Kikuchi-Fujimoto disease.
Abstract: * Kikuchi-Fujimoto disease, or histiocytic necrotizing lymphadenitis, is a self-limited condition, characterized by benign lymphadenopathy with associated fevers and systemic symptoms. It most commonly affects adults younger than 40 years of age and of Asian descent. Involved lymph nodes demonstrate paracortical areas of apoptotic necrosis with abundant karyorrhectic debris and a proliferation of histiocytes, plasmacytoid dendritic cells, and [CD8.sup.+] T cells in the absence of neutrophils. Kikuchi-Fujimoto disease is thought to have 3 evolving phases: proliferative, necrotizing, and xanthomatous. The etiology is unknown, although viruses and autoimmune mechanisms have been proposed. No specific laboratory tests contribute to the diagnosis. Diagnosis requires histopathologic examination and exclusion of other factors by ancillary studies. Non-Hodgkin lymphoma and systemic lupus erythematosus should be ruled out before diagnosis of Kikuchi-Fujimoto disease, given the overlapped clinical and histologic features as well as the different therapeutic approaches. Treatment involves supportive measures, and the symptoms usually resolve spontaneously within 4 months.
Article Type: Disease/Disorder overview
Subject: Lymphatic diseases (Development and progression)
Lymphatic diseases (Diagnosis)
Lymphatic diseases (Care and treatment)
Author: Hutchinson, Charles Blake
Pub Date: 02/01/2010
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165
Issue: Date: Feb, 2010 Source Volume: 134 Source Issue: 2
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230245852
Full Text: Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, was first described in 1972 simultaneously by Kikuchi (1) and Fujimoto and colleagues (2) as a lymphadenitis with focal proliferation of histiocytic cells and abundant karyorrhectic debris. It is a rare cause of lymphadenopathy, commonly seen in individuals of Asian descent and frequently associated with fever and, sometimes, other systemic symptoms. (3,4) Despite many case reports and case studies, the etiology and pathogenesis of KFD remain unclear since its initial description. Morphologic examination of involved lymph nodes is the mainstay of the correct diagnosis of KFD; however, the recognition by morphology frequently presents a challenge to many pathologists, even to hematopathologists, because of its features simulating non-Hodgkin lymphoma or reactive lymphadenopathy of other causes. Here, we provide a brief review of KFD with emphasis on the histopathologic diagnosis.

CLINICAL FEATURES

Although it was originally reported in young Japanese females by Kikuchi1 and by Fujimoto et al, (2) the condition has been described in both genders and in a variety of ethnic backgrounds. (5) Overall, women are affected more often.6 The onset of KFD is usually acute or subacute. It typically manifests as cervical lymphadenopathy with low-grade fever in a previous healthy young individual. The enlarged lymph nodes, ranging from 0.5 to 4 cm in size, are tender and painful; lymphadenopathy is reported in 59% of patients. Although lymphadenopathy involving other anatomic sites has been described in 2% to 40% of the cases, a generalized lymphadenopathy is infrequent. (3,4,7) Extranodal involvement by KFD is uncommon, but cutaneous lesions associated with KFD have been well documented in the literature. (8,9) These skin lesions are most frequently located on the face or upper body and include erythematous papules, plaques, indurated lesions, and ulcers. Rare cases with hepatomegaly or splenomegaly have been described in literature. (10) The fever is usually associated with upper respiratory symptoms and typically lasts for 1 week, although it could persist for up to 1 month in rare cases. Other uncommon symptoms include fatigue, joint pain, nausea, vomiting, and sore throat. Weight loss and night sweats, the 2 systemic symptoms frequently seen in lymphoid malignancy, are rare but have been reported. (7,10) Of note, these systemic symptoms are observed more frequently in the cases with extranodal involvement.

