Kikuchi-Fujimoto Disease

Carlos E. Bueso-Ramos, MD, PhD

Key Facts

Clinical Issues

Self-limited clinical course in most patients
Might represent phenotype of diverse disease entities
Prognosis is different according to underlying cause
Young patients
Acute tender cervical lymphadenopathy
Low-grade fever; systemic symptoms
Systemic survey and follow-up is recommended to rule out systemic lupus erythematosus

Microscopic Pathology

Multiple, pale circumscribed foci are found in paracortical area of lymph node
Lack of extension of process into perinodal tissue
3 phases: Proliferative, necrotizing, xanthomatous
Lesions are composed of mononuclear cells with round to irregular nuclei
Abundant karyorrhectic debris
Plasmacytoid dendritic cells are present
Paracortical areas of coagulative necrosis are seen
Large numbers of histiocytes, including crescentic histiocytes and activated lymphoid cells
Absence of neutrophils

Ancillary Tests

Predominance of CD3(+), CD8(+) T cells
Histiocytes express myeloperoxidase, lysozyme and CD68
↑ plasmacytoid dendritic cells expressing CD68, CD123, CD303
No evidence of monoclonal Ig or TCR rearrangements

Cervical lymph node involved by Kikuchi-Fujimoto disease. The paracortex shows a circumscribed, wedgeshaped area of necrosis that extends to the capsule.

MIP FDG-PET scan of Kikuchi-Fujimoto disease. This image reveals an area of FDG uptake in the right cervical region that was interpreted as suspicious for lymphoma

TERMINOLOGY

Abbreviations

Kikuchi-Fujimoto disease (KFD)

Synonyms

Necrotizing lymphadenitis without granulocytic infiltration
Histiocytic necrotizing lymphadenitis
Kikuchi-Fujimoto lymphadenopathy

Definitions

Self-limited, benign form of lymphadenopathy characterized by
- Proliferation of histiocytes and plasmacytoid monocytes
- Apoptosis with abundant karyorrhectic debris
- Systemic symptoms and low-grade fever in subset of patients

ETIOLOGY/PATHOGENESIS

Unknown

Viral, infectious, or autoimmune cause has been suggested
Exuberant T-cell-mediated response to variety of stimuli in genetically susceptible people
Cytokine-mediated mechanisms
- ↑ interleukin-6, interferon-α, FAS ligand
Viruses suggested to be involved in KFD include
- Epstein-Barr virus (EBV) and human herpes virus 6 (HHV6)
- Identified in small subset of cases; unlikely to be cause

CLINICAL ISSUES

Epidemiology

Age
- Usually < 30 years (range: 2-75 years)
Gender
- Women are affected more often
  - Female to male ratio is 4:1
Ethnicity
- KFD has been described in a variety of ethnic backgrounds
  - Asian descent most common

Site

Lymphadenopathy
- Cervical lymph nodes most often involved

Presentation

Fever typically lasts for 1 week
- Can persist for up to 1 month
Upper respiratory symptoms
Most common initial manifestations are
- Tender and painful lymphadenopathy
- Lymphadenopathy with fever
Uncommon manifestations
- Weight loss, night sweats, nausea, vomiting
- Generalized lymphadenopathy
- Joint pain
- Extranodal involvement by KFD
- Splenomegaly, hepatomegaly

Laboratory Tests

Rule out other causes of necrotizing lymphadenopathy
No specific tests are available for detecting KFD
Anemia
Elevated lactate dehydrogenase levels
Granulocytopenia and atypical lymphocytosis in peripheral blood (50%)
Elevated erythrocyte sedimentation rates
Polyclonal hypergammaglobulinemia
Negative serologic studies for
- EBV, Cytomegalovirus, influenza, adenovirus
- Toxoplasmosis, Mycoplasma, Q fever
Usually negative autoimmune laboratory studies
- Antinuclear antibodies, rheumatoid factor, antidouble-strand DNA antibodies
- Rare patients with KFD are subsequently diagnosed to have systemic lupus erythematosus

