Cholangiocarcinoma (S+DT)

3 types:

• Hilar cholangiocarcinoma: Most Common = 40- 60%
• Distal Cholangiocarcinoma = 20-30%
• Intrahepatic Cholangiocarcinoma (IHCC) = least common

Intrahepatic Cholangiocarcinoma:

Etiology and Risk Factors:

• Western Countries: 90% no recognized risk factor
• Primary Sclerosing Cholangitis (PSC):
  • Most common risk factor in Western countries
  • Cumulative risk: 1.5% per year
  • Prevalence: 8%-40% ( 9-15% SKF)
  • Increased risk with inflammatory bowel disease: 10-year (14%), 20-year (31%)
  • Age of onset: PSC (30-50 years) vs. sporadic (60-70 years)
  • Poor prognosis due to advanced stage at diagnosis
• Hepatic Cirrhosis and Viral Infections:
  • Cirrhosis: 10.7% vs. 0.7% in general population
  • Hepatitis C: 3.5% at 10 years; RR 2.55
  • Hepatitis B: 11.5% vs. 5.5%; RR 1.8
  • Co-infection (Hepatitis B and Opisthorchis viverrini or Clinorchis sinensis): High incidence in Asia
  • Nonalcoholic steatohepatitis: Present in up to 20% of IHCC patients
  • HIV: Cholangiocarcinoma in 0.5% vs. 0.1% in controls
• Benign Biliary Tumors:
  • Biliary cystadenocarcinomas from cystadenomas: Rare, higher risk without ovarian stromal tissue
  • Pathologic precursor lesions: BillN, IPNB, ITNB
• Chemical Agents:
  • Thorotrast: 300x increased risk; latency period 16-45 years
  • Other agents: Asbestos, vinyl chloride, nitrosamines, isoniazid, first-generation oral contraceptives
• General Risk Factors:
  • Surgical biliary-enteric bypass, sphincteroplasty
  • Tobacco smoking: Significant risk in PSC patients
  • Congenital hepatic fibrosis: Increased risk in later life

Summary: Risk Factors for Cholangiocarcinoma

• Primary Sclerosing Cholangitis (PSC):
  • Greatest risk factor for cholangiocarcinoma.
  • PSC is an autoimmune process causing chronic inflammation and stricturing of the bile ducts.
  • Lifetime cholangiocarcinoma incidence in PSC patients: 6% to 20%.
  • Yearly risk of cholangiocarcinoma development: 0.6% to 1.5%.
• Biliary Cystic Disease (Choledochal Cysts):
  • Congenital dilations of the biliary tree.
  • Lifetime risk of cholangiocarcinoma: 6% to 30%.
• Chronic Hepatolithiasis:
  • Associated with chronic inflammation of the bile ducts and biliary stasis.
  • Seen more frequently in East Asia, with an incidence of 20% to 30% in patients undergoing surgery for gallstone disease.
  • Can lead to recurrent pyogenic cholangitis.

These factors highlight the importance of recognizing and monitoring patients with these conditions due to their increased risk of developing cholangiocarcinoma.

(Source: Blumgart 6th edition, page 818)

Pathologic classification

• Premature lesions of IHCC:
  • Biliary intraepithelial neoplasm ( Flat)
  • Intraductal papillary mucinous neoplasm (IPNB)
  • Intraductal tubulopapillary neopasm ( ITNB)
  • Von meyenberg complex = Association

Pathologic Subtypes and Mode of Spread:

• Macroscopic Appearance:
  • Firm, white sclerotic tumors
  • Satellite lesions nearby
  • IHCC Subtypes (Liver Study Group of Japan):
    1. Mass-forming (MF) Type:
       • Most common (65%)
       • Well-delineated, firm, nonencapsulated mass
       • No discernible connection to a bile duct
    2. Periductal Infiltrating (PI) Type:
       • 6% of IHCC
       • Growth spreads along portal tracts
       • Biliary stenoses and proximal biliary dilation
    3. Intraductal Growth (IG) Type:
       • 4% of IHCC
       • Polypoid or papillary lesion
       • Grows within lumen of large bile duct
    4. Mixed Growth Pattern:
       • 25% of IHCC
       • Features of several other growth patterns
  • Prognostic Implications:
    • MF type: Better 5-year survival than PI type
    • IG type: Rare lymph node metastases
  • Metastases:
    • Intrahepatic metastases common (vascular invasion)
    • Intraabdominal lymph nodes: Present in up to 75%
    • Remote organ metastases (lung, bone): Up to two thirds at presentation
    • Right lobar tumors: Hepaticoduodenal ligament lymph node metastases
    • Left lobar tumors: 50% distant nodal metastases (cardia, lesser curvature of the stomach)
• Microscopic Appearance:
  • Well-to-moderately differentiated adenocarcinomas
  • Varying degrees of desmoplasia
• Immunohistochemistry:
  • CK 7 and CK 19 expression (biliary subtype cytokeratin)
  • Increased N-cadherin in IHCC
  • Occasional hepatocyte markers (HepPar1, arginase 1)
  • Albumin mRNA in-situ hybridization for distinguishing IHCC from other malignancies

Diagnosis and Evaluation:

• Key Diagnostic Steps:
  • Radiologic Imaging:
    • Hypovascular mass on cross-sectional imaging
  • Exclude Gastrointestinal Metastases:
    • Upper and lower gastrointestinal endoscopies
  • Exclude Other Primary Malignancies:
    • Imaging of chest, abdomen, and pelvis
• Tumor Biopsy:
  • Not recommended for resectable tumors
  • Indicated for irresectable disease only
• Irresectability:
  • Determined by local tumor factors (vascular supply, biliary drainage)
  • Presence of metastatic disease
• Staging Laparoscopy:
  • Exclude peritoneal disease, nodal disease, abdominal wall invasion
  • Useful when suspected on preoperative imaging

Screening:

