Kikuchi Disease

The cause of Kikuchi disease is unknown, although infectious and autoimmune etiologies have been proposed.[26] 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. Case reports of Kikuchi disease associated with other autoimmune disorders, including Hashimoto thyroiditis, also support the hypothesis of an autoimmune etiology.[27]

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. Several viral candidates have been proposed, including cytomegalovirus, Epstein-Barr virus,[28] 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.[13, 15, 16, 18]  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.

Although uncommon, Kikuchi disease has been reported throughout the world and in all races. Most cases have been reported from East Asia and Japan, with fewer cases from Europe and North America.[2]

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.[13] In a study of 91 cases from France, Dumas et al reported increased risk for severe disease in patients of North African origin.[19]

Kikuchi disease is reported more often in women, with a female-to-male ratio as high as 4:1 in some studies.[2] However, other studies have shown a smaller female preponderance, with a ratio closer to 2:1.[29]

A study of Korean patients by Jung et al reported clinical differences between males and females with Kikuchi disease. Females were more likely to have autoimmune features, including antinuclear antibodies, while males were more likely to present with a profile of fever, headache, bilateral lymphadenopathy, thrombocytopenia, and elevated levels of liver enzymes, C-reactive protein, and lactate dehydrogenase (LDH).[30]

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). In a Korean study of children with severe Kikuchi disease, the mean age was 13.2 years, and the male-to-female ratio was 1:1.32.[31]

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, who had concurrent systemic lupus erythematosus, died from complications of hemophagocytic syndrome and severe infection.[2, 23]

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

Lymphadenopathy features are as follows:

• 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 signs and symptoms:

• Headache
• Nausea, vomiting
• Malaise, fatigue
• Weight loss
• Arthralgias, myalgias
• Night sweats
• Rash (up to 30%)
• Thoracic/abdominal pain

Characteristics of lymphadenopathy are as follows:

• Lymphadenopathy is isolated to a single 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 are as follows:

• Skin[32, 33] : 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 systemic lupus erythematosus (SLE); skin lesions resolve in a few weeks to months

• Hepatosplenomegaly: This finding is not uncommon; monitor lactate dehydrogenase (LDH) levels

• Neurologic involvement: Neurologic involvement is rare but has included conditions such as aseptic meningitis, acute cerebellar ataxia, and encephalitis[34] ; 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: Asymmetric polyarthritis, enthesitis, and dactylitis of the toes was reported in the case of a 14-year-old boy[35]

• Widespread involvement of multiple organ systems in Kikuchi disease has been described in solid-organ transplant patients

In patients with Kikuchi disease, laboratory and radiologic test findings are nonspecific. Although results of fine-needle aspiration (FNA) of an affected lymph node may be suggestive,[36, 37] the diagnosis of Kikuchi disease is confirmed only by excisional lymph node biopsy.

Complete blood cell (CBC) count findings include the following:

• Mild granulocytopenia is observed in 20-50% of patients.
• Leukocytosis is present in 2-5% of patients.

Additional blood study findings include the following:

• Atypical lymphocytes are observed in 25% of patients
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels may be elevated
• Elevated lactate dehydrogenase (LDH) levels suggest hepatic involvement

Results of autoimmune antibody studies—including lupus erythematosus (LE) preparation, rheumatoid factor (RF), and antinuclear antibody (ANA) studies—are generally negative. Those findings may help the clinician distinguish Kikuchi disease from SLE.

Diagnostic imaging studies confirm the presence of enlarged lymph nodes in the affected areas, but they cannot specifically confirm a diagnosis of Kikuchi disease.

On computed tomography (CT) scanning and magnetic resonance imaging (MRI), uniform enlargement of lymph nodes in affected areas is noted. Postcontrast enhancement may be observed.

