Definition/General
Introduction:
Villitis of unknown etiology (VUE) is a chronic inflammatory condition of the placenta
It involves infiltration of maternal T-lymphocytes into chorionic villi
It represents maternal anti-fetal cellular immune response
It is the most common inflammatory lesion of the placenta.
Origin:
Pathogenesis involves maternal immune response against fetal antigens
Maternal T-cells cross the intervillous space
Infiltrate villous stroma and cause villous destruction
May represent allograft rejection-like process
Specific triggering antigens remain unknown.
Classification:
Classified as chronic villitis when duration >1 week
Low-grade VUE: Focal involvement, minimal destruction
High-grade VUE: Extensive involvement, significant destruction
May be focal, multifocal, or diffuse.
Epidemiology:
Incidence approximately 5-15% of term pregnancies
More common in third trimester
Higher incidence with advanced maternal age
Associated with recurrent pregnancy loss
More frequent in pregnancies with fetal growth restriction.
Clinical Features
Presentation:
Fetal growth restriction (most common association)
Stillbirth (in severe cases)
Preterm delivery
Oligohydramnios
Non-reassuring fetal heart rate patterns
Often asymptomatic (incidental finding)
Recurrent pregnancy complications.
Symptoms:
Usually no specific maternal symptoms
May present with decreased fetal movements
Signs of fetal compromise during monitoring
Measuring small for dates
Abnormal fetal Doppler studies
Signs of chronic fetal hypoxia.
Risk Factors:
Advanced maternal age (>35 years)
Previous pregnancy with VUE (recurrence rate 10-15%)
Autoimmune disorders
History of recurrent pregnancy loss
Maternal diabetes mellitus
Chronic hypertension.
Screening:
Fetal growth monitoring by ultrasound
Doppler studies of uterine and umbilical arteries
Amniotic fluid assessment
Non-stress testing
Maternal antibody screening
Placental examination essential for diagnosis.
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Gross Description
Appearance:
Placenta may appear grossly normal or show subtle changes
Pale, firm areas may be present
Decreased placental weight in severe cases
Maternal surface may show shallow implantation
Cut surface may reveal granular texture.
Characteristics:
Placental weight often below 10th percentile for gestational age
Firm consistency in affected areas
May show irregular maternal surface
Chorionic plate usually normal
Cotyledons may appear pale and firm.
Size Location:
May affect any area of placenta
Often multifocal distribution
Can involve peripheral or central regions
Skip lesions common
Extent varies from focal to diffuse involvement.
Multifocality:
Characteristically shows patchy distribution
Multiple foci of involvement
Random pattern throughout placenta
Normal areas interspersed with affected regions
Confluent areas in severe cases.
Microscopic Description
Histological Features:
Lymphocytic infiltration of villous stroma
Villous architecture disruption
Syncytiotrophoblast loss in affected areas
Villous fibrosis and sclerosis
Chronic inflammatory cells predominantly T-lymphocytes
Progressive villous destruction.
Cellular Characteristics:
Infiltrating cells are predominantly CD8+ cytotoxic T-lymphocytes
CD4+ helper T-cells also present
Plasma cells may be seen
Macrophages present in chronic stages
Neutrophils typically absent
Lymphoid aggregates may form.
Architectural Patterns:
Focal to diffuse villous involvement
Villous agglutination may occur
Loss of normal villous branching pattern
Avascular villi in severely affected areas
Intervillous fibrin deposition
Chronic deciduitis may be present.
Grading Criteria:
Low-grade: <5 villi per focus, minimal destruction
High-grade: ≥5 villi per focus, significant destruction
Based on number of affected villi and degree of architectural disruption
Extent scoring: focal, multifocal, or diffuse.
Immunohistochemistry
Positive Markers:
CD3 (highlights T-lymphocytes)
CD8 (cytotoxic T-cells, predominant population)
CD4 (helper T-cells)
CD68 (macrophages in chronic cases)
Granzyme B (cytotoxic function)
Perforin (cytotoxic granules).
Negative Markers:
CD20 (B-cells typically absent)
CD15 (neutrophils absent)
Tryptase (mast cells minimal)
Infectious agents (CMV, HSV, etc.) negative
Bacterial cultures negative.
Diagnostic Utility:
CD8 immunostaining confirms T-cell predominance
Helps distinguish from infectious villitis
Quantifies inflammatory infiltrate
Rules out specific infectious causes
Essential for accurate diagnosis.
Molecular Subtypes:
Not applicable for routine classification
HLA typing may show maternal-fetal incompatibility
T-cell receptor analysis shows polyclonal population
Cytokine studies show Th1 response pattern.
Molecular/Genetic
Genetic Mutations:
No specific genetic mutations identified
HLA incompatibility may predispose
Maternal immune response genes may influence susceptibility
Complement system variants
Cytokine gene polymorphisms.
Molecular Markers:
T-cell activation markers (CD25, CD69)
Cytotoxic markers (Granzyme B, Perforin)
Inflammatory cytokines (TNF-α, IFN-γ)
HLA class I and II expression
Complement activation products.
Prognostic Significance:
High-grade VUE associated with worse fetal outcomes
Recurrence risk 10-15% in subsequent pregnancies
Associated with increased risk of stillbirth
Long-term neurodevelopmental outcomes may be affected
Growth restriction correlation.
Therapeutic Targets:
No specific treatment currently available
Enhanced fetal surveillance recommended
Early delivery may be considered in severe cases
Immunosuppressive therapy experimental
Antioxidant supplementation studied.
Differential Diagnosis
Similar Entities:
Infectious villitis (CMV, HSV, Listeria, Toxoplasma)
Acute villitis (neutrophilic infiltrate)
Chronic deciduitis (confined to decidua)
Villous infarction (no inflammation)
Maternal floor infarction.
Distinguishing Features:
VUE: Lymphocytic infiltrate, no organisms
VUE: CD8+ T-cell predominance
Infectious: Organisms identified
Infectious: Mixed inflammatory infiltrate
Acute villitis: Neutrophils predominant
Chronic deciduitis: Limited to decidua.
Diagnostic Challenges:
Ruling out infectious causes (special stains, cultures, PCR)
Distinguishing from acute inflammatory conditions
Sampling adequacy for accurate grading
Clinical correlation essential
Immunohistochemistry helpful.
Rare Variants:
VUE with plasma cells (suggestive of chronic infection)
Granulomatous villitis
Massive chronic villitis
Combined with chronic chorioamnionitis
Recurrent VUE in subsequent pregnancies.
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
Placenta weighing [weight]g ([percentile] for gestational age) with [focal/multifocal/diffuse] involvement
Diagnosis
Villitis of Unknown Etiology (Chronic Villitis)
Classification
Classification: [Low-grade/High-grade] VUE with [focal/multifocal/diffuse] distribution
Histological Features
Shows chronic lymphocytic infiltration of villous stroma with villous architectural disruption
Immunohistochemistry
CD3: Positive (T-lymphocytes), CD8: Predominant population, CD20: Negative (no B-cells)
Severity Grading
Grade: [Low/High] based on number of affected villi and degree of destruction
Infectious Studies
Special stains for organisms: Negative. No evidence of infectious etiology.
Clinical Significance
Associated with [fetal outcomes]. Recurrence risk 10-15% in future pregnancies.
Final Diagnosis
Villitis of Unknown Etiology, [Grade], with [extent] involving [percentage]% of examined tissue