Aust.
525
N . Z . J . Surg. 1992,62,525-529
EARLY BILE DUCT CARCINOMA KOJI YAMAGUCHI Department of Surgery I , Kyushu University Faculty of Medicine, Fukuoka, Japan The clinocopathologic features of seven patients with early bile duct carcinoma are reported. Early bile duct carcinoma has been defined as bile duct carcinoma limited to the bile duct wall. The seven patients included six men and one woman ranging in age from 44 to 77 years. Six patients complained of jaundice and the other presented with right hypochondralgia. Ultrasonography showed a dilated proximal bile duct in the seven with a polypoid mass in three. Computerized tomography showed a dilated biliary tree in the seven together with a polypoid mass in two. Direct visualization of the bile duct with endoscopic retrograde cholangiography and/ or percutaneous transhepatic cholangiography showed a polypoid tumour of the bile duct and a dilated proximal biliary tree in all seven. Each of the seven polypoid tumours were well differentiated papillary or tubular adenocarcinoma restricted to the bile duct wall with minimal stromal invasion. There was neither any lymph node metastasis nor perineural invasion. Five of the seven patients were doing well at 24-1 12 months after a complete resection. One patient died from multiple liver metastases 21 months after intervention. The other patient died from other diseases 138 months after operation. These seven cases can be classified as early bile duct carcinoma due to both the limited invasion and favourable prognosis. The clinical features of the seven patients were quite similar to those of usual bile duct carcinoma. However there are still no proper diagnostic clues for early bile duct carcinoma and these patients represent fortunate cases that clinicians happened to discover by chance.
Key words: bile duct carcinoma, early bile duct carcinoma.
the other three cases were kindly provided by three affiliated hospitals. Early bile duct carcinoma was Despite recent advances of diagnostic and therapeudefined as bile duct carcinoma limited to the bile tic facilities, the clinical course of patients with duct wall by microscopy. Three patients were treatextrahepatic bile duct carcinoma remains gloomy. ed at Kyushu University Hospital, one at National There have been some case reports of early bile Fukuoka Higashi Hospital, one at Fukuoka Red duct ~ a r c i n o m a , ~but - ~no definite criteria of early Cross Hospital, one at Hamanomachi Hospital, and bile duct carcinoma have yet been e ~ t a b l i s h e d . ~ ~ ” another at Usa Gunshi Ishikai Hospital. Complete The clinicopathologic features of 86 cases of extraclinical records were available for all seven hepatic bile duct carcinoma have been reported patients. The seven patients included six men and previously and it was proposed that bile duct carcione woman ranging from 44 to 77 years of age with noma of the polypoid type, which was restricted to a mean of 61.3 years. Radiologic features were the wall with minimal invasion and demonstrated available on the seven patients and were as follows: no lymph node metastasis, could be classified as abdominal plain film for all seven patients; upper early bile duct carcinoma.’ This paper reports the gastrointestinal X-ray series for seven; ultrasonogclinical and histopathologic features of seven raphy for seven, computerized tomography for six, patients with early bile duct carcinoma in order to endoscopic retrograde cholangiography for five, introduce potential clues for the successful clinical percutaneous transhepatic cholangiography for diagnosis of this highly morbid carcinoma. two, operative cholangiography through a choledochotomy for two; through an intrahepatic bile duct Methods drain for one; and an angiography for three. Six patients underwent a pancreatoduodenectomy while Four of the seven cases of early bile duct carcinoma the other had a bile duct resection. All the speciwere selected from a series of 86 cases of bile duct mens were examined by cutting step-wise tissue carcinoma that had been previously reported’ while sections at 5 mm intervals. All the tissue sections were stained with haematoxylin and eosin and obCorrespondence: Koji Yamaguchi, MD, Department of Surgery I, Kyushu University Faculty of Medicine, 3-1-1 Maidashi, served by the author (KY). The clinical follow-up Higashi-ku, Fukuoka, Japan. was current as of 30 May 1991 and follow-up information was available on all seven patients. Accepted for publication 30 January 1992 Introduction
’,*
526
YAMAGUCHI
Table 1. Clinical features of seven patients with early bile duct carcinoma Case Age/ no. sex
Chief complaint
Site of origin
Macroscopic Microscopic Lymph node type type metastasis Clinical course
1
Jaundice Jaundice Jaundice Jaundice Abdominal pain Jaundice Jaundice
Middle Inferior Inferior Inferior Superior Middle Superior
Polypoid Polypoid Polypoid Polypoid Polypoid Polypoid Polypoid
2 3 4 5 6 7
64/M 77/M 44/M 66/F 66/M 62/M 50/M
PAP TUB 1 PAP TUB 1 TUB 1 PAP PAP
No No No No No No No
Alive 24 months later Alive 26 months later Alive 47 months later Alive 108 months later Alive 112 months later Died 21 months later Died 138 months later
PAP: papillary carcinoma;TUB 1 : well differentiated tubular adenocarcinoma.
