1. Choledochal Cyst Perceptor: Professor Pramod Garg Speaker: Dr. Praneeth

2. Overview Epidemiology Classification Pathophysiology Clinical presentation Risk of malignancy Pathology Diagnosis Treatment

3. Typical case scenario in GE OPD A young female patient with vague abdominal pain – found to have gallstones with dilated CBD (=22 mm) on USG abdomen EUS: small stones in distal CBD After ERCP + CBD clearance + CBD stenting, on follow-up ERCP, persistently dilated CBD but no stones

4. Introduction Choledochal cysts (CC) are a rare congenital cystic dilation of the biliary tract Improved imaging modalities have facilitated the diagnosis at any time from antenatal to adult life.

5. Epidemiology 80% of CC are diagnosed in infants & young children within the first decade of life 1 Incidence: 1 in 100,000-150,000 individuals in West 2 to 1:13,000 in Japan 3 Incidence in India: ?? Frequency in females : males = 3-4:1 4 1.Wiseman K et al. Am J Surg 2005 2.Lee HK et al. Korean J Radiol 2009 3.Sato M et al. Abdom Imaging 2001 4.Huang CS et al. J Gastrointest Surg 2010

6. PATHOGENESIS CC may be either be congenital or acquired Most cysts are congenital If it is acquired, what is the evidence and what is the pathogenesis?

7. Babbitt’s theory Choledochal cysts may be the result of an abnormal pancreaticobiliary junction (APBJ)/APBDU 1 APBJ is a rare congenital anomaly, with a prevalence of < 2% in general population 2, in 80-96% of paediatric CC & 30-70% of patients with CC 3 1.Cha SW. J Comput Assist Tomogr 2008 2.Nagi B. Abdom Imaging 2003 3.Huang CS et al. J Gastrointest Surg 2010

8. APBDU - definition APBDU/Long (most commonly ≥ 1.5 cm) common channels are arbitrarily defined in terms of length (from 1 to 4.5 cm), with wide variation based on imaging modality and angles. 1 Okada et al recommend defining a long common channel as any pancreaticobiliary junction that lies outside of the duodenal wall and thus could result in pancreobiliary reflux and mixing. 2 1.Davenport M et al. J Pediatr Surg. 1995 2.Okada A et al. J Hepatobiliary Pancreat Surg. 2002

9. APBDU without and with CCs (AIIMS archive)

10. APBDU – BP & PB types Patients with CC were more likely to have BP type, whereas biliary pancreatitis, gallbladder cancer and adenomyomatosis of GB were more likely to have PB alternate 1 1.Wang HP et al. Gastrointest Endosc. 1998

11. Komi’s classification of APBJ

12. Evidences supporting Babbitt’s Iatrogenic APBDU in murine models demonstrated cystic dilation of CBD 1 Evidence for reflux of pancreatic juice into the biliary system: – Amylase levels in the fluid in GB and CC are typically elevated in patients with APBDU 2 – High trypsinogen and PLA2 in CC bile 3 – Administration of secretin, which increases pancreatic secretion, has been shown to dilate the CBD and gallbladder in patients with CC, whereas controls showed duodenal filling only. 4 1.Yamashiro Y et al. J Pediatr Gastroenterol Nutr 1984 2.Iwai N et al. Ann Surg 1992 3.Okada A et al. J Hepatobiliary Pancreat Surg 2002 4.Oguchi Y et al. Surgery 1988

13. Evidences against Babbitt’s APBDU is observed in only 30-80% of CCs CCs detected antenatally don’t have pancreatic juice reflux and neonatal acini don’t secrete sufficient pancreatic enzymes 1 1.Imazu et al. Eur J Pediatr Surg 2001

14. Other hypotheses Unequal proliferation of embryologic biliary epithelial cells (before bile duct cannulation is complete) (eg: due to fetal viral infection) 1 Distal obstruction of CBD 2 Weak bile duct wall Sustained increased intrabiliary pressure Inadequate autonomic innervation Abnormally few ganglion cells in distal CBD resulting in proximal dilation 3 Sphincter of Oddi dysfunction (may result in pancreatic juice reflux) 4 1.Yotuyangi S. Gann (Tokyo) 1936. 2.Spitz L et al. J Pediatr Surg 1977 3.Kusunoki M et al. Arch Surg 1988 4.Ponce J et al. Dig Dis Sci 1989

