AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Kikuchi disease, also called histiocytic necrotizing lymphadenitis or Kikuchi-Fujimoto disease, is an uncommon, idiopathic, generally self-limited cause of lymphadenitis.^{1, 2} Kikuchi first described the disease in 1972 in Japan. Fujimoto and colleagues independently described Kikuchi disease in the same year.

The most common clinical manifestation of Kikuchi disease is cervical lymphadenopathy, with or without systemic signs and symptoms.^{3, 4, 5, 6} Clinically and histologically, the disease can be mistaken for lymphoma or systemic lupus erythematosus (SLE).^{1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15} Kikuchi disease almost always runs a benign course and resolves in several weeks to months. Disease recurrence is unusual, and fatalities are rare, although they have been reported.¹

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Swollen Lymph Glands and Lymphoma.

Related eMedicine topics:
Cutaneous Kikuchi Disease
Fever of Unknown Origin
Histiocytosis
Lymph Node Disorders
Lymphadenopathy

Related Medscape topics:
Resource Center Chronic Leukemia
Resource Center Hodgkin's Lymphoma
Resource Center Non-Hodgkin's Lymphoma
Morphologic and Immunophenotypic Variants of Nodal T-Cell Lymphomas and T-Cell Lymphoma Mimics

Pathophysiology

The cause of Kikuchi disease is unknown, although infectious and autoimmune etiologies have been proposed. The most favored theory proposes that Kikuchi disease results when one or more unidentified agents trigger a self-limited autoimmune process. Lymphadenitis results from apoptotic cell death induced by cytotoxic T lymphocytes. Some human leukocyte antigen (HLA) class II genes are more frequent in patients with Kikuchi disease, suggesting a genetic predisposition to the proposed autoimmune response.

Features that support a role for an infectious agent include the generally self-limited course of the disease and its frequent association with symptoms similar to those of upper respiratory tract infections (URTIs). Several viral candidates have been proposed, including cytomegalovirus, Epstein-Barr virus,¹⁶ human herpesvirus, varicella-zoster virus, parainfluenza virus, parvovirus B19, and paramyxovirus. However, serologic and molecular studies have failed to link Kikuchi disease to a specific pathogen, and more than one pathogen may be capable of triggering the characteristic hyperimmune reaction leading to Kikuchi disease.

Several authors have reported an association between Kikuchi disease and SLE. Kikuchi disease has been diagnosed before, during, and after a diagnosis of SLE was made in the same patient. Additionally, the histologic appearance of lymph nodes in patients with Kikuchi disease is similar to that of lymph nodes in patients with SLE lymphadenitis. Some authors have suggested that Kikuchi disease may represent a forme fruste SLE, but this theory has not been substantiated, and the association of Kikuchi disease with SLE, if any, remains unclear.

Frequency

United States

Kikuchi disease is uncommon. Only isolated cases are reported in North America.

International

Although rare, Kikuchi disease has been reported throughout the world and in all races. Only isolated cases are reported in Europe.

Mortality/Morbidity

The course of Kikuchi disease is generally benign and self-limited. Lymphadenopathy most often resolves over several weeks to 6 months, although the disease occasionally persists longer. The disease recurs in about 3% of cases. Three deaths have been reported that occurred during the acute phase of generalized Kikuchi disease. One patient died from cardiac failure; the second, from the effects of hepatic and pulmonary involvement; and the last, from an acute lupuslike syndrome. Another fatality has been reported in which Kikuchi disease appeared concurrently with SLE and was complicated with hemophagocytic syndrome and severe infection.¹

Race

Kikuchi disease was first diagnosed and described in Japan. To date, most cases have been reported from East Asia. More recently, the disease has been reported throughout the world and in all races. Outside of Asia, it is possible that Kikuchi disease has been underdiagnosed and therefore underreported. Dorfman and Berry reported 108 cases, including 68 in the United States; 63% of the 108 patients were white.

Sex

The initial studies of Kikuchi disease reported women were affected more often than men by a ratio of approximately 3:1. However, more recent studies have shown a smaller female preponderance, with a ratio closer to 1.25:1.

