Perihilar cholangiocarcinoma

Overview

Perihilar cholangiocarcinoma (pCCA), historically termed a Klatskin tumour, is a malignant neoplasm arising from the epithelial cells of the bile ducts at the hepatic hilum—specifically, the confluence of the right and left hepatic ducts. It represents the most common anatomical subtype of cholangiocarcinoma (CCA), accounting for 50–60% of all biliary tract cancers.

Unlike intrahepatic CCA (which arises within the liver parenchyma) or distal CCA (which arises in the common bile duct), pCCA presents unique anatomical and surgical challenges due to its proximity to critical vascular structures (portal vein, hepatic artery) and the bifurcation of the biliary tree. Early diagnosis remains elusive, and the disease carries a historically poor prognosis, though advances in multimodal therapy and surgical techniques are incrementally improving outcomes.

Cholangiocarcinoma = Bile duct cancer. Perihilar = At the hilum (doorway) of the liver. Klatskin Tumour* = Eponym for tumours involving the bifurcation of the common hepatic duct.

Epidemiology and Risk Factors

Global Incidence

The incidence of pCCA varies significantly geographically. It is relatively rare in Western countries (incidence 0.5–1.5 per 100,000 person-years) but endemic in Southeast Asia (particularly Thailand and Korea), where rates exceed 80–100 per 100,000 due to the high prevalence of liver fluke infection (Opisthorchis viverrini, Clonorchis sinensis).

Demographics

• Age: Median age at diagnosis is 65–70 years.
• Sex: Slight male predominance (Male:Female ratio ~1.3:1), though this varies by aetiology.
• Trends: Incidence of intrahepatic CCA is rising globally; pCCA rates appear stable or slightly increasing in the West, potentially linked to metabolic syndrome and NAFLD/NASH epidemics.

Established Risk Factors

Pathophysiology and Molecular Biology

Anatomy of the Hepatic Hilum

Understanding pCCA requires precise knowledge of hilar anatomy. The hepatic hilum (porta hepatis) contains:

1. Biliary: Common Hepatic Duct (CHD) → Bifurcation → Right Hepatic Duct (RHD) & Left Hepatic Duct (LHD). Segmental ducts (e.g., Sectoral ducts for segments IV, V, VIII) drain near the hilum.
2. Vascular: Portal Vein (PV) bifurcation (Right/Left Portal Veins), Proper Hepatic Artery (HA) bifurcation.
3. Lymphatic: Rich network draining to cystic duct node (Calot’s), periportal nodes, coeliac axis, and superior mesenteric artery nodes.

Molecular Pathogenesis

pCCA arises via a stepwise progression: Normal Epithelium → Biliary Intraepithelial Neoplasia (BilIN) / Intraductal Papillary Neoplasm of the Bile Duct (IPNB) → Invasive Carcinoma.

Key Molecular Alterations (Frequency in pCCA):

• IDH1/IDH2 Mutations: ~10–20% (Targetable with ivosidenib).
• FGFR2 Fusions/Translocations: ~10–15% (Almost exclusive to intrahepatic/perihilar; targetable with pemigatinib, infigratinib, futibatinib).
• KRAS Mutations: ~30–40% (Associated with worse prognosis).
• TP53 Mutations: ~30–50% (Late event, genomic instability).
• SMAD4 Loss: ~15–20%.
• BAP1, ARID1A, PBRM1: Chromatin remodeling genes.
• HER2 (ERBB2) Amplification/Mutation: ~5–10% (Targetable with trastuzumab deruxtecan / pertuzumab combinations).

Clinical Relevance: Comprehensive genomic profiling (NGS) is now standard of care for advanced/metastatic disease to identify actionable targets.

Classification and Staging Systems

Accurate staging dictates resectability and prognosis. Three systems are used concurrently.

1. Bismuth-Corlette Classification (Anatomical / Surgical)

Describes the longitudinal extent of tumour along the biliary tree. Does not assess vascular invasion or nodal status.

Clinical Pearl:** >90% of pCCA are Bismuth Type II, IIIa, or IIIb. Type IV implies bilateral involvement, usually precluding curative resection.

