- Email: [email protected]
Primary carcinoma of the gallbladder
SURGICAL
REVIEW
Primary
Carcinoma
C. DOUGLAS SAWYER, M.D.*
AND
of the Gallbladder
J. F.
c
MINNIS,
Neu> York
JR., M.D., Brooklyn,
cinema should be equated to some commonly accepted denominator, i.e., cholecystectomies, CholeIithiasis, autopsies or patient admissions. However, the literature is variable; one series is a ratio of cancer to autopsies, another to choleiithiasis (proved and suggested by chole-
HOLECYSTICdisease has long been a subject of controversy among surgeons and internists alike. Recent years have seen the resolution of most of the essential differences among surgeons; however, many internists persist in advocating great caution in regard to operative approaches for this disease The problem of the “siIent” stone, entity. non-calculous cholecystitis and acute choIecystitis persists both in diagnosis and management. Technical hazards of operation and complications are well recognized. In view of the many probIems of diagnosis, management and operative technic confronting the surgeon in diseases of the gallbIadder, malignancy is relegated to undeserved obscurity. At the Rlethodist HospitaI of Brooklyn, 1,752 cholecvstectomies were performed in a fifteen-year “period from January, 1939 to December, 1953, A pathoIogic diagnosis of carcinoma of the gallbladder was primary proved in twenty-seven cases during this time, an incidence of 1.54 per cent. Four cases have been excluded from this series. In two a biops\ specimen was taken of a metastatic site, which was reported histologically as being compatible with origin in the gallbladder or bile ducts. In the other two no tissue specimen was obtained for histopathologic esamination, the surgeon being convinced of inoperable carcinoma of the gallbladder. LamI reports that 6,300 persons in the United States die each year of primar? carcinoma of the gallbladder, giving an incidence of 2.8 to 6 per cent of all malignant lesions.?s’6
TABLE INCIDEkCE
OF I’OUND
CARCINOMA AT
I OF
THE
(;ALLBLADDER
CHOLECXTECTO?11
( No. of
ChoIecys-
Series
’
Methodist HospitaI. Russell and Brown2’. Swinton and Becker?. Finney and Johnson8 Childs and Johnson’
.1 / I
1,752 1,488 49554
1,192 III
Pcrcent-
age
I tectomies
I
1.5 1.‘) 0.9 1.5 13.5
cystogram). We have elected, because of wider accepted preference, to quote our incidence in relation to cholecystectomies even though three of our cases were autopsy findings in patients who had not undergone surgery. Table I provides a brief r&sum& of incidence rates at various clinics reported in the recent literature.4~8~Z’~22The incidence figure presently most accepted is I to 1.3 per cent. In 1939 lClohardt’* reported an incidence of I ~I 2 per cent in 35,000 operations on the galIbIadder. Swinton and Beckerz2 postulate that since more patients are coming to surgery for cholecystic disease earlier, the incidence of primary carcinoma of the gallbladder has decreased in recent years. Our study has revealed that the incidence of malignancy of the gallbladder has not varied appreciably in the fifteen years reviewed. However, indications for cholecystectomy at the Methodist Hospital of Brooklyn for this period have been those which are
INCIDENCE There is considerable discrepancy in the reported incidences of primary malignancy of the galIbIadder. In attempting to establish an incidence rate, the number of cases of car* Deceased. 99
Sawyer
and Mink
presently accepted and, perhaps, may account for the reIativeIy constant incidence of malignancy. Age and Sex. Patients with primary carcinoma of the gaIIbIadder are reported in age groups between twenty-three and ninety TABLE INCIDENCE
OF
CARCINOMA IN
finding was equivocal, we have not included it in our statistics. (TabIe III.) As earIy as 1931 GrahamlO stated that “The occurrence of most, if not a11 cases of carcinoma of the gall-btadder couId be prevented by cholecystectomy in cases which
II
TABLE
OF
THE
GALLBLADDER
INCIDENCE
CHOLELITHIASIS
OF
I
Percent_
1,202
OF THE
206 564 15,422 450 540
AND
IN
CARCINOMA
GALLBLADDER
5.4 8.5 2.0
2.9 4. I 4.5
Pcrcentage
Carcinoma
hlethodist tIospital, ........ Howard12. ................. Dan&. ................... Benjamin’. ................ Childs and Johnson’. ....... Coopers. ................... Judd and Gray’“. ...........
2.2
92.6 86.4 100 86 67
27 22 26 70 I5 48
ii.6
212
-
i
present evidence of gaII-stones, regardIess of the presence of those symptoms which wouId ordinariIy compel a patient to have an operation.” Since the operative mortaIity in surgery of the gaIIbIadder approximates the incidence of malignant disease of that organ, it wouId be falIacious to advocate cholecystectomy for cholelithiasis in a11 patients soIeIy for the prevention of cancer. We concur with a statement attributed to Mayo” some twenty-five years ago that there are no siIent gaIIstones, that sooner or Iater these patients will present symptoms referabIe to their gaIIstones. This is particuIarIy pertinent in view of the Ionger Iife expectancy of today. Laheyls has stated: “If one deaIs with gaI1 stone patients in large number, one cannot help being impressed with the fact that this philosophy (the non-remova of a11 gaIIbIadders with caIcuIi) resuIts in many situations, and in many fatalities which would not have occurred had the operative procedure been undertaken earIier.” Carcinoma of the gallbIadder is an integra1 part of these fatalities occurring in Iater life.
years.22 In our series the majority were in the fifth and sixth decades; the youngest was fortyone and the oldest was eighty-eight years of age. It is well to note that 60 per cent of the maIignancies occurred in persons over the age are more commonIy of sixty years. Women affected than men, the generaIIy accepted ratio being 4 : I. CHOLELITHIASIS
THE
Series
age
I--/-
Methodist HospitaI. Illinois Research Hospital’3 Grahamlo. Judd and Gray’4.. Deaver and Bortz?.. Good Samaritan HospitaI, PortIand, Oregon. RlohardtlR.
