Clinical Experience of Biliary Tract Carcinoma Associated with Anomalous Union of the Pancreaticobiliary Ductal System Tetsuo OHTA,Takukazu NAGAKAWA,Keiichi UENO, Kiichi MAEDA,Nobuhiko UEDA, Masato KAYAHARA,Takayoshi AFJYAMA, Masahiro KANNO,Ichiroh KONISm, Ryouhei IZUMI, Kohji KONISHI and Itsuo MIYAZAKI ABSTRACT: Between 1978 and 1988, 15 patients with gallbladder cancer and 2 patients with bile duct cancer were seen among 49 patients with anomalous union of the pancreaticobiliary ductal system. Radiographic findings revealed two types of this anomalous condition: one in which the pancreatic duct entered the c o m m o n bile duct (type 1) and one in which the c o m m o n bile duct entered the pancreatic duct (type 2). In gallbladder cancer, the c o m m o n bile duct presented no dilatation, or in some patients, mild dilatation, and type-1 anomalous union was frequently found among these patients. In contrast, the two patients with bile duct cancer had cystic dilatation of the c o m m o n bile duct and type-2 anomalous union. T h e bile amylase level, which was determined in seven patients, was extremely high in all the patients. Histopathologically, the tumors in most patients showed papillary to papillo-tubular proliferation in the mucosal layer while atypical epithelial hyperplasia was noted in the vicinity o f the tumor area. These findings suggest that this congenital anomaly in both ducts results in a loss o f the normal sphincteric mechanism of the duodenal papilla, and that chronic relapsing cholecystitis or cholangitis, caused by the reflux o f pancreatic juice into the biliary tract, can induced progressive changes to atypical epithelial hyperplasia which may develop into carcinoma. KEY WORDS: biliary tract carcinoma, anomalous union of the pancreaticobiliary ductal system, atypical epithelial hyperplasia of the bile duct

INTRODUCTION A n o m a l o u s union o f the pancreaticobiliary ductal system (AUPBD), which forms the socalled elongated c o m m o n terminal duct, and in which the bile duct and pancreatic duct join too soon at a position distant from the The Second Department of Surgery, School of Medicine, Kanazawa University, Kanazawa, Japan Reprint requests to: Tetsuo Ohta, MD, The Second Department of Surgery, School of Medicine, Kanazawa University, t3-t Takara-machi, Kanazawa 920, Japan

duodenal papilla, pTobably occurs more frequently in Japan than in the western world? In Japan, the incidence of AUPBD is 1 per cent to 3 per cent o f all patients undergoing endoscopic retrograde cholangiopancreaticography (ERCP)3 ,3 This anomalous condition is said to be frequently accompanied not only by biliary tract lesions such as congenital biliary dilatation, choledocholithiasis and biliary tract carcinoma, but also by pancreatic lesions such as pancreatitis and pancreaticolithiasis. Moreover, the incidence of biliary tract carcinoma related to AUPBD, is especially considered to be much higher than

JAPANESEJOURNALOFSURGERY,VOL. 20, NO. 1 pp. 36-43, 1990

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37

Biliary tract carcinoma and AUPBD

A

B

Fig. 1. Classification of the mode of anomalous union of the pancreaticobiliary ductal system (black arrows). A, Type-1 anomalous union: the pancreatic duct entering the common bile duct; B, Type-2 anomalous union: the common bile duct entering the pancreatic duct.

previously asumed. 4-8 The aim of the present p a p e r is to describe the clinical features ofbiliary tract carcinoma related to AUPBD a n d detail the m o r p h o logical findings o b t a i n e d from resected specimens. MATERIALS AND METHODS

From January, 1978, through December, 1988, 49 patients with AUPBD were treated in the Second Department o f Surgery at Kanazawa University Hospital and its affiliated hospitals. O f these 49 patients, 15 (30.6 per cent) were diagnosed as having gallbladder cancer and two (4 per cent) were diagnosed as having bile duct cancer related to AUPBD, by histopathological or operative findings. Sex, age at the time of operation, clinical symptoms, laboratory, radiographic, operative and histopathological findings were recorded. In this study, AUPBD was defined as the presence of the so-called abnormally long c o m m o n terminal duct and connection

of the c o m m o n bile and main pancreatic ducts above the narrow distal segment made by the sphincter muscle of the papilla Vater on radiographic studies2 T h e m o d e of AUPBD was classified according to the m e t h o d o f Kimura et al., ~ based on radiographic findings (Fig. 1): patients in w h o m the pancreatic duct entered the c o m m o n bile duct were classified as type 1 and patients in w h o m the c o m m o n bile duct entered the pancreatic duct were classified as type 2. Eleven of the 15 patients with gallbladder cancer underwent a cholecystectomy and one of the two patients with bile duct cancer underwent a pancreaticoduodenectomy. All of the resected specimens were fixed in 10 p e r cent formalin and e m b e d d e d in paraffin. T h e sections were cut at a thickness o f 4-6 microns and stained with hematoxylin a n d eosin (HE), periodic acid-Schiff (PAS) and alcian blue in a p H 2.5 solution.