• Screening Criteria:
  • Patients ≥40 years old
  • History of liver fluke infection or consumption of uncooked freshwater fish
• Screening Protocol:
  • Hepatic ultrasound every 12 months
  • Every 6 months for patients with:
    • Periductal fibrosis
    • Steatosis
    • Cirrhosis

Biomarkers for Cholangiocarcinoma:

• Serum Tumor Markers:
  • CA 19-9:
    • Sensitivity: 72%
    • Specificity: 84%
  • CEA:
    • Sensitivity: 42%-85%
    • Specificity: 70%-89%
  • Prognostic Indicators:
    • Elevated CA 19-9 and CEA levels
• Additional Biomarkers (Investigational):
  • Osteopontin
  • IL-6
  • Matrix metalloproteinase 7
  • S110A6
  • DKK1
  • SSP411
  • KL-6 mucin
  • MUC5AC
  • hTERT mRNA
  • RCAS1
  • Cytokeratin fragment 19
  • C-reactive protein
• Multiple Tumor Markers:
  • Combination of CEA, CA 19-9, cytokeratin-19 fragment, and matrix metalloproteinase-7
    • Sensitivity: 92%
    • Specificity: 96%
  • CA 19-9, C-reactive protein, and neutrophil-to-lymphocyte ratio: Predictive of poor survival
• Bile Markers for Cholangiocarcinoma:
  • Used in diagnosing biliary obstruction
  • Common markers:
    • WFA-L1Cam
    • SSP411
    • Mac-2BP
    • Micro-RNAs
  • Limited use for IHCC due to uncommon biliary obstruction presentation

Staging of Intrahepatic Cholangiocarcinoma:

• MEGNA criteria for survival prediction of IHCC:
  • Multifocality
  • Extrahepatic Extension
  • High GRADE tumor
  • Lymph Node positivity
    • AGE IS NOT A COMPONENT OF THE CRITERIA
• Lymphadenectomy in IHCC:
  • 30-40% Lymph node positive
  • Left side tumors Dont involve HDL, but cardia and lesser curvature of stomach group are involved
  • Not routinely recommended.

Treatment options of IHCC:

• Resectable:
  • Resection
  • Liver Transplant = 5yrs survival is 40-45% if milan criteria satisified ( for hcc 70-75% 5 yr survival)
  • Adjuvant and Neoadjuvant Chemotherapy =
    • gemcitabine and platinum based
    • BILCAP trial = capecitabine vs observation = survival benefit seen
    • PRODIGE 12 = oxaliplatin + gemcitabine = no advantage
• Unresectable:
  • TACE / TARE = TACE with cisplatin , doxorubicin and mitomycin C ; Drug Eluting Beads DEB TACE = doxorubicin, oxaliplatin or irinotecan
  • Ablation
  • Hepatic Arterial Infusional therapy ( HAI) = FUDR ; 5FU and oxaliplatin

  • External Beam Radiotherapy ( EBRT)

    

Extrahepatic Cholangiocarcinoma

Epidemiology and Risk Factors

• Incidence:
  • Cholangiocarcinoma accounts for 3% of all digestive cancers.
  • It is divided into three subtypes:
    • Intrahepatic Cholangiocarcinoma (ICC): 20% of all cholangiocarcinoma cases in the U.S.
    • Extrahepatic Cholangiocarcinoma (EHC): Includes perihilar cholangiocarcinoma (HC) (50%-60%) and distal cholangiocarcinoma (DC) (20%-30%).
  • The incidence of both ICC and EHC has been increasing over time.
  • EHC incidence rose 20% from 1973 to 2012.
  • In the U.S., there are approximately 2500 new cases of EHC annually.
• Demographics:
  • EHC incidence is evenly distributed between sexes.
  • Rates are increasing among blacks and whites, in contrast to Hispanics and non-Hispanic ethnicities.
  • Although most EHC cases occur in older patients, 20% are diagnosed before age 60, with the largest rise in incidence seen in the 18- to 44-year-old age group.
• Risk Factors:
  • Primary Sclerosing Cholangitis (PSC)
  • Choledochal cysts
  • Recurrent pyogenic cholangiohepatitis
  • Hepatolithiasis
  • Biliary parasites
  • Cholestatic liver diseases such as congenital hepatic fibrosis, Caroli disease, and choledochal cysts.
  • Genetic disorders: Lynch syndrome, bile salt transporter protein gene defects.
  • Metabolic conditions: Type 2 diabetes, nonalcoholic fatty liver disease, obesity, dyslipidemia, and hypertension.
  • These conditions are associated with cholestasis and chronic inflammation.

Tumor Location and Histopathology

• Tumor Location:
  • Extrahepatic cholangiocarcinoma can arise anywhere from first-order bile ducts within the liver down to the ampulla of Vater.
  • Perihilar Cholangiocarcinoma (HC or Klatskin Tumors):
    • Comprises 50% of all cholangiocarcinomas.
    • Arises in the right or left hepatic duct or at the confluence of these ducts.
  • Distal Cholangiocarcinoma (DC):
    • Arises in the common bile duct distal to the cystic duct takeoff.
• Histopathology:
  • Adenocarcinoma is the dominant histologic group, comprising more than 75% of extrahepatic biliary tumors.
  • Precancerous lesions include:
    • Biliary intraepithelial neoplasia.
    • Intraductal papillary neoplasm of the biliary tract.
    • Intraductal tubular papillary neoplasm.
    • Mucinous cystic neoplasm.
  • Common immunohistochemical markers: Mucin, MUC5AC, MUC6, S100P, SMAD4 loss, BAP1.
  • Adenocarcinoma Subtypes:
    • Sclerosing
    • Nodular
    • Papillary: Seen in up to 25% of EHCs and associated with improved survival compared with nodular sclerosing lesions.

