|Year : 2018 | Volume
| Issue : 1 | Page : 56-59
Kikuchi–Fujimoto disease presenting as pyrexia of unknown origin
Prasanta Padhan1, Krishna Prasad Tripathy2, Saroj Ranjan Sahoo3, Debasish Maikup2, Nachiketa Mahapatra4
1 Department of Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
2 Department of Medicine, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
3 Department of Surgical Oncology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
4 Department of Pathology, Apollo Hospitals, Bhubaneswar, Odisha, India
|Date of Web Publication||26-Feb-2018|
Dr. Prasanta Padhan
Department of Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar - 751 024, Odisha
Source of Support: None, Conflict of Interest: None
Kikuchi–Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare benign, self-limiting disorder of unknown etiology. Mostly prevalent among Asian women, KFD manifests mostly with cervical and rarely generalized or retroperitoneal lymphadenopathy in addition to fever. It can closely mimic infective and immunological disorders. Here, we report a 23-year-old female who presented with fever of unknown origin with other constitutional symptoms. The infectious and malignancy screen was negative on extensive workup. The patient was found to have multiple abdominal and cervical lymph nodes on imaging, biopsy and immunohistochemistry revealed histiocytic necrotizing lymphadenitis, which confirmed the diagnosis of KFD. Although rare, clinicians should be aware of KFD condition, as early recognition of the disease will minimize potentially harmful and unnecessary evaluation and treatments.
Keywords: Histiocytic necrotizing lymphadenitis, Kikuchi-Fujimoto disease, Systemic lupus erythematosus
|How to cite this article:|
Padhan P, Tripathy KP, Sahoo SR, Maikup D, Mahapatra N. Kikuchi–Fujimoto disease presenting as pyrexia of unknown origin. Indian J Rheumatol 2018;13:56-9
| Introduction|| |
Kikuchi–Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is an uncommon, idiopathic, generally self-limited cause of lymphadenitis. Kikuchi first described the disease in 1972 in Japan. The pathogenesis is still poorly understood but is thought to include a hyperimmune reaction induced by different antigenic stimuli or an autoimmune-mediated process in which apoptosis plays a major role. The most frequent clinical manifestations are fever and painless cervical lymphadenitis. Lymph node histopathology is diagnostic and treating physicians should be aware of this entity as it may mimic other systemic diseases such as systemic lupus erythematosus, tuberculosis (TB), malignant lymphoma, and more rarely adenocarcinoma. Key features on lymph node biopsy are fragmentation, necrosis, and karyorrhexis.
| Case Report|| |
A 23-year-old female presented to us with fever of 1-week duration. There was no history of cough, dyspnea, chest pain, pain abdomen, dysuria, joint pain, rashes, and convulsions. There was no previous history of TB or contact with TB. The patient did not have prior history of fever with detectable cervical adenopathy. She did not have history of any drug intake or atopy. On general examination, she had mild pallor. The blood pressure was 124/86 mmHg and the pulse rate was 112/min. She was febrile (102°F). She did not have palpable lymphadenopathy. Her cardiovascular, respiratory, and neurological system examination was normal. The abdomen was soft with normal bowel sounds and no organomegaly. Skin and throat examination were normal. Laboratory investigations revealed high serum lactate dehydrogenase (LDH) (1351 U/L), elevated ferritin (2000 ng/ml) with bicytopenia (leukopenia, total leukocyte count 2600/cmm, and anemia, hemoglobin 8.8 g/dl) with elevated acute phase reactants (erythrocyte sedimentation rate [ESR] = 97 mm in 1st h and C-reactive protein [CRP] 25 mg/dl). Peripheral smear showed microcytic hypochromic anemia with mild leucopenia. Bone marrow biopsy revealed micronormoblastic erythropoiesis with mild dyserythropoietic changes. Bone marrow examination staining for acid–fast bacilli was also negative. Bone marrow examination did not reveal features of lymphoma and granulomas, TB polymerase chain reaction was also negative. Serology for Epstein–Barr virus (EBV), hepatitis B virus, hepatitis C virus, and HIV were negative. Renal and liver function tests were normal. Routine urine examination was normal. Blood and urine cultures were negative. Tests for malaria parasite and scrub typhus and enteric fever were negative. Mantoux test showed induration of 4 mm. Chest radiograph and two-dimensional echocardiography were normal. Antinuclear antibody and anti-DNA antibody were negative. Ultrasonography of abdomen and pelvis shows enlarged few mesenteric lymph node which also corroborated with abdominal computed tomography scan. Family refused for a laparoscopic mesenteric lymph node biopsy. As she continued to have fever in the hospital without any response to broad-spectrum antibiotics, in the 4th week of her continued febrile illness, PET scan was done which showed cervical (bilateral level 2 lymph nodes, largest size 0.9 cm × 0.7 cm, left supraclavicular lymph node size 0.8 cm × 0.5 cm and abdominal (splenic, portocaval, mesenteric, and inguinal lymphadenopathy). Lymph node biopsy of cervical region was done. Histopathologic examination revealed an effaced nodal architecture [Figure 1] with foci of necrosis containing karyorrhectic debris, and sheets of xanthoma-like foam cells [Figure 2]. The histiocytes had clear cytoplasm and round nuclei. The large cells (histiocytes) observed in Kikuchi's disease are positive for CD68 [Figure 3] and myeloperoxidase [Figure 4] in immunohistochemistry. Neutrophils, atypical cells, Reed–Sternberg cells, or granulomas were not identified in any section. Stains and cultures for bacteria, fungi, and mycobacteria were negative. These findings were consistent with a histological diagnosis of histiocytic necrotizing lymphadenitis. The patient was treated symptomatically with Naproxen 500 mg twice daily and complete remission occurred in 2 weeks. On follow-up after 6 months, she did not have recurrence.