38

]pn. J. Surg. January lOO0

Ohta et al. RESULTS

Patients and symptoms T h e clinicopathological features of the 15 patients with gallbladder cancer and the two with bile duct cancer are given in Table 1. T h e r e were 4 men and 13 women whose ages ranged from 37 to 70 years, with a mean age of 53 years. T h e main symptom was right upper quadrant abdominal pain, which occurred in 16 patients (94A per cent) while jaundice, fever and loss of weight occurred in 5 patients (29.4 per cent) each. T h e period from the onset of initial symptoms to the detection o f carcinoma ranged from one month to 29 years. O f the 17 patients, one (case 17) had undergone a choledochocystoduodenostomy 5 years prior to developing carcinoma.

Radiographic findings An anomalous union between the common bile and main pancreatic ducts was clearly demonstrated in all patients: by percutaneous transhepatic cholangiography (PTC) in five patients, by ERCP in 10 patients and by operative cholangiography in 2 patients. The length of the abnormally long common terminal duct, measured on direct pancreaticocholangiograms, ranged from 12 to 38 mm, with a mean length of 24 mm, whereas the length of the c o m m o n terminal duct below the union of the c o m m o n bile and main pancreatic ducts in 15 control patients without biliary or pancreatic lesions ranged from 2 to 12 mm. Common bile duct dilatation was seen in 10 of the 17 patients (58.8 per cent); in the form o f spindle or cylindrical configuration in 6, cystic configuration in 3, and rosary configuration in 1. O f the 15 patients with gallbladder cancer, 13 (86.7 per cent) had type-1 anomalous union while the other 2 had type 2. Cholangiograms of the gallbladder cancer patients with type-1 anomalous union showed a normalsized to mildly dilated c o m m o n bile duct in each patient. In contrast, both the patients with bile duct cancer had type-2 anomalous

union and cystic dilatation of the c o m m o n bile duct. Stones in the c o m m o n bile duct were found in only two patients (cases 6 and 7), but no stones were found in the gallbladder.

Operative findings Five of the patients with gallbladder cancer (cases 1-5) underwent curative cholecystectomy with hepatic resection and regional lymph node dissection, 6 patients (cases 6-11) received a palliative cholecystectomy, and the other 3 patients (cases 12-15) had an exploratory operation as a result of direct extention to the liver a n d / o r distant nodal metastases. One patient with bile duct cancer arising in a congenitally dilated bile duct (case 16) underwent a palliative pancreaticoduodenectomy, while the other (case 17) received an exploratory operation. T h e bile amylase level which was determined in seven cases, was extremely high (2,135-449,100 IU/1) in all the patients.

Histopathological findings Biliary tract carcinoma related to AUPBD was recognized as a papillary lesion in 4 patients, a nodular lesion in 3, and a diffusely infiltrating lesion in 5, based on the results of macroscopically examining the surgically resected specimens. O f the 12 patients that underwent tumor resection, microscopic examination revealed papillary adenocarcin o m a in 5, tubular adenocarcinoma in 4, poorly differentiated a d e n o c a r c i n o m a in two, and squamous cell carcinoma in 1. Histologic diagnosis was unable to be determined in the 5 patients who underwent an exploratory operation. In the cases of moderately or well-differentiated adenocarcinoma, various degrees of hyperplastic foci of the epithelial layer were found in the vicinity of the tumor, in association with chronic cholecystitis or cholangitis, characterized by a proliferation o f fibrous connective tissue with a large n u m b e r of inflammatory cells and glandular elements (Fig. 2, 3). These hyperplastic foci showed moderate to severe atypia, such as a loss of polarity, an increase in the nuclear-cytoplasmic ratio, hyperchro-

Volume 20 Number 1

Bilia~y tract carcinoma and AUPBD

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40

Fig. 2. High power view of gallbladder cancer. This lesion shows well-differentiated papillary adenocarcinoma (HE, X48).

