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Case Reports in Otolaryngology
Volume 2012 (2012), Article ID 497604, 5 pages
Kikuchi-Fujimoto Disease: A Case Report and Literature Review
Otolaryngology, Freeman Hospital, NE7 7DN Newcastle upon Tyne, UK
Received 12 February 2012; Accepted 9 April 2012
Academic Editors: C. F. Hwang, A. Kakigi, A. Rapoport, A. Taş, and L.-F. Wang
Copyright © 2012 Vikrant Veer et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Case. 38-year-old lady was referred to the ENT clinic with history of right-sided facial pain, otalgia, and odynophagia. Clinical examination revealed enlarged right-sided lymph nodes in the neck. Further radiological scans showed a mass near the carotid and enlarged level V lymph nodes. Lymphoma was initially suspected. Fine-needle aspiration and excision biopsy were undertaken. Histological analysis later suggested Kikuchi-Fujimoto disease, also known as histiocytic necrotising lymphadenitis. Literature Review. Kikuchi-Fujimoto disease (KFD) was described in 1972 as lymphadenitis with focal proliferation of reticular cells accompanied by numerous histiocytes and extensive nuclear debris. KFD, frequently found in East Asian countries, is rare in the UK. No definite aetiology of KFD is known despite autoimmune and infection factors being suggested. The diagnostic hallmark is histological findings from lymph nodes. Malignancy should be excluded. This condition is mainly self-limiting; hence, management is limited to supportive care. Steroid therapy could be used in severe cases. KFD is relatively unknown in the UK and this case report aims to highlight its occurrence in our population.
Cervical lymphadenopathy persisting for greater than three weeks should be referred to a head and neck clinic as a suspected case of cancer according NICE guidance. In this article, we examined a case of persistent tender cervical lymphadenopathy which had confounded diagnosis until a histological specimen was obtained from the lymph tissue which encased the internal carotid artery close to the base of skull. It emerged that our patient had Kikuchi-Fujimoto disease (KFD), otherwise known as histiocytic necrotising lymphadenitis. We also performed a literature review of KFD to provide an evidence-based understanding of this disease.
2. Case Report
A 38-year-old Filipino nurse presented to her general practitioner in the summer of 2009 with a one-year history of right neck pain, right otalgia, and odynophagia. Clinical examination could only demonstrate a cyst on the right tonsils without any specific cervical lymphadenopathy. However, ultrasonography at that time revealed some enlarged right-sided nodes. Subsequent biopsy of the tonsillar cyst showed chronic tonsillitis with dilated crypts. A fortnight later, she presented to the otorhinolaryngology (ENT) department for uncontrolled right facial pain. A second ultrasound noted a mildly enlarged parotid gland and similar right-sided reactive cervical lymph nodes but larger in size. Head and neck radiology team proposed an MRI which then showed a 3.8 cm × 2.5 cm × 1.2 cm mass surrounding the internal carotid artery just inferior to the skull base. Other smaller lymph nodes were found at level V. Fine-needle aspirate of these level V lymph nodes found evidence of atypical cell of which low-grade lymphoma could not be excluded. Hence, an excision biopsy of these nodes was then undertaken. The diagnosis of Kikuchi-Fujimoto disease was finally suggested based on the histological findings.
3. Literature Review
3.1. History of KFD
In 1972, Dr. Masahiro Kikuchi presented a case of lymphadenitis characterised by focal proliferation of reticular cells accompanied by numerous histiocytes and extensive nuclear debris  in the Japanese Journal of the Haematological Society. In the same month, Dr. Fujimoto presented a similar case in a separate Japanese journal .
KFD represents a condition most frequently found in East Asian and Japanese populations. The incidence is unknown but is rare in the UK and continental Europe. Extrapolating from the larger case series reports, the male to female ratio is roughly equal with slight female preponderance  and largely affects young adults (<30 years old).
The authors were unable to find any definitive evidence of an aetiological factor in the literature. Most articles on this subject concentrate on either an infective cause or an autoimmune disorder.
Yersinia enterocolitica , Brucellosis , Bartonella henselae , Entamoeba histolytica , Mycobacterium szulgai , and Toxoplasma gondii  have been isolated in case reports. However, subsequent studies have failed to support these findings. The fact that most patients with KFD are unresponsive to antibiotics suggests that these microbiological organisms were incidental findings.