Age

Kikuchi disease occurs in a wide age range of patients (ie, 2-75 y), but it typically affects young adults (mean age, 20-30 y).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Kikuchi disease most frequently manifests as a relatively acute onset of cervical adenopathy associated with fever and a flulike prodrome.

• Lymphadenopathy
• • Cervical nodes are affected in about 80% of cases.
  • Posterior cervical nodes are frequently involved (65-70% of cases).
  • Lymphadenopathy is isolated to a single location in 83% of cases, but multiple chains may be involved.
  • Cases of generalized adenopathy involving axillary, inguinal, and mesenteric nodes are unusual.
• A flulike prodrome with fever is present in 50% of cases. The following are less common symptoms:
• • Headache 
  • Nausea, vomiting
  • Malaise, fatigue
  • Weight loss
  • Arthralgias, myalgias
  • Night sweats
  • Rash (up to 30%)
  • Thoracic/abdominal pain

Physical

• Lymphadenopathy
• • Lymphadenopathy is isolated to 1 location in 83% of patients, although multiple nodal chains may be involved.
  • Cervical nodes are affected in 80% of patients; of these, 65-70% involve posterior triangle cervical nodes.
  • Less commonly affected nodes include those in axillary, mediastinal, celiac, abdominal, and inguinal locations.
  • The nodes are usually described as painless or mildly tender.
  • The nodes tend to be 2-3 cm in diameter, although masses of multiple nodes may reach 6 cm.
  • The nodes are usually firm and mobile, but they are not fluctuant or draining.
• Extranodal findings
• • Skin^{17, 18}
    • The incidence of skin involvement varies from 5-30%.
    • Findings are varied and nonspecific and include maculopapular lesions, morbilliform rash, nodules, urticaria, and malar rash, which may resemble that of SLE.
    • Skin lesions resolve in a few weeks to months.
  • Hepatosplenomegaly
    • This finding is not uncommon.
    • Monitor lactase dehydrogenase (LDH) levels.
  • Neurologic involvement
  • • Neurologic involvement is rare but has included conditions such as aseptic meningitis, acute cerebellar ataxia, and encephalitis.¹⁹
    • Patients with aseptic meningitis may report headache, but they do not exhibit nuchal rigidity or positive Kernig or Brudzinski signs. Cerebrospinal fluid (CSF) findings are similar to those noted in patients with aseptic meningitis of viral etiology.
  • Rarely involved extranodal sites include the bone marrow, myocardium, uvea, and thyroid and parotid glands.
  • Arthritic involvement was reported in the case of a 14-year-old body.²
  • Widespread involvement of multiple organ systems in Kikuchi disease has been described in solid-organ transplant patients.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to Be Considered

The main diagnostic problems encountered by clinicians and histopathologists is distinguishing Kikuchi disease from malignant lymphoma and SLE. In Dorfman and Berry's series, 40% of patients with Kikuchi disease were initially misdiagnosed as having lymphoma and were consequently overtreated with chemotherapy. This pitfall remains an active source of diagnostic error.

Kikuchi disease can also mimic SLE. Both can present with lymphadenopathy and fever, and the cutaneous findings seen in 30% of Kikuchi disease patients can resemble those seen in SLE. Results from autoimmune antibody studies may help distinguish Kikuchi disease from SLE. In Kikuchi disease, antinuclear antibodies (ANA), rheumatoid factor (RF), and lupus erythematosus (LE) preparations are usually, although not always, negative.

Kikuchi disease and SLE can also have similar histopathologic appearances. Kikuchi disease is suggested by the absence or paucity of the hematoxylin bodies, plasma cells, and neutrophils usually seen in SLE. Additionally, T lymphocytes predominate in Kikuchi disease, whereas B lymphocytes predominate in SLE.

