Primary Carcinoma of the Gallbladder Jeffrey
M.
Piehler, MD, Robert W. Crichlow,
MD
clinical records of 48 patients with primary carcinoma of gallbladder seen at the Dartmouth-Hitchcock Medical Center
\s=b\ The
the
the past 25 years were reviewed. Of the 37 patients with unresected tumors, there were no survivors. Of the 11 patients with resected tumors, one survived five years, two died before five years without evidence of recurrence, and the remainder died with locally recurrent tumor. This experience reemphasizes the inadequacy of the present surgical approach to the disease. The tendency of carcinoma of the gallbladder to spread initially by local invasion of the liver bed and by metastases to regional lymph nodes has often been neglected by those treating the disease. Wedge resection of the liver and regional lymphadenectomy in addition to cholecystectomy are theoretically advantageous and should be striven for in the case of resectable tumors, even if reoperation is required.
order to determine whether approach is warranted.
over
(Arch Surg 112:26-30, 1977)
carcinoma of the gallbladder remains a source frustration to surgeons. Despite recent advances in cancer detection and management, no concom¬ itant improvement in survival has resulted for patients with this disease, and five-year survivors continue to be rare. Nevertheless, the disease is sufficiently common, occurring in 1.4% of all biliary tract operations from large collected series,1 that most surgeons will be faced with the disease at some point in their careers. The poor prognosis for patients with this tumor is due to advanced age, lack of specific symptoms or means for establishing the diagnosis early, a propensity for early invasion of vital surrounding structures, and the seeming unavailability of a successful surgical approach. These factors have resulted in an attitude of therapeutic nihilism among surgeons. We have reviewed the clinical records of patients with histologically proved carcinoma of the gall¬ bladder seen at this institution over the past 25 years in
Primarygreat of
for publication June 29, 1976. From the Department of Surgery, Dartmouth-Hitchcock Medical Center, Hanover, NH. Reprint requests to the Department of Surgery, Dartmouth Medical School, Hanover, NH 03755 (Dr Crichlow).
Accepted
a more
aggressive surgical
SUBJECTS AND METHODS The clinical records of 48 patients with histologically proved carcinoma of the gallbladder seen at the Mary Hitchcock Memorial Hospital in a 25-year period ending December 1974 were reviewed. The histologie diagnosis was made at laparotomy in 34 patients (71%), by postoperative pathological examination in nine patients (19%), and at postmortem examination in five nonsurgical patients. Follow-up studies were completed in all cases. There were 11 men and 37 women, a ratio of 1:3, which corresponds to published results from other series.1 Ages ranged from 49 to 85 years, with a mean age of 68.7 years. The patients were divided into four groups according to the scheme of Beltz and Condon.' Group A consisted of eight patients in whom the diagnosis of gallbladder carcinoma was made postoperatively by pathological study of resected specimens after biliary tract procedures for was comprised of three presumed benign disease. Group patients in whom the diagnosis was made intraoperatively and who underwent what was thought to be a curative resection by the operating surgeon. In all of these patients, the resection margins were free of tumor by histologie examination. Two of these patients were incidental discoveries at operation for other nonbiliary tract procedures. Group C consisted of 18 patients who at operation were found to have metastatic disease that precluded resection but who underwent a palliative procedure primarily for relief of biliary or gastrointestinal obstruction. Group D consisted of 19 patients who at operation were found to have widely metastatic disease that precluded resection and who underwent diagnostic biopsies only. Also included in this group were the five nonsurgical patients whose tumors were discovered at autopsy. There were no significant differences in age or sex distribution among the four groups. The clinical presentations differed somewhat for each group. Patients with early resectable lesions (groups A and B) tended to have symptoms of benign biliary tract disease. These had been present for a mean period of 3.6 weeks. Patients with more extensive disease in groups C and D had symptoms of diffuse intraabdominal malignancy present for a mean period of 10.4 weeks. There were, however, no presenting symptoms that were specific for the disease or for any group. Of 44 patients with symptomatic tumors, no symptoms were referable to the biliary
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·-
Table
2.—Operative Procedures Group
Table
1—Physical Findings
in Carcinoma of the
Gallbladder Resectable Tumors
Group A Group (n 8) (n 3) =
Palpable mass (including gallbladder) Hepatomegaly Jaundice Abdominal tenderness Ascites
4
2 3
...
...
%
=
=
36 18
7 8
12
27
8
4
82
9 1
13 4
9
8
1
0
14
14
19
48
With bowel resection
43 54 32 59 14
With gastroenterostomy Gastroenterostomy With right hemicolectomy Right hemicolectomy Colostomy Biopsy alone No surgery Total
18
...
