Definition/General
Introduction:
Focal Nodular Hyperplasia (FNH) is the second most common benign liver lesion after hemangioma
It represents a hyperplastic response to vascular malformation
FNAC shows normal hepatocytes with bile ductules and Kupffer cells
It is a non-neoplastic lesion with no malignant potential.
Origin:
Arises from hyperplastic response to congenital arteriovenous malformation
Represents polyclonal proliferation of hepatocytes
Associated with central stellate scar containing artery and bile ducts
Not a true neoplasm but rather hamartomatous proliferation
Results from hyperperfusion injury.
Classification:
Classified as classic FNH (90% cases) with central scar
Non-classic FNH (10% cases): telangiectatic, mixed hyperplastic-adenomatous
Multiple FNH (20% cases)
Large FNH (>5 cm)
Associated with hepatic adenomas in adenomatosis
FNH-like nodules in cirrhotic livers.
Epidemiology:
Second most common benign liver tumor (prevalence 0.9-8%)
Strong female predominance (F:M = 8:1)
Peak incidence in 3rd-4th decades
Associated with oral contraceptive use
Often discovered incidentally
Stable lesion with no malignant potential
Indian women: increasing detection with widespread imaging.
Clinical Features
Presentation:
Usually completely asymptomatic (>95% cases)
Incidental finding on imaging studies
Rarely: vague right upper quadrant discomfort
No hepatomegaly typically
Normal liver function tests
No association with hepatitis or cirrhosis
Pregnancy-related growth rare.
Symptoms:
Asymptomatic in vast majority
Vague abdominal discomfort (large lesions, >8 cm)
No constitutional symptoms
Normal appetite and weight
No nausea or vomiting
No hormonal symptoms
Rarely: mass effect symptoms in giant lesions.
Risk Factors:
Oral contraceptive use (controversy regarding causation vs detection bias)
Female gender (strong association)
Reproductive age (20-50 years)
Vascular malformations (underlying cause)
No association with alcohol or hepatitis
Genetic factors (familial cases rare).
Screening:
Usually detected on routine imaging
Ultrasound: isoechoic to hyperechoic mass
CT triphasic: arterial enhancement with central scar
MRI: T1 iso/hypointense, T2 iso/hyperintense
Sulfur colloid scan: Kupffer cell uptake (pathognomonic)
Normal AFP and other tumor markers.
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Gross Description
Appearance:
FNAC yields highly cellular hepatocyte-rich aspirate
Normal-appearing hepatocytes in sheets and trabeculae
Bile ductules and cholangiocytes present
Kupffer cells scattered throughout
Background shows minimal blood and debris
Fibrous tissue from central scar.
Characteristics:
Cellular aspirate resembling normal liver parenchyma
Hepatocytes: uniform size with abundant cytoplasm
Bile ductules: small glandular structures
Kupffer cells: stellate cells with pigment
Endothelial cells lining sinusoids
Fibrous connective tissue fragments.
Size Location:
Variable size: typically 2-5 cm
Any hepatic segment can be affected
Subcapsular location common
Well-demarcated from surrounding parenchyma
Central stellate scar (pathognomonic feature)
Multiple lesions in 20% cases.
Multifocality:
Solitary lesion in 80% cases
Multiple FNH in 20% cases
Bilateral distribution when multiple
Associated with hepatic adenomas (adenomatosis)
Vascular anomalies may be present
No extrahepatic manifestations typically.
Microscopic Description
Histological Features:
Normal hepatocytes arranged in trabeculae and sheets
Bland nuclear morphology with uniform size
Bile ductules proliferation (cholangiolar proliferation)
Kupffer cells with brown pigment (lipofuscin)
Sinusoidal endothelial cells
Fibrous connective tissue with vessels.
Cellular Characteristics:
Hepatocytes: polygonal cells with abundant eosinophilic cytoplasm
Central nuclei with prominent nucleoli
Binucleated forms common (normal finding)
Cholangiocytes: cuboidal cells lining bile ductules
Kupffer cells: stellate morphology with pigment
No cellular atypia or pleomorphism.
Architectural Patterns:
Trabecular pattern mimicking normal liver architecture
Nodular arrangement with fibrous septa
Bile ductular proliferation at periphery of nodules
Sinusoidal pattern preserved
Central fibrous scar with vessels and bile ducts
No mass effect or compression.
