Kikuchi-Fujimoto Disease

We talk about a lot of common, not-to-miss diagnoses here at the Morsel Bakery, but we also talk about remaining vigilant for more subtle or uncommon diagnoses.  We have spoken about causes to consider when working up a Fever of Unknown Origin including Myocarditis, Osteomyelitis, Acute Rheumatic Fever, and Lemierres syndrome.  Today’s topic is a very uncommon diagnosis (estimated <5000 people in the U.S. with this disease, though likely under-diagnosed), but is worth talking about when considering alternatives to other life-altering diseases that cause lymph node enlargement – Leukemia, Kawasaki Disease, Missed Kawasaki Disease, Neonatal Leukemia, or even Cat Scratch Disease.  One of our pediatrics residents, Dr. Andrew Robinson, admitted a child for prolonged fever of unknown origin with lymphadenopathy, and this diagnosis was on the short list after lymph node biopsy!  So, let’s find out more about Kikuchi-Fujimoto Disease.

Kikuchi-Fujimoto Disease: Basics 

  • Non-malignant condition of lymph nodes 
  • Also known as Histiocytic Necrotizing Lymphadenitis [Perry 2018, Selvanathan 2020, Fusconi 2023, Boone 2023] 
  • First described in 1972 by Kikuchi and Fujimoto independently [Perry 2018, Boone 2023] 
  • Seen worldwide, but higher prevalence in Japanese and other Asian populations [Perry 2018, Fusconi 2023] 
  • Found in both sexes, reports vary as to female vs male predominance [Fusconi 2023] 
  • Usually in children and young adults, but can be any age [Fusconi 2023] 
  • Unclear etiology but infectious and autoimmune causes are sometimes suggested [Perry 2018, Fusconi 2023, Boone 2023] 
    • Suspected that an infectious agent (viral, bacterial, otherwise) triggers an inflammatory response 
  • There may be a genetic predisposition to it as there are some HLA class 2 genes that are more frequent in patients who have the disease [Boone 2023] 

Kikuchi-Fujimoto Disease: Presentation and Exam

  • Can present with regional lymph node swelling (cervical, axillary, supraclavicular) [Perry 2018, Selvanathan 2020, Fusconi 2023, Boone 2023] 
    • Lymph nodes tend to be 2-3 cm in size but can be up to 6 cm 
    • Lymph nodes are firm and mobile but not fluctuant or draining  
  • Frequent symptoms are fever, night sweats, myalgia, leukopenia, anemia [Selvanathan 2020, Fusconi 2023, Boone 2023] 
  • Less commonly weight loss, nausea, vomiting, pharyngitis, rash, abdominal pain [Selvanathan 2020, Fusconi 2023, Boone 2023] 
  • Rarely hepatomegaly, splenomegaly [Fusconi 2023] 
  • Rare extra nodal sites of involvement- bone marrow, myocardium, uvea, thyroid and parotid glands [Boone 2023] 
  • Neurologic involvement is rare [Boone 2023] 
    • Aseptic meningitis 
    • Cerebellar ataxia 
    • Encephalitis 
  • Lab findings: leukopenia, elevated ESR, elevated liver enzymes [Boone 2023] 

Kikuchi-Fujimoto Disease: Differential 

  • Other things to consider on the differential [Perry 2018, Boone 2023] 

Kikuchi-Fujimoto Disease: Diagnosis  

  • By lymph node biopsy– histological analysis and immunohistochemistry [Perry 2018, Fusconi 2023, Boone 2023] 
    • Paracortical necrosis 
    • Histiocytes 
    • Lymphocytes 
    • Plasmacytoid monocytes 
    • Macrophages 
    • T cell immunoblasts 
    • Karyorrhexis 
    • Absent or rare- neutrophils, granulomas, plasma cells 
  • 3 phases of disease [Perry 2018, Boone 2023] 
    • Proliferative phase– typical findings as noted above 
    • Necrotizing phase– necrosis destroys architecture of lymph node 
    • Xanthomatous phase (“foamy cell”)- recovery, resolving necrosis 
  • CBC may show [Boone 2023] 
    • Mild granulocytopenia (20-50%) 
    • Leukocytosis (2-5%) 
    • Atypical lymphocytes (25%) 
  • May have Elevated ESR and CRP or elevated LDH [Boone 2023] 
  • Rheumatoid factor (RF), Antinuclear antibody (ANA) and other autoimmune antibody studies usually are negative 
  • Must rule out other critical diagnoses- lymphoma, metastasis or tuberculous adenitis  
  • Histology may reveal [Fusconi 2023] 
    • Follicular hyperplasia with paracortical infiltration of histiocytes and lymphocytes 
    • Absence of neutrophils and eosinophils (in the proliferative stage) 
    • Necrotic foci with a high degree of karyorrhexis (in the necrotizing stage) 
  • Imaging [Boone 2023] 
    • Some studies suggest that CT imaging can help differentiate Kikuchi disease from tuberculous lymphadenopathy with a different distribution of lymph node involvement 
    • Ultrasound can be used but is also not diagnostic 
    • Chest X Ray is not helpful for Kikuchi disease specifically, but should be obtained to evaluate for tuberculosis or malignancy