Results CLINICAL FEATURES
Six of the seven patients with early bile duct carcinoma presented with jaundice and the other patient showed hypochondralgia (Table 1). One of the seven patients was diabetic. The serum carcinoembryonic antigen (CEA) level was elevated in three of the seven patients and carbohydrate antigen 19-9 (CAI9-9) was elevated in one of the two examined patients. One of the seven patients had cholelithiasis and another choledocholithiasis. One patient had had a cholecystectomy for cholelithiasis. Another patient had had a choledochotomy for ,
Fig. 1. Ultrasonography shows a hyperechoic mass in the dilated bile duct.
bleeding from percutaneous transhepatic cholangiodrainage. Ultrasonography showed a hyperechoic mass in the bile duct and a proximal dilated biliary duct in three (Fig. 1) and only a dilatation of the proximal bile duct in four. Cholelithiasis was evident in one. Computerized tomography showed a polypoid mass of soft tissue density in the bile duct and a dilated proximal bile duct in two (Fig. 2) and only a dilated biliary tree in four. Neither regional lymphadenopathy nor distant metastasis was evident. However, the gall-bladder was enlarged and had a thickened wall in all patients. Endoscopic retrograde cholangiography (ERC) was successful for all seven patients. Percutaneous transhepatic cholangiography (PTC) was done for the determination of extension of bile duct carcinoma in two, and operative cholangiography through choledochotomy in two and intrahepatic bile duct drain in one. Percutaneous transhepatic cholangiodrainage (PTCD) was done in one. Operative choledochus drainage was done in two. Direct visualization of the biliary tree with ERCP and/or PTC revealed a polypoid tumour in the bile duct and dilated proximal bile duct in all seven patients. Angiography showed neither encasement of the vessels, neovascularity, nor tumour staining in three examined patients. Two of the seven patients underwent
Fig. 2. Computerized tomography shows a soft tissue density mass in the bile duct (white arrow).
521
EARLY BILE DUCT CARCINOMA
chemotherapy; consisting of a combination of mitomycin C and 5-fluorouracil(5-FU) in one and 5-FU only in another. No patient underwent radiation therapy. HISTOPATHOLOGIC FEATURES
Three of the seven tumours were located in the inferior portion of the extrahepatic bile duct, two in the middle and two others in the superior. All seven tumours were polypoid in shape (Fig. 3) and mostly limited to the bile duct wall with minimal stromal invasion. No tumour of either nodular or sclerosing shape was restricted within the bile duct wall. The tumours mainly grew intraluminally and minimally invaded the bile duct wall. The pancreas and adjacent fibro-adipose tissue were free of invasion. Seven tumours consisted of a well differentiated papillary or tubular proliferation of malignant cells (Fig. 4 ) . Tumour cells were focally so well differentiated that it was difficult to distinguish adenocarcinoma from adenoma. The adenomatous epithelium gradually changed into unequivocal
adenocarcinoma. Well differentiated cancer cells often showed intestinal differentiation including goblet cells, brush borders, Paneth cells, and argentaffin cells. No tumour showed any lymph node metastasis, perineural invasion, or venous invasion. In five cases, the surrounding bile duct was lined by dysplastic epithelium of a moderate to severe degree (carcinoma in situ). The surgical margins were free of cancer cells. The cytologic examination of bile from intrahepatic cholangiodrainage was negative in one case while that from percutaneous transhepatic cholangiodrainage revealed adenocarcinoma in another. The biopsy specimens taken intra-operatively through a choledochotomy showed adenocarcinoma of the bile duct in two cases. CLINICAL C O U R S E
Five of the seven patients were doing well from 24 to 1 12 months after operation. One patient died 2 1 months after intervention. The post-mortem examination revealed multiple metastases in the liver, diaphragm, lung, rib, pleura and lymph nodes in the para-pancreatic, para-aortic, pulmonary hilar and para-bronchial regions. The remaining patient died 138 months after operation from another disease.
