CANCER OF THE GALLBLADDER* REPORT OF A FIVE*YEAR CURE OF ANAPLASTIC
ROBERT J. BOOHER, M.D. AND
GEORGE T. PACK, M.D.
Neu! I’ork, New Elork
of the gaIIbIadder can seldom be surgicalty removed and even when successfuIIy excised by radicaI technica procedures is not often cured. One is prone to accept the viewpoint expressed by Finney and Johnson’ that “In many ways, it seems hardIy worth while to offer a paper on such a surgicaIIy hopeless condition as carcinoma of the galITo encourage an optimistic bIadder.” surgical attitude, even in the face of metastases from cancer of the gaBbladder, we wish to present a unique, Iong-term survivat of a patient with a cancer of high-grade histoIogic marignancy and with lymph node metastases. The insidious nature of gaIIbIadder cancer and its Iow rate of resectabiiity are we11 recognized. The graduaIIy increasing number of one-, two- and three-year survivaIs after resection for cancer of the gaIIbIadder and even for contiguous, invaded Iiver bed, shows considerable progress since BiaIock’s2 extensive statistical study in 1924 of 888 cases of biliary tract disease occurring at the Johns Hopkins Hospital from the time of its opening to that date. After his survey of the forty-two biIiary cancers, of which twenty-two were primary in the gaIIbIadder, he concluded that “in malignancy of the gaIIbIadder, when a positive diagnosis can be made without expIoration, no operation should be performed, inasmuch as it onIy shortens the patient’s Iife.” The incidence of carcinoma of the gallLIadder varies considerabIy in different series, but the high incidence of 5 per cent in 405 surgicaIIy resected gallbladders by Mayo3 in 1902 (who beIieved the true proANCER
* From the Gastric Service of the Memorial August,
portion to be probabfy higherj is much greater than we find today. ~~arshaI1 and Morgan4 in a study of 1,336 gaIIbIadders removed from 1928 to 1937 found a cancer incidence of 1.4 per cent with a resectabiIity of 20 per cent. Finney and Johnson found carcinoma in 1.5 per cent of I, 192 specimens. Gray5 in 1934 in surveying 22,365 operations on the biIiary tract, found the incidence to be 0.9 per cent, whereas Mohardt” in his coIIected review of the probIem pfaced the incidence at about 0.5 per cent, Cooper? in a survey of forty-eight cases seen at the New York HospitaI from 1915 to x935 contrasted the incidence of 3 per cent in 1,500 operations with 0.61 per cent in 2,941 autopsies. Vadheim, Gray and Dockerty8 found 291 cases of cancer of the gaIlbIadder occurring in 33,500 operations of the biIiary tract at the Mayo Clinic from ‘go7 to 1940 incIusive, an incidence of 0.87 per cent; seventy-seven of these carcinomatous gailbladders could be removed which is a resectabiIity rate of 26.5 per cent. In 29.2 per cent of seventy-five cases metastases to Iymph nodes had occurred; in 43.06 per cent direct extension alone had occurred and in 28.2 per cent both means of spread were found. In Lam’s9 series of thirty-four patients six presented Iymph node metastases and fifteen direct invasion of the liver. In Cooper’s series direct extension to the Iiver occurred in 66 per cent of the cases and in 52 per cent metastases occurred in the cystic nodes. The progressive and rapid spread of this disease by the time it produces death is shown by the necrops!, figures of KozalI and Kirschbaum”’ in which direct liver extension was found in
Hospitai for Cancer and AIIied Diseases, New York, N. 3..
