Definition/General
Introduction:
Splenic Niemann-Pick disease represents splenic involvement in Niemann-Pick disease, a group of autosomal recessive lysosomal storage disorders
It results from deficiency of acid sphingomyelinase (Types A and B) or NPC1/NPC2 proteins (Type C)
The spleen shows massive enlargement due to accumulation of sphingomyelin and cholesterol in macrophages, creating characteristic foam cells.
Origin:
Caused by genetic mutations affecting lipid metabolism
Type A and B: SMPD1 gene mutations affecting acid sphingomyelinase
Type C: NPC1 (95%) or NPC2 (5%) gene mutations affecting cholesterol transport
Lysosomal dysfunction: Impaired lipid degradation and transport
Progressive accumulation: Lipids accumulate in macrophages over time.
Classification:
Type A (Classical infantile): Severe neurodegeneration, early death
Type B (Visceral): Hepatosplenomegaly, minimal neurologic involvement
Type C: Variable neurologic progression, cholesterol storage
By severity: Severe (Type A), intermediate (Type B), variable (Type C)
By age of onset: Infantile, juvenile, adult.
Epidemiology:
Overall incidence: 1 in 120,000-150,000 births
Type A: Higher in Ashkenazi Jews (1 in 40,000)
Type B: More common in certain populations (North Africa, Turkey)
Type C: 1 in 150,000 globally
Gender: Equal male-female distribution
Ethnic clustering: Founder effects in isolated populations.
Clinical Features
Presentation:
Hepatosplenomegaly (90-95% of patients): Often massive, spleen larger than liver
Growth retardation (80%): Failure to thrive in children
Neurologic symptoms: Variable depending on type
Pulmonary involvement (60-70%): Interstitial infiltrates, recurrent infections
Hematologic abnormalities: Thrombocytopenia, anemia.
Symptoms:
Abdominal symptoms: Massive abdominal distension
Early satiety and discomfort
Respiratory symptoms: Recurrent pneumonia, chronic cough
Dyspnea on exertion
Neurologic symptoms (Types A and C): Developmental delay, ataxia, seizures
Systemic symptoms: Fatigue, poor feeding in infants.
Risk Factors:
Family history: Autosomal recessive inheritance
Consanguinity: Increased risk in consanguineous marriages
Ethnic background: Higher prevalence in certain populations
Carrier status: Both parents must be carriers
Previous affected siblings: 25% recurrence risk.
Screening:
Enzymatic assay: Acid sphingomyelinase activity (Types A/B)
Genetic testing: SMPD1, NPC1, NPC2 gene sequencing
Biomarkers: Chitotriosidase, CCL18, lysosphingomyelin
Imaging studies: Chest X-ray for pulmonary involvement
Bone marrow examination: Foam cells demonstration.
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Gross Description
Appearance:
Massive splenomegaly: Weight 500-3000g (normal 150g)
Firm, rubbery consistency
Smooth capsular surface
Cut surface: Tan to yellow color with foam cell infiltration
Loss of normal architecture: Difficulty distinguishing red and white pulp.
Characteristics:
Proportional enlargement: Maintains splenic shape despite size
Uniform involvement: Entire parenchyma affected
Yellow discoloration: Due to lipid accumulation
Firm texture: Due to cellular infiltration
No necrosis: Unless complicated by infarction.
Size Location:
Massive enlargement: May extend well below costal margin
Weight correlation: Reflects extent of foam cell accumulation
Architectural effacement: Normal splenic landmarks obliterated
Capsular integrity: Usually preserved
Associated hepatomegaly: Liver also enlarged in most cases.
Multifocality:
Diffuse involvement: Uniform foam cell infiltration throughout spleen
Associated organ involvement: Liver universally involved
Lung involvement common
Bone marrow involvement: Foam cells in bone marrow
Systemic disease pattern: Part of multiorgan storage disease.
Microscopic Description
Histological Features:
Foam cells (Niemann-Pick cells): Large macrophages with foamy, vacuolated cytoplasm
Diffuse infiltration: Throughout splenic red pulp and white pulp
Architectural replacement: Normal splenic elements compressed
Variable fibrosis: Increases with disease duration
Sea-blue histiocytes: May be present (ceroid pigment).
Cellular Characteristics:
Foam cells: 20-50 μm diameter with abundant foamy cytoplasm
Cytoplasmic vacuoles: Multiple clear vacuoles containing stored lipids
Central nuclei: Round to oval, often eccentric
PAS-negative material: Unlike Gaucher cells
Sudanophilic material: Lipid-positive with fat stains.