III
CHOLELITHIASIS
I Lithiasis in ChoIecystectomy
Series
OF
MALIGNANCY
GALLBLADDER
The incidence of maIignancy of the gaIIbIadder in caIcuIous ChoIecystitis paraIIeIs that in choIecystectomy aIthough, quite naturally, the ratio is s1ightIy higher since a11 gaIIbIadders removed at Iaparotomy do not contain calculi. (TabIe II.) It is notabIy significant that smaIIer series generaIIy report higher occurrence rates>~‘0,‘2-14 The reIationship of ChoIeIithiasis to primary carcinoma of the gaIIbIadder has Ied certain investigators, prominentry Petrov and Krotkina,’ to posit Iithiasis as an etioIogic factor in the deveIopment of cancer of the gaIIbIadder. The incidence of ChoIeIithiasis in patients with malignancy of the gaIIbIadder is uniformIy high, u,S,*~ varying from IOO per cent reported by Danzi9 to 64.6 per cent reported by Judd and Gray.14 In our series twenty-five patients defIniteIy had ChoIeIithiasis. One other patient may have had caIcuIi; however, since this
SYMPTOMS
AND
SIGNS
There are no earIy symptoms of carcinoma of the gaIIbIadder. The symptoms and signs which are first encountered are usuaIIy those of the associated ChoIeIithiasis and are typica of that disease. Symptoms cIassicaIIy ascribed to maIig100
Primary
Carcinoma
of Gallbladder
nancy are pain, anorexia or dyspepsia, weight loss and jaundice, usually of the obstructive type. *” The pain is similar to that of chronic choIecystitis although it is typically more constant and becomes progressively worse in the two to three weeks prior to admission.
One patient Ivas admitted with small bowel obstruction secondary to “gallstone ileus.” She underwent two operative procedures for intestinal obstruction and died following a storm?; downhill postoperative course. Carcinoma, primary in the gallbladder, was an
TABLE Lv SIGNS AND SYMPTOMS OF CARCINOMA OF THE I;ALLBLADDER
TABLE v ROENTGENOGRAMS
Signs
and Symptoms
Typical chronic cholecyst’tis. Typical acute cholecystitis. Previous history of jaundice. Weight loss. Jaundice on admission. PaIpabIe liver. PaIpabIe gaIlbladder. Abdominal mass (not definitely bIadder)
Cholecystograms: Negative. N 0nvrsuaLLa _ 1’. t’ran . .._.... lithiasis. Poor function. “Pathologic response”. FIate plate: Negative. Calculi suggestive of cholelithiasis. 1ntestinal obstruction, Gastrointestinal series: Negative. I)uodenaI ulcer.. Extrinsic pressure defect. Barium enema of colon: Negative. lixtrinsic pressure defect
No. of Patients
1
‘4 ID* 71 4
5 L0 /
7
5 gall2
* These patients gave a history which couId distinguished from chronic or acute cholecystitis.
not
be
Clinical findings of icterus, a palpable gallbladder or some other mass in the right upper quadrant, and hepatomegaIy are considered characteristic.‘” It is our opinion that these signs and symptoms are Iate manifestations. Sixteen of the patients in our series gave a history which could not be distinguished from chronic or acute cholecystitis. (‘Table IV.) These patients were the only ones for whom there was any possibility of cure. Except for two persons having an apparent initial attack of acute cholecystitis, the duration of symptoms in these sixteen patients was one to twenty years, the mean being six years. Findings described as typical of primary carcinoma of the gaIlbladder were not the usual in this series: Four patients gave a history of jaundice although they were not icteric on admission. Five gave a history of weight 10s~. Ten patients were jaundiced on admission. In seven a mass was palpable in the right upper quadrant which was uniformly tender; of these, five were interpreted as gallbladder. Anemia (less than IO gm. of hemoglobin) was present in only one. While leukocytosis (over 10,000 cells) was present in a majority (fifteen patients), we cannot attribute any particular significance to this finding in reference to malignant disease.
‘4
o II z I I*
.,.
1 .
4
z I 5 2 2
It 2
I It
* Performed t Same
elsewhere. patient with same
area of defect.
“incidental” autopsy finding. In another case the onIy symptoms were dull, constant right lower quadrant pain and anorexia, beIieved to be chronic appendicitis on admission. During work-up prior to exploratory celiotomy, cholecystogram showed non-visualization of the gaIIbIadder. There was no suggestion of mahgnancy at Iaparotomy, and uneventful choIecystectomy was performed. The patient died seventeen days postoperativeIy after emboli had been showered to the lower extremities and brain. Two patients had associated symptomatic duodenal ulcers. These four cases have been mentioned briefly merely to point up the insidious nature of carcinoma of the gahbladder and to demonstrate the false sense of security inherent in non-operative management of the “innocuous” silent gallstone. X-ray studies were of diagnostic value in seventeen of twenty-three patients subjected to some form of roentgen examination. (Table v.) Cholecystograms, quite naturally, proved the most vahrable aid of this type Fourteen patients were subjected to cholecystography: EIeven cholecystograms showed IO1
Sawyer
and Minnis bladder had been compIeted. Gray and SharpelI reported a series of 291 cases of primary carcinoma of the gaIlbladder in which 8g per cent showed spread ‘of the tumor into the liver, regiona lymph nodes or omentum at the time of operation.
