Cholangiocarcinoma - Classifications & Treatment

Cholangiocarcinoma
Dr. Anahita Sharma
ST5 Registrar, Arrowe Park Hospital

Learning objectives
• To develop an understanding of the anatomic and
histopathological classification of cholangiocarcinoma and
how this influences its subsequent evaluation.
• To be aware of the key risk factors for development of
cholangiocarcinoma.
• To be able to appropriately work-up a patient presenting
with cholangiocarcinoma (laboratory investigations,
imaging, endoscopic investigations).
• To be aware of the treatment options available for this
group of patients and how the classification informs these.

Background:
• Most commonly diagnosed biliary tract
cancer (a category comprising of
cholangiocarcinoma, gallbladder and
ampulla of Vater cancers);
• Tumour arising from cholangiocytes;
• Paucicellular, desmoplastic and
enmeshed in an inflammatory
extracellular matrix (termed the tumour
microenvironment);
• Typically high mortality as presentation
often too late for surgical resection and/or
transplantation;
• Classified by location within biliary tree,
and furthermore by histopathological
subtype

Epidemiolo
gy
• Median age of diagnosis in the U.K. is 75, with
95% of diagnoses made in patients >50
years;
• Rising incidence, predominantly due to rise in
cases of iCCA;
• Overall survival <10%;
• Approx. 50% of diagnoses are made during
emergency presentations;
• Highest prevalence worldwide is in Northeast
Thailand (incidence of 100 per 100,000 in men,
and 50 per 100,000 in women, compared to 0.5-
2.0 per 100,000 in the West);
• iCCA is the second most common form of
primary liver cancer, after HCC – but accounts
for only 20% of cholangiocarcinomas.

Source: Rizvi and Gores, 2013. Pathogenesis, Diagnosis and Management of
Cholangiocarcinoma. Reviews in Basic and Clinical Gastroenterology and Hepatology.

Classificatio
n
• Intrahepatic (iCCA; 20%) - arising above the second-
order bile ducts;
• Perihilar aka Klatskin tumours (pCCA; 50-60%) - arising
from right or left hepatic duct, or their confluence;
• Distal (dCCA; 20-30%) - arising below the cystic duct.
• pCCA and dCCA are often not distinguished in clinical
practice and are collectively referred to as
extrahepatic cholangiocarcinoma.
Classification by location within the biliary
tree:
• 90% adenocarcinoma;
• Other histological subtypes include intestinal-type,
clear cell, signet-ring, adenosquamous, squamous cell
and small cell carcinoma;
• Desmoplastic stroma and genetic heterogenity
contribute to the resistance of cholangiocarcinoma to
therapy.
Classification by histopathological
subtype:

Cholangiocarcinoma - Classifications & Treatment

Sub-classification of
peri-hilar CCA
('Klatskin tumours'):
Bismuth-Corlette
• Type I: Common hepatic
duct, distal to bifurcation
• Type II: At the union of the
left and right hepatic duct
• Type IIIa/b: Involving
union +/- R/L hepatic duct
• Type IV: Multifocal,
involving union AND both
ducts

Intra-hepatic cholangiocarcinoma:
Subclassification
• Macroscopic:
o Mass-forming (majority of iCCA): invades hepatic parenchyma lymphatics;
→
o Periductal-infiltrating: spreads along lymphatics;
o Intraductal growing (now re-classified as intra-ductal papillary neoplasm);
o Mixed
• Histological:
o Large-duct type iCCA: Arise near large ducts; more aggressive phenotype
compared to small-duct iCCA; mucin-producing; associated with PSC,
hepatolithiasis, liver fluke infection; resemble perihilar and extrahepatic forms
o Small-duct type iCCA: More peripheral; less aggressive phenotype; associated
with non-biliary chronic liver disease (e.g. viral hepatides and metabolic
syndrome)
 IDH1/2 mutations and FGR2 mutations, favouring use of targeted therapies

Histopathological
classification of
other neoplastic
lesions of the bile
ducts

Molecular
profiling
• Immunohistochemistry and molecular profiling
used in cases of diagnostic uncertainty
(particularly if pre-existing cancer) to confirm
biliary phenotype of cancer cells;
• FGFR2 and NTRK fusions are required to be
detected prior to the use of FGFR inhibitors

