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The continuing challenge of gallbladder cancer
The Continuing Challenge of Gallbladder Cancer Survey of Thirty Years’ Experience at the University of Chicago
A. Ft. Moossa, BSc, MB, ChB, FRCS, FRCS (Edinb), Maria Anagnost,
Chicago, Illinois
MD, Chicago, Illinois
A. W. Hall, MB, ChB, FRCS, FRCS (Edinb),
Chicago, Illinois
A. Moraldi, MD, Chicago, Illinois D. B. Skinner,
MD, FACS, Chicago, Illinois
Much has been written about carcinoma of the gallbladder since it was first described by de Stoll in 1777 [I]. The disease primarily affects elderly white women, especially those of Mexican, American, and Japanese extraction, in the United States [2]. Although not common, it has an annual incidence of 2.5 per 100,000 in the United States [3] and accounts for approximately 6,500 deaths yearly [4]. It constitutes between 3 and 4 per cent of all malignant lesions of the gastrointestinal tract [5] and is fifth in incidence, being exceeded by cancer of the rectum, colon, pancreas, and stomach [6]. It is less frequent in Britain, but it still remains the most common malignant disease of the biliary tract [7]. The numerous recorded series uniformly report few, if any, survivors beyond the five year period after diagnosis. This appalling prognosis prompted Blalock [8] in 1924 to suggest that operation be avoided when a positive diagnosis can be made without exploration. Since then, there have been occasional reports of cure after hepatic resection with regional lymphadenectomy. However, no significant improvement in the survival figures has been reported. Fromthe Department of Surgery, the University of Chicago Hospitals, Chicago, Illinois. Reprint requests should be addressed to A. R. Moossa, MD, the Department of Surgery, the University of Chicago Hospitals, 950 East 59th Street, Chicago, Illinois 60637.
Volume 130, July 1975
The results of therapy for carcinoma of the gallbladder at the University of Chicago over a thirty year period are assessed and form the basis of this report. The current concepts of the etiologic factors and mode of spread are discussed. The role of therapy for this condition is reviewed, and a program is suggested to determine the relative value of new investigative tools and the various modes of therapy.
Etiologic Factors and Mode of Spread
An association between cholelithiasis and cancer of the gallbladder has long been recognized, but the reported incidence varies. Strauch [9] found it to be 72 per cent in his cumulative study, with a range of 54.3 per cent to 96.9 per cent. Irritation of the cholecystic mucosa by gallstones cannot be the total explanation since, in all series except that of McLaughlin [IO] who reported a 100 per cent correlation, at least some patients have had carcinoma of the gallbladder without associated gallstones. Experimental work on this subject has not been revealing. The implantation of foreign bodies has been studied by several investigators. Petrov and Krotkina [II] implanted sterile glass tubes, with and without radium, into the gallbladder in fiftyone guinea pigs. In five animals, carcinoma devel-
57
Moossa et al
oped within fourteen months and three of these had had plain glass tube implantation. The same carcinogenic effect has been demonstrated in other species using methylchblanthrene pellets [12,13]. Failures have been reported after implantation of plaster of Paris pills with and without 1,2:5,6 dibenzanthracene, fragments of sterile marine sponges soaked in mutton fat containing 1,2:5,6 dibenzanthracene, glass beads, cholesterol pellets, and methylcholanthrene-impregnated cholesterol pellets [14]. Of particular interest, however, is the work of Kowalewski and Todd [15], which may indicate the true correlation between gallstones and carcinoma. They showed that dimethylnitrosamine (DMN) administered orally caused dysplasia throughout the bile ducts and carcinoma of the bile ducts in a large proportion of hamsters. Carcinoma of the gallbladder developed in 68 per cent of the hamsters so treated that also had had cholesterol pellets implanted in the gallbladder. Carcinoma of the gallbladder developed in only one of those without pellet implantation. The modes of spread have been fully discussed by Fahim et al [16]. Cancer of the gallbladder may spread by lymphatic, vascular, or neuronal routes, by dipect extension, or by intraductal or intraperitoneal invasion. Lymphatic spread occurs in 35 to 70 per cent of cases [16]. The mural lymphatics, which are primarily on the inferior surface of the gallbladder, drain either directly or via the cystic node to nodes at the porta hepatis. These, in turn, drain via the superior pancreaticoduodenal nodes to nodes around the celiac axis and superior mesenteric artery. The venous plexus of the gallbladder adventitia forms the cholecystic veins, which drain either through the gallbladder bed or via a venous plexus surrounding the extrahepatic bile ducts to a capillary bed within the quadrate lobe of the liver and then into the hepatic veins [17,18]. On very rare occasions, the cystic vein drains into the portal vein; normally there is no communication with the portal system. This is important because it implies that. invasion of the liver even by the venous route is initially localized and not disseminated as in other neoplasms of the gastrointestinal tract. Perineuronal spread occurs by direct extension along the neuronal sheath. This is seen in about 25 per cent of cases, but the area of spread is excised in any operation that includes adequate lymphatic clearance and local resection. Local spread occurs initially through the gallbladder bed to the liver.