15. CC may be acquired 20% of CC present for first time in adults But only a few case reports have documented previously normal bile ducts and CC later Polido WT et al. WMC002920/Jan 2012

16. Some speculated that all adult cysts are acquired due to distal obstruction (eg: SOD or scarring & stone formation from APBDJ), with longer, narrower stenosis leading to round lesions and shorter wider stenosis leading to fusiform lesions Singham et al. Can J Surg 2009

17. CC & Age Does CC increase in size with age ? Yes in intrauterine life (unlike CBA) Probably not after birth– Neither studies nor case reports Is the mean diameter of CC larger in infants than in adults ? Probably yes (as evidenced by presentation as abdominal mass in infants)- needs prospective studies – may suggest acquired origin & a milder variant ??

19. Choledochocele/Type-III CC More evenly distributed between sexes 1 Much lower incidence of malignant transformation (2.5%) 2 APBDU is less common 1 H/o previous cholecystectomy – more likely 1 Pancreatitis is common 1 Biliary tract symptoms – less common 1 More likely to be diagnosed during ERCP and managed enodscopically 1 1.Ziegler KM et al. Ann Surg 2010 2.Ziegler KM et al. Adv Surg 2011

20. Distinction of types-I and IVA CCs is arbitrary as there is some intrahepatic involvement in both types 1 Clinical courses, complications and management of 5 types of CCs are different 1 Visser et al: Diverticula, choledochoceles, and Caroli’s disease are completely unrelated to CC ---- propose abandoning Todani classification 1 1. Visser et al. Arch Surg 2004

21. CC-types-I & IV (AIIMS archive)

22. Associated congenital anomalies Double CBD, Multiseptate gallbladder Biliary, duodenal & colonic atresias, Imperforate anus, FAP Congenital hepatic fibrosis Pancreatic cysts, AVMs, Annular pancreas, Heterotopic pancreas 1 Hemifacial microsomia with extracraniofacial anomalies Congenital absence of portal vein ARPKD & ADPKD Congenital cardiac anomalies (VSD, Aortic hypoplasia) in 30% of paediatric CCs – manifest during infancy 2 1.Xie XY et al. Hum Pathol 2003 2.Murphy AJ et al. J Surg Res 2012

23. CLINICAL MANIFESTATIONS 75% of patients present at <10 years of age In more recent reports from the West, upto 74% of newly diagnosed CCs are in adults (due to improved imaging) 1 Triad: Abdominal mass + jaundice + abdominal pain 82 % of children present with ≥ 2 symptoms, whereas symptoms are found in only 23% of adult patients 2 1.K Soreide et al. British Journal of Surgery 2004 2.Lipsett PA et al. Annals of Surgery 1994

24. Infant group: CC - presentation Abdominal mass (82%) Jaundice (64%) Abdominal pain is usually not evident Typical triad - found in 85% (only 17% in more recent series) of infants o Neonates detected antenatally are usually asymptomatic at birth but it has to be intervened early before the onset of complications Tadokoro H et al. Open journal of Gastroenterology 2012

25. Classical paediatric/adult group: CC - presentation Chronic abdominal pain (70-90 %) Symptomatic gallstones (45-70%) or Acute cholecystitis Recurrent cholangitis (20-50 %) Hepatomegaly (20%) Pancreatitis (10-20%) Abdominal mass (3-20 %) Tadokoro H et al. Open journal of Gastroenterology 2012

26. Biliary calculi In a retrospective analysis of 57 adult CCs managed surgically from 1988-2003, 35 (61.4%) of patients had cystolithiasis and among them, 57% had GB stones (- APBDU was seen only in 14%) 7 patients had hepatolithiasis, 6 of them had type-IVA CC Both gallstones, cystolithiasis, choledocholithiasis and cholangitis in: Adult CCs > Paediatric CCs Jesudason SRB et al. HPB 2006