non-visualization and in one of these radiopaque caIcuIi were demonstrable. Two showed Iithiasis. One showed poor function without lithiasis, and one, performed eIsewhere, was reported simpIy as “pathoIogic response.” These figures correspond with others reported in recent series.20v21
HISTOPATHOLOGY
DIAGNOSIS
The correct diagnosis was made preoperativeIy in onIy two cases in which Iaparotomy was performed, and in no case in which the patient was not subjected to surgery. Diagnostic accuracy, then, was 7.4 per cent. Carcinoma of the galIbIadder was suggested in the differential diagnosis in four other patients. This point is offered not to beIittle the diagnostic acumen of the interested physicians but rather to demonstrate the eIusive character of this disease diagnosticaIIy, particuIarIy in view of the significant number of earIy cases discovered in the series. Cholecystitis and/or choIedocholithiasis were the preoperative diagnoses considered primariIy in twenty patients. Primary malignant disease which is Iimited to the gaIIbIadder often may not be obvious at Iaparotomy or during choIecystectomy. Acute inflammation of that organ may mask an underIying carcinoma by distention of the viscus and edema of its waIIs and adjacent tissues. This is particuIarIy true in the resoIving phase of acute cholecystitis. Indeed, the subsiding edema, fibrosis and earIy scarring most often may not be distinguished by external examination from a malignant process confined to the galIbIadder. Twenty-four of our cases came to Iaparotomy. The diagnosis of maIignant disease was considered in onIy fourteen cases or in fifty-eight per cent; however, in a11 fourteen instances the primary site of malignancy was considered to be the gaIIbIadder. Four cases were diagnosed as chronic choIecystitis and five as acute choIecystitis. One patient had intestina1 obstruction due to impacted gaIIstone at the iIeoceca1 vaIve. Swinton and Beckerz2 report that in onIy two of their series of twenty cases the diagnosis of primary carcinoma was discovered by the pathoIogist, the gaIIbIadder having been removed for conditions other than malignancy. Puestow20 presented a series of twenty-nine cases: in five of the twenty-six patients operated upon the diagnosis of primary carcinoma was not SUSpetted unti1 pathoIogic studies of the galI102
Foot9 divides primary carcinoma of the gallbIadder into two types, nameIy, adenocarcinema and epidermoid carcinoma. Adenocarcinoma is said to arise usuaIIy in the neck of the organ. It may be poIypoid in type or, more commonIy, infiItrating and scirrhous. MetapIastic epithelium in the gaIIbIadder may produce the epidermoid type of malignant disease. Gray and Sharpe” report that squamous ceII carcinoma occurs in about 4.4 per cent of primary malignancies of the gaIlbladder. Adenocarcinoma was the most frequent carcinoma occurring in our series. We have not attempted to break down the adenocarcinomas further as to papiIIary, scirrhous, etc. Squamous carcinoma was found in four cases, or 13 per cent, which is an occurrence rate of about three times that usuaIIy reported. CorreIation of surviva1 period in patients having adenocarcinoma with those having squamous cell carcinoma would be faIIacious in such a smaI1 series; suffice it to say that a11 patients having epidermoid carcinoma died within six months of the time of hospital admission. In 40 per cent of our cases the tumor was apparently limited to the gaIlbIadder itseIf. We have been most fortunate to have had so many earIy cases. Other series report a much Iower incidence of cases in which the maIignant process is confined to the gaIIbIadder. An interesting finding was that seven, or 26 per cent, of the patients had acute choIecystitis, histoIogicaIIy, at Iaparotomy. In reviewing the Iiterature we have found no mention of the occurrence of acute cholecystitis incident to primary carcinoma of that The diff&Ity encountered in the organ. recognition of malignant disease grossIy, in the presence of acute inflammation, has been presented heretofore. TREATMENT
AND
RESULTS
To date, the onIy treatment for primary carcinoma of the gaIIbIadder is surgery. Finney and Johnson8 have expressed the foIIowing sentiment, common to most surgeons, in regard
Primary
Carcinoma
of GaIlbladder
TABLE OPERATIVE
j Definitive
AND
-.--
---
(
i Under 2 wk. _(___’
~~
Cholecystectomy I3 ChoIecystostomy 1 z Biopsy.................. . . . . ..I 3 Choledochotomy and biopsy. z ChoIecystectomv, wedge resection of Iiver.. I and omentecCholecystectorny tomy....... ..,. ._._....... I Cholecystectomy, wedge resection of liver, resection of gastrohepatic omentum and regiona lymph nodes.. I Cholecystectomy, transverse colostomy (;2likulicz1, and partial 1 duodenectomy.
SURVIVAL
SurvivaI
/
i No. /
Procedure
VI
PROCEDURES
2-
12 wk.
I-
I
I I
/
;
3-6 mo.
/
1ncidencc
6-12 mo.
( 1-3 yr. ‘4-5 yr. ( Over 5 vr.
2
2
I
3”
1
3*
2
I
I
2
I
i
)
1
II
1 I
I 1
24
Totd. * One patient
is living and well
3
7
4
4
I
I I
2
I
I I !< yr. postoperatively. varying radical operations; the longest survivor died within seven months. This patient underwent choIecystectomy, the hnding of primary carcinoma being discovered by the pathologist. Three weeks later the patient was reoperated upon in the hope that radical dissection might result in a five-year cure. At the second procedure no residua1 or metastatic tumor was seen: a wide wedge of liver in the region of the gallbIadder bed was resected and radical resection of the gastrohepatic omentum and regional lymph nodes was performed. Microscopic examination of tissue reveaIed tumor infiltration in the Iiver segment and some Iymph nodes. Booker and Pack3 reported a case of anaplastic carcinoma of the gallprimary bIadder with regiona metastases in which the patient was subjected to similar radical surgery and survived eight years. It is the rare case such as this one that provides impetus to attempt radical surgery, even in the face of regional extension. However, the anatomy of the galIbIadder area, with its vital structures (common duct, hepatic artery and portal vein) is such as to preclude true “cancer surgery.” We believe that the pIace of radical surgery in primary malignancy of the gahbladder must await further appraisal.
hopeto this disease: “. . . such a surgically less condition as carcinoma of the gallbladder.” Five-year survivals, regardless of limitations of the malignant process and/or how radical the operative procedure, are quite uncommon. The operative procedures employed at the Methodist HospitaI of Brooklyn, with the survival incidence for each procedure, are listed in Table VI. Twenty-four patients were subjected to surgery: Seven underwent purely palliative or diagnostic procedures (two cholecystostomy, three biopsy alone and two choledochotomy and biopsy). Thirteen patients underwent cholecystectomy and four were subjected to various forms of radical surgery (choIecystectomy with wedge resection of liver; choIecystectomy and omentectomy; cholecystectomy, wedge resection of liver, resection of gastrohepatic omentum and regional lymph nodes; and cholecystectomy, transverse colostomy and partial duodenectomy). The over-all operative mortality (death within two weeks of surgery) was three, I 2.5 per cent; the hospita1 mortaIity was nine, 37.5 per cent. All of the seven patients who had undergone only pahiative procedures were dead within five months. ResuIts were unimpressive in the four cases in which patients underwent ‘03
Sawyer
and
the tumor and aIIaying metastases. Thus the maIignant process may be made more amenable to surgical extirpation.