Discussion
Fig. 3. A polypoid tumour in the bile duct
Fig. 4. A polypoid tumour is composed of papillary proliferation of atypical epithelium and limited to the bile duct wall (haematoxylin and eosin, x 6 ) .
Despite recent advances in the diagnostic and therapeutic modalities, the clinical course of patients with bile duct carcinoma remains gloomy. Most patients with bile duct carcinoma present with jaundice and are advanced in stage. There have been some case reports of early bile duct carcinoma, but there have been no acceptable criteria established for identifying early bile duct carcinoma. In this study, early bile duct carcinoma was defined as carcinoma restricted to the bile duct wall by microscopy. All seven tumours were polypoid in shape. However, early bile duct carcinoma of flat type also exists, since some gall-bladders resected for cholelithiasis harbour carcinoma in situ with a flat shape. There was no experience of flat early bile duct carcinoma in this study because of the difficulties in pre-operative diagnosis. Todoroki er al. said that a polypoid tumour on cholangiography fared better than a nodular, annular constrictive or sclerosing tumour. l s It was previously reported that, macroscopically, a polypoid tumour fared better than a nodular or sclerosing tumour,' as described by Cattell. l9Microscopically, well differentiated adenocarcinoma fared better than moderately or poorly differentiated adenocarcinoma. Not all patients with polypoid bile duct carcinoma fared well. Only the clinical outcome of patients with polypoid carcinoma restricted within
528
the bile duct was was good, and the clinical course of patients with polypoid carcinoma invading the surrounding organs was as poor as that of nodular or sclerosing carcinoma. The clinical course of patients with bile duct carcinoma showing lymph node metastases, perineural invasion and cancer cells at the surgical margins was worse than those without these factors. The seven early bile duct carcinomas demonstrated all the preferable factors and were expected to have a favourable clinical course. It has been reported previously that patients with non-icteric ampullary carcinoma fare better than those with icteric ampullary carcinoma because of the high incidence of early am ullary carcinoma and papillary adenocarcinoma.' In the present study, only one of the seven patients was diagnosed as having bile duct carcinoma and underwent surgical intervention at the non-icteric period. The patient had developed abdominal pain and fever caused by cholangitis. Serum CEA and/or CA19-9 levels are known to be elevated in some patients with hepatobiliary carcinoma. In addition, the CEA and CA19-9 levels have been reported to correspond to the stages of the disease and are useful in the clinical follow-up in order to detect any recurrence. Carbohydrate antigen 19-9 mass screening has not been useful in the detection of early pancreas carcinoma. The serum CEA level was elevated in three of the seven patients and CA19-9 was elevated in one of the two examined patients. Thus, the measurement of CEA and CA19-9 did not prove useful in the diagnosis of early bile duct carcinoma. Regarding imaging techniques, ultrasonography and/or computerized tomography only showed a dilatation of the proximal bile duct and sometimes failed to visualize a polypoid tumour of the bile duct. However direct visualization of the biliary tree by endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography did reveal a polypoid tumour of both the bile duct and a dilated proximal bile duct. Ultrasonography or computerized tomography is thus considered useful in detecting a dilatation of the biliary tree. Direct visualization by ERC and/or PTC after ultrasonography is valuable for revealing polypoid early bile duct carcinoma. Ultrasonography is not painful and is easily performed even at the outpatient department. While most clinicians would indeed obtain an ultrasound early in the evaluation of jaundice, it is considered that cholangiography is essential to properly evaluate these patients. Ultrasound seems to provide little information and in fact it missed the polypoid nature of the lesion in the majority of patients in this study. The clinical and histopathologic features of seven patients with early bile duct carcinoma were reported. Four of the seven patients were selected
YAMAGUCHI
from a series of 86 surgical cases of bile duct carcinoma,' with an incidence of 4.1%. The clinical features of the seven patients were similar to those with usual bile duct carcinoma and were not distinctive. All seven polypoid carcinomas were well differentiated papillary or tubular adenocarcinomas limited to the bile duct. Neither lymph node metastasis nor perineural invasion was evident. Five of the seven patients were doing well at 24 to 112 months after operation. The present study revealed that all seven early bile duct carcinomas were polypoid in shape. These seven patients consisted of fortunate cases that clinicians had discovered by chance. This study did not produce any valuable clue for clinical detection of early bile duct carcinoma.