no biliary tract disease was diagnosis. Of this group, three had
(25%) patients, and
entertained in the differential
symptoms of upper gastrointestinal obstruction
at the distal and gastric outlet levels, and three patients had symptoms of large bowel obstruction. The remainder had nonspe¬ cific symptoms of malignancy-lethargy, weight loss, anorexia, and dull abdominal pain. As expected, none of these patients had resectable lesions. Four patients had the clinical diagnosis of acute cholecystitis, three in group A, one in group D. Eight patients (17%) had roentgenographic evidence of biliary calculi or of abnormal gallbladder function antedating the diag¬ nosis of cancer by more than five years. An additional eight patients (17%) had symptoms of chronic biliary tract dysfunction that had led them to their physicians more than five years earlier, but cholecystography was not performed. Ultimately, gallstones were found in 40 patients (83%) and were definitely not present in two (4%), while no information was available in six cases (13%). Pertinent physical findings categorized by clinical groups are presented in Table 1. The nonspecific nature of these findings is evident, as is the lack of statistically significant differences between findings in patients with resectable and unresectable tumors. The absolute association of ascites with unresectability is noted. While the more extreme laboratory derangements were found in patients with more extensive disease, there were no consistent findings that determined resectability. Roentgenographic studies did not contribute significantly to diagnosis, but they served to point out the wide diversity of findings in these patients. Plain abdominal roentgenograms were abnormal in 15 of 33 patients. Six roentgenograms showed gastrointestinal obstruction; one at the duodenal, and five at the colonie level. Five showed only the presence of gallstones, three showed soft tissue abdominal masses, and one roentgenogram showed a right upper-quadrant extraintestinal gas collection. None of 15 oral cholecystograms visualized the gallbladder. Intra¬ venous cholangiography was performed twice without visualiza¬ tion. Upper gastrointestinal barium contrast roentgenograms were abnormal in 13 of 35 patients, showing duodenal or gastric displacement medially by a mass in nine patients, gastric outlet obstruction in three, and a duodenal ulcer in one patient with normal gastric acid studies. Barium enema roentgenograms were abnormal in seven of 25 individuals, showing partially obstructing colonie lesions in five patients, hepatic flexure irritability in one, and a duodenocolic fistula in one. Three of four liver scans showed
esophageal
Totals
Partial, with external drainage Choledochostomy (decompressive)
Group C Group D (n 18)(n 19)
...
...
tract in 11
=
Unresectable Tumors
D
Cholecystostomy Cholecystectomy With choledochostomy (diagnostic) With choledochostomy (decompressive) With hepatic wedge resection
evidence of metastatic disease. In one individual, percutaneous transhepatic cholangiography demonstrated a presumed benign common duct obstruction found to be due to tumor at exploration. Chest roentgenograms, performed on all patients, showed diffuse metastatic disease in two individuals. A percutaneous liver biopsy performed on two patients showed adenocarcinoma preoperatively in one. With the exception of nonvisualization on oral cholecystography, abnormal findings on the roentgenograms were usually associated with advanced tumors. The correct diagnosis was made preoperatively in only six patients (14%) and was based more on clinical suspicion than on specific laboratory or roentgenographic
findings. Operative procedures performed are listed in Table 2, subdi¬ vided by clinical group. Seven patients underwent reoperation after their initial procedures: two patients (both group A) were reexplored to increase the scope of resection, and the other patients were reexplored for palliation of subsequent obstructive symptoms. Survival data
are
Group A
C D All
patients
summarized in the
Figure: Mean Survival, 21.5 22.5 3.2 1.7 7.5
mo
There is no statistically significant difference in survival between ( > .01). There is one six-year survivor who groups A and subsequently died of an unrelated cause, one three-year survivor who died without clinical evidence of recurrence but without postmortem examination, and one patient who is currently alive without evidence of recurrence 2% years after surgery. All of these patients are in group A. All remaining patients have died as a direct result of their disease. Thus, the five-year survival rate of all patients is 2.1%. Of those with resectable tumors, the survival rate is 9.1%, and of those in group A, the rate is 12.5%. The operative mortality (within 30 days of operation) after primaryprocedures was 30% (13 of 43 patients), all in groups C and D. An additional two patients died within 30 days of secondary palliative
procedures. The histology of the resected specimens vs associated mean survival figures is given in Table 3. Of note is the association of papillary adenocarcinoma with resectability and good prognosis
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%·-·- -
GROUP
j—»
6
MONTHS Survival
curves
by
AFTER
clinical group for
anaplastic tumors with unresectability and prognosis. Of those patients with tumors grossly evident at surgery or postmortem examination (groups B, C, and D), three had localized disease or resectable extension of tumor into adjacent liver (group B). Twenty-one patients considered unresectable had disease localized in the gallbladder, liver, hepatoduodenal ligament, and duodenal area; review of the operative reports in this group and the association of poor
suggests that in three instances, the tumor could have been removed had wedge resection of the liver been done. Sixteen individuals had unresectable disease that had metastasized to noncontiguous organs, both intra- and extraperitoneally. This latter group demonstrated métastases to almost all major organs, including omentum, peritoneal surfaces, kidney, adrenal glands, small and large bowel, stomach, pancreas, diaphragm, pleura, lung, and brain, as well as para-aortic lymph nodes. Two patients (one in group C, one in group D) were treated with fluorouracil via an indwelling common hepatic artery catheter. Both patients died three months after diagnosis, and there was no indication that the course of the disease was altered by the chemotherapy. The cause of death in those patients surviving surgery was almost universally obstructive hepatic failure, often with diffuse intra-abdominal carcinomatosis.
