Characterization of Plasmacytoid Dendritic Cells, Microbial Sequences, and Identification of a Candidate Public T-Cell Clone in Kikuchi-Fujimoto Disease.

OBJECTIVES: Kikuchi-Fujimoto disease (KFD) is a self-limited lymphadenitis of unclear etiology. We aimed to further characterize this disease in pediatric patients, including evaluation of the CD123 immunohistochemical (IHC) staining and investigation of potential immunologic and infectious causes. METHODS: Seventeen KFD cases and 12 controls were retrospectively identified, and the histologic and clinical features were evaluated. CD123 IHC staining was quantified by digital image analysis. Next generation sequencing was employed for comparative microbial analysis via RNAseq (5 KFD cases) and to evaluate the immune repertoire (9 KFD cases). RESULTS: In cases of lymphadenitis with necrosis, >0.85% CD123+ cells by IHC was found to be six times more likely in cases with a final diagnosis of KFD (sensitivity 75%, specificity 87.5%). RNAseq based comparative microbial analysis did not detect novel or known pathogen sequences in KFD. A shared complementarity determining region 3 (CDR3) sequence and use of the same T-cell receptor beta variable region family was identified in KFD LNs but not controls, and was not identified in available databases. CONCLUSIONS: Digital quantification of CD123 IHC can distinguish KFD from other necrotizing lymphadenitides. The presence of a unique shared CDR3 sequence suggests that a shared antigen underlies KFD pathogenesis.

Facial and limb angioedema with parotitis and Kikuchi-like necrotizing lymphadenitis preceding neuropsychiatric systemic lupus erythematosus in a young African American male.

Angioedema has been observed in a few cases secondary to systemic lupus erythematosus (SLE). Herein, we report a rare case where a young healthy male initially presented with angioedema, lymphadenopathy and parotitis and later on developed neuropsychiatric manifestations at the very onset of his SLE disease. This case illustrates the importance of prompt clinical consideration of lupus with unusual and atypical preceding manifestations.

[Clinicopathologic characteristics and immunophenotypes of histiocytic necrotizing lymphadenitis: an analysis of 84 cases].

OBJECTIVE: To study the clinical manifestation, pathologic features and immunophenotype of histiocytic necrotizing lymphadenitis (HNL). METHODS: The clinicopathologic data of 84 patients with HNL from 2005 to 2014 were retrospectively studied. Immunohistochemical staining using EliVision method for CD20, PAX5, CD3, CD45RO, CD4, CD8, CD56, CD68, CD123, granzyme-B, TIA1 and MPO was carried out. In-situ hybridization for Epstein-Barr virus RNA was performed on archival lymph node biopsy tissue. RESULTS: Immunohistochemical study showed that the lesional cells were predominantly histiocytes (CD68+), plasmacytoid dendritic cells (CD123+) and T lymphocytes (CD3+ and CD45RO+). Clusters of CD68-positive cells with strong and diffuse MPO expression were identified. T lymphocytes with CD4 and CD8 positivity were noted. CD56+ natural killer cells and CD20+/PAX5 B cells were rare. Apoptosis-related markers, including TIA1 and granzyme B were expressed by T lymphocytes and histiocytes in lymph nodes of HNL. In-situ hybridization for Epstein-Barr virus RNA was positive in only 10.0% of the cases. CONCLUSIONS: HNL shows no specific clinical and laboratory findings. Recognition of the characteristic histopathologic changes in lymph node biopsy of HNL is the key to correct diagnosis. Immunohistochemical study using a panel of markers, including CD3, CD4, CD8, MPO, CD123, granzyme-B and TIA1, is helpful in the differential diagnosis of HNL.

Plasmacytoid Dendritic Cells Producing Interferon-α (IFN-α) and Inducing Mx1 Play an Important Role for CD4(+) Cells and CD8(+) Cells in Necrotizing Lymphadenitis.

