Carcinoma of the Cystic Duct: Case Report Akira NISHIMURA,Sokou MAYAMA,Kikuo NAKANO,Yasuo SEKI and *Noboru TANAKA A B S T R A C T : A case of carcinoma of the cystic duct is presented and comprehensive review of the literature was provided. Since no characteristic clinical signs are present, the diagnosis can only be made incidentally at the time of laparotomy for non-visualizing gallbladder. Even then histological study of the resected specimen is mandatory. In our present case after the confirmation of the diagnosis the second look exploration was done. However, careful examination of the bile duct system failed to find evidence of carcinomatous involvement suggesting that carcinoma found in the cystic duct was of a primary and not a secondary invasion. The present case constitutes the nineteenth case which meets completely the criteria proposed by Farrar. Since the only hope of cure lies with the early diagnosis of the disease, early exploratory laparotomy and prophylactic removal of nonfunctioning or calculous gallbladder are recommended. K E Y W O R D S : carcinoma of the cystic duct, Farrar's criteria, direct view irradiation therapy. INTRODUCTION P r i m a r y carcinoma of the cystic duct is rare. In J a p a n Nagamitsu H, in collecting 14 cases of early carcinoma of the gallbladder and bile ducts, found one case of cancer of the cystic duct. Recently Hibino 7 presented three cases of the lesion, of which one underwent radical operation and in the other two the lesion had already invaded the confluence on laparotomy. But further details were not given in these two reports. Our present case of primary cystic duct carcinoma seems to conform the criteria proposed by Farrar 6, and was treated with the direct view irradiation therapy combined with adjuvant chemotherapy after the removal of the tumor. A review of the cases so far reported is provided. CASE REPORT Y. H., a 52-year-old m a n visited the Chiba Cancer Center Hospital on J a n u a r y 30, 1973 with the chief complaint of epigastric pain four days previously. Similar attacks occurred several times before. The patient remained asymptomatic until November 13, 1973 when pain in the right upper quadrant recurred. Both the gallbladder and biliary tract were not visualized on the combined peroral and drip infusion cholangiography. The pain lasted for two weeks and then he was admitted on November 28, 1973. Laboratory findings were not remarkable. There was no increase in serum bilirubin level. From the Chiba Cancer Center Hospital, Nitona, Chiba, 280 Japan. *Chiba Cancer Center Research Institute, Department of Pathology, Nitona, Chiba, 280 Japan. Mailing address: Dr. Akira Nishimura, Division of Gastroenterology, Chiba Cancer Center Hospital, Nitona, Chiba, 280 Japan. JAPANESEJOURNAL OF SURGERY, VOL. 5, NO. 2, pp 109-117, 1975
Nishimura, et al.
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Jap. J. Surg. June 1975
Fig. 1.
Percutaneous transhepatic cholangiogram showing an unopacified gallbladder and normal common duct.
Fig. 2.
Surgical specimen of the gallbladder--the mucosal side. mass in the cystic duct.
Note the tumor
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Serial hepatic and biliary tract scintigraphies with 131I-BSP were done with the finding of non-visualization of the gallbladder. An upper gastrointestinal barium study was normal. Endoscopic pancreato-cholangiogram showed no dilatation, stenosis or abnormal run of the pancreatic duct but failed to visualize biliary tract. Combined peroral and drip infusion cholangiography was repeated with tomography which showed a filling defect in the lightly visualized gallbladder. Percutaneous transhepatic cholangiograpy (Fig. 1) failed to show the gallbladder but the common duct and intrahepatic ducts were well visualized without dilation or obstruction. Laparotomy on December 20, 1973 revealed enlarged and distended gallbladder with the markedly thickened wall. After aspiration of black, thick, flocculent and purulent bile stone was not palpated. Cytology of the aspirated bile was undetermined because of a scant number of cells and destruction of the cellular components. The cystic duct was neither dilated nor elongated. The duct had hard consistency in general but an ovoid mass of 1.4 cm length with quite firm consistency was present close to the common duct resembling a stone impaction in the cystic duct. The common duct and the common hepatic duct were not dilated. Since the common duct wall seemed to be not involved, cholecystectomy was done with the severance of the cystic duct just proximal to the tumor mass. Cholangiograpy via T tube placed in the choledochotomy opening did not show the presence of biliary calculi. The resected specimen consisted of a gallbladder including a portion of the cystic duct. The cystic duct was 1.4 cm in length with thickened and firm wall. The mucosal surface was smooth and flat. Foci of extensive hemorrhage were present in the mucosa (Fig. 2). Histological examination by serial sections of the cystic duct including the neck of the gallbladder revealed relatively well differentiated tubular and partially papillary type of adenocarcinoma infiltrating the cystic duct wall (Fig. 3). The mucosal structure was completely