Risk Factors:
Associated with chronic inflammation of biliary epithelium and bile stasis
Caroli's disease (OR 38 for iCCA, 97 for eCCA)
Primary sclerosing cholangitis (OR 22 for iCA, 41 for eCCA) - most common risk factor in the West
Choledochal cyst (OR 27.6 for iCCA, 34.9 for eCCA)
Cirrhosis (OR 15.3 for iCCA, 3.8 for eCCA)
Liver fluke infection – Opisthorchis or Clonorchis (OR 5 iCCA > eCCA)
Majority of cases are sporadic with no identifiable risk factor

Source: BSG Guidelines
for
Cholangiocarcinoma
(2023)

CCA and PSC
Accounts for 10% of
all
cholangiocarcinoma
s;
Annual incidence of
0.6-1.5%, with
cumulative 20% risk
over 30 years;
27-37% diagnosed
within the first year
of diagnosis of PSC.

Clinical
Presentatio
n
• Insidious;
• Dependent on location:
o pCCA and dCCA: obstructive jaundice
(=malignant biliary tract obstruction or
MBTO), constitutional symptoms
o iCCA: weight loss, anorexia, nausea,
malaise, abdominal pain/discomfort
• Bacterial cholangitis (10% of
presentations);
• "Atrophy-Hypertrophy" complex:
o Atrophy of the affected lobe as a result of
vascular and bile ductal obstruction;
o Hypertrophy of the contralateral,
unaffected lobe.

Evaluation:
History
Age of presentation;
Country of origin;
Travel Hx;
Constitutional symptoms and weight loss;
Hx of prior HPB surgery, pancreatitis, CLD or IBD;
Family Hx of IBD & malignancy (familial cancer syndromes);
Prior Ix of biliary strictures.

Differentials
• Distal and hilar biliary strictures are
indeterminate until positive cytological
or histo-pathological confirmation is
obtained;
• >80% prove to be malignant;
• Causes of malignant DBTO include CCA,
pancreatic, ampullary and
periampullary tumours.

Evaluation: Laboratory
LFTs/yGT: Cholestatic pattern;
Serum IgG4 (if indeterminate stricture);
CA19-9 (sensitivity 79%, specifity 98% at a cut-off of 129 U/mL in PSC; sensitivity
of 53% in patients without PSC);
• CA19-9 >1000 U/mL associated with metastatic CCA
• Lewis-antigen negative individuals (5-10% of population) will have undetectable levels

Evaluation: Imaging (1)
Intrahepatic:
• CT/MRI (need triple-phase to help differentiate from HCC, particularly if background of
cirrhosis) - progressive enhancement of CCA will be seen on delayed venous phase as
opposed to washout;
• PET-CT for detection of nodal metastases (high sensitivity and specificity)
Extrahepatic:
• CT for assessment of vascular structures/resectability;
• Cholangiography (ERCP/PTC/MRCP) for anatomical information regarding stricture;
• PET-CT can be false-positive in this setting, therefore reserved for indeterminate cases (slide to
follow);
• EUS can also inform tumour dimension and anatomic location, and allow sampling of lymph
nodes by FNA or FNB (Bx of primary lesion is discouraged due to risk of tumour spread)

Evaluation: Tissue Diagnosis
Intra-hepatic/peri-hilar cholangiocarcinoma: Tissue diagnosis is limited to non-resectable cases, as biopsy
will inform choice of therapy;
• Percutaneous liver (US or CT-guided), or ERCP/PTC/Spyglass-guided where possible;
Extra-hepatic (peri-hilar and distal) cholangiocarcinoma: Tissue diagnosis is desirable, but challenging to
obtain due to pauci-cellular nature of tumour;
• Intraductal forceps biopsy or brush cytology during ERCP (43% sensitivity, 100% specificity with traditional cytology techniques, increased to
93% and 100% respectively with FISH probes) - lower risk of seeding than transperitoneal Bx;
• Linear EUS with FNA or FNB of regional lymph nodes (preferable, particularly if non-jaundiced);
• Side-viewing duodenoscopy with surface Bx if suspected ampullary lesion;
• Cholangioscopy-directed biopsy (Spyglass) reserved for indeterminate strictures where high level of suspicion is present.
• Transperitoneal biopsy is not recommended due to risk of seeding.
If metastatic, organ (e.g. liver), serosal fluid sample (e.g. pleural, ascites, pericardial) or peritoneal biopsy.