Molecular Profiling

• HC (Perihilar Cholangiocarcinoma):
  • Common mutations: KRAS (55%) and TP53 (40%).
• ICC (Intrahepatic Cholangiocarcinoma):
  • More common mutations: IDH, EPHA2, BAP1, FGFR2 fusions.
• EHC (Extrahepatic Cholangiocarcinoma):
  • Contains PRKACA and PRKACB fusions.
  • Mutations in ELF3, ERBB2, and ARID1B.
  • Targetable mutations in EHC are rare, unlike ICC.

Bullet Points to Remember

• 2 types:
  • Hilar CCA = involvement of Hilar bile duct between right side of Umbilical portion of left portal vein and left side of origin of Right Posterior portal vein
  • Distal CCA
• Men = women
• Metabolic , Lynch syndrome, ABCB 4 and 11 defects
• Less targeted mutations compared to IHCC
• Hilar > 50% of Cholangiocarcinomas
• Most Commonst Common symptom ⇒90% obstructive jaundice > abdominal pain
• PET CT = not a routine in protocol as uptake is not great( BUT useful in Ca Gallbladder)
• Good CT imaging is sufficient
• 10-15% malignant masquerades = out of 100 cases resected 10-15 cases are benign and diagnosed as:
  • IgG4 cholangiopathy ( autoimmune)
  • HIV cholangiopathy

Summary: Histologic Subtypes of Cholangiocarcinoma

• Majority:
  • Cholangiocarcinomas are primarily adenocarcinomas.
• Histologic Subtypes:
  1. Sclerosing:
     • Most common subtype.
     • Extends in a subepithelial manner.
     • Causes annular thickening of the bile ducts.
     • Lacks a prominent intraductal obstructing mass component.
  2. Nodular:
     • Not detailed in this summary, but generally presents as a more defined mass.
  3. Papillary:
     • Also not detailed here, typically has a polypoid growth pattern.

This classification helps in understanding the different presentations and potential challenges in diagnosing and treating cholangiocarcinoma.

(Source: Blumgart 6th edition, page 819, Fig 51A.1)

PREOPERATIVE BILIARY DRAINAGE FOR HILAR CCA:

• INDICATIONS FOR BILIARY DRAINAGE IN HILAR CCA:
  • Cholangitis
  • Hepatic Insufficiency
  • Need for NACT
  • Need for PVE
    • Malnutrition induced Hyper bilirubinemia = relative indication not absolute
    • If major hepatectomy is planned in cases of Hilar CCA, Total Bilirubin > 3mg/dl possess a risk of post op hepatic failure and hence to Preop Biliary drainage needs to be done here
    • If it is a Distal CCA, Upfront Pancreaticoduodenectomy can be done
• Percutaneous and endoscopic approaches to biliary drainage are both acceptable.
• Internal drainage is preferred to limit bile loss, malabsorption, and de- hydration.
• But Most Commonly performed is PTBD because higher the lesion the success rates of ERCP and ENBD OR EBD are very less
• Drainage is done from FLR
• AIM of Biliary Drainage:
  • One segment drainage to reduce pruritis
  • 30% parenchyma needs to be drained to reduce jaundice
  • Parenchymal disease will require more are to drained to reduce jaundice ( eg; CLD)
    • Y drainage for hilar block not done routinely

Summary: Indications for Portal Vein Embolization (PVE)

• Indications for PVE:
  1. Future Liver Remnant (FLR) 25% or Less:
     • Applies to patients with a normal liver where the FLR is 25% or less.
  2. Scheduled Concomitant Extrahepatic Surgery or Complex Hepatectomy:
     • PVE is indicated when complex procedures are planned.
  3. Major Hepatectomy in Patients with Chronic Disease or Injured Liver:
     • Includes conditions like chemotherapy-induced injury, major steatosis, or cholestasis.
• PVE Procedure Considerations:
  • Right Hemihepatectomy or Right/Left Trisectionectomy:
    • PVE is often indicated, and the right anterior sector is always resected.
    • The right anterior portal branch is typically punctured during PVE.
• PVE in Specific Conditions:
  • FLR Less than 40%:
    • PVE is indicated when the FLR is less than 40%, and is often performed alongside biliary drainage.
  • Perihilar Cholangiocarcinoma:
    • Most patients with this condition are candidates for PVE due to their cholestatic liver, which requires biliary drainage, and the need for extensive hepatectomy with possible vascular resection.

These guidelines help in determining when PVE should be performed to optimize patient outcomes during major liver surgeries.

(Source: Blumgart 6th edition, page 841)

IMAGING of Hilar CCA:

• CT abdomen:
  • Hypovascular lesion
  • Atrophy of lobe
  • Vascular Invasion
• Duplex USG:
  • Extent of Ductal involvement with Vascular involvement
• MRCP:
  • Evaluation of proximal ductal system excluded by tumor
  • Lobar atrophy
  • Satellite Nodules

Bismuth Corlette Classification of Hilar CCA:

Not only the extension of which side of biliary duct involved but also the side of Lobar Atrophy of liver matters during Resection of Hilar CCA

AJCC TNM Staging for Perihilar Bile Duct Tumors (8th ed., 2017)

• T (Primary Tumor) Staging:

  • TX: Primary tumor cannot be assessed.
  • T0: No evidence of primary tumor.
  • Tis: Carcinoma in situ/high-grade dysplasia.
  • T1: Tumor confined to the bile duct, invades up to the muscle layer.
  • T2a: Tumor invades beyond the bile duct to surrounding adipose tissue.
  • T2b: Tumor invades adjacent hepatic parenchyma.
  • T3: Tumor invades unilateral branches of the portal vein or hepatic artery.
  • T4: Tumor invades the main portal vein or its branches bilaterally, or the common hepatic artery.

• N (Regional Lymph Nodes) Staging:

  • NX: Regional lymph nodes cannot be assessed.
  • N0: No regional lymph node metastasis.
  • N1: Metastasis in 1-3 regional lymph nodes.
  • N2: Metastasis in 4 or more regional lymph nodes.

• M (Distant Metastasis) Staging:

  • M0: No distant metastasis.
  • M1: Distant metastasis present.

