Cholangiocarcinoma

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 Cholangiocarcinoma

I. Definition and Overview

Cholangiocarcinoma (CCA) is a malignant epithelial neoplasm that arises from the biliary ductal epithelium. It represents a diverse group of cancers characterized by distinct genetic, anatomical, and clinical profiles, and is broadly classified into intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) subtypes, based on the anatomical location within the biliary tree.


II. Cause and Etiology

1. Risk Factors

Cholangiocarcinoma is associated with a variety of predisposing conditions and environmental factors that differ by geographic region:

  • Primary Sclerosing Cholangitis (PSC):
    • A well-established risk factor in Western countries.
    • Up to 10–15% lifetime risk of developing CCA in patients with PSC.
  • Liver Fluke Infestation:
    • Opisthorchis viverrini and Clonorchis sinensis are strongly implicated in Southeast Asia.
    • Chronic inflammation and epithelial hyperplasia underlie carcinogenesis.
  • Biliary Stone Disease:
    • Intrahepatic and extrahepatic cholelithiasis, particularly hepatolithiasis, predispose to chronic ductal inflammation.
  • Choledochal Cysts and Biliary Anomalies:
    • Associated with a markedly elevated lifetime risk (10%–30%) of CCA due to chronic epithelial irritation and dysplasia.
  • Chronic Viral Hepatitis (HBV, HCV):
    • Particularly associated with iCCA. HBV-associated iCCA is more prevalent in endemic areas like East Asia.
  • Cirrhosis and Non-alcoholic Steatohepatitis (NASH):
    • Emerging as risk factors in the West, potentially related to the metabolic syndrome.
  • Exposure to Thorotrast, Asbestos, Dioxins:
    • Historical exposure to thorium dioxide (Thorotrast) is linked to iCCA.
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III. Pathophysiology

1. Cellular Origin

Cholangiocarcinomas arise from biliary epithelial cells (cholangiocytes), but may also originate from hepatic progenitor cells, especially in iCCA. The cellular microenvironment, including chronic inflammation and stromal reaction, plays a critical role in tumorigenesis.

2. Molecular Pathways

The pathogenesis of cholangiocarcinoma involves several key molecular alterations:

  • KRAS and TP53 mutations: Common in pCCA and dCCA.
  • IDH1/2 mutations and FGFR2 fusions: Enriched in iCCA.
  • Epigenetic modifications: Promoter hypermethylation of tumor suppressor genes like p16INK4a, RASSF1A.
  • Inflammation-driven oncogenesis:
    • Chronic inflammation activates NF-κB and STAT3 pathways, promoting proliferation, evasion of apoptosis, and angiogenesis.
  • Epithelial-Mesenchymal Transition (EMT):
    • Facilitates tumor invasion and metastasis, often driven by TGF-β and hypoxia-inducible factors.

3. Tumor Microenvironment

  • Extensive desmoplastic stroma, rich in cancer-associated fibroblasts (CAFs), immune cells, and extracellular matrix components.
  • TGF-β, PDGF, and VEGF are pivotal in modulating stromal remodeling and angiogenesis.


IV. Epidemiology

1. Global Incidence

  • Worldwide: Incidence is rising globally, particularly for intrahepatic CCA.
  • High prevalence regions:
    • Southeast Asia (Thailand, Laos, Cambodia): Due to liver fluke infections.
    • The incidence in endemic areas exceeds 85 per 100,000.
  • Western countries: The incidence of iCCA is rising, possibly due to improved diagnostic techniques and increasing NASH.

2. Age and Gender

  • Typically affects individuals aged 50–70 years.
  • Slight male predominance (M:F ratio ≈ 1.2–1.5:1), although variation exists by region and CCA subtype.

3. Prognostic Disparities

  • Prognosis is poorer in low-resource settings due to late presentation and limited access to care.
  • Differences in molecular profiles between East and West may also contribute to variation in treatment response.


V. Clinical Presentation

1. Intrahepatic CCA (iCCA)

  • Often asymptomatic in early stages.
  • Nonspecific symptoms: Right upper quadrant pain, weight loss, fatigue.
  • Advanced disease: Hepatomegaly, palpable mass, constitutional symptoms.

2. Perihilar CCA (Klatskin tumor)

  • Most common subtype (~50–60% of all CCA).
  • Presents with painless progressive jaundice, cholestatic pruritus, dark urine, and acholic stools.
  • May have cholangitis due to biliary obstruction.

