Definition/General
Introduction:
Splenic amyloidosis is the deposition of amyloid protein in splenic tissue as part of systemic amyloidosis
Amyloid consists of misfolded proteins arranged in beta-pleated sheet configuration
The spleen is commonly involved in AA and AL amyloidosis
Splenic involvement occurs in 60-80% of systemic amyloidosis cases and may cause splenomegaly and hypersplenism.
Origin:
Results from abnormal protein folding and extracellular deposition
AL amyloidosis: Misfolded immunoglobulin light chains
AA amyloidosis: Serum amyloid A protein deposits secondary to chronic inflammation
Systemic disease: Spleen involved as part of multiorgan process
Progressive accumulation: Deposits increase over time, causing organ dysfunction.
Classification:
By protein type: AL amyloidosis (light chain)
AA amyloidosis (serum amyloid A)
AH amyloidosis (heavy chain)
Hereditary amyloidosis (various proteins)
By distribution: Systemic amyloidosis
Localized amyloidosis (rare in spleen)
By underlying disease: Primary (AL)
Secondary (AA)
Hereditary.
Epidemiology:
Age distribution: AL amyloidosis - median age 65 years
AA amyloidosis - any age depending on underlying disease
Gender: AL amyloidosis - male predominance (2:1)
AA amyloidosis - equal gender distribution
Geographic variation: AA amyloidosis more common in developing countries (chronic infections)
Incidence: Splenic involvement in 60-80% of systemic cases.
Clinical Features
Presentation:
Splenomegaly (80-90% of splenic involvement cases): Usually massive (>1000g)
Hypersplenism (40-50%): Thrombocytopenia, anemia, leukopenia
Left upper quadrant discomfort: Due to massive splenomegaly
Early satiety: Gastric compression
Constitutional symptoms: Related to systemic amyloidosis.
Symptoms:
Abdominal symptoms: Left upper quadrant fullness and pain
Abdominal distension
Hematologic symptoms: Easy bruising (thrombocytopenia)
Fatigue (anemia)
Systemic symptoms: Depend on other organ involvement (heart, kidney, GI tract)
Bleeding complications: Due to platelet dysfunction and sequestration.
Risk Factors:
Underlying plasma cell disorders: Multiple myeloma, MGUS, Waldenstrom macroglobulinemia
Chronic inflammatory diseases: Rheumatoid arthritis, inflammatory bowel disease, chronic infections
Familial syndromes: Hereditary amyloidosis syndromes
Age factor: Elderly patients more susceptible
Geographic factors: Endemic infections predisposing to AA type.
Screening:
Plasma protein studies: Serum protein electrophoresis, immunofixation
Laboratory studies: Free light chain assay, SAA levels
Imaging studies: Echocardiography, abdominal CT
Tissue biopsy: Congo red staining for diagnosis
Fat pad biopsy: Less invasive screening test.
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Gross Description
Appearance:
Massively enlarged spleen: Weight often >1000g (normal 150g)
Firm, waxy consistency: Characteristic "lardaceous" appearance
Smooth capsular surface
Homogeneous cut surface: Pink-gray with waxy appearance
Loss of normal architecture: Difficult to distinguish red and white pulp.
Characteristics:
Uniform enlargement: Proportional enlargement maintaining splenic shape
Increased weight: May reach 2000-3000g in severe cases
Smooth contour: No surface irregularities or nodules
Firm consistency: Due to protein deposits
No areas of necrosis or hemorrhage: Unless complicated.
Size Location:
Massive splenomegaly: Length may exceed 20-25 cm
Uniform involvement: Entire splenic parenchyma affected
Weight correlation: Correlates with extent of amyloid deposition
Splenic shape preserved: Enlargement maintains anatomic configuration
Extension: May extend into pelvis in severe cases.
Multifocality:
Diffuse involvement: Entire spleen uniformly affected
No focal lesions: Uniform protein deposition pattern
Associated organ involvement: Liver (80%), kidney (70%), heart (50%)
Systemic pattern: Part of multiorgan disease
Hilar involvement: May affect splenic vessels.
Microscopic Description
Histological Features:
Eosinophilic amorphous deposits: Homogeneous pink material in vessel walls and parenchyma
Vascular involvement: Deposits in arteriolar and capillary walls
Follicular involvement: White pulp follicles may show deposits
Red pulp involvement: Deposits in sinusoidal walls and cords
Progressive replacement: Normal architecture replaced by amyloid.
Cellular Characteristics:
Amyloid deposits: Extracellular, homogeneous, eosinophilic material
Surrounding cells: Atrophic due to pressure from deposits
Inflammatory cells: Usually minimal unless complicated
Giant cells: May be present around deposits (foreign body reaction)
Vascular changes: Vessel wall thickening and luminal narrowing.
