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Joint Hospital Surgical Joint Hospital Surgical Grand Round Grand Round

1818thth April 2009 April 2009

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Biliary Papillomatosis: Biliary Papillomatosis: unrecognised unrecognised preoperative preoperative

diagnosisdiagnosis

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►Law, SYLaw, SY►F/ 68F/ 68►HT & DM on medicationsHT & DM on medications►Open cholecystectomy (symptomatic Open cholecystectomy (symptomatic

gallstone) for 10 years agogallstone) for 10 years ago►CBD stones with ERCP for removal in CBD stones with ERCP for removal in

20042004

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► c/o mild RUQ pain in OPD FUc/o mild RUQ pain in OPD FU► LFT normalLFT normal► Elective US Elective US –– a 4.9 cm lobulated mainly a 4.9 cm lobulated mainly

echogenic mass is present in the left lobe echogenic mass is present in the left lobe involving the medial and lateral segment, involving the medial and lateral segment, with dilatation of the left intrahepatic ducts. with dilatation of the left intrahepatic ducts. Left lobe liver mass causing focal ductal Left lobe liver mass causing focal ductal dilatation, consistent with a tumourdilatation, consistent with a tumour

► All blood investigations (include tumour All blood investigations (include tumour markers) markers) –– NAD NAD

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Private CT scanPrivate CT scan

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ERCPERCP

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►Biopsy and stent insertion doneBiopsy and stent insertion done►Biopsy result: cellular atypiaBiopsy result: cellular atypia

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► Laparotomy & ECBDLaparotomy & ECBD► Intra-operative finding: tumour at left intrahepatic Intra-operative finding: tumour at left intrahepatic

duct filling whole left duct and extending down to duct filling whole left duct and extending down to common bile duct and right hepatic duct. Tumour common bile duct and right hepatic duct. Tumour extension stop short of branching anterior and extension stop short of branching anterior and posterior right duct.posterior right duct.

► ECBD done and operative cholangioscopy done and ECBD done and operative cholangioscopy done and only inflammatory changes and atypia with frozen only inflammatory changes and atypia with frozen sectionsection

► CBD and right hepatic duct divided at branching site CBD and right hepatic duct divided at branching site of ant. & post. Ductof ant. & post. Duct

► Distal CBD and proximal right hepatic duct margin Distal CBD and proximal right hepatic duct margin sent for frozen section sent for frozen section –– no tumour involvement no tumour involvement

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►Left hepatectomyLeft hepatectomy►Right hepatico-jejunostomyRight hepatico-jejunostomy

►Postop uneventfulPostop uneventful►Discharge on D10Discharge on D10

►Final pathological diagnosis Final pathological diagnosis –– biliary biliary papillomatopapillomatosissis

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►Since the first case of biliary Since the first case of biliary papillomatosis reported by Chappet in papillomatosis reported by Chappet in 1894, approximately 140 cases have 1894, approximately 140 cases have been published in the literaturebeen published in the literature

►BP is characterized by numerous BP is characterized by numerous papillary tumours of variable papillary tumours of variable distribution in the intrahepatic and/ or distribution in the intrahepatic and/ or extrahepatic biliary tree, extending extrahepatic biliary tree, extending superficially along the bile duct superficially along the bile duct mucosa.mucosa.

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Biliary papillomatosis (BP) is a rare Biliary papillomatosis (BP) is a rare disease entity with malignant potential.disease entity with malignant potential.

BP was considered in the past to be a BP was considered in the past to be a disease with low malignant potential.disease with low malignant potential.

41%41%

highighh

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►Histological analysis along with Histological analysis along with expression pattern of mucin core expression pattern of mucin core proteins (MUC) and mucin proteins (MUC) and mucin carbohydrate antigens suggests that carbohydrate antigens suggests that BP is a borderline or low grade BP is a borderline or low grade malignant neoplasm with a high malignant neoplasm with a high malignant potential.malignant potential.

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Biliary papillomatosis (BP) is defined Biliary papillomatosis (BP) is defined as papillary proliferation of the lining as papillary proliferation of the lining epithelium of the bile duct tree, further epithelium of the bile duct tree, further classified into 5 classes according to classified into 5 classes according to the degree cytological and structural the degree cytological and structural atypiaatypia

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Class 1 Class 1

Class 2 Class 2

Class 3Class 3

Class 4Class 4

Class 5Class 5

is defined as BP with low-grade is defined as BP with low-grade atypiaatypia

as BP with high-grade atypiaas BP with high-grade atypia

as BP with in situ carcinomaas BP with in situ carcinoma

as BP with microscopic foci of as BP with microscopic foci of stromal invasionstromal invasion

BP with definite invasion into the BP with definite invasion into the hepatic parenchyma or hepatic parenchyma or fibromuscular layer of the bile duct fibromuscular layer of the bile duct wallwall