27. Cholangitis & AP – How in CCs ? Dilated cysts & distal stricture (due to chronic inflammation) → bile stasis → stone formation & infected bile → cholangitis & further obstruction Bile stasis, sludge and stones →Bacterial colonization of dilated IHBRs → Recurrent cholangitis seen in few cases of type IVA and Caroli’s disease [Chronic inflammation + formation of albumin-rich exudates or hypersecretion of mucin (from dysplastic epithelium)] → [protein plugs in PD] [± distal CBD stone] → pancreatitis Bhavsar MS et al. The Saudi Journal of Gastroenterology 2012

28. CC & Cirrhosis Secondary Biliary cirrhosis (SBC) may develop due to chronic obstruction ± recurrent cholangitis. SBC is the presenting symptom in 10% of children 1 40-50% of patients of CCs had cirrhosis in biopsies during surgery 2 SBC affects surgical outcome emphasizing the prompt early treatment of CCs 1.Samuel M et al. Eur J Pediatr Surg 1996 2.Nambirajan L et al. Trop Gastroenterol 2000

29. Rarer presentations of CCs Spontaneous intraperitoneal rupture often at the junction of cystic duct and CBD (typically only in infants) Portal hypertension due to obstruction of portal vein by CCs GOO (in type-III CCs) ← obstruction of duodenal lumen or intussusception. Bleeding due to erosion into adjacent vessels

30. Clinical features due to APBDU

31. Risk of malignancy in CCs Site of cancer: extrahepatic duct in 50–62%, GB in 38–46%, IHBs in 2.5%, and in liver & pancreas in about 0.7% cases 1 CC-biliary malignancy is associated with unfavorable outcomes, with a reported median survival of 6 to 21 months. 2 APBDU may be a significant risk factor for malignancy with the cyst. 3 In addition, patients with APBJ without biliary cysts appear to be at a markedly increased risk for gallbladder cancer 4 1. Bhavsar MS et al. The Saudi Journal of Gastroenterology 2012 2.Lee SE et al. Arch Surg 2011 3.Cha SW. J Comput Assist Tomogr 2008 4.Okamura K et al. J Gastroenterol. 2000

32. Choledochal cyst & associated cancers in adults: a multicenter survey in South Korea Retrospective study of 15 tertiary hospitals 808 adults with CCs underwent surgery from 1990-2007 Type I was most common (499 [68.2%]) followed by type IVa (208 [28.4%]). Of 654 patients, APBDU was identified in 467 patients (71.4%) Biliary tract cancer was associated in 80 patients (9.9%); 40 had bile duct cancer (50.0%), 35 had gallbladder cancer (43.8%), 3 had periampullary cancer, and 2 had synchronous gallbladder and bile duct cancer. 22 patients (26.3%) had a recurrence, with a median follow-up duration of 51.8 months. Lee SE et al. Arch Surg 2011

33. Choledochal cyst-cancer

34. CC with cholangiocarcinoma

36. More patients with gallbladder cancer underwent curative resection than patients with bile duct cancer (P =.004)

37. AuthorJourna l YearnCancerType of study Cancer detected – how ? Gong et al Am surg201222124 (10.9%) Retrospective Akaravip uth et al. J Med Assoc Thai 2005171 (6%)Retrospective (of operated CCs) Diagnosed simultaneously Lee et alAsian J surg 2005255 (20%)RetrospectiveSimultaneous (3-cyst wall, 1- IHBR, 1-GB) WisemanAm J Surg 2005514 (8%)Retrospective2-H/o previous cystenterostomy, 2- simultaneous JordanAm J surg 2004160Prospective (of operated patients) ZhengJ Korean Med Sci 2004725 (7%)Retrospective (from 1985- 2002) 4/37 who did not undergo surgery (10) or underwent non-cyst excision (eg: cystojejunostomy) (27) had cancers metachronously

38. Malignancy in choledochal cysts 80 adults with CCs treated from Jan 1979 to Dec 1995 were reviewed retrospectively 4 patients had synchronous and 4 had metachronous carcinomas (Incidence: 10%) arising in CC Cholangitis in 5 patients, GOO in 2 and RUQ pain + weight loss in 1 Postoperative survival time ranged from 4-13 months with a mean of 6.2 months Jan YY et al. Hepatogastroenterology 2000

