Preferable operative age of choledochaldilation types to prevent patientswith pancreaticobiliary maljunctionfrom developing biliary tractcarcinogenesisSusumu Kobayashi, MD,a,c Naomi Ohnuma, MD,b Hideo Yoshida, MD,b Yasuhiro Ohtsuka, MD,b

Keita Terui, MD,b Takehide Asano, MD,a Munemasa Ryu, MD,c and Takenori Ochiai, MD,a

Chiba, Japan

Background. Pancreaticobiliary maljunction (PBM), which frequently accompanies choledochaldilation, is a high risk factor for biliary tract (gallbladder, bile duct) carcinoma because of thecontinuous reflux of pancreatic juice into the biliary tract. The aim of this study was to clarify thepreferable operative age in PBM patients for the prevention of biliary tract carcinogenesis, with referenceto the dilation types of bile ducts.Methods. There were 165 PBM patients in total studied, including 92 pediatric patients (#15 y)(cystic, 63; spindle-like, 29; nondilation, 0) and 73 adult patients (>15 y) (cystic, 45; spindle-like, 18;nondilation, 10) who underwent operative excision of extrahepatic bile ducts or cholecystectomy. Weinvestigated incidence by age of biliary tract malignancies and the risk according to types of dilation.Results. In the pediatric group, no carcinoma case could be found preoperatively or postoperatively (meanfollow-up period, 11.7 y). In the adult group, bile duct carcinomas could be detected in 6 cases of a cystictype (6 of 45; 13.3%) (3 preoperative, 3 postoperative). Among the bile duct carcinoma cases, theyoungest patient was a 21-year-old woman who had undergone excision of an extrahepatic bile duct 3years previously. Gallbladder carcinomas were detected in 16 patients: 3 of 45 cystic (6.7%), 6 of 18spindle-like (33.3%), and 8 of 10 nondilation (80.0%), in whom the youngest patient was a 41-year-old woman with a spindle-like type.Conclusions. To prevent biliary tract carcinogenesis in PBM patients, cystic-dilated choledochusshould be excised in childhood before the development to a precancerous stage. In spindle-likeand nondilation types, cholecystectomy is absolutely necessary in early adulthood before age 40.(Surgery 2006;139:33-8.)

From the Department of Academic Surgery,a Department of Pediatric Surgery,b Graduate School of Medicine,Chiba University, Japan; and the Department of Surgery, Chiba Prefecture Hospital of Sawara, Chiba, Japanc

PANCREATICOBILIARY MALJUNCTION (PBM) is detectedin the vast majority of congenital choledochal dila-tion (CD).1 Frequent association of biliary tractcarcinomas with congenital CD led to the etiologicconsensus that reflux of pancreatic juice intothe biliary tract as a result of PBM was the most im-portant factor in the development of biliary tract

Accepted for publication July 15, 2005.

Reprint requests: Susumu Kobayashi, MD, Department of Sur-gery, Chiba Prefecture Hospital of Sawara, I-2285 Sawara, SawaraCity, Chiba 287-0003, Japan. E-mail: s.kbysh57@mc.pref.chiba.jp.

0039-6060/$ - see front matter

� 2006 Mosby, Inc. All rights reserved.

doi:10.1016/j.surg.2005.07.028

carcinogenesis in congenital CD patients.2 Clinicalimaging, such as magnetic resonance cholangio-pancreatography or endoscopic retrograde cholan-giopancreatography, showed that some PBM caseshad normal choledochus, which had been dis-covered frequently among gallbladder carcinoma(GBCa) patients.3 PBM might generate biliary tractcarcinomas irrespective of the type of choledochaldilation. In Japan, there is consensus as to thenecessity of excision of dilated bile ducts to reducethe risk for biliary tract carcinogenesis in PBMpatients with CD.4,5 However, there is controversyas to the necessity of excision of choledochus incases of nondilation-type PBM because bile ductcarcinoma (BDCa) is very rare, irrespective offrequent detection of GBCa.6,7

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34 Kobayashi et al

Congenital CD patients undergo operativeexcision of dilated choledochus with choledocho-jejunostomy to relieve complaints such as abdom-inal pain or to prevent the development of BDCa.The age at which the operation takes place variesfrom infancy to old age, according to the degree ofthe complaint. Some patients develop biliary tractcarcinoma before the excision.8 Although earlyexcision of choledochus decreases the rate of carci-nogenesis, parents of young patients, and theirdoctors, tend to delay the operation until adoles-cence if the complaint is mild. The aim of thisstudy was to clarify the preferable operative agein PBM patients for the prevention of the develop-ment of biliary tract carcinoma in PBM cases,according to the types of choledochal dilation.