The patients subjected to choIecystectomy alone had the best resuIts. It must be remembered that it was in these patients, subjected solely to remova of the gaIIbladder, that evidence of malignancy was not recognized at the time of Iaparotomy. It is therefore assumed that extension or metastases were minimaI. Six patients Iived Ionger than one year postoperatively. There were three five-year survivaIs? giving an over-al1 five-year “cure” rate of 12.5 per cent in patients subjected to surgery. AI1 patients except one are dead. The one Iiving patient is apparentIy free of maIignant disease I I .3 years postoperatively. CASE
Minnis
SUMMARY
AND
CONCLUSIONS
Primary carcinoma of the gaIIbIadder is uncommon. It may be considered a Iate compIication of ChoIeIithiasis. In our opinion ChoIeIithiasis is a surgica1 problem, and choIecystectomy with its Iow operative mortality is the treatment of choice. By this bold surgical attitude the incidence of malignancy may be reduced. Cognizance of the possibiIity of carcinoma of the gaIIbIadder and attempted definitive diagnosis at the time of Iaparotomy, perhaps together with more radical surgery and cancer chemotherapeutic agents which are stiI1 in the experimenta stage, may appreciabIy improve the prognosis of this aImost uniformIy fata disease.
REPORT
R. A., a fifty-six year oId white woman, was admitted to the Methodist HospitaI of Brooklyn on September 27, 1942, with a diagnosis of chronic cholecystitis with ChoIeIithiasis. The history was typical of that disease; the patient had had intermittent “attacks” of biliary coIic and jaundice during the three to five years prior to admission, the Iast “attack” being three months previously. She was afebrile but Ieukocytosis was revealed; the white blood count was 17,400, with g4 per cent poIymorphonucIear leukocytes. The foIlowing morning the patient was subjected to uncompIicated maIignancy not being suschoIecystectomy, pected at that time. Convalescence was uneventfu1 and the patient was discharged on October I Ith, thirteen days postoperatively. The pathologist’s report was adenocarcinoma with invasion of a Iymph node (sentine1 cystic duct Iymph node had been incIuded in the specimen), acute ChoIecystitis and cholelithiasis.
REFERENCES I. BENJAMIN,
analysis
E. G. Carcinoma of the gallbIadder; of 70 cases. Minnesota Med., 3 I : 537,
1948. 2. BOCKUS, H. L. Gastroenterology, vol. 3, chapt. 104, p. 633. Philadelphia, 1943. W. B. Saunders Co. 3. BOOKER, R. J. and PACK, G. T. Carcinoma of the gaIIbIadder; report of a five year cure of anaplastic carcinoma with metastases. Am. J. Surg., 78: 175, ‘949. 4. CHILDS, S. B. and JOHNSON, M. E. Carcinoma of the gaIIbIadder. Am. J. Surg., 83: 212, 1952. 5. COOPER, W. A. Carcinoma of the gaIlbIadder. Arch. Surg., 35: 431, 1937. 6. DANZIS, M. Carcinoma of the gallbladder; a report of 26 cases. J. M. Sot. New Jersey, 45: 274, 1948. 7. DEAVER and BORTZ. Cited by Howard.12 8. FINNEY, J. M. T., JR. and JOHNSON, M. L. Primary carcinoma of the gaI!bIadder; an additional reason for removing the catculous gaI.bIadder. Ann. Surg., 121: 425, 1943. g. FOOT, N. C. Pathology in Surgery. Philadelphia, 1945. J. B. Lippincott Co. IO. GRAHAM, E. A. Prevention of carcinoma of the gaIIbladder. Ann. Surg., g3 : 3 17, I 93 I. I I. GRAY, H. K. and SHARPE, W. S. Carcinoma of the gaIIbIadder, extrahepatic bile ducts and major duodena1 papiIIa. S. Clin. Nortb America, 21: 1117, 1941. 12. HOWARD, M. A. Carcinoma of the gaI1 bladder and biIe ducts. Am. J. Surg., 84: 408, 1952. 13. IIIinois Research HospitaI. Cited by Howard.12 14. JUDD, E. S. and GRAY, H. K. Carcinoma of the gaIIbIadder and biIe ducts. Szcrg., Gynec. @ Obst., 55: 308, 1932. 15. LAHEY, F. H. Common and hepatic duct stones. Am. J. Surg., 40: 209, 1938.
COMMENT
Our surviva1 rate, aIthough far from encouraging, is higher than that reported in the recent Iiterature;4,2”J2 some authors have faiIed to mention end resuIts. Bockus* states that, in his survey of the literature, cure may not be expected in more than one of forty (2.3 per cent) patients surviving surgery. Various adjuncts in the management of primary carcinoma of the gaIIbIadder have been and are being tried. Irradiation has proved of no vaIue. Recently KIopp and Biermannz3 have reported encouraging resuIts with the use of nitrogen mustard in shrinking the size of 104
Primary
Carcinoma
of the hiliary tract, pancreas and spleen. Chicago, 1953. Year Book Publishers, Inc. 21. RI_SSELL, P. W. and BROW%, C. El. Primary carcinoma of the gallbladder; report of zg cases. Ann. Sure., 132: 121, ,950. 22. SWINTON, N. W. and BECKER, W. F. Tumors of the gallbladder. S. Clin. North Americu, 28: 660,
20.
16. LAM, C. K. Present status of carcinoma of the gallbladder; study of 34 chnical cases. Ann. Surg., 111: 403, 1940. I-/. MAYO, W. Cited by Howard.12 18. MOHARDT, J. H. Carcinoma of the gallbladder; collective review. Internat. Abstr. Surg., 69: 440, 1939. 19. PETROV, N. N. and KKOPKINA, N. A. Experimental carcinoma of the gallbladder. Ann. Surg., 125: 241,
of Gallbladder PUESTOW, C. B. Surgery
1948. 23. KLOPP :rnd BIEKM~N\. Cited by Ho\vard.‘P
1941.
\\‘e recommertd: Clinical Aspects of the Autonomic Nervous System. By L. A. Gill&m, M.U. 316 pages, illustrated. Boston, 1954. Little, Brown & Co. Price $6.50. Fluid Therapy. By James D. Hardy, M.D. 255 pages, illustrated. Philadelphia, 1954. Lea & Febiger. Price $5.50. Tumors of Lymphoid Tissue. By George Lumb, M.D. 204 pages, Zustrated, some in coIor. BaItimore, 1954. Williams Bi WiIkins Co. Price $8.00.