Epstein-barr virus , herpes viruses [11–13], cytomegalovirus , parvovirus , paramyxovirus [16, 17], parainfluenza virus , rubella , hepatitis B  virus, Human Immunodeficiency Virus (HIV) , human T-lymphotropic virus type 1 , and the Dengue virus  have all been implicated in the aetiology of KFD. None of these have been found to be consistently associated with this condition [22–24].
Immunological screening of patients with KFD rarely reveals any autoimmune component in these patients. Imamura et al. in 1982  performed an ultra-structural analysis of pathological tissue from patients with KFD, which drew some similarities with the histological findings in patients with systemic lupus erythematous (SLE). However, association of Kikuchi with SLE remains unclear.
There is also evidence of a genetic susceptibility for KFD. Tanaka et al.  found certain human leukocyte antigen (HLA) class II genes were more common found in those with KFD. These genes were found to be more common in Asian populations compared to Caucasian groups. The implication of this evidence is that KFD represents a self-limiting autoimmune response to an upper respiratory tract viral infection in genetically-susceptible individuals. Some evidence suggests that KFD can initiate the onset of SLE, or is a short-lived version of SLE [27–33].
4. Clinical Features
The typical pattern of presentation is one of general flu-like symptoms with posterior cervical, tender lymphadenopathy. Other less common nonspecific symptoms are headache, nausea, fatigue, and arthralgia. The disease process continues for approximately two to three months before resolving spontaneously [34–36].
The diagnosis of KFD is rather problematical due to its relative obscurity, nonspecific symptoms, and imprecise histological diagnosis . Currently, the only reliable method of diagnosis is histological examination of a lymph node excision biopsy. Unfortunately, samples from a fine-needle aspiration are generally not sensitive enough to provide a reliable diagnosis with an overall accuracy of 56.3% . Blood tests classically show a mild neutropenia with mildly raised in the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) .
Imaging techniques such as CT, MRI, PET/CT scanning also rarely provide conclusive diagnostic results [39–42]. An incorrect provisional diagnosis of lymphoma or tuberculosis is made in many instances. In a study of 96 retrospective scans of confirmed KFD, Kwon et al.  found that on CT scanning cases of KFD had the following typical appearances:(i)multiple homogeneous lymphadenopathy involving levels II to V,(ii)94% were smaller than 2.5 cm, this allows some differentiation from lymphoma which typically produces few but larger nodes,(iii)perinodal infiltration and necrosis is commonly found (Figure 1).
Ultrasonography scans frequently show lymph nodes with a hypoechoic center and a hyperechoic rim . Again, these features have a low specificity for KFD [37, 44]. These findings certainly do not allow the diagnosis of KFD with imaging techniques. However, linked to the clinical history, one may at least be suspicious of KFD rather than a neoplastic lesion.
5.1. Histological Findings
A 2010 study by Kim et al. noted the following in cutaneous Kikuchi disease patients:(i)slight predominance of CD8+ lymphocytes,(ii)lymphohistiocytic infiltration and nonneutrophilic karyorrhexis (usually).
The immunophenotype of Kikuchi disease is primarily composed of mature CD8-positive and CD4-positive T lymphocytes. Lymphocytes and histiocytes also exhibit a high rate of apoptosis. There are relatively few B cells and natural killer (NK) cells are present. Positive immunostaining results by monoclonal antibody Ki-M1P are seen in Kikuchi disease but not in malignant lymphoma (Figure 2).
5.2. Differential Diagnoses
These are among(i)lymphoma,(ii)systemic lupus erythematous (SLE),(iii)infectious mononucleosis,(iv)kawasaki disease,(v)sarcoidosis,(vi)tuberculosis,(vii)syphilis.
KFD is a self-limiting condition that rarely requires specific treatment in most cases. Management is, therefore, based on supportive therapy, such as analgesia and anti-inflammatory medication. In patients with neurological symptoms or in those cases where KFD is found with another medical condition, immunosuppression with corticosteroids appears to improve the patient’s condition rapidly. A high initial oral dose of prednisolone with a subsequent reducing dose is the advocated regime [45, 46]. There are reports of excellent responses to hydroxychloroquine [47, 48], immunoglobulins , and minocycline . Recurrence of KFD is approximately 3% .
KFD is a rare condition, particularly in the Western world. There is a substantial amount of research into KFD. Unfortunately, the aetiology, pathology, diagnosis, and management of this disease are all still relatively uncertain and are subject to debate. Further scientific studies in this disease may also provide valuable insight into a number of other autoimmune conditions.
- M. Kikuchi, “Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytosis,” Nippon Ketsueki Gakkai Zasshi, vol. 35, pp. 379–380, 1972.