METHODS

Patients. Therewere 165patients studied in total,including 92 patients in the pediatric group (#15 y)and 73 patients in the adult group (>15 y), amongwhom PBM could be identified by preoperativeimagings. Table I shows the patient outlines in pedi-atric and adult groups. Female patients overwhelm-ingly were more dominant in number thanmales inboth groups. Ninety-two patients in the pediatricgroup underwent total excision of the extrahepaticbile ducts with reconstruction from March of 1978to December of 2004 at the Department of PediatricSurgery of Chiba University Hospital. Seventy-threepatients in the adult groupunderwent total excisionof the extrahepatic bile ducts with reconstructionor cholecystectomy alone from August of 1974 toDecember of 2004 at the Second Department ofSurgery of Chiba University Hospital. Two patientsin the adult group underwent probe laparotomybecause of a progressive cancer stage.

Table I. Patients outlines in pediatric and adultcases.

Pediatric Adult

Age (mean ± SD) 2.5 ± 3.3 40.3 ± 17.6Sex

Man 23 11Woman 69 62

OperationBile duct excision 92 66Cholecystectomy 0 5Probe laparotomy 0 2

Tumor presencePreoperative 0 19Postoperative 0 3

All of the patients had PBM, which is definedin Japan as a congenital anomaly in which the unionof the pancreatic and biliary duct is located outsidethe duodenal wall.9 The diagnoses of PBM wereperformed by magnetic resonance cholangiopan-creatography, endoscopic retrograde cholangio-pancreatography, or percutaneous transhepaticcholangiography to confirm that the pancreaticduct and choledochus connect with a conspicuouslylong common channel or they unite in an appar-ently anomalous form.

We classified PBM into 3 types (according tocomplications of choledochal dilation): cystic dila-tion, spindle-like dilation, and nondilation types byusing endoscopic retrograde cholangiopancrea-tography or percutaneous transhepatic cholangi-ography findings. Although Todani’s classificationof types of bile duct dilation have been acceptedwidely, it includes very rare types such as types II,III, IV-B, and V.5 Therefore, we applied the simpleclassification that has been used commonly inJapan. We showed case numbers according to ourapplied classification and Todani’s classificationin Table II. The nondilation type was defined ashaving a maximal choledochal diameter of lessthan 10 mm, and those of the other 2 types weregreater than 10 mm. The cystic dilation type wasdefined as a ratio ofmaximal choledochal diametersto minimal choledochal diameters of hepatic portalareas in more than 2, and the spindle-like dilationtype was defined as having a ratio of less than 2.

Clinical detection of carcinoma. It was possibleto diagnose preoperatively all of the carcinomas bymeans of clinical imaging tools such as computedtomography or ultrasonography. According to thepreoperative diagnosis of cancer progression, weselected radical operative procedures involvingadditional hepatectomy and pancreatoduodenec-tomy. When tumors were suspected, patho-histologic examinations were performed duringthe operation by using frozen tissue sections

Table II. Classification of PBM cases accordingto types of choledochal dilation and Todanitypes in pediatric and adult groups

Pediatric Adult

Todani Todani

Cystic 63 Ia 40 45 Ia 25Iva 23 Iva 20

Spindle-like 29 Ic 29 18 Ic 18Nondilation 0 10Total 92 73

PBM, Pancreaticobiliary maljunction.