• Prognostic Groups:

  • Stage 0: Tis N0 M0
  • Stage I: T1 N0 M0
  • Stage II: T2a or T2b N0 M0
  • Stage IIIA: T3 N0 M0
  • Stage IIIB: T1-3 N1 M0
  • Stage IVA: T4 N0-1 M0
  • Stage IVB: Any T N2 M0 or Any T Any N M1

• Histologic Grade (G):

  • G1: Well-differentiated
  • G2: Moderately differentiated
  • G3: Poorly differentiated

MSK criteria for Hilar CCA:

• Not only the extension of which side of biliary duct involved but also the Lobar Atrophy of liver matters during Resection of Hilar CCA
  • T2 = Resectable
    • Even if there is no extension of tumor into second order biliary radicles if there is involvement of I/L portal vein or I/L Hepatic Lobar atrophy then I/L hepatic Resection is mandatory and are considered resectable
  • T3 = Unresectable
    • C/L or B/L portal vein involvement
    • C/L hepatic lobar atrophy

Treatment Algorithm for Hilar CCA:

• Surgical Management includes:
  • Diagnostic LAP to rule out Metastasis = for > T2 cases
  • Preoperative drainage of FLR
  • Partial Hepatectomy ( longitudinal Intraductal spread) = Segment IV resected always
  • Caudate Lobectomy = must for Hilar CCA
  • Excision of Extrahepatic Biliary tree
  • Portal Lymphadenectomy done
• ALPPS for Hilar CCA:
  • More morbidity vs Non Biliary tumors
  • More Non Local Complications = bile leaks, Cholangitis, SSI’s etc
  • Modified ALPPS involves = Transection and PVE
  • No Survival Benefit over NON ALPPS Hilar CCA’s
• Transplant In Hilar CCA:
  • Initial Liver Transplantation Outcomes:
    • Dismal results for unresectable hilar cholangiocarcinoma (HC)
    • 2-year overall survival: 48%
    • High recurrence: 50% within 2 years
  • Mayo HC Transplant Protocol:
    • Neoadjuvant chemotherapy, radiation, and operative assessment
    • Eligibility:
      • Mass lesion at biliary stricture
      • Tissue diagnosis via endoluminal biopsy
      • CA19-9 > 100
    • Contraindications:
      • Tumors > 3 cm
      • Positive nodal or metastatic disease
      • Previous resection or transperitoneal biopsy
      • History of prior malignancy
      • Previous therapy precluding neoadjuvant therapy completion
  • Comparative Studies:
    • US Extrahepatic Biliary Malignancy Consortium:
      • Transplant vs. resection: 5-year survival (64% vs. 18%)
    • Mayo Group:
      • Transplant vs. resection: No difference in overall survival after adjustments
    • TRANSPHIL Study:
      • Ongoing multicenter study comparing transplant vs. resection in potentially resectable HC
  • Applicability:
    • Limited due to specific selection criteria
    • High incidence of lymph node and distant metastases
    • No level 1 data comparing resection vs. transplant for resectable HC
    • R0 resection preferred for resectable tumors
    • Transplant for unresectable locally advanced HC or HC with PSC

Risk Factors for Postoperative Mortality after resection:

Portal Vein Reconstruction is not significant risk factor as p value > 0.05

Patient related variables:

• Age
• Sarcopenia
• Albumin < 3.5 g/dl
  • OBESITY IS not a risk factor

Endoscopic Palliation in Unresectable Hilar CCA:

• Metallic stent -
  • Transpapillary ( with routine ERCP)
  • Hepaticogastrostomy
  • Choledochoduodenostomy
    • ENBD = is not used in cases of unresectable cases;

MCQ’s

Question Title: Management of Hilar Cholangiocarcinoma with Right Duct Involvement

Question:

A 55-year-old male presents with obstructive jaundice. CECT shows a hilar mass extending into the right duct. The main portal vein (MPV) and common hepatic artery (CHA) are free. Bilirubin is 22 mg/dL, OT is 155, PT is 80, and TLC count is 8000. Volumetry shows the future liver remnant (FLR) to be 25%. What is the next course of action?

Options: A) Proceed to right extended hepatectomy

B) PTBD of left lobe followed by right portal vein embolization and right extended hepatectomy

C) PTBD of right lobe followed by left portal vein embolization and left extended hepatectomy

D) PTBD of left lobe followed by right portal vein embolization and right extended hepatectomy + caudate lobectomy

Correct Answer:D) PTBD of left lobe followed by right portal vein embolization and right extended hepatectomy + caudate lobectomy

Explanation:

• Bilirubin is elevated, indicating the need for drainage of the FLR (left lobe) via PTBD (Percutaneous Transhepatic Biliary Drainage).
• Since the FLR is 25%, portal vein embolization (PVE) of the involved lobe (right lobe) is necessary to increase the FLR before proceeding with surgery.

• After PVE, the appropriate surgical approach is right extended hepatectomy with caudate lobectomy.

  Key Points:

  • For right lobe resections, the bilirubin cutoff is <5 mg/dL.
  • For left lobe resections, the bilirubin cutoff is <10 mg/dL.

Question Title: Management of Hilar Cholangiocarcinoma with Right Lobe Atrophy

Question:

A 40-year-old male presents with obstructive jaundice. CECT shows a hilar mass with right lobe atrophy. Bilirubin is 10 mg/dL, and TLC count is 10,000. What is the next step?

Options: A) PTBD of left lobe followed by right hepatectomy

B) Right hepatectomy + caudate lobectomy

C) PTBD of left lobe followed by right portal vein embolization and right hepatectomy

D) None of the above

Correct Answer:B) Right hepatectomy + caudate lobectomy

Explanation:

• Biliary drainage is not necessary if the patient is undergoing left hepatectomy or left extended hepatectomy, provided the FLR is >40%, even if bilirubin is >10 mg/dL.
• In cases of liver atrophy, it is assumed that the contralateral lobe is already hypertrophied, so biliary drainage and portal vein embolization are not required, even if bilirubin is elevated.