- Y. Fujimoto, Y. Kojima, and K. Yamaguchi, “Cervical subacute necrotizing lymphadenitis,” A New Clinicopathological Entity, vol. 20, pp. 920–927, 1972.
- H. C. Lin, C. Y. Su, C. C. Huang, C. F. Hwang, and C. Y. Chien, “Kikuchi's disease: a review and analysis of 61 cases,” Otolaryngology, vol. 128, no. 5, pp. 650–653, 2003.
- J. Heikens, W. Tel, J. van de Stadt, J. de Koning, and C. H. H. Ten Napel, “Kikuchi's lymphadenitis: report of a Yersinia enterocolitica-associated case and an overview of aetiology and clinical outcome,” Netherlands Journal of Medicine, vol. 41, no. 5-6, pp. 222–228, 1992.
- K. Charalabopoulos, V. Papalimneou, A. Charalabopoulos, M. Bai, and N. Agnantis, “Brucella melitensis infection stimulates an immune response leading to Kikuchi-Fujimoto disease,” In Vivo, vol. 17, no. 1, pp. 51–53, 2003.
- J. Y. Chung, W. K. Sang, H. H. Tae, and J. L. Sung, “Detection of the Bartonella henselae gene sequence in lymph nodes of children with Kikuchi's disease,” Pediatrics, vol. 115, no. 4, p. 1112, 2005.
- T. Aydogan, M. Kanbay, C. Uraldi et al., “Kikuchi Fujimoto disease secondary to entamoeba histolytica: case report,” Journal of Infection, vol. 53, no. 4, pp. e171–e173, 2006.
- W. Maek-a-nantawat and P. Viriyavejakul, “Mycobacterium szulgai lymphadenitis mimicking Kikuchi's disease in Thailand,” Southeast Asian Journal of Tropical Medicine and Public Health, vol. 32, no. 3, pp. 537–540, 2001.
- M. Kikuchi, T. Yoshizumi, and H. Nakamura, “Necrotizing lymphadenitis: possible acute toxoplasmic infection,” Virchows Archiv, vol. 376, no. 3, pp. 247–253, 1977.
- H. Y. Lee, Y. C. Huang, T. Y. Lin et al., “Primary Epstein-Barr virus infection associated with Kikuchi's disease and hemophagocytic lymphohistiocytosis: a case report and review of the literature,” Journal of Microbiology, Immunology and Infection, vol. 43, no. 3, pp. 253–257, 2010.
- M. Lamande, A. Cleuziou, I. Quintin-Roux, P. T. Tien, V. Narbonne, and A. Cénac, “Kikuchi-Fujimoto's disease concomitant to a type 1 Herpes simplex primary infection,” Presse Medicale, vol. 31, no. 27, p. 1268, 2002.
- S. D. Hudnall, T. Chen, S. Amr, K. H. Young , and K. Henry, “Detection of human herpesvirus DNA in Kikuchi-Fujimoto disease and reactive lymphoid hyperplasia,” International Journal of Clinical and Experimental Pathology, vol. 1, pp. 362–368, 2008.
- Y. Sumiyoshi, M. Kikuchi, T. Minematu, K. Ohshima, M. Takeshita, and Y. Manamishima, “Analysis of herpesvirus genomes in Kikuchi's disease,” Virchows Archiv, vol. 424, no. 4, pp. 437–440, 1994.
- D. Adoue, O. Rauzy, and F. Rigal-Huguet, “Kikuchi syndrome, cytomegalovirus infection and lupus,” La Revue de Médecine Interne, vol. 18, no. 4, p. 338, 1997.
- O. Meyer, M. F. Kahn, M. Grossin et al., “Parvovirus B19 infection can induce histiocytic necrotizing lymphadenitis (Kikuchi's disease) associated with systemic lupus erythematosus,” Lupus, vol. 1, no. 1, pp. 37–41, 1991.
- Y. Yufu, M. Matsumoto, T. Miyamura, J. Nishimura, H. Nawata, and K. Ohshima, “Parvovirus B19-associated haemophagocytic syndrome with lymphadenopathy resembling histiocytic necrotizing lymphadenitis (Kikuchi's disease),” British Journal of Haematology, vol. 96, no. 4, pp. 868–871, 1997.
- S. Asano, Y. Akaike, T. Muramatsu et al., “Necrotizing lymphadenitis: a clinicopathological and immunohistochemical study of four familial cases and five recurrent cases,” Virchows Archiv, vol. 418, no. 3, pp. 215–223, 1991.
