Cervical lymphadenopathy secondary to Kikuchi-Fujimoto disease in a child: case report.

Abstract

While most cases of cervical lymphadenopathy resolve with conservative management, persistent adenopathy can lead to costly investigations and invasive treatments. One cause of persistent adenopathy, as well as a variety of other associated systemic symptoms, is Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis). This rare entity can be diagnosed only by excisional biopsy on the basis of its characteristic histologic appearance. We describe a case of persistent cervical lymphadenopathy secondary to Kikuchi-Fujimoto disease in an 11-year-old girl.

Introduction

Cervical lymphadenopathy is a common problem in the pediatric population. Concomitant systemic signs and symptoms are variable and may not be helpful in establishing a diagnosis. While most cases resolve with conservative management, persistence of adenopathy can lead to costly investigations and invasive treatments. One cause of persistent adenopathy, as well as a variety of other associated systemic symptoms, is Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis). Otolaryngologists should be aware of this rare condition as patients with persistent cervical adenopathy are often referred to us for evaluation and treatment. We describe a new case of persistent cervical lymphadenopathy secondary to Kikuchi-Fujimoto disease.

Case report

An 11-year-old girl with no previous medical problems presented to the pediatric service with a 4-week history of rash, joint pain, and intermittent fevers. Her rash, which was maculopapular in character, had started on her thighs and buttocks and later appeared on her left arm. Her arthralgia was concentrated in both knees and ankles and in her left wrist and left thumb. She denied cough, runny nose, and urinary disorders, and she had no known sick contacts.

On physical examination, the patient was in no acute distress. Her temperature was 38.9[degrees]C. Prominent left cervical lymphadenopathy was present as a 4 x 8-cm conglomerate of level II and III nodes, which were tender to palpation. No axillary or inguinal adenopathy was found. Findings on heart and lung examinations were normal, but the abdominal examination elicited a small amount of epigastric tenderness. Examination of the extremities revealed a limited range of motion of the ankles and left wrist secondary to discomfort, but there was no joint swelling, erythema, or warmth. A fine papular rash was present on the anterior left forearm.

Abnormal laboratory values included the erythrocyte sedimentation rate (ESR), 85 mm/hr (range of normal: 0 to 20); C-reactive protein level, 10.9 mg/L (0 to 0.8); ferritin concentration, 337 mg/ml (20 to 180); and lactic dehydrogenase level, 227 U/L (60 to 200). Normal values included the white blood cell count, 4.7 x [10.sup.9] L (42% neutrophils, 54% lymphocytes, and 4% monocytes); hemoglobin, 12 g/dl; hematocrit, 36%; and platelets, 330 [10.sup.3] [micro]l. Likewise, normal results were obtained on tests for mononucleosis, cat-scratch fever, toxoplasmosis, human immunodeficiency virus, purified protein derivative, antinuclear antibody (ANA), anti-DNA B-cell antibodies, antistreptolysin O, hepatitis, parvovirus B 19, HLA-B27, Brucella abortus, and uric acid. Blood and urine cultures were negative. Computed tomography (CT) of the neck revealed diffuse cervical lymphadenopathy, including a 2 x 2-cm mass in left level II (figure 1). Additional CT of the chest, abdomen, and pelvis revealed no further adenopathy.

The patient was admitted to the hospital and placed on broad-spectrum antibiotics. Her temperature continued to spike to 41[degrees]C despite scheduled acetaminophen and ibuprofen. She was taken to the operating room for open cervical biopsy for suspected lymphoma.

Histologically, the lymph node demonstrated extensive infarctive-type necrosis with adjacent subcapsular proliferation of mononuclear cells of varying sizes in addition to lymphocytes (figure 2, A). On higher magnification, the necrotic areas demonstrated single-cell necrosis and abundant karyorrhexis (figure 2, B). The cellular areas were made up of atypical histiocytes with elongated, twisted nuclei and scant cytoplasm; immunoblasts (transformed lymphocytes) with vesicular chromatin, large round nuclei, and prominent nucleoli; and lymphocytes (figure 2, C). Immunohistochemical staining revealed positivity for histiocytic markers MAC387 and CD68 in most of the larger cells (figure 2, D). Neutrophils and plasma cells were not seen. Flow cytometry was negative for monoclonality. A diagnosis of Kikuchi-Fujimoto disease was made.

In addition to nonsteroidal medication, the patient was treated with 1 week of steroids followed by a taper. She became afebrile after 48 hours of treatment, and she experienced a significant reduction in her adenopathy after 1 week.

