Fibrolamellar Carcinoma (FLC) of the Liver

Overview

Epidemiology & Risk Factors

• Affects children and young adults, typically age 10-35 years (some sources cite 5-35 years)
• Arises in a non-cirrhotic, otherwise normal liver - no underlying chronic liver disease
• No known predisposing factors (no viral hepatitis, alcohol, or metabolic liver disease association)
• Slightly more common in females
• Roughly equal incidence worldwide (no strong geographic predilection)

Pathogenesis & Molecular Genetics

• DNAJB1::PRKACA gene fusion is present in 80-100% of cases - a ~400 kb deletion on chromosome 19 that fuses the heat shock protein gene DNAJB1 with the protein kinase A catalytic subunit gene PRKACA
• This fusion oncogene leads to constitutive activation of protein kinase A (PKA) signaling
• Very few additional mutations exist (<10% of cases have other alterations) - FLC has a remarkably simple mutational landscape compared to conventional HCC
• A small subset of cases (without the fusion) carry inactivating mutations in PRKAR1A (the regulatory subunit of PKA), sometimes associated with Carney complex
• The DNAJB1::PRKACA fusion is now central to diagnosis and is being targeted therapeutically

Recent update (2025): The fusion has also been reported in intraductal oncocytic papillary neoplasm and intraductal papillary mucinous neoplasm, so molecular analysis alone is insufficient for diagnosis - morphology + IHC + molecular testing are all required (Einarsson & Graham, Modern Pathology 2025, PMID 39814265).

Pathology & Histology

• Solitary, large, lobulated, well-demarcated tumor
• Characteristic central fibrous scar (radiating fibrous bands)
• Punctate calcification within the scar in >50% of cases

• Large, polygonal hepatocytes with abundant granular eosinophilic (oncocytic) cytoplasm (due to abundant mitochondria)
• Round nuclei with prominent, centrally-placed macronucleoli
• Separated by parallel lamellae of dense fibrous tissue (the "fibrolamellar" pattern - this is the eponymous feature)
• Pale bodies (cytoplasmic inclusions) and ground-glass inclusions may be present

• Positive: CK7, CK19, HepPar-1, CD68, DNAJB1 (C-terminus antibody useful)
• Loss of PRKAR1A expression on IHC is a useful diagnostic marker
• AFP is typically negative or weakly positive (unlike conventional HCC)

Clinical Presentation

• Abdominal pain or discomfort (right upper quadrant)
• Palpable abdominal mass
• Weight loss, malaise, fatigue
• Symptoms often present late (large tumor at diagnosis)
• AFP is usually normal - this is clinically important because it makes screening and monitoring difficult
• Gynecomastia (due to aromatase production by the tumor) has been reported
• Lymph node metastases are common at presentation (~50% of patients)

Imaging

• Well-defined, lobulated low-attenuation mass on unenhanced CT
• Central scar with even lower attenuation and radial linear components
• Punctate calcification within the scar (present in >50%) - this is a key distinguishing feature from FNH
• Non-specific arterial enhancement; delayed enhancement of the scar may occur (mimicking FNH)

• Central scar is low signal on both T1 and T2 - this distinguishes FLC from FNH (where the scar is typically high signal on T2)
• Punctate calcification is rarely demonstrated on MRI
• Heterogeneous mass with fibrous central region showing limited enhancement post-contrast

• Increased echogenicity (hyperreflective mass)
• Central scar and calcification may be visible

Fig. 23.53E - Fibrolamellar Carcinoma: Arterial phase T1-weighted MRI showing large heterogeneous lesion with fibrous central region. (Grainger & Allison's Diagnostic Radiology)

Diagnosis

1. Morphology (histology as above)
2. IHC - loss of PRKAR1A, positive DNAJB1 C-terminus staining
3. Molecular analysis - DNAJB1::PRKACA fusion by FISH, PCR, or next-generation sequencing

Staging & Prognosis

• FLC has a better prognosis than conventional HCC, partly because of younger patient age and absence of cirrhosis (allows more aggressive resection)
• 5-year survival after resection: ~60%
• Median survival after resection: ~70 months (retrospective series of 575 cases)
• At advanced (unresectable) stages: expected survival <20 months
• Recurrence is common, even after R0 resection; lymph node metastases and peritoneal spread are frequent patterns
• Distant metastases to lung, bone, and adrenal glands occur

Treatment

• Surgical resection is the primary treatment - indications are less restrictive than for HCC since the underlying liver is normal
• R0 resection offers the best chance of cure
• Liver transplantation has been explored for unresectable disease; the EASL 2024 position paper notes it as an option for selected cases

• No established standard systemic therapy for advanced/recurrent FLC
• FLC does not respond well to conventional HCC regimens (sorafenib, lenvatinib)
• Clinical trials are focused on:
  • Kinase inhibitors targeting the PRKACA fusion protein (e.g., PKA inhibitors)
  • Immunotherapy (checkpoint inhibitors - pembrolizumab, nivolumab) given the relatively immune-infiltrated microenvironment
  • Targeted therapies based on the unique molecular profile

Summary Table

• Harrison's Principles of Internal Medicine 22E (2025), p. 556-558
• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 853
• Grainger & Allison's Diagnostic Radiology, p. 649-652
• Einarsson & Graham, Modern Pathology 2025 (PMID 39814265)
• Wege et al., EASL Position Paper on Rare Primary Liver Cancers, J Hepatol 2024 (PMID 39289102)