately a very rare condition as there do not appear to be any significant ultrasonic signs to differentiate it from the wide spectrum of appearances associated with gallstones (infection, xanthogranulomatous cholecystitis, etc). To place undue emphasis on the possibility of curable in situ carcinoma would appear meddlesome, yet not to do so risks failing to find such cases. However, our series and others in the literature must awaken interest in the relationship between gallstones and the development of gallbladder carcinoma. The development of carcinomas requires a promoting and an initiating influence, and in the case of the gallbladder by damaging the mucosa it seems likely that a predisposed epithelium remains. Whether removal of the gallstones removes the initiating factor remains to be seen, but until more detailed experimental studies establish this, patients will need close follow-up; this is likely to be even more relevant with techniques such as ESWL where the technique itself produces unknown long-term effects. These fears may well ultimately lead to an increased employment of techniques that are able to remove gallstones and ablate the gallbladder mucosa simultaneously.
References I Adson MA. Carcinoma of the gallbladder. Surg Clin North Am 1973;53: 1203-16. 2 Muir IM, Morris DL. Carcinoma of the gallbladder. Br Hosp Med 1986;36:278-80. 3 Ohlsson EG, Aronsen KF. Carcinoma of the gallbladder; a study of 181 cases. Acta Chir Scand 1974;140:475-80. 4 Richard PF, Cantin J. Primary carcinoma of the gallbladder; a study of 108 cases. CanJ_ Surg 1976;19:27-32. S Carmo M, Perpetuo MO, Valdivieso M et al. Natural history of gallbladder cancer. Cancer 1978;42:330-35. 6 Tashiro S, Konno T, Mochinaga M et al. Primary carcinoma of the gallbladder; a review of 67 cases. Kumamoto Med J 1981;34: 1-12. 7 Paraskevopoulos JA, Dennison AR, Johnson AG. Primary carcinoma of the gallbladder. HPB Surgery 1991;4:277-89. 8 Tarpila E, Borch K, Kullman E, Liedberg G. Gallbladder cancer; current status in clinical practice. Eur Jr Surg Oncol
1988;14: 51-4. 9 Hart J, Modan B. Factors affecting survival of patients with
gallbladder neoplasms. Arch Intern Med 1972;129:931-4. Received 18 October 1991
Primary carcinoma of the gallbladder: a 10-year experience John A Paraskevopoulos MD FRCS
Bryan Ross MD FRCR
Surgical Registrar
Consultant Radiologist
Ashley R Dennison MD FRCS
Alan G Johnson MChir FRCS
Senior Surgical Registrar
Professor of Surgery
University Department of Surgery, Royal Hallamshire Hospital, Sheffield Key words: Gallbladder carcinoma; Gallstones
New developments in the management of galistone disease, and particularly percutaneous and extracorporeal treatments that leave the mucosa intact, have renewed interest in the relationship between cholelithiasis and carcinoma. These treatments are both available in our hospital and to examine this question we studied the patients presenting between 1980 and 1990 with gallbladder cancer. The study comprised 21 patients with histologically proven carcinoma. The M:F ratio was 1:4 with a mean age of 76 years. Galistones were present in 18 patients (85.7%). Ten patients remain alive today and in the 11 who died the median survival was 4 months. A preoperative diagnosis was made by ultrasound in only two patients. The lack of a preoperative diagnosis in the majority of patients is clearly a cause for concern and while our figures, like other series, do not establish a causal relationship with gallbladder carcinoma, it is vital to be diligent in the follow-up of high-risk patients (stones > 3 cm) with intact gallbladder mucosa after the treatment of stone disease.
Primary carcinoma of the gallbladder is the most common malignancy of the biliary tract (1), being found in approximately 1% of cholecystectomy operations in the United Kingdom (2). The disease has a poor prognosis mainly due to its non-specific clinical symptoms and a presentation which is almost invariably similar to gallstone disease. This generally produces a considerable delay before the definitive diagnosis becomes apparent, with a consequent worsening of the prognosis. Furthermore, although a wide range of investigations has been used in an attempt to identify these lesions at a treatable stage, none has yet emerged which is likely to be useful on a routine basis. Correspondence to: John A Paraskevopoulos MD FRCS, University Department of Surgery, Floor K, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF
These problems assume greater importance when an institution has free access to methods of gallstone treatment which leave the gallbladder mucosa intact, particularly after prolonged exposure to stones. Both extracorporeal shock wave lithotripsy (ESWL) and percutaneous gallstone extraction (PGSE) are used in our hospital and this served as the stimulus for this study. We hoped by reviewing our cases of gallbladder cancer to ascertain whether it was possible to develop a management policy which incorporated these new techniques but allowed a diligent approach to the detection and treatment of early gallbladder carcinoma in high-risk patients (stones > 3 cm).