39. Bile duct cancer can develop even after excision of CC In the Japanese patients with CC and/or APBDU, the incidence of cancer was 16.2% (219/1353). The incidence of cancer development after cyst excision in this population, of whom 1291/1353 underwent surgery, was assumed to be 0. 7%. In the 23 patients of biliary tract cancers developing after excision of CC, age at cyst excision: 1-55 years (mean, 23.0 +/- 13.7 years), and cancers were detected at 18-60 years (mean, 32.1 +/- 12.2 years), with intervals between cyst excision and cancer detection of 1-19 years (mean, 9.0 +/- 5.5 years). Sites of cancer development were: intrahepatic, six; anastomotic, eight; hepatic side residual cyst, three; and the intrapancreatic duct, six. Watanabe et al. J Hepatobiliary Pancreat Surg 1999

40. CC & cancer-is the link convincing ? Long-term prospective studies on patients of unoperated CC with aim to study natural history/development of cancers during follow-up are lacking in literature The majority of tumors and CCs are diagnosed simultaneously Such studies- difficult to do because CCs are uncommon and anyway the majority with newly diagnosed CC are getting operated soon after the diagnosis 1. Soreide K et al. Annals of Surgical Oncology 2007

41. H/o Cholangitis, drainage procedures (eg: Cystenterostomy) and incomplete resection of cysts increase risk of malignancy 1 Liu et al. observed 33.3% malignancy in patients with incomplete cyst resection vs 6% in complete cyst resection patients 2 Patients who had undergone cystenterostomy in childhood should be advised reoperation 1. Bhavsar MS et al. The Saudi Journal of Gastroenterology 2012 2.Liu YB et al. Chin Med J 2007

42. Carcinogenesis Carcinogenesis occurs via multistep genetic events where early K-ras and p53 mutations are seen in > 60% of CC-related carcinomas followed by a late occurring DPC-4 gene inactivation 1 Cancer occurs as a result of chronic inflammation, cell regeneration and DNA breaks, leading to dysplasia. 2 The inflammation can be from either recurrent cholangitis or pancreaticobiliary reflux. 1.Shimotake T et al. J Pediatr Surg 2003 2.Bhavsar MS et al. The Saudi Journal of Gastroenterology 2012

43. CC-carcinogenesis (contd..) ↑ Biliary amylase in CC patients is associated with higher expression of iNOS - ↑ carcinogenesis 1 Chronic postobstructive infection by gram-negative bacteria such as Escherichia coli metabolizes bile acids into carcinogens 2 The fraction of cholic acid tended to be lower, and that of deoxycholic acid slightly higher in iatrogenic APBDJ-dogs, while UDCA in APBDJ-dogs was significantly decreased (compared with controls) 3 1.Zhan JH et al. Hepatobiliary Pancreat Dis Int. 2004 2.Bismuth H et al. Ann Oncol. 1999 3. Katsuhiro Masamune et al. J. Med. Invest 1997

44. Unanswered questions Is size of CC linked to risk of malignancy ?? – no data Is it possible that CC and bile duct cancer have a common causative agent and we are assuming CC to be the cause of the tumor but on the contrary, it is only a bystander ? Is the risk similar in pediatric and adult CC? Is the prognosis of CC-linked tumors more dismal than biliary tract cancers without CC ? Is there a genetic mutation commoner in CC-associated cancer compared to those with CC alone ? Are we getting CCs operated at a higher rate than required, especially in adults ?

