Kikuchi Disease

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Practice Essentials

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

The most common clinical manifestation of Kikuchi disease is cervical lymphadenopathy, with or without systemic signs and symptoms.[2, 3, 4, 5] Clinically and histologically, the disease can be mistaken for lymphoma or systemic lupus erythematosus (SLE).[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]

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, 17]

In a retrospective study of 24 cases of Kikuchi disease in southern India over a 4-year period, the findings included the following[18] :

Treatment of Kikuchi disease is generally supportive. (See Treatment.) Pharmacologic therapy that has been recommended includes the following:

See also Cutaneous Kikuchi Disease

For patient education resources, see Swollen Lymph Nodes and Lymphoma.

Pathophysiology

The cause of Kikuchi disease is unknown, although infectious and autoimmune etiologies have been proposed.[19] 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.[20]

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,[21] 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.[6, 8, 9, 11] {ref1239-INVALID REFERENCE} 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.

 

Epidemiology

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.[1]

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. Four deaths have been reported, from hemophagocytic syndrome and severe infection, pulmonary hemorrhage, acute heart failure, and multiorgan failure and disseminated intravascular coagulation.[22]

Race-, Sex-, and Age-related Demographics

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.[6] In a study of 91 cases from France, Dumas et al reported increased risk for severe disease in patients of North African origin.[12]

Kikuchi disease is reported more often in women, with a female-to-male ratio as high as 4:1 in some studies.[1] However, other studies have shown a smaller female preponderance, with a ratio closer to 2:1.[23]

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).[24]

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.[25]

History

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:

A flulike prodrome with fever is present in 50% of cases. The following are less common signs and symptoms:

Physical

Characteristics of lymphadenopathy are as follows:

Extranodal findings are as follows:

Laboratory Studies

In patients with Kikuchi disease, diagnostic laboratory and radiologic test findings are nonspecific. Although results of fine-needle aspiration (FNA) of an affected lymph node may be suggestive,[30, 31] the diagnosis of Kikuchi disease is confirmed only by excisional lymph node biopsy.

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

Additional blood study findings include the following:

 

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.

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[32] :

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.[23]

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.[33]

On ultrasonography, Ryoo et al reported that the following lymph node characteristics are typical of Kikuchi disease[34] :

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.[7]

Procedures

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:

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

Histologic Findings

The three histologic phases of Kikuchi disease are as follows[5] :

Immunohistochemical studies reveal the following:

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:

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:

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.[35]

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.[29, 36] Clinical and related laboratory indications for corticosteroid use include the following:

Jang and colleagues recommended expanding the indications for corticosteroid use to less-severe disease.[36] 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.[1, 12, 37]

Medication Summary

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.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

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

Class Summary

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

Hydroxychloroquine

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

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, who had concurrent systemic lupus erythematosus, died from complications of hemophagocytic syndrome and severe infection .[1]

What is Kikuchi disease?What is the pathophysiology of Kikuchi disease?Which geographic areas have the highest prevalence of Kikuchi disease?What is the morbidity and mortality associated with Kikuchi disease?What are the racial predilections of Kikuchi disease?What are the sexual predilections of Kikuchi disease?Which age groups have the highest prevalence of Kikuchi disease?What are the signs and symptoms of Kikuchi disease?Which physical findings are characteristic of Kikuchi disease?What are common misdiagnoses of Kikuchi disease?How is systemic lupus erythematosus (SLE) differentiated from Kikuchi disease?Which conditions are included in the differential diagnoses of Kikuchi disease?What are the differential diagnoses for Kikuchi Disease?What is the role of lab testing in the workup of Kikuchi disease?What is the role of imaging studies in the workup of Kikuchi disease?What is the role of biopsy in the workup of Kikuchi disease?What are the histologic phases of Kikuchi disease?Which histologic findings are characteristic of Kikuchi disease?What are the histologic differences between Kikuchi disease and lymphoma?What are the histologic differences between Kikuchi disease and systemic lupus erythematosus (SLE)?How is Kikuchi disease treated?What is the role of medications in the treatment of Kikuchi disease?Which medications in the drug class Immunosuppressants are used in the treatment of Kikuchi Disease?Which medications in the drug class Corticosteroids are used in the treatment of Kikuchi Disease?What is the prognosis of Kikuchi disease?

Author

John Boone, MD, Consulting Staff, Department of Otolaryngology, Naval Hospital Oak Harbor

Disclosure: Nothing to disclose.

Coauthor(s)

Charles S Kuzma, MD, Consulting Staff, Clinical Research Coordinator, First Health of the Carolinas Cancer Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Lawrence H Brent, MD, Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Disclosure: Stock ownership for: Johnson & Johnson.

Chief Editor

Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Disclosure: Nothing to disclose.

Additional Contributors

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

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