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 (KD) was reported for the first time in 1972 in Japan by Kikuchi and by Fujimoto and his colleagues. KD is an idiopathic, self-limited necrotizing lymphadenitis. KD commonly presents with cervical lymphadenopathy accompanied by fever, myalgia, neutropenia, and rash in one third of cases. Involvement of extranodal sites is unusual but is described, especially in Asia where KD is more common than in North America or Europe. It is most common in young women.

KD can clinically and histologically mimic Hodgkin disease or high-grade lymphoma. It can also resemble the lymphadenitis of systemic lupus erythematosus (SLE).

For additional information on related topics, see the following:

• Hodgkin Disease (hematology focus)
• Hodgkin Disease (pediatric focus)
• Lymphoma, High-Grade Malignant Immunoblastic
• Lymphadenitis
• Systemic Lupus Erythematosus
• Medscape's Lupus Resource Center

Pathophysiology

Investigators have postulated that apoptosis plays an important part in the pathogenesis of KD. They believe that cytotoxic T lymphocytes are apoptotic effectors as well as target cells and that histiocytes could possibly enhance apoptosis in KD. The trigger of this process may have either a viral pathogenesis or an autoimmune pathogenesis.

Plasmacytoid monocytes have been suggested to play a role in the pathogenesis of KD via a cell-mediated cytotoxic immune response.

KD has been reported in 2 nontwin sisters with HLA-identical phenotypes, who presented 10 years apart.

Zhang et al¹ described an association between parvovirus B19 and Kikuchi-Fujimoto disease. Specifically, from one case of KD, they reported that the in situ hybridization and immunohistochemistry double-staining assay results revealed that parvovirus B19–infected cells were mainly lymphocytes and a small number of histiocytes.

Frequency

United States

KD is rare.

International

KD is more prevalent among Asians and is a relatively common disorder among Koreans.

In Taiwan, Chuang et al² studied 64 patients younger than 18 years with pathologic proof of KD. In this group of 35 males and 29 females, the age range was 2-18 years, with a median age of 16.63 years for the males.

The female patients had cervical lymphadenopathy, and 1 had generalized lymphadenopathy. In 50% of patients, the lymph nodes were painful, tender, or both. In 82.5% of patients, the lymphadenopathy was unilateral. In 32.8% of patients, the lymphadenopathy was associated with fever.

Rash, hepatomegaly, or weight loss occurred in less than one third of the patients. Leukopenia was present, and 3% had leukocytosis. Mild liver dysfunction was present in approximately 25% of patients. Most patients had normal virologic or immunologic study results. Patients with prolonged fever were more likely to have leukopenia (P <.05). All 64 patients had remissions of KD, but 1 developed SLE 5 years later and another had a vasculitis syndrome 2 years later.

Rau and Kini³ reported 20 patients with KD from an Indian referral center, one of whom had skin involvement.

Mortality/Morbidity

• KD is benign; thus, besides the pain associated with the condition, it has minimal mortality and morbidity.
• If KD occurs in patients who have undergone transplantation, it can be fatal.
• KD can evolve into lupus, in which case morbidity and mortality are substantially increased.

Race

This disease affects Asians more than other races, but it has been reported worldwide.

Sex

Females are more commonly affected than males, with a female-to-male ratio of 4:1.

Age

KD affects a wide age range from 10 months to 75 years, with a mean patient age in the third decade.

CLINICAL

Section 3 of 10  

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

History

KS commonly presents with cervical lymphadenopathy accompanied by fever, myalgia, and neutropenia. A rash occurs in one third of patients. The range of symptoms and abnormalities is wide; Lima et al⁴ described a case of a 27-year-old woman presenting with fever, urinary tract infections, skin rash, polyarthritis, generalized lymphadenopathy, pancytopenia, hepatic cytolysis and cholestasis, abnormal coagulation test results, and elevated serum lactate dehydrogenase levels.

KD can be associated with cervical pain in as many as one half of patients. Most cases resolve within 2 months, but recurrences have been reported. The time from onset of symptoms to diagnosis ranges from 1-24 months.