In a study of 96 patients with Kikuchi disease, Kwon et al reported the following CT findings[38] :

• Homogeneous lymph node enlargement (83.3% of patients)
• Perinodal infiltration (81.3%)
• Prominent areas of low attenuation suggestive of focal necrosis (16.7%)

Shim et al reported that CT imaging pattern analysis of cervical lymph nodes can be used to help differentiate Kikuchi disease from tuberculous lymphadenopathy and reactive hyperplasia. In their study, high cortical attenuation combined with an indistinct nodal architecture supported the diagnosis of Kikuchi disease. In cases of non-necrotic lymphadenopathy, the ratio of nodal cortical attenuation to the adjacent muscle (NCA/M) was significantly higher in Kikuchi disease: 1.67 ± 0.20, compared with1.49 ± 0.20 in reactive hyperplasia and 1.47 ± 0.21 in tuberculous lymphadenopathy.[29]

In a study by Kato et al of MRI findings in nine patients with Kikuchi disease, cervical lymphadenopathy showed predominantly a unilateral distribution at levels II-V. On T2-weighted images, areas of hypointensity were visible at the peripheries of enlarged cervical nodes; these corresponded to histopathological findings of coagulative necrosis.[39]

On ultrasonography, Ryoo et al reported that the following lymph node characteristics are typical of Kikuchi disease[40] :

• Echogenic hilum
• Posterior neck involvement
• Absence of internal calcification
• Absence of necrosis (rarely, presence of partial necrosis)
• Normal vascular pattern on power Doppler ultrasound (ie, hilar vascular structures are central or branch radially from the hilum in both longitudinal and transverse planes)

Chest radiography findings are generally unremarkable in Kikuchi disease. However, a chest radiograph is recommended in the evaluation of cervical adenopathy to look for evidence of tuberculosis or malignancy.[14]

A definitive diagnosis of Kikuchi disease can be made only by tissue evaluation. Cytologic examination by fine needle aspiration (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 characteristics include the following:

• FNA findings are most often nonspecific; some authors believe that the diagnosis can be confirmed when supported by typical clinical findings, but 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[36]

• Characteristic cytologic findings in Kikuchi disease include extracellular debris and intracellular apoptotic debris embedded in the cytoplasm of crescentic and phagocytic macrophages[37, 41]

• Definitive diagnosis by FNA is uncommon; prudent pathologists are likely to report results as "suggestive of" or "compatible with" Kikuchi disease

Excisional lymph node biopsy can reveal histologic findings consistent with Kikuchi disease, as follows:

• 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 include neutrophils, granulomas, and plasma cells

The three histologic phases of Kikuchi disease are as follows[12] :

• Proliferative phase – Initial phase with typical findings as noted in Procedures
• 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 reveal the following:

• 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 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 Kikuchi disease from SLE

Kikuchi disease and SLE have similar histopathologic appearances. Distinguishing the two entities can be difficult. Kikuchi disease is suggested by the absence or paucity of the following:

• Hematoxylin bodies
• Plasma cells
• Neutrophils

Tabata et al reported that CD30 immunostaining may help in the differentation of Kikuchi disease from SLE. In a study that included 30 patients with Kikuchi disease and six with SLE, CD30-positive cells were significantly more numerous in Kikuchi disease than in SLE and most of these CD30-positive cells were located around necrotic areas. Double immunohistochemical staining showed that these CD30-positive cells were CD8-positive cytotoxic T cells, suggesting that activated cytotoxic T cells around necrotic areas are a characteristic feature of this disease. Cases with abundant CD30-positive cells occurred predominantly in female patients with only mild symptoms and normal laboratory data.[42]

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.[35, 43] Clinical and related laboratory indications for corticosteroid use include the following:

• Neurologic involvement – Aseptic meningitis, cerebellar ataxia
• Hepatic involvement – Elevated lactate dehydrogenase (LDH) level
• Severe lupuslike syndrome – Positive antinuclear antibody (ANA) titers

Jang and colleagues recommended expanding the indications for corticosteroid use to less-severe disease.[43] 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.

In steroid-resistant and recurrent Kikuchi disease, case reports have described successful use of hydroxychloroquine and intravenous immunoglobulin.[2, 19, 44]

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are most often employed. Hydroxychloroquine has been used in steroid-resistant and recurrent cases.

Class Summary

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

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Hydroxychloroquine

Mechanism of action unknown; may impair complement-dependent antigen-antibody reactions; inhibits locomotion of neutrophils and chemotaxis of eosinophils