Acknowledgements The author thanks Professor Masazumi Tsuneyoshi, MD, Department of Pathology 11, Kyushu University Faculty of Medicine, Fukuoka, Japan, for his continuous encouragement. The author also thanks the following four hospitals for permission to use their cases: National Fukuoka Higashi Hospital, Fukuoka Red Cross Hospital, Hamanomachi Hospital, and Usa Gunshi Ishikai Hospital. The author is grateful to Mr Brian T. Quinn (Kyushu University) for his critical reading of t h i s manuscript.
References 1. YAMAGUCHI K., ENIOJIM. & NAKAYAMA F. (1988) Extrahepatic bile duct cancer: A clinicopathologic study for immunohistochemistry for CEA, CA19-9 andp.21. WorldJ. Surg. 12, 11-17. 2. ALBORES-SAAVEDRA J. & HENSON.D. E. (1984)
3.
4.
5.
6.
7.
Tumors of the gallbladder and extrahepatic bile ducts. In: Atlas of Tumor Pathology Second Series, Fascicle 22. The Armed Forces Institute of Pathology, Washington DC. TSUNODA T., OHTUT., SHINOZAK~ T. er al. (1981) A study of two patients with early bile duct carcinoma. Tan to Sui (Journal of Biliary Tract and Pancreas) 2, 747-51. (in Japanese) NISHIMURA O., IWSUKA Y., TAMURA N., ADACHI H. & KOGAS. (1982) Early stage Carcinoma of the common hepatic duct, report of a case - Preoperative confirmed as such by PTC and biliary cytology. I to Cho (Stomach and Intestine) 17, 637-40. (in Japanese with English abstract) ONOY., KAWAMURA T., TSURUMARU M. et al. (1982) Early cancer of the distal bile duct, Report of a case. I fo Cho (Stomach and Intestine) 17,633-6. (in Japanese with English abstract) KIDOKORO T . , MATSUMOTO H., NAKAGAWA H . , MAE KAWA T., WAKAI K. & KONUMA I. (1982) Early cancer of the upper biliary tract. Report of a case. I to Cho (Stomach and Intestine) 17, 629-32. (in Japanese with English abstract) SHIMAGUMI S., ARIYAMA H., SHIRAKABE H., SUYAMA M., Ri S., IKENAGA H. & SHIRAKABE H. (1982) Early
EARLY BILE DUCT CARCINOMA
8.
9.
10.
11. 12. 13.