58
Spread also occurs by direct extension to adjacent organs which then become adherent to the gallbladder. Intraductal spread results from direct invasion, from intraluminal dissemination, and probably also from multicentric origin of the tumor. It occurs in approximately 4 per cent of cases. Intraperitoneal diffuse dissemination is rare and occurs only at a very late stage of the disease. Clinical Data
The records of all patients with carcinoma of the gallbladder referred to the University of Chicago Hospitals and Clinics in the thirty years between 1944 and 1973 were reviewed. During this time 325,804 patients were admitted to this institution. Of these, eighty-two were found to have carcinoma of the gallbladder, accounting for 0.025 per cent of all admissions, compared with figures of 0.018 per cent reported by Gerst [19] and 0.04 per cent reported by Strauch [9]. During the same period approximately 4,200 operations were performed on the biliary tract. Malignant lesions of the gallbladder therefore account for less than 2 per cent of all biliary disease seen in this institution. Over the same period 26,376 cases of malignant disease were reported to our tumor registry. Carcinoma of the gallbladder therefore accounts for 0.3 per cent of all malignant lesions seen in this hospital. This figure is about half that quoted in several other series; the discrepancy is probably explained by the high incidence of leukemia and lymphoma at this hospital, for which it has been a national referral center during much of this period. There were sixty-one females and twenty-one males, a ratio of females to males of 3:l. Seventy-one patients were white, ten black, and one from another racial group. Their ages ranged from 31 to 86 years with an average of 63.8 years; there was no significant difference in age distribution between the sexes. The mode of presentation was the same as that in all other reported series, that is, the majority of patients presented with pain in the right upper abdominal quadrant, often of long duration and suggestive of benign biliary tract disease. Some, however, did present with jaundice, and in others the disease was an incidental finding at either laparotomy or autopsy. Sixty-one of the eightytwo patients had concomitant gallstones, an incidence of 74.6 per cent. Treatment
and Results
Forty patients received no treatment at all. Of those treated, twenty-eight underwent operation only, two underwent operation and received irradiation, three had irradiation only, five received chemotherapy, and four had a combination of radiotherapy and chemotherapy. Apart from three patients in whom partial hepatectomy was performed (none of whom survived longer than six
The American Journal of Surgery
Gallbladder Cancer
months), the only curative procedure attempted was radical cholecystectomy with regional lymphadenectomy. Of the eighty-two patients considered herein, forty-two (51.2 per cent) had died within three months of diagnosis, fifty-seven (79 per cent) within six months, and seventy-two (88 per cent) within one year. The overall five year survival was 5 per cent (four patients). However, as previously mentioned, a very large proportion of the patients in this series received no therapy at all. The survival of those receiving therapy was therefore considered separately. When all forms of treatment are taken into account, the group consists of forty-two patients. Of these, fourteen (33 per cent) died in the first three months. However, nineteen (45 per cent) were still alive at six months, and ten (24 per cent) were alive at one year. The five year survival of this group was 9.5 per cent (four patients, as in the overall survey). When patients undergoing operation only are considered, the results appear to be even better. Of these twenty-eight patients, twenty-two (79 per cent) survived operation and the first three postoperative months. Fourteen (50 per cent) were still alive at six months, and eight (28.5 per cent) were alive at one year. The five year survival in this group was 14.3 per cent (four patients, as noted before). It must be stressed that much of this apparent improvement is due to exclusion of those patients with disease diagnosed at postmortem examination and those too ill to undergo operation rather than due to the success of therapy. Those patients surviving longer than one year from initial diagnosis will now be considered in detail. Of these ten patients, seven were female and three male. In this and all other respects, there was a close correlation with the findings in the overall series. All had a preoperative history suggestive of cholelithiasis and cholecystitis, varying in duration from six months to twenty years; in every case this was the reason for initial laparotomy. In only four of these patients was carcinoma suspected at laparotomy, and these four died at one year and two months, two years and two months, two years and six months, and three years and three months. In all other patients the diagnosis was made on pathologic study. Among these patients, one died from metastatic carcinoma of the gallbladder one year and ten months after the original operation; re-exploration had been necessary eighteen months postoperatively because of duodenal obstruction.
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1975
Of the other five patients, one died at twentytwo years and five months from unrelated causes, and another died at six years from carcinoma of the floor of the mouth. There was no evidence of carcinoma of the gallbladder at the time of death. The remaining three patients are alive and apparently free of recurrence at twelve years and six months, six years, and two years. Among the patients undergoing a combination of operation and radiotherapy, one had obvious carcinoma at the time of the procedure and died of residual disease at two years and six months. In the other, diagnosis was established by pathologic examination of the specimen. As histologic study showed anaplastic carcinoma extending to subserosal fat with lymphatic and perineural invasion, the patient was subjected to a full course of radiotherapy. He remains well and apparently free of recurrence at two years. Palliative surgery played only a minor role in the management of patients in this series. Two patients who had originally undergone cholecystectomy later required operative relief of duodenal obstruction, gastrojejunostomy being performed in both cases. Two patients with obstructive jaundice also underwent re-exploration for possible bypass; in neither case was any such procedure technically feasible. Discussion and Conclusions Our experience with carcinoma of the gallbladder at the University of Chicago confirms and underlines. the experience of others with this extremely serious condition. In our series, as in many others, the only long-term survivors were patients in whom carcinoma was an incidental finding at operation. There is widespread agreement that preoperative diagnosis of cancer of the gallbladder is rare. The symptoms are those of inflammatory biliary disease until at least local spread has occurred, when their quality and severity may alter. Preoperative diagnosis and prediction of the extent of disease would be advantageous for two reasons. First, the patient and surgeon would be prepared for major curative resection if this were deemed feasible. Second, when disease had progressed too far, operation could be postponed until essential for palliation of intestinal obstruction or obstructive jaundice. Previously, these possibilities have been academic; however, two recent papers, by Sato et al 1201 from Japan and Sprayregen and Mkssinger [21j in this country, have reported highly encouraging results with celiac axis arteri-
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Moossa et al