Other problems to be considered include the following:

• Atypical mycobacterial lymphadenitis
• Lymphoma
• Metastatic carcinoma
• Other viral- or bacterial-caused lymphadenitis
• Rheumatoid arthritis lymphadenitis
• Still disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• In patients with Kikuchi disease, diagnostic laboratory and radiologic test findings are nonspecific. Although results of fine-needle aspiration (FNA) may be suggestive,^{20, 21} the diagnosis of Kikuchi disease is confirmed only by excisional lymph node biopsy.
• • Complete blood cell (CBC) count
  • • Mild granulocytopenia is observed in 20-50% of patients. Leukocytosis is present in 2-5% of patients.
    • Atypical lymphocytes are observed in 25% of patients.
  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels may be elevated.
  • Elevated LDH levels suggest hepatic involvement.
  • Results from autoimmune antibody studies, including LE preparation and RF and ANA studies, are generally negative. These findings may help the clinician distinguish Kikuchi disease from SLE.

Related Medscape topics:
Specialty Site Pathology & Lab Medicine
Specialty Site Radiology

Imaging Studies

• Diagnostic imaging studies confirm the presence of enlarged lymph nodes in the affected areas, but they cannot specifically confirm a diagnosis of Kikuchi disease.
• • Computed tomography (CT) scanning and magnetic resonance imaging (MRI)
  • • Uniform enlargement of lymph nodes in affected areas is noted.
    • Postcontrast enhancement may be observed.
    • Kwon et al reported CT findings in 96 people with Kikuchi disease.²² The authors found homogeneous lymph node enlargement in 83.3% of the patients, perinodal infiltration in 81.3%, and prominent areas of low attenuation suggestive of focal necrosis in 16.7%.
  • Ultrasonography²³
  • • Enlarged nodes may be either homogeneous or heterogeneous.
    • The nodes often have hyperechoic rims.
  • Chest radiography: Although radiographic findings are generally unremarkable in Kikuchi disease, a chest radiograph is recommended in the evaluation of cervical adenopathy to look for evidence of tuberculosis or malignancy.⁸

Procedures

• A definitive diagnosis of Kikuchi disease can be made only by tissue evaluation. Cytologic examination by FNA can suggest the diagnosis of Kikuchi disease, especially when supported by typical clinical findings, but excisional biopsy of an involved lymph node is needed to confirm the diagnosis in doubtful cases.
• FNA
• • FNA findings are most often nonspecific, Although some authors believe that the diagnosis can be confirmed when supported by typical clinical findings. Most authors recommend confirmation by excisional biopsy.
  • In a retrospective study of 44 patients, FNA had an overall accuracy of 56.75% in diagnosing Kikuchi disease.²⁰
  • Characteristic cytologic findings in Kikuchi disease include crescentic histiocytes, plasmacytoid monocytes, and extracellular debris.
  • Definitive diagnosis by FNA is uncommon; prudent pathologists are likely to report results as "suggestive of" or "compatible with" Kikuchi disease.
  • Confirm the diagnosis of Kikuchi disease by excisional biopsy in doubtful cases.
• Excisional lymph node biopsy
• • Histologic findings consistent with Kikuchi disease
  • • Paracortical necrosis may be patchy or confluent, and the degree of necrosis varies considerably from patient to patient.
    • Histocytes – Crescent-shaped nuclei (crescentic nuclei)
    • Other cells – Lymphocytes, plasmacytoid monocytes, macrophages, and immunoblasts (predominantly T cells)
    • Karyorrhexis – Histiocytes and macrophages containing phagocytized debris from degenerated lymphocytes
  • Absent or rare features in Kikuchi disease – Neutrophils, granulomas, plasma cells