- K. J. Cho, S. S. Lee, and S. K. Khang, “Histiocytic necrotizing lymphadenitis—a clinico-pathologic study of 45 cases with in situ hybridization for Epstein-Barr virus and hepatitis B virus,” Journal of Korean Medical Science, vol. 11, no. 5, pp. 409–414, 1996.
- S. A. Pileri, E. Sabattini, P. Costigliola et al., “Kikuchi's lymphadenitis and HIV infection,” AIDS, vol. 5, no. 4, pp. 459–461, 1991.
- K. Atarashi, N. Yoshimura, H. Nodera, K. Tsukimoto, H. Beppu, and M. Kanayama, “Recurrent histiocytic necrotizing lymphadenitis (Kikuchi's disease) in an human T lymphotropic virus type I carrier,” Internal Medicine, vol. 35, no. 10, pp. 821–825, 1996.
- V. K. Harris, D. Danda, N. S. Murali et al., “Unusual association of Kikuchi's disease and dengue virus infection evolving into systemic lupus erythematosus,” Journal of the Indian Medical Association, vol. 98, no. 7, pp. 391–393, 2000.
- H. C. Hollingsworth, S. C. Peiper, L. M. Weiss, M. Raffeld, and E. S. Jaffe, “An investigation of the viral pathogenesis of Kikuchi-Fujimoto disease: lack of evidence for Epstein-Barr virus or human herpesvirus type 6 as the causative agents,” Archives of Pathology and Laboratory Medicine, vol. 118, no. 2, pp. 134–140, 1994.
- T. I. George, C. D. Jones, J. L. Zehnder, R. A. Warnke, and R. F. Dorfman, “Lack of human herpesvirus 8 and Epstein-Barr virus in Kikuchi's histiocytic necrotizing lymphadenitis,” Human Pathology, vol. 34, no. 2, pp. 130–135, 2003.
- J. Huh, H. S. Chi, S. S. Kim, and G. Gong, “A study of the viral etiology of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease),” Journal of Korean Medical Science, vol. 13, no. 1, pp. 27–30, 1998.
- M. Imamura, H. Ueno, A. Matsuura, et al., “An ultrastructural study of subacute necrotizing lymphadenitis,” American Journal of Pathology, vol. 107, no. 3, pp. 292–299, 1982.
- T. Tanaka, M. Ohmori, S. Yasunaga, K. Ohshima, M. Kikuchi, and T. Sasazuki, “DNA typing of HLA class II genes (HLA-DR, -DQ and -DP) in Japanese patients with histiocytic necrotizing lymphadentis (Kikuchi's disease),” Tissue Antigens, vol. 54, no. 3, pp. 246–253, 1999.
- F. Goldblatt, J. Andrews, A. Russell, and D. Isenberg, “Association of Kikuchi-Fujimoto's disease with SLE,” Rheumatology, vol. 47, no. 4, pp. 553–554, 2008.
- S. Hu, T. T. Kuo, and H. S. Hong, “Lupus lymphadenitis simulating Kikuchi's lymphadenitis in patients with systemic lupus erythematosus: a clinicopathological analysis of six cases and review of the literature,” Pathology International, vol. 53, no. 4, pp. 221–226, 2003.
- C. Martínez-Vázquez, G. Hughes, J. Bordon et al., “Histiocytic necrotizing lymphadenitis, Kikuchi-Fujimoto's disease, associated with systemic lupus erythemotosus,” Monthly Journal of the Association of Physicians, vol. 90, no. 8, pp. 531–533, 1997.
- K. M. El-Ramahi, A. Karrar, and M. A. Ali, “Kikuchi disease and its association with systemic lupus erythematosus,” Lupus, vol. 3, no. 5, pp. 409–411, 1994.
- M. D. Litwin, B. Kirkham, D. R. F. Henderson, and S. C. Milazzo, “Histiocytic necrotising lymphadenitis in systemic lupus erythematosus,” Annals of the Rheumatic Diseases, vol. 51, no. 6, pp. 805–807, 1992.
- B. Tumiati, A. Belleli, I. Portioli, and S. Prandi, “Kikuchi's disease in systemic lupus erythematosus: an independent or dependent event?” Clinical Rheumatology, vol. 10, no. 1, pp. 90–93, 1991.
- D. Khanna, A. Shrivastava, P. R. Malur, and R. Kangle, “Necrotizing lymphadenitis in systemic lupus erythematosus: is it Kikuchi-Fujimoto disease?” Journal of Clinical Rheumatology, vol. 16, no. 3, pp. 123–124, 2010.