We confirmed the characteristic clinical features of necrotizing lymphadenitis (NEL) in 66 cases (23 male, 43 female) in Japan, which included high fever (38-40°), painful cervical lymphadenopathy (62/66, 93.9%), and leukopenia (under 4,000/mm(3)) (25/53, 47.2%), without seasonal occurrence, in a clinicopathological, immunohistochemical, electron microscopic serological study. Patient age varied from 3-55 years, and 72.7% (44/66) of patients were younger than 30 years. Histopathology of NEL was characterized by the presence of CD8(+) immunoblasts, CD123(+) cells (plasmacytoid dendritic cells; PDCs), histiocytes and macrophages phagocytizing CD4(+) apoptotic lymphocytes, but no granulocytes or bacteria. The number of PDCs and CD8(+) cells in lesions tended to increase with time, and PDCs tended to be larger and irregular in the lesions compared with the non-lesion tissue of the lymph nodes. In addition, PDCs showed no temporal morphological change in the lymph nodes. The number of CD4(+) cells in the lymph node lesions sharply decreased from the 2nd to the 4th week, and then tended to increase; however, CD4(+) cells gradually decreased with time in non-lesion tissue. PDCs may produce interferon-α (IFN-α), which induces Mx1 expression. Strong Mx1 immunoreactivity is indicative of IFN-α production. IFN-α induces transformation of CD8(+) cells into immunoblasts, as well as phagocytosis of apoptotic cells derived from CD4(+) cells by macrophages. Thus, PDCs may play an important role with immune cells, including CD8(+) and CD4(+) cells, in necrotizing lymphadenitis.

Aberrant phenotypes in Kikuchi's disease.

Initial reports emphasized the immunophenotypic similarities between benign and malignant T cell populations, while some previous studies indicating that aberrant T-cell antigen loss is a good marker for detecting malignant T-cell proliferation. Recently, we found a very interesting and thought-provoking phenomenon: In benign disease-28 of 38 (73.7%) cases of Kikuchi's disease also showed aberrant phenotypes with loss of pan-T cell antigens, which makes the differential diagnosis between Kikuchi's disease and T cell lymphoma more challenging. In our study, 38 cases of Kikuchi's disease and 30 cases of reactive lymphoid hyperplasia (RLH) were studied by EliVision immunohistochemical staining. As well as TCR gene rearrangement using PCR was negative in 10 tested cases of the Kikuchi's disease. Among these cases, the most common antigen deficiency was CD5 (22 cases), then CD7 (11 cases), CD2 (8 cases) and CD3 (2 cases). Compared with proliferative and xanthomatous types of Kikuchi's disease, antigens tended to be lost in necrotizing type. Based on follow-up data, a correlation was not found between the occurrence of aberrant phenotypes and prognosis. In RLH, obvious pan-T cell antigen loss was also not found. In conclusion, this is the first study to demonstrate distinct patterns of antigen loss in Kikuchi's disease, suggesting that T cell antigen loss is not reliable as an auxiliary diagnostic standard for T cell lymphoma.

Histiocytic necrotizing lymphadenitis diagnosed by conventional cytology and liquid based cytology.

Histiocytic necrotizing lymphadenitis (HNL; Kikuchi-Fujimoto disease) is a rare benign disorder. The diagnosis of HNL is established on recognizing the characteristic histologic findings from biopsy of the enlarged lymph nodes. Though diagnosis of HNL by fine-needle aspiration (FNA) was reported, the characteristic fine-needle aspiration cytologic features with conventional cytology and a liquid based cytology test (LCT) have not been well documented. In this study, 42 cases of suspicious necrotic lymph nodes were subjected to cytology and biopsy diagnosis. The lymph nodes were aspirated using a 10 mL disposable syringe with the percutaneous ultrasound guided. Samples were used for conventional cytology and LCT. Among 42 cases of suspicious necrotic lymph nodes, 37 of cases were histologically confirmed as HNL; 3 of cases were hyperplasia of lymphoid tissue; 1 case was tuberculosis of lymph node, and 1 case was classical Hodgkin lymphoma (nodular sclerosis type). 31 out of 37 (83.8%) cases of HNL were diagnosed by conventional cytology, 33 out of 37 (89.2%) were diagnosed by LCT. Our results indicate that no significant difference on accuracy rate between conventional cytology and LCT, but LCT has its advantages in the diagnosis of HNL.

Cutaneous lesions of Kikuchi's disease: evolution of histopathological findings.

We report a 38-year-old male patient who presented with cutaneous lesions mimicking widespread discoid lupus erythematosus with high-grade fever, arthralgia and lymphadenopathy. Additional lymph node and skin biopsies, however, revealed karyorrhectic debris without neutrophils and numerous CD68-positive cells, a characteristic finding of Kikuchi's disease (KD). Comparing skin biopsies on different occasions, we could see different forms of histopathology. The histopathology of skin lesions of KD may vary during the clinical course, which may reflect the stage of the disease.