2. TNM Staging (AJCC 8th Edition / UICC 8th Edition) – Perihilar Specific

Stage Grouping (Simplified):

• Stage I: T1 N0 M0
• Stage II: T2–3 N0 M0
• Stage IIIA: T4 N0 M0
• Stage IIIB: Any T, N1 M0
• Stage IIIC: Any T, N2 M0
• Stage IV: Any T, Any N, M1

3. Memorial Sloan Kettering (MSK) / Blumgart T-Staging (Pre-operative Resectability Focus)

Incorporates vascular invasion and lobar atrophy better than TNM for surgical planning.

How Does It Look? (Radiological, Gross & Microscopic Appearance)

This section details the visual phenotype of pCCA across diagnostic modalities, essential for radiologists, pathologists, and surgeons.

1. Cross-Sectional Imaging (CT & MRI/MRCP) – The Cornerstone

Multiphasic Contrast-Enhanced CT (Triphasic Liver Protocol) & MRI with MRCP are the primary staging tools. MRI/MRCP is superior for biliary tree mapping; CT is superior for vascular enhancement and extrahepatic spread.

Primary Tumour Morphology (Imaging Phenotypes)

pCCA exhibits three main growth patterns, often mixed:

Critical “How It Looks” Signs for Staging

2. Advanced Functional Imaging

• FDG PET-CT:
• Sensitivity ~80–90% for primary tumour (lower for pure mucinous/intraductal types).
• High value: Detecting occult nodal (N2) or distant metastatic disease (M1) missed on CT/MRI. Changes management in 15–25% of “resectable” candidates.
• Gadoxetate Disodium (Eovist/Primovist) MRI:
• Hepatocyte-specific contrast. Assesses functional Future Liver Remnant (FLR). Hypointense FLR on hepatobiliary phase = poor function → higher risk of post-hepatectomy liver failure (PHLF).

3. Intraductal Imaging (Cholangioscopy / SpyGlass™)

• Direct Visualisation: Peroral (ERCP) or percutaneous (PTC) approach.
• Appearance:
• Mass-forming: Extrinsic compression, irregular mucosa.
• Infiltrating: Fragile, ulcerated, vascular, irregular mucosa; “tumour vessels” (irregular, looping).
• Intraductal (IPNB): Papillary, frond-like, villous projections; “fish-egg” appearance.
• Targeted Biopsy: Increases diagnostic yield from ~30–50% (brush cytology) to >85–90%.

4. Gross Pathology (Macroscopic Appearance)

Upon surgical resection (Whipple, Hepatectomy, or Bile Duct Resection):

Key Gross Feature: Perineural Invasion (PNI) is often visible grossly as tumour tracking along nerve sheaths in the hepatoduodenal ligament fat.

5. Microscopic Histopathology (Light Microscopy)

Diagnosis requires tissue confirmation (except highly selected transplant protocols).

• Cell Type: >95% are Adenocarcinomas (mucin-producing glandular epithelium).
• Architectural Patterns:
• Glandular / Tubular: Well-formed glands (Well differentiated).
• Papillary: Fibrovascular cores lined by epithelium (Papillary type).
• Solid / Cribriform: Sheets of cells, poor gland formation (Poorly differentiated).
• Signet Ring Cell: Intracytoplasmic mucin pushing nucleus to periphery (Aggressive).
• Stroma: Desmoplasia (dense collagenous fibrosis) is hallmark. Explains delayed enhancement on imaging and firm consistency.
• Mucin: Intracytoplasmic (PAS-D / Alcian Blue positive) and extracellular pools.
• Invasion Markers (Prognostic):
• Perineural Invasion (PNI): >80% of resected cases. Independent poor prognostic factor.
• Lymphovascular Invasion (LVI): ~40–60%.
• Margins: R0 (negative >1mm), R1 (microscopic positive), R2 (macroscopic residual). R0 is the single most important surgical prognostic factor.

Immunohistochemistry (IHC) Panel (Diagnostic Confirmation):

Differential Diagnosis on Biopsy:

1. Metastatic Adenocarcinoma (Pancreas, Colon, Lung, Breast) → Clinical correlation + extended IHC (e.g., SATB2 for colorectal, NKX6.1/TTF1 for lung/pancreas).
2. IgG4-Related Sclerosing Cholangitis → IgG4+ plasma cells >10/HPF, storiform fibrosis, obliterative phlebitis. Serum IgG4 elevated.
3. PSC / Benign Stricture → Reactive atypia: uniform nuclei, preserved polarity, minimal mitoses. Difficult on small biopsy; clinical context + FISH/p53 IHC helps.