45. Important differential diagnosis Cystic biliary atresia (CBA) – obstructive jaundice at < 3 months, 1/3 develop liver failure or require LT CBA cysts appear smaller with less IHBRD and are associated with atretic/elongated narrow GB USG in CBA: Triangular cord sign (Thick echogenic anterior wall of RPV just proximal to RPV bifurcation), Presence of biliary sludge CD56-positive hepatocytes & increased hepatic fibrosis in liver biopsy Soares KC et al. J Am Coll Surg 2014

46. Pathology No diagnostic/pathognomonic features The cyst wall is thin, fibrous, and frequently devoid of a true epithelial surface Fibrous cyst wall lined with columnar epithelium and lymphocytic infiltration is typical in pediatric CC Adult CC may show evidence of inflammation & hyperplasia Soares KC et al. J Am Coll Surg 2014

47. Pathology – types of CC Type I (and sometimes type IV) CC lack biliary mucosa Type II CC closely resemble gallbladder duplication Type III cysts are lined by duodenal mucosa, while type V cysts can have extensive hepatic fibrosis IHC demonstrates an increasing rate of epithelial metaplasia and biliary intraepithelial neoplasia in walls of CC with advancing age. Soares KC et al. J Am Coll Surg 2014

48. Investigations

49. Transabdominal ultrasound First imaging modality used for the evaluation Not detect type III cysts sensitivity of 71 to 97 % Can not detect APBDU

50. MRI + MRCP Highly sensitive (73 - 100 %) and specific (90- 100%) in CC diagnosis, classification 1 Reliably identifies APBDU (especially with Secretin), may identify associated CCA, CBD calculi 2 Limited in ability to identify minor ductal abnormalities or small choledochoceles 1 less sensitive than direct cholangiography for excluding obstruction 1.Park DH et al. Gastrointest Endosc 2005 2.Matsufuji H et al. J Pediatr Surg 2006

51. Endoscopic ultrasound(EUS) Used mainly to rule out distal obstructing lesion Can detect APBDU and choledochoceles accurately Can differentiate pancreatic cysts from type-II CC accurately in cases of dilemma 1 Can exclude malignancy in CC by demonstrating smooth walls 1.Oduyebo I et al. Surg Endosc. 2014

52. Cholangiography Direct cholangiography (whether intraoperative, percutaneous, or endoscopic) has a sensitivity of up to 100% for diagnosing biliary cysts and previously was a commonly obtained test. In cases with filling defects, persistent dilation despite stenting suggests CC Due to APBDU: increases the risk of post-ERCP pancreatitis

53. Imaging-pitfalls in CC-linked CCA Except the size and shape of CBD, preoperative imaging only occasionally can be useful to differentiate (Type-I CC + Cholangiocarcinoma) presenting for first time from CCA without CC Thick walled & grossly dilated CBD may suggest CCA in CC CBD stone + significantly dilated bile duct: Confusion How to resolve? ERCP+stenting - if dilatation persists, likely CC

54. CT (± cholangiography)  has high sensitivities for visualizing the biliary tree (93%), biliary cysts (90%)  However, its sensitivity is lower for imaging the pancreatic duct (64 %)

55. Intraductal ultrasound (IDUS) May be more sensitive than direct cholangiography for detecting early malignancy in the cyst wall.

56. Management In the past, some patients were treated with internal drainage via cystenterostomy (+ cholecystectomy) This resulted in high rates of infection, pancreatitis, cholangitis, cholangiocarcinoma and recurrent stenosis

57. Current treatment strategies TypeTypical procedureExtra Procedures Type IComplete excision + Roux-en-Y HJ + Cholecystectomy Type IIDiverticular excision with ductoplastyT-tube placement Type III< 3mm: Endoscopic Sphincterotomy > 3mm: Excision (Transduodenal approach) Reimplantation of pancreatic duct Type IVComplete excision of extrahepatic component + Roux-en-Y HJ + Cholecystectomy Intrahepatic components left untouched Lobar excision for intrahepatic components if with stone, strictures, or hepatic abscess or coalescing in one lobe Type VMedical managementLiver transplant if two lobes are affected.