carcinoma of the common bile duct. Report of a case. I to Cho (Stomach and Intestine) 17,625-8. (in Japanese with English abstract) HAYASHI H . , UEDAN . , NAMIKI M. et al. Probable multicentric carcinoma in situ in the bile duct. Report of a case. I to Cho (Stomach and Intestine) 17, 61923. (in Japanese with English abstract) WATANABE H . , YAMAGIWA I. & IWASHITA A. (1982) Definition and diagnosis of early carcinoma of the biliary tract - From the pathological viewpoint. I to Cho (Stomach and Intestine) 17, 608-12. (in Japanese with English abstract) TAKEMOTO T. & Fun T. (1982) Definition and diagnosis of early cancer of the biliary tract - From the clinical viewpoint. I to Cho (Stomach and Intestine) 17, 613-18. (in Japanese with English abstract) NAGAKAWA T. (1991) Concept of early carcinoma of the biliary tract. Tan to Sui (Journal of Biliary Tract and Pancreas) 12, 347-5 1. (in Japanese) KOYAMA K . , KATOHS. & TANAKA J. (1987) Surgical problems of early bile duct cancer. Rinshou Geka 42, 1207-13. (in Japanese) SATOT., KOYAMAK . , YAMAUCHI H. & CHIBAJ. (1980) Early bile duct carcinoma. Geka 42, 151 I18. (in Japanese)
529 K . , YAMAGUCHI A . , KONDOHS. el al. 14. HACHISUKA (1983) Early bile duct carcinoma. Geka 45, 154550. (in Japanese) I., NAGAKAWA T., AKIYAMA T. et al. (1984) 15. KONISHI The condition of early bile duct carcinoma judged from the pathological findings. Tan to Sui (Journal of Biliary Tract and Pancreas) 5, 1413-17. (in Japanese) 16. NAKAZAWA S . , YAMADA Y . , NAITOH Y. et al. (1989) Diagnosis of early bile duct carcinoma. Kan Tan Sui 18, 909-14. (in Japanese) 17. OGURA Y . , KUSUDA T., MATSUDA N. & MIZUMOTO R. (1989) Definition and cancer spreadings on early cancer of the bile duct. Kan Tan Sui 18, 883-93. (in Japanese) 18. TOWROKI T., OKAMURA T . , FUKAOK. et al. (1980) Gross appearance of carcinoma of the main hepatic duct and its prognosis. Surg. Gynecol. Ubsfet. 150, 33-40. 19. CATTELL R . B., BRAASCH J . W. & KAHNF. (1962) Polypoid epithelial tumors of the gallbladder. N . Engl. J . Med. 266, 57-61. 20. YAMAGUCHI K . , ENJOJI M. & KITAMURA K. (1990) Non-icteric ampullary carcinoma with a favorable prognosis. Am. J . Gastroenterol. 85, 994-9.
525
N . Z . J . Surg. 1992,62,525-529
EARLY BILE DUCT CARCINOMA KOJI YAMAGUCHI Department of Surgery I , Kyushu University Faculty of Medicine, Fukuoka, Japan The clinocopathologic features of seven patients with early bile duct carcinoma are reported. Early bile duct carcinoma has been defined as bile duct carcinoma limited to the bile duct wall. The seven patients included six men and one woman ranging in age from 44 to 77 years. Six patients complained of jaundice and the other presented with right hypochondralgia. Ultrasonography showed a dilated proximal bile duct in the seven with a polypoid mass in three. Computerized tomography showed a dilated biliary tree in the seven together with a polypoid mass in two. Direct visualization of the bile duct with endoscopic retrograde cholangiography and/ or percutaneous transhepatic cholangiography showed a polypoid tumour of the bile duct and a dilated proximal biliary tree in all seven. Each of the seven polypoid tumours were well differentiated papillary or tubular adenocarcinoma restricted to the bile duct wall with minimal stromal invasion. There was neither any lymph node metastasis nor perineural invasion. Five of the seven patients were doing well at 24-1 12 months after a complete resection. One patient died from multiple liver metastases 21 months after intervention. The other patient died from other diseases 138 months after operation. These seven cases can be classified as early bile duct carcinoma due to both the limited invasion and favourable prognosis. The clinical features of the seven patients were quite similar to those of usual bile duct carcinoma. However there are still no proper diagnostic clues for early bile duct carcinoma and these patients represent fortunate cases that clinicians happened to discover by chance.