fifty-one of fifty-five cases and thirty-four of the same series presented Iymph node metastases. One particuIar finding of Vadh&m, Gray and Dockerty seems of specia1 and not too usuahy recognized significance. They found that 17.3 per cent of their cases presented intravascuIar invoIvement by the tumor process. While the most acceptabIe technics for galibladder dissection caI1 for preIiminary management of the cystic artery and vein, this finding wouId indicate its necessity in choIecystectomy for cancer in the hope of prevention of spread of the process by tumor emboIi. SheinfeIdll has recently summarized the surgical management of cancer of the gaIIbIadder that presented direct extension into the bed of the Iiver. In thirty-six cases coIIected in which the gaIIbIadder and the contiguous invaded Iiver tissue was resected, a tota operative mortahty of 13.08 per cent occurred. Recurrence in Iess than one year was noted in 38.08 per cent of the patients and good paIIiation or possibIy good Iong-term resuIts were secured in 19.04 per cent of these patients. Three were aIive at fourteen, fifteen and eighteen months, and one, six and one-haIf years after operation. He concIudes from a survey of these coIIected cases that Iiver resection associated with choIecystectomy, if possibIe, appears to be of definite pahiative vaIue. The resuhs, however, are poor when compared with the accomplishments of radica1 surgery for carcinoma of other organs. Webbe? f&t appIied the Broders system of grading to carcinoma of the gaIIbIadder in 1927. In thirty patients with primary carcinoma of the gaIIbIadder, treated by choIecystectomy, the specimen was studied to determine the existence of the reIation between the Iength of Iife after operation and the grade of mahgnancy of the tumor removed. TweIve patients with carcinoma, graded II or Iower, Iived an average of two years and ten months. Fourteen patients with carcinoma graded III or higher, Iived an average of 4.8 months. Two patients with carcinoma graded III
of GaIIbIadder or higher were living at that time, one remaining in good heaIth six years and seven months, and the other one year and one month after the operation. Of tweIve tumors graded II or Iower, four were found at operation to show gross or microscopic evidence of extension or metastases; and of fourteen tumors graded III or higher, thirteen were found at operation to be associated with simiIar evidence of extension or metastases. In Vadheim, Gray and Dockerty’s report, they found 25 per cent of grade I Iesions, 64 per cent of grade II Iesions, 88 per cent of grade IIX Iesions and IOO per cent of grade rv lesions were associated with metastases. Thus it appears that the frequency of spread beyond the confines of the gaIlbIadder varies directIy with the grade of the cancer. In this same study they showed that 45 per cent of the patients with grade I lesions survived five years, one surviving twenty-eight and onehaIf years. Four and three-tenths per cent of the patients with grade II cancers survived five years and no patients with grade III or IV carcinomas survived to a five-year definitive cure rate. Because of the unique occurrence of carcinoma of the gaIIbIadder of grade III histoIogic mahgnancy compIicated by Iymph node metastases in which the patient has survived for aImost eight years since operation, we believe the folIowing case report is worthy of detai1: . CASE
R. D., a sixty-four year oId, married, white femaIe, was admitted to the h4emoriaI Hospita1 on JuIy 28, 1941 on the IvledicaI Service of Dr. LIoyd Craver. She had been referred by Dr. DanieI KornbIum who had made a most compIete survey of her probIem. She complained that her present symptoms began four months previously with an attack of postprandial pain in the right upper quadrant. Severai weeks before admission hiccoughing started with aggravation of the pain. She had a gradua1 Ioss of appetite and with the anorexia had Iost 3 pounds. She vomited only occasionaIIy but there was never bIood in the em&. Before her hospitaI admission she had begun to have generaIized itching and sIight American Journal of Surgery