replaced by carcinoma. Superficial spread extended into the gallbladder, but was limited to the neck portion. The whole thickness of the cystic duct wall was invaded by carcinoma. The main location of carcinoma was limited to the cystic duct. In an attempt to the complete removal of the carcinomatous spread, the second operation combined with direct view irradiation 24 was carried out on J a n u a r y 18, 1974. Marked adhesion was present in the liver hilum. Neither ascites nor regional lymph nodes swelling were found. The cystic duct stump was normal on inspection and palpation. A tumor dose of 3,000 rads was delivered around the confluence area with 9 MeV electron beam through a lead tube, 4 cm in diameter. T tube was left in situ. Before closure, 4 mg Mitomycin C was sprinkled around the region. Oral administration of F T 207 (1-(2tetrahydrofuryl)-5-fluorouracil) was started on J a n u a r y 28 with daily dose of 800 mg. Uneventful recovery and discharge followed on the fifteenth postoperative day. Postoperative cholangiography via common duct T tube was normal. DISCUSSION
The presence of carcinoma of cystic duct established by Farrar 6 can only be applied in its early stage of development before carcinoma extends to the neighboring biliary tract. Usually malignancy in the region is either discovered incidentally or in an already far advanced state involving surrounding organs. The reasons for the apparent rarity of the reported cases of cystic duct carcinoma must be attributable either to the rarity of the tumor at this site, or to the difficulty of pinpointing its origin in the majority of the cases. Definite diagnosis of the lesion seems only possible upon postmortem examination, since an early direct spread of the lesion to neighboring structures, such as gallbladder, confluence
112
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Fig. 3. Top: Tubular, partially papillary adenocarcinoma, infiltrating the submucosal layer of the cystic duct. H.E. Bottom: Same portion but higher magnification. (10 • 10), H.E. of the ducts, common hepatic duct and common duct is the rule. Stewart et al. 23, in their extensive study of carcinoma of the extrahepatic bile duct in 1940, stated that among 27 cases of carcinoma of the cystic duct collected from the literature, " n o proved case has yet been reported of a malignant growth arising primarily in the cystic duct". Sako et al. 2~ in 1957 reviewed the accessible world literature from 1935 through 1954 and found 34 cases with carcinoma of the cystic duct in 570 of primary carcinomas of the extrahepatic bile ducts. In 1962, Smith and his associates 22 observed that no cases of cystic duct malignancy could be found in their 2,952 autopsies and 1,664 surgical explorations of the biliary tract. However, the review of the literature revealed the reports of 118 additional cases of cystic duct carcinoma. Thus total cases amounted to 287 including the reported cases of Stewart et al., in which the carcinoma appeared to be localized entirely within the cystic duct segment in 59 patients. Furthermore, in a 10-year-period extending from 1954 through 1963, Van Heerden et al. 26 found four cases of carcinoma of the cystic duct in 78 cases of malignant tumor of the extrahepatic bile ducts at the Mayo Clinic.
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113
Details of cases reported in the literature since 1940 (*uncertain case not satisfying Farrar's criteria)
Case
Sex Age
Gallbladder
Common bile duct
Histology
1. *Brunschwig and Clark 3 ( 1941 )
M 63
Small Contained dark bile Stone (--)
Obstructed by pressure
Adenoearcinoma Some alveolar formation with infiltration about the common bile duct and the hepatic artery Gallbladder normal
2. Weimershaus 27 ( 1941 )
M 71
Distended Stone ( -- )
No obstruction
Adenocarcinoma Chronic cholecystitis
3. Oppenheimer 13 (1942)
M 57
Distended with white bile Stone (--)
Obstructed by pressure
Adenocarcinoma Gallbladder normal
4. Ciocatto 4 (1945)
F 50
Distended Stone (-V)
5. Farrar 6 ( 1951 )
M 66
Distended Dark bile Stone ( - - )
No obstruction
Adenocarcinoma Subacute cholecystitis
6. R e d m o n d and MajeranowskP 9 (1954)
M 73
Collapsed Stone ( + )
No obstruction
Adenocarcinoma, moderately differentiated
7. *Irons 9 (1955)
M 78
Small, empty Stone ( - - )
No obstruction
Adenocarcinoma, moderately well differentiated A few irregular glands with malignant cells were seen in that portion of the wall of the common duct
8. Rabinovitch 18 (1960) I
F 54
Distended with its gangrenous wall Stone ( + )
9. Rabinovitch 18 (1960) II
F 60
Empyema Stone ( + )
10. Edelmann 5 (1963)
M 58
Distended Stone (--)
11. Pallette et al. 15 (1963)
M 68
Stone ( - - )
12. *Aoki and Nakamura 2 (1964)
M 72
Distended Filled with white bile Stone ( - - )
13. P a r k e r 16 (1965)
M 53
Empyema, No obstruction perforated. Filled with purulent material. Stone (--)
Adenocarcinoma, well-differentiated Cholecystitis
14. Hoerr and Hazard 8 (1966)
M 70
Distended Stone (--)
Adenocarcinoma Acute cholecystitis
Adenocarcinoma
Adenocarcinoma Acute and chronic cholecystitis Cholelithiasis No obstruction
Adenocarcinoma Acute cholecystitis Cholelithiasis Neoplastic cells (-~)
Obstructed and invaded
No obstruction
Adenocarcinoma
Nishimura, et al.