A case series of autoimmune diseases accompanied by incidentally diagnosed monoclonal gammopathy: is there a link between the two diseases?

AIM: Although the etiology of plasma cell dyscrasia is poorly understood, there is evidence for immune dysregulation or sustained immune stimulation playing a pivotal role in the pathogenesis of these diseases, including chronic infection and autoimmune disorders. In this study, we report four autoimmune disease cases where monoclonal gammopathy (MG) was incidentally found during follow-up. METHODS: We retrospectively reviewed the medical charts and laboratory test results in the following four cases: neuromyelitis optica, Kikuchi disease, Sjögren syndrome and ankylosing spondylosis. RESULTS: The four patients were older than 55 years and the male-to-female ratio was 2 : 2. The autoimmune disease in each case developed differently because two patients had coincidental detection of MG, whereas MG was detected 2 years and 10 years after diagnosis in the other two patients. The amount of M-components in the blood for two cases was ≤ 1 g/dL. For the other two subjects, M-components were ≥ 3 g/dL. CONCLUSION: A high prevalence of MG of undetermined significance (MGUS) has been noted in a series of patients with immune disorders, suggesting a possible association with MG. Further studies should focus on determining how MG relates to various clinical information and laboratory parameters, such as disease duration, disease activity and higher sedimentation rate. In the future, we also need to identify which stimuli, such as cytokine types and levels, can induce lymphocyte clonal transformation and the production of monoclonal antibodies.

Splenic manifestations of chronic autoimmune disorder: a report of five cases with histiocytic necrotizing change in four cases.

AIMS: Autoimmune diseases (AD) are associated with lymphadenopathy and splenomegaly. Changes in the spleen have not been characterized completely in AD; we describe splenectomy specimens from five patients with chronic AD, highlighting the presence of necrotizing histiocytosis. METHODS AND RESULTS: Of the patients (three males and two females; mean 40 years), four had systemic lupus erythematosus; one had rheumatoid arthritis. All had moderate splenomegaly (213-803 g, mean 421 g). Four cases exhibited necrosis with apoptosis and karyorrhectic debris occurring in the white pulp and minimal acute inflammation; one showed florid follicular hyperplasia. Splenic involvement ranged from focal to extensive. Plasma cells were negative for IgG4. Haematoxylin bodies were not identified. Stains for infectious organisms were negative. Immunohistochemical studies showed that lymphocytes surrounding the necrosis were a mixture of CD4(+) and CD8(+) T cells; CD123-positive plasmacytoid dendritic cells were not present, and staining for kappa and lambda light chains showed no clonality. 16S rDNA PCR was performed; no amplification was seen in three of four cases tested for bacteria specific rDNA. Epstein-Barr virus-encoded RNA (EBER) in situ hybridization studies highlighted rare positive cells in four cases. CONCLUSIONS: Splenomegaly in AD is thought to be hyperplasic, but we present four cases showing histiocytic necrosis, a finding which should be considered part of the spectrum of AD in the spleen.

Encephalitis and CSF increased level of interferon-α in Kikuchi-Fujimoto disease.

Neurological manifestations have been reported in Kikuchi-Fujimoto disease (KFD). Characteristics of brain lesions are not defined. In addition, no biological indexes are known to help clinicians along the diagnosis process. The authors describe encephalitis associated with KFD. Brain MRI, positron emission tomography (PET) scan and a large biological assessment including interferon α (INF-α) level measurement in cerebrospinal fluid (CSF) were performed. A 39-year-old man with chronic headaches developed diplopia, slow ideation and behavioural disturbances. MRI showed brain lesions particularly in the pontine region and internal temporal lobes with enhancement of the perivacular space and the walls of the lateral ventricle. The IFN-α level was increased in the CSF without viral infection. Cervical and mediastinal adenitis were evident as a hypermetabolic focus on a PET scan, and biopsy confirmed the diagnosis of KFD. The encephalitis spontaneously remitted. The authors characterised brain lesions especially related to KFD in association with increased of IFN-α level in the CSF.

Kikuchi-Fujimoto disease mimicking tuberculous lymphadenitis.