Architectural Patterns:
Diffuse pattern: Widespread deposition throughout spleen
Perivascular pattern: Prominent deposits around blood vessels
Follicular pattern: White pulp follicles expanded by deposits
Sinusoidal pattern: Red pulp sinusoids thickened
Nodular pattern: Rare, focal accumulations.
Grading Criteria:
Mild amyloidosis: Minimal deposits, preserved architecture
Moderate amyloidosis: Moderate deposits with architectural distortion
Severe amyloidosis: Extensive deposits with marked architectural effacement
End-stage: Near-complete replacement of normal tissue.
Immunohistochemistry
Positive Markers:
Congo red stain: Pathognomonic apple-green birefringence under polarized light
Thioflavin T: Fluorescent staining of amyloid
Specific protein markers: Lambda/kappa light chains (AL type)
SAA protein (AA type)
Amyloid P component: Universal amyloid component.
Negative Markers:
Other protein markers: Negative for unrelated proteins
Infectious stains: Negative for organisms
Tumor markers: Negative (helps exclude neoplasia)
Inflammatory markers: Usually minimal unless secondary changes.
Diagnostic Utility:
Congo red staining: Gold standard for amyloid diagnosis
Protein typing: Essential for determining amyloid type and treatment
Quantification: Extent of deposition assessment
Monitoring: Response to treatment evaluation.
Molecular Subtypes:
AL amyloidosis: Light chain restriction (kappa or lambda)
AA amyloidosis: SAA protein positive
AH amyloidosis: Heavy chain positive
Hereditary types: Specific protein markers (transthyretin, fibrinogen, etc.).
Molecular/Genetic
Genetic Mutations:
Immunoglobulin genes: Light chain variable region mutations in AL type
SAA genes: Polymorphisms affecting AA amyloid formation
Hereditary mutations: Transthyretin, fibrinogen, lysozyme mutations
Plasma cell disorders: Associated with AL amyloidosis.
Molecular Markers:
Free light chains: Elevated kappa or lambda chains in blood
SAA levels: Elevated in AA amyloidosis
Proteinuria: If renal involvement present
Cardiac biomarkers: If cardiac involvement (troponin, BNP)
Liver enzymes: If hepatic involvement.
Prognostic Significance:
Amyloid type: AL type has worse prognosis than AA
Extent of involvement: Multiple organ involvement worsens prognosis
Cardiac involvement: Major prognostic factor
Response to treatment: Hematologic response improves outcomes
Splenic involvement: May cause hypersplenism complications.
Therapeutic Targets:
AL amyloidosis: Chemotherapy targeting plasma cells (melphalan, bortezomib)
AA amyloidosis: Treatment of underlying inflammatory disease
Supportive care: Management of organ dysfunction
Splenectomy: For severe hypersplenism
Stem cell transplant: Selected AL patients.
Differential Diagnosis
Similar Entities:
Other protein deposits: Light chain deposition disease (LCDD)
Fibrillary glomerulonephritis
Storage diseases: Gaucher disease, Niemann-Pick disease
Infections: Chronic granulomatous inflammation
Malignancies: Lymphomas, plasma cell disorders
Autoimmune diseases: Systemic lupus erythematosus.
Distinguishing Features:
Amyloid vs LCDD: Congo red positive vs negative
Fibrillar vs granular deposits
Amyloid vs storage disease: Different staining patterns and cell types
Congo red staining: Pathognomonic for amyloid
Clinical correlation: Systemic symptoms and laboratory findings.
Diagnostic Challenges:
Small deposits: May be missed in small biopsies
Processing artifacts: May affect Congo red staining
Mixed deposits: Different amyloid types in same patient
Atypical staining: Some variants may not show classic birefringence.
Rare Variants:
Localized splenic amyloidosis: Very rare, isolated to spleen
Mixed amyloid types: Both AL and AA in same patient
Amyloid with rupture: Massive splenomegaly with spontaneous rupture
Calcified amyloid: Chronic deposits with dystrophic calcification
Inflammatory amyloidosis: With prominent inflammatory reaction.
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 [systemic symptoms]
Gross Description
Massively enlarged spleen with [waxy consistency] and [homogeneous cut surface]
Microscopic Findings
Extensive eosinophilic amorphous deposits in [vessel walls] and [splenic parenchyma]
Congo Red Stain
Congo red stain positive with characteristic apple-green birefringence under polarized light
Protein Typing
Immunohistochemistry shows [lambda/kappa/SAA] positivity consistent with [AL/AA] amyloidosis
Diagnosis
Splenic amyloidosis, [AL/AA] type, extensive
Systemic Implications
Part of systemic [AL/AA] amyloidosis - recommend evaluation of [heart/kidney/liver]
Recommendations
Clinical correlation with [plasma cell studies/inflammatory markers] and multidisciplinary management