Fig. 3. Histological appearance of the area within the vicinity of the tumor. Atypical epithelial hyperplasia is noted in association with chronic cholecystitis (HE, X40). matic nuclei and a few mitotic figures. In regard to metaplastic change, goblet cells were observed in 4 patients (Fig. 4), but Paneth's cells were not found in any patient. O n the other hand, in the case o f poorly differentiated a d e n o c a r c i n o m a a n d squamous cell carcinoma, hyperplastic foci of the epithelial layer adjacent to the tumor were sparse and no metaplastic change was found. In contrast to the specimens from within the vicinity of the tumor, almost all specimens that were remote from the tumor presented findings of chronic inflammation characterized by detachment of epithelium, infiltration o f small round cells, fibrosis, and mu-

Jpn. J. Surg. January 1990

Fig. 4. Atypical epithelial hyperplasia with Goblet cells can be observed in the area within the vicinity of tile tumor (periodic acid-Schiff and alcian blue, •

Fig. 5. Mucous glands stained positively with PAS and alcian blue are present in mucosal layer remote from the tumor area (HE, X60). cous glands stained positive with PAS and alcian blue (Fig. 5). However, goblet cells and Paneth's cells were not found in any case. DISCUSSION

Clinical and radiological features of biliary tract carcinoma associated with AUPBD In 1985, the theme "various problems related to carcinogenesis in AUPBD" was discussed at the 8th meeting of the Study Group for Anomalous Union o f the Pancreaticobiliary Ductal System in Japan. The results of a questionnaire survey on AUPBD and biliary tract cancer sent to 51 facilities in

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Bilia,y tract carcinoma and AUPBD

Japan, reported on that occasion, are as follows. During the previous five years, 569 patients were diagnosed as having AUPBD, and biliary tract cancer was found in 131 (23 per cent) o f them. Gallbladder cancer was found in 93 patients, accounting for a large proportion o f the 131 patients (71 per cent), while cancer in the middle or lower portion of the bile duct was found in 24 patients (18.3 per cent), cancer in the upper portion of the bile duct or intrahepatic bile duct was found in 7 (5.4 per cent) and cancer of unknown origin was found in 7 (5.4 per cent). Patients with bile duct cancer and gallbladder cancer associated with AUPBD accounted for about 5 per cent and 10 per cent o f those who had biliary tract cancer during the same period, respectively. T h e age of patients who had bile duct cancer and gallbladder cancer with AUPBD at the time of diagnosis o f their disease peaked in the forties and fifties, respectively. O n the other hand, the age o f patients with biliary tract cancer without AUPBD peaked in the sixties. Both types of cancer were frequently found in females. Morphological studies o f biliary dilatation in patients with gallbladder cancer associated with AUPBD showed that about half, or 50.6 per cent, o f the patients had no dilatation, while 39.1 per cent and 10.3 per cent had mild dilatation or cystic dilatation, respectively. Type 1, type 2 a n d other specific types of anomalous union accounted for 66.7 per cent, 19.4 per cent and 13.9 per cent, respectively. The incidence of gallbladder stones was significantly lower (about 10 per cent) than in patients with gallbladder cancer without AUPBD (40-70 per cent). In contrast, 70 per cent, 16.7 per cent and 13.3 per cent o f patients with bile duct cancer associated with AUPBD had cystic dilatation, mild dilatation and no dilatation of the c o m m o n bile duct, respectively. Type and type 2 anomalous union accounted for 38.5 per cent and 61.5 per cent, respectively and the incidence of choledocholithiasis was about 20 per cent. The above results of the Study Group for AUPBD in J a p a n were in accordance Mth

41

those obtained from the present study. An analysis of the results from the present study characterized the clinical features o f patients with biliary tract carcinoma associated with AUPBD as follows: (1) The age of patients at the time o f diagnosis of the disease is slightly younger than that o f patients with biliary tract carcinoma without AUPBD, reaching a peak in the forties and fifties. (2) T h e disease was more frequently found in females. (3) T h e frequency of cholelithiasis was very low. (4) In gallbladder cancer, the c o m m o n bile duct presented no dilatation or in some cases, only mild dilatation, and type-1 anomalous union was frequently found among these patients. (5) A large proportion o f patients with bile duct cancer had cystic dilatation of the c o m m o n bile duct and type2 anomalous union. Carcinogenic factors Such various factors as chronic inflammation associated with mechanical stimulation by stones, adenomatous lesions o f the biliary tract, and metabolic products o f bile components (bile acid in particular), have b e e n assumed to be factors responsible for biliary tract carcinoma. 1~ Moreover, the reflux of pancreatic juice in the biliary tract due to anomalous union has recently been noted as an important carcinogenic factor in biliary tract carcinoma associated with AUPBD for the following reasons: biliary tract carcinoma is frequent among patients with AUPBD; biliary tract carcinoma with AUPBD is less frequently complicated by cholelithiasis and is manifested at a younger age than biliary tract carcinoma without AUPBD; and amylase levels in the biliary tract are markedly high. 4 It is well known that various proteinases and lipases derived from pancreatic juice are a c t i v a t e d in t h e b i l e o f p a t i e n t s with AUPBD. 13Among these, phospholipase A~ in pancreatic juice hydrolyzes lecithin, a bile component, into lysolecithin and free fatty acid. Lysolecithin reportedly acts on the biliary tract epithelium as a strong cytotoxin, presumably causing cancerous transforma-

aPn. J. Surg. uary 1990

Ohta et al.