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Kobayashi et al 35

Fig 1. Agedistribution of patients whounderwent operation for pancreaticobiliarymaljunction. Therewere165 patients studied in total, including 92 patients in the pediatric group (#15 y) and 73 patients in the adultgroup (>15 y). Three different shaded rectangles denote cystic, spindle, and nondilation type, respectively.

immediately after excision. After operation, weperformed pathohistologic examinations of ex-cised gallbladders and bile ducts in all cases bystaining with hematoxylin-eosin. Confirmations ofcarcinoma were made by 2 pathologists in ourhospital.

The postoperative status of patients was followed-up in our hospital or other clinics. A search fornewly developed carcinoma was conducted every6 months, mainly by ultrasonography, with specialattention to intrahepatic bile ducts. In postopera-tive carcinoma cases, carcinoma was confirmedusing tissues from operation or autopsy.

RESULTS

Age distribution of patients. Figure 1 shows thedistribution of patients according to the age whenthey underwent operations for PBM. The peakin the number of patients is located in ages 1 to4 in the pediatric group. The number of patientsis distributed evenly among ages 20 to 65 yearsold, although it gradually decreases with age in

cystic types. Ninety-two of a total of 165 patientsunderwent operation by the age of 15 in our pedi-atric surgery unit. All pediatric patients had cystic(63 patients) or spindle-like dilation (29 patients)of choledochuses, and were diagnosed as havingcongenital CD. The operative procedure was exci-sion of extrahepatic bile ducts with hepatico-jejunostomy. There were no carcinoma patientspreoperatively or postoperatively in the pediatricgroup, in which the mean postoperative follow-up period was 11.7 years (maximal follow-upperiod, 25 y).

Seventy-three of the 165 patients underwentoperation in our Surgery Department after the ageof 15. The 73 adult cases included 45 cases of cystictype, 18 cases of spindle-like type, and 10 cases of thenondilation type. Ten nondilation cases underwentoperation after age 47. Nondilation patients hadmild complaints such as epigastral discomfort butthe operation was performed because elevatedlesions had been detected in their gallbladders.The raised lesions were GBCa in 8 of 10 cases.

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36 Kobayashi et al

Carcinoma cases in the pediatric group. NeitherGBCa nor BDCa was found in operative specimensof 92 pediatric patients preoperatively or post-operatively (Table I).

Carcinoma cases in the adult group. Tumorswere detected in 19 preoperative and 3 postoper-ative cases (Table I).

Age of carcinoma patients with cystic-type dilation.Preoperative carcinoma cases: In 73 adult cases, GBCawas observed in 3 cases of 45 cystic-dilation cases(6.7%). The ages of these 3 patients were 46, 50,and 56 years (Fig 2); whereas BDCa was observedin 3 cases among 45 cystic-dilation cases (6.7%).All BDCa cases showed the cystic-dilation type asTodani’s type IV-A. The patients were 40, 50, and55 years (Fig 2). One 50-year-old patient hadGBCa and BDCa simultaneously. Therefore, biliarytract carcinomas were detected in 5 cases.

Postoperative carcinoma cases: Another 3 patientsamong the 40 tumor-free cystic-type cases (7.5%)in the adult group developed BDCa postopera-tively on the walls of the residual bile duct after

Fig 2. Age of GBCa and BDCa patients in 3 differentdilation types. Arrows indicate the intervals betweenprimary surgery and occurrence of carcinoma. *Ageof detection of GBCa or BDCa. dAge of primary opera-tion. GBCa, gallbladder carcinoma; BDCa, bile ductcarcinoma.

excision of extrahepatic bile ducts. They were 18,25, and 35 years old at the time of the primaryoperation (Fig 2). All 3 cases of BDCa were classi-fied as Todani’s type IV-A. The 3 cases were foundto have developed carcinomas in residual dilatedbile ducts at the age of 21 (29 mo after operation),34 (104 mo after operation), and 54 years (19.5 yafter operation).10 The youngest patient was 21,and had undergone primary resection of the cystic-dilated choledochus at age 18. She was admitted toour hospital with symptoms of pneumonia. How-ever, her clinical symptoms progressed rapidly andshe died of respiratory failure. The autopsy dis-closed undifferentiated adenocarcinoma originat-ing in the bile duct of the left lobe with directinvasion to the lungs and heart.

