Definition/General
Introduction:
Kikuchi disease, also known as histiocytic necrotizing lymphadenitis, is a benign, self-limiting inflammatory condition of lymph nodes
First described by Kikuchi and Fujimoto in Japan in 1972
It is characterized by necrotizing inflammation with prominent histiocytes and absence of neutrophils
The condition shows female predominance and predilection for young adults.
Origin:
Etiology remains unknown but likely represents an aberrant immune response to viral infection or other trigger
Autoimmune mechanism suggested by association with SLE and other autoimmune diseases
Viral etiology proposed (EBV, HHV-6, parvovirus B19) but not consistently proven
Genetic predisposition may play a role given higher prevalence in Asian populations
Environmental factors may trigger the inflammatory cascade.
Classification:
Histologically classified into three phases: Proliferative phase (early stage with histiocytic proliferation)
Necrotizing phase (extensive necrosis with karyorrhexis)
Xanthomatous phase (resolution with foamy macrophages)
Clinical classification: Typical form (isolated lymphadenopathy)
Systemic form (with extranodal manifestations)
Cutaneous form (skin lesions present).
Epidemiology:
Peak incidence in 2nd and 3rd decades of life (20-30 years)
Female predominance with F:M ratio of 3-4:1
Higher prevalence in Asian populations (Japan, Korea, China)
Rare in Western countries but increasingly recognized
Seasonal clustering reported in some studies
Association with SLE in 20-30% of cases in some series.
Clinical Features
Presentation:
Unilateral cervical lymphadenopathy (most common - 70-80%)
Painful lymph nodes (distinguishes from malignancy)
Fever (60-80% of cases) often low-grade
Node size typically 1-6 cm
Posterior cervical triangle most commonly involved
Bilateral involvement in 10-20% of cases
Generalized lymphadenopathy rare.
Symptoms:
Constitutional symptoms: fever, malaise, weight loss
Upper respiratory symptoms may precede lymphadenopathy
Myalgia and arthralgia (30-40% of cases)
Skin rash (10-15% of cases)
Hepatosplenomegaly rare but reported
Neurological symptoms (aseptic meningitis) very rare
Night sweats less common than in malignancy.
Risk Factors:
Female gender (3-4 times higher risk)
Young age (peak in 20s-30s)
Asian ethnicity (genetic predisposition)
Recent viral infection (possible trigger)
Autoimmune disease predisposition (SLE association)
Seasonal factors (some studies suggest clustering)
Family history rarely reported.
Screening:
Clinical examination focusing on lymph node characteristics
Laboratory studies: CBC (may show leukopenia), ESR, CRP
Viral studies: EBV, CMV, parvovirus B19 serology
Autoimmune markers: ANA, anti-dsDNA (SLE screening)
Imaging studies: ultrasound, CT for extent assessment
Fine needle aspiration often non-diagnostic, excisional biopsy preferred.
Master Kikuchi Disease Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Enlarged lymph nodes with smooth, intact capsule
Cut surface shows patchy areas of gray-white necrosis
Firm consistency with areas of softening due to necrosis
No suppuration or abscess formation
Capsular thickening may be present
Hemorrhagic areas occasionally visible
Size ranges from 1-6 cm typically.
Characteristics:
Multinodular appearance with alternating firm and soft areas
Geographic necrosis pattern visible on cut surface
No calcification or caseous material
Preserved capsule without perforation
Vascular congestion may be prominent
No lymphangitic extension
Adjacent soft tissue usually uninvolved.
Size Location:
Cervical lymph nodes most commonly affected (80-90%)
Posterior cervical triangle preferentially involved
Supraclavicular and submandibular nodes less commonly
Axillary involvement reported in 10-15% of cases
Mediastinal lymphadenopathy rare
Generalized involvement exceptional
Size correlation with phase of disease.
Multifocality:
Unilateral involvement typical (80-90% of cases)
Multiple lymph nodes within same cervical chain commonly affected
Bilateral cervical involvement in minority of cases
Regional spread pattern following lymphatic drainage
No distant metastatic pattern
Contiguous lymph node involvement common.
Microscopic Description
Histological Features:
Paracortical expansion with histiocytic infiltration and focal necrosis
Coagulative necrosis with extensive karyorrhexis
Prominent histiocytes with crescentic, twisted nuclei
Absence of neutrophils (diagnostic hallmark)
Plasmacytoid dendritic cells (CD123 positive)
Apoptotic debris abundant in necrotic areas
Preserved follicular architecture with reactive germinal centers.
Cellular Characteristics:
Histiocytes with irregular, crescentic nuclei and abundant cytoplasm
Karyorrhectic debris from apoptotic lymphocytes
Plasmacytoid dendritic cells with oval nuclei and moderate cytoplasm
CD8+ T-lymphocytes predominant in infiltrate
Immunoblasts scattered throughout
Absence of eosinophils and plasma cells
Mitotic activity variable but not atypical.
Architectural Patterns:
Paracortical necrotizing pattern (most common)
Geographic necrosis with sharp demarcation
Preserved cortical follicles with reactive changes
Interfollicular expansion with histiocytic infiltrate
Subcapsular involvement common
Capsular fibrosis and thickening
Vascular prominence with endothelial swelling.
Grading Criteria:
Phase-based classification: proliferative, necrotizing, xanthomatous
Proliferative phase: histiocytic proliferation without significant necrosis
Necrotizing phase: extensive necrosis with karyorrhexis
Xanthomatous phase: foamy macrophages and resolution changes
Mixed phases commonly seen in single specimens
No malignant potential grading as condition is benign.