3. Distal CCA

  • Similar presentation to pancreatic head tumors.
  • Obstructive jaundice is the dominant symptom.
  • May cause early biliary dilation visible on imaging.


VI. Imaging Features

1. Ultrasound (US)


  • Initial tool for detecting biliary ductal dilatation.
  • May reveal an intrahepatic mass or ductal thickening.

2. Computed Tomography (CT)


  • iCCA: Hypodense mass with peripheral rim enhancement on arterial phase, progressive centripetal enhancement on delayed phases.
  • pCCA/dCCA: Poorly enhancing mass at biliary bifurcation or distal duct, causing upstream biliary dilation.

3. Magnetic Resonance Imaging (MRI) / MRCP


  • Superior soft tissue characterization.
  • MRCP: Noninvasive delineation of biliary anatomy and stricture localization.
  • T2 hyperintense, T1 hypointense masses with progressive delayed enhancement.

4. Positron Emission Tomography (PET)

Comparison of 18F-FDG PET/MR and PET/CT for pretreatment TNM staging of hilar cholangiocarcinoma. doi:10.1007/s00261-023-03925-x 

  • Limited sensitivity, but may assist in detecting occult metastases.

5. Endoscopic Retrograde Cholangiopancreatography (ERCP) / PTC


  • Used for diagnostic brushing and biliary stenting.
  • Intraductal ultrasound (IDUS) enhances sensitivity for mural invasion.


VII. Histology and Diagnosis

  • Adenocarcinoma in >90% of cases; well to moderately differentiated.
  • Mucin production variable.
  • Immunohistochemical markers:
    • Positive: CK7, CK19, EMA.
    • Variable: CK20, CEA, CA19-9.
  • Biopsy Techniques:
    • Fine needle aspiration (FNA), brush cytology, or core biopsy.
    • Fluorescence in situ hybridization (FISH) improves sensitivity.


VIII. Treatment

1. Surgical Resection

  • Only potentially curative option.
  • iCCA: Hepatic lobectomy with negative margins.
  • pCCA: Extended hemihepatectomy with caudate lobectomy.
  • dCCA: Pancreaticoduodenectomy (Whipple procedure).
  • Criteria: Resectable tumor, no distant metastases, preserved liver function.
  • 5-year survival with R0 resection: 30–40% (iCCA), 25–30% (pCCA).

2. Liver Transplantation

  • Viable for select cases of pCCA with neoadjuvant chemoradiation (Mayo protocol).
  • Contraindicated for iCCA except small, early-stage tumors under trial protocols.

3. Chemotherapy

  • First-line (advanced/unresectable): Cisplatin + Gemcitabine (ABC-02 trial standard).
  • Second-line: FOLFOX (as per ABC-06 trial).
  • Targeted agents (FGFR, IDH1/2 inhibitors) are under evaluation and increasingly approved.

4. Targeted Therapies

  • FGFR2 fusion-positive iCCA:
    • Pemigatinib, Infigratinib (FDA-approved).
  • IDH1 mutations:
    • Ivosidenib (positive results in ClarIDHy trial).
  • HER2 amplification, BRAF V600E, MSI-high, NTRK fusions: Targetable in small subsets.

5. Radiotherapy

  • Used as an adjuvant, palliative, or part of a transplant protocol.
  • Stereotactic body radiotherapy (SBRT) is gaining interest.

6. Endoscopic and Palliative Therapies

  • Biliary drainage (ERCP/PTC) for jaundice and cholangitis.
  • Stent placement: Plastic for short-term, metal for long-term palliation.


IX. Prognosis

1. Prognostic Factors

  • Surgical margin status (R0 vs R1/R2).
  • Tumor stage and lymph node involvement.
  • Histologic grade and molecular subtype.
  • Presence of vascular invasion or perineural spread.

2. Survival Outcomes

  • Localized, resectable disease:
    • 5-year survival: 25–40% with surgery.
  • Unresectable disease:
    • Median survival: 11–14 months with chemotherapy.
  • Metastatic disease:
    • Median survival < 1 year without systemic therapy.

3. Recurrence

  • High recurrence rate (up to 60% within 2 years post-resection).
  • Common sites: Liver remnant, peritoneum, lymph nodes.


X. Future Directions

  • Development of molecular profiling to personalize therapy.
  • Early detection strategies using liquid biopsy, methylation markers.
  • Immunotherapy (checkpoint inhibitors, vaccines) is under active investigation.
  • Improved transplant protocols and donor matching.
  • Integration of AI in radiologic and histopathologic diagnosis.


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