Symptoms and Clinical Presentation

pCCA is notoriously insidious. Symptoms typically arise late, caused by biliary obstruction, local invasion, or systemic effects. The median duration of symptoms before diagnosis is 3–6 months.

1. The “Classic Triad” of Biliary Obstruction (Present in ~70–90% eventually)

2. Pain and Discomfort

• Right Upper Quadrant (RUQ) Pain / Discomfort: Dull, aching, constant. Caused by capsular stretching of the liver (due to lobar atrophy/hypertrophy or mass effect) or peritoneal irritation.
• Epigastric Pain: If tumour invades pancreas, duodenum, or celiac plexus (late sign).
• Character: Unlike biliary colic (stones), pCCA pain is typically non-colicky, progressive, and unrelieved by antispasmodics.

3. Cholangitis (Acute Bacterial Infection of Bile)

• Charcot’s Triad: Fever/Chills + Jaundice + RUQ Pain (Sensitivity ~50–70%).
• Reynolds’ Pentad: Charcot’s Triad + Hypotension (Septic Shock) + Altered Mental Status.
• Mechanism: Tumour stricture → biliary stasis → bacterial overgrowth (E. coli, Klebsiella, Enterococcus).
• Clinical Alert: Any fever in a jaundiced pCCA patient = Cholangitis until proven otherwise. Requires urgent biliary drainage (ERCP/PTC) + IV antibiotics before definitive surgery/chemo.

4. Constitutional / Systemic Symptoms (Indicate Advanced Disease)

5. Physical Examination Findings

6. Paraneoplastic Syndromes (Rare but Specific)

• Hypercoagulability / Trousseau’s Syndrome: Mucin-producing adenocarcinomas secrete tissue factor / cancer procoagulant → migratory thrombophlebitis, DVT, PE, arterial thrombosis.
• Hypertrophic Osteoarthropathy (HOA): Clubbing, periostitis, arthralgias.
• Dermatomyositis / Acanthosis Nigricans: Rare associations.

7. Presentation in Special Populations

• Primary Sclerosing Cholangitis (PSC) Patients:
• Dominant Stricture: Worsening jaundice, cholangitis episodes, rising CA19-9.
• Diagnostic Difficulty: Distinguishing benign inflammatory stricture from malignancy is extremely hard. Surveillance with MRI/MRCP + CA19-9 + Brush Cytology/FISH annually is standard.
• Symptoms may be masked by baseline PSC symptoms (fatigue, pruritus, intermittent cholangitis).
• Incidental Finding: Increasingly diagnosed on imaging (CT/MRI) performed for unrelated reasons (e.g., trauma, renal colic, screening). These patients are often asymptomatic or have vague fatigue. Best prognosis.

Diagnostic Workup Algorithm

Goal:** Tissue diagnosis + Accurate Staging (Resectability Assessment) + Fitness for Surgery.

Step 1: Initial Laboratory Evaluation

Step 2: Cross-Sectional Imaging (Staging)

1. Contrast-Enhanced MDCT (Abdomen/Pelvis/Chest): Vascular assessment, nodal/metastatic survey, lung mets.
2. MRI/MRCP (Liver-Specific Protocol): Gold standard for biliary anatomy (Bismuth typing). Hepatobiliary phase (Gadoxetate) for FLR function.
3. (Optional) FDG PET-CT: If curative intent planned, to rule out occult M1/N2 disease.

Step 3: Biliary Drainage & Tissue Acquisition

• Principle: Drainage first (if cholangitis, bilirubin >15–20 mg/dL, neoadjuvant planned, or major surgery delayed >2 weeks). Avoid routine pre-op drainage if surgery within 1–2 weeks and bilirubin <15 mg/dL (reduces wound infection risk).
• Approach:
• ERCP: Preferred for distal/Type I-II. Allows brush cytology, biopsy, SpyGlass cholangioscopy. Risk: Pancreatitis, seeding (theoretical), introduces duodenal flora into biliary tree (complicates future transplant).
• PTC (Percutaneous Transhepatic Cholangiography): Preferred for Bismuth III/IV (proximal access), altered anatomy (post-Whipple), or failed ERCP. Allows unilateral/bilateral drainage. Risk: Bleeding, bile leak, tract seeding (rare).
• Tissue Diagnosis:
• Brush Cytology: Specificity ~100%, Sensitivity ~30–50%.
• Intraductal Biopsy (Forceps): Sensitivity ~50–60%.
• FISH (Fluorescence In Situ Hybridization) on Brushings: Polysomy (gain of ≥3 chromosomes) → Sensitivity ~50–60%, Specificity ~90%. Adjunct to cytology.
• Cholangioscopy-guided Biopsy (SpyGlass DS): Sensitivity >85%. Current standard for indeterminate strictures.