Discussion

Kikuchi-Fujimoto disease was first reported in 1972 independently by Japanese pathologists Kikuchi (1) and Fujimoto et al. (2) They described a distinctive syndrome of necrotizing lymphadenitis with a characteristic histologic appearance. It is generally believed that prior to their descriptions, many patients with this disease had been erroneously diagnosed with lymphoma. (3)

Epidemiology. The incidence of Kikuchi-Fujimoto disease is unknown, but we do know that it is more prevalent in women than men (ratio: 4:1). (4) It is most common in the Asian population, but it has been reported in many countries and in different racial groups. While the reported age of onset ranges between 20 and 70 years, most affected patients are younger than 30 years. (4) Only a few pediatric cases have been reported. (5)

Presentation. Symptoms typically develop over a period of 2 to 3 weeks. The most common clinical feature is cervical adenopathy that is typically tender to palpation. Other lymph node basins may be affected. Relapsing lymphadenopathy occurs in 3 to 4% of patients. (6) Fever is present in 30 to 50% of cases. (6) Rash and arthralgia, as experienced by our patient, have been well described, but they are not universal. (7) Other potential signs include weight loss, nausea, headache, and fatigue. Laboratory studies commonly detect leukopenia, and lymphocytosis and atypical lymphocytes are often seen in peripheral blood. The ESR is frequently elevated, as are lactate dehydrogenase and transaminase levels.

[FIGURE 1 OMITTED]

Pathology. Kikuchi-Fujimoto disease can be diagnosed only by excisional biopsy on the basis of its characteristic histologic appearance. The histopathologic features of Kikuchi-Fujimoto disease include patchy paracortical necrosis with abundant karyorrhexis surrounded by histiocytes, plasmacytoid monocytes, immunoblasts, foamy macrophages, and cytotoxic Tlymphocytes. (8) Immunohistochemically, the histiocytes and plasmacytoid monocytes are positive for CD4, CD43, CD68, Ki-M1P, and MAC387. (9) B-cell lymphocyte markers are typically negative. Neutrophils and plasma cells are conspicuously absent, which aids in the diagnosis.

The histologic differential diagnosis for Kikuchi-Fujimoto disease includes systemic lupus erythematosus (SLE) and malignant lymphoma, which both exhibit lymph node necrosis and karyorrhexis. However, these entities can be distinguished histologically. SLE exhibits a diffuse pattern of necrosis, characteristic hematoxyphilic bodies, DNA deposition along vessel walls, and plasma cell infiltrate. Non-Hodgkin lymphoma has a more monotonous population of B lymphocytes, whereas Hodgkin disease exhibits Reed-Sternberg cells and neutrophilic infiltrates, which form microabscesses.

[FIGURE 2 OMITTED]

In our patient, the lymph node demonstrated paracortical necrosis, histiocytes, immunoblasts, and an absence of neutrophils and plasma cells--findings consistent with Kikuchi-Fujimoto disease.

Etiology. The etiology of Kikuchi-Fujimoto disease is unknown. An infectious or autoimmune basis has been suggested. The clinical and histologic presentation suggests a hyperimmune reaction of T cells, but the identity of the trigger for this reaction remains elusive. Several infectious agents--including Brucella and Yersinia spp, toxoplasmosis, herpes simplex virus 6, hepatitis B virus, cytomegalovirus, parvovirus B 19, parainfluenza virus, and Epstein-Barr virus (EBV)--have been investigated. In fact, EBV has been studied extensively because many of its clinical features are similar to those of Kikuchi-Fujimoto disease, but no link has yet been identified. (10) Autoimmune diseases, such as SLE and adult Still disease, have had variable associations with Kikuchi-Fujimoto disease. SLE has been found to precede, coincide with, or follow the clinical features of Kikuchi-Fujimoto disease, so some investigators advocate repeat ANA testing for patients with the latter. (7)

Treatment. The standard of care for patients with Kikuchi-Fujimoto disease is symptomatic treatment with nonsteroidal anti-inflammatory medications. (11) In general, the prognosis is excellent. (12) Spontaneous improvement and resolution of symptoms can be expected within months. In rare cases, the disease may persist for years and relapse may occur. (8) Systemic steroids have been found to be beneficial in a small number of patients with severe or recurrent symptoms. (13) Myocarditis, aseptic meningitis, cerebellar ataxia, delirium, and death have been reported in rare cases. (14-16)

In conclusion, although Kikuchi-Fujimoto disease is rare, otolaryngologists should be familiar with it as a cause of persistent cervicallymphadenopathy in the pediatric population. In the setting of persistent adenopathy, high fevers, and other systemic signs and symptoms, early open biopsy maybe warranted. With Kikuchi-Fujimoto disease considered as part of the differential diagnosis, otolaryngologists can prompt pathologists to look for the features specific to this disease process. Early biopsy and diagnosis can help minimize unnecessary testing and potentially harmful treatments.

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Steven P. Chase, MD; Jerry W. Templer, MD; Ronald Miick, MD; Alberto A. Diaz-Arias, MD

From the Department of Otolaryngology-Head and Neck Surgery (Dr. Chase and Dr. Templer) and the Department of Pathology and Anatomic Sciences (Dr. Miick and Dr. Diaz-Arias), University of Missouri School of Medicine, Columbia.

Corresponding author: Steven P. Chase, MD, Southern Utah Ear, Nose, and Throat, 1490 E. Foremaster Dr., Suite 350, St. George, UT 84790-4507. Phone: [phone]; fax: [phone]; e-mail: [e-mail]