Age of carcinoma patients with spindle-likedilation. There was no cases of BDCa in thespindle-like adult group. However, GBCa was ob-served in 6 cases of 18 spindle-like dilation cases(33.3%). The ages of the 6 patients were 41, 49, 55,60, 62, and 79 years (Fig 2).

Age of carcinoma patients with nondilation-typedilation. The nondilation type with PBM was iden-tified exclusively in adult cases. We had no cases ofBDCa in the nondilation group. Among 10 non-dilation cases, 8 cases could be identified as havingdeveloped GBCa. The ages of 8 patients were 49,55, 57, 61, 62, 62, 67, and 71 years (Fig 2). In theGBCa cases, the youngest patient was 49 years.

DISCUSSION

Congenital CD, or choledochal cyst, presentsclinical manifestations more commonly in infancyand childhood than among adults. Although symp-toms of abdominal pain and jaundice occur inchildhood among the majority of PBM cases, 20%to 30% of the patients survive childhood withoutoperation and reach adulthood.11,12 However, con-genital CD patients sometimes develop biliary tractcarcinomas early in adulthood because of the con-tinuous reflux of pancreatic juice into the biliarytract caused by the associated PBM. Kasai et al4

reported that extrahepatic bile ducts should beremoved and replaced with hepaticojejunostomyin a Roux-en-Y fashion, even in children, to reducepostoperative morbidity and prevent cancer occur-rence in congenital CD patients.4 This conceptgradually has gained wide acceptance throughoutthe world over the past few decades. With accumu-lating evidence concerning congenital CD, we pos-tulated that the essential aspect of this operativeprocedure might be the termination of reflux ofpancreatic juice into the bile duct through hepati-cojejunostomy in Roux-en-Y fashion because the

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Kobayashi et al 37

mixture of pancreatic enzymes with bile might beinvolved in the pathophysiologic mechanism to de-velop bile duct carcinomas.13,14 The early termina-tion of pancreatic juice reflux into the biliary tractmay serve to stop the development of biliary tractcarcinoma in PBM patients.

In our series, we found no carcinoma casesamong 92 pediatric patients who were age 15 yearsor younger, either preoperatively or in the postop-erative follow-up period (mean follow-up period,11.7 y). Among preoperative cases with a cystic-typelesion, the youngest BDCa patient was 40 years.However, we had 3 cases of postoperative bile ductcarcinoma that developed in the residual bileducts on the liver side. The youngest patient was21 years old and had undergone excision of theextrahepatic bile ducts as primary operation 2 yearsand 5 months earlier at the age of 18.10 Thispatient was the youngest with carcinoma in thisstudy among all PBM patients. Does this patient in-dicate that operative termination of pancreaticjuice reflux does not serve to stop the developmentof bile duct carcinoma in PBM patients? The keyfactor may instead be operative age because wehave never experienced postoperative biliary tractcarcinoma among pediatric operative patients.The primary excision specimens indicated dysplas-tic changes on the mucosa line of the resectedbile duct in several of our adult patients, includ-ing the youngest one. Carcinogenic stress causedby refluxed pancreas juice might promote carcino-genesis on bile duct walls until the excision ofthe extrahepatic bile duct.15 The tissues of bileduct walls might reach the precancerous stage bythe time of primary operation among the adults.The fact that there were no postoperative carci-noma cases in the pediatric group may indicatethat the bile duct was excised before tissue malig-nancy reached the precancerous stage becausethe operation was performed in childhood. There-fore, it might be better if the dilated bile duct isexcised in childhood in PBM cases.

In PBM cases of the spindle-like and nondila-tion type, the complaints generally are mild. In anondilation group, all PBM was detected by meansof the clues presented by elevated lesions in thegallbladder using ultrasonography. We have neverfound BDCa in our department among PBM casesof the spindle-like and nondilation type. In Japan,there has been discussion about the excision ofextrahepatic bile ducts in cases of PBM without CDbecause of the low frequency of its coexistencewith BDCa despite the reflux of pancreatic juiceinto the biliary tract as a result of PBM.7,16 In ouroperative group, we do not excise the extrahepatic

bile duct in cases of the nondilation type and insome cases of spindle-like type.6 However, the fre-quency of association with GBCa is extremelyhigh. The youngest patients were 49 years oldwith GBCa in the nondilation type and 41 yearsold with GBCa in the spindle-like type. For PBMcases of the spindle-like and nondilation type, pro-phylactically we should perform cholecystectomybefore the patients are 40 years old.

