Joint Hospital Surgical Grand Round

1. Joint Hospital Surgical Grand Round 18th April 2009

2. Biliary Papillomatosis: unrecognised preoperative diagnosis

3. Law, SY • F/ 68 • HT & DM on medications • Open cholecystectomy (symptomatic gallstone) for 10 years ago • CBD stones with ERCP for removal in 2004

4. c/o mild RUQ pain in OPD FU • LFT normal • Elective US – a 4.9 cm lobulated mainly echogenic mass is present in the left lobe involving the medial and lateral segment, with dilatation of the left intrahepatic ducts. Left lobe liver mass causing focal ductal dilatation, consistent with a tumour • All blood investigations (include tumour markers) – NAD

5. Private CT scan

6. ERCP

7. Biopsy and stent insertion done • Biopsy result: cellular atypia

8. Laparotomy & ECBD • Intra-operative finding: tumour at left intrahepatic duct filling whole left duct and extending down to common bile duct and right hepatic duct. Tumour extension stop short of branching anterior and posterior right duct. • ECBD done and operative cholangioscopy done and only inflammatory changes and atypia with frozen section • CBD and right hepatic duct divided at branching site of ant. & post. Duct • Distal CBD and proximal right hepatic duct margin sent for frozen section – no tumour involvement

11. Left hepatectomy • Right hepatico-jejunostomy • Postop uneventful • Discharge on D10 • Final pathological diagnosis – biliary papillomatosis

12. Since the first case of biliary papillomatosis reported by Chappet in 1894, approximately 140 cases have been published in the literature • BP is characterized by numerous papillary tumours of variable distribution in the intrahepatic and/ or extrahepatic biliary tree, extending superficially along the bile duct mucosa.

13. Biliary papillomatosis (BP) is a rare disease entity with malignant potential. BP was considered in the past to be a disease with low malignant potential. 41% high

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

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

16. is defined as BP with low-grade atypia as BP with high-grade atypia as BP with in situ carcinoma as BP with microscopic foci of stromal invasion BP with definite invasion into the hepatic parenchyma or fibromuscular layer of the bile duct wall Class 1 Class 2 Class 3 Class 4 Class 5

17. Course of the disease Malignant transformation Chronic cholestasis Septic cholangitis Hepatic failure

18. Unusual • Older than 60 years-old • Male-female ratio of 2:1 • Mucin-hypersecreting (MBP) • Non-producing (NMBP)

19. The clinical picture of BP • recurrent colicky abdominal pain • repeated episodes of acute cholangitis • Fever • Jaundice • extrahepatic ducts • both extra- and intra-hepatic • intrahepatic ducts 58% 9% 33%

20. Several pathogenetic mechanisms have been proposed, but a definite one remains to be proved. • Recurrent pyogenic cholangitis, congenital choledochal cyst and chronic stimulation from stone, infection or pancreatic juice are some of the mechanisms reported to be associated with the papillary appearance of the bile duct epithelium. • It is not clear whether any racial, geographical, or cultural factors may account for this apparent differences.

21. Preoperative diagnosis is usually difficult. • The presentation of obstructive jaundice is not specific to biliary papillomatosis. • CA 19-9 antigen level might be elevated in 40% of cases. • No diagnostic radiological features have been documented. • Brushing cytologies are seldom diagnostic.

22. US

23. CT

24. MRCP

25. Endocsopy

26. Cholangioscopy

27. ERCP

28. An enlarged intrahepatic and/ or common bile duct with concomitant ill-defined defects consist the primary imaging features of BP • However, diagnosis is frequently delayed due to the resemblance of the clinical picture and radiological findings to bile duct stones.

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

30. The sloughed tumour debris and mucin plugs - • Cystically dilated bile ducts should be differential from - might be similar to bile duct stones. cystadenoma, cystadenicarcinoma and liver abscess.

31. BP was considered in the past to be a disease with low malignant potential. However, a current review of the English literature revealed a high rate of malignant occurrence of approximately 41% • The reasons for the high malignancy rate may be multifactorial.

32. malignant transformation may not be properly excluded in the ‘benign’ cases reported in the literature. • First, • Second, • Third, prolonged follow-up may allow detection of malignant transformation. Progression from epithelial dysplasia to carcinoma in situ and to frank invasive adenocarcinoma has been suggested (25-42%). chronic biliary irritation or injury may play a contributory role.

33. Resection (55%) is the treatment of choice when BP is localized according to preoperative imaging workup and with the support of intraoperative ultrasound or cholangioscopy. • If the patient cannot withstand or is not willing to undergo major surgery, local ablation, stenting, or drainage palliative procedures are considered but have been associated with high incidence of recurrence.

34. Bile duct resection, pancreaticoduodenectmy and hepatic lobectomy appear to be a logical approach when the involved area can be resected completely. • Even after resection with adequate clear margins, recurrence still occur in the remaining intrahepatic ducts. • The multicentricity and diffuse pattern of BP explains the high recurrence rate after surgical resection of the underlying lesion.

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

36. Thus, bilobar or recurrent disease, as well as the high risk of malignant transformation should favour total hepatectomy and liver transplantation to be considered as the ultimate curative approach. • Lee et al report that after curative resection the 5-year survival rate is 81%, while in patients undergoing palliative drainage the mean survival is 37 months, significantly longer than that of cholangiocarcinoma.

37. Alternative treatments have been reported. • Gunven et al. reported a case treated with intraluminal iridium-192 therapy, and they achieved a 6 year recurrence free survival. • Meng et al. reported a case of multifocal BP treated with exploration, and choledochoscopic laser ablation of the lesions followed by repeated laser ablation through a T-tube to achieve complete ablation.

38. Curative resection achieves a mean survival of months which is far better than those without surgery for which the survival time is less than months. 28 11

39. BP should not be considered to be a benign disease. The clinical behaviour, the high recurrence rate and the even higher malignant transformation occurrence, as well as the presence of carcinogenetic indicators (K-ras mutation, overexpression of p53, MUC, and Tn antigens) strongly support that BP is a low-grade neoplasm with high malignant potential. • Radial surgery and liver transplantation should be considered as the only curative treatment options in order to prolong survival.

40. Conclusion • BP is a rare precancerous neoplastic disease of the intra- and/or extra-hepatic bile ducts • It usually presents similar clinical manifestations to other benign and malignant biliary tree diseases that cause biliary obstruction • Preoperative radiological studies can demonstrate the extent of disease. • Intraoperative choledochoscopic evidence of numerous tumours growing in the papillary and frozen section study can confirm the diagnosis. • Curative resection of the involved liver and biliary trees is the proper option for treatment. • Regular postoperative follow-up for possible recurrence of the disease is mandatory.

41. The End