ography. Selective hepatic artery catheterization with magnification radiography is essential. The technic is not useful for early diagnosis but may prove valuable in detecting local extension to the liver and the presence of regional node metastases. This investigation appears justifiable in any patient older than fifty years of age with symptoms of gallbladder disease that have recently changed. Only a high index of suspicion will allow preoperative diagnosis of cancer of the gallbladder when it is still at a curable stage. Tumor immunology offers the best hope for the future. Tests for tumorassociated antigens in the peripheral blood, for example, carcinoembryonic antigen (CEA) and alpha fetoprotein, may yet prove useful diagnostic adjuncts. Since the gallbladder develops from the embryonic foregut, it seems logical to investigate the production of ectopic hormones, for example, gastrin, calcitonin, parathormone, and chorionic gonadotrophin, by malignant tumors of the gallbladder. The place of routine duodenal intubation and drainage studies remains to be determined. Positive results of cytologic study of the duodenal juice collected after injection of cholecystokinin are virtually diagnostic. Since the cystic duct is ocreaction, or cluded by a stone, inflammatory tumor in a large percentage of cases, the number of false-negative results of cytologic study may be extremely high. Under normal conditions carcinoembryonic antigen is present in fairly high concentration in the bile. Whether its pattern of excretion is altered in inflammatory or neoplastic disorders of the biliary tract is unknown. The relative merits of these new investigative technics in the early diagnosis of biliary and pancreatic cancer are currently being evaluated at the University of Chicago Hospitals and Clinics. Palliative surgery is sometimes desirable in the late stages of this condition to relieve intestinal obstruction or obstructive jaundice. For the former, standard bypass procedures are usually adequate and relatively straightforward. Conversely, relief of obstructive jaundice in these cases can be extremely difficult or impossible. When it is possible to transect the biliary tract above the level of the obstruction, hepaticojejunostomy using a Roux-en-Y loop of small bowel and hepatostomy tube splinting, as described by Smith [22], may be performed. When such a procedure is impossible because of extensive involvement of the porta hepatis by neoplastic infiltration, internal intubation of the bile ducts after dilatation through the tumor, as described by Whelton et al [7] and modified by Ritchie and MacLean [23], should be con-
60
sidered. In suitable cases, when the junction of the right and left hepatic ducts is involved, the U-tube hepatostomy procedure [24] may be used for palliation. Even when the tumor is so small that it is only discovered incidentally at operation, the results of therapy could be much improved. Three such patients in our own series died within one year of diagnosis. This problem may be dealt with in three ways: prophylactic cholecystectomy, more radical resection, or the addition of chemotherapy and/or radiotherapy to “curative” local resection. The rationale for prophylaxis is the frequent coexistence of cholelithiasis and carcinoma of the gallbladder. As pointed out previously, the etiologic significance of this is dubious; however, removal of the diseased gallbladder in all patients older than fifty would eliminate 70 to 80 per cent of cases of cancer of the gallbladder. The risk of cancer developing in the diseased gallbladder is 1 to 3 per cent [25,26]. This incidence increases with age [27] but is probably not significantly different from the risk of operation at any particular age. The argument is largely academic, as the risk of morbidity from “silent” stones is well documented and appears to be 33 to 50 per cent over a period of five to twenty years [28]. There is, therefore, adequate justification for recommending cholecystectomy for reasons other than cancer whenever gallstones are discovered in a reasonably fit patient. However, this is already standard practice in most centers; to make it more effective, all persons over fifty years of age would have to be screened on a nationwide basis, and this is obviously impractical due to limitation of available resources. Therefore, the current trend in therapy must be reassessed. A more radical surgical approach has been proposed by Glenn and Hays [27] who suggested en bloc cholecystectomy, partial hepatectomy, and removal of the local lymphatic field. An even more radical approach, right hepatic lobectomy, was advocated by Pack, Miller, and Brasfield [29] in 1955. To date, only ten patients surviving longer than five years after extensive operation for cancer of the gallbladder have been reported in the literature. Aiga [30] performed en bloc removal of the gallbladder and contiguously involved common bile duct. Thorbjarnarson and Glenn [31] reported similar success after cholecystectomy and excision of involved cystic duct lymph nodes. Booker and Pack [32] demonstrated the efficacy of cholecystectomy with pericholedochal lymphadenectomy. Appleman et al [33] found cholecystectomy and extraction of free pieces of
The American Journal of Surgery
Gallbladder
from the common bile duct successful. Long-term survival after wedge excision of infiltrated liver parenchyma and the gallbladder lesion was reported by Finsterer [34], Fahim et al [16], and Sheinfeld [35]. Brasfield [36] also achieved cure in one patient by performing right hepatic lobectomy for a tumor invading the liver bed. Adson [37] attributed the long-term survival of two patients to radical operation. The proportion of gallbladder lesions amenable to extensive operation cannot accurately be estimated due to the paucity of available data. Vaittinen’s excellent review [38] of 300 patients treated surgically attempted to answer this question. Cancer was confined to the gallbladder in 6.2 per cent of cases, had infiltrated the liver in 83 per cent, had metastasized to regional nodes in 38 per cent, was adherent or had infiltrated other organs in 42 per cent, and had metastasized to distant sites in 38 per cent. He deduced that 28.7 per cent of these 300 patients could have had removal of all microscopic tumor by en bloc excision of the gallbladder, its bed, and its regional lymphatic drainage. Such theoretic curability is affected by other important factors, such as the patient’s general condition, microscopic dissemination of tumor, and the surgeon’s operative ability. Relatively few surgeons performing routine cholecystectomy are familiar with the technic of hepatic resection. For these reasons, radical operation has had a disappointingly limited trial, and the biologic behavior of cancer of the gallbladder has been overemphasized without adequate attention to the anatomic factors. Thus, Adson [37] has commented that patients with cancer of the gallbladder fall into two groups-the untreated and the undertreated. In the past, radiotherapy and chemotherapy have been used with little success in advanced cases of carcinoma of the gallbladder. It is clear from this and other series that operation alone, even in early cases, produces unsatisfactory results. It is possible that by combining operation with radiotherapy and/or chemotherapy the survival in these cases might be improved. This approach has been used in one of our patients and the result at two years is encouraging. Even for carcinoma unsuspected at operation, the results of localized resection are poor, and currently there is no statistical evidence that a radical.procedure is better. A controlled trial of these methods should therefore be undertaken. This should include all early cases of carcinoma found at operation; in all cases the resected gallbladder should be opened in the operating room and any suspicious areas tumor
Volume 130, July 1975
Cancer
subjected to frozen section study. The patients should then be placed at random into two groups for local or radical resection. In view of the current high mortality it is believed that such a study would be ethically justifiable. Since even in large institutions there are only one or two suitable cases per year, this clinical trial would have to be carried out on a widespread collaborative basis, involving several centers.