but questionabIe jaundice. The urine was examined about a week before she was admitted to the hospital and found to contain bile and the icteric index then was 16.6 units. The stooIs had never shown the presence of blood nor had they been achoIic. There had been a simiIar attack of pain about twenty years previousIy which was aIso worse foIIowing meaIs and also radiated to the right shouIder bIade and inferior angle of the scapuIa. This was entireIy managed by dietetic treatment. AI1 other historic data were irrelevant. Physical examination revealed a woman whose genera1 condition was quite good, but who had a slight icteric tint in the sclera. There were no cervica1 nodes to be palpated and a pilot node could not be felt. The lungs \vere cIear to auscuItation and percussion. The heart was not enlarged and no murmurs were heard. The bIood pressure was I 10/70. On abdomina1 examination a firm, irreguIar, slightIy tender ma?s, the size of a cIenched fist, was feIt in the right upper quadrant. This was distinctIy connected with the inferior surface of the Iiver and seemed to originate in the region of the gaIIbIadder. The Iiver itself was not enIarged and there was no other tenderness. There were several smaI1 ecchymotic areas on the anterior abdomina1 waI1 just below the gaIIbIadder itself. The mass in the right upper quadrant descended with inspiration. Recta1 and vagina1 examinations were normaI. Laboratory studies revealed the foIIowing: red blood ceIIs, 4,800,000; hemogIobin, 93 per 7,200, with norma cent; Lvhite ceI1 count, differentia1 distribution. Blood chemica1 studies 2.15 mg. per cent; revealed serum bilirubin serum protein 7.1 Gm. per cent; sodium chloride 617 mg. per cent. The prothrombin Ievel was I00 per cent of normal. UrinaIysis was entireIy normal; there was a trace of albumin but there was no evidence of bile. The x-ray studies had been done by Dr. DanieI Kornblum. On JuIy 24th choIecystograms were done tweIve hours after the admincIye and istration of 7 Gm. of gaIIbIadder there was faint visualization of a mildly enlarged galIbIadder. No evidence of caIcuIi was seen and there was failure of the gallbIadder to evacuate foIIowing a fatty meal. A soft tissue mass measuring approximately 5 cm. across was noted overIying the Iower August,
FIG. I. Photograph of x-rays taken after the ingestion of barium shows the downward and medial displacement of the duodenal bulb and first portion of the descending duodenum.
poIe of the liver and on the Iower part of it; the mass couId be cIearIy made out but the upper border couId not be seen. The gastrointestina1 series showed a norma esophagus and stomach save for spasm in the pyIorus and antrum. The shadow previously noted in the gaIIbIadder seemed to be quite cIoseIy approximated to the second portion of the duodenum. The duodena1 cap and the second portion of the descending portion of the duodenum were dispIaced downward and mediaIIy. (Fig. I.) However, in about three hours $0 per cent of the barium was stiI1 in the stomach and the end of the coIumn was in the termina1 iIeum. The smaI1 bowe1 pattern was normaI. On barium enema examination no obstruction of the injection was noted in the coIon and no poIyps or diverticuIae were seen. However, in the region of the hepatic fIexure there seemed to be fixation of the descending coIon around the lower border of the soft tissue mass which was noted in the fiIms of the gaIIbIadder. The mass seemed to be a little larger in the anteroposterior view. After admission to the hospita1 a repeat fluoroscopic gastrointestina1 examination was done without securing additiona1 information. Dr. LIoyd Craver made a tentative diagnosis of carcinoma of the gaIIbIadder. Iaparotomy On JuIy I, 1941, an expIoratory was done. Under gas oxygen ether anesthesia upper quadrant, vertica1, rectusa right, spIitting incision was made. No free fIuid \~as
FIG. 2. Photograph of the galIbIadder and contained stones. The cancer measures 3 by 3fP by 3 cm.