|Figure 1: Loss of architecture of lymph node and replacement by foam-like xanthoma cells (H and E, ×10)|
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|Figure 2: Foci of necrosis containing karyorrhectic debris between xanthoma-like foam cells (H and E, ×40)|
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| Discussion|| |
This is a rare case of KFD who presented us as pyrexia of unknown origin (PUO) without any specific clinical clues. After excluding infection and malignancy by various investigations, finally histopathology of cervical lymph node along with immunohistochemistry confirmed the diagnosis. KFD is a benign, self-limiting condition that more commonly affects females (male-to-female ratio, 1:4) under the age of 30 years (mean, 29 years). Often, it can be misdiagnosed as TB. Its etiology has not yet been fully determined; however, it is believed it may be of viral origin, EBV, HHV6, and 8 have been suggested. Kikuchi's disease might represent an exuberant T-cell-mediated hyperresponse to certain antigenic stimuli in genetically susceptible individuals. It tends to affect a young population under 30 years of age, including children, although the latter are less commonly affected. The most common clinical manifestation is cervical lymphadenopathy with or without fever. Fever may be of high grade and lymphadenopathy may appear late in the course of illness. Sore throat, weight loss, sweating, chills, myalgia, arthralgia, splenomegaly, and skin rash may accompany the lymphadenopathy. Laboratory findings may include leukopenia, and elevated serum transaminase and serum LDH. The course is benign and is followed by complete recovery within 1–3 months in almost all cases. Recurrences may occur but are infrequent, and fatalities are unusual.
Routine laboratory investigations usually does not aid in the diagnosis except for ESR and CRP which might be elevated and many patients have a low white blood count. Moreover, 25% to 31% of patients have atypical peripheral blood lymphocytes. Fine-needle aspiration cytology only has a limited role in establishing the diagnosis of Kikuchi's disease with the overall diagnostic accuracy estimated at 56%. Diagnosis is based on histopathological findings of a lymph node biopsy. In a series by Mohan et al., for the evaluation of etiology for peripheral lymphadenopathy, 2% were due to KFD, in whom cervical and submandibular lymph nodes were involved. Lymphocytes are predominantly CD8+ T-cells in Kikuchi, in contrast to mainly CD4+ T-cells in other types of reactive lymphadenopathy with T-zone expansion. The degree of necrosis varies considerably from one case to another. Based on the histopathology, it has been proposed to classify KFD into 3 evolving 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. It is classified as being in the necrotizing phase once a necrosis of any degree is observed in the lesion. If foamy histiocytes predominate in the lesions, the case is categorized as being in the xanthomatous phase, despite the presence or absence of necrosis. Our case falls into this category.
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.
Commonest histological differential diagnosis:
- Lymphoid malignancies, particularly non-Hodgkin lymphomas
- Lymphadenopathy due to autoimmune disorders, primarily SLE; and
- Reactive lymphadenopathy due to infectious etiologies, such as EBV, 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.
Classic Hodgkin's lymphoma could cause necrosis and have histiocytic infiltrate, but the presence of large Reed-Sternberg cells More Details 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+ T-cells predominate in KFD, peripheral T-cell lymphomas are mainly CD4+ cell types and usually have certain pan-T-cell antigen loss or carry some aberrant antigen markers.
Systemic lupus erythematosus
Systemic lupus erythematosus presents the most challenging differential consideration, and sometimes its histologic presentation may be identical to KFD. 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; and abundant plasma cells. Features that favor KFD includes predominance of CD8+ 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.
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+ T-cells. Diagnosis of infectious mononucleosis can be made by characteristic clinical, hematologic, and serologic findings.
Long-term follow-up of these patients is necessary as recurrent cases of KFD have been reported, and there is some belief that KFD may be a precursor for SLE, as both diseases have had concurrent and coexisting disease patterns in the same patients. Association between Kikuchi's disease and SLE has been reported, with some patients of Kikuchi's disease developing a full-blown SLE.
No specific treatment is available for Kikuchi's disease. Treatment is generally supportive. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to alleviate lymph node tenderness and fever. The use of corticosteroids has been recommended in recurrence, severe forms of disease with extranodal involvement such as the central nervous system and lungs. Intravenous Immunoglobulin has also been tried with some success. The disease usually runs a benign course and the condition is self-limiting, usually resolves in several weeks to months, with a recurrence rate of 3%–4%.
| Conclusion|| |
Although the incidence of KFD is rare, this disorder must be considered with any patient with PUO with or without regional lymphadenopathy. Many patients have a self-limiting course as in this case; however, these patients need follow-up on for possible recurrence and association of this disease with rheumatological diseases. Prompt recognition of this rare disease is important in reducing unnecessary evaluation and treatments.
The authors would like to thank Mr. Suriya Kumar Mohanty, for his efforts to compile all the patient's data.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]