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Course of the diseaseCourse of the disease

Malignant transformationMalignant transformation Chronic cholestasisChronic cholestasis

Septic cholangitisSeptic cholangitis

Hepatic failureHepatic failure

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►Unusual Unusual ►Older than 60 years-oldOlder than 60 years-old►Male-female ratio of 2:1Male-female ratio of 2:1

►Mucin-hypersecreting (MBP) Mucin-hypersecreting (MBP) ►Non-producing (NMBP)Non-producing (NMBP)

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The clinical picture of BPThe clinical picture of BP►recurrent colicky abdominal painrecurrent colicky abdominal pain►repeated episodes of acute cholangitis repeated episodes of acute cholangitis ►FeverFever► JaundiceJaundice

►extrahepatic ducts extrahepatic ducts ►both extra- and intra-both extra- and intra-

hepatic hepatic ► intrahepatic ductsintrahepatic ducts

58%58%9%9%33%33%

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► Several pathogenetic mechanisms have been Several pathogenetic mechanisms have been proposed, but a definite one remains to be proposed, but a definite one remains to be proved. proved.

► Recurrent pyogenic cholangitis, congenital Recurrent pyogenic cholangitis, congenital choledochal cyst and chronic stimulation from choledochal cyst and chronic stimulation from stone, infection or pancreatic juice are some of stone, infection or pancreatic juice are some of the mechanisms reported to be associated with the mechanisms reported to be associated with the papillary appearance of the bile duct the papillary appearance of the bile duct epithelium.epithelium.

► It is not clear whether any racial, geographical, It is not clear whether any racial, geographical, or cultural factors may account for this apparent or cultural factors may account for this apparent differences.differences.

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► Preoperative diagnosis is usually difficult.Preoperative diagnosis is usually difficult.► The presentation of obstructive jaundice is The presentation of obstructive jaundice is

not specific to biliary papillomatosis.not specific to biliary papillomatosis.► CA 19-9 antigen level might be elevated in CA 19-9 antigen level might be elevated in

40% of cases.40% of cases.►No diagnostic radiological features have No diagnostic radiological features have

been documented.been documented.► Brushing cytologies are seldom diagnostic.Brushing cytologies are seldom diagnostic.

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USUS

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CTCT

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MRCPMRCP

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EndocsopyEndocsopy

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CholangioscopyCholangioscopy

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ERCPERCP

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► An enlarged intrahepatic and/ or common An enlarged intrahepatic and/ or common bile duct with concomitant ill-defined bile duct with concomitant ill-defined defects consist the primary imaging features defects consist the primary imaging features of BPof BP

►However, diagnosis is frequently delayed However, diagnosis is frequently delayed due to the resemblance of the clinical due to the resemblance of the clinical picture and radiological findings to bile duct picture and radiological findings to bile duct stones.stones.

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►Therefore, a past medical history with Therefore, a past medical history with recurrent episodes of cholangitis and recurrent episodes of cholangitis and the lack of stone retrieval during ERCP the lack of stone retrieval during ERCP should be considered as highly should be considered as highly suspicious in differentially diagnosing suspicious in differentially diagnosing BP.BP.

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►The sloughed tumour debris and mucin The sloughed tumour debris and mucin plugs -plugs -

►Cystically dilated bile ducts should be Cystically dilated bile ducts should be differential from -differential from -

might be similar to bile duct stones.might be similar to bile duct stones.

cystadenoma, cystadenoma, cystadenicarcinoma and liver cystadenicarcinoma and liver abscess.abscess.

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►BP was considered in the past to be a BP was considered in the past to be a disease with low malignant potential. disease with low malignant potential. However, a current review of the However, a current review of the English literature revealed a high rate English literature revealed a high rate of malignant occurrence of of malignant occurrence of approximately 41%approximately 41%

►The reasons for the high malignancy The reasons for the high malignancy rate may be rate may be multifactorialmultifactorial..

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► First,First,

► Second,Second,

► Third,Third,

malignant transformation may not be malignant transformation may not be properly excluded in the properly excluded in the ‘‘benignbenign’’ cases reported in the literature.cases reported in the literature.

prolonged follow-up may allow prolonged follow-up may allow detection of malignant detection of malignant transformation. Progression from transformation. Progression from epithelial dysplasia to carcinoma in epithelial dysplasia to carcinoma in situ and to frank invasive situ and to frank invasive adenocarcinoma has been adenocarcinoma has been suggested suggested (25-42%).(25-42%).chronic biliary irritation or chronic biliary irritation or injury may play a contributory injury may play a contributory role.role.