Summary
The current concepts of the etiologic factors and spread of carcinoma of the gallbladder are discussed. The experience at the University of Chicago with this condition over a period of thirty years is reviewed. Of eighty-two cases diagnosed during this time, 88 per cent of the patients died within one year of diagnosis and the five year survival rate was 5 per cent. The difficulties in diagnosis of cholecystic neoplasms are considered, and the possibility of increasing diagnostic accuracy by the use of celiac axis angiography, immunologic tests for tumorassociated antigens, peptide hormone assays, and cytologic study of duodenal juice is discussed. The place of palliative surgery in the management of cancer of the gallbladder is outlined. Means of improving the current high mortality of this condition are evaluated, and a plea is made for a controlled trial of the various forms of treatment that have been suggested. References 1. de Stall M: Rationis Medendi in Noscomio Practice Vindobonensi. Quoted by Rolleston HD, McNee JS: Diseases of the Liver, Gallbladder and Bile Ducts, 3rd ed. London, Macmillan, 1929, p 691. 2. Krain LS: Carcinoma of the gallbladder in California: 19551969. J Chronic Dis 25: 65, 1972. 3. Burdette WJ: Carcinoma of the gallbladder. Ann Surg 145: 832, 1957. 4. Bossart PA, Patterson AH, Zintel HA: Carcinoma of the gallbladder. A report of seventy-six cases. Am J Surg 103: 366, 1962. 5. Hardy MA, Volk H: Primary Carcinoma of the gallbladder. A ten year review. Am J Surg 120: 600, 1970. 6. Holmes SL, Mark JBD: Carcinoma of the gallbladder. Surg GynecolObstet 133: 561, 1971. 7. Whelton MJ, Petrelli M, George P, Young WB, Sherlock S: Carcinoma at the junction of the main hepatic ducts. 0 J Med3a: 211, 1969. 8. Blalock A: A statistical study of 888 cases of biliary tract disease. Bull Johns Hopkins Hosp 35: 39 1, 1924. 9. Strauch GO: Primary carcinoma of the gallbladder. Surgery 47: 368, 1960. 10. McLaughlin CW: Carcinoma of the gallbladder, an added hazard in untreated calculous cholecystitis in older patients. Sw7ery 56: 757, 1964.
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11. Petrov NN, Krotkina NA: Experimental carcinoma of the gallbladder. Ann Surg 125: 241, 1947. 12. Fortner JG: The experimental induction of primary carcinoma of the gallbladder. Cancer 8: 689, 1955. 13. Fortner JG, Lefall LD: Carcinoma of the gallbladder in dogs. Cancer 14: 1127, 1961. 14. Burrows H: Gall-stones and cancer: a problem of aetiology, with special reference to the role of irritation. Br J Surg 27: 166, 1939. 15. Kowalewski K, Todd EF: Carcinoma of the gallbladder induced in hamsters by insertion of cholesterol pellets and feeding dimethylnitrosamine. froc Sot Exp Biol Med 136: 482, 1971. 16. Fahim RB, McDonald JR, Richards JC, Ferris DO: Carcinoma of the gallbladder: a study of its modes of spread. Ann Surg 156: 114, 1962. 17. Karlmark E: Die Lokalisationstendenz bei Metastasierung durch die Venenin die Leber. Acta fathol Microbial Stand (Suppl) 13: 1, 1932. 18. Petren T: Die extrahepatischen Gallenwegsvenen und ihre pathologischanatomische Bedeutung. Verh Anat Ges 41: 139, 1932. 19. Gerst PH: Primary carcinoma of the gallbladder. Ann Surg 153: 369, 1961. 20. Sato T, Watanebe K, Saitoh Y, Koyama K, Suda Y: Selective arteriography for gallbladder diseases. Arch Surg 99: 598, 1969. 21. Sprayregen S, Messinger NH: Carcinoma of the gallbladder: diagnosis and evaluation of regional spread by angiography. Am J Roentgenol Radium Ther Nucl Med 116: 382, 1972. 22. Smith R: Hepaticojejunostomy: choledochojejunostomy: a method of intrajejunal anastomosis. Br J Surg 51: 183, 1964. 23. Ritchie HD, MacLean ADW: A palliative procedure for high bile duct carcinoma. Ann R Cot/ Surg Engt51: 389, 1972. 24. Terblanche J, Louw JH: U-tube drainage in the palliative therapy of carcinoma of the main hepatic duct junction.
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Surg Clin North Am 53: 1245, 1973. 25. Cooke L, Jones FA, Keech MK: Carcinoma of the gallbladder. Lancet 2: 585, 1953. 26. Gradisar IA, Kelly TR: Primary carcinoma of the gallbladder. Arch Surg 100: 232, 1970. 27. Glenn F, Hays DM: The scope of radical surgery in the treatment of malignant tumors of the extrahepatic biliary tract. Surg Gynecol Obstet 99: 529, 1954. 28. Lund J: Surgical indications in cholefiihiasis: prophylactic cholecystectomy elucidated on the basis of long-term follow-up on 526 nonoperated cases. Ann Surg 151: 153, 1960. 29. Pack GT. Miller TR, Brasfield RD: Total right hepatic lobectomy for cancer of the gallbladder. Ann Surg 142: 6, 1955. 30. Aiga Y: Uber einen seltenen Fall von operativ dauernd geheiltem Gallenblasenkarzinom. Zentralbl Chir 62: 2 12, 1935. 31. Thorbjarnarson B, Glenn F: Carcinoma of the gallbladder. Cancer 12: 1009, 1959. 32. Booher RJ, Pack GT: Carcinoma of the gallbladder-report of a five-year cure of anaplastic carcinoma with metastases. Am J Surg 78: 175. 1949. 33. Appleman RM, Morlock CG, Dahlin DC, et al: Long term survival in carcinoma of the gallbladder. Surg Gynecol Obstet 117: 459, 1963. 34. Finsterer H: Das Karzinom der Gallenblase. Med K/in 28: 432, 1932. 35. Sheinfeld W: Cholecystectomy and partial hepatectomy for carcinoma of the gallbladder with local liver extension. Surgery 22: 48, 1947. 36. Brasfield RD: Right hepatic lobectomy for carcinoma of the gallbladder: a five-year cure. Ann Surg 153: 563. 1961. 37. Adson MA: Carcinoma of the gallbladder. Surg C/in North Am 53: 1203, 1973. 38. Vaittinen E: Carcinoma of the gallbladder: a study of 390 cases diagnosed in Finland 1953-1967. Ann Chir GynaecolFenn (Suppl) 168: 1, 1970.