58. Hepaticojejunostomy Roux-en-Y

59. When to operate in infants ? Fetal and newborn diagnosis is associated with early progression to liver fibrosis, especially in type-IV CC Diao et al demonstrated that early (< 1 month old) CC excision in prenatally diagnosed asymptomatic CC resulted in significantly less fibrosis and improved the rate of LFT normalisation 1 1. Diao M et al. J Pediatr Surg 2012

60. HD vs HJ Hepaticoduodenostomy has been associated with increased rates of gastric cancer (due to bile reflux) and biliary cancer. 1 A recent meta-analysis comparing RYHJ with hepaticoduodenostomy reported significantly more postoperative reflux and gastritis with hepaticoduodenostomy. 2 1.Shimotakahara A et al. Pediatr Surg Int 2005 2.Narayanan SK et al. J Pediatr Surg 2013

61. Complicated CC Resection of complicated CC is associated with worse outcomes In CC-associated chronic pancreatitis and atrophic pancreatic head due to APBDU, pancreaticoduodenectomy may be indicated Severely ill CC patients may benefit from staged procedures consisting of external drainage followed by complete cyst excision and hepaticoenterostomy. Soares KC et al. J Am Coll Surg 2014

62. Treatment of CC-Type-V Localized/unilobar cystic disease is best managed with hepatic resection Asymptomatic bilobar disease is typically managed nonoperatively, with aggressive surveillance for malignant transformation Although prophylactic OLT is not indicated, complicated bilobar Caroli’s disease with cholangitis, portal hypertension, or suspicion of early malignant transformation is definitively best managed with OLT Soares KC et al. J Am Coll Surg 2014

63. Outcomes of surgery Postoperative complications in: Adults >> children Late complications (> 30 days postoperatively) occur in 40% of adult patients and include anastomotic stricture, cancer, cholangitis, and cirrhosis Type IVA cysts are most commonly associated with complications after surgery including intrahepatic stones and anastomotic stricture Shah OJ et al. World J Surg 2009

64. Prognosis Overall, CC resection has an excellent prognosis, with an 89% event-free rate and 5- year overall survival rates well over 90% The risk of biliary malignancy remains elevated even > 15 years after CC excision Long-term surveillance (with which modality and how often ??) for biliary malignancy is warranted postoperatively, particularly in instances with persistent IHBRD Lee SE et al. Arch Surg 2011

65. Alternatives to surgery In patients who refuse surgical resection or who are poor surgical candidates, lesser interventions (such as LC or ERCP) may treat symptoms caused by gallstones or sludge. No proven effective method of screening biliary cysts for dysplasia or intramucosal cancer. If screening is attempted, an intraductal ultrasound is probably the most sensitive test for detecting early malignancy in the cyst wall.

66. Conclusion CC: Either Congential or acquired Presentation: Abdominal mass, Jaundice, Abdominal pain Malignant degeneration is the main concern More studies are warranted on natural history of CCs Diagnosis: MRCP best modality, D/D may be difficult if – (i) cancer at lower third of CBD (ii) Stone + with significant dilatation Surgery is the standard of care Long-term postoperative surveillance is recommended

67. Thank you

68. APBDU & gallbladder carcinoma In a retrospective study of 680 cholangiograms, APBDU was identified in 59 (8.7%) while 5/8 (62.5%) gallbladder carcinomas, 9/27 (33%) CBD cancers and 6/12 Adenomyomatoses coexisted with APBDU 1 In a retrospective study, gallbladder cancer was identified in 5 out of 14 patients with APBDU 2 Gallbladder cancer was found in 12-39% of ‘form fruste’ CCs (= Abnormal APBDU- present with abdominal pain + jaundice but without dilated bile duct) 3 1.LY Chang et al. Hepatogastroenterology 1998 2.Jung et al. Hepatogastroenterology. 2004 3.Bhavsar MS et al. The Saudi Journal of Gastroenterology 2012

69. Patients with APBDU presented with GB cancer at a younger median age, often without GB stones In (APBDU + dorsal PD prominence); the concentration of amylase in bile is significantly less and rates of GB carcinoma are lower Kang JK et al. Korean J Gastroenterol. 1998

70. CC diagnosed de novo in elderly

71. Radiology

72. MRCP

74. Intraductal ultrasound (IDUS)

75. Hepatobiliary scintigraphy using radio-labeled dyes : technetium-99m-labeled hepatic iminodiacetic acid (HIDA), which is selectively taken-up by hepatocytes and excreted into the bile. HIDA scanning is useful for extrahepatic cysts, with a sensitivity up to 100% for type I cysts. However, it is inadequate at visualizing the intrahepatic bile ducts HIDA scanning may also be useful in cases of cyst rupture

76. HIDA SCAN