Related Medscape topic:
Specialty Site Pathology & Lab Medicine

Histologic Findings

• The 3 histologic phases of Kikuchi disease⁶
• • Proliferative phase – Initial phase with typical findings noted above
  • Necrotizing phase – Extensive necrosis that may destroy the normal architecture of the lymph node
  • Xanthomatous ("foamy cell") phase – The recovery phase with resolution of necrosis
• Immunohistochemical studies
• • The immunophenotype of Kikuchi disease is primarily composed of mature CD8-positive and CD4-positive T lymphocytes. Lymphocytes and histiocytes also exhibit a high rate of apoptosis.
  • Relatively few B cells and natural killer (NK) cells are present.
  • Positive immunostaining results by monoclonal antibody Ki-M1P are seen in Kikuchi disease but not in malignant lymphoma.
• Distinguishing Kikuchi disease from lymphoma
• • The numerous atypical monocytes and T-cell immunoblasts observed in Kikuchi disease may lead to an erroneous diagnosis of lymphoma, especially high-grade non-Hodgkin's lymphoma.
  • Features of Kikuchi disease that may help prevent its misdiagnosis as malignant lymphoma include the following:
  • • Incomplete architectural effacement with patent sinuses
    • Presence of numerous reactive histiocytes
    • Relatively low mitotic rates
    • Absence of Reed-Sternberg cells
• Distinguishing KD from SLE
• • Kikuchi disease and SLE have similar histopathologic appearances. Distinguishing the 2 entities can be difficult.
  • Kikuchi disease is suggested by the absence or paucity of the following:
  • • Hematoxylin bodies
    • Plasma cells
    • Neutrophils

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment of Kikuchi disease is generally supportive. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used to alleviate lymph node tenderness and fever. The use of corticosteroids, such as prednisone, has been recommended in severe extranodal or generalized Kikuchi disease.^{2, 24} Indications for corticosteroid use include the following:

• Neurologic involvement
• • Aseptic meningitis
  • Cerebellar ataxia
• Hepatic involvement – Elevated LDH level
• Severe lupuslike syndrome – Positive ANA titers

Jang and colleagues recommended expanding the indications for corticosteroid use to less severe disease.²⁴ They administered prednisone when patients had prolonged fever and annoying symptoms lasting more than 2 weeks despite NSAID therapy, as well as for recurrent disease and for patients who desired a faster return to work.

Immunosuppressants have been recommended as an adjunct to corticosteroids in severe, life-threatening disease.

Related eMedicine topics:
Corticosteroid-Induced Myopathy
Immunosuppression
Toxicity, Nonsteroidal Anti-inflammatory Agents

Surgical Care

Excisional lymph node biopsy for the purpose of confirming the diagnosis is the only surgery indicated in Kikuchi disease.

Consultations

Surgical consultation may be indicated for a diagnostic excisional lymph node biopsy.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Corticosteroids

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• Kikuchi disease is generally a self-limited disease with a favorable prognosis. Lymphadenopathy usually resolves within 1-6 months after onset, although it may persist longer. About 3% of patients experience recurrence.
• Four deaths have been reported. Three patients died during the acute phase of generalized Kikuchi disease. One patient died from cardiac failure; another from the effects of hepatic and pulmonary involvement; and a third, from an acute lupuslike syndrome. A fourth patient died from complications of hemophagocytic syndrome and severe infection in a patient with Kikuchi disease and concurrent SLE.¹

Patient Education

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Clinically and histologically, Kikuchi disease can be mistaken for malignant lymphoma. Dorfman and Berry reviewed 108 cases of Kikuchi disease⁷; 40% of the patients were thought to have a lymphoma and were consequently overtreated with chemotherapy. Greater awareness of Kikuchi disease among clinicians and pathologists has reduced, but not eliminated, this diagnostic pitfall.

Related Medscape topics:
Resource Center Cancer: Biologic Therapies
Resource Center Medical Malpractice and Legal Issues
Specialty Site Oncology
Specialty Site Pathology & Lab Medicine