A 28-year-old woman was referred to our hospital for treatment of tuberculous lymphadenitis, after presenting with fever, left cervical lymphadenopathy, and a positive interferon-gamma release assay (QuantiFERON®-TB Gold In-Tube; QFT) result. Surprisingly, biopsy specimens of the cervical lymph nodes showed necrotic lesions with prominent nuclear debris and a proliferation of histiocytes, consistent with Kikuchi-Fujimoto disease (KFD). A diagnosis was made of KFD complicated by latent tuberculosis infection (LTBI), and all symptoms had resolved completely two months post-diagnosis. KFD may be misdiagnosed as tuberculous lymphadenitis, and antibiotics unnecessarily prescribed. Careful attention should therefore be paid when diagnosing cervical lymphadenopathy.

[A rare cause of febrile polyadenopathy in children: Kikuchi-Fujimoto disease]. / Une cause rare chez l'enfant de poly-adénopathie fébrile : la maladie de Kikuchi-Fujimoto.

Kikuchi disease is a histiocytic necrotizing lymphadenitis revealed by cervical lymphadenopathy and prolonged fever. It occurs predominantly in young Asian women. The pathophysiology is unknown; the main hypothesis is an autoimmune process. Although the disease usually resolves spontaneously in a few weeks or months, it may progress to systemic lupus erythematosus. Kikuchi disease is rare in children, but it should be considered a potential diagnosis in case of polyadenopathy. We relate a case of Kikuchi-Fujimoto disease in a 13-year-old boy with sickle-cell anemia. The diagnosis, which was established after 3 weeks of hospitalization, enabled us to avoid unnecessary extensive investigations and prolonged empirical treatments that may result in unintended adverse side effects.

Why is Kikuchi-Fujimoto disease misleading?

BACKGROUND: Kikuchi-Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is a rare, benign, autoimmune condition characterized by lymphadenopathy, fever, and neutropenia. KFD has also been frequently reported in association with systemic lupus erythematosus (SLE). REPORT: We report a case of skin manifestations in KFD characterized by malar rash, photosensitivity, panniculitic lesions, positive antinuclear antibodies and nDNA, and negative extractable nuclear antigen. A biopsy performed on deep nodules on the arms revealed an infiltrate of monocytic cells. Electron microscopy showed no lymphocytic infiltrate at or below the basal membrane and no necrotic keratinocytes within the basal cells of the epidermis. CONCLUSION: Histological and ultrastructural data showed that skin manifestations of KFD and SLE share some common features. Electron microscopy analysis can help discriminate between the two diagnoses.

Cutaneous manifestations associated with adult-onset Still's disease: important diagnostic values.

Adult-onset Still's disease (AOSD) is a systemic inflammatory condition, characterized by a high spiking fever, leukocytosis with neutrophilia, arthralgia, and skin rash. Typical skin rash is an evanescent, salmon-pink erythema predominantly involving extremities, which is included as one of the diagnostic criteria; however, recent findings show that not only typical evanescent rash but also various skin lesions are associated with AOSD. The representative characteristic skin lesion among the non-classical skin rash is called persistent pruritic papules and plaques, which presents erythematous, slightly scaly papules with linear configuration on the trunk. Interestingly, persistent pruritic papules and plaques show unique histological features such as peculiar, distinctive distribution of dyskeratotic keratinocytes in the cornified layers as well as in the epidermis. Other non-classical skin lesions include urticaria. Current insights suggest that several inflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-18, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) play a pathogenic role in AOSD. In particular, IL-18 is suggested to play a crucial role in activating macrophages, favoring Th1 type cytokine production. IL-18 induces IFN-γ, IL-17, and TNF-α, which may play an important pathogenic role in AOSD. It is important to recognize the common and/or uncommon skin conditions of AOSD for early correct diagnosis. In this review, various skin lesions are introduced, and the complication with histiocytic necrotizing lymphadenitis (Kikuchi disease) is further discussed.

Autoimmune manifestations of Kikuchi disease.