114
Case
Sex Age
Gallbladder
Common bile duct No obstruction
Jap. J. Surg. June 1975
Histology
15. Smith, B.B., Huergo and Cullen 21 (1967)
F 48
Distended Stone (--)
Carcinoma, undifferentiated, scirrhous Chronic cholecystitis and hydrops
16. Lombard Dehalleux and DrezO 0 (1967)
F 72
Soft
17. Pack and Tenga4 (1968)
M 61
Enormous hydrops markedly distended. Filled with 1600cc of cloudy, yellow brown material Stone ( + )
No obstruction
Papillary adenocarcinoma Chronic cholecystitis Hydrops of the gallbladder Cholelithiasis
18. Phillips and Estrin 17 (1969)
M 57
6 years previously extirpated because of cholelithiasis
Obstructed by the bandlike residual cystic artery
Adenocarcinoma Liver metastases
19. Vaittinen~5 (1972) I
M 38
Distended. Filled with grey vicid fluid. Stone (--)
No obstruction
Adenocarcinoma, micro-cellular, invasive
20. *Vaittinen ~5 (1972) II
M 62
Distended Stone (--)
Obstructed. Inva- Scirrhous ded the hepatico- adenocarcinoma choledochal duct
21. *Vaittinen 25 (1972) I I I
M 66
Collapsed Stone ( + )
Minor invasion Adenocarcinoma into the gallbladder and into the common bile duct
22. Vaittinen 2~ (1972) IV
M 70
Collapsed. Filled with viscid fluid Stone ( + )
No obstruction
Adenocarcinoma with neural invasion
23. *Vaittinen 25 (1972) V
M 75
Distended. Filled Obstructed and with a thick yellow invaded sludge. Stone (--)
Scirrhous adenocarcinoma
24. Vaittinen 25 (1972) VI
F 75
Not distended Stone (--)
Anaplastic carcinoma of solid type
25. Author (1975)
M 52
Distended. Filled with black, thick, ttocculent and purulent material Stone (--)
Papillary adenocarcinoma
No obstruction
Tubular adenocarcinoma, well-differentiated Cholecystitis
F a r r a r was the first to establish the criteria for the diagnosis o f the p r i m a r y c a r c i n o m a o f the cystic duct. H e r e p o r t e d one case a n d found four o t h e r cases in reviewing the literatures. T h e criteria a r e consisting of (1) the g r o w t h m u s t be restricted to the cystic duct, (2) there must be no neoplastic process in the g a l l b l a d d e r , h e p a t i c or c o m m o n d u c t a n d (3) a histological e x a m i n a t i o n o f the g r o w t h must confirm the presence of c a r c i n o m a cells. Since the i n t r o d u c t i o n of F a r r a r ' s criteria eighteen cases of the i n d i s p u t a b l e lesion
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115
were reported. Total of 25 cases was listed in Table 1 including our own. The age distribution of the patients reported varies from 38 to 78 years old, averaging 63, similar to those in any other cancers of the body 18. The incidence in favor of males, 3 to 1, sharply contrasts well documented female preponderance in carcinoma of the gallbladder. No pathognomonic feature of cystic duct carcinoma was present. Most cases demonstrated the signs and symptoms of cholecystitis, with varying degrees of epigastric or right hypogastric pain, nausea and vomiting. Five cases (cases 1, 8, 12, 18 and 20) had jaundice and abdominal pain and four cases (cases 3, 21, 23 and 24) had obvious jaundice but no pain. One case (case 8) had latent jaundice. The other 16 cases (64 per cent) were not icteric indicating that the tumor was restricted within the cystic duct. Palpable abdominal mass was present in 15 cases (60 per cent), of which eight were apparently considered being gallbladder (53 per cent) and 10 being of liver origin (66 per cent). In three cases both gallbladder and liver were palpable. Rabinovitch et al.lS concluded that symptoms of carcinoma of the cystic duct were not entirely dependent on the factors inherent in the growth itself but were influenced by a variety of other factors, the most important of which was the anatomic configuration of the affected part, the type and the location of the tumor, the extent of dissemination of the lesion, and the secondary inflammatory changes which so often were parts of the pathologic picture. The clinical feature is dominated by the acute cholecystitis because the primary tumor is rather small. Two cases had already been treated with cholecystectomy due to benign diseases, i.e., a symptomatic, non-functioning, non-calculous cholecystitis (case 11) and cholelithiasis (case 18). A preoperative diagnosis was not definite in all 25 cases including the present case, in 19 of which clinical diagnosis was tentatively made as cholecystopathy and six were suspected as miscellaneous lesions or not described. Unanimous opinion was expressed that the correct diagnosis cannot be made until the lesion is surgically interfered with and pathologically examined. Three major symptoms, i.e., jaundice , pain and loss of weight for the carcinoma of the extrahepatic bile ducts as designated by Neibling and his associates 12 were not encountered in the present case. Oppenheimer 13 recommended the radical operation, if possible, even in the presence of regional lymph node metastases, since excellent palliative results had occasionally been reported. Smith B. B. 21 resorted to the conservative resection, since the lesion appeared to be localized and the high incidence of complication after the radical operation. Pallette 15 even advocated the prophylactic removal of non-functioning or calculous gallbladders. In the present series of 25 cases cholecystectomy and the removal of the tumor including the entire cystic duct were performed in 13 cases (52 per cent). Partial resection of the common duct was added in the remaining eight cases (32 per cent) because of the adherence of the tumor to the common duct wall. Four cases were diagnosed on autopsy. Although no detectable lymph node metastasis was present in the present case, "the direct view irradiation 1, 24,, i.e., single dose electron beam therapy during surgical exposure of the tumors was done 29 days after the primary operation with a hope of reducing the recurrence rate by suppressing the remaining microscopic foci. Postradiation symptoms were not observed. The radiotherapy has two advantages 1, i.e., the location and the size of the field being irradiated can precisely be determined, since the tumor in the abdomen is visible and normal organs adjacent to the tumor can be mobilized in the field. However the ultimate appreciation of the radiotherapy has to wait further detailed study. The gallbladder either at operation or autopsy was found to be distended in 15, contracted or collapsed in seven and undescribed in three cases. In cases of distended gallbladder, the common duct was found to be not obstructed in nine cases (60 per cent) meeting Farrar's criteria, and obstructed in four (27 per cent). Calculus was present in the gallbladder in