The
American Journal
of Surgery
A. Ft. Moossa, BSc, MB, ChB, FRCS, FRCS (Edinb), Maria Anagnost,
Chicago, Illinois
MD, Chicago, Illinois
A. W. Hall, MB, ChB, FRCS, FRCS (Edinb),
Chicago, Illinois
A. Moraldi, MD, Chicago, Illinois D. B. Skinner,
MD, FACS, Chicago, Illinois
Much has been written about carcinoma of the gallbladder since it was first described by de Stoll in 1777 [I]. The disease primarily affects elderly white women, especially those of Mexican, American, and Japanese extraction, in the United States [2]. Although not common, it has an annual incidence of 2.5 per 100,000 in the United States [3] and accounts for approximately 6,500 deaths yearly [4]. It constitutes between 3 and 4 per cent of all malignant lesions of the gastrointestinal tract [5] and is fifth in incidence, being exceeded by cancer of the rectum, colon, pancreas, and stomach [6]. It is less frequent in Britain, but it still remains the most common malignant disease of the biliary tract [7]. The numerous recorded series uniformly report few, if any, survivors beyond the five year period after diagnosis. This appalling prognosis prompted Blalock [8] in 1924 to suggest that operation be avoided when a positive diagnosis can be made without exploration. Since then, there have been occasional reports of cure after hepatic resection with regional lymphadenectomy. However, no significant improvement in the survival figures has been reported. Fromthe Department of Surgery, the University of Chicago Hospitals, Chicago, Illinois. Reprint requests should be addressed to A. R. Moossa, MD, the Department of Surgery, the University of Chicago Hospitals, 950 East 59th Street, Chicago, Illinois 60637.
Volume 130, July 1975
The results of therapy for carcinoma of the gallbladder at the University of Chicago over a thirty year period are assessed and form the basis of this report. The current concepts of the etiologic factors and mode of spread are discussed. The role of therapy for this condition is reviewed, and a program is suggested to determine the relative value of new investigative tools and the various modes of therapy.
Etiologic Factors and Mode of Spread
An association between cholelithiasis and cancer of the gallbladder has long been recognized, but the reported incidence varies. Strauch [9] found it to be 72 per cent in his cumulative study, with a range of 54.3 per cent to 96.9 per cent. Irritation of the cholecystic mucosa by gallstones cannot be the total explanation since, in all series except that of McLaughlin [IO] who reported a 100 per cent correlation, at least some patients have had carcinoma of the gallbladder without associated gallstones. Experimental work on this subject has not been revealing. The implantation of foreign bodies has been studied by several investigators. Petrov and Krotkina [II] implanted sterile glass tubes, with and without radium, into the gallbladder in fiftyone guinea pigs. In five animals, carcinoma devel-
57
Moossa et al
oped within fourteen months and three of these had had plain glass tube implantation. The same carcinogenic effect has been demonstrated in other species using methylchblanthrene pellets [12,13]. Failures have been reported after implantation of plaster of Paris pills with and without 1,2:5,6 dibenzanthracene, fragments of sterile marine sponges soaked in mutton fat containing 1,2:5,6 dibenzanthracene, glass beads, cholesterol pellets, and methylcholanthrene-impregnated cholesterol pellets [14]. Of particular interest, however, is the work of Kowalewski and Todd [15], which may indicate the true correlation between gallstones and carcinoma. They showed that dimethylnitrosamine (DMN) administered orally caused dysplasia throughout the bile ducts and carcinoma of the bile ducts in a large proportion of hamsters. Carcinoma of the gallbladder developed in 68 per cent of the hamsters so treated that also had had cholesterol pellets implanted in the gallbladder. Carcinoma of the gallbladder developed in only one of those without pellet implantation. The modes of spread have been fully discussed by Fahim et al [16]. Cancer of the gallbladder may spread by lymphatic, vascular, or neuronal routes, by dipect extension, or by intraductal or intraperitoneal invasion. Lymphatic spread occurs in 35 to 70 per cent of cases [16]. The mural lymphatics, which are primarily on the inferior surface of the gallbladder, drain either directly or via the cystic node to nodes at the porta hepatis. These, in turn, drain via the superior pancreaticoduodenal nodes to nodes around the celiac axis and superior mesenteric artery. The venous plexus of the gallbladder adventitia forms the cholecystic veins, which drain either through the gallbladder bed or via a venous plexus surrounding the extrahepatic bile ducts to a capillary bed within the quadrate lobe of the liver and then into the hepatic veins [17,18]. On very rare occasions, the cystic vein drains into the portal vein; normally there is no communication with the portal system. This is important because it implies that. invasion of the liver even by the venous route is initially localized and not disseminated as in other neoplasms of the gastrointestinal tract. Perineuronal spread occurs by direct extension along the neuronal sheath. This is seen in about 25 per cent of cases, but the area of spread is excised in any operation that includes adequate lymphatic clearance and local resection. Local spread occurs initially through the gallbladder bed to the liver.