• The atrophic lobe should always be resected, and the caudate lobe and Segment IV must be resected in every case.

  Key Points:

  • PVE should be performed after biliary drainage if bilirubin is <5 mg/dL (preferably <3 mg/dL) and if FLR is less than 30%.

Indications of Biliary Drainage

• Avoidance of Preoperative Biliary Drainage:
  • If FLR > 40%, preoperative biliary drainage can be avoided.
  • Can be avoided in left hepatectomy if bilirubin < 10 mg/dL.
  • Right extended hepatectomy can proceed if bilirubin < 3 mg/dL.
  • Cholangitis or when the FLR needs to be drained are key indications for biliary drainage.

Preoperative Biliary Drainage Guidelines

• Bilirubin <3 mg/dL:
  • Major hepatectomy can be performed without the need for routine biliary drainage.
• Bilirubin <5 mg/dL:
  • Portal vein embolization (PVE) can be performed in preparation for surgery.
• Routine Biliary Drainage:
  • Not necessary unless specific conditions like cholangitis, pruritis, or poor nutrition are present.
• Avoiding Biliary Drainage:
  • Can be avoided if:
    • FLR > 40%
    • Left hepatectomy if bilirubin < 10 mg/dL
    • Lobar atrophy is present.

Question Title: Contraindications for Surgical Resection of Hilar Cholangiocarcinoma

Question:

Which of the following is not a contraindication for surgical resection of hilar cholangiocarcinoma?

Options:

A) Type 4 Bismuth

B) Main Portal vein involvement

C) Ipsilateral atrophy with contralateral vascular involvement

D) Ipsilateral 2nd order biliary radicle with contralateral vascular involvement

Correct Answer:A) Type 4 Bismuth

Explanation:

• Main portal vein (MPV) involvement is now considered a relative contraindication because reconstruction is possible if feasible. However, MPV + hepatic artery (HA) involvement remains an absolute contraindication.

• In the present era, Type 4 Bismuth classification is no longer considered a contraindication, as the 8th edition of the AJCC staging system has removed bilateral involvement of second-order biliary radicles from the T4 staging category.

  Contraindications:

  • Atrophy of one lobe with contralateral portal vein involvement.
  • Atrophy of one lobe with contralateral secondary order bile duct involvement.
  • Bilateral vascular involvement.
  • Liver metastases, and lymph nodes outside the hepatoduodenal ligament (e.g., para-aortic lymph nodes).

AJCC TNM Staging for Distal Bile Ducts Tumors (8th ed., 2017)

• T (Primary Tumor) Staging:

  • TX: Primary tumor cannot be assessed.
  • T0: No evidence of primary tumor.
  • Tis: Carcinoma in situ/high-grade dysplasia.
  • T1: Tumor invades the bile duct wall with a depth of less than 5 mm.
  • T2: Tumor invades the bile duct wall with a depth of 5–12 mm.
  • T3: Tumor invades the bile duct wall with a depth greater than 12 mm.
  • T4: Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery.

• N (Regional Lymph Nodes) Staging:

  • NX: Regional lymph nodes cannot be assessed.
  • N0: No regional lymph node metastasis.
  • N1: Metastasis in 1-3 regional lymph nodes.
  • N2: Metastasis in 4 or more regional lymph nodes.

• M (Distant Metastasis) Staging:

  • M0: No distant metastasis.
  • M1: Distant metastasis present.

• Prognostic Groups:

  • Stage 0: Tis N0 M0
  • Stage I: T1 N0 M0
  • Stage IIA: T2 N0 M0
  • Stage IIB: T1-2 N1 M0
  • Stage IIIA: T3 N0 M0
  • Stage IIIB: T3 N1 M0 or T4 N0-1 M0
  • Stage IV: Any T, Any N, M1

• Histologic Grade (G):

  • GX: Grade cannot be assessed.
  • G1: Well-differentiated.
  • G2: Moderately differentiated.
  • G3: Poorly differentiated.

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IHCC [Doctutorials]

Risk Factors for Intrahepatic Cholangiocarcinoma (IHCC)

Which of the following does not predispose to intrahepatic cholangiocarcinoma (IHCC)?

a) Clonorchiasis

b) Fasciola

c) HBV, HCV, HIV

d) Opistorchis

Answer:

b) Fasciola

Explanation:

• Clonorchiasis and Opistorchis infections are known risk factors for IHCC due to their association with chronic biliary inflammation.
• HBV, HCV, and HIV are also associated with an increased risk of IHCC.
• Fasciola infection, while it affects the liver, is not typically associated with an increased risk of intrahepatic cholangiocarcinoma.

Premalignant Lesions of Intrahepatic Cholangiocarcinoma (IHCC)

• Biliary Intraepithelial Neoplasm (Flat)
• Intraductal Papillary Mucinous Neoplasm (IPNB)
• Intraductal Tubulopapillary Neoplasm (ITNB)
• Von Meyenburg Complex (association)

New Classification of Intrahepatic Cholangiocarcinoma (IHCC)

Komuta et al. Classification:

• Mucin-IHCC (large bile duct type) = present as infiltrating one
• Mixed-IHCC (small bile duct type)
• Cholangiocellular carcinoma

Sempoux et al. Classification:

• Conventional IHCC
• Unconventional IHCC:
  • Trabecular subtype
  • Hilar subtype
  • Intraductal neoplasia of intrahepatic bile ducts
    • Intraductal papillary neoplasm of the bile duct
    • Intraductal tubulopapillary neoplasm of the bile duct
  • IHCC with ductal plate malformation
  • Cholangiocellular carcinoma

AJCC Staging for Intrahepatic Cholangiocarcinoma (IHCC)

T Staging:

• T1:
  • T1A: Solitary tumor ≤5 cm, no vascular invasion.
  • T1B: Solitary tumor >5 cm, no vascular invasion.
• T2: Solitary tumor with vascular invasion or multiple tumors.
• T3: Tumor perforating the visceral peritoneum.
• T4: Tumor involving extrahepatic structures by direct invasion.