COMMENT
series of what new information he has to contribute. Previous reports have emphasized the dismal facts of the disease: that at opera¬ tion, only about 10% to 25% of the patients have resectable tumors, that the five-year survival rate for all patients is generally less than 5%, and that the only survivors, by and large, are those few patients whose carcinomas are inci¬ dental pathologic findings in gallbladders removed for presumed benign biliary disease.'·3"8 It is traditional to accept poor survival from carcinoma of the gallbladder as a result of its discovery at an unfavorably late stage for treatment. And yet, review of the literature and of our own experience suggests that a significant proportion of those
only logical to ask an author reporting patients with carcinoma of the gallbladder It is
a
24
18
12
_l_
30
42
36
48
54
60
DIAGNOSIS
patients with carcinoma of gallbladder.
Table 3.—Tumor
vs Survival in Carcinoma of the Gallbladder
Histology
Group
_
Tumor Histology Adenocarcinoma Papillary adenocarcinoma
Anaplastic Epidermoid
A 4
B 2
_
C 18 3 10 0 0 1 10 0
D 11
0 1
Mean Survival 4.4 40.9
(mo)
0.9
with resectable lesions are being undertreated and that the prevalent attitude of hopelessness in treating this tumor may contribute to the poor patient survival. The low resectability rate for this tumor stems from the nonspecific nature of the clinical, laboratory, and roent¬ genographic presentations that call attention to those patients with extensive disease and leave undetected those with early, resectable tumors.-79" These factors, com¬ bined with a low level of clinical suspicion, result in a preoperative diagnostic accuracy of only 14% in this series and of 0% to 19% in others.1-14-"' Thus, the surgeon's encounter with carcinoma of the gallbladder is too often both unexpected and unsatisfying, emphasizing the need for a planned surgical approach to those few patients fortuitously found to have resectable disease. The failure of traditional surgical management of those patients with resected tumors was evident from this series. In 1962, Fahim et al17 reported the modes of spread of gallbladder cancer determined from dissection of operative specimens. They concluded the following: (1) The spread of the tumor is by local invasion without distant métastases until very late in the disease course. (2) Lymphatic spread of tumor is to the cystic node, pericholedochal nodes, and in late stages, to the superior and posterior pancreaticoduodenal and para-aortic nodes. (3) Vascular spread is uncommon (14%) and leads to adjacent liver involvement via penetrating vessels in the gallbladder bed initially and
patients
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to diffuse vascular infiltration in the liver or other organs. (4) Intraperitoneal spread is common and involves adjacent organs well before the development of disseminated intraperitoneal métastases. (5) Neural spread occurs relatively frequently (24%) and is associated with more aggressive tumors but is otherwise of uncertain significance. (6) Intraductal spread is least common and is seen most frequently in cases of papillary adenocarcinoma. The tendency of the papillary cell-type to grow intraluminally rather than invasively explains the better prognosis for these patients, which has been noted by many authors.!'ls In this series, all of the papillary adenocarci¬ nomas were resected, and a mean survival period of 40.9 months was seen, consistently better than for any other
only later
cell-type. These findings support the conclusion that the minimum operation for minimally invasive adenocarcinomas consists of cholecystectomy with wedge resection of liver with a margin of normal tissue and nodal dissection encompass¬ ing the cystic and pericholedochal nodes to the periaortic nodes.17 The extent of hepatic resection and node dissection must be individualized but aggressive. Although exten¬ sive liver resection has been performed,1" a concomitant lymph node dissection, though suggested by many,"-8-11'1--13'1" has been practiced by few.7-8 As Fahim et al17 noted lymphatic spread in 26% of his series, the omission of lymph node dissection may preclude successful resection in a significant number of patients. Indeed, Vaittinen's7 extensive review reports only 1.2% of the operations for this disease involved cholecystectomy, liver resection, and lymph node dissection. Those who have applied radical resection to carcinoma of the gallbladder have come to different conclusions concerning its effect on survival. Glenn and Hays-" reported five three-year survivors and two five-year survi¬ vors among 19 patients undergoing curative resection, 15 of whom had the radical procedure. He concluded that extensive resection would not result in improved survival. HowTever, two of their longest survivors had invasive cancers, and one four-year survivor had metastatic carci¬ noma in a resected regional lymph node. In the Mayo Clinic experience reported by Adson," three patients survived 3]/2 to 12 years after radical resection in which the excised
specimens contained metastatic carcinoma in either the liver or regional lymph nodes. There were no postoperative deaths in nine patients who underwent the procedure. He concluded that the unusually long survival in these patients was
due to the radical nature of the resection. Vaittinen7
reports that in 16.7% of the patients undergoing cholecys¬ tectomy, wedge resection of liver and lymph node dissec¬
tion survived five years as opposed to 10.6% after what was thought to be a curative cholecystectomy alone. While the available data are insufficient to establish the role of radical surgery, continued trial is certainly warranted. The fact that the majority of successes in treatment have come after simple cholecystectomy only points out that, not unexpectedly, there is a stage when the tumor is localized and curable.7 Further improvement in survival might be gained by removal of tissue along the known paths of