Key words: bile duct carcinoma, early bile duct carcinoma.
the other three cases were kindly provided by three affiliated hospitals. Early bile duct carcinoma was Despite recent advances of diagnostic and therapeudefined as bile duct carcinoma limited to the bile tic facilities, the clinical course of patients with duct wall by microscopy. Three patients were treatextrahepatic bile duct carcinoma remains gloomy. ed at Kyushu University Hospital, one at National There have been some case reports of early bile Fukuoka Higashi Hospital, one at Fukuoka Red duct ~ a r c i n o m a , ~but - ~no definite criteria of early Cross Hospital, one at Hamanomachi Hospital, and bile duct carcinoma have yet been e ~ t a b l i s h e d . ~ ~ ” another at Usa Gunshi Ishikai Hospital. Complete The clinicopathologic features of 86 cases of extraclinical records were available for all seven hepatic bile duct carcinoma have been reported patients. The seven patients included six men and previously and it was proposed that bile duct carcione woman ranging from 44 to 77 years of age with noma of the polypoid type, which was restricted to a mean of 61.3 years. Radiologic features were the wall with minimal invasion and demonstrated available on the seven patients and were as follows: no lymph node metastasis, could be classified as abdominal plain film for all seven patients; upper early bile duct carcinoma.’ This paper reports the gastrointestinal X-ray series for seven; ultrasonogclinical and histopathologic features of seven raphy for seven, computerized tomography for six, patients with early bile duct carcinoma in order to endoscopic retrograde cholangiography for five, introduce potential clues for the successful clinical percutaneous transhepatic cholangiography for diagnosis of this highly morbid carcinoma. two, operative cholangiography through a choledochotomy for two; through an intrahepatic bile duct Methods drain for one; and an angiography for three. Six patients underwent a pancreatoduodenectomy while Four of the seven cases of early bile duct carcinoma the other had a bile duct resection. All the speciwere selected from a series of 86 cases of bile duct mens were examined by cutting step-wise tissue carcinoma that had been previously reported’ while sections at 5 mm intervals. All the tissue sections were stained with haematoxylin and eosin and obCorrespondence: Koji Yamaguchi, MD, Department of Surgery I, Kyushu University Faculty of Medicine, 3-1-1 Maidashi, served by the author (KY). The clinical follow-up Higashi-ku, Fukuoka, Japan. was current as of 30 May 1991 and follow-up information was available on all seven patients. Accepted for publication 30 January 1992 Introduction
’,*
526
YAMAGUCHI
Table 1. Clinical features of seven patients with early bile duct carcinoma Case Age/ no. sex
Chief complaint
Site of origin
Macroscopic Microscopic Lymph node type type metastasis Clinical course
1
Jaundice Jaundice Jaundice Jaundice Abdominal pain Jaundice Jaundice
Middle Inferior Inferior Inferior Superior Middle Superior
Polypoid Polypoid Polypoid Polypoid Polypoid Polypoid Polypoid
2 3 4 5 6 7
64/M 77/M 44/M 66/F 66/M 62/M 50/M
PAP TUB 1 PAP TUB 1 TUB 1 PAP PAP
No No No No No No No
Alive 24 months later Alive 26 months later Alive 47 months later Alive 108 months later Alive 112 months later Died 21 months later Died 138 months later
PAP: papillary carcinoma;TUB 1 : well differentiated tubular adenocarcinoma.
Results CLINICAL FEATURES
Six of the seven patients with early bile duct carcinoma presented with jaundice and the other patient showed hypochondralgia (Table 1). One of the seven patients was diabetic. The serum carcinoembryonic antigen (CEA) level was elevated in three of the seven patients and carbohydrate antigen 19-9 (CAI9-9) was elevated in one of the two examined patients. One of the seven patients had cholelithiasis and another choledocholithiasis. One patient had had a cholecystectomy for cholelithiasis. Another patient had had a choledochotomy for ,
Fig. 1. Ultrasonography shows a hyperechoic mass in the dilated bile duct.