116
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Jap. J. Surg. June 1975
seven cases, i.e., o n l y a b o u t o n e t h i r d o f the cases. Bile d u c t was n o t d i l a t e d in 13 cases (52 p e r cent), p a r t i a l l y o r c o m p l e t e l y o b s t r u c t e d by the t u m o r in seven. T h e size o f t h e t u m o r is u s u a l l y small. T h e d i a m e t e r r a n g e d f r o m 0.4 c m to 3.2 cm, a v e r a g i n g 1.3 c m in 10 explicitly d o c u m e n t e d cases. R e g i o n a l l y m p h n o d e s w e r e a s c e r t a i n e d in 12 cases, in w h i c h six s h o w e d m e t a s t a t i c i n v a s i o n b y n e o p l a s t i c cells, t h r e e o f w h i c h w e r e free f r o m c a n c e r metastasis a n d t h r e e n o t i t e m i z e d . A d e n o c a r c i n o r n a was f o u n d m o s t c o m m o n l y in 22 cases (88 p e r cent). O u t o f these f o u r w e r e classified i n t o t w o m o d e r a t e l y d i f f e r e n t i a t e d type and two well-differentiated. T h e u l t i m a t e prognosis o f the lesion is difficult to be d e t e r m i n e d b e c a u s e o f the s c a r c i t y o f the r e p o r t . N i n e cases w e r e r e p o r t e d to be a l i v e a n d well w i t h o u t a n y signs of r e c u r r e n c e r a n g i n g f r o m 2 to 52 m o n t h s after t h e o p e r a t i o n . Six cases d i e d w i t h i n o n e m o n t h after the a d m i s s i o n or the o p e r a t i o n , f o u r after o n e m o n t h to 11 m o n t h s , a n d n o f o l l o w - u p d a t a w e r e a v a i l a b l e in five cases. T h e c a u s e o f d e a t h in four cases is a t t r i b u t e d to the h e p a t i c or s u b s e q u e n t b i l i a r y diseases, t h o u g h f o u r d i e d f r o m the u n r e l a t e d causes. ACKNOWLEDGEMENT
The authors wish to express their appreciation to Toshiaki Hiura, M. D., of the Department of Surgery, Funabashi Central Hospital, Funabashi, for his assistance in the preparation of the manuscript. (Received for publication on J u n e 9, 1975)
References 1. Abe, M., Yarnano, K., Imura, T. and Matsuda, S. : Intraoperative Radiotherapy of Abdominal Tumors. Part 1. Intraoperative irradiation to carcinoma of the pancreas head and biliary system. Nippon Igaku Hoshasen Gakkai Zasshi (Nippon Aeta Radiol), 29: 75 85, 1969 (in Japanese). 2. Aoki, N. and Nakamura, T. : A Resected Case of the Carcinoma of the Cystic Duct. AomoriKenritsu Chuo Byoin Ishi, 9: 16-18, 1964 (in Japanese). 3. Brunschwig, A. and Clark, D. E." Carcinoma of the Cystic Duct. Arch Surg, 42: 10941100, 1941. 4. Ciocatto, E.: Carcinoma primitivo del dotto cistico. Minerva Med, 1 : 160-162, 1945. 5. Edelmann, G., Boutelier, P. et Cahnettes, M.: Le Cancer du canal cystique. Arch Mat Appar Dig, 52: 1021-1026, 1963. 6. Farrar, D. A. T.: Carcinoma of the Cystic Duct. B r J Surg, 39: 183-185, 1951. 7. Hibino, K. : Carcinoma of the confluence with special reference to the cystic duct. Nippon Shokakibyo Gakkai Zasshi (Jap J Gastroenterol), 71: 622, 1974 (in Japanese). 8. Hoerr, S. O. and Hazard, J. B.: Acute Cholecystitis without Gallbladder Stones. Am J Surg, 111: 47-55, 1966. 9. Irons, H. S. Jr.: Carcinoma of Cystic Duct. Surgery, 38: 396-401, 1955.
10. Lombard, R., Dehalleux, E. et Dreze, C.: Papillome cancdris6 due canal cystique. Acta Gastroenterol Belg, 30: 452-459, 1967. 11. Nagamitsu, S.: On Early Cancer of the Gallbladder and the Bile Duct. Nippon Shokakibyo Gakkai Zasshi (Jap J Gastroenterol), 67 : 776-779, 1970 (in Japanese). 12. Neibling, H. A., Dockerty, M. B. and Waugh, J. M.: Carcinoma of the Extrahepatic Bile Ducts. Surg Gynecol Obstet, 89: 429-438, 1949. 13. Oppenheimer, G. D.: Common Duct Obstruction due to Primary Carcinoma of the Cystic Duct. Ann Surg, 116:141 146, 1942. 14. Pack, G. T. and Teng, P. K.: Carcinoma of Cystic Duct Leading to Hydrops of Gallbladder. JAMA, 203: 175-176, 1968. 15. Pallette, E. M., Harrington, R. W. and Pallette, E. C.: Carcinomas of the Extrahepatic Biliary System. Am Surg, 29: 719-723, 1963. 16. Parker, R. H.: Carcinoma of the Cystic Duct with Gallbladder Perforation, Ann Intern. Med, 63: 475-480, 1965. 17. Phillips, S. J. and Estrin, J.: Primary Adenocarcinoma in a Cystic Duct Stump. Report of a Case and Review of the Literature. Arch Surg, 98: 225-227, 1969. I8. Rabinovitch, J., Arlen, M., Grayzel, D., Roberts, M. and Rabinovitch, P.: Primary Carcinoma of the Cystic Duct. Report of
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Carcinoma of the Cystic Duct
Two Cases. Arch Surg, 80: 424-433, 1960. 19. Redmond, A. D. and Majeranowski, J. F.: Systemic Spread of a Cystic Duct Carcinoma: A Case Report. Ann Intern Med, 40: 632~i40, 1954. 20. Sako, K., Seitzinger, G. L. and Garside, E.: Carcinoma of the extrahepatic bile ducts. Surgery, 41 : 416-437, 1957. 21. Smith, B. B., Huergo, M. and Cullen, P. S." Carcinoma of the Cystic Duct. Tex Med, 63: 75-77, 1967. 22. Smith, V. M., Feldman, M. Sr. and Warner, C. G. : Neoplasms of the Cystic and Hepatic Ducts. A m J Dig Dis, 7: 804-816, 1962. 23. Stewart, H. L., Lieber , M. M. and Morgan, D. R.: Carcinoma of the Extrahepatic Bile Ducts. Arch Surg, 41 : 662-713, 1940.