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Kampitak T. Fatal Kikuchi-Fujimoto disease associated with SLE and hemophagocytic syndrome: a case report. Clin Rheumatol. Aug 2008;27(8):1073-5. [Medline].
2. Singh YP, Agarwal V, Krishnani N, Misra R. Enthesitis-related arthritis in Kikuchi-Fujimoto disease. Mod Rheumatol. May 10 2008;epub ahead of print. [Medline].
3. Bosch X, Guilabert A, Miquel R, Campo E. Enigmatic Kikuchi-Fujimoto disease: a comprehensive review. Am J Clin Pathol. Jul 2004;122(1):141-52. [Medline]. [Full Text].
4. Lin HC, Su CY, Huang CC, Hwang CF, Chien CY. Kikuchi's disease: a review and analysis of 61 cases. Otolaryngol Head Neck Surg. May 2003;128(5):650-3. [Medline].
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10. Poulose V, Chiam P, Poh WT. Kikuchi's disease: a Singapore case series. Singapore Med J. May 2005;46(5):229-32. [Medline]. [Full Text].
11. Scagni P, Peisino MG, Bianchi M, et al. Kikuchi-Fujimoto disease is a rare cause of lymphadenopathy and fever of unknown origin in children: report of two cases and review of the literature. J Pediatr Hematol Oncol. Jun 2005;27(6):337-40. [Medline].
12. Hedia G, Jamel A, Maher A, et al. Kikuchi-Fujimoto disease associated with systemic lupus erythematosus. J Clin Rheumatol. Dec 2005;11(6):341-2. [Medline].
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14. Spies J, Foucar K, Thompson CT, LeBoit PE. The histopathology of cutaneous lesions of Kikuchi's disease (necrotizing lymphadenitis): a report of five cases. Am J Surg Pathol. Sep 1999;23(9):1040-7. [Medline].
15. Sierra ML, Vegas E, Blanco-González JE, et al. Kikuchi's disease with multisystemic involvement and adverse reaction to drugs. Pediatrics. Aug 1999;104(2):e24. [Medline]. [Full Text].
16. Hudnall SD. Kikuchi-Fujimoto disease. Is Epstein-Barr virus the culprit?. Am J Clin Pathol. Jun 2000;113(6):761-4. [Medline]. [Full Text].
17. Atwater AR, Longley BJ, Aughenbaugh WD. Kikuchi's disease: case report and systematic review of cutaneous and histopathologic presentations. J Am Acad Dermatol. Jul 2008;59(1):130-6. [Medline].
18. Yasukawa K, Matsumura T, Sato-Matsumura KC, et al. Kikuchi's disease and the skin: case report and review of the literature. Br J Dermatol. Apr 2001;144(4):885-9. [Medline].
19. Sato Y, Kuno H, Oizumi K. Histiocytic necrotizing lymphadenitis (Kikuchi's disease) with aseptic meningitis. J Neurol Sci. Mar 1 1999;163(2):187-91. [Medline].
20. Tong TR, Chan OW, Lee KC. Diagnosing Kikuchi disease on fine needle aspiration biopsy: a retrospective study of 44 cases diagnosed by cytology and 8 by histopathology. Acta Cytol. Nov-Dec 2001;45(6):953-7. [Medline].
21. Viguer JM, Jiménez-Heffernan JA, Pérez P, et al. Fine-needle aspiration cytology of Kikuchi's lymphadenitis: a report of ten cases. Diagn Cytopathol. Oct 2001;25(4):220-4. [Medline].
22. Kwon SY, Kim TK, Kim YS, et al. CT findings in Kikuchi disease: analysis of 96 cases. AJNR Am J Neuroradiol. Jun-Jul 2004;25(6):1099-102. [Medline]. [Full Text].
23. Youk JH, Kim EK, Ko KH, Kim MJ. Sonographic features of axillary lymphadenopathy caused by Kikuchi disease. J Ultrasound Med. Jun 2008;27(6):847-53. [Medline].
24. Jang YJ, Park KH, Seok HJ. Management of Kikuchi's disease using glucocorticoid. J Laryngol Otol. Sep 2000;114(9):709-11. [Medline].
25. Hamdan AL, Jaber M, Tarazi A, Tawil A, Fuleihan N. Kikuchi Fujimoto disease: case report and review of the literature. Scand J Infect Dis. 2002;34(1):69-71. [Medline].
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Article Last Updated: Jul 30, 2008