- H. Duskin-Bitan, S. Kivity, D. Olchovsky, G. Schiby, D. Ezra, and M. Mouallem, “Kikuchi-Fujimoto disease,” Israel Medical Association Journal, vol. 12, no. 10, pp. 617–621, 2010.
- C. B. Hutchinson and E. Wang, “Kikuchi-Fujimoto disease,” Archives of Pathology & Laboratory Medicine, vol. 134, no. 2, pp. 289–293, 2010.
- X. Bosch and A. Guilabert, “Kikuchi-Fujimoto disease,” Orphanet Journal of Rare Diseases, vol. 1, no. 1, article 18, 2006.
- X. Bosch, A. Guilabert, R. Miquel, and E. Campo, “Enigmatic Kikuchi-Fujimoto disease: a comprehensive review,” American Journal of Clinical Pathology, vol. 122, no. 1, pp. 141–152, 2004.
- T. R. Tong, O. W. Chan, and K. C. Lee, “Diagnosing Kikuchi disease on fine needle aspiration biopsy: a retrospective study of 44 cases diagnosed by cytology and 8 by histopathology,” Acta Cytologica, vol. 45, no. 6, pp. 953–957, 2001.
- K. Ito, M. Morooka, and K. Kubota, “Kikuchi disease: 18F-FDG positron emission tomography/computed tomography of lymph node uptake,” Japanese Journal of Radiology, vol. 28, no. 1, pp. 15–19, 2010.
- W. T. Miller Jr. and L. A. Perez-Jaffe, “Cross-sectional imaging of Kikuchi disease,” Journal of Computer Assisted Tomography, vol. 23, no. 4, pp. 548–551, 1999.
- C. H. Kim, O. J. Hyun, I. R. Yoo, S. H. Kim, H. S. Sohn, and S. K. Chung, “Kikuchi disease mimicking malignant lymphoma on FDG PET/CT,” Clinical Nuclear Medicine, vol. 32, no. 9, pp. 711–712, 2007.
- D. G. Na, T. S. Chung, H. S. Byun, H. D. Kim, Y. H. Ko, and J. H. Yoon, “Kikuchi disease: CT and MR findings,” American Journal of Neuroradiology, vol. 18, no. 9, pp. 1729–1732, 1997.
- S. Y. Kwon, T. K. Kim, Y. S. Kim, K. Y. Lee, N. J. Lee, and H. Y. Seol, “CT findings in Kikuchi disease: analysis of 96 cases,” American Journal of Neuroradiology, vol. 25, no. 6, pp. 1099–1102, 2004.
- M. Douglas, R. Bradbury, S. Kannangara, and D. Mitchell, “Arthritis as an unusual manifestation of Kikuchi-Fujimoto disease,” Rheumatology, vol. 42, no. 8, pp. 1010–1012, 2003.
- Y. J. Jang, K. H. Park, and H. J. Seok, “Management of Kikuchi's disease using glucocorticoid,” Journal of Laryngology and Otology, vol. 114, no. 9, pp. 709–711, 2000.
- A. Mahmood, R. Mir, S. R. Salama, R. M. Miarrostami, C. Lapidus, and F. Pujol, “Kikuchi's disease: an unusual presentation and a therapeutic challenge,” Yale Journal of Biology and Medicine, vol. 79, no. 1, pp. 27–33, 2006.
- K. Rezai, S. Kuchipudi, V. Chundi, R. Ariga, J. Loew, and B. E. Sha, “Kikuchi-Fujimoto disease: hydroxychloroquine as a treatment,” Clinical Infectious Diseases, vol. 39, no. 12, pp. e124–e126, 2004.
- P. H. Chen, Y. F. Huang, C. W. Tang, S. R. Wann, and H. T. Chang, “Kikuchi-Fujimoto disease: an amazing response to hydroxychloroquine,” European Journal of Pediatrics, vol. 169, no. 12, pp. 1557–1559, 2010.
- M. Noursadeghi, N. Aqel, P. Gibson, and G. Pasvol, “Successful treatment of severe Kikuchi's disease with intravenous immunoglobulin,” Rheumatology, vol. 45, no. 2, pp. 235–237, 2006.
- K. Takada, K. Suzuki, T. Hidaka et al., “Immediate remission obtained by minocycline in a patient with histiocytic necrotizing lymphadenitis,” Internal Medicine, vol. 40, no. 10, pp. 1055–1058, 2001.