58
Spread also occurs by direct extension to adjacent organs which then become adherent to the gallbladder. Intraductal spread results from direct invasion, from intraluminal dissemination, and probably also from multicentric origin of the tumor. It occurs in approximately 4 per cent of cases. Intraperitoneal diffuse dissemination is rare and occurs only at a very late stage of the disease. Clinical Data
The records of all patients with carcinoma of the gallbladder referred to the University of Chicago Hospitals and Clinics in the thirty years between 1944 and 1973 were reviewed. During this time 325,804 patients were admitted to this institution. Of these, eighty-two were found to have carcinoma of the gallbladder, accounting for 0.025 per cent of all admissions, compared with figures of 0.018 per cent reported by Gerst [19] and 0.04 per cent reported by Strauch [9]. During the same period approximately 4,200 operations were performed on the biliary tract. Malignant lesions of the gallbladder therefore account for less than 2 per cent of all biliary disease seen in this institution. Over the same period 26,376 cases of malignant disease were reported to our tumor registry. Carcinoma of the gallbladder therefore accounts for 0.3 per cent of all malignant lesions seen in this hospital. This figure is about half that quoted in several other series; the discrepancy is probably explained by the high incidence of leukemia and lymphoma at this hospital, for which it has been a national referral center during much of this period. There were sixty-one females and twenty-one males, a ratio of females to males of 3:l. Seventy-one patients were white, ten black, and one from another racial group. Their ages ranged from 31 to 86 years with an average of 63.8 years; there was no significant difference in age distribution between the sexes. The mode of presentation was the same as that in all other reported series, that is, the majority of patients presented with pain in the right upper abdominal quadrant, often of long duration and suggestive of benign biliary tract disease. Some, however, did present with jaundice, and in others the disease was an incidental finding at either laparotomy or autopsy. Sixty-one of the eightytwo patients had concomitant gallstones, an incidence of 74.6 per cent. Treatment
and Results
Forty patients received no treatment at all. Of those treated, twenty-eight underwent operation only, two underwent operation and received irradiation, three had irradiation only, five received chemotherapy, and four had a combination of radiotherapy and chemotherapy. Apart from three patients in whom partial hepatectomy was performed (none of whom survived longer than six
The American Journal of Surgery
Gallbladder Cancer
months), the only curative procedure attempted was radical cholecystectomy with regional lymphadenectomy. Of the eighty-two patients considered herein, forty-two (51.2 per cent) had died within three months of diagnosis, fifty-seven (79 per cent) within six months, and seventy-two (88 per cent) within one year. The overall five year survival was 5 per cent (four patients). However, as previously mentioned, a very large proportion of the patients in this series received no therapy at all. The survival of those receiving therapy was therefore considered separately. When all forms of treatment are taken into account, the group consists of forty-two patients. Of these, fourteen (33 per cent) died in the first three months. However, nineteen (45 per cent) were still alive at six months, and ten (24 per cent) were alive at one year. The five year survival of this group was 9.5 per cent (four patients, as in the overall survey). When patients undergoing operation only are considered, the results appear to be even better. Of these twenty-eight patients, twenty-two (79 per cent) survived operation and the first three postoperative months. Fourteen (50 per cent) were still alive at six months, and eight (28.5 per cent) were alive at one year. The five year survival in this group was 14.3 per cent (four patients, as noted before). It must be stressed that much of this apparent improvement is due to exclusion of those patients with disease diagnosed at postmortem examination and those too ill to undergo operation rather than due to the success of therapy. Those patients surviving longer than one year from initial diagnosis will now be considered in detail. Of these ten patients, seven were female and three male. In this and all other respects, there was a close correlation with the findings in the overall series. All had a preoperative history suggestive of cholelithiasis and cholecystitis, varying in duration from six months to twenty years; in every case this was the reason for initial laparotomy. In only four of these patients was carcinoma suspected at laparotomy, and these four died at one year and two months, two years and two months, two years and six months, and three years and three months. In all other patients the diagnosis was made on pathologic study. Among these patients, one died from metastatic carcinoma of the gallbladder one year and ten months after the original operation; re-exploration had been necessary eighteen months postoperatively because of duodenal obstruction.
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Of the other five patients, one died at twentytwo years and five months from unrelated causes, and another died at six years from carcinoma of the floor of the mouth. There was no evidence of carcinoma of the gallbladder at the time of death. The remaining three patients are alive and apparently free of recurrence at twelve years and six months, six years, and two years. Among the patients undergoing a combination of operation and radiotherapy, one had obvious carcinoma at the time of the procedure and died of residual disease at two years and six months. In the other, diagnosis was established by pathologic examination of the specimen. As histologic study showed anaplastic carcinoma extending to subserosal fat with lymphatic and perineural invasion, the patient was subjected to a full course of radiotherapy. He remains well and apparently free of recurrence at two years. Palliative surgery played only a minor role in the management of patients in this series. Two patients who had originally undergone cholecystectomy later required operative relief of duodenal obstruction, gastrojejunostomy being performed in both cases. Two patients with obstructive jaundice also underwent re-exploration for possible bypass; in neither case was any such procedure technically feasible. Discussion and Conclusions Our experience with carcinoma of the gallbladder at the University of Chicago confirms and underlines. the experience of others with this extremely serious condition. In our series, as in many others, the only long-term survivors were patients in whom carcinoma was an incidental finding at operation. There is widespread agreement that preoperative diagnosis of cancer of the gallbladder is rare. The symptoms are those of inflammatory biliary disease until at least local spread has occurred, when their quality and severity may alter. Preoperative diagnosis and prediction of the extent of disease would be advantageous for two reasons. First, the patient and surgeon would be prepared for major curative resection if this were deemed feasible. Second, when disease had progressed too far, operation could be postponed until essential for palliation of intestinal obstruction or obstructive jaundice. Previously, these possibilities have been academic; however, two recent papers, by Sato et al 1201 from Japan and Sprayregen and Mkssinger [21j in this country, have reported highly encouraging results with celiac axis arteri-