105
REVIEW
Primary
Carcinoma
C. DOUGLAS SAWYER, M.D.*
AND
of the Gallbladder
J. F.
c
MINNIS,
Neu> York
JR., M.D., Brooklyn,
cinema should be equated to some commonly accepted denominator, i.e., cholecystectomies, CholeIithiasis, autopsies or patient admissions. However, the literature is variable; one series is a ratio of cancer to autopsies, another to choleiithiasis (proved and suggested by chole-
HOLECYSTICdisease has long been a subject of controversy among surgeons and internists alike. Recent years have seen the resolution of most of the essential differences among surgeons; however, many internists persist in advocating great caution in regard to operative approaches for this disease The problem of the “siIent” stone, entity. non-calculous cholecystitis and acute choIecystitis persists both in diagnosis and management. Technical hazards of operation and complications are well recognized. In view of the many probIems of diagnosis, management and operative technic confronting the surgeon in diseases of the gallbIadder, malignancy is relegated to undeserved obscurity. At the Rlethodist HospitaI of Brooklyn, 1,752 cholecvstectomies were performed in a fifteen-year “period from January, 1939 to December, 1953, A pathoIogic diagnosis of carcinoma of the gallbladder was primary proved in twenty-seven cases during this time, an incidence of 1.54 per cent. Four cases have been excluded from this series. In two a biops\ specimen was taken of a metastatic site, which was reported histologically as being compatible with origin in the gallbladder or bile ducts. In the other two no tissue specimen was obtained for histopathologic esamination, the surgeon being convinced of inoperable carcinoma of the gallbladder. LamI reports that 6,300 persons in the United States die each year of primar? carcinoma of the gallbladder, giving an incidence of 2.8 to 6 per cent of all malignant lesions.?s’6
TABLE INCIDEkCE
OF I’OUND
CARCINOMA AT
I OF
THE
(;ALLBLADDER
CHOLECXTECTO?11
( No. of
ChoIecys-
Series
’
Methodist HospitaI. Russell and Brown2’. Swinton and Becker?. Finney and Johnson8 Childs and Johnson’
.1 / I
1,752 1,488 49554
1,192 III
Pcrcent-
age
I tectomies
I
1.5 1.‘) 0.9 1.5 13.5
cystogram). We have elected, because of wider accepted preference, to quote our incidence in relation to cholecystectomies even though three of our cases were autopsy findings in patients who had not undergone surgery. Table I provides a brief r&sum& of incidence rates at various clinics reported in the recent literature.4~8~Z’~22The incidence figure presently most accepted is I to 1.3 per cent. In 1939 lClohardt’* reported an incidence of I ~I 2 per cent in 35,000 operations on the galIbIadder. Swinton and Beckerz2 postulate that since more patients are coming to surgery for cholecystic disease earlier, the incidence of primary carcinoma of the gallbladder has decreased in recent years. Our study has revealed that the incidence of malignancy of the gallbladder has not varied appreciably in the fifteen years reviewed. However, indications for cholecystectomy at the Methodist Hospital of Brooklyn for this period have been those which are
INCIDENCE There is considerable discrepancy in the reported incidences of primary malignancy of the galIbIadder. In attempting to establish an incidence rate, the number of cases of car* Deceased. 99
Sawyer
and Mink
presently accepted and, perhaps, may account for the reIativeIy constant incidence of malignancy. Age and Sex. Patients with primary carcinoma of the gaIIbIadder are reported in age groups between twenty-three and ninety TABLE INCIDENCE
OF
CARCINOMA IN
finding was equivocal, we have not included it in our statistics. (TabIe III.) As earIy as 1931 GrahamlO stated that “The occurrence of most, if not a11 cases of carcinoma of the gall-btadder couId be prevented by cholecystectomy in cases which
II
TABLE
OF
THE
GALLBLADDER
INCIDENCE
CHOLELITHIASIS
OF
I
Percent_
1,202
OF THE
206 564 15,422 450 540
AND
IN
CARCINOMA
GALLBLADDER
5.4 8.5 2.0
2.9 4. I 4.5
Pcrcentage
Carcinoma
hlethodist tIospital, ........ Howard12. ................. Dan&. ................... Benjamin’. ................ Childs and Johnson’. ....... Coopers. ................... Judd and Gray’“. ...........
2.2
92.6 86.4 100 86 67
27 22 26 70 I5 48
ii.6
212
-
i
present evidence of gaII-stones, regardIess of the presence of those symptoms which wouId ordinariIy compel a patient to have an operation.” Since the operative mortaIity in surgery of the gaIIbIadder approximates the incidence of malignant disease of that organ, it wouId be falIacious to advocate cholecystectomy for cholelithiasis in a11 patients soIeIy for the prevention of cancer. We concur with a statement attributed to Mayo” some twenty-five years ago that there are no siIent gaIIstones, that sooner or Iater these patients will present symptoms referabIe to their gaIIstones. This is particuIarIy pertinent in view of the Ionger Iife expectancy of today. Laheyls has stated: “If one deaIs with gaI1 stone patients in large number, one cannot help being impressed with the fact that this philosophy (the non-remova of a11 gaIIbIadders with caIcuIi) resuIts in many situations, and in many fatalities which would not have occurred had the operative procedure been undertaken earIier.” Carcinoma of the gallbIadder is an integra1 part of these fatalities occurring in Iater life.
years.22 In our series the majority were in the fifth and sixth decades; the youngest was fortyone and the oldest was eighty-eight years of age. It is well to note that 60 per cent of the maIignancies occurred in persons over the age are more commonIy of sixty years. Women affected than men, the generaIIy accepted ratio being 4 : I. CHOLELITHIASIS
THE
Series
age
I--/-
Methodist HospitaI. Illinois Research Hospital’3 Grahamlo. Judd and Gray’4.. Deaver and Bortz?.. Good Samaritan HospitaI, PortIand, Oregon. RlohardtlR.