found in the peritonea1 cavity. The gaIIbIadder was markedIy enIarged, measuring approximately 12 cm. in Iength. After a trocar was inserted into the fundus of the gaIIbIadder, a quantity of paIe biIe was aspirated. PaIpation then reveaIed a firm indurated area in the region of the ampuIIa of the gaIIbIadder which, however, was entireIy intracystic in nature. Many smaI1 faceted stones couId be feIt after the tenseness of the gaIIbIadder had been relieved. PaIpation of the gastrohepatic omenturn near the foramen of WinsIow reveaIed a circumscribed, firm round mass, 1.3 cm. in diameter. When the peritoneum over this area was incised and the common duct identitied, the mass was seen to be an enIarged Iymph node rather than a caIcuIus in the duct as was first suspected. The gaIIbIadder was dissected free from its bed with no great di&uIty, save over the region of the ampuIIa where sharp dissection was necessary to free it from the Iiver. The cystic duct was dissected down to its entrance into the common duct, sectioned between cIamps and the gaIIbIadder removed. The cystic duct was suture-Iigated, and then the noduIe in the gastrophrenic omentum was enucIeated and sent to the Iaboratory for a frozen section. The report was made of metastatic carcinoma in a Iymph node. The common duct was then explored and found to be entireIy normaI. No stones couId be feIt upon probing and a smaI1 T tube was sutured into
of GaIIbIadder the duct with fine interrupted bIack silk sutures. Realizing that there was metastatic carcinoma in this region, a compIete expIoration of the abdomina1 cavity a second time failed to revea1 any further evidence of carcinoma, save that which had been identified after remova of the gaIIbIadder, as arising in the gaIIbIadder itself. The abdomina1 wound was cIosed in the conventiona manner. The postoperative course was entireIy uneventfu1, save for the usua1 T tube drainage, and a rather profuse amount of serosanguineous drainage during the first three days subsequent to the operation. The serum bilirubin by the third postoperative day was 8 mg. per cent, and by the seventh postoperative day was down to 5 mg. per cent; the prothrombin IeveI was 80 per cent of normaI. The maximum postoperative temperature was a febriIe I o I .2’F. on the sixth postoperative day aIthough daiIy febrile eIevations occurred unti1 the tenth postoperative day. SubsequentIy a normal course ias run during the hospita1 stay which was complete on the twenty-first postoperative day. There was stiI1 considerabIe drainage after removing the common duct tube on the twentieth day after the operation, after having it cIamped for severa days without any change in symptoms or findings. By September 9, 1941, there was no further drainage from the drain site and the wound was compIeteIy heaIed. Frequent foIIow-up examinations have been made, and on October 27, 1943, a gastrointestinaI series was done which showed an entireIy norma duodena1 cap without any evidence of spasm or any evidence of duodena1 niche. At the time of the patient’s Iast examination on May 31, 1949, she was free of compIaints other than those engendered by a miId upper respiratory infection. No piIot nodes couId be found. The examination of the abdomen presented no enIargement of liver or spIeen, and rectovaginaI-abdomina1 examination was entireIy negative. The patient did note, however, that she feIt much better when she was on a fat poor, high protein diet. The pathoIogic report No. 0-1868, by Dr. Fred Stewart, was as foIIows: “The gaIIbIadder in its unopened state measures I 3 by 7 by 6 cm. On paIpation the fundus of the gaIIbIadder feeIs as though it was fiIIed with stones. The proxima1 portion near the Iine of transection is very firm. There appears to be a mass invoIving this part of the specimen, which American
Journal of Surgery
3B 3A FIG. 3. A, photomicrograph of the gaIIbIadder wall showing complete infiltration by the adenocarcinoma. Histologic grade of malignancy, III; B, photomicrograph of one of the two Iymph nodes showing compkte repIacement of noda architecture by the adenocarcinoma.