N Staging:

• N0: No regional lymph node metastases.
• N1: Regional lymph node metastases.

M Staging:

• M1: Distant metastases.

Question: MEGNA CRITERIA; Prognostic scoring

Which of the following is not a component of the MEGNA criteria for survival prediction in intrahepatic cholangiocarcinoma (IHCC)?

a) Multifocality

b) Extrahepatic extension

c) High grade tumor

d) Lymph node positivity

e) Age > 50 years

Answer:

e) Age > 50 years

Explanation:

• The MEGNA criteria include multifocality, extrahepatic extension, high-grade tumor, and lymph node positivity as components for survival prediction in IHCC.
• Age > 50 years is not a component of the MEGNA criteria.

Question: Lymphadenectomy in IHCC

Which of the following is not true about lymphadenectomy in intrahepatic cholangiocarcinoma (IHCC)?

a) 30-40% LN positive

b) Left side tumors don't involve HDL, but cardia and lesser curvature of stomach

c) Not routinely recommended

d) None of the above

Answer:

d) None of the above

Explanation:

• Option a: True. Approximately 30-40% of patients with IHCC have lymph node positivity.
• Option b: True. Left-sided tumors tend to involve lymph nodes near the cardia and lesser curvature of the stomach, rather than the hepatoduodenal ligament (HDL).
• Option c: True. Lymphadenectomy is not routinely recommended in all cases of IHCC.
• Option d: None of the statements are false, making "None of the above" the correct answer.

Treatment Options for Intrahepatic Cholangiocarcinoma (IHCC)

Resectable IHCC:

• Resection:
  • Considered the primary treatment.
  • Liver Transplantation (LTP):
    • 5-year survival rate: 40-45% if Milan criteria are satisfied.

Adjuvant and Neoadjuvant Therapy:

• Adjuvant therapy: Administered post-surgery to reduce recurrence risk.
• Neoadjuvant therapy: Administered pre-surgery to shrink the tumor and improve resectability.

Unresectable IHCC:

• TACE (Transarterial Chemoembolization) / TARE (Transarterial Radioembolization):
  • Used to control tumor growth and improve survival in patients with unresectable disease.
• Ablation:
  • Radiofrequency Ablation (RFA) or Microwave Ablation (MWA) can be used for smaller tumors.
• HAI (Hepatic Arterial Infusion):
  • Delivers chemotherapy directly to the liver, targeting the tumor more effectively.
• EBRT (External Beam Radiation Therapy):
  • Can be used to control local tumor growth or alleviate symptoms in advanced disease.

Hilar Cholangiocarcinoma

Extrahepatic Cholangiocarcinoma (EHCC)

• Gender Prevalence:
  • Men = Women: No significant gender difference in incidence.
• Genetic and Metabolic Factors:
  • Metabolic Disorders, Lynch Syndrome, ABCB4 and ABCB11 defects are associated with an increased risk.
• Genetic Mutations:
  • Fewer targeted mutations [TP53 , KRAS etc] identified compared to Intrahepatic Cholangiocarcinoma (ICCA).
• Hilar Cholangiocarcinoma:
  • Accounts for >50% of cholangiocarcinoma cases.
• Imaging Protocol:
  • PET CT is not routinely included in the diagnostic protocol.
  • a good CECT is diagnostic.
• Malignant Masquerades:
  • 10-15% of cases may present with features mimicking malignancy, complicating diagnosis. = IgG4 / HIV cholangiopathy

Obstructive Jaundice Associated with Hilar Cholangiocarcinoma (HC) vs. Middle/Distal Bile Duct Cancer

• Drainage Approaches:
  • Distal bile duct cancer: Typically managed with a single catheter or stent for complete biliary drainage.
  • Hilar Cholangiocarcinoma (HC): Often requires multiple biliary drainage catheters to ensure complete drainage, particularly of the future liver remnant (FLR).
• Biliary Drainage Considerations:
  • Both percutaneous and endoscopic approaches are acceptable.
  • Internal drainage is preferred over external drainage to prevent bile loss, malabsorption, and dehydration.
• Indications for Immediate Biliary Decompression:
  • Cholangitis.
  • Jaundiced patients requiring systemic chemotherapy.
  • Patients with hyperbilirubinemia-induced malnutrition.
  • Hepatic insufficiency.
  • Jaundiced patients undergoing portal vein embolization (PVE).
• Resectable HC and Biliary Drainage:
  • Routine biliary drainage before resection to reduce bilirubin to <3 mg/dL is debated.
  • Selective biliary drainage improves outcomes in patients with a small FLR (<30%).
  • Biliary drainage is not recommended for patients with a large FLR (>50%) due to increased risk of mortality.
• Methods of Biliary Drainage:
  1. Percutaneous Transhepatic Biliary Drainage (PTBD):
     • Allows for precise placement of drainage catheters in the FLR.
     • Helps delineate tumor involvement in the biliary tree for surgical planning.
     • Associated with discomfort and tract seeding risks.
  2. Endoscopic Biliary Drainage (EBD):
     • Avoids external drains but may lead to stent misplacement.
     • High incidence of cholangitis, particularly when multiple ducts are not adequately drained.
     • Less effective in cases of complex hilar obstructions.
  3. Endoscopic Nasobiliary Drainage (ENBD):
     • Mainly used in Asian centers.
     • Associated with decreased complication rates and more durable biliary drainage but causes significant patient discomfort due to nasal drainage.
  4. Note: PTBD vs EBD vs ENBD: EBD and ENBD are better than PTBD but PTBD is most commonly performed in higher types like 3a and 3b or 4.
• Internal vs. External Drainage:
  • Internal drainage is preferred to maintain intestinal barrier function and reduce infectious morbidity associated with prolonged external drainage.
• Randomized Controlled Trials (RCTs) on Biliary Drainage:
  • A multicenter RCT in the Netherlands comparing PTBD vs. EBD in resectable HC was terminated early due to increased mortality in the PTBD group.
  • ENBD vs. EBD studies suggest ENBD may have lower reintervention rates, but patient discomfort is a significant drawback.