III
CHOLELITHIASIS
I Lithiasis in ChoIecystectomy
Series
OF
MALIGNANCY
GALLBLADDER
The incidence of maIignancy of the gaIIbIadder in caIcuIous ChoIecystitis paraIIeIs that in choIecystectomy aIthough, quite naturally, the ratio is s1ightIy higher since a11 gaIIbIadders removed at Iaparotomy do not contain calculi. (TabIe II.) It is notabIy significant that smaIIer series generaIIy report higher occurrence rates>~‘0,‘2-14 The reIationship of ChoIeIithiasis to primary carcinoma of the gaIIbIadder has Ied certain investigators, prominentry Petrov and Krotkina,’ to posit Iithiasis as an etioIogic factor in the deveIopment of cancer of the gaIIbIadder. The incidence of ChoIeIithiasis in patients with malignancy of the gaIIbIadder is uniformIy high, u,S,*~ varying from IOO per cent reported by Danzi9 to 64.6 per cent reported by Judd and Gray.14 In our series twenty-five patients defIniteIy had ChoIeIithiasis. One other patient may have had caIcuIi; however, since this
SYMPTOMS
AND
SIGNS
There are no earIy symptoms of carcinoma of the gaIIbIadder. The symptoms and signs which are first encountered are usuaIIy those of the associated ChoIeIithiasis and are typica of that disease. Symptoms cIassicaIIy ascribed to maIig100
Primary
Carcinoma
of Gallbladder
nancy are pain, anorexia or dyspepsia, weight loss and jaundice, usually of the obstructive type. *” The pain is similar to that of chronic choIecystitis although it is typically more constant and becomes progressively worse in the two to three weeks prior to admission.
One patient Ivas admitted with small bowel obstruction secondary to “gallstone ileus.” She underwent two operative procedures for intestinal obstruction and died following a storm?; downhill postoperative course. Carcinoma, primary in the gallbladder, was an
TABLE Lv SIGNS AND SYMPTOMS OF CARCINOMA OF THE I;ALLBLADDER
TABLE v ROENTGENOGRAMS
Signs
and Symptoms
Typical chronic cholecyst’tis. Typical acute cholecystitis. Previous history of jaundice. Weight loss. Jaundice on admission. PaIpabIe liver. PaIpabIe gaIlbladder. Abdominal mass (not definitely bIadder)
Cholecystograms: Negative. N 0nvrsuaLLa _ 1’. t’ran . .._.... lithiasis. Poor function. “Pathologic response”. FIate plate: Negative. Calculi suggestive of cholelithiasis. 1ntestinal obstruction, Gastrointestinal series: Negative. I)uodenaI ulcer.. Extrinsic pressure defect. Barium enema of colon: Negative. lixtrinsic pressure defect
No. of Patients
1
‘4 ID* 71 4
5 L0 /
7
5 gall2
* These patients gave a history which couId distinguished from chronic or acute cholecystitis.
not
be
Clinical findings of icterus, a palpable gallbladder or some other mass in the right upper quadrant, and hepatomegaIy are considered characteristic.‘” It is our opinion that these signs and symptoms are Iate manifestations. Sixteen of the patients in our series gave a history which could not be distinguished from chronic or acute cholecystitis. (‘Table IV.) These patients were the only ones for whom there was any possibility of cure. Except for two persons having an apparent initial attack of acute cholecystitis, the duration of symptoms in these sixteen patients was one to twenty years, the mean being six years. Findings described as typical of primary carcinoma of the gaIlbladder were not the usual in this series: Four patients gave a history of jaundice although they were not icteric on admission. Five gave a history of weight 10s~. Ten patients were jaundiced on admission. In seven a mass was palpable in the right upper quadrant which was uniformly tender; of these, five were interpreted as gallbladder. Anemia (less than IO gm. of hemoglobin) was present in only one. While leukocytosis (over 10,000 cells) was present in a majority (fifteen patients), we cannot attribute any particular significance to this finding in reference to malignant disease.
‘4
o II z I I*
.,.
1 .
4
z I 5 2 2
It 2
I It
* Performed t Same
elsewhere. patient with same
area of defect.
“incidental” autopsy finding. In another case the onIy symptoms were dull, constant right lower quadrant pain and anorexia, beIieved to be chronic appendicitis on admission. During work-up prior to exploratory celiotomy, cholecystogram showed non-visualization of the gaIIbIadder. There was no suggestion of mahgnancy at Iaparotomy, and uneventful choIecystectomy was performed. The patient died seventeen days postoperativeIy after emboli had been showered to the lower extremities and brain. Two patients had associated symptomatic duodenal ulcers. These four cases have been mentioned briefly merely to point up the insidious nature of carcinoma of the gahbladder and to demonstrate the false sense of security inherent in non-operative management of the “innocuous” silent gallstone. X-ray studies were of diagnostic value in seventeen of twenty-three patients subjected to some form of roentgen examination. (Table v.) Cholecystograms, quite naturally, proved the most vahrable aid of this type Fourteen patients were subjected to cholecystography: EIeven cholecystograms showed IO1
Sawyer
and Minnis bladder had been compIeted. Gray and SharpelI reported a series of 291 cases of primary carcinoma of the gaIlbladder in which 8g per cent showed spread ‘of the tumor into the liver, regiona lymph nodes or omentum at the time of operation.