Step 4: Surgical Resectability Assessment (Multidisciplinary Tumour Board – MDT)

Criteria for Resectability (Curative Intent):

1. T Stage: No main PV/SMV invasion (T4). Unilateral vascular involvement (T3) may be resectable with vascular reconstruction in high-volume centers.
2. N Stage: No N2 disease (≥4 nodes). N1 is not absolute contraindication but worsens prognosis.
3. M Stage: M0 mandatory.
4. Future Liver Remnant (FLR): Must be ≥20–30% (healthy liver) or ≥40% (cirrhosis/steatosis/chemo-injured). Calculated via volumetric CT/MRI.
5. Patient Fitness: ECOG 0–1, adequate cardiopulmonary reserve, no frailty.

If Borderline Resectable (Insufficient FLR / Unilateral Vascular Invasion):

• Portal Vein Embolization (PVE) / ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy): To induce FLR hypertrophy (4–6 weeks for PVE).

Treatment Strategies

Treatment is stage-dependent and requires a Hepatobiliary MDT.

1. Curative Intent: Surgery (The Only Chance for Cure)

Lymphadenectomy: Systematic (D2) Lymphadenectomy is standard. Stations: 12a, 12b, 12p, 8, 9, 13, 14. Minimum ≥6–10 nodes for accurate staging.

Surgical Outcomes (High Volume Centers):

• R0 Resection Rate: 60–80% (for explored patients).
• 90-Day Mortality: <5% (specialized centers).
• Major Complication Rate (Clavien-Dindo ≥III): 30–50% (Bile leak, PHLF, hemorrhage, infection).
• Median OS (R0): 30–50 months. 5-Year OS: 25–40%.

2. Neoadjuvant Therapy (Pre-Operative)

• Standard of Care? Controversial / Evolving. Not standard for upfront resectable disease outside clinical trials.
• Indications: Borderline resectable (vascular involvement), high-risk features (CA19-9 very high, large nodes borderline), downstaging for transplant protocols.
• Regimens: Gemcitabine + Cisplatin (GemCis) ± Nab-paclitaxel; FOLFOX; GemCis + Durvalumab (Immunotherapy – trial data emerging).
• Goal: Downstaging, treating micrometastases, assessing tumour biology (if progresses on chemo → spare futile surgery).

3. Adjuvant Therapy (Post-Operative)

• Standard (Based on BILCAP & PRODIGE/ACCORD Trials):
• Capecitabine (Xeloda) 1250 mg/m² BID Days 1–14 q21d x 8 cycles (6 months).
• Evidence: BILCAP trial showed OS benefit (HR 0.75) for Capecitabine vs Observation in biliary tract cancer (mostly gallbladder/distal, but subgroup pCCA benefit).
• Alternative: Gemcitabine + Cisplatin (PRODIGE 12 / ACCORD 18 – negative for OS but DFS benefit in subgroups; used if Capecitabine intolerant).
• Radiotherapy (Adjuvant Chemoradiation): Controversial. SWOG S0809 (Gem/Cis + RT) showed promising 2-yr OS. Consider for R1 resection or Node Positive (N1/N2) disease. Modern techniques (IMRT/SBRT) reduce liver toxicity.

4. Liver Transplantation (Highly Selected Protocol)

• Mayo Clinic Protocol (Neoadjuvant Chemoradiation + Transplant): For Unresectable Bismuth Type III/IV (no M1, no N1, tumour <3cm radial extent).
• Protocol: External Beam RT (45–50 Gy) + Sensitizing 5-FU/Capecitabine → Brachytherapy boost → Staging Laparotomy → Transplant.
• Outcomes: 5-yr OS 65–80% (intent-to-treat ~50%). Recurrence ~15–20%.
• Strict Criteria: No prior malignant biopsy (seeding risk), CA19-9 <100–500 (trending down), no M1/N1.