spread. The tendency of the tumor for aggressive local invasion that soon reaches unresectable proportions limits the number of patients to whom this procedure can be applied with expectations of improved survival. Nevertheless, in our series, 14 of our 43 operative patients (32%) had disease that could have been encompassed in a radical resection, a figure that agrees with the estimates of others.7-8-" The fact that none of our patients and only 1.2% of patients in large collected series underwent the described resection indicates that a considerable number of patients are being denied a procedure that is theoretically advantageous in improving survival. The majority of these undertreated patients are those whose tumors are incidental findings in pathologic spec¬ imens (group A), and consideration should be given to reoperation for regional lymphadenectomy and wedge
resection of the liver. At the present time, surgery is the only means of cure for this tumor; a nonoperative approach is universally associated with patient death in a few months. Radiation therapy and systemic or regional chemotherapy have no apparent effect on the course of the tumor. Furthermore, the 12.5% five-year survival of group A patients in this series, comparable to that in other
series' -' is certainly not grounds for complacency, espe¬ cially when one realizes that these tumors are so early in their evolution as to be unrecognizable by the surgeon. All of the group A patients in this series who died from carcinoma had locally recurrent disease, indicating further the failure of simple cholecystectomy to consistently encompass the tumor. When reexplored because of evidence of recurrence, three of these five patients had a tumor in the hepatoduodenal ligament, suggesting inad¬ equate excision of involved regional lymph nodes, and a fourth had primarily local hepatic involvement. The fifth patient fell by definition into group A rather than group C because of the surgeon's misinterpretation of locally exten¬ sive tumor as periduodenal adhesions. Marcial-Rojos and Medina- have reported a case where reoperation on a group A patient led to a partial hepatectomy, with removal of microscopically invaded liver. The patient was clinicallyfree of disease five years after surgery. The case for reoperation and radical resection in these patients appears
strong.
Identification of the small percentage of patients with gallbladder carcinoma that can be cured by cholecystec¬ tomy alone would eliminate the need for reoperation in some cases. Tumor was confined to the mucosa and muscularis layers of the three group A patients who are either alive or died free of disease, supporting the recent obser¬ vation by Nevin et al'-'1 that tumors localized to these layers are often cured by cholecystectomy. On the other hand, one group patient in this series underwent subtotal cholecys¬ tectomy for a papillary adenocarcinoma localized to the mucosa. Although the resection margins were free of tumor, the patient died with local recurrence. While stronger conclusions could be drawn from this case if technical considerations had not precluded complete chole¬ cystectomy, it does appear that local spread can result from
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superficial tumors-' and that there are no dependable criteria at this time for selecting tumors best treated by cholecystectomy alone, as long as more radical procedures can be performed with acceptable mortality. The poor survival rates in carcinoma of the gallbladder further emphasizes the importance of prophylaxis. More than one third of all patients in this series had significant biliary tract symptoms at least five years before diagnosis, and half of these patients had definite roentgenographic evidence of cholelithiasis at the time. While the indications
for
cholecystectomy should not be broadened for the specific purpose of preventing cancer, prophylactic chole¬ cystectomy should be considered in any patient with stones whose expected longevity places him at risk for the devel¬ opment of biliary tract complications, including cancer. Improvement in mortality from this disease can only come about at the present time with more aggressive surgery— both prophylactic and therapeutic. This investigation Foundation.
was
supported
in
part by the Sidney R. Rosenau
References
Straugh
GO: Primary carcinoma of the gallbladder: Presentation of from the Rhode Island Hospital and a cumulative review of the last ten years of the American literature. Surgery 47:368-383, 1960. 2. Arminski TC: Primary carcinoma of the gallbladder: A collective review with the addition of twenty-five cases from the Grace Hospital, Detroit, Michigan. Cancer 2:379-399, 1949. 3. Beltz WR, Condon RE: Primary carcinoma of the gallbladder. Ann Surg 180:180-184, 1974. 4. Fahim RB, Ferris DO, McDonald JR: Carcinoma of the gallbladder: An appraisal of its surgical treatment. Arch Surg 86:334-341, 1963. 5. Holmes SL, Mark JBD: Carcinoma of the gallbladder. Surg Gynecol Obstet 133:561-564, 1971. 6. Ram MD: Carcinoma of the gallbladder. Surg Gynecol Obstet 132:1044\x=req-\ 1048, 1971. 7. Vaittinen E: Carcinoma of the gallbladder: A study of three hundred and ninety cases diagnosed in Finland, 1953-1967. Ann Chir Gynaecol Fenn 168(suppl):7-81, 1970. 8. Adson MA: Carcinoma of the gallbladder. Surg Clin N Am 53:1203\x=req-\ 1216, 1973. 9. Tanga MR, Ewing JB: Primary malignant tumors of the gallbladder: Report of forty-three cases. Surgery 67:418-426, 1970. 10. Chandler JJ, Fletcher WS: A clinical study of primary carcinoma of the gallbladder. Surg Gynecol Obstet 117:297-300, 1963. 11. Hendricks J, Beckers J, Franssen G, et al: Primary carcinoma of the gallbladder. Tijdschr Gastroenterol 13:11-25, 1970. 1.