non-visualization and in one of these radiopaque caIcuIi were demonstrable. Two showed Iithiasis. One showed poor function without lithiasis, and one, performed eIsewhere, was reported simpIy as “pathoIogic response.” These figures correspond with others reported in recent series.20v21
HISTOPATHOLOGY
DIAGNOSIS
The correct diagnosis was made preoperativeIy in onIy two cases in which Iaparotomy was performed, and in no case in which the patient was not subjected to surgery. Diagnostic accuracy, then, was 7.4 per cent. Carcinoma of the galIbIadder was suggested in the differential diagnosis in four other patients. This point is offered not to beIittle the diagnostic acumen of the interested physicians but rather to demonstrate the eIusive character of this disease diagnosticaIIy, particuIarIy in view of the significant number of earIy cases discovered in the series. Cholecystitis and/or choIedocholithiasis were the preoperative diagnoses considered primariIy in twenty patients. Primary malignant disease which is Iimited to the gaIIbIadder often may not be obvious at Iaparotomy or during choIecystectomy. Acute inflammation of that organ may mask an underIying carcinoma by distention of the viscus and edema of its waIIs and adjacent tissues. This is particuIarIy true in the resoIving phase of acute cholecystitis. Indeed, the subsiding edema, fibrosis and earIy scarring most often may not be distinguished by external examination from a malignant process confined to the galIbIadder. Twenty-four of our cases came to Iaparotomy. The diagnosis of maIignant disease was considered in onIy fourteen cases or in fifty-eight per cent; however, in a11 fourteen instances the primary site of malignancy was considered to be the gaIIbIadder. Four cases were diagnosed as chronic choIecystitis and five as acute choIecystitis. One patient had intestina1 obstruction due to impacted gaIIstone at the iIeoceca1 vaIve. Swinton and Beckerz2 report that in onIy two of their series of twenty cases the diagnosis of primary carcinoma was discovered by the pathoIogist, the gaIIbIadder having been removed for conditions other than malignancy. Puestow20 presented a series of twenty-nine cases: in five of the twenty-six patients operated upon the diagnosis of primary carcinoma was not SUSpetted unti1 pathoIogic studies of the galI102
Foot9 divides primary carcinoma of the gallbIadder into two types, nameIy, adenocarcinema and epidermoid carcinoma. Adenocarcinoma is said to arise usuaIIy in the neck of the organ. It may be poIypoid in type or, more commonIy, infiItrating and scirrhous. MetapIastic epithelium in the gaIIbIadder may produce the epidermoid type of malignant disease. Gray and Sharpe” report that squamous ceII carcinoma occurs in about 4.4 per cent of primary malignancies of the gaIlbladder. Adenocarcinoma was the most frequent carcinoma occurring in our series. We have not attempted to break down the adenocarcinomas further as to papiIIary, scirrhous, etc. Squamous carcinoma was found in four cases, or 13 per cent, which is an occurrence rate of about three times that usuaIIy reported. CorreIation of surviva1 period in patients having adenocarcinoma with those having squamous cell carcinoma would be faIIacious in such a smaI1 series; suffice it to say that a11 patients having epidermoid carcinoma died within six months of the time of hospital admission. In 40 per cent of our cases the tumor was apparently limited to the gaIlbIadder itseIf. We have been most fortunate to have had so many earIy cases. Other series report a much Iower incidence of cases in which the maIignant process is confined to the gaIIbIadder. An interesting finding was that seven, or 26 per cent, of the patients had acute choIecystitis, histoIogicaIIy, at Iaparotomy. In reviewing the Iiterature we have found no mention of the occurrence of acute cholecystitis incident to primary carcinoma of that The diff&Ity encountered in the organ. recognition of malignant disease grossIy, in the presence of acute inflammation, has been presented heretofore. TREATMENT
AND
RESULTS
To date, the onIy treatment for primary carcinoma of the gaIIbIadder is surgery. Finney and Johnson8 have expressed the foIIowing sentiment, common to most surgeons, in regard
Primary
Carcinoma
of GaIlbladder
TABLE OPERATIVE
j Definitive
AND
-.--
---
(
i Under 2 wk. _(___’
~~
Cholecystectomy I3 ChoIecystostomy 1 z Biopsy.................. . . . . ..I 3 Choledochotomy and biopsy. z ChoIecystectomv, wedge resection of Iiver.. I and omentecCholecystectorny tomy....... ..,. ._._....... I Cholecystectomy, wedge resection of liver, resection of gastrohepatic omentum and regiona lymph nodes.. I Cholecystectomy, transverse colostomy (;2likulicz1, and partial 1 duodenectomy.
SURVIVAL
SurvivaI
/
i No. /
Procedure
VI
PROCEDURES
2-
12 wk.
I-
I
I I
/
;
3-6 mo.
/
1ncidencc
6-12 mo.
( 1-3 yr. ‘4-5 yr. ( Over 5 vr.
2
2
I
3”
1
3*
2
I
I
2
I
i
)
1
II
1 I
I 1
24
Totd. * One patient
is living and well
3
7
4
4
I
I I
2
I
I I !< yr. postoperatively. varying radical operations; the longest survivor died within seven months. This patient underwent choIecystectomy, the hnding of primary carcinoma being discovered by the pathologist. Three weeks later the patient was reoperated upon in the hope that radical dissection might result in a five-year cure. At the second procedure no residua1 or metastatic tumor was seen: a wide wedge of liver in the region of the gallbIadder bed was resected and radical resection of the gastrohepatic omentum and regional lymph nodes was performed. Microscopic examination of tissue reveaIed tumor infiltration in the Iiver segment and some Iymph nodes. Booker and Pack3 reported a case of anaplastic carcinoma of the gallprimary bIadder with regiona metastases in which the patient was subjected to similar radical surgery and survived eight years. It is the rare case such as this one that provides impetus to attempt radical surgery, even in the face of regional extension. However, the anatomy of the galIbIadder area, with its vital structures (common duct, hepatic artery and portal vein) is such as to preclude true “cancer surgery.” We believe that the pIace of radical surgery in primary malignancy of the gahbladder must await further appraisal.
hopeto this disease: “. . . such a surgically less condition as carcinoma of the gallbladder.” Five-year survivals, regardless of limitations of the malignant process and/or how radical the operative procedure, are quite uncommon. The operative procedures employed at the Methodist HospitaI of Brooklyn, with the survival incidence for each procedure, are listed in Table VI. Twenty-four patients were subjected to surgery: Seven underwent purely palliative or diagnostic procedures (two cholecystostomy, three biopsy alone and two choledochotomy and biopsy). Thirteen patients underwent cholecystectomy and four were subjected to various forms of radical surgery (choIecystectomy with wedge resection of liver; choIecystectomy and omentectomy; cholecystectomy, wedge resection of liver, resection of gastrohepatic omentum and regional lymph nodes; and cholecystectomy, transverse colostomy and partial duodenectomy). The over-all operative mortality (death within two weeks of surgery) was three, I 2.5 per cent; the hospita1 mortaIity was nine, 37.5 per cent. All of the seven patients who had undergone only pahiative procedures were dead within five months. ResuIts were unimpressive in the four cases in which patients underwent ‘03
Sawyer
and
the tumor and aIIaying metastases. Thus the maIignant process may be made more amenable to surgical extirpation.