bleeding from percutaneous transhepatic cholangiodrainage. Ultrasonography showed a hyperechoic mass in the bile duct and a proximal dilated biliary duct in three (Fig. 1) and only a dilatation of the proximal bile duct in four. Cholelithiasis was evident in one. Computerized tomography showed a polypoid mass of soft tissue density in the bile duct and a dilated proximal bile duct in two (Fig. 2) and only a dilated biliary tree in four. Neither regional lymphadenopathy nor distant metastasis was evident. However, the gall-bladder was enlarged and had a thickened wall in all patients. Endoscopic retrograde cholangiography (ERC) was successful for all seven patients. Percutaneous transhepatic cholangiography (PTC) was done for the determination of extension of bile duct carcinoma in two, and operative cholangiography through choledochotomy in two and intrahepatic bile duct drain in one. Percutaneous transhepatic cholangiodrainage (PTCD) was done in one. Operative choledochus drainage was done in two. Direct visualization of the biliary tree with ERCP and/or PTC revealed a polypoid tumour in the bile duct and dilated proximal bile duct in all seven patients. Angiography showed neither encasement of the vessels, neovascularity, nor tumour staining in three examined patients. Two of the seven patients underwent
Fig. 2. Computerized tomography shows a soft tissue density mass in the bile duct (white arrow).
521
EARLY BILE DUCT CARCINOMA
chemotherapy; consisting of a combination of mitomycin C and 5-fluorouracil(5-FU) in one and 5-FU only in another. No patient underwent radiation therapy. HISTOPATHOLOGIC FEATURES
Three of the seven tumours were located in the inferior portion of the extrahepatic bile duct, two in the middle and two others in the superior. All seven tumours were polypoid in shape (Fig. 3) and mostly limited to the bile duct wall with minimal stromal invasion. No tumour of either nodular or sclerosing shape was restricted within the bile duct wall. The tumours mainly grew intraluminally and minimally invaded the bile duct wall. The pancreas and adjacent fibro-adipose tissue were free of invasion. Seven tumours consisted of a well differentiated papillary or tubular proliferation of malignant cells (Fig. 4 ) . Tumour cells were focally so well differentiated that it was difficult to distinguish adenocarcinoma from adenoma. The adenomatous epithelium gradually changed into unequivocal
adenocarcinoma. Well differentiated cancer cells often showed intestinal differentiation including goblet cells, brush borders, Paneth cells, and argentaffin cells. No tumour showed any lymph node metastasis, perineural invasion, or venous invasion. In five cases, the surrounding bile duct was lined by dysplastic epithelium of a moderate to severe degree (carcinoma in situ). The surgical margins were free of cancer cells. The cytologic examination of bile from intrahepatic cholangiodrainage was negative in one case while that from percutaneous transhepatic cholangiodrainage revealed adenocarcinoma in another. The biopsy specimens taken intra-operatively through a choledochotomy showed adenocarcinoma of the bile duct in two cases. CLINICAL C O U R S E
Five of the seven patients were doing well from 24 to 1 12 months after operation. One patient died 2 1 months after intervention. The post-mortem examination revealed multiple metastases in the liver, diaphragm, lung, rib, pleura and lymph nodes in the para-pancreatic, para-aortic, pulmonary hilar and para-bronchial regions. The remaining patient died 138 months after operation from another disease.
Discussion
Fig. 3. A polypoid tumour in the bile duct
Fig. 4. A polypoid tumour is composed of papillary proliferation of atypical epithelium and limited to the bile duct wall (haematoxylin and eosin, x 6 ) .