seventy
cases
12. Warren KW, Hardy KJ, O'Rourke MGE: Primary neoplasia of the gallbladder. Surg Gynecol Obstet 126:1036-1040, 1968. 13. Hardy MA, Volk H: Primary carcinoma of the gallbladder: A ten-year review. Am J Surg 120:800-803, 1970. 14. Keill RH, DeWeese MS: Primary carcinoma of the gallbladder. Am J Surg 125:726-729, 1973. 15. Litwin MS: Primary carcinoma of the gallbladder: A review of seventy-eight patients. Arch Surg 95:236-240, 1967. 16. Bossart PA, Patterson AH, Zintel HA: Carcinoma of the gallbladder: A report of seventy-six cases. Am J Surg 103:366-369, 1962. 17. Fahim RB, McDonald JR, Richards JC, et al: Carcinoma of the gallbladder: A study of its modes of spread. Ann Surg 156:114-124, 1962. 18. Hart J, Modan B: Factors affecting survival of patients with gallbladder neoplasms. Arch Intern Med 129:931-934, 1972. 19. Pack GT, Miller TR, Brasfield RD: Total right hepatic lobectomy for cancer of the gallbladder: Report of three cases. Ann Surg 142:6-16, 1955. 20. Glenn F, Hays DM: The scope of radical surgery in the treatment of malignant tumors of the extrahepatic biliary tract. Surg Gynecol Obstet
99:529-541, 1954. 21. Frank SA, Spjut HJ: Inapparent carcinoma of the gallbladder. Am Surg 33:367-372, 1967. 22. Marcial-Rojos RA, Medina R: Unsuspected carcinoma of the gallbladder in acute and chronic cholelithiasis. Ann Surg 153:289-298, 1961. 23. Nevin JE, Moran TJ, Kay S, et al: Carcinoma of the gallbladder. Cancer 37:141-148, 1976.
Downloaded From: http://archsurg.jamanetwork.com/ by a University of Iowa User on 06/17/2015
M.
Piehler, MD, Robert W. Crichlow,
MD
clinical records of 48 patients with primary carcinoma of gallbladder seen at the Dartmouth-Hitchcock Medical Center
\s=b\ The
the
the past 25 years were reviewed. Of the 37 patients with unresected tumors, there were no survivors. Of the 11 patients with resected tumors, one survived five years, two died before five years without evidence of recurrence, and the remainder died with locally recurrent tumor. This experience reemphasizes the inadequacy of the present surgical approach to the disease. The tendency of carcinoma of the gallbladder to spread initially by local invasion of the liver bed and by metastases to regional lymph nodes has often been neglected by those treating the disease. Wedge resection of the liver and regional lymphadenectomy in addition to cholecystectomy are theoretically advantageous and should be striven for in the case of resectable tumors, even if reoperation is required.
order to determine whether approach is warranted.
over
(Arch Surg 112:26-30, 1977)
carcinoma of the gallbladder remains a source frustration to surgeons. Despite recent advances in cancer detection and management, no concom¬ itant improvement in survival has resulted for patients with this disease, and five-year survivors continue to be rare. Nevertheless, the disease is sufficiently common, occurring in 1.4% of all biliary tract operations from large collected series,1 that most surgeons will be faced with the disease at some point in their careers. The poor prognosis for patients with this tumor is due to advanced age, lack of specific symptoms or means for establishing the diagnosis early, a propensity for early invasion of vital surrounding structures, and the seeming unavailability of a successful surgical approach. These factors have resulted in an attitude of therapeutic nihilism among surgeons. We have reviewed the clinical records of patients with histologically proved carcinoma of the gall¬ bladder seen at this institution over the past 25 years in
Primarygreat of
for publication June 29, 1976. From the Department of Surgery, Dartmouth-Hitchcock Medical Center, Hanover, NH. Reprint requests to the Department of Surgery, Dartmouth Medical School, Hanover, NH 03755 (Dr Crichlow).
Accepted
a more
aggressive surgical
SUBJECTS AND METHODS The clinical records of 48 patients with histologically proved carcinoma of the gallbladder seen at the Mary Hitchcock Memorial Hospital in a 25-year period ending December 1974 were reviewed. The histologie diagnosis was made at laparotomy in 34 patients (71%), by postoperative pathological examination in nine patients (19%), and at postmortem examination in five nonsurgical patients. Follow-up studies were completed in all cases. There were 11 men and 37 women, a ratio of 1:3, which corresponds to published results from other series.1 Ages ranged from 49 to 85 years, with a mean age of 68.7 years. The patients were divided into four groups according to the scheme of Beltz and Condon.' Group A consisted of eight patients in whom the diagnosis of gallbladder carcinoma was made postoperatively by pathological study of resected specimens after biliary tract procedures for was comprised of three presumed benign disease. Group patients in whom the diagnosis was made intraoperatively and who underwent what was thought to be a curative resection by the operating surgeon. In all of these patients, the resection margins were free of tumor by histologie examination. Two of these patients were incidental discoveries at operation for other nonbiliary tract procedures. Group C consisted of 18 patients who at operation were found to have metastatic disease that precluded resection but who underwent a palliative procedure primarily for relief of biliary or gastrointestinal obstruction. Group D consisted of 19 patients who at operation were found to have widely metastatic disease that precluded resection and who underwent diagnostic biopsies only. Also included in this group were the five nonsurgical patients whose tumors were discovered at autopsy. There were no significant differences in age or sex distribution among the four groups. The clinical presentations differed somewhat for each group. Patients with early resectable lesions (groups A and B) tended to have symptoms of benign biliary tract disease. These had been present for a mean period of 3.6 weeks. Patients with more extensive disease in groups C and D had symptoms of diffuse intraabdominal malignancy present for a mean period of 10.4 weeks. There were, however, no presenting symptoms that were specific for the disease or for any group. Of 44 patients with symptomatic tumors, no symptoms were referable to the biliary
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·-
Table
2.—Operative Procedures Group
Table
1—Physical Findings
in Carcinoma of the
Gallbladder Resectable Tumors
Group A Group (n 8) (n 3) =
Palpable mass (including gallbladder) Hepatomegaly Jaundice Abdominal tenderness Ascites
4
2 3
...