Architectural Patterns:
Diffuse replacement pattern: Foam cells replace normal architecture
Red pulp predominance: Extensive infiltration of red pulp cords and sinuses
White pulp compression: Follicles compressed by foam cell infiltration
Sinusoidal pattern: Foam cells fill sinusoidal spaces
Capsular extension: May involve splenic capsule.
Grading Criteria:
Mild involvement: Scattered foam cells, preserved architecture
Moderate involvement: Extensive infiltration, architectural distortion
Severe involvement: Near-complete replacement, massive splenomegaly
End-stage disease: Complete architectural effacement, fibrosis.
Immunohistochemistry
Positive Markers:
CD68: Strongly positive in foam cells (macrophage origin)
Oil Red O: Positive for lipid content (frozen sections)
Sudan stains: Positive for lipid material
Lysozyme: Positive in foam cells.
Negative Markers:
PAS stain: Negative (unlike Gaucher cells)
Congo red: Negative (excludes amyloidosis)
Cytokeratins: Negative in foam cells
Melanoma markers: S-100, Melan-A negative.
Diagnostic Utility:
Confirmation of macrophage origin: CD68 positivity
Demonstration of lipid storage: Fat stains positive
Differential diagnosis: From other storage diseases
Distinguishing from Gaucher: PAS negativity.
Molecular Subtypes:
Classical foam cells: Typical vacuolated appearance
Sea-blue histiocytes: With ceroid pigment accumulation
Mixed populations: Different stages of lipid accumulation
Treatment response: Minimal change with current therapies.
Molecular/Genetic
Genetic Mutations:
SMPD1 gene mutations: >180 mutations identified (Types A and B)
NPC1 gene mutations: >500 mutations (95% of Type C)
NPC2 gene mutations: Fewer mutations (5% of Type C)
Common mutations: Population-specific founder mutations.
Molecular Markers:
Enzyme activity: Acid sphingomyelinase deficiency (Types A/B)
Cholesterol transport: Impaired in Type C
Biomarkers: Chitotriosidase (elevated), lysosphingomyelin, oxysterols
Filipin staining: Abnormal cholesterol accumulation (Type C).
Prognostic Significance:
Disease type: Type A - severe, early death
Type B - better survival
Type C - variable progression
Age of onset: Earlier onset indicates severe disease
Neurologic involvement: Major prognostic factor
Pulmonary disease: Affects survival in Type B.
Therapeutic Targets:
Substrate reduction therapy: Miglustat for Type C
Enzyme replacement: Olipudase alfa for Type B (investigational)
Symptomatic treatment: Supportive care for organ dysfunction
Lung transplant: For severe pulmonary disease
Bone marrow transplant: Limited success.
Differential Diagnosis
Similar Entities:
Gaucher disease: Different cytoplasmic appearance, different enzyme deficiency
Other storage diseases: GM1 gangliosidosis, Wolman disease
Sea-blue histiocyte syndrome: Acquired condition with similar cells
Malignancies: Lymphomas with histiocytic reaction
Infections: Histoplasmosis with macrophage infiltration.
Distinguishing Features:
Niemann-Pick vs Gaucher: Foamy vs striated cytoplasm
PAS negative vs positive
Niemann-Pick vs sea-blue histiocytes: Primary vs secondary condition
Enzyme deficiency vs normal enzymes
Clinical correlation: Age of onset, family history, ethnic background.
Diagnostic Challenges:
Type differentiation: Requires enzyme assays and genetic testing
Mixed pathology: Concurrent conditions may complicate diagnosis
Minimal disease: Early cases may be difficult to recognize
Atypical presentations: Variant forms with unusual features.
Rare Variants:
Adult-onset Type A: Rare late-onset form
Type C with minimal neurologic involvement: Predominantly visceral disease
Atypical storage cells: Variants in cellular morphology
Combined deficiencies: Multiple enzyme defects
Pseudo-Niemann-Pick: Secondary foam cell accumulation.
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.
Specimen Information
Splenectomy specimen weighing [X]g with clinical history of [hepatosplenomegaly] and [neurologic symptoms]
Gross Description
Massively enlarged spleen with [firm consistency] and [tan-yellow cut surface]
Microscopic Findings
Diffuse infiltration by foam cells with [vacuolated cytoplasm] and [architectural replacement]
Foam Cell Morphology
Large macrophages with abundant foamy, vacuolated cytoplasm and [central nuclei]
Special Stains
Oil Red O: positive for lipid content. PAS stain: negative. CD68: positive in foam cells
Diagnosis
Splenic Niemann-Pick disease with massive foam cell infiltration
Type Classification
[Type A/B/C] Niemann-Pick disease based on [clinical features and enzyme studies]
Recommendations
Recommend [genetic counseling], [enzyme studies], and multidisciplinary management for systemic disease