5. Palliative / Locoregional Therapy (Unresectable / Metastatic)

A. Systemic Chemotherapy (1st Line Standard)

B. Targeted Therapy (Biomarker Driven – 2nd Line+)

Requires NGS Testing (Tissue or Liquid Biopsy).

C. Biliary Drainage (Palliation of Obstruction)

• Goal: Relieve jaundice, pruritus, cholangitis risk, enable chemo.
• Method: Metal Stents (SEMS – Self-Expanding Metal Stents) preferred over plastic (longer patency ~6–9 mo vs 3–4 mo).
• Unilateral vs Bilateral: Drain ≥50% liver volume. For Bismuth III/IV, bilateral preferred if feasible. “Drain what you can.”
• Route: ERCP (first line usually) vs PTC (if ERCP failed, altered anatomy, high bifurcation).
• Occluded Stent: Re-intervention (stent-in-stent, mechanical cleaning, radiofrequency ablation via cholangioscopy).

D. Locoregional Therapies (Liver-Dominant Disease)

• SIRT / TARE (Yttrium-90): Radioembolization. For liver-dominant disease, post-chemo progression. Can downstage / bridge.
• TACE / DEB-TACE: Transarterial Chemoembolization. Less common for CCA (hypovascular) but used.
• SBRT (Stereotactic Body RT): High dose focused RT. Local control for oligometastatic / unresectable primary. Biliary toxicity risk (stricture/ulcer).
• Hepatic Arterial Infusion (HAI) Pump: Floxuridine pump. High response rates in experienced centers. Requires dedicated team.

Prognosis and Survival Statistics

Prognosis is heavily dependent on Resection Margin Status (R0 vs R1), Nodal Status, and Vascular Invasion.

Prognostic Nomograms: Used post-resection (e.g., MSKCC, Wang et al.) incorporating: T-stage, N-stage, Margin status, Grade, PNI, LVI, CA19-9, Adjuvant Therapy.

Follow-Up and Survivorship Care

High Risk of Recurrence: 50–65% recur within 2 years. Most recurrences are systemic (liver, peritoneum, lung) or local-regional (anastomotic, nodal).

Surveillance Protocol (Typical High-Volume Center)

Long-Term Management Issues

1. Biliary Strictures (Anastomotic): 10–20% post-hepatectomy/hepaticojejunostomy. Managed by ERCP/PTC dilation/stenting.
2. Post-Hepatectomy Liver Failure (PHLF) Sequelae: Portal hypertension, splenomegaly, thrombocytopenia.
3. Nutritional Deficiencies: Fat-soluble vitamins (A, D, E, K), B12 (if terminal ileum resected/radiated), Iron. Monitor annually.
4. Metabolic Syndrome / NAFLD: Risk factor for de novo HCC in remnant liver. Lifestyle modification.
5. Psychosocial Support: Fear of recurrence, financial toxicity, caregiver burden.

Prevention and Risk Reduction

While not all cases are preventable, risk modification targets known aetiologies:

1. Liver Fluke Endemic Areas: Mass drug administration (Praziquantel), improved sanitation, health education (avoid raw/fermented fish).
2. PSC Management: Annual MRI/MRCP + CA19-9 surveillance. UDCA (Ursodeoxycholic acid) at standard doses (13–15 mg/kg) may reduce risk (controversial, high dose harmful).
3. Choledochal Cysts: Prophylactic excision (cyst excision + hepaticojejunostomy) in childhood/early adulthood eliminates malignant potential.
4. Metabolic Health: Weight loss, diabetes control, treatment of NASH (currently lifestyle, future pharmacotherapy) to reduce CCA risk.
5. Occupational Safety: Regulation of Thorotrast (historical), asbestos, nitrosamines.
6. Hepatitis B Vaccination: Reduces cirrhosis burden.

Frequently Asked Questions (FAQ)

Q: Is Perihilar Cholangiocarcinoma the same as Klatskin Tumour?

A: Yes. “Klatskin tumour” is the historical eponym specifically for tumours involving the bifurcation of the common hepatic duct (Bismuth Type II, III, IV). The modern, anatomically precise term is Perihilar Cholangiocarcinoma (pCCA), which includes Type I (distal to bifurcation) as well.

Q: Why is surgery so complex for this cancer?

A: The tumour sits at the “crossroads” of the liver: the bile duct bifurcation, the portal vein bifurcation, and the hepatic artery bifurcation. Removing the tumour safely usually requires removing a large portion of the liver (hepatectomy) and reconstructing the bile drainage (hepaticojejunostomy) and often reconstructing blood vessels. It requires highly specialized hepatobiliary surgeons.