...
%
=
=
36 18
7 8
12
27
8
4
82
9 1
13 4
9
8
1
0
14
14
19
48
With bowel resection
43 54 32 59 14
With gastroenterostomy Gastroenterostomy With right hemicolectomy Right hemicolectomy Colostomy Biopsy alone No surgery Total
18
...
no biliary tract disease was diagnosis. Of this group, three had
(25%) patients, and
entertained in the differential
symptoms of upper gastrointestinal obstruction
at the distal and gastric outlet levels, and three patients had symptoms of large bowel obstruction. The remainder had nonspe¬ cific symptoms of malignancy-lethargy, weight loss, anorexia, and dull abdominal pain. As expected, none of these patients had resectable lesions. Four patients had the clinical diagnosis of acute cholecystitis, three in group A, one in group D. Eight patients (17%) had roentgenographic evidence of biliary calculi or of abnormal gallbladder function antedating the diag¬ nosis of cancer by more than five years. An additional eight patients (17%) had symptoms of chronic biliary tract dysfunction that had led them to their physicians more than five years earlier, but cholecystography was not performed. Ultimately, gallstones were found in 40 patients (83%) and were definitely not present in two (4%), while no information was available in six cases (13%). Pertinent physical findings categorized by clinical groups are presented in Table 1. The nonspecific nature of these findings is evident, as is the lack of statistically significant differences between findings in patients with resectable and unresectable tumors. The absolute association of ascites with unresectability is noted. While the more extreme laboratory derangements were found in patients with more extensive disease, there were no consistent findings that determined resectability. Roentgenographic studies did not contribute significantly to diagnosis, but they served to point out the wide diversity of findings in these patients. Plain abdominal roentgenograms were abnormal in 15 of 33 patients. Six roentgenograms showed gastrointestinal obstruction; one at the duodenal, and five at the colonie level. Five showed only the presence of gallstones, three showed soft tissue abdominal masses, and one roentgenogram showed a right upper-quadrant extraintestinal gas collection. None of 15 oral cholecystograms visualized the gallbladder. Intra¬ venous cholangiography was performed twice without visualiza¬ tion. Upper gastrointestinal barium contrast roentgenograms were abnormal in 13 of 35 patients, showing duodenal or gastric displacement medially by a mass in nine patients, gastric outlet obstruction in three, and a duodenal ulcer in one patient with normal gastric acid studies. Barium enema roentgenograms were abnormal in seven of 25 individuals, showing partially obstructing colonie lesions in five patients, hepatic flexure irritability in one, and a duodenocolic fistula in one. Three of four liver scans showed
esophageal
Totals
Partial, with external drainage Choledochostomy (decompressive)
Group C Group D (n 18)(n 19)
...
...