Natural History

Diagnosis is usually established by lymph node biopsy
- Excisional biopsy is often required because KFD can be patchy
  - Assessment of lymph node architecture is very helpful in establishing diagnosis
Spontaneous resolution occurs, usually within 1-4 months
Small (˜ 3%) subset of patients develop relapse

Treatment

No specific therapy required
Anti-inflammatory agents

Prognosis

Excellent

IMAGE FINDINGS

CT Findings

Computed tomography (CT) is preferred modality
Cervical lymph nodes in KFD tend to be located in posterior triangle
Lymph nodes appear as clusters
- < 4 cm in greatest dimension
- Nonenhancing necrosis
Any lymph node group can be involved in KFD

MACROSCOPIC FEATURES

General Features

Size: 0.5-4.0 cm

MICROSCOPIC PATHOLOGY

Histologic Features

Lymph node
- Architecture: Partial or extensive involvement
  - Often patchy in early stages
- KFD begins in paracortex and near capsule
  - Degree of apoptosis/necrosis varies from one case to another
  - No granulocytes identified in necrotic areas
  - Plasma cells usually absent or rare
  - Process does not extend into perinodal tissues
  - Immunoblasts are numerous in viable paracortex contiguous with necrosis
  - No hematoxylin bodies identified
- Sinuses are patent or compressed
  - Can be filled by histiocytes or monocytoid B cells
- Hyperplastic lymphoid follicles in uninvolved areas
- ± thrombosed blood vessels
- 3 histologic subtypes of KFD have been described
  - Lymphohistiocytic/proliferative; thought to be early stage
  - Necrotic
  - Phagocytic/foamy cell; thought to be late stage
- > 1 stage of KFD can be present within lymph node
- Lymphohistiocytic/proliferative type
  - Proliferation of histiocytes (including C-shaped forms)
  - Increased plasmacytoid dendritic cells
  - Small lymphocytes and immunoblasts are present
  - Relatively little apoptosis or necrotic debris
- Necrotic type
  - Abundant apoptosis within distinct foci of necrosis associated with eosinophilic debris
  - Histiocytes and plasmacytoid dendritic cells undergo apoptosis
  - Fibrin thrombi may be present in blood vessels
- Phagocytic/foamy cell type
  - Numerous histiocytes containing phagocytosed debris (foamy cytoplasm)
  - Histiocytes often form rim surrounding necrotic areas

Cytologic Features

Diagnosis can be suggested in touch imprints of lymph node
- Highlights cytologic characteristics of plasmacytoid dendritic cells (pDC)
- Touch imprint often better than fine needle aspiration (FNA) smears
Frequency of CD123(+) pDC is high in KFD
- Valuable indicator for diagnosis of KFD
- Useful for distinguishing KFD from reactive lymphadenopathy and neoplasms

Skin

Most frequently located on face or upper body
KFD in skin can grossly present as
- Erythematous papules
- Indurated lesions or plaques
- Ulcers
Histologic findings in skin include
- Dermal lymphohistiocytic infiltrate; most common
- Epidermal changes
  - Necrotic keratinocytes
  - Nonneutrophilic karyorrhectic debris
  - Basal vacuolar change
- Edema of papillary dermis

ANCILLARY TESTS

Immunohistochemistry

Histiocytes are CD4(+), CD68(+), lysozyme(+), myeloperoxidase(+, dim)
Plasmacytoid dendritic cells are
- CD68(+), CD123(+), CD303(+)
- Myeloperoxidase(-), fascin(-)
T cells are predominantly CD8(+)
Immunoblasts are CD30(+) and of CD8(+) T-cell lineage
B cells are rare or absent in areas of necrosis

Flow Cytometry

Predominance of CD8(+) T cells without aberrancies
Rare polytypic B cells
Insufficient to establish diagnosis of KFD
- Helpful to exclude non-Hodgkin lymphoma

PCR