Question: Biliary drainage in hilar cholangiocarcinoma (CCA)

Which of the following is not an indication for biliary drainage in hilar cholangiocarcinoma (CCA) patients?

a) Cholangitis

b) Hepatic insufficiency

c) Needing NACT

d) Needing PVT

e) Malnutrition induced hyperbilirubinemia

Answer:

e) Malnutrition induced hyperbilirubinemia

Explanation:

• Cholangitis, hepatic insufficiency, needing neoadjuvant chemotherapy (NACT), and needing portal vein embolization (PVE) are all valid indications for biliary drainage in hilar CCA patients.
• Malnutrition induced hyperbilirubinemia is not typically an indication for biliary drainage; rather, hyperbilirubinemia induced malnutrition which is a relative indication, and biliary drainage may be performed to manage hyperbilirubinemia, not the reverse.

Imaging of Hilar Cholangiocarcinoma

CT Abdomen:

• Hypovascular lesion identification.
• Detection of lobe atrophy.
• Assessment of vascular invasion.

Duplex Ultrasonography (USG):

• Evaluates extent of ductal involvement.
• Assesses vascular involvement alongside ductal structures.

MRCP (Magnetic Resonance Cholangiopancreatography):

• Detailed evaluation of the proximal ductal system obstructed by the tumor.
• Identification of lobar atrophy.
• Detection of satellite nodules.

Bismuth-Corlette Classification of Peri Hilar Cholangiocarcinoma

• Type I:
  • Involves the common hepatic duct below the confluence of the right and left hepatic ducts.
• Type II:
  • Involves the hepatic duct confluence without extension into the right or left hepatic ducts.
• Type IIIa:
  • Involves the confluence and extends into the right hepatic duct.
• Type IIIb:
  • Involves the confluence and extends into the left hepatic duct.
• Type IV:
  • Involves the confluence with extension into both right and left hepatic ducts (bilateral 2nd order involvement).

Note: A limitation of the Bismuth classification is that it does not describe involvement of vascular structures, resectability, or prognosis.

Analysis of Resections for Different Types of Hilar Cholangiocarcinoma with Liver Atrophy

The image illustrates surgical approaches to different types of hilar cholangiocarcinoma (HC) based on the Bismuth-Corlette classification. The depiction also takes into account associated liver atrophies and the extent of liver resection required for effective management.

Type I:

• Tumor Involvement:
  • Tumor is limited to the common hepatic duct below the confluence.
• Liver Atrophy:
  • Typically, no significant liver atrophy is observed.
• Resection Strategy:
  • A Extra Hepatic bile duct resection alone may be sufficient.
  • No liver resection is generally required unless other factors (e.g., liver disease) dictate.

Type II:

• Tumor Involvement:
  • Tumor involves the hepatic duct confluence.
• Liver Atrophy:
  • Minimal or no liver atrophy is observed.
• Resection Strategy:
  • Resection of the bile duct confluence with possible limited liver resection.
  • Potential resection of part of the caudate lobe due to its proximity to the confluence.

Type IIIa:

• Tumor Involvement:
  • Tumor extends into the right hepatic duct.
• Liver Atrophy:
  • Atrophy of the right lobe may be present due to compromised bile flow.
• Resection Strategy:
  • Right hepatectomy (removal of the right lobe).
  • Resection of the bile duct up to the confluence and beyond, depending on the tumor spread.

Type IIIb:

• Tumor Involvement:
  • Tumor extends into the left hepatic duct.
• Liver Atrophy:
  • Atrophy of the left lobe may be present.
• Resection Strategy:
  • Left hepatectomy (removal of the left lobe).
  • Bile duct resection similar to Type IIIa, tailored to the left side.

Type IV:

• Tumor Involvement:
  • Involvement of both right and left hepatic ducts, extending into both lobes.
• Liver Atrophy:
  • Significant atrophy of either or both lobes may be observed.
• Resection Strategy:
  • Extensive liver resection may be required, potentially including a left or right trisectionectomy, depending on the extent of atrophy and tumor spread.
  • In some cases, liver transplantation may be considered if the remaining liver volume is insufficient.

Management Considerations

• Liver Atrophy: The presence of liver atrophy influences surgical decisions. In cases where significant atrophy is present, resecting the affected lobe(s) becomes crucial to ensure adequate bile drainage and to remove the tumor burden.
• Extent of Resection: The choice between partial hepatectomy, trisectionectomy, or liver transplantation depends on tumor spread, liver atrophy, and the patient's overall liver function.
• Biliary Drainage: Preoperative biliary drainage is often required to manage jaundice and cholangitis, especially in cases where significant liver atrophy is present, to optimize the liver remnant's function.
• Multidisciplinary Approach: Given the complexity of hilar cholangiocarcinoma, a multidisciplinary team should evaluate each case to tailor the surgical approach, considering both the extent of tumor involvement and the health of the liver parenchyma.

Memorial Sloan Kettering Preoperative T-Stage Criteria for Hilar Cholangiocarcinoma

T1:

• Tumor involving the biliary confluence ± unilateral extension to second-order biliary radicles.

T2:

• Tumor involving the biliary confluence ± unilateral extension to second-order biliary radicles and ipsilateral portal vein involvement ± ipsilateral hepatic lobar atrophy.

T3: Unresectable

• Tumor involving the biliary confluence ± unilateral extension to second-order biliary radicles; or
• Unilateral extension to second-order biliary radicles with contralateral portal vein involvement; or
• Unilateral extension to second-order biliary radicles with contralateral hepatic lobar atrophy; or
• Main or bilateral portal venous involvement.