LABORATORY FINDINGS

Despite lack of consistent laboratory findings in KFD, many cases have been reported in association with anemia and with elevated lactate dehydrogenase levels, liver function enzymes, and erythrocyte sedimentation rates. Mild leucopenia has been seen in 20% to 58% of patients, probably due to cytokine-mediated mechanisms. (7,10) Up to 25% of patients have been reported as having atypical lymphocytes identified in their peripheral blood, supporting the proposed viral etiology of the disease discussed in the next section. (9)

HISTOPATHOLOGY

Involved lymph nodes characteristically demonstrate architecture partially effaced by paracortical expansion composed of circumscribed foci of apoptotic necrosis with abundant karyorrhectic debris and numerous histiocytes of different types at the edge of the necrotic foci (Figure 1, A and B). These histiocytes are bland in appearance, including both nonphagocytic and phagocytic forms. The so-called crescentic histiocytes are typically seen in necrotic foci with prominent karyorrhectic debris (Figure 2, A). The plasmacytoid dendritic cells, although hardly recognized when present singly, tend to cluster, particularly at the margins of the necrotic foci (Figure 1, B). Admixed are many small to large lymphocytes. In some cases, large transformed lymphocytes with immunoblast morphology are markedly increased, in a background of karyorrhectic debris and scattered tingible body macrophages, which gives a histologic picture resembling high-grade lymphoma (Figure 2, B). Neutrophils and eosinophils are characteristically absent, and plasma cells are scarce or absent. (5,11) Regions peripheral to the necrosis may demonstrate thrombosed vessels, but these are not always present. Reactive lymphoid follicles are observed in most cases (Figure 1, A). The degree of necrosis varies considerably from one case to another. Kuo, (10) basing on the histopathologic features, proposed to classify KFD into 3 evolving histologic phases: proliferative, necrotizing, and xanthomatous. The initial proliferative phase features an expanded paracortex with increases in various histiocytes and plasmacytoid dendritic cells, which are admixed with a variable number of lymphocytes and karyorrhectic nuclear debris. The case is classified as being in the necrotizing phase once a necrosis of any degree is observed in the lesion described above. If foamy histiocytes predominate in the lesions, the case is categorized as being in the xanthomatous phase, despite the presence or absence of necrosis. Of all cases studied, the necrotizing phase constitutes more than half. These 3 histologic types of KFD could represent different evolving stages of the disease; however, this speculation has not been confirmed because of a lack of studies with sequential biopsies of individual patient.

[FIGURES 1-3 OMITTED]

Although a diagnosis of KFD is largely based on morphologic evaluation, immunohistochemical analysis has utility and is commonly used to rule out malignant lymphoma. The histiocytes of KFD characteristically express myeloperoxidase (Figure 3, A), in addition to lysozyme, CD68 (Figure 3, B), and CD4. (12) Plasmacytoid dendritic cells express neither histiocytic markers nor myeloperoxidase. (13) Lymphocytes are predominantly [CD8.sup.+] T cells, in contrast to mainly [CD4.sup.+] T cells in other types of lymphadenopathy with T-zone expansion. Immunoblasts adjacent to affected areas have mainly T-cytotoxic phenotypes with a rare B-cell immunoprofile. (7,14)

In cases of KFD with cutaneous involvement, morphologic examination and immunohistochemical studies have demonstrated pathologic changes in keeping with those seen in lymph nodes, although other changes, such as leukocytoclastic vasculitis and polymorphous light eruption, among others, have also been reported. (8,9)

It needs to be emphasized that an excisional biopsy of involved lymph node is necessary for a diagnosis of KFD. Although cytologic evaluation of fine needle aspiration material has been studied and suggested for the use in diagnosis, (15) fine-needle aspiration biopsies alone, or even with flow-cytometric analysis or other ancillary studies, is insufficient to establish a diagnosis of KFD, according to our experience.

ANCILLARY STUDIES

Flow-cytometric analysis is helpful in the evaluation of lymphadenopathy and may be used to exclude the possibility of non-Hodgkin lymphoma. In contrast to other reactive lymphadenopathy, KFD typically shows predominance of T cells with most being phenotypically unremarkable [CD8.sup.+] cells in flow-cytometric analysis. (7,14) To be brief, a specific finding of a laboratory abnormality for KFD has not been identified, and thus, the primary role of laboratory evaluation remains to rule out other causes of necrotizing lymphadenopathy. In general, polymerase chain reaction-based, immunoglobulin H, T-cell receptor gene rearrangement studies are not required for diagnosis.

