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| ORIGINAL ARTICLE |
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| Year : 2016 | Volume
: 5
| Issue : 3 | Page : 134-137 |
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Kikuchi's disease: A study of 96 cases over a 12-year period
Vijayalakshmi Susheelan1, Renu Thambi2, Siji Mathew3
1 Division of Pathology, Doctors Diagnostic and Research Laboratory, Kottayam, Kerala, India
2 Department of Pathology, Government Medical College, Kottayam, Kerala, India
3 Department of Pathology, Government Medical College, Alappuzha, Kerala, India
| Date of Web Publication | 14-Dec-2016 |
Correspondence Address:
Renu Thambi
Department of Pathology, Government Medical College, Kottayam, Kerala
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2278-0521.195818
Background: Kikuchi-Fujimoto disease was first described in 1972 in Japan and since then it has been reported worldwide. It is a self-limiting disorder typically seen in young females involving cervical lymph nodes and easily mistaken for tuberculosis or lymphoma. Objectives: The objective of this study is to analyze the clinical and histopathological details of Kikuchi's disease. Methods: Lymph node biopsy specimen of 96 cases of Kikuchi's disease was studied during a period of 12 years. Clinical data including the age, sex, presenting symptoms and sites of lymph node enlargement were recorded. Detailed histological sections were studied with hematoxylin and eosin, periodic acid-Schiff, and acid-fast stains. Results: Seventy-six out of 96 cases occurred in females (female: male ratio 3.5:1). The predominant age group affected was the second to third decade. The most common presenting symptom was cervical lymphadenopathy in 80/96 cases. Histology of lymph node showed multifocal necrosis, with pyknotic nuclear debris and absence of neutrophils. No vasculitis was observed. In all the cases, Mantoux test and special stains for infective organisms were negative. Conclusion: It is of paramount importance that awareness of this disorder should always be borne in mind and exclude lymphoma, tuberculosis, or autoimmune disorder such as systemic lupus erythematosus. These patients should be followed up with supportive treatment, since it is a self-limiting disorder. Keywords: India, Kikuchi′s disease, subacute necrotizing lymphadenitis
How to cite this article:
Susheelan V, Thambi R, Mathew S. Kikuchi's disease: A study of 96 cases over a 12-year period. Saudi J Health Sci 2016;5:134-7 |
| Introduction | |  |
Kikuchi-Fujimoto disease was first described simultaneously by Kikuchi and Fujimoto in 1972 in Japan. It is a benign self-limiting lymph node enlargement typically seen in young females involving cervical lymph nodes and easily mistaken for tuberculosis or lymphoma. [1],[2]
The etiology of Kikuchi disease is still debated, although infectious and autoimmune causes have been suggested, none has been proved. One of the hypotheses is that Kikuchi disease results from an unidentified agent which triggers a self-limited autoimmune process. However, serologic tests for autoimmune antibodies including antinuclear antibodies (ANAs), rheumatoid factor, and anti-double-strand DNA antibodies have been consistently inconsistent in patients with Kikuchi disease. Despite these, associations between Kikuchi disease and systemic lupus erythematosus (SLE) have been well documented in literature. [3],[4]
| Methods | | |
Lymph node biopsy specimens received in our laboratory in South India as cases of clinical lymphadenopathy which were histologically diagnosed as Kikuchi's disease were retrieved and studied in detail. These included 96 cases of Kikuchi's disease over a period of 12 years from 2003 to 2015. Clinical data including the age, sex, presenting symptoms, and sites of lymph node enlargement were recorded. Formalin-fixed paraffin-embedded tissue was studied. Four micrometer thick tissue sections, stained with hematoxylin and eosin, were studied. Special stains - periodic acid-Schiff, Gomori methenamine silver, and acid-fast stain - were done in all cases. Immunohistochemistry to exclude lymphoma was done in suspicious cases. Once the diagnosis of Kikuchi disease was given, serum ANA test was done to exclude SLE.
| Results | | |
The predominant age group affected in our study was between second and third decades; detailed age distribution of all cases is shown in [Table 1]. Seventy-six out of 96 cases (76/96) occurred in females with an female:male ratio of 3.5:1. The most common presenting symptom was cervical lymphadenopathy in 80 out of 96 cases. [Table 2] shows the different sites of involved lymph nodes. Systemic manifestations such as fever and organomegaly were noted only in one case which later on developed recurrent lymphadenopathy (1%) within a span of a month. The patient recovered fully with systemic steroid treatment. None of the other cases showed hepatosplenomegaly, anemia, or major systemic symptoms. No fatal outcome or multicentric presentations were observed. No familial incidence or clustering of cases were observed.