The patients subjected to choIecystectomy alone had the best resuIts. It must be remembered that it was in these patients, subjected solely to remova of the gaIIbladder, that evidence of malignancy was not recognized at the time of Iaparotomy. It is therefore assumed that extension or metastases were minimaI. Six patients Iived Ionger than one year postoperatively. There were three five-year survivaIs? giving an over-al1 five-year “cure” rate of 12.5 per cent in patients subjected to surgery. AI1 patients except one are dead. The one Iiving patient is apparentIy free of maIignant disease I I .3 years postoperatively. CASE
Minnis
SUMMARY
AND
CONCLUSIONS
Primary carcinoma of the gaIIbIadder is uncommon. It may be considered a Iate compIication of ChoIeIithiasis. In our opinion ChoIeIithiasis is a surgica1 problem, and choIecystectomy with its Iow operative mortality is the treatment of choice. By this bold surgical attitude the incidence of malignancy may be reduced. Cognizance of the possibiIity of carcinoma of the gaIIbIadder and attempted definitive diagnosis at the time of Iaparotomy, perhaps together with more radical surgery and cancer chemotherapeutic agents which are stiI1 in the experimenta stage, may appreciabIy improve the prognosis of this aImost uniformIy fata disease.
REPORT
R. A., a fifty-six year oId white woman, was admitted to the Methodist HospitaI of Brooklyn on September 27, 1942, with a diagnosis of chronic cholecystitis with ChoIeIithiasis. The history was typical of that disease; the patient had had intermittent “attacks” of biliary coIic and jaundice during the three to five years prior to admission, the Iast “attack” being three months previously. She was afebrile but Ieukocytosis was revealed; the white blood count was 17,400, with g4 per cent poIymorphonucIear leukocytes. The foIlowing morning the patient was subjected to uncompIicated maIignancy not being suschoIecystectomy, pected at that time. Convalescence was uneventfu1 and the patient was discharged on October I Ith, thirteen days postoperatively. The pathologist’s report was adenocarcinoma with invasion of a Iymph node (sentine1 cystic duct Iymph node had been incIuded in the specimen), acute ChoIecystitis and cholelithiasis.
REFERENCES I. BENJAMIN,
analysis
E. G. Carcinoma of the gallbIadder; of 70 cases. Minnesota Med., 3 I : 537,
1948. 2. BOCKUS, H. L. Gastroenterology, vol. 3, chapt. 104, p. 633. Philadelphia, 1943. W. B. Saunders Co. 3. BOOKER, R. J. and PACK, G. T. Carcinoma of the gaIIbIadder; report of a five year cure of anaplastic carcinoma with metastases. Am. J. Surg., 78: 175, ‘949. 4. CHILDS, S. B. and JOHNSON, M. E. Carcinoma of the gaIIbIadder. Am. J. Surg., 83: 212, 1952. 5. COOPER, W. A. Carcinoma of the gaIlbIadder. Arch. Surg., 35: 431, 1937. 6. DANZIS, M. Carcinoma of the gallbladder; a report of 26 cases. J. M. Sot. New Jersey, 45: 274, 1948. 7. DEAVER and BORTZ. Cited by Howard.12 8. FINNEY, J. M. T., JR. and JOHNSON, M. L. Primary carcinoma of the gaI!bIadder; an additional reason for removing the catculous gaI.bIadder. Ann. Surg., 121: 425, 1943. g. FOOT, N. C. Pathology in Surgery. Philadelphia, 1945. J. B. Lippincott Co. IO. GRAHAM, E. A. Prevention of carcinoma of the gaIIbladder. Ann. Surg., g3 : 3 17, I 93 I. I I. GRAY, H. K. and SHARPE, W. S. Carcinoma of the gaIIbIadder, extrahepatic bile ducts and major duodena1 papiIIa. S. Clin. Nortb America, 21: 1117, 1941. 12. HOWARD, M. A. Carcinoma of the gaI1 bladder and biIe ducts. Am. J. Surg., 84: 408, 1952. 13. IIIinois Research HospitaI. Cited by Howard.12 14. JUDD, E. S. and GRAY, H. K. Carcinoma of the gaIIbIadder and biIe ducts. Szcrg., Gynec. @ Obst., 55: 308, 1932. 15. LAHEY, F. H. Common and hepatic duct stones. Am. J. Surg., 40: 209, 1938.
COMMENT
Our surviva1 rate, aIthough far from encouraging, is higher than that reported in the recent Iiterature;4,2”J2 some authors have faiIed to mention end resuIts. Bockus* states that, in his survey of the literature, cure may not be expected in more than one of forty (2.3 per cent) patients surviving surgery. Various adjuncts in the management of primary carcinoma of the gaIIbIadder have been and are being tried. Irradiation has proved of no vaIue. Recently KIopp and Biermannz3 have reported encouraging resuIts with the use of nitrogen mustard in shrinking the size of 104
Primary
Carcinoma
of the hiliary tract, pancreas and spleen. Chicago, 1953. Year Book Publishers, Inc. 21. RI_SSELL, P. W. and BROW%, C. El. Primary carcinoma of the gallbladder; report of zg cases. Ann. Sure., 132: 121, ,950. 22. SWINTON, N. W. and BECKER, W. F. Tumors of the gallbladder. S. Clin. North Americu, 28: 660,
20.
16. LAM, C. K. Present status of carcinoma of the gallbladder; study of 34 chnical cases. Ann. Surg., 111: 403, 1940. I-/. MAYO, W. Cited by Howard.12 18. MOHARDT, J. H. Carcinoma of the gallbladder; collective review. Internat. Abstr. Surg., 69: 440, 1939. 19. PETROV, N. N. and KKOPKINA, N. A. Experimental carcinoma of the gallbladder. Ann. Surg., 125: 241,
of Gallbladder PUESTOW, C. B. Surgery
1948. 23. KLOPP :rnd BIEKM~N\. Cited by Ho\vard.‘P
1941.
\\‘e recommertd: Clinical Aspects of the Autonomic Nervous System. By L. A. Gill&m, M.U. 316 pages, illustrated. Boston, 1954. Little, Brown & Co. Price $6.50. Fluid Therapy. By James D. Hardy, M.D. 255 pages, illustrated. Philadelphia, 1954. Lea & Febiger. Price $5.50. Tumors of Lymphoid Tissue. By George Lumb, M.D. 204 pages, Zustrated, some in coIor. BaItimore, 1954. Williams Bi WiIkins Co. Price $8.00.
105