tract in 11
=
Unresectable Tumors
D
Cholecystostomy Cholecystectomy With choledochostomy (diagnostic) With choledochostomy (decompressive) With hepatic wedge resection
evidence of metastatic disease. In one individual, percutaneous transhepatic cholangiography demonstrated a presumed benign common duct obstruction found to be due to tumor at exploration. Chest roentgenograms, performed on all patients, showed diffuse metastatic disease in two individuals. A percutaneous liver biopsy performed on two patients showed adenocarcinoma preoperatively in one. With the exception of nonvisualization on oral cholecystography, abnormal findings on the roentgenograms were usually associated with advanced tumors. The correct diagnosis was made preoperatively in only six patients (14%) and was based more on clinical suspicion than on specific laboratory or roentgenographic
findings. Operative procedures performed are listed in Table 2, subdi¬ vided by clinical group. Seven patients underwent reoperation after their initial procedures: two patients (both group A) were reexplored to increase the scope of resection, and the other patients were reexplored for palliation of subsequent obstructive symptoms. Survival data
are
Group A
C D All
patients
summarized in the
Figure: Mean Survival, 21.5 22.5 3.2 1.7 7.5
mo
There is no statistically significant difference in survival between ( > .01). There is one six-year survivor who groups A and subsequently died of an unrelated cause, one three-year survivor who died without clinical evidence of recurrence but without postmortem examination, and one patient who is currently alive without evidence of recurrence 2% years after surgery. All of these patients are in group A. All remaining patients have died as a direct result of their disease. Thus, the five-year survival rate of all patients is 2.1%. Of those with resectable tumors, the survival rate is 9.1%, and of those in group A, the rate is 12.5%. The operative mortality (within 30 days of operation) after primaryprocedures was 30% (13 of 43 patients), all in groups C and D. An additional two patients died within 30 days of secondary palliative
procedures. The histology of the resected specimens vs associated mean survival figures is given in Table 3. Of note is the association of papillary adenocarcinoma with resectability and good prognosis
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%·-·- -
GROUP
j—»
6
MONTHS Survival
curves
by
AFTER
clinical group for
anaplastic tumors with unresectability and prognosis. Of those patients with tumors grossly evident at surgery or postmortem examination (groups B, C, and D), three had localized disease or resectable extension of tumor into adjacent liver (group B). Twenty-one patients considered unresectable had disease localized in the gallbladder, liver, hepatoduodenal ligament, and duodenal area; review of the operative reports in this group and the association of poor
suggests that in three instances, the tumor could have been removed had wedge resection of the liver been done. Sixteen individuals had unresectable disease that had metastasized to noncontiguous organs, both intra- and extraperitoneally. This latter group demonstrated métastases to almost all major organs, including omentum, peritoneal surfaces, kidney, adrenal glands, small and large bowel, stomach, pancreas, diaphragm, pleura, lung, and brain, as well as para-aortic lymph nodes. Two patients (one in group C, one in group D) were treated with fluorouracil via an indwelling common hepatic artery catheter. Both patients died three months after diagnosis, and there was no indication that the course of the disease was altered by the chemotherapy. The cause of death in those patients surviving surgery was almost universally obstructive hepatic failure, often with diffuse intra-abdominal carcinomatosis.
COMMENT
series of what new information he has to contribute. Previous reports have emphasized the dismal facts of the disease: that at opera¬ tion, only about 10% to 25% of the patients have resectable tumors, that the five-year survival rate for all patients is generally less than 5%, and that the only survivors, by and large, are those few patients whose carcinomas are inci¬ dental pathologic findings in gallbladders removed for presumed benign biliary disease.'·3"8 It is traditional to accept poor survival from carcinoma of the gallbladder as a result of its discovery at an unfavorably late stage for treatment. And yet, review of the literature and of our own experience suggests that a significant proportion of those
only logical to ask an author reporting patients with carcinoma of the gallbladder It is
a
24
18
12
_l_
30
42
36
48
54
60
DIAGNOSIS
patients with carcinoma of gallbladder.
Table 3.—Tumor
vs Survival in Carcinoma of the Gallbladder
Histology
Group
_
Tumor Histology Adenocarcinoma Papillary adenocarcinoma
Anaplastic Epidermoid
A 4
B 2
_
C 18 3 10 0 0 1 10 0
D 11
0 1
Mean Survival 4.4 40.9
(mo)
0.9
with resectable lesions are being undertreated and that the prevalent attitude of hopelessness in treating this tumor may contribute to the poor patient survival. The low resectability rate for this tumor stems from the nonspecific nature of the clinical, laboratory, and roent¬ genographic presentations that call attention to those patients with extensive disease and leave undetected those with early, resectable tumors.-79" These factors, com¬ bined with a low level of clinical suspicion, result in a preoperative diagnostic accuracy of only 14% in this series and of 0% to 19% in others.1-14-"' Thus, the surgeon's encounter with carcinoma of the gallbladder is too often both unexpected and unsatisfying, emphasizing the need for a planned surgical approach to those few patients fortuitously found to have resectable disease. The failure of traditional surgical management of those patients with resected tumors was evident from this series. In 1962, Fahim et al17 reported the modes of spread of gallbladder cancer determined from dissection of operative specimens. They concluded the following: (1) The spread of the tumor is by local invasion without distant métastases until very late in the disease course. (2) Lymphatic spread of tumor is to the cystic node, pericholedochal nodes, and in late stages, to the superior and posterior pancreaticoduodenal and para-aortic nodes. (3) Vascular spread is uncommon (14%) and leads to adjacent liver involvement via penetrating vessels in the gallbladder bed initially and
patients
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to diffuse vascular infiltration in the liver or other organs. (4) Intraperitoneal spread is common and involves adjacent organs well before the development of disseminated intraperitoneal métastases. (5) Neural spread occurs relatively frequently (24%) and is associated with more aggressive tumors but is otherwise of uncertain significance. (6) Intraductal spread is least common and is seen most frequently in cases of papillary adenocarcinoma. The tendency of the papillary cell-type to grow intraluminally rather than invasively explains the better prognosis for these patients, which has been noted by many authors.!'ls In this series, all of the papillary adenocarci¬ nomas were resected, and a mean survival period of 40.9 months was seen, consistently better than for any other