Lymph node biopsy showed multifocal paracortical necrosis, pyknotic nuclear debris, plasmacytoid dendritic cells, and absence of neutrophils, eosinophils, granuloma, or giant cells [Figure 1]a. Predominant pattern was necrotic with crescentic histiocytes [Figure 1]b. Rare patterns observed were foam cell and proliferative [Figure 1]c and d. Prominent plasma cell infiltrate and immunoblasts were noted in few cases. None of our cases showed vasculitis. In all the cases, Mantoux test, special stains for infective organisms, and ANA were negative. Histopathology of lymph node in the recurrent case showed similar picture, but with massive necrosis. | Figure 1: (a) Extensively involved lymph node with multiple patchy areas of necrosis. Inset shows cresentic histiocyte (H and E, ×40). (b) Nodular aggregates of histiocytes with coagulative necrosis, nuclear debris, and crescentic histiocytes - necrotic pattern (H and E, ×40). (c) Nodular aggregates of foamy histiocytes without necrosis - foam cell pattern (H and E, ×40). (d) Nodular aggregates of histiocytes and plasmacytoid monocytes with pyknotic nuclei and scattered nuclear debris and devoid of overt necrosis - proliferative pattern (H and E, ×40)
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| Discussion | | |
Kikuchi disease is a benign self-limiting lymph node disease reported frequently in the Asian population and rarely from rest of the world and in all races. [5],[6],[7],[8],[9],[10],[11] Only few cases are reported from India. [5],[8],[9],[10],[11],[12],[13] Women are affected more often than men, by a ratio of approximately 3:1. However, recent reports suggest a decline in female:male ratio. [4],[5],[6],[12],[14] In our case series, there was marked female preponderance comparable with previous studies. Kikuchi disease occurs in a wide age range of patients (i.e., 2-75 years), and it typically affects young adults. Our cases showed a mean age group of 22.5 years consistent with most previous studies. The common presentation is cervical adenopathy with characteristic involvement of the posterior cervical group of nodes. Multiple unilateral and bilateral slightly enlarged lymph nodes with perinodal infiltration are picked up by radiology. [9],[12],[14] Multicentric or generalized adenopathy, though rare, is described. [4],[7],[15],[16],[17] Majority of our cases presented as cervical adenopathy and no generalized lymph node enlargement was observed. Associated features described are fever, flu-like syndrome, rashes, and anemia. Extranodal manifestations such as skin lesions and hepatosplenomegaly are also reported. [4],[7],[12],[14],[15],[16],[17] In our case series, only one case showed systemic involvement, and none of the patients had skin manifestations. Comparison of clinicopathological features of Kikuchi's disease in different case series is given in [Table 3]. | Table 3: Comparison of clinical features from different reported case series (original)
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Kikuchi disease is thought to be due to hyperimmune response of T-cells, activated by unidentified pathogen infectious, chemical, physical, and neoplastic agents. Etiology of Kikuchi disease is not definite although autoimmune causes and some infectious agents are implicated. Features that support a role for an infectious agent include preceding upper respiratory tract infections, association with Toxoplasma, Yersinia enterocolitica, and several viral pathogens such as cytomegalovirus, Epstein-Barr virus, human herpesvirus, varicella-zoster virus, parainfluenza virus, parvovirus B19, and paramyxovirus. Serological markers of infection were present in few cases but not all, and no success was made to isolate an infectious agent from any case, thus excluding it as the sole cause for Kikuchi disease. [4] Association with autoimmune diseases such as SLE, antiphospholipid syndrome, polymyositis, systemic juvenile idiopathic arthritis, bilateral uveitis, and necrotizing vasculitis is documented. [13] The clinical and histological features show some similarity with SLE, but the serological tests such as ANA and dsDNA showed inconsistent results. [3],[4],[7],[12],[14]
Apoptotic cell death induced by cytotoxic T-cells produce the characteristic histo-morphology in Kikuchi disease. The proliferating cells in Kikuchi disease are cytotoxic CD8 positive cells which themselves undergo apoptosis. [4] Plasmacytoid monocytes or plasmacytoid T-cells have been reported to be a striking histopathologic finding in Kikuchi disease. Plasmacytoid monocytes or plasmacytoid T-cells are a striking histopathologic finding in Kikuchi disease; which are infact predendritic cells expressing immature dendritic cell markers such as CD1c, CD303, and CD123 and depending on micro-environmental stimuli they differentiate into potent antigen-presenting cells. [19] Plasmacytoid dendritic cells may contribute in the pathogenesis of Kikuchi disease by producing large amounts of Type I interferon (IFN), thus promoting a helper 1 T-cell response and the aforementioned immune reaction. Monocyte and macrophage lineage cells have been proposed to amplify the apoptotic event. Presence of elevated levels of inflammatory mediators such as IFN-γ, FasL, and interleukin-6 has been reported during the acute phase of Kikuchi disease, raising the possibility that these cytokines could have a role in the pathogenesis of this condition. [4] Human leukocyte antigen Class II genes are more frequent in patients with Kikuchi disease, suggesting a genetic predisposition to the proposed autoimmune response. At present, it is presumed that exuberant T-cell-mediated immune response in a genetically susceptible individuals to a variety of etiological agents is the basis of Kikuchi disease. None of our cases were associated with SLE, and serology for double-stranded DNA in all cases were negative. Neither small vessel vasculitis nor renal symptoms were present in any case. In none of our cases, we could elicit a history of previous or active infection. Unfortunately in our study, we were unable to identify any etiological factors for Kikuchi's disease.