Grading Criteria:
No grading system for FNH (benign lesion)
Assessment based on architectural preservation
Hepatocyte morphology: normal vs slightly enlarged
Bile ductule density: increased vs normal
Kupffer cell content: normal vs decreased
Fibrous tissue amount: minimal vs prominent.
Immunohistochemistry
Positive Markers:
Hepatocyte marker (positive in hepatocytes)
Arginase-1 (hepatocyte marker)
CK7 (positive in bile ductules)
CK19 (cholangiocyte marker)
CD68 (Kupffer cells)
Glutamine synthetase (heterogeneous pattern, unlike adenoma).
Negative Markers:
AFP (negative, excludes HCC)
Glypican-3 (negative, excludes HCC)
CD34 (negative in sinusoids, unlike adenoma)
Cytokeratin 8/18 (variable in hepatocytes)
Beta-catenin (membranous pattern)
p53 (negative).
Diagnostic Utility:
Limited utility in FNAC setting
Hepatocyte marker confirms hepatocytic nature
CK7/CK19 highlight bile ductules (key feature)
Glutamine synthetase: heterogeneous (unlike adenoma's homogeneous)
CD34 negativity helps vs adenoma
Excludes HCC (AFP-, Glypican-3-).
Molecular Subtypes:
No specific molecular subtypes
Polyclonal lesion (not true neoplasm)
Normal karyotype in most cases
Telomerase activity absent
No specific oncogene activation
Vascular remodeling genes may be upregulated.
Molecular/Genetic
Genetic Mutations:
No specific somatic mutations characteristic of FNH
Polyclonal proliferation (reactive hyperplasia)
Normal chromosomal profile
Rare chromosomal imbalances (non-specific)
Vascular malformation genes may be involved
No tumor suppressor gene alterations.
Molecular Markers:
Normal hepatocyte markers expression
Angiogenesis factors: VEGF, angiopoietin
Proliferation markers: low Ki-67 index
Apoptosis markers: normal levels
Matrix remodeling: collagen, fibronectin
Cytochrome P450 enzymes normal.
Prognostic Significance:
Excellent prognosis (benign lesion)
No malignant transformation risk
Stable size over time typically
No liver dysfunction
Pregnancy effect: minimal size change
Oral contraceptive effect: controversial
Complications extremely rare.
Therapeutic Targets:
Observation for asymptomatic lesions
No specific treatment needed
Discontinue OCP if size increase
Follow-up imaging to confirm stability
Surgery only for symptomatic giant lesions
No chemotherapy or targeted therapy needed.
Differential Diagnosis
Similar Entities:
Hepatic adenoma (true neoplasm, homogeneous GS staining)
Well-differentiated HCC (malignant hepatocytes)
Regenerative nodule (in cirrhotic liver)
Normal liver parenchyma (FNAC sampling)
Fibrolamellar HCC (young patients, central scar)
Nodular regenerative hyperplasia.
Distinguishing Features:
FNH: bile ductules present, Kupffer cells present, heterogeneous GS staining
Adenoma: no bile ductules, CD34+ sinusoids, homogeneous GS staining
HCC: cellular atypia, AFP elevation, Glypican-3+
Normal liver: less cellular, portal tracts present
Fibrolamellar HCC: oncocytic cells, lamellar fibrosis.
Diagnostic Challenges:
Distinguishing from hepatic adenoma (major differential)
Well-differentiated HCC vs FNH
Normal liver parenchyma in FNAC
Regenerative nodule in cirrhotic background
Atypical FNH without central scar
Multiple FNH vs adenomatosis.
Rare Variants:
Telangiectatic FNH (prominent vascular spaces)
Mixed hyperplastic-adenomatous lesion
Large FNH with mass effect
Multiple FNH (adenomatosis-like)
FNH with steatosis
Inflammatory FNH (increased inflammatory cells).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Clinical Information
Patient with liver lesion on imaging, [clinical presentation]
Specimen Adequacy
Adequate for evaluation with high cellularity
Cytomorphological Features
Shows [normal hepatocytes, bile ductules, Kupffer cells] without atypia
Background
Background shows [minimal blood, fibrous tissue fragments]
Imaging Correlation
Imaging shows [central scar, characteristic enhancement pattern]
Differential Diagnosis
Differential includes [hepatic adenoma, well-differentiated HCC, normal liver]
Final Cytological Diagnosis
Benign hepatocytic lesion consistent with Focal Nodular Hyperplasia
Recommendations
Recommend [imaging correlation, clinical follow-up]