Q: My CA 19-9 is normal, does that rule out cancer?

A: No. Approximately 5–10% of Caucasians (and higher in other ethnicities) are Lewis antigen negative (Le a-b-) and cannot synthesize CA 19-9. In these patients, CA 19-9 is always normal regardless of tumour burden. CEA, imaging, and tissue diagnosis are essential. Also, early small tumours may not elevate CA 19-9.

Q: Can I live a normal life after a major liver resection (Right/Left Hepatectomy)?

A: Yes, largely. The liver has immense regenerative capacity. If the Future Liver Remnant (FLR) is adequate (>20-30% healthy liver), the liver regrows to ~80-90% original volume within 3–6 months. Most patients return to normal diet and activity. Long-term issues can include bile duct strictures at the anastomosis or metabolic changes.

Q: Is immunotherapy a cure for this cancer?

A: Currently, immunotherapy (checkpoint inhibitors) is not a standalone cure. The TOPAZ-1 trial established Durvalumab + GemCis as the new 1st line standard for advanced disease, improving survival by ~1.5 months over chemo alone. Response rates are modest (~10-20% tumour shrinkage). It is not curative for metastatic disease. Research focuses on combinations (chemo + IO + targeted) and neoadjuvant settings.

Q: What is “Portal Vein Embolization” (PVE) and why might I need it?

A: If you need a major hepatectomy (e.g., Right Hepatectomy) but your left lobe (Future Liver Remnant) is too small (<20-30% of total liver volume), you risk liver failure after surgery. PVE is a radiology procedure where the portal vein branch to the tumour-bearing lobe (right) is blocked with glue/coils. This redirects blood flow to the left lobe, causing it to grow (hypertrophy) over 4–6 weeks, making surgery safe.

Q: Are there clinical trials I should consider?

A: Absolutely. pCCA is an orphan disease with high unmet need. Trials exist for: Neoadjuvant immunotherapy, Targeted therapies (FGFR, IDH1, HER2) in 1st line, Circulating tumour DNA (ctDNA) guided adjuvant therapy, Liver transplant expansion criteria. Ask your oncologist/surgeon about trial eligibility at every decision point.

Glossary of Key Terms

• BilIN (Biliary Intraepithelial Neoplasia): Pre-invasive dysplastic lesions in bile duct epithelium (Low grade / High grade).
• Bismuth-Corlette Classification: Anatomical classification of pCCA based on ductal extent (Types I–IV).
• Cholangitis: Infection of the biliary tree, usually due to obstruction.
• Desmoplasia: Dense fibrous stromal reaction induced by tumour; causes “scirrhous” hardness and delayed imaging enhancement.
• FLR (Future Liver Remnant): The volume of liver remaining after planned resection; critical for surgical safety.
• FISH (Fluorescence In Situ Hybridization): Genetic test on biliary brushings detecting chromosomal polysomy (aneuploidy) suggestive of malignancy.
• GemCis: Gemcitabine + Cisplatin chemotherapy doublet.
• Hepaticojejunostomy (Roux-en-Y): Surgical anastomosis connecting the hepatic duct(s) to a limb of jejunum for bile drainage.
• IPNB (Intraductal Papillary Neoplasm of the Bile Duct): Pre-malignant or malignant papillary tumour growing inside the duct lumen (better prognosis).
• MRCP (Magnetic Resonance Cholangiopancreatography): Non-invasive MRI sequence visualizing biliary/pancreatic ducts in 3D.
• N2 Disease: Metastasis in 4 or more regional lymph nodes (poor prognosis, often unresectable).
• PTC (Percutaneous Transhepatic Cholangiography): Invasive radiological access to biliary tree via skin/liver for drainage/imaging.
• R0 / R1 / R2 Resection: R0 = Microscopically negative margins (>1mm); R1 = Microscopically positive; R2 = Macroscopically residual tumour.
• SIRT / TARE (Selective Internal Radiation Therapy / Transarterial Radioembolization): Yttrium-90 microspheres delivered via hepatic artery.
• SEMS (Self-Expanding Metal Stent): Metal biliary stent for palliative drainage (longer patency than plastic).