In conclusion, to prevent biliary tract carcino-genesis, we should excise dilated bile ducts ofPBM patients, especially those with cystic dilations,during childhood. However, in the spindle-likeand nondilation-type cases, cholecystectomy isabsolutely necessary in adulthood before the ageof 40.

REFERENCES

1. Komi N, Kuwashima T, Kuramoto M, Udaka H, OgasawaraK, Aoki Y, et al. Anomalous arrangement of pancreaticobili-ary ductal system in cases with choledochal cyst. TokushimaJ Exp Med 1976;23:37-48.

2. Todani T, Watanabe Y, Urushihara N, Morotomi Y, Maeba T.Choledochal cysts, pancreatobiliary malunion, and cancer.J Hepatobiliary Pancreat Surg 1994;1:247-51.

3. Sugiyama M, Atomi Y. Anomalous pancreaticobiliary junc-tion without congenital choledochal cyst. Br J Surg 1998;85:911-6.

4. Kasai M, Asakura Y, Taira Y. Surgical treatment of chole-dochal cyst. Ann Surg 1970;172:844-51.

5. Todani T. Congenital choledochal dilatation: classification,clinical features, and long-term results. J HepatobiliaryPancreat Surg 1997;4:276-82.

6. Kobayashi S, Asano T, Yamasaki M, Kenmochi T, Saigo K,Ochiai T. Prophylactic excision of the gallbladder and bileduct for patients with pancreaticobiliary maljunction.Arch Surg 2001;136:759-63.

7. Tashiro S, Imaizumi T, Ohkawa H, Okada A, Katoh T, Kawa-harada Y, et al. Pancreaticobiliary maljunction: retrospectiveand nationwide survey in Japan. J Hepatobiliary PancreatSurg 2003;10:345-51.

8. Rossi RL, Silverman ML, Braasch JW, Munson JL, ReMineSG. Carcinoma arising in cystic conditions of the bileducts. A clinical and pathologic study. Ann Surg 1987;205:377-84.

9. The Japanese Study Group on Pancreaticobiliary Mal-junction (JSPBM). Diagnostic criteria of pancreaticobili-ary maljunction. J Hepatobiliary Pancreat Surg 1994;1:219-21.

10. Kobayashi S, Asano A, Yamasaki M, et al. The risk of bileduct carcinogenesis after the excision of extrahepatic bileducts in pancreaticobiliary maljunction. Surgery 1999;126:939-44.

11. Yamaguchi M. Congenital choledochal cyst. Am J Surg1980;140:653-7.

12. Chaudhary A, Dhar P, Sachdev A, Kumar N, Vij JC, Sarin SK,et al. Choledochal cysts—differences in children and adults.Br J Surg 1996;83:186-8.

13. Shimada K, Yanagisawa J, Nakayama F. Increased lysophos-phatidylcholine and pancreatic enzyme content in bile ofpatients with anomalous pancreaticobiliary ductal junction.Hepatology 1991;13:438-44.

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38 Kobayashi et al

14. Sugiyama Y, Kobori H, Hakamada K, et al. Altered bile com-position in the gallbladder and common bile duct of pa-tients with anomalous pancreaticobiliary ductal junction.World J Surg 2000;24:17-21.

15. Hanada K, Itoh M, Fujii K, Tsuchida A, Hirata M, IshimaruS, et al. Pathology and cellular kinetics of gallbladder with

The I. V.

an anomalous junction of the pancreaticobiliary duct. AmJ Gastroenterol 1996;91:1007-11.

16. Tanaka K, Ikoma A, Hamada N, Nishida S, Kadono J, TairaA. Biliary tract cancer accompanied by anomalous junctionof pancreaticobiliary ductal system in adults. Am J Surg1998;175:218-20.

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