• Harris et al⁵ reported a case of a dengue viral infection causing an abnormal immune response leading initially to KD and later to SLE.
• KD has been associated with a case of Still disease.
• KD has also been linked to parvovirus B19 and antiphospholipid syndrome.
• Fever is present in 33-50% of patients.
• Constitutional symptoms may include diarrhea, chills, sweats, nausea, vomiting, chest pain, abdominal pain, and rash.
• Childhood hemophagocytic syndrome associated with KD in children has been reported.
• Brachial plexus neuritis and mononeuritis multiplex have been reported in association with KD.
• Mycobacterium szulgai lymphadenitis mimicking KD has been reported in Thailand.
• Bilateral panuveitis has been reported as a possible association with KD.
• KD with aseptic meningitis has been reported.
• One case report has associated KD with brucellosis.
• In 2003, Viseux et al⁶ reported KD associated with cutaneous manifestations evoking Wells syndrome.
• Corynebacterium pseudotuberculosis necrotizing lymphadenitis is an infectious cause of necrotizing lymphadenitis that should not be confused with KD.⁷
• Carlson et al⁸ noted a cefprozil-induced rash in a patient with infectious mononucleosis and a minocycline-associated drug hypersensitivity syndrome for which histology studies demonstrated an acute vacuolar interface superficial and deep perivascular and interstitial lymphocytic dermatitis. CD8⁺ lymphocytes predominated in conjunction with non-neutrophilic nuclear (karyorrhectic) debris and numerous small CD68⁺ and CD123⁺ monocytes—findings similar to those of KD. Both patients had serologic but not cutaneous polymerase chain reaction evidence of active and chronic-active Epstein-Barr virus (EBV) infection.

Physical

KD can affect the lymph nodes, the liver, the spleen, and the skin. Physical findings involve these organ systems.

• Skin changes occur in about one third of patients (16-40%) and are often of a nonspecific nature.
• • Most cutaneous lesions present as erythematous macules, papules, plaques, nodules, or ulcers on the upper part of the body, such as the trunk, the upper extremities, and the face.
  • Kim et al⁹ reported a case of Kikuchi-Fujimoto disease with a papulopustular eruption over the torso, arms, and legs.
  • Imai et al¹⁰ described a patient with lip edema. This patient had facial, neck, and arm desquamation and erosions and transient indurated erythematous papules. Kaur et al¹¹ described a patient with KD with erythema multiforme–like lesions and a facial rash.
  • In some cases, KD is associated with cutaneous lupus erythematosus.
  • Rao et al¹² presented a case of a 32-year-old woman with fever and swelling in the axillae for 8 weeks, facial erythema, fluid-filled lesions on the trunk, oral ulcers, crusting of the lips, and a 3-day history of injection and watering of the eyes who ultimately was diagnosed with KD and SLE.
  • A case of KD manifested with eyelid edema.¹³
  • Letawe et al¹⁴ noted arciform papulonodular lesions on the face in a patient with KD.
  • Erosion and ulcerated gingivae have been reported.
• KD with leukocytoclastic vasculitis has been reported in a 10-year-old girl.
• KD usually demonstrates adenopathy at a single site, predominantly in the cervical region, but it may also affect other and multiple lymph node regions, including axillary, supraclavicular, mediastinal, inguinal, intraparotid, iliac, celiac, and peripancreatic groups. Pain and tenderness of the lymph nodes may be present. Reports note generalized lymphadenopathy.
• Splenomegaly and hepatomegaly are rare.
• Kim and Oh¹⁵ noted KD in association with a transient eruption in a 7-year-old boy.

Causes

The etiology of KD is not yet well known. Viral triggering on KD has been suggested as its cause. In particular, EBV and parvovirus B19 have been linked to cases of KD.

• Huh et al¹⁶ used polymerase chain reaction tests for herpes simplex virus type 1, herpes simplex virus type 2, cytomegalovirus, or EBV on the lymph nodes of 12 patients with KD and could not isolate viral material.
• Aqel et al¹⁷ performed immunofluorescence studies on tissue from involved and uninvolved cheek and forehead samples. They found immunoglobulins and complement deposited at the dermoepidermal junction and in dermal blood vessel walls. These researchers believed these findings supported an autoimmune basis for KD.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Lymphoma
Leukemia
Systemic lupus erythematosus
Sweet syndrome
Hodgkin disease

WORKUP

Section 5 of 10  

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

Lab Studies

• Patients with KD can have elevated erythrocyte sedimentation rates, neutropenia, and atypical lymphocytosis.
• Some reports note that leukopenia occurs in 25-43% of patients; leukocytosis, in 2.9-5% of patients; and atypical lymphocytosis, in 25% of patients.
• Murine and in vitro experiments have shown that the expression/induction of T-bet, the master regulator of Th1 differentiation, can be achieved by obligate intracellular pathogens involved with lymphadenitis and by KD, suggesting the KD is somehow related to obligate intracellular pathogens.¹⁸
• Eboriadou et al¹⁹ reported KD associated with extreme leukopenia and thrombocytopenia in an adolescent boy.