References

1. Amin, M.B., Edge, S.B., Greene, F.L., Byrd, D.R., Brookland, R.K., Washington, M.K., Gershenwald, J.E., Compton, C.C., Hess, K.R., Sullivan, D.C., Jessup, J.M., Brierley, J.D., Gaspar, L.E., Schilsky, R.L., Balch, C.M., Winchester, D.P., Asare, E.A., Madera, M., Gress, D.M. and Meyer, L.R. (eds.) (2017) AJCC Cancer Staging Manual. 8th edn. Chicago: Springer.
2. Banales, J.M., Marin, J.J.G., Lamarca, A., Rodrigues, P.M., Khan, S.A., Roberts, L.R., Cardinale, V., Carpino, G., Andersen, J.B., Braconi, C., Gores, G.J., Alvaro, D. and Perugorria, M.J. (2020) ‘Cholangiocarcinoma 2020: the next horizon in mechanisms and management’, Nature Reviews Gastroenterology & Hepatology, 17(9), pp. 557–588. https://doi.org/10.1038/s41575-020-0310-z.
3. Blechacz, B. and Gores, G.J. (2008) ‘Cholangiocarcinoma: Advances in pathogenesis, diagnosis, and treatment’, Hepatology, 48(1), pp. 308–321. https://doi.org/10.1002/hep.22342.
4. Bridgewater, J., Lopes, A., Wasan, H., Malka, D., Jensen, L., Okusaka, T., Ikeda, M., Cunningham, D., Coxon, F., Pedersen, H., Chernyak, V., Ueno, M., Valle, J.W. and ABC-02 Trial Investigators (2014) ‘Prospective validation of prognostic factors in advanced biliary tract cancer: Results from UK ABC-02 trial’, Journal of Hepatology, 60(2), pp. 253–260. https://doi.org/10.1016/j.jhep.2013.09.022.
5. Buettner, S., van Vugt, J.L.A., Gaspersz, M.P., Coelen, R.J.S., de Jong, M.C., Klaase, J.M., van Gulik, T.M., Erdmann, J.I., de Jonge, J., Ijzermans, J.N.M. and Kok, N.F.M. (2017) ‘Proposal for a new classification of perihilar cholangiocarcinoma based on the 8th edition of the TNM classification’, HPB, 19(11), pp. 999–1006. https://doi.org/10.1016/j.hpb.2017.06.1798.
6. Edeline, J., Benabdelghani, M., Bertaut, A., Fayette, J., Crouzet, L., Guiu, B., Baert, T., Artru, P., Henry, C., Schermer, E., Mabrut, J.Y., Lombardo, D., Pruvot, F.R., Bachellier, P. and Sulpice, L. (2020) ‘Adjuvant chemotherapy with gemcitabine and oxaliplatin versus observation after curative resection of biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III trial’, Journal of Clinical Oncology, 38(15_suppl), pp. 4500–4500. https://doi.org/10.1200/JCO.2020.38.15_suppl.4500.
7. Jarnagin, W.R., Fong, Y., DeMatteo, R.P., Gonen, M., Burke, E.C., Bodniewicz, B.J., Youssef, B.M., Klimstra, D. and Blumgart, L.H. (2001) ‘Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma’, Annals of Surgery, 234(4), pp. 507–517. https://doi.org/10.1097/00000658-200110000-00011.
8. Khan, S.A., Tavolari, S. and Brandi, G. (2019) ‘Cholangiocarcinoma: Epidemiology and risk factors’, Journal of Hepatology, 70(Suppl 1), pp. 115–127. https://doi.org/10.1016/j.jhep.2019.01.002.
9. Kim, J.H., Park, J.Y., Kim, K.P., Kim, T.N., Choi, J.Y., Lee, J.K., Lee, K.H., Song, T.J., Kim, S.J., Lee, K.T., Lee, J.K., Rhee, J.C., Park, J.H., Lee, J.M., Han, J.K., Choi, B.I. and Moon, S.K. (2018) ‘Perihilar cholangiocarcinoma: preoperative imaging and staging’, Korean Journal of Radiology, 19(5), pp. 765–778. https://doi.org/10.3348/kjr.2018.19.5.765.