Evaluation: Staging
TNM ('T' considered to be inadequate for CCA);
Bismuth-Corlette considered to be poor at distinguishing resectability;
Memorial Sloan-Kettering Cancer Centre (MSKCC) well-validated;
• Hepatic duct involvement (unilateral vs bilateral)
• Portal vein involvement
• Ipisilateral hepatic hemi-atrophy
• Tumour extension
• Hepatic artery involvement
• Regional lymph nodes
Key features:

Unresectable
disease (85% of
cases)
Extensive local disease (including
vascular & nodal involvement)
Distant metastases
Co-morbidities
Local factors:
• Hepatic artery/portal vein involvement on
side of the future remnant liver
• Extensive infiltration into secondary biliary
radicles
• Massive extension into local liver
parenchyma

Source: Sleisenger & Fordtran's (11th edition, 2021)

Role of endotherapy
1. Establish tissue/cytological diagnosis;
o If operable distal CCA – EUS-guided FNA/FNB of lymph nodes or ERCP-directed trans-papillary
brushings or side-viewing scope for suspected ampullary lesions +/- ERCP if jaundiced;
o If operable peri-hilar CCA – EUS + sampling of LNs (sampling of perihilar mass not recommended)
+/- stenting, nasobiliary drainage or PTC if jaundiced (particularly drainage of remnant liver);
2. Biliary decompression to facilitate surgery and chemotherapy;
o Threshold level of 250 uM is cited as a cut-off point in BSG guidelines, although patients with
intractable pruritis, cholangitis and organ dysfunction are likely to benefit from pre-operative biliary
decompression;
o If stented: fully-covered metal stent for DMTO, >1 plastic stent for PMTO if surgery expected to be
delayed;
3. Palliative relief of jaundice and improvement in QoL.
Endotherapy should not be undertaken prior to primary diagnostic and staging imaging

Role of EUS in CCA
• Cholangiocarcinoma detection and staging (if biliary duct dilatation but no
mass seen on CT):
o Performed at level of duodenal bulb or distal antrum
o T-staging (accuracy 60-81%) and N-staging (66-81%)
• Stricture characterisation
o Location and malignant characteristics (sensitivity 79-93%)
• Tissue acquisition from mass, stricture or lymph nodes (EUS-FNA/FNB) for
unresectable tumours/metastatic CCAs (theoretical risk of peritoneal seeding
therefore avoided in resectable disease)
Source: Endoscopic Ultrasound in the Diagnosis of Extrahepatic Cholangiocarcinoma.
Diagnostics (Basel). Orzan et al, 2023.

Distal
cholangiocarcino
ma on ERCP

Perhilar
cholangiocarcinom
a on ERCP

Intra-hepatic
cholangiocarcinoma

Cholangioscopic views of bile
duct cancer

EUS images of
cholangiocarcinom
a (generally used
for staging rather
than tissue
acquisition)

Treatment: iCCA (Surgical/Loco-Regional)
• Surgical resection:
o Solitary intrahepatic → hepatic segmentectomy/lobectomy
(30% of cases found to be unresectable intra-operatively with surgical
inspection + intra-op US + frozen section)
o High recurrence rates (40-63% 5-years of R0 resection; overall rates of
recurrence 22-42% at 5-years)
• Liver Transplantation:
o Traditionally been considered a contraindication in iCCA;
o Now may be option for cirrhotic patients with very early iCCA (single
tumours < 2-cm).
• Locoregional therapies (e.g. TACE/ablation):
o For unresectable disease

Functional liver remnant (FLR)
Post-operative liver failure is the most frequent cause of mortality post-extended
hepatectomy;
Augmentation of FLR to reduce likelihood of hepatic insufficiency post-resection
(needed if estimated FLR is <30%);
Used in patients with hilar CCA type 3A or right-sided intrahepatic malignancy;
Approaches:
• Portal vein embolisation (favoured approach)
• Portal vein ligation
• Associated Liver Partition and Portal Vein Ligation