Despite recent advances in the diagnostic and therapeutic modalities, the clinical course of patients with bile duct carcinoma remains gloomy. Most patients with bile duct carcinoma present with jaundice and are advanced in stage. There have been some case reports of early bile duct carcinoma, but there have been no acceptable criteria established for identifying early bile duct carcinoma. In this study, early bile duct carcinoma was defined as carcinoma restricted to the bile duct wall by microscopy. All seven tumours were polypoid in shape. However, early bile duct carcinoma of flat type also exists, since some gall-bladders resected for cholelithiasis harbour carcinoma in situ with a flat shape. There was no experience of flat early bile duct carcinoma in this study because of the difficulties in pre-operative diagnosis. Todoroki er al. said that a polypoid tumour on cholangiography fared better than a nodular, annular constrictive or sclerosing tumour. l s It was previously reported that, macroscopically, a polypoid tumour fared better than a nodular or sclerosing tumour,' as described by Cattell. l9Microscopically, well differentiated adenocarcinoma fared better than moderately or poorly differentiated adenocarcinoma. Not all patients with polypoid bile duct carcinoma fared well. Only the clinical outcome of patients with polypoid carcinoma restricted within
528
the bile duct was was good, and the clinical course of patients with polypoid carcinoma invading the surrounding organs was as poor as that of nodular or sclerosing carcinoma. The clinical course of patients with bile duct carcinoma showing lymph node metastases, perineural invasion and cancer cells at the surgical margins was worse than those without these factors. The seven early bile duct carcinomas demonstrated all the preferable factors and were expected to have a favourable clinical course. It has been reported previously that patients with non-icteric ampullary carcinoma fare better than those with icteric ampullary carcinoma because of the high incidence of early am ullary carcinoma and papillary adenocarcinoma.' In the present study, only one of the seven patients was diagnosed as having bile duct carcinoma and underwent surgical intervention at the non-icteric period. The patient had developed abdominal pain and fever caused by cholangitis. Serum CEA and/or CA19-9 levels are known to be elevated in some patients with hepatobiliary carcinoma. In addition, the CEA and CA19-9 levels have been reported to correspond to the stages of the disease and are useful in the clinical follow-up in order to detect any recurrence. Carbohydrate antigen 19-9 mass screening has not been useful in the detection of early pancreas carcinoma. The serum CEA level was elevated in three of the seven patients and CA19-9 was elevated in one of the two examined patients. Thus, the measurement of CEA and CA19-9 did not prove useful in the diagnosis of early bile duct carcinoma. Regarding imaging techniques, ultrasonography and/or computerized tomography only showed a dilatation of the proximal bile duct and sometimes failed to visualize a polypoid tumour of the bile duct. However direct visualization of the biliary tree by endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography did reveal a polypoid tumour of both the bile duct and a dilated proximal bile duct. Ultrasonography or computerized tomography is thus considered useful in detecting a dilatation of the biliary tree. Direct visualization by ERC and/or PTC after ultrasonography is valuable for revealing polypoid early bile duct carcinoma. Ultrasonography is not painful and is easily performed even at the outpatient department. While most clinicians would indeed obtain an ultrasound early in the evaluation of jaundice, it is considered that cholangiography is essential to properly evaluate these patients. Ultrasound seems to provide little information and in fact it missed the polypoid nature of the lesion in the majority of patients in this study. The clinical and histopathologic features of seven patients with early bile duct carcinoma were reported. Four of the seven patients were selected
YAMAGUCHI
from a series of 86 surgical cases of bile duct carcinoma,' with an incidence of 4.1%. The clinical features of the seven patients were similar to those with usual bile duct carcinoma and were not distinctive. All seven polypoid carcinomas were well differentiated papillary or tubular adenocarcinomas limited to the bile duct. Neither lymph node metastasis nor perineural invasion was evident. Five of the seven patients were doing well at 24 to 112 months after operation. The present study revealed that all seven early bile duct carcinomas were polypoid in shape. These seven patients consisted of fortunate cases that clinicians had discovered by chance. This study did not produce any valuable clue for clinical detection of early bile duct carcinoma.
Acknowledgements The author thanks Professor Masazumi Tsuneyoshi, MD, Department of Pathology 11, Kyushu University Faculty of Medicine, Fukuoka, Japan, for his continuous encouragement. The author also thanks the following four hospitals for permission to use their cases: National Fukuoka Higashi Hospital, Fukuoka Red Cross Hospital, Hamanomachi Hospital, and Usa Gunshi Ishikai Hospital. The author is grateful to Mr Brian T. Quinn (Kyushu University) for his critical reading of t h i s manuscript.
References 1. YAMAGUCHI K., ENIOJIM. & NAKAYAMA F. (1988) Extrahepatic bile duct cancer: A clinicopathologic study for immunohistochemistry for CEA, CA19-9 andp.21. WorldJ. Surg. 12, 11-17. 2. ALBORES-SAAVEDRA J. & HENSON.D. E. (1984)
3.
4.
5.
6.
7.
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