Imaging Studies

• Many different patterns of computed tomographic appearance of KD have been reported. They include enlarged lymph nodes with a hypodense center and peripheral ring enhancement.
• Many small, clustered lymph nodes may be a characteristic imaging feature of KD.
• The abdominal extent of disease may be underreported if cross-sectional imaging is not performed.
• Kim et al²⁰ described a 10-year-old girl with KD that mimicked malignant lymphoma on fluorodeoxyglucose positron emission tomography scans.

Other Tests

• Flow cytometric studies performed on the affected lymph node, bone marrow aspirate, and peripheral blood reveal a relative expansion of mature activated T lymphocytes, predominantly expressing a CD8⁺ phenotype.

Procedures

• Lymph node biopsy and skin biopsy are useful procedures.

Histologic Findings

Skin biopsy specimens show a dense, lymphohistiocytic, superficial, deep perivascular and interstitial infiltrate; papillary dermal edema; and abundant nuclear debris with a conspicuous absence of neutrophils, paralleling the nodal histology of KD.

CD68 immunohistochemistry shows many plasmacytoid monocytes. CD3, CD4, and CD8 immunohistochemistry shows highly variable staining. Only rare staining with T-cell intracytoplasmic antigen and CD30 occurs.

With immunofluorescence, deposition of immunoglobulins and complement can be seen at the dermoepidermal junction and in the walls of dermal blood vessels.

In one case, histologic findings from a cutaneous lesion revealed dermal patchy infiltrates composed of large lymphoreticular cells and scattered cells that resembled Hodgkin or Reed-Sternberg cells. Subsequent immunohistochemical studies demonstrated they were activated fibroblasts.

In 2004, Yen et al²¹ suggested that interface change might be one of the pathological features of the cutaneous manifestations of Kikuchi-Fujimoto disease.

TREATMENT

Section 6 of 10  

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

Medical Care

Once the diagnosis is established, no specific medical care is indicated because this is a self-limited condition.

• One case report has noted that minocycline was helpful in abating KD.
• Another report has noted that systemic steroids can be helpful in cases that do not abate or are recurrences.
• In 2007, Khan et al²² described a 40-year-old Nepali man who was admitted to the hospital with a 1-month history of fever associated with swelling, pain, and redness on the right side of his neck. His biopsy results showed the hemophagocytosis and typical necrotizing lymphadenitis of KD. He took naproxen at 500 mg twice daily orally for 10 days, and his fever and lymphadenopathy resolved. Because KD is self-limited, the role of therapy in this case report is uncertain.

Surgical Care

No surgical care is needed besides performing a lymph node biopsy to make the diagnosis.

Consultations

Consultation from a dermatologist, a pathologist, a surgeon, and an otolaryngologist can be helpful in establishing the diagnosis.

MEDICATION

Section 7 of 10  

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

No specific medical therapy is indicated.

FOLLOW-UP

Section 8 of 10  

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

Complications

• KD can evolve into lupus, but this linkage remains to be defined.

Prognosis

• KD is a self-limited condition that can recur in about 3% of cases. Therefore, the prognosis is excellent.

Patient Education

• Patients must know that they have a benign and self-limited condition.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• The primary medicolegal pitfall is misdiagnosis of a malignant lymphoma.

REFERENCES

Section 10 of 10

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

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2. Chuang CH, Yan DC, Chiu CH, Huang YC, Lin PY, Chen CJ, et al. Clinical and laboratory manifestations of Kikuchi's disease in children and differences between patients with and without prolonged fever. Pediatr Infect Dis J. Jun 2005;24(6):551-4. [Medline].
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18. Jöhrens K, Anagnostopoulos I, Dürkop H, Stein H. Different T-bet expression patterns characterize particular reactive lymphoid tissue lesions. Histopathology. Mar 2006;48(4):343-52. [Medline].
19. Eboriadou M, Tragiannidis A, Markou K, Athanassiadou F. Kikuchi-fujimoto disease associated with extreme leukopenia and thrombocytopenia in an adolescent boy. J Pediatr Hematol Oncol. Dec 2007;29(12):864. [Medline].
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27. Lopez C, Oliver M, Olavarria R, et al. Kikuchi-Fujimoto necrotizing lymphadenitis associated with cutaneous lupus erythematosus: a case report. Am J Dermatopathol. Aug 2000;22(4):328-33. [Medline].
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Article Last Updated: Feb 12, 2008