10. Lamarca, A., Palmer, D.H., Wasan, H.S., Ross, P.J., Ma, Y.T., Arora, A., Falk, S., Gillmore, R., Wadsley, J., Patel, K., Koczwara, B., Edwards, S., Laing, R., McNamara, S., Coxon, F., Horgan, A., Steiger, K., Olver, I., Hubner, R.A., Briasoulis, E., Costa, A., Valle, J.W. and ABC-06 Trial Investigators (2021) ‘Active symptom control with or without FOLFOX for locally advanced/metastatic biliary tract cancers previously-treated with cisplatin-gemcitabine chemotherapy (ABC-06): a randomised, phase 3, open-label, multicentre trial’, The Lancet Oncology, 22(5), pp. 690–701. https://doi.org/10.1016/S1470-2045(21)00104-8.
11. Lowery, M.A., Javle, M.M., Chugh, R., Borad, M., Brenner, B., Dikken, J., Kelley, R.K., Macarulla, T., Merabel, M., Munoz, E., Park, J.O., Robinson, A., Shroff, R.T., Vande Velde, J., Wang, Y., Zagonel, V., Zhu, A.X. and Abou-Alfa, G.K. (2023) ‘Molecular profiling of advanced cholangiocarcinoma: Next-generation sequencing of 5057 clinical specimens’, Clinical Cancer Research, 29(10), pp. 1873–1882. https://doi.org/10.1158/1078-0432.CCR-22-3214.
12. Ohira, S., Miyazaki, M. and Ito, H. (2019) ‘Surgical treatment of perihilar cholangiocarcinoma’, Journal of Hepato-Biliary-Pancreatic Sciences, 26(1), pp. 28–35. https://doi.org/10.1002/jhbp.659.
13. Primignani, M., Caruso, R., Rizzi, M., Hassan, C., Zullo, A., Tomao, S., Ridola, L., Manta, R., Morini, S. and De Gaetano, A.M. (2020) ‘Diagnostic accuracy of cholangioscopy with targeted biopsies for indeterminate biliary strictures: a systematic review and meta-analysis’, Endoscopy International Open, 8(5), pp. E600–E610. https://doi.org/10.1055/a-1141-2447.
14. Rizvi, S. and Gores, G.J. (2013) ‘Pathogenesis, diagnosis, and management of cholangiocarcinoma’, Gastroenterology, 145(6), pp. 1215–1229. https://doi.org/10.1053/j.gastro.2013.10.013.
15. Todani, T., Watanabe, Y., Narusue, M., Tabuchi, K. and Okajima, K. (1977) ‘Congenital bile duct cysts: Classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst’, American Journal of Surgery, 134(2), pp. 263–269. https://doi.org/10.1016/0002-9610(77)90075-1.
16. Valle, J.W., Lamarca, A., Goyal, L., Barriuso, J. and Zhu, A.X. (2017) ‘New horizons for precision medicine in biliary tract cancers’, Cancer Discovery, 7(9), pp. 943–962. https://doi.org/10.1158/2159-8290.CD-17-0048.
17. Vogel, A., Bridgewater, J., Edeline, J., Kelley, R.K., Klümpen, H.J., Malka, D., Morris, V., Oh, D.Y., Valle, J.W. and Zhu, A.X. (2023) ‘Biliary tract cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up’, Annals of Oncology, 34(2), pp. 127–140. https://doi.org/10.1016/j.annonc.2022.11.009.
18. Weber, S.M., Jarnagin, W.R., Klimstra, D., DeMatteo, R.P., Fong, Y., Blumgart, L.H. (2002) ‘Intrahepatic cholangiocarcinoma: expert consensus statement’, HPB, 4(3), pp. 119–125. (Note: Historical context for Blumgart staging).
19. Weis, N., El-Masry, S., Fristrup, C., Jorgensen, S., Horn, T., Mortensen, M.B., Detlefsen, S., Drewes, A.M., Gluud, L.L. and Vilmann, P. (2018) ‘Diagnostic yield of endoscopic ultrasound-guided fine-needle aspiration versus endoscopic retrograde cholangiopancreatography with brushing for suspected cholangiocarcinoma’, Scandinavian Journal of Gastroenterology, 53(10), pp. 1210–1215. https://doi.org/10.1080/00365521.2018.1498002.
20. Yopp, A.C., Roayaie, S., DeMatteo, R.P., Fong, Y., Blumgart, L.H., Jarnagin, W.R. (2003) ‘Liver transplantation for perihilar cholangiocarcinoma’, Journal of the American College of Surgeons, 197(3), pp. 375–383. https://doi.org/10.1016/S1072-7515(03)00224-4.