117
24. Umegaki, Y., Urano, M. and Nakano, M.: Optimum Dose Fractionation Schemes in Radiotherapy of Human Cancer. Fraction Size in Radiobiology and Radiotherapy, Edited by T, Sugahara, L. Rdv~sz and O. Scott. pp. 188-199. Igaku Shoin I,td., Tokyo, Japan, 1973. 25. Vaittinen, E.: Carcinoma of the Cystic Duct. Ann Chir Gynaecol Fenn, 61: 190 194, 1972. 26. Van Heerden, J. A.,Judd, E. S. and Dockerty, M. B.: Carcinoma of the Extrahepatic Bile Ducts. Clinicopathologic Study. Am J Surg, 113:49 56, 1967. 27. Weimershaus, P.: Das Karzinom des Ductus Cysticus. Zentralbl Chir, 68: 1622 1625, 1941.
Nishimura, et al.
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Jap. J. Surg. June 1975
Fig. 1.
Percutaneous transhepatic cholangiogram showing an unopacified gallbladder and normal common duct.
Fig. 2.
Surgical specimen of the gallbladder--the mucosal side. mass in the cystic duct.
Note the tumor
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Carcinoma of the Cystic Duct
111
Serial hepatic and biliary tract scintigraphies with 131I-BSP were done with the finding of non-visualization of the gallbladder. An upper gastrointestinal barium study was normal. Endoscopic pancreato-cholangiogram showed no dilatation, stenosis or abnormal run of the pancreatic duct but failed to visualize biliary tract. Combined peroral and drip infusion cholangiography was repeated with tomography which showed a filling defect in the lightly visualized gallbladder. Percutaneous transhepatic cholangiograpy (Fig. 1) failed to show the gallbladder but the common duct and intrahepatic ducts were well visualized without dilation or obstruction. Laparotomy on December 20, 1973 revealed enlarged and distended gallbladder with the markedly thickened wall. After aspiration of black, thick, flocculent and purulent bile stone was not palpated. Cytology of the aspirated bile was undetermined because of a scant number of cells and destruction of the cellular components. The cystic duct was neither dilated nor elongated. The duct had hard consistency in general but an ovoid mass of 1.4 cm length with quite firm consistency was present close to the common duct resembling a stone impaction in the cystic duct. The common duct and the common hepatic duct were not dilated. Since the common duct wall seemed to be not involved, cholecystectomy was done with the severance of the cystic duct just proximal to the tumor mass. Cholangiograpy via T tube placed in the choledochotomy opening did not show the presence of biliary calculi. The resected specimen consisted of a gallbladder including a portion of the cystic duct. The cystic duct was 1.4 cm in length with thickened and firm wall. The mucosal surface was smooth and flat. Foci of extensive hemorrhage were present in the mucosa (Fig. 2). Histological examination by serial sections of the cystic duct including the neck of the gallbladder revealed relatively well differentiated tubular and partially papillary type of adenocarcinoma infiltrating the cystic duct wall (Fig. 3). The mucosal structure was completely replaced by carcinoma. Superficial spread extended into the gallbladder, but was limited to the neck portion. The whole thickness of the cystic duct wall was invaded by carcinoma. The main location of carcinoma was limited to the cystic duct. In an attempt to the complete removal of the carcinomatous spread, the second operation combined with direct view irradiation 24 was carried out on J a n u a r y 18, 1974. Marked adhesion was present in the liver hilum. Neither ascites nor regional lymph nodes swelling were found. The cystic duct stump was normal on inspection and palpation. A tumor dose of 3,000 rads was delivered around the confluence area with 9 MeV electron beam through a lead tube, 4 cm in diameter. T tube was left in situ. Before closure, 4 mg Mitomycin C was sprinkled around the region. Oral administration of F T 207 (1-(2tetrahydrofuryl)-5-fluorouracil) was started on J a n u a r y 28 with daily dose of 800 mg. Uneventful recovery and discharge followed on the fifteenth postoperative day. Postoperative cholangiography via common duct T tube was normal. DISCUSSION
The presence of carcinoma of cystic duct established by Farrar 6 can only be applied in its early stage of development before carcinoma extends to the neighboring biliary tract. Usually malignancy in the region is either discovered incidentally or in an already far advanced state involving surrounding organs. The reasons for the apparent rarity of the reported cases of cystic duct carcinoma must be attributable either to the rarity of the tumor at this site, or to the difficulty of pinpointing its origin in the majority of the cases. Definite diagnosis of the lesion seems only possible upon postmortem examination, since an early direct spread of the lesion to neighboring structures, such as gallbladder, confluence
112
Nishimura, et al.