6 by 4 by 4 cm. The specimen is sectioned in the IongitudinaI pIane. The fundus is compIeteIy HIed with approxi200 faceted gaIIstones. No bile is mateIy present in the gaIIbIadder. The waI1 is somewhat thickened in the proxima1 portion of the specimen. There is a firm, pinkish-yeIIow lesion which measures 3 by 335 by 3 cm. It is compIeteIy anguIar and apparentIy bIocks off the cystic duct. The cystic duct is diIated. There appears to be a narrow margin of normal tissue at the Iine of transection. of (Fig. 2.) The mass has the appearance tumor tissue. The second specimen consists of two Iymph nodes, one measuring 2 by 255 by 2 cm., the other measuring I cm. in diameter, both of which, on cut section, appear to be Iymph nodes repIaced with tumor tissue.” Microscopic diagnosis of the Iesion in the gaIIbladder was an adenocarcinoma of grade III histoIogic maIignancy, chronic ChoIecystitis. examination of the two (Fig. 3A.) Microscopic August,
Iymph nodes was reported as showing metastatic adenocarcinoma. (Fig. 3B.) The final diagnosis was chronic ChoIecystitis with choIeIithiasis; adenocarcinoma of the gaIIbIadder, grade III with metastases to regiona Iymph nodes. SUMMARY I. A case report is given of cancer of the gaIlbladder of high-grade histologic mahgnancy with regiona Iymph node metastases. The patient has survived cholecystectomy and dissection of the cystic nodes for nearIy eight years. 2. Despite marked anapIasia and regiona1 node metastases, cancer of the gaIlbIadder is a curable disease and an attempt to controI this cancer is aIways in order. REFERENCES I. FINNEY,J. M. T., JR. and JOHNSON, M. T. Primary carcinoma of the gaIlbladder, an additional
reason for earIy removal of the calculus gallbladder. Ann. Surg., 121: 425-434, 1945. BLALOCK, A. A statistical study of 888 cases of bibary tract disease. Johns Hoplzins Hosp. Rd.,
35: 39r-409, 1924. 3. MAYO, W. J. MaIignant disease involving the galIbIadder. M. News, 81: I 105-1107, 1902. 4. MARSHALL, S. F. and MORGAN, E. S. Carcinoma of the gallbladder. S. C&n. North America, 18: 687-693, 3. GRAY, H. K.
Squamous ceII epithelioma of gaIIbIadder and liver, choIecystectomy and partial hepatectomy. Report of a case. S. Clin. Nortb America, 14: 717-720, 1934. 6. MOHARDT, J. H. Carcinoma of the galIbIadder: coIIective review. Internat. Abstr. Surg., 69: 44o451, 1939.
of GaIIbIadder 7. COOPER, W. A. Carcinoma of the gahbladder. Arch. Surg., 35: 431-448, 1937. 8. VADHEI~~,J. S., GRAY, H. K. and DOCKERTY, M. B. Carcinoma of the galIbIadder: a cIinica1 and pathologic study. Am. J. Surg., 63: 173-180, 1940. g. LA~$, C. R. The present status of carcinoma of the gaIIbIadder. Ann. Surg., I I I : 403-410, 1940. IO. KOZOLL, D. D. and KIRSCHBAUM,J. D. Carcinoma of the gaIIbIadder and extrahepatic bile ducts. Surg., Gpec. Ed Obst., 73: 740-754, 1941. II. SHEINFELD, W. Cholecystectomy and partiaI hepatectomy for carcinoma of the gaBbladder with local Iiver extension. Surgery, 22: 48-58, 1947. 12. WEBBER, I. M. Grades of malignancy in primary carcinoma of the galIbIadder. Surg., Gynec. @ Obst., 44: 756-760, 1927.
IN 1774 PercivaI Pott described scrota1 cancer occurring in chimney sweeps and correctly suggested that the accumuIated soot apparentIy had a cancer-producing effect in these particuIar subjects. RecentIy we discovered that workers on fluorescent watch dials died of “radium disease” as did miners working with radioactive ores. In addition to these radioactive eIements we now know that chemica1 and parasitic factors may equaIIy we11 produce cancer, especiaIly in “susceptible” individuaIs. The better known physical agents apparentIy capabIe of producing cancer under proper conditions are: X- and gamma rays, uItravioIet, beta and aIpha rays. The commonIy known carcinogenic inorganic chemicals are: asbestos, possibIy beryIIium, arsenic, nickeI carbony and the chromates; aIso these organic chemicals: benzo1, poIycyIic hydrocarbons, soot, benzo1, aromatic amines, carbon bIack, paraffin and shale oils, certain types of minera oiIs, anthracene oi1, tar and pitch, and creosote. UndoubtedIy, under certain conditions, the estrogens, the azo dyes and the aniIine dyes aIso have carcinogenic properties. The parasitic agents that occasionaIIy seem capable of producing cancer are the viruses. In fact, I beIieve the viruses wiII eventuaIIy be found to be the most common cause of cancer. Other parasitic agents that shouId be mentioned in this connection are schistosoma hematobium and, possibIy, cIonorchis sinensis. (Richard A. Leonardo, M.D.)