42

tion through hyperplasia or intestinal metaplastic changes in the process of repeated destruction and regeneration of the biliary tract epithelium. 14 H o w e v e r , the precise m e c h a n i s m o f the activation of those enzymes without the mediation of enterokinase is still uncertain and further studies n e e d to be done in order to clarify this.

Histopathological findings T h e r e is no doubt that intestinal metaplasia is closely associated with the developm e n t of well-differentiated a d e n o c a r c i n o m a in the stomach? ~,16 Intestinal metaplasia in biliary tract epithelium has also b e e n noted as an important lesion associated with carcinogenesis in both biliary tract carcinoma and gastric cancer? 7-~9 I n an experiment using AUPBD models, Komi et al? ~ indicated the possibility that metaplastic changes in biliary tract epithelium might develop in the process of repair of the bile duct wall with repeated destruction and regeneration caused by the reflux o f pancreatic juice into the bile duct in AUPBD. Furthermore, histological studies o f patients with bile duct dilatation associated with AUPBD, indicated an increased fi'equency o f epithelial metaplasia of the bile duct with the a p p e a r a n c e of mucous glands, goblet cells and argyrophilic cells, which may be regarded as intestinal metaplasia, with aging. Komi et al.2~ also reported the a p p e a r a n c e of immunologically active e n d o c r i n e cells with gastrin a n d somatostatin in the metaplastic epithelium, stressing the importance of intestinal metaplasia as the background lesion for biliary tract carcinoma in AUPBD. O n the other hand, different reports ~1 h a v e indicated that intestinal metaplasia does not provide a sufficient explanation for the high incidence o f cancerous transformation in AUPBD because it is less frequently f o u n d in patients with AUPBD, than in those with gallbladder cancer complicated by gallbladder stones but without AUPBD. Similarly, the histological study of our patients indicated that metaplasia with goblet ceils was present in only about 30 per cent of the

patients with well differentiated adenocarcinoma while proliferation of mucous glands was frequently noted in non-cancerous mucosa, providing no positive findings suggestive of the relation between intestinal metaplasia a n d cancerous transformation. I n contrast, almost all patients presented such findings o f chronic inflammation as detachment of epithelium, infiltration of small r o u n d cells, proliferation of mucous glands and fibrosis in non-cancerous mucosa, and epithelium showing a transition from hyperplasia to atypical hyperplasia as it comes closer to the cancerous focus. T h e above findings suggested the importance of atypical hyperplasia o f the biliary tract epithelium as the back ground lesion in the presence o f underlying chronic inflammation caused by the reflux o f p a n c r e a t i c juice. H o w e v e r , the lesion surrounding the cancerous focus is not necessarily considered to be a pre-cancerous lesion, but possibly a para-cancerous lesion. Fun_her histological studies must be done on a g r e a t e r n u m b e r of patients with early biliary tract carcinoma in order to elucidate the b a c k g r o u n d lesion o f cancer in this region. (Received for publication o n Jan. 94, 1989) REFERENCES 1. KomiN, Udaka H, Ikeda N, KashiwagiY. Congenital dilatation of the biliary tract; New classification and study with particular reference to anomalous arrangement of the pancreaticobiliary ducts. GastroenterolJpn 1977; t2: 293-304. 2. Mutoh K, Nagashima K, Ikeda S, Hyodoh H. Radiological daignosus on the abnormal pancreatico-cholangio connection. Tan to Sui (Biliary tract and Pancreas) 1982; 3: 477-485. (in Japanese) 3. UnozawaT, KimuraK, Ohto M, Saisho H, Morita M, Ebara M, Kasutani N, Tsuchiya K, Okuda K. Clinical study on relationship between anomalous pancreatico-biliaryductal union and carcinoma of the gallbladder. Nippon ShokakibyoGakkaiZasshi (Jpn J Gastroenterol) 1985; 82: 473-482. (in Japanese with English Abst.) 4. Nagakawa T, Ohm T, Takeshita Y, Konishi K, Miyazaki I. Clinical study on anomalous union of pancreatico-biliary duct system with special refer-

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