only later
cell-type. These findings support the conclusion that the minimum operation for minimally invasive adenocarcinomas consists of cholecystectomy with wedge resection of liver with a margin of normal tissue and nodal dissection encompass¬ ing the cystic and pericholedochal nodes to the periaortic nodes.17 The extent of hepatic resection and node dissection must be individualized but aggressive. Although exten¬ sive liver resection has been performed,1" a concomitant lymph node dissection, though suggested by many,"-8-11'1--13'1" has been practiced by few.7-8 As Fahim et al17 noted lymphatic spread in 26% of his series, the omission of lymph node dissection may preclude successful resection in a significant number of patients. Indeed, Vaittinen's7 extensive review reports only 1.2% of the operations for this disease involved cholecystectomy, liver resection, and lymph node dissection. Those who have applied radical resection to carcinoma of the gallbladder have come to different conclusions concerning its effect on survival. Glenn and Hays-" reported five three-year survivors and two five-year survi¬ vors among 19 patients undergoing curative resection, 15 of whom had the radical procedure. He concluded that extensive resection would not result in improved survival. HowTever, two of their longest survivors had invasive cancers, and one four-year survivor had metastatic carci¬ noma in a resected regional lymph node. In the Mayo Clinic experience reported by Adson," three patients survived 3]/2 to 12 years after radical resection in which the excised
specimens contained metastatic carcinoma in either the liver or regional lymph nodes. There were no postoperative deaths in nine patients who underwent the procedure. He concluded that the unusually long survival in these patients was
due to the radical nature of the resection. Vaittinen7
reports that in 16.7% of the patients undergoing cholecys¬ tectomy, wedge resection of liver and lymph node dissec¬
tion survived five years as opposed to 10.6% after what was thought to be a curative cholecystectomy alone. While the available data are insufficient to establish the role of radical surgery, continued trial is certainly warranted. The fact that the majority of successes in treatment have come after simple cholecystectomy only points out that, not unexpectedly, there is a stage when the tumor is localized and curable.7 Further improvement in survival might be gained by removal of tissue along the known paths of
spread. The tendency of the tumor for aggressive local invasion that soon reaches unresectable proportions limits the number of patients to whom this procedure can be applied with expectations of improved survival. Nevertheless, in our series, 14 of our 43 operative patients (32%) had disease that could have been encompassed in a radical resection, a figure that agrees with the estimates of others.7-8-" The fact that none of our patients and only 1.2% of patients in large collected series underwent the described resection indicates that a considerable number of patients are being denied a procedure that is theoretically advantageous in improving survival. The majority of these undertreated patients are those whose tumors are incidental findings in pathologic spec¬ imens (group A), and consideration should be given to reoperation for regional lymphadenectomy and wedge
resection of the liver. At the present time, surgery is the only means of cure for this tumor; a nonoperative approach is universally associated with patient death in a few months. Radiation therapy and systemic or regional chemotherapy have no apparent effect on the course of the tumor. Furthermore, the 12.5% five-year survival of group A patients in this series, comparable to that in other
series' -' is certainly not grounds for complacency, espe¬ cially when one realizes that these tumors are so early in their evolution as to be unrecognizable by the surgeon. All of the group A patients in this series who died from carcinoma had locally recurrent disease, indicating further the failure of simple cholecystectomy to consistently encompass the tumor. When reexplored because of evidence of recurrence, three of these five patients had a tumor in the hepatoduodenal ligament, suggesting inad¬ equate excision of involved regional lymph nodes, and a fourth had primarily local hepatic involvement. The fifth patient fell by definition into group A rather than group C because of the surgeon's misinterpretation of locally exten¬ sive tumor as periduodenal adhesions. Marcial-Rojos and Medina- have reported a case where reoperation on a group A patient led to a partial hepatectomy, with removal of microscopically invaded liver. The patient was clinicallyfree of disease five years after surgery. The case for reoperation and radical resection in these patients appears
strong.
Identification of the small percentage of patients with gallbladder carcinoma that can be cured by cholecystec¬ tomy alone would eliminate the need for reoperation in some cases. Tumor was confined to the mucosa and muscularis layers of the three group A patients who are either alive or died free of disease, supporting the recent obser¬ vation by Nevin et al'-'1 that tumors localized to these layers are often cured by cholecystectomy. On the other hand, one group patient in this series underwent subtotal cholecys¬ tectomy for a papillary adenocarcinoma localized to the mucosa. Although the resection margins were free of tumor, the patient died with local recurrence. While stronger conclusions could be drawn from this case if technical considerations had not precluded complete chole¬ cystectomy, it does appear that local spread can result from
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superficial tumors-' and that there are no dependable criteria at this time for selecting tumors best treated by cholecystectomy alone, as long as more radical procedures can be performed with acceptable mortality. The poor survival rates in carcinoma of the gallbladder further emphasizes the importance of prophylaxis. More than one third of all patients in this series had significant biliary tract symptoms at least five years before diagnosis, and half of these patients had definite roentgenographic evidence of cholelithiasis at the time. While the indications
for
cholecystectomy should not be broadened for the specific purpose of preventing cancer, prophylactic chole¬ cystectomy should be considered in any patient with stones whose expected longevity places him at risk for the devel¬ opment of biliary tract complications, including cancer. Improvement in mortality from this disease can only come about at the present time with more aggressive surgery— both prophylactic and therapeutic. This investigation Foundation.
was
supported
in
part by the Sidney R. Rosenau
References
Straugh
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