EASL Guidelines – Treatment
for iCCA

Treatment:
eCCA
(Surgical/Loc
o-Regional)
• Surgical resection (non-PSC only):
o Lobar or extended lobar hepatic and biliary duct
resection with regional lymphadenectomy, with
Roux-en-Y hepaticojejunostomy (for peri-hilar
CCA);
§ 5-year survival:
• 20%-67% R0 N0 peri-hilar
• 27-37% R0 N0 peri-hilar
§ Pre-operative portal vein embolisation can optimise
resectability by increasing volume of the remnant liver
o Whipple’s resection (for distal CCA).
• Liver transplantation (PSC):
o If CCA is <3 cm and no extrahepatic disease;
o Surgical resection contra-indicated in these
patients due to risk of liver failure and
development of a 2nd cholangiocarcinoma;
o Neoadjuvant radiotherapy and brachytherapy and
oral maintenance chemotherapy prior to
transplantation

Extended
hepatectomy with
Roux-en-Y
hepaticojejunostomy

Chemotherapy
Adjuvant capecitabine for 24 months post-curative resection (BILCAP trial);
Combined cisplatin-gemcitabine (patients who do not receive this have a
typically short life expectancy of 3-4 months);
2nd-line therapy is FOLFOX (5-FU and oxaliplatin);
Addition of PD-L1 immunotherapy (durvalumab) to 1st-line chemotherapy
reduces risk of death further by 20% (effects show beyond 6 month phase);
FGR2 inhibitors (pemigatinib, infigratinib) used for cancers with FGR2
alterations (usually ICCA);
Ivosidenib used for patients with IDH1 mutations (usually iCCA).

Radiothera
py
• Neoadjuvant radiotherapy/SBRT can be
given prior to liver transplantation or resection
of locally advanced disease;
• Adjuvant chemoradiotherapy is
recommended for iCCA;
• Definitive chemoradiotherapy and SBRT
shows benefit in inoperable disease
(insufficient evidence to support the use of
radiotherapy alone);
• Palliative radiotherapy can be used to
manage pain and bleeding caused by
metastatic disease.

Treatment: Palliative Biliary
Decompression
• Biliary decompression/drainage:
o Endoscopic or percutaneous (stenting)
approached, as surgical techniques
(choledocho- or hepatico-jejunostomy
bypass) have a higher rate of
complications;
o Bilateral restoration of flow is associated
with increased survival;
o Cross-sectional imaging is crucial prior
to placement of stent to ensure
feasibility, as retrograde injection of
contrast without drainage is associated
with a high risk of iatrogenic
cholangitis.

Stent blockage
• BSG recommends:
o Serial monitoring of LFTs during
active oncology/palliative follow-up;
o Helpline;
o Access to antibiotics if they develop
stent cholangitis.
• Options:
o Replacement of covered stent;
o Sweeping the stent to clear debris;
o Plastic stent within metal stent;
o Metal stent within metal stent;
o EUS/PTC-guided biliary drainage

Treatment:
Palliative
Care
• Access to HPB specialist nurse as a point of contact;
• Access to dietitian/nutritionist;
• Regular follow-up post-resection (3-monthly visits at
the specialist centre for first 2 years due to high risk
of recurrence);
• Palliative care team input.

Local tips (from a recent HPB
fellow)
• All suspected CCA should be discussed at a regional meeting:
o If mid- and distal CBD → RLH
o If proximal CBD, hilum or intrahepatic → AUH
• Diagnosis is made through brushings, intraductal biopsies and cholangioscopy-guided biopsies (each
increasing the chance of diagnosis), occasionally EUS with FNA/FNB if local lymph nodes present
• Resectable or potentially resectable distal cholangiocarcinomas should NEVER have a fully covered
metal stent inserted for drainage (unless deemed unresectable via MDT)
• Proximal/hilar strictures should generally be done in tertiary centres, with a choice between
draining both sides of the liver if possible (or preferably the right side)
• PSC should also be done in tertiary centres (high-risk patients for cholangitis)

Sources
• BSG Guidelines for Cholangiocarcinoma
(2023)
• EASL-ICA Clinical Practice Guidelines on
intrahepatic cholangiocarcinoma (2023)
• ESMO Guidelines for Biliary Tract Cancers
(2022)
• Sleisenger's & Fordtran's, 11e
• Cholangiocarcinoma – evolving concepts &
therapeutic strategies (Rizvi et al., 2018,
Nat Rev Clin Onc)
• Pathogenesis, Diagnosis and Management
of Cholangiocarcinoma (Rizvi & Gores,
2013)

Source:
Challenging biliary strictures: pathophysiological features, differential diagnosis, diagnostic algor
ithms, and new clinically relevant biomarkers - part 1.
Dumonceau et al, 2020.

Cholangiocarcinoma - Classifications & Treatment

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