Patients and methods All patients operated on at the Royal Hallamshire Hospital between 1980 and 1990 and found to have carcinoma of the gallbladder are included. Data was obtained from the hospital's diagnostic index, pathology laboratory reports, theatre records and hospital discharge reports. Patients' notes were then reviewed to establish details of presentation, preoperative assessment, provisional diagnosis and follow-up.
Results Between January 1980 and January 1990, 3197 patients had routine cholecystectomies. Among these, 21 were found to have carcinoma of the gallbladder at operation. The mean age was 76 years. A correct preoperative diagnosis was made in only two patients, despite the fact that all but one had ultrasound examination (which
Pnimaty carcinoma of the gallbladder Table I. Clinical features of gallbladder carcinoma at the Royal Hallamshire Hospital: 1980-1990 1. 2. 3.
4.
5.
6. 7. 8. 9. 10.
11.
12. 13.
No. 21 M:F ratio, 1:4 Duration of presenting symptoms (weeks) Median, 11 Range, 0.5-1040 Age (years) Mean, 75.9 Range, 49-90 Presenting symptoms and signs RUQ pain, 15 Jaundice, 6 Weight loss, 5 Vomiting, 5 Acute cholecystitis, 4 Palpable gallbladder, 3 Acute pancreatitis, 2 Previous biliary surgery, 0 Preoperative ultrasound performed, 20 Preoperative diagnosis of gallstones, 18 (85.7%) Correct preoperative diagnosis, 2 Operative treatment Cholecystectomy, 13 Cholecystectomy + bypass procedure, 2 Cholecystectomy + hepatic resection, 2 Bypass procedure, 1 Biopsy, 3 Follow-up (months) Alive (n = 10) Median, 9 Range, 1-108 Survival (months) Died (n = 11) Median, 4 Range, 0-56 Cause of death Myocardial infarction, 2 Carcinomatosis, 9
revealed gallstones in 18). No patient had previous
biliary surgery. The clinical features, surgical procedures performed and ultimate outcome are reviewed in detail in Table I. Gallbladder carcinoma was much more common in women (17) than men (4) with a ratio of over 4: 1, the same as gallstone disease in our hospital. Presenting symptoms were invariably those that would be consistent with benign biliary disease (with a mean duration of 11 weeks). There was no correlation between age and duration of symptoms (r = 0.179). The ultrasound appearances correlated with the findings at surgery rather than the subsequent histopathology and fall broadly into three groups. In the first group where the ultrasound findings were abnormal in respect of the gallbladder, carcinoma was only suggested by the radiologist on two occasions and in both these patients tumour was obvious at operation. In the remainder of this group (four patients where carcinoma was not mentioned in the definitive report) features such as a thickened wall or frankly very abnormal appearances
223
were noted and were present on review; the usual comment in these cases was that appearances were
compatible with cholecystitis (probably in view of the ubiquitous gallstone(s) identified in all patients). In one patient the radiologist commented on the lack of tenderness over the abnormal gallbladder yet labelled it cholecystitis, carcinoma being found at laparotomy. Also in this group must be included two cases in which a solid solitary tumour of the liver was identified on ultrasound contiguous to the gallbladder. Carcinoma was confirmed by biopsy or laparotomy although the gallbladder looked relatively normal. The second group (six patients) were those presenting with obstructive jaundice. In all these patients the fact of and site of the obstruction was correctly identified as was the presence of the gallstones. Thereafter, the investigation centred on delineating details about the site. In all these cases the only surgical option was palliation. The third group (17 patients) were in situ tumours where the radiologist reported no more than gallbladder wall thickening plus stones, a very common finding in biliary ultrasound. There were no discernible features which would suggest the diagnosis of carcinoma, and indeed in none of these cases was the diagnosis even suggested at surgery (only at subsequent histopathology examination). This group was the only one in which long-term survival was seen. Cholecystectomy was performed in 13 of the patients as the only surgical treatment. Ten patients are still alive but the median survival (in the 11 who died) was only 4 months (Table I).