Jap. J. Surg. June 1975
Fig. 3. Top: Tubular, partially papillary adenocarcinoma, infiltrating the submucosal layer of the cystic duct. H.E. Bottom: Same portion but higher magnification. (10 • 10), H.E. of the ducts, common hepatic duct and common duct is the rule. Stewart et al. 23, in their extensive study of carcinoma of the extrahepatic bile duct in 1940, stated that among 27 cases of carcinoma of the cystic duct collected from the literature, " n o proved case has yet been reported of a malignant growth arising primarily in the cystic duct". Sako et al. 2~ in 1957 reviewed the accessible world literature from 1935 through 1954 and found 34 cases with carcinoma of the cystic duct in 570 of primary carcinomas of the extrahepatic bile ducts. In 1962, Smith and his associates 22 observed that no cases of cystic duct malignancy could be found in their 2,952 autopsies and 1,664 surgical explorations of the biliary tract. However, the review of the literature revealed the reports of 118 additional cases of cystic duct carcinoma. Thus total cases amounted to 287 including the reported cases of Stewart et al., in which the carcinoma appeared to be localized entirely within the cystic duct segment in 59 patients. Furthermore, in a 10-year-period extending from 1954 through 1963, Van Heerden et al. 26 found four cases of carcinoma of the cystic duct in 78 cases of malignant tumor of the extrahepatic bile ducts at the Mayo Clinic.
Volume 5 Number 2
Carcinoma of the Cystic Duct T a b l e 1.
113
Details of cases reported in the literature since 1940 (*uncertain case not satisfying Farrar's criteria)
Case
Sex Age
Gallbladder
Common bile duct
Histology
1. *Brunschwig and Clark 3 ( 1941 )
M 63
Small Contained dark bile Stone (--)
Obstructed by pressure
Adenoearcinoma Some alveolar formation with infiltration about the common bile duct and the hepatic artery Gallbladder normal
2. Weimershaus 27 ( 1941 )
M 71
Distended Stone ( -- )
No obstruction
Adenocarcinoma Chronic cholecystitis
3. Oppenheimer 13 (1942)
M 57
Distended with white bile Stone (--)
Obstructed by pressure
Adenocarcinoma Gallbladder normal
4. Ciocatto 4 (1945)
F 50
Distended Stone (-V)
5. Farrar 6 ( 1951 )
M 66
Distended Dark bile Stone ( - - )
No obstruction
Adenocarcinoma Subacute cholecystitis
6. R e d m o n d and MajeranowskP 9 (1954)
M 73
Collapsed Stone ( + )
No obstruction
Adenocarcinoma, moderately differentiated
7. *Irons 9 (1955)
M 78
Small, empty Stone ( - - )
No obstruction
Adenocarcinoma, moderately well differentiated A few irregular glands with malignant cells were seen in that portion of the wall of the common duct
8. Rabinovitch 18 (1960) I
F 54
Distended with its gangrenous wall Stone ( + )
9. Rabinovitch 18 (1960) II
F 60
Empyema Stone ( + )
10. Edelmann 5 (1963)
M 58
Distended Stone (--)
11. Pallette et al. 15 (1963)
M 68
Stone ( - - )
12. *Aoki and Nakamura 2 (1964)
M 72
Distended Filled with white bile Stone ( - - )
13. P a r k e r 16 (1965)
M 53
Empyema, No obstruction perforated. Filled with purulent material. Stone (--)
Adenocarcinoma, well-differentiated Cholecystitis
14. Hoerr and Hazard 8 (1966)
M 70
Distended Stone (--)
Adenocarcinoma Acute cholecystitis
Adenocarcinoma
Adenocarcinoma Acute and chronic cholecystitis Cholelithiasis No obstruction
Adenocarcinoma Acute cholecystitis Cholelithiasis Neoplastic cells (-~)
Obstructed and invaded
No obstruction
Adenocarcinoma
Nishimura, et al.