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► Resection (55%) is the treatment of choice Resection (55%) is the treatment of choice when BP is localized according to preoperative when BP is localized according to preoperative imaging workup and with the support of imaging workup and with the support of intraoperative ultrasound or cholangioscopy.intraoperative ultrasound or cholangioscopy.

► If the patient cannot withstand or is not willing If the patient cannot withstand or is not willing to undergo major surgery, local ablation, to undergo major surgery, local ablation, stenting, or drainage palliative procedures are stenting, or drainage palliative procedures are considered but have been associated with considered but have been associated with high incidence of recurrence.high incidence of recurrence.

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► Bile duct resection, Bile duct resection, pancreaticoduodenectmy and hepatic pancreaticoduodenectmy and hepatic lobectomy appear to be a logical approach lobectomy appear to be a logical approach when the involved area can be resected when the involved area can be resected completely.completely.

► Even after resection with adequate clear Even after resection with adequate clear margins, recurrence still occur in the margins, recurrence still occur in the remaining intrahepatic ducts.remaining intrahepatic ducts.

► The multicentricity and diffuse pattern of BP The multicentricity and diffuse pattern of BP explains the high recurrence rate after explains the high recurrence rate after surgical resection of the underlying lesion.surgical resection of the underlying lesion.

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► In the case of diffuse BP liver In the case of diffuse BP liver transplantation is the treatment of transplantation is the treatment of choice.choice.

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► Thus, bilobar or recurrent disease, as well as Thus, bilobar or recurrent disease, as well as the high risk of malignant transformation the high risk of malignant transformation should favour total hepatectomy and liver should favour total hepatectomy and liver transplantation to be considered as the transplantation to be considered as the ultimate curative approach.ultimate curative approach.

► Lee et al report that after curative resection Lee et al report that after curative resection the 5-year survival rate is 81%, while in the 5-year survival rate is 81%, while in patients undergoing palliative drainage the patients undergoing palliative drainage the mean survival is 37 months, significantly mean survival is 37 months, significantly longer than that of cholangiocarcinoma.longer than that of cholangiocarcinoma.

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► Alternative treatments have been reported.Alternative treatments have been reported.►Gunven et al. reported a case treated with Gunven et al. reported a case treated with

intraluminal iridium-192 therapyintraluminal iridium-192 therapy, and they , and they achieved a 6 year recurrence free survival.achieved a 6 year recurrence free survival.

►Meng et al. reported a case of multifocal BP Meng et al. reported a case of multifocal BP treated with exploration, and treated with exploration, and choledochoscopic choledochoscopic laser ablationlaser ablation of the of the lesions followed by repeated laser ablation lesions followed by repeated laser ablation through a T-tube to achieve complete through a T-tube to achieve complete ablation.ablation.

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►Curative resection achieves a mean Curative resection achieves a mean survival of months which is far better survival of months which is far better than those without surgery for which the than those without surgery for which the survival time is less than months.survival time is less than months.1111

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► BP should not be considered to be a benign BP should not be considered to be a benign disease. The clinical behaviour, the high disease. The clinical behaviour, the high recurrence rate and the even higher malignant recurrence rate and the even higher malignant transformation occurrence, as well as the transformation occurrence, as well as the presence of carcinogenetic indicators (K-ras presence of carcinogenetic indicators (K-ras mutation, overexpression of p53, MUC, and Tn mutation, overexpression of p53, MUC, and Tn antigens) strongly support that BP is a low-antigens) strongly support that BP is a low-grade neoplasm with high malignant potential. grade neoplasm with high malignant potential.

► Radial surgery and liver transplantation should Radial surgery and liver transplantation should be considered as the only curative treatment be considered as the only curative treatment options in order to prolong survival. options in order to prolong survival.

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ConclusionConclusion► BP is a rare precancerous neoplastic disease of the intra- BP is a rare precancerous neoplastic disease of the intra-

and/or extra-hepatic bile ductsand/or extra-hepatic bile ducts► It usually presents similar clinical manifestations to other It usually presents similar clinical manifestations to other

benign and malignant biliary tree diseases that cause benign and malignant biliary tree diseases that cause biliary obstructionbiliary obstruction

► Preoperative radiological studies can demonstrate the Preoperative radiological studies can demonstrate the extent of disease.extent of disease.

► Intraoperative choledochoscopic evidence of numerous Intraoperative choledochoscopic evidence of numerous tumours growing in the papillary and frozen section study tumours growing in the papillary and frozen section study can confirm the diagnosis.can confirm the diagnosis.

► Curative resection of the involved liver and biliary trees is Curative resection of the involved liver and biliary trees is the proper option for treatment.the proper option for treatment.

► Regular postoperative follow-up for possible recurrence of Regular postoperative follow-up for possible recurrence of the disease is mandatory.the disease is mandatory.

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The EndThe End