Immunohistochemistry
Positive Markers:
CD68 positive in histiocytes (KP1 clone often weak)
CD163 strongly positive in macrophages
Lysozyme positive in histiocytes
CD123 highlights plasmacytoid dendritic cells
CD8 shows predominant T-cell population
Myeloperoxidase positive in rare myeloid cells
S-100 positive in dendritic cells.
Negative Markers:
Neutrophil markers (CD15, CD66b) characteristically absent
CD20 shows B-cells limited to follicles
CD30 negative (excludes lymphoma)
CD1a negative (excludes Langerhans cell histiocytosis)
EBV/EBER typically negative
CMV negative
Bacterial markers negative.
Diagnostic Utility:
CD68 and CD163 confirm histiocytic nature of infiltrate
CD123 highlights characteristic plasmacytoid dendritic cells
Absence of CD15+ neutrophils supports diagnosis
CD8 predominance among T-cells typical
Negative infectious organism stains exclude specific infections
Ki-67 shows variable proliferation activity
p53 may be positive in reactive cells.
Molecular Subtypes:
No molecular subtypes recognized for Kikuchi disease
Polyclonal T-cell population demonstrated by flow cytometry
No clonal T-cell receptor rearrangements
Cytokine expression studies show inflammatory profile
Viral studies usually negative or inconclusive
Gene expression profiling shows reactive inflammatory pattern.
Molecular/Genetic
Genetic Mutations:
No specific genetic mutations associated with Kikuchi disease
HLA associations reported in some populations (HLA-DPA1, HLA-DPB1)
Viral integration studies generally negative
p53 overexpression may occur as reactive phenomenon
Apoptosis-related gene expression altered during active phase
Cytokine gene polymorphisms may influence susceptibility.
Molecular Markers:
Elevated pro-inflammatory cytokines (IL-6, TNF-α, IL-1β)
Type I interferon signature in some cases
Increased apoptosis markers (caspase-3, TUNEL positive cells)
Heat shock protein expression in histiocytes
Viral nucleic acids inconsistently detected
Autoantibody production in SLE-associated cases.
Prognostic Significance:
Excellent prognosis with spontaneous resolution in most cases
Resolution time typically 2-4 months
Recurrence rate low (5-10% of cases)
SLE development risk (20-30% in some series)
Long-term monitoring recommended for SLE screening
No malignant transformation reported
Chronic/relapsing forms very rare.
Therapeutic Targets:
Supportive care primary approach (observation, symptom management)
NSAIDs for pain and inflammation
Corticosteroids for severe symptoms (controversial)
Immunosuppressive agents for refractory cases
Anti-TNF agents reported in resistant cases
SLE monitoring and treatment when associated
Surgical excision for diagnostic purposes primarily.
Differential Diagnosis
Similar Entities:
Lymphoma (Hodgkin and non-Hodgkin)
SLE lymphadenopathy (hematoxylin bodies)
Viral lymphadenitis (EBV, CMV)
Tuberculosis (caseous necrosis)
Cat scratch disease (stellate abscesses)
Necrotizing granulomatous inflammation
Metastatic carcinoma with necrosis
Drug-induced lymphadenopathy.
Distinguishing Features:
Kikuchi disease: absence of neutrophils, crescentic histiocytes, CD123+ plasmacytoid cells
SLE: hematoxylin bodies, ANA positive
Tuberculosis: caseous necrosis, epithelioid granulomas, AFB positive
Cat scratch: stellate abscesses, neutrophils present, Warthin-Starry positive
Lymphoma: monomorphic population, clonal markers
Viral: immunoblasts, viral inclusions.
Diagnostic Challenges:
Early phase may lack characteristic necrosis
Systemic lupus erythematosus overlap (shared features)
Atypical presentations with minimal necrosis
Extranodal involvement (skin, bone marrow)
Recurrent disease may suggest alternative diagnosis
Age extremes (pediatric or elderly patients)
Unusual anatomic sites (mediastinal, retroperitoneal).
Rare Variants:
Cutaneous Kikuchi disease (skin lesions without lymphadenopathy)
Systemic Kikuchi disease (multiorgan involvement)
Chronic/relapsing form (prolonged or recurrent course)
SLE-associated variant (concurrent autoimmune features)
Extranodal variant (bone marrow, spleen involvement)
Pediatric variant (different clinical behavior).
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
Lymph node biopsy from [cervical/axillary/other] region, measuring [X.X] cm in greatest dimension
Diagnosis
Kikuchi disease (histiocytic necrotizing lymphadenitis), [proliferative/necrotizing/xanthomatous] phase
Phase Classification
Phase: [proliferative/necrotizing/xanthomatous/mixed], extent: [focal/extensive]
Histological Features
Shows [paracortical expansion] with [histiocytic infiltration] and [geographic necrosis/karyorrhexis] without neutrophils
Size and Extent
Size: [X.X] cm, necrosis: [focal/extensive], architecture: [preserved follicles/paracortical expansion]
Cellular Composition
Cellular infiltrate includes [crescentic histiocytes/plasmacytoid dendritic cells/CD8+ T-cells] with [karyorrhectic debris/absence of neutrophils]
Special Studies
IHC: CD68 [histiocytes], CD123 [plasmacytoid cells], CD8 [T-cells], CD15 [negative for neutrophils]
Special stains: GMS [negative], AFB [negative], Gram [negative]
Molecular: [if performed] T-cell gene rearrangement [polyclonal]
Final Diagnosis
Kikuchi disease (histiocytic necrotizing lymphadenitis), [specific phase], consistent with benign self-limiting condition