114
Case
Sex Age
Gallbladder
Common bile duct No obstruction
Jap. J. Surg. June 1975
Histology
15. Smith, B.B., Huergo and Cullen 21 (1967)
F 48
Distended Stone (--)
Carcinoma, undifferentiated, scirrhous Chronic cholecystitis and hydrops
16. Lombard Dehalleux and DrezO 0 (1967)
F 72
Soft
17. Pack and Tenga4 (1968)
M 61
Enormous hydrops markedly distended. Filled with 1600cc of cloudy, yellow brown material Stone ( + )
No obstruction
Papillary adenocarcinoma Chronic cholecystitis Hydrops of the gallbladder Cholelithiasis
18. Phillips and Estrin 17 (1969)
M 57
6 years previously extirpated because of cholelithiasis
Obstructed by the bandlike residual cystic artery
Adenocarcinoma Liver metastases
19. Vaittinen~5 (1972) I
M 38
Distended. Filled with grey vicid fluid. Stone (--)
No obstruction
Adenocarcinoma, micro-cellular, invasive
20. *Vaittinen ~5 (1972) II
M 62
Distended Stone (--)
Obstructed. Inva- Scirrhous ded the hepatico- adenocarcinoma choledochal duct
21. *Vaittinen 25 (1972) I I I
M 66
Collapsed Stone ( + )
Minor invasion Adenocarcinoma into the gallbladder and into the common bile duct
22. Vaittinen 2~ (1972) IV
M 70
Collapsed. Filled with viscid fluid Stone ( + )
No obstruction
Adenocarcinoma with neural invasion
23. *Vaittinen 25 (1972) V
M 75
Distended. Filled Obstructed and with a thick yellow invaded sludge. Stone (--)
Scirrhous adenocarcinoma
24. Vaittinen 25 (1972) VI
F 75
Not distended Stone (--)
Anaplastic carcinoma of solid type
25. Author (1975)
M 52
Distended. Filled with black, thick, ttocculent and purulent material Stone (--)
Papillary adenocarcinoma
No obstruction
Tubular adenocarcinoma, well-differentiated Cholecystitis
F a r r a r was the first to establish the criteria for the diagnosis o f the p r i m a r y c a r c i n o m a o f the cystic duct. H e r e p o r t e d one case a n d found four o t h e r cases in reviewing the literatures. T h e criteria a r e consisting of (1) the g r o w t h m u s t be restricted to the cystic duct, (2) there must be no neoplastic process in the g a l l b l a d d e r , h e p a t i c or c o m m o n d u c t a n d (3) a histological e x a m i n a t i o n o f the g r o w t h must confirm the presence of c a r c i n o m a cells. Since the i n t r o d u c t i o n of F a r r a r ' s criteria eighteen cases of the i n d i s p u t a b l e lesion
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Carcinoma of the Cystic Duct
115
were reported. Total of 25 cases was listed in Table 1 including our own. The age distribution of the patients reported varies from 38 to 78 years old, averaging 63, similar to those in any other cancers of the body 18. The incidence in favor of males, 3 to 1, sharply contrasts well documented female preponderance in carcinoma of the gallbladder. No pathognomonic feature of cystic duct carcinoma was present. Most cases demonstrated the signs and symptoms of cholecystitis, with varying degrees of epigastric or right hypogastric pain, nausea and vomiting. Five cases (cases 1, 8, 12, 18 and 20) had jaundice and abdominal pain and four cases (cases 3, 21, 23 and 24) had obvious jaundice but no pain. One case (case 8) had latent jaundice. The other 16 cases (64 per cent) were not icteric indicating that the tumor was restricted within the cystic duct. Palpable abdominal mass was present in 15 cases (60 per cent), of which eight were apparently considered being gallbladder (53 per cent) and 10 being of liver origin (66 per cent). In three cases both gallbladder and liver were palpable. Rabinovitch et al.lS concluded that symptoms of carcinoma of the cystic duct were not entirely dependent on the factors inherent in the growth itself but were influenced by a variety of other factors, the most important of which was the anatomic configuration of the affected part, the type and the location of the tumor, the extent of dissemination of the lesion, and the secondary inflammatory changes which so often were parts of the pathologic picture. The clinical feature is dominated by the acute cholecystitis because the primary tumor is rather small. Two cases had already been treated with cholecystectomy due to benign diseases, i.e., a symptomatic, non-functioning, non-calculous cholecystitis (case 11) and cholelithiasis (case 18). A preoperative diagnosis was not definite in all 25 cases including the present case, in 19 of which clinical diagnosis was tentatively made as cholecystopathy and six were suspected as miscellaneous lesions or not described. Unanimous opinion was expressed that the correct diagnosis cannot be made until the lesion is surgically interfered with and pathologically examined. Three major symptoms, i.e., jaundice , pain and loss of weight for the carcinoma of the extrahepatic bile ducts as designated by Neibling and his associates 12 were not encountered in the present case. Oppenheimer 13 recommended the radical operation, if possible, even in the presence of regional lymph node metastases, since excellent palliative results had occasionally been reported. Smith B. B. 21 resorted to the conservative resection, since the lesion appeared to be localized and the high incidence of complication after the radical operation. Pallette 15 even advocated the prophylactic removal of non-functioning or calculous gallbladders. In the present series of 25 cases cholecystectomy and the removal of the tumor including the entire cystic duct were performed in 13 cases (52 per cent). Partial resection of the common duct was added in the remaining eight cases (32 per cent) because of the adherence of the tumor to the common duct wall. Four cases were diagnosed on autopsy. Although no detectable lymph node metastasis was present in the present case, "the direct view irradiation 1, 24,, i.e., single dose electron beam therapy during surgical exposure of the tumors was done 29 days after the primary operation with a hope of reducing the recurrence rate by suppressing the remaining microscopic foci. Postradiation symptoms were not observed. The radiotherapy has two advantages 1, i.e., the location and the size of the field being irradiated can precisely be determined, since the tumor in the abdomen is visible and normal organs adjacent to the tumor can be mobilized in the field. However the ultimate appreciation of the radiotherapy has to wait further detailed study. The gallbladder either at operation or autopsy was found to be distended in 15, contracted or collapsed in seven and undescribed in three cases. In cases of distended gallbladder, the common duct was found to be not obstructed in nine cases (60 per cent) meeting Farrar's criteria, and obstructed in four (27 per cent). Calculus was present in the gallbladder in
116
Nishimura, et al.