Discussion Primary carcinoma of the gallbladder is the most common malignancy of the biliary tract, yet despite the tremendous advances in diagnostic methods (particularly ultrasonography, computed tomography and endoscopic retrograde cholangiopancreatography) the prognosis remains dismal. Results in our series are in accord with others where a F: M ratio of 4.5 to 5.1 has been reported (3-5) and where a clinical picture of gallbladder disease is usual. Correct preoperative diagnosis is also the exception rather than the rule in these series and ultrasound (the most commonly used diagnostic method) which is often used alone, has a very low diagnostic rate (3-5). While invasive diagnostic techniques such as coeliac or selective hepatic angiography will improve the rate of diagnosis (6), these can only be employed when a more routine method of investigation has questioned the diagnosis. In our patients there was an 85.7% incidence of gallstones consistent with but towards the upper end of other reported series (45-100%) (7). Simple cholecystectomy was the most commonly performed operative procedure, either because it was all that was possible or because even at operation the diagnosis of malignancy was not entertained. While this undoubtedly contributed to the dismal survival in our series (only one
224
J A Paraskevopoulos et al.
patient survived 5 years), it is nevertheless in keeping with other series, emphasising the diagnostic difficulties in these patients (8). Furthermore, the finding of an improved survival in patients with localised disease and short histories (9), suggests that the situation will only improve significantly when a diagnosis can be reached earlier. It is worth noting in respect of the ultrasound findings that all the cases in this series occurred over a 10-year period which saw a remarkable development in ultrasound equipment and its use. The equipment used in diagnosis ranged from grey scale B-scope to the latest realtime imaging equipment, and was accompanied by a concomitant increase in the experience of the operators. It is also now standard practice in our hospital for radiologists to scan the whole abdomen whatever the organ of interest originally indicated by the clinician, which will result in an increase of the 'incidental' finding of gallstones. While the latest equipment has the best chance of making an early diagnosis of gallbladder carcinoma, this study suggests that the findings of such patients may not only be difficult but at the expense of a gross overdiagnosis, which may not be in the patients' best interests, since many asymptomatic gallstones are discovered as a result of routine scanning. For the sonographer to make the diagnosis (differential) it would be necessary to bring to the attention of the referring clinician the possibility of in situ carcinoma in every case of gallstones where the wall shows any thickening. The surgical yield will be small but this approach would appear to be the only one to alter the outlook in a lethal condition significantly. The challenge is to be able to treat all cases of gallstones (with the ever-increasing number of methods available) leaving no patients with undiagnosed malignancy or with a significantly increased risk of developing it. Reviewing our hospital series and the world literature we suggest the following treatment policies: 1 Symptomatic patients with large stones (>3 cm) who, after treatment, have an intact gallbladder mucosa need regular follow-up. 2 In patients over 65 years of age, a preoperative diagnosis of 'a thickened gallbladder wall' when large stones are present should be treated with suspicion and intra-operative frozen sections may be necessary to determine the most appropriate procedure. 3 If stones recur after minimal invasive methods that leave the mucosa intact (percutaneous stone extrac-
tion and ESWL), then the gallbladder should be removed, especially in young patients. Carcinoma of the gallbladder is fortunately a very rare condition as there do not appear to be any significant ultrasonic signs to differentiate it from the wide spectrum of appearances associated with gallstones (infection, xanthogranulomatous cholecystitis, etc). To place undue emphasis on the possibility of curable in situ carcinoma would appear meddlesome, yet not to do so risks failing to find such cases. However, our series and others in the literature must awaken interest in the relationship between gallstones and the development of gallbladder carcinoma. The development of carcinomas requires a promoting and an initiating influence, and in the case of the gallbladder by damaging the mucosa it seems likely that a predisposed epithelium remains. Whether removal of the gallstones removes the initiating factor remains to be seen, but until more detailed experimental studies establish this, patients will need close follow-up; this is likely to be even more relevant with techniques such as ESWL where the technique itself produces unknown long-term effects. These fears may well ultimately lead to an increased employment of techniques that are able to remove gallstones and ablate the gallbladder mucosa simultaneously.
References I Adson MA. Carcinoma of the gallbladder. Surg Clin North Am 1973;53: 1203-16. 2 Muir IM, Morris DL. Carcinoma of the gallbladder. Br Hosp Med 1986;36:278-80. 3 Ohlsson EG, Aronsen KF. Carcinoma of the gallbladder; a study of 181 cases. Acta Chir Scand 1974;140:475-80. 4 Richard PF, Cantin J. Primary carcinoma of the gallbladder; a study of 108 cases. CanJ_ Surg 1976;19:27-32. S Carmo M, Perpetuo MO, Valdivieso M et al. Natural history of gallbladder cancer. Cancer 1978;42:330-35. 6 Tashiro S, Konno T, Mochinaga M et al. Primary carcinoma of the gallbladder; a review of 67 cases. Kumamoto Med J 1981;34: 1-12. 7 Paraskevopoulos JA, Dennison AR, Johnson AG. Primary carcinoma of the gallbladder. HPB Surgery 1991;4:277-89. 8 Tarpila E, Borch K, Kullman E, Liedberg G. Gallbladder cancer; current status in clinical practice. Eur Jr Surg Oncol
1988;14: 51-4. 9 Hart J, Modan B. Factors affecting survival of patients with
gallbladder neoplasms. Arch Intern Med 1972;129:931-4. Received 18 October 1991