PATHOGENESIS

Kikuchi-Fujimoto disease is an uncommon disease. The causes and pathogenesis of the disease remain unclear since its initial description by Kikuchi (1) and Fujimoto et al (2), despite many case reports and case studies. Nevertheless, infectious causes, particularly viruses, have been hypothesized on the basis of clinical presentation, disease course, and histologic features. (5,11,16) Numerous inciting agents have been proposed, including Epstein-Barr virus, human herpes virus 6, human herpes virus 8, human immunodeficiency virus, herpes simplex virus, hepatitis B, Human T-lymphotrophic virus type 1, parvovirus B 19, paramyxovirus and parainfluenza viruses, Yersinia enterocolitica, and toxoplasma; further studies, however, have not confirmed a causative link between these infectious agents and KFD. Findings consistent with viral etiology include upper respiratory prodrome, lack of response to antibiotics, circulating atypical lymphocytes, expansion of paracortex (T zone), proliferation of immunoblasts of cytotoxic T-cell phenotype, and elevated interferon [alpha], as well as other cytokines. Among the viral agents listed above, Epstein-Barr virus has been studied most extensively (16) in KFD, but no causal relationship has been demonstrated. (17) The typical ethnic distribution of KFD has enticed a search for particular genetic markers that are responsible for the high incidence of KFD in Asian descendents; however, a specific genomic profile has not yet been identified. Based on clinical presentation, histopathologic features, and laboratory findings, it has been hypothesized that KFD might represent an exuberant T-cell-mediated hyperresponse to certain antigen stimuli in genetically susceptible individuals. (11) Some studies (10) have shown that the primary proliferative cells are the [CD8.sup.+] T lymphocytes, which induce target cell apoptosis and also undergo apoptosis themselves, accounting for the characteristic necrosis and nuclear debris seen in KFD. In addition, some reports indicate that levels of inflammatory mediators, such as interleukin-6 and Fas ligand, wax and wane along with the clinical course, which would support an immune-mediated etiology. (18,19)

Electron microscopic studies have revealed tubular reticular structures in the cytoplasm of activated lymphocytes and histiocytes in KFD. (20) Similar structures have also been identified in endothelial cells and lymphocytes in patients with systemic lupus erythematosus (SLE) and other autoimmune disorders; thus, a hypothesis was proposed that KFD might represent a SLE-like, autoimmune-type lymphadenitis, triggered by viruses or other infectious agents. However, serologic test findings for autoimmune antibodies, including antinuclear antibodies, rheumatoid factor and anti-double-strand DNA antibodies, have been consistently negative in patients with KFD, providing no support for an autoimmune mechanism of the disease. (3) Despite these negative results, there seems to be some association between KFD and SLE, which cannot be explained by random coincidence. (21)

DIFFERENTIAL DIAGNOSIS

Histologic differential diagnoses of KFD should include primarily the following entities: lymphoid malignancies, particularly non-Hodgkin lymphomas; lymphadenopathy due to autoimmune disorders, primarily SLE; and infectious etiologies, such as Epstein-Barr virus, herpes simplex virus, Bartonella henselae, and toxoplasmosis. Because of their differences in management from KFD, these entities must be excluded before a diagnosis of KFD can be made.

Lymphoid Malignancy

Kikuchi-Fujimoto disease must be distinguished from malignant lymphoma, either non-Hodgkin or Hodgkin disease, because both entities share similar clinical presentations and, sometimes, histologic features. Classic Hodgkin lymphoma could cause necrosis and have histiocytic infiltrate, but the presence of large Reed-Sternberg cells or variants, which are stained with CD30 or CD15 or both, and numerous eosinophils, as well as neutrophils, make its recognition relatively easier. In addition, the absence of CD30 expression by the histiocytes and plasmacytoid dendritic cells would make anaplastic large-cell lymphoma unlikely. Similarly, lack of expression of CD20 or other B-cell markers, such as CD79a or PAX5, within the large-cell population would make a lymphoma of B-cell lineage unlikely. A proliferation of immunoblasts and clusters of plasmacytoid dendritic cells, either in the proliferative phase or at the margins of the necrosis in the necrotizing phase, could potentially mimic a large-cell lymphoma, especially peripheral T-cell lymphoma, given the expansion of paracortex in both entities. In difficult cases, flow-cytometric analysis may be helpful in distinguishing KFD from non-Hodgkin lymphoma. Although [CD8.sup.+] T cells predominate in KFD, peripheral T-cell lymphomas are mainly [CD4.sup.+] cell types and usually have certain pan-T-cell antigen loss or carry some aberrant antigen markers. Of note, the diagnostic difficulty in distinguishing KFD from lymphoma has been emphasized in a case study in the United Kingdom, in which approximately 60% of the referring cases of KFD were initially thought to be malignant lymphoma before being sent for an expert opinion. (22) In addition, about one-third of the cases with a diagnosis of KFD were referred for staging and treatment following initial diagnosis of lymphoma at referring hospitals. Therefore, correct diagnosis of KFD would limit unnecessary diagnostic procedures and avoid toxic exposure for the patients.