Jap. J. Surg. June 1975
seven cases, i.e., o n l y a b o u t o n e t h i r d o f the cases. Bile d u c t was n o t d i l a t e d in 13 cases (52 p e r cent), p a r t i a l l y o r c o m p l e t e l y o b s t r u c t e d by the t u m o r in seven. T h e size o f t h e t u m o r is u s u a l l y small. T h e d i a m e t e r r a n g e d f r o m 0.4 c m to 3.2 cm, a v e r a g i n g 1.3 c m in 10 explicitly d o c u m e n t e d cases. R e g i o n a l l y m p h n o d e s w e r e a s c e r t a i n e d in 12 cases, in w h i c h six s h o w e d m e t a s t a t i c i n v a s i o n b y n e o p l a s t i c cells, t h r e e o f w h i c h w e r e free f r o m c a n c e r metastasis a n d t h r e e n o t i t e m i z e d . A d e n o c a r c i n o r n a was f o u n d m o s t c o m m o n l y in 22 cases (88 p e r cent). O u t o f these f o u r w e r e classified i n t o t w o m o d e r a t e l y d i f f e r e n t i a t e d type and two well-differentiated. T h e u l t i m a t e prognosis o f the lesion is difficult to be d e t e r m i n e d b e c a u s e o f the s c a r c i t y o f the r e p o r t . N i n e cases w e r e r e p o r t e d to be a l i v e a n d well w i t h o u t a n y signs of r e c u r r e n c e r a n g i n g f r o m 2 to 52 m o n t h s after t h e o p e r a t i o n . Six cases d i e d w i t h i n o n e m o n t h after the a d m i s s i o n or the o p e r a t i o n , f o u r after o n e m o n t h to 11 m o n t h s , a n d n o f o l l o w - u p d a t a w e r e a v a i l a b l e in five cases. T h e c a u s e o f d e a t h in four cases is a t t r i b u t e d to the h e p a t i c or s u b s e q u e n t b i l i a r y diseases, t h o u g h f o u r d i e d f r o m the u n r e l a t e d causes. ACKNOWLEDGEMENT
The authors wish to express their appreciation to Toshiaki Hiura, M. D., of the Department of Surgery, Funabashi Central Hospital, Funabashi, for his assistance in the preparation of the manuscript. (Received for publication on J u n e 9, 1975)
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10. Lombard, R., Dehalleux, E. et Dreze, C.: Papillome cancdris6 due canal cystique. Acta Gastroenterol Belg, 30: 452-459, 1967. 11. Nagamitsu, S.: On Early Cancer of the Gallbladder and the Bile Duct. Nippon Shokakibyo Gakkai Zasshi (Jap J Gastroenterol), 67 : 776-779, 1970 (in Japanese). 12. Neibling, H. A., Dockerty, M. B. and Waugh, J. M.: Carcinoma of the Extrahepatic Bile Ducts. Surg Gynecol Obstet, 89: 429-438, 1949. 13. Oppenheimer, G. D.: Common Duct Obstruction due to Primary Carcinoma of the Cystic Duct. Ann Surg, 116:141 146, 1942. 14. Pack, G. T. and Teng, P. K.: Carcinoma of Cystic Duct Leading to Hydrops of Gallbladder. JAMA, 203: 175-176, 1968. 15. Pallette, E. M., Harrington, R. W. and Pallette, E. C.: Carcinomas of the Extrahepatic Biliary System. Am Surg, 29: 719-723, 1963. 16. Parker, R. H.: Carcinoma of the Cystic Duct with Gallbladder Perforation, Ann Intern. Med, 63: 475-480, 1965. 17. Phillips, S. J. and Estrin, J.: Primary Adenocarcinoma in a Cystic Duct Stump. Report of a Case and Review of the Literature. Arch Surg, 98: 225-227, 1969. I8. Rabinovitch, J., Arlen, M., Grayzel, D., Roberts, M. and Rabinovitch, P.: Primary Carcinoma of the Cystic Duct. Report of
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Carcinoma of the Cystic Duct
Two Cases. Arch Surg, 80: 424-433, 1960. 19. Redmond, A. D. and Majeranowski, J. F.: Systemic Spread of a Cystic Duct Carcinoma: A Case Report. Ann Intern Med, 40: 632~i40, 1954. 20. Sako, K., Seitzinger, G. L. and Garside, E.: Carcinoma of the extrahepatic bile ducts. Surgery, 41 : 416-437, 1957. 21. Smith, B. B., Huergo, M. and Cullen, P. S." Carcinoma of the Cystic Duct. Tex Med, 63: 75-77, 1967. 22. Smith, V. M., Feldman, M. Sr. and Warner, C. G. : Neoplasms of the Cystic and Hepatic Ducts. A m J Dig Dis, 7: 804-816, 1962. 23. Stewart, H. L., Lieber , M. M. and Morgan, D. R.: Carcinoma of the Extrahepatic Bile Ducts. Arch Surg, 41 : 662-713, 1940.
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24. Umegaki, Y., Urano, M. and Nakano, M.: Optimum Dose Fractionation Schemes in Radiotherapy of Human Cancer. Fraction Size in Radiobiology and Radiotherapy, Edited by T, Sugahara, L. Rdv~sz and O. Scott. pp. 188-199. Igaku Shoin I,td., Tokyo, Japan, 1973. 25. Vaittinen, E.: Carcinoma of the Cystic Duct. Ann Chir Gynaecol Fenn, 61: 190 194, 1972. 26. Van Heerden, J. A.,Judd, E. S. and Dockerty, M. B.: Carcinoma of the Extrahepatic Bile Ducts. Clinicopathologic Study. Am J Surg, 113:49 56, 1967. 27. Weimershaus, P.: Das Karzinom des Ductus Cysticus. Zentralbl Chir, 68: 1622 1625, 1941.