Laboratory findings include anemia, leukopenia, elevated erythrocyte sedimentation rate, and presence of atypical lymphocytes in peripheral blood. Biopsy of the involved lymph nodes with immunohistochemistry is diagnostic. [3],[5],[7],[12] The characteristic histological features include lymph nodes with multifocal paracortical necrosis, pyknotic nuclear debris, proliferating histiocytes, and plasmacytoid dendritic cells. Different patterns described are necrotic, foam cell, and proliferative. Most common pattern being necrotic, characterized by paracortical necrosis with crescentic histiocytes. The different patterns could be the different stages of the disease starting with a proliferative to necrotic and phagocytic phases and resolving with foamy pattern. [12],[14],[16] Other features include presence of lymphocytes, plasmacytoid monocytes, macrophages, and immunoblasts. Immunohistochemistry shows CD68-positive macrophages, CD8- and CD4-positive T-cells, and CD123-positive plasmacytoid dendritic cell infiltrate. [3],[4],[12] Fine-needle aspiration cytology has been used to suggest the diagnosis of Kikuchi disease, when supported by typical clinical findings, but excision biopsy of an involved lymph node is needed to confirm the diagnosis. [4],[6],[12],[14]
Differential diagnosis of fever and cervical lymphadenopathy in Kikuchi disease often leads to an extensive work-up, and definitive diagnosis is achieved only by histopathology examination. Histological features along with special stains for fungus and acid-fast stain (acid-fast Bacillus [AFB]) help to exclude infectious etiology. Tuberculosis has always been a common clinical diagnosis in our setting. No AFB could be documented in tissue sections, and Mantoux test was negative in these cases. Infectious mononucleosis is another differential diagnosis. In our case series, peripheral smear study was noncontributory and serology was negative. Paracortical necrosis, patchy or confluent infiltrated with pyknotic or karyorrhectic nuclear debris and characteristic absence of neutrophils clinch the diagnosis. Histological features of autoimmune diseases such as vasculitis, prominent plasma cell infiltration, and hematoxyphilic bodies should be looked for. [13] Clinically and histopathologically, Kikuchi disease can be mistaken for non-Hodgkin's lymphomas, notably T-cell lymphomas, and differentiation is vital and radiological and histological features are of help. [9] Incomplete effacement of normal lymph node architecture, patent sinuses, reactive histiocytes, polyclonal infiltrate, and low mitotic index indicate the benign nature of the lesion. [9],[12],[14]
Clinical course: Kikuchi's disease typically is benign and self-limited, and lasts 1-4 months, recurrence is rare with 3-4% reported. [4],[9],[18] Fatal Kikuchi's disease though very rare is reported, the cause of death being excessive immune reaction or the effect of immunosuppressive therapy. [7] Supportive management with analgesics, antipyretics, immunosuppressant, and rest is needed.
Limitations of our study include unavailability of complete patient details in few cases and selection bias, as it was a retrospective study. Summarizing, it is of paramount importance that awareness of Kikuchi's disease should always be borne in mind and exclude lymphoma, tuberculosis, or autoimmune disorder such as SLE. These patients should be followed up with supportive treatment, since it is a self-limiting disorder.
| Conclusion | | |
Kikuchi's disease should be considered as one among the differential diagnosis of cervical lymphadenopathy and always exclude lymphoma, tuberculosis or autoimmune disorder like systemic lupus erythematosus in such cases. These patients should be followed up with supportive treatment, since it is a self limiting disorder.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1], [Table 2], [Table 3]
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