Kikuchi-Fujimoto Disease: Treatment  

  • Symptomatic treatment! Antipyretics, analgesics, NSAIDs [Fusconi 2023, Boone 2023] 
  • Corticosteroids used rarely but for severe cases [Fusconi 2023] 
  • For steroid-resistant cases or recurrence [Boone 2023] 
    • Hydroxychloroquine 
    • Intravenous immunoglobulin (IVIG) 
  • Monitor for several years to look for possible development of SLE 
  • Spontaneously resolves in 1-6 months [Perry 2018, Fusconi 2023, Boone 2023] 

Kikuchi-Fujimoto Disease:  Complications 

  • Sometimes associated with systemic lupus erythematosus [Fusconi 2023, Boone 2023] 
  • May have co-occurrence with other autoimmune diseases- relapsing polychondritis, Sjögren-Larsson syndrome, systemic sclerosis or antiphospholipid syndrome [Fusconi 2023] 
    • May suggest that the immune systems of patients are altered 
  • Development of hemophagocytic lymphohistiocytosis HLH reported [Selvanathan 2020] 
  • May have recurrence 3-4% or up to 12.2% of the time [Selvanathan 2020, Fusconi 2023] 
  • Fatal cases have been reported, but are very rare [Fusconi 2023] 
  • If misdiagnosed with lymphoma first, may receive unnecessary treatment with chemotherapy [Dorfman 1988] 
  • Many receive antibiotics at first presentation, which may come with their own complications [Selvanathan 2020] 

Moral of the Morsel 

  • Stay Vigilant! There are other things besides malignancy that can cause fever, lymphadenopathy, and weight loss. 
  • Be Supportive! Supportive care for Kikuchi Disease is the main treatment, but even before you know this diagnosis, do what you can to make your patient comfortable. 
  • Misery Loves Company! Be cognizant that SLE is closely associated with Kikuchi Disease and may present concurrently or years later. 

Where to Find Out More: 

GARD- The Genetic and Rare Diseases Information Center

NORD- National Organization for Rare Diseases

References: 

  1. Anamarija M. Perry, Sarah M. Choi; Kikuchi-Fujimoto Disease: A Review. Arch Pathol Lab Med 1 November 2018; 142 (11): 1341–1346. doi: https://doi.org/10.5858/arpa.2018-0219-RA  
  1. Selvanathan SN, Suhumaran S, Sahu VK, Chong CY, Tan NWH, Thoon KC. Kikuchi-Fujimoto disease in children. J Paediatr Child Health. 2020 Mar;56(3):389-393. doi: 10.1111/jpc.14628. Epub 2019 Oct 1. PMID: 31576642. 
  1. Fusconi, M. and Zaccharelli, F. (2023) Knowledge on rare diseases and orphan drugs, Orphanet: Kikuchi-Fujimoto disease. Available at: https://www.orpha.net/en/disease/detail/50918 (Accessed: 02 September 2024).  
  1. John Boone, M. and Charles, K.S. (2023) Kikuchi disease. Available at: https://emedicine.medscape.com/article/210752-overview?form=fpf (Accessed: 03 September 2024).  
  1. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin Diagn Pathol. 1988 Nov;5(4):329-45. PMID: 3217625.  
  1. Kikuchi-Fujimoto Disease Genetic and Rare Diseases Information Center. Available at: https://rarediseases.info.nih.gov/diseases/6834/kikuchi-fujimoto-disease (Accessed: 02 September 2024). 

Author

Christyn Magill
Christyn Magill
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