Systemic Lupus Erythematosus

Systemic lupus erythematosus presents the most challenging differential consideration, and sometimes its histologic presentation may be identical to KFD. (23) Similar to KFD, SLE lymphadenitis may have variable degrees of paracortical necrosis with karyorrhectic debris and inflammatory cell response, including histiocytic infiltrate. In contrast to KFD, SLE lymphadenitis often demonstrates aggregates of degenerated nuclear debris (so-called hematoxylin bodies); aggregates of degenerated nuclear material present in the walls of blood vessels (Azzopardi phenomenon); prominent, reactive follicular hyperplasia; abundant plasma cells; and capsular or pericapsular inflammation, as well as sparse, cytotoxic T cells. Features that favor KFD include predominance of [CD8.sup.+] T cells, absence of neutrophils, and a relative paucity of plasma cells. Careful evaluation of the patient's clinical history and laboratory data, including dermatologic, neurologic, and constitutional symptoms, as well as the evaluation of antinuclear antibodies and complement levels (CH50, C3, and C4), would be helpful in difficult cases with ambiguous histology. (5,21) It should be emphasized that lupus lymphadenopathy can mimic KFD morphologically, and clinicians should be notified of this possibility in patients with a clinical suspicion of SLE to prevent delay in treatment. (23)

Infection

Several infectious etiologies, especially viruses, can present with paracortical expansion with necrosis and histiocytic infiltrate, thus mimicking KFD morphologically. In general, however, viral lymphadenitis, in contrast to KFD, has less-prominent histiocytic infiltrates, more neutrophils, more plasma cell proliferations, and predominant [CD4.sup.+] T cells. In addition, some viruses, like herpes simplex virus infections, may be distinguished by the presence of viral cytopathic features, such as viral inclusions. Specifically, infectious mononucleosis caused by EpsteinBarr virus may present with architectural effacement or alteration due to marked paracortical expansion by proliferation of immunoblasts, follicular hyperplasia with characteristic mottled edges, prominent monocytoid B cells, abundant plasma cells, and varying degrees of necrosis. These findings may be more extensive in immunocompromised patients. Infection with Toxoplasma gondii may present with histiocytic infiltrate and perifollicular granuloma formation; however, necrosis is uncommon. Necrotizing granulomatous lymphadenitis of tuberculosis, histoplasmosis, leprosy, and cat-scratch disease display proliferations of epithelioid cells, giant cells, and granuloma formation. Necrotizing lymphadenitis in syphilis is usually accompanied by perivascular plasma cell infiltrates; in Yersinia infection, by eosinophils; and in bacterial infection, by large numbers of neutrophils. In all these infectious lymphadenitis diseases, etiologic agents may be identified by special stains or immunohistochemical stains. These infectious agents could also be suggested by serologic tests or detected by molecular diagnostic studies. (11,16,24)

DISEASE COURSE AND THERAPY

Kikuchi-Fujimoto disease is a self-limiting condition, usually resolving within 4 months, but a low recurrence rate of 3% to 4% has been reported. (11) Rare fatal cases have been documented in the literature, including one patient with heart failure whose postmortem examination revealed focal areas of necrosis with a dilated heart (25) and another with associated hemophagocytic syndrome. (26) Because of its unknown etiology, a specific treatment for KFD is currently unavailable but may not be necessary. In general, therapy is targeted toward symptomatic relief, including relief of fever and lymph node tenderness with use of analgesics and antipyretics. Corticosteroids are reserved for severe cases or relapsing disease. Because of the association with SLE, it is suggested that patients receive a systemic survey and follow-up to evaluate subsequent development of SLE. (21,26)

References

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Accepted for publication May 21, 2009.

From the Department of Pathology, Duke University Medical Center, Durham, North Carolina.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Charles Blake Hutchinson, MD, Department of Pathology, Duke University Medical Center, 1 Trent Dr, Box 3712, Durham, NC 27710 (e-mail: blake.hutchinson@duke.edu).

Charles Blake Hutchinson, MD; Endi Wang, MD, PhD
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