OBJECTIVES: Kikuchi's disease (KD) has been associated with the presence of autoantibodies, systemic lupus erythematosus (SLE), and other autoimmune diseases. The aim of this study was to assess the frequency of autoimmune manifestations in a KD cohort with a long follow-up. METHODS: Twenty patients with histologically confirmed KD since January 1990 until December 2010 were studied; 12 of them were periodically followed up as outpatients. Another 7 patients were contacted by telephone to offer them a specific consultation and a complete autoimmunity study. RESULTS: Thirteen of 20 patients were women (65%) with a mean age of 29 years (range, 15-79). The age at diagnosis was higher in men (44 vs 27 years, P < 0.05). Lymphopenia was present in 75% of the patients (15/20) and was the more frequent hematological abnormality. The mean follow-up of the 17 patients included in the autoimmunity study was 119 months (range, 15-252). Autoimmune diseases were detected in 9 women (53%): SLE was diagnosed in 4 patients (2 SLE before, 1 simultaneous, and 1 after KD), 2 patients developed primary Sjögren's syndrome after KD, 1 thyroiditis before KD, 1 SLE-like, and 1 antiphospholipid antibodies after KD. Leukocytoclastic vasculitis was found in 2 patients; 1 of them eventually developed SLE. Female sex, painful adenopathies, and cytopenias were significantly associated with autoimmune diseases. CONCLUSIONS: Among patients with KD, only women developed autoimmune manifestations. Therefore, long-term follow-up and active surveillance of autoimmune diseases in patients with KD, especially women, are recommended.

[Loss of pan-T cell antigens CD2, CD3, CD5 and CD7 in Kikuchi's disease].

OBJECTIVE: To study the possible loss of pan-T cell antigens CD2, CD3, CD5 and CD7 in Kikuchi's disease and to evaluate the role of T cell antigen loss in distinguishing benign from malignant T-cell lymphoid lesions. METHODS: Formalin-fixed and paraffin-embedded tissues of 33 cases of Kikuchi's disease and 15 cases of reactive lymphoid hyperplasia were studied by EliVision immunohistochemical staining for CD2, CD3, CD5 and CD7. RESULTS: Twenty-four of the 33 (72.7%) cases of Kikuchi's disease lost one or more of the pan-T cell antigens, including the loss of CD5 only (13 cases), CD7 only (1 case), CD2 only (1 case), CD2 and CD7 (2 cases), CD5 and CD7 (4 cases), CD2 and CD5 (2 cases), and CD2, CD7 and CD5 (1 case). Amongst these cases, the commonest antigen loss was CD5 (20 cases, 60.6%), followed by CD7 (8 cases, 24.2%) and CD2 (6 cases, 18.2%). Compared with the xanthomatous subtype of Kikuchi's disease, the loss of antigens was more commonly seen in the proliferative and necrotizing subtypes. Analysis of follow-up data showed that the loss of antigens in Kikuchi's disease was not significantly associated with the prognosis. In reactive lymphoid hyperplasia, the expression of CD2, CD3, CD5 and CD7 was seen in all cases with similar intensity, with no obvious pan-T cell antigen loss. CONCLUSION: Loss of one or more pan-T cell antigens in Kikuchi's disease is demonstrated in present study, suggesting that the immunophenotypic pattern is not unique in T cell lymphoma.

Clinical presentations, laboratory results and outcomes of patients with Kikuchi's disease: emphasis on the association between recurrent Kikuchi's disease and autoimmune diseases.

BACKGROUND/PURPOSE: Kikuchi's disease (KD), also known as histiocytic necrotizing lymphadenitis, is a benign and self-limiting disease of unknown etiology that mainly affects young women. There is limited data on the long-term prognosis of patients with KD. METHODS: We describe the clinical manifestations and outcomes of 195 patients, diagnosed as having KD at National Taiwan University Hospital from March 1989 to September 2006. RESULTS: All together, 53.3% of our patients presented with tender lymphadenopathy, 37.9% with fever and 16.9% with headache. The most common laboratory findings were elevated erythrocyte sedimentation rate (78.9%), elevated serum lactate dehydrogenase (52.5%), elevated C-reactive protein (38.3%), monocytosis (26.9%), elevated serum alanine aminotransferase (23.3%) and leukopenia (18.9%). A total of 183 patients followed a benign course, with spontaneous resolution of fever and lymphadenopathy. However, 14 patients (14.6%) with follow-up of more than 6 months had clinical recurrence of KD; hence, long-term follow-up is suggested. Five of these patients developed an autoimmune disease, namely, systemic lupus erythematosus (n = 2), Graves' disease (n = 2), or mixed connective tissue disease (n = 1). One patient with recurrent KD died of intracranial hemorrhage due to thrombocytopenia. CONCLUSION: The prognosis for KD patients is generally optimistic; however, a concurrent autoimmune disease or the risk of developing an autoimmune disease requires careful monitoring.