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ography. Selective hepatic artery catheterization with magnification radiography is essential. The technic is not useful for early diagnosis but may prove valuable in detecting local extension to the liver and the presence of regional node metastases. This investigation appears justifiable in any patient older than fifty years of age with symptoms of gallbladder disease that have recently changed. Only a high index of suspicion will allow preoperative diagnosis of cancer of the gallbladder when it is still at a curable stage. Tumor immunology offers the best hope for the future. Tests for tumorassociated antigens in the peripheral blood, for example, carcinoembryonic antigen (CEA) and alpha fetoprotein, may yet prove useful diagnostic adjuncts. Since the gallbladder develops from the embryonic foregut, it seems logical to investigate the production of ectopic hormones, for example, gastrin, calcitonin, parathormone, and chorionic gonadotrophin, by malignant tumors of the gallbladder. The place of routine duodenal intubation and drainage studies remains to be determined. Positive results of cytologic study of the duodenal juice collected after injection of cholecystokinin are virtually diagnostic. Since the cystic duct is ocreaction, or cluded by a stone, inflammatory tumor in a large percentage of cases, the number of false-negative results of cytologic study may be extremely high. Under normal conditions carcinoembryonic antigen is present in fairly high concentration in the bile. Whether its pattern of excretion is altered in inflammatory or neoplastic disorders of the biliary tract is unknown. The relative merits of these new investigative technics in the early diagnosis of biliary and pancreatic cancer are currently being evaluated at the University of Chicago Hospitals and Clinics. Palliative surgery is sometimes desirable in the late stages of this condition to relieve intestinal obstruction or obstructive jaundice. For the former, standard bypass procedures are usually adequate and relatively straightforward. Conversely, relief of obstructive jaundice in these cases can be extremely difficult or impossible. When it is possible to transect the biliary tract above the level of the obstruction, hepaticojejunostomy using a Roux-en-Y loop of small bowel and hepatostomy tube splinting, as described by Smith [22], may be performed. When such a procedure is impossible because of extensive involvement of the porta hepatis by neoplastic infiltration, internal intubation of the bile ducts after dilatation through the tumor, as described by Whelton et al [7] and modified by Ritchie and MacLean [23], should be con-
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sidered. In suitable cases, when the junction of the right and left hepatic ducts is involved, the U-tube hepatostomy procedure [24] may be used for palliation. Even when the tumor is so small that it is only discovered incidentally at operation, the results of therapy could be much improved. Three such patients in our own series died within one year of diagnosis. This problem may be dealt with in three ways: prophylactic cholecystectomy, more radical resection, or the addition of chemotherapy and/or radiotherapy to “curative” local resection. The rationale for prophylaxis is the frequent coexistence of cholelithiasis and carcinoma of the gallbladder. As pointed out previously, the etiologic significance of this is dubious; however, removal of the diseased gallbladder in all patients older than fifty would eliminate 70 to 80 per cent of cases of cancer of the gallbladder. The risk of cancer developing in the diseased gallbladder is 1 to 3 per cent [25,26]. This incidence increases with age [27] but is probably not significantly different from the risk of operation at any particular age. The argument is largely academic, as the risk of morbidity from “silent” stones is well documented and appears to be 33 to 50 per cent over a period of five to twenty years [28]. There is, therefore, adequate justification for recommending cholecystectomy for reasons other than cancer whenever gallstones are discovered in a reasonably fit patient. However, this is already standard practice in most centers; to make it more effective, all persons over fifty years of age would have to be screened on a nationwide basis, and this is obviously impractical due to limitation of available resources. Therefore, the current trend in therapy must be reassessed. A more radical surgical approach has been proposed by Glenn and Hays [27] who suggested en bloc cholecystectomy, partial hepatectomy, and removal of the local lymphatic field. An even more radical approach, right hepatic lobectomy, was advocated by Pack, Miller, and Brasfield [29] in 1955. To date, only ten patients surviving longer than five years after extensive operation for cancer of the gallbladder have been reported in the literature. Aiga [30] performed en bloc removal of the gallbladder and contiguously involved common bile duct. Thorbjarnarson and Glenn [31] reported similar success after cholecystectomy and excision of involved cystic duct lymph nodes. Booker and Pack [32] demonstrated the efficacy of cholecystectomy with pericholedochal lymphadenectomy. Appleman et al [33] found cholecystectomy and extraction of free pieces of
The American Journal of Surgery
Gallbladder
from the common bile duct successful. Long-term survival after wedge excision of infiltrated liver parenchyma and the gallbladder lesion was reported by Finsterer [34], Fahim et al [16], and Sheinfeld [35]. Brasfield [36] also achieved cure in one patient by performing right hepatic lobectomy for a tumor invading the liver bed. Adson [37] attributed the long-term survival of two patients to radical operation. The proportion of gallbladder lesions amenable to extensive operation cannot accurately be estimated due to the paucity of available data. Vaittinen’s excellent review [38] of 300 patients treated surgically attempted to answer this question. Cancer was confined to the gallbladder in 6.2 per cent of cases, had infiltrated the liver in 83 per cent, had metastasized to regional nodes in 38 per cent, was adherent or had infiltrated other organs in 42 per cent, and had metastasized to distant sites in 38 per cent. He deduced that 28.7 per cent of these 300 patients could have had removal of all microscopic tumor by en bloc excision of the gallbladder, its bed, and its regional lymphatic drainage. Such theoretic curability is affected by other important factors, such as the patient’s general condition, microscopic dissemination of tumor, and the surgeon’s operative ability. Relatively few surgeons performing routine cholecystectomy are familiar with the technic of hepatic resection. For these reasons, radical operation has had a disappointingly limited trial, and the biologic behavior of cancer of the gallbladder has been overemphasized without adequate attention to the anatomic factors. Thus, Adson [37] has commented that patients with cancer of the gallbladder fall into two groups-the untreated and the undertreated. In the past, radiotherapy and chemotherapy have been used with little success in advanced cases of carcinoma of the gallbladder. It is clear from this and other series that operation alone, even in early cases, produces unsatisfactory results. It is possible that by combining operation with radiotherapy and/or chemotherapy the survival in these cases might be improved. This approach has been used in one of our patients and the result at two years is encouraging. Even for carcinoma unsuspected at operation, the results of localized resection are poor, and currently there is no statistical evidence that a radical.procedure is better. A controlled trial of these methods should therefore be undertaken. This should include all early cases of carcinoma found at operation; in all cases the resected gallbladder should be opened in the operating room and any suspicious areas tumor
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Cancer
subjected to frozen section study. The patients should then be placed at random into two groups for local or radical resection. In view of the current high mortality it is believed that such a study would be ethically justifiable. Since even in large institutions there are only one or two suitable cases per year, this clinical trial would have to be carried out on a widespread collaborative basis, involving several centers.