Surgical Management of Hilar Cholangiocarcinoma

• Diagnostic Laparoscopy:
  • Purpose: Rule out metastasis before proceeding with curative surgery.
• Preoperative Drainage of FLR:
  • Goal: Optimize the future liver remnant (FLR) for a successful recovery post-resection.
• Partial Hepatectomy:
  • Indication: Address longitudinal intraductal spread of the tumor.
• Caudate Lobectomy:
  • Rationale: Remove the caudate lobe due to its frequent involvement in hilar cholangiocarcinoma.
• Excision of Extrahepatic Biliary Tree:
  • Objective: Achieve clear margins by removing the entire extrahepatic biliary tree.
• Portal Lymphadenectomy:
  • Purpose: Excise regional lymph nodes to improve staging and reduce recurrence risk.

Question: ALLPS in Hilar CCA

Which of the following is not true regarding ALPPS (Associating Liver Partition and Portal Vein Embolization for Staged Hepatectomy) for hilar cholangiocarcinoma (CCA)?

a) More morbidity vs non-biliary tumors

b) More local complications

c) Modified ALPPS involves transection and PVE

d) Survival of ALPPS tumors better than non-ALPPS hilar CCA

Answer:

d) Survival of ALPPS tumors better than Non-ALPPS hilar CCA

Explanation:

• Option a: True. ALPPS for hilar CCA is associated with higher morbidity compared to non-biliary tumors.
• Option b: True. ALPPS for hilar CCA has a higher incidence of local complications, such as infectious issues due to bactibilia.
• Option c: True. Modified ALPPS involves partial parenchymal transection with PVE during the first stage.
• Option d: False. The survival of patients undergoing ALPPS for hilar CCA is worse compared to those who undergo standard resection, with a median survival of 6 months in the ALPPS group versus 29 months in the matched control group.

Transplantation for Hilar Cholangiocarcinoma (CCA)

Mayo Clinic HC Transplant Protocol:

• Pre-Transplant Steps:
  • Neoadjuvant Chemotherapy
  • Radiation Therapy
  • Operative Assessment: Includes evaluation of regional lymph nodes and ruling out distant metastases before proceeding with the transplant.

Eligibility Criteria for Transplant:

• Mass lesion at the biliary stricture.
• Tissue diagnosis obtained via endoluminal biopsy.
• CA19-9 levels greater than 100.

Contraindications to Transplant:

• Tumor size greater than 3 cm.
• Positive nodal involvement or metastatic disease.
• Previous resection attempt or transperitoneal biopsy.
• History of prior malignancy.
• Previous therapy that precludes completing neoadjuvant therapy.

Question:Biliary Drainage

Which of the following is not an aim of biliary drainage?

a) One segment drainage to reduce pruritus

b) 30% parenchyma drainage to reduce jaundice

c) Y drainage for hilar block routinely

d) Parenchymal disease will require more area to be drained to reduce jaundice

Answer:

c) Y drainage for hilar block routinely

Explanation:

• Option a: True. Draining even a single segment can reduce symptoms like pruritus.
• Option b: True. Draining 30% of the liver parenchyma can be sufficient to reduce jaundice.
• Option c: False. Y drainage is not routinely used for hilar blocks; the drainage strategy is usually tailored to the extent and location of the blockage.
• Option d: True. More extensive drainage is needed in parenchymal disease to effectively reduce jaundice.

Patient-Related Variables in Predicting Postoperative Outcomes for Perihilar Cholangiocarcinoma (pCCA)

Key Prognostic Factors:

• Age:
  • Most critical factor; advanced age significantly increases the risk of postoperative liver failure and mortality.
• Preoperative Conditions:
  • Cholangitis: Presence of preoperative cholangitis is a strong predictor of poor outcomes.
  • Hyperbilirubinemia: Total bilirubin levels above 3 mg/dL are associated with higher postoperative risk.
  • Low Serum Albumin: Albumin level below 3.5 mg/dL indicates a higher risk of postoperative liver failure.
• FLR (Future Liver Remnant) Considerations:
  • FLR Volume < 30%: Associated with a higher risk of postoperative mortality and liver failure.
  • Incomplete Biliary Drainage of FLR: Particularly risky if FLR volume is less than 50%.
• Surgical Factors:
  • Portal Vein Reconstruction: Increases the complexity of surgery and postoperative risks.

Risk Stratification:

• Low Risk (0-2 points): 2% predicted 90-day postoperative mortality.
• Intermediate Risk (3-4 points): 11% predicted 90-day postoperative mortality.
• High Risk (5-9 points): 37% predicted 90-day postoperative mortality.

Question: Prognostic scoring

Which of the following is not a patient-related factor associated with postoperative mortality in Hilar Cholangiocarcinoma (CCA)?

a) Age

b) Sarcopenia

c) Albumin < 3.5 g/dL

d) Obesity

Answer:

d) Obesity

Explanation:

• Option a: True. Age is a significant factor associated with increased postoperative mortality.
• Option b: True. Sarcopenia (loss of muscle mass) is linked to poorer surgical outcomes.
• Option c: True. Low albumin levels (< 3.5 g/dL) are associated with higher risk of postoperative liver failure and mortality.
• Option d: False. While obesity can affect surgical outcomes, it is not specifically highlighted as a primary factor associated with postoperative mortality in the context of Hilar CCA.

Question: Endoscopic Palliation

Which of the following is not a technique for endoscopic palliation in unresectable Hilar Cholangiocarcinoma (CCA)?

a) Hepaticogastrostomy

b) Choledochoduodenostomy

c) Metallic stent - transpapillary

d) ENBD

Answer:

d) ENBD

Explanation:

• ENBD (Endoscopic Nasobiliary Drainage) is typically used in resectable cases, not as a palliative measure in unresectable Hilar CCA.
• Hepaticogastrostomy, choledochoduodenostomy, and metallic stent placement (transpapillary) are techniques used for endoscopic palliation in unresectable cases.

Hepaticogastrostomy ⇒