Summary
The current concepts of the etiologic factors and spread of carcinoma of the gallbladder are discussed. The experience at the University of Chicago with this condition over a period of thirty years is reviewed. Of eighty-two cases diagnosed during this time, 88 per cent of the patients died within one year of diagnosis and the five year survival rate was 5 per cent. The difficulties in diagnosis of cholecystic neoplasms are considered, and the possibility of increasing diagnostic accuracy by the use of celiac axis angiography, immunologic tests for tumorassociated antigens, peptide hormone assays, and cytologic study of duodenal juice is discussed. The place of palliative surgery in the management of cancer of the gallbladder is outlined. Means of improving the current high mortality of this condition are evaluated, and a plea is made for a controlled trial of the various forms of treatment that have been suggested. References 1. de Stall M: Rationis Medendi in Noscomio Practice Vindobonensi. Quoted by Rolleston HD, McNee JS: Diseases of the Liver, Gallbladder and Bile Ducts, 3rd ed. London, Macmillan, 1929, p 691. 2. Krain LS: Carcinoma of the gallbladder in California: 19551969. J Chronic Dis 25: 65, 1972. 3. Burdette WJ: Carcinoma of the gallbladder. Ann Surg 145: 832, 1957. 4. Bossart PA, Patterson AH, Zintel HA: Carcinoma of the gallbladder. A report of seventy-six cases. Am J Surg 103: 366, 1962. 5. Hardy MA, Volk H: Primary Carcinoma of the gallbladder. A ten year review. Am J Surg 120: 600, 1970. 6. Holmes SL, Mark JBD: Carcinoma of the gallbladder. Surg GynecolObstet 133: 561, 1971. 7. Whelton MJ, Petrelli M, George P, Young WB, Sherlock S: Carcinoma at the junction of the main hepatic ducts. 0 J Med3a: 211, 1969. 8. Blalock A: A statistical study of 888 cases of biliary tract disease. Bull Johns Hopkins Hosp 35: 39 1, 1924. 9. Strauch GO: Primary carcinoma of the gallbladder. Surgery 47: 368, 1960. 10. McLaughlin CW: Carcinoma of the gallbladder, an added hazard in untreated calculous cholecystitis in older patients. Sw7ery 56: 757, 1964.
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11. Petrov NN, Krotkina NA: Experimental carcinoma of the gallbladder. Ann Surg 125: 241, 1947. 12. Fortner JG: The experimental induction of primary carcinoma of the gallbladder. Cancer 8: 689, 1955. 13. Fortner JG, Lefall LD: Carcinoma of the gallbladder in dogs. Cancer 14: 1127, 1961. 14. Burrows H: Gall-stones and cancer: a problem of aetiology, with special reference to the role of irritation. Br J Surg 27: 166, 1939. 15. Kowalewski K, Todd EF: Carcinoma of the gallbladder induced in hamsters by insertion of cholesterol pellets and feeding dimethylnitrosamine. froc Sot Exp Biol Med 136: 482, 1971. 16. Fahim RB, McDonald JR, Richards JC, Ferris DO: Carcinoma of the gallbladder: a study of its modes of spread. Ann Surg 156: 114, 1962. 17. Karlmark E: Die Lokalisationstendenz bei Metastasierung durch die Venenin die Leber. Acta fathol Microbial Stand (Suppl) 13: 1, 1932. 18. Petren T: Die extrahepatischen Gallenwegsvenen und ihre pathologischanatomische Bedeutung. Verh Anat Ges 41: 139, 1932. 19. Gerst PH: Primary carcinoma of the gallbladder. Ann Surg 153: 369, 1961. 20. Sato T, Watanebe K, Saitoh Y, Koyama K, Suda Y: Selective arteriography for gallbladder diseases. Arch Surg 99: 598, 1969. 21. Sprayregen S, Messinger NH: Carcinoma of the gallbladder: diagnosis and evaluation of regional spread by angiography. Am J Roentgenol Radium Ther Nucl Med 116: 382, 1972. 22. Smith R: Hepaticojejunostomy: choledochojejunostomy: a method of intrajejunal anastomosis. Br J Surg 51: 183, 1964. 23. Ritchie HD, MacLean ADW: A palliative procedure for high bile duct carcinoma. Ann R Cot/ Surg Engt51: 389, 1972. 24. Terblanche J, Louw JH: U-tube drainage in the palliative therapy of carcinoma of the main hepatic duct junction.
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Surg Clin North Am 53: 1245, 1973. 25. Cooke L, Jones FA, Keech MK: Carcinoma of the gallbladder. Lancet 2: 585, 1953. 26. Gradisar IA, Kelly TR: Primary carcinoma of the gallbladder. Arch Surg 100: 232, 1970. 27. Glenn F, Hays DM: The scope of radical surgery in the treatment of malignant tumors of the extrahepatic biliary tract. Surg Gynecol Obstet 99: 529, 1954. 28. Lund J: Surgical indications in cholefiihiasis: prophylactic cholecystectomy elucidated on the basis of long-term follow-up on 526 nonoperated cases. Ann Surg 151: 153, 1960. 29. Pack GT. Miller TR, Brasfield RD: Total right hepatic lobectomy for cancer of the gallbladder. Ann Surg 142: 6, 1955. 30. Aiga Y: Uber einen seltenen Fall von operativ dauernd geheiltem Gallenblasenkarzinom. Zentralbl Chir 62: 2 12, 1935. 31. Thorbjarnarson B, Glenn F: Carcinoma of the gallbladder. Cancer 12: 1009, 1959. 32. Booher RJ, Pack GT: Carcinoma of the gallbladder-report of a five-year cure of anaplastic carcinoma with metastases. Am J Surg 78: 175. 1949. 33. Appleman RM, Morlock CG, Dahlin DC, et al: Long term survival in carcinoma of the gallbladder. Surg Gynecol Obstet 117: 459, 1963. 34. Finsterer H: Das Karzinom der Gallenblase. Med K/in 28: 432, 1932. 35. Sheinfeld W: Cholecystectomy and partial hepatectomy for carcinoma of the gallbladder with local liver extension. Surgery 22: 48, 1947. 36. Brasfield RD: Right hepatic lobectomy for carcinoma of the gallbladder: a five-year cure. Ann Surg 153: 563. 1961. 37. Adson MA: Carcinoma of the gallbladder. Surg C/in North Am 53: 1203, 1973. 38. Vaittinen E: Carcinoma of the gallbladder: a study of 390 cases diagnosed in Finland 1953-1967. Ann Chir GynaecolFenn (Suppl) 168: 1, 1970.
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