J Emerg Crit Care Med. Vol. 25, No. 1, 201412

Received: September 14, 2014 Accepted for publication: December 15, 2014From the 1Department of Pediatrics, Taoyuan Armed Forces General Hospital, 2National Defense Medical CenterAddress reprint requests and correspondence: Dr. Sheng-Chih ChuDepartment of Pediatrics, Taoyuan Armed Forces General Hospital10F, 94 Section 1, Dachang Road, Longtan District, Taoyuan City 325, Taiwan (R.O.C.)Tel: 0937-511185E-mail: ndmchenry@msn.com

An Unusual Reason for Neck Masses: A Case Report

Sheng-Chih Chu1,2

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a benign and self-limited disease. Enlargement of lymph nodes with pain is a common manifestation of KFD especially within the cervical region. However, the etiology and management of this disease are still relatively uncertain. Therefore, KFD is easily misdiagnosed or missed. I present a case of an 8-year-old boy who presented to our pediatric emergency department with a 2-week history of prolonged fever and painful neck mass previously had been treated with antibiotics at clinic. KFD was diagnosed after lymph node biopsy and he recovered under supportive treatment.

Key words: Kikuchi-Fujimoto disease, histiocytic necrotizing lymphadenitis, lymphadenopathy, rare diseases, child

Introduction

In the pediatr ic emergency department, physicians often encounter patients with enlarged cervical lymph nodes. Up to 90% of children between the ages of 4 to 8 have experienced p a l p a b l e c e r v i c a l l y m p h n o d e s. M o s t l y, lymphadenopathy represents a transient response to a benign local inflammatory process. Around 15% of biopsied cervical lymph nodes in children result in malignancy(1,2). Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a benign, self-limiting and rare differential diagnosis of cervical lymphadenopathy. There is no definite etiology. The most common manifestations are persisted fever and localized enlarged lymph nodes. Neither specific diagnostic laboratory tests nor imaging studies are available despite of pathological confirmation(3-6). Therefore, KFD is easily misdiagnosed as other diseases initially such

as tuberculous lymphadenitis, cat scratch disease or lymphoma(7,8).

Case Report

An 8-year-old Asia boy was brought to our pediatric emergent department in November 2013 after presenting with fever and a painful lesion over right cervical region for 12 days without other symptoms. He had been in good health in the past. Furthermore, he had already been treated with oral amoxicillin prescribed from local clinics for a week without improvement.

On physical exam, he had right neck mass measured around 4×5cm in size and daily fever up to 40°C. His complete blood count revealed 5200 cells/uL of white blood cells with 38% of neutrophil. C-reactive protein (CRP) was 0.87 mg/dL. Viral capsid antigen (VCA) IgG for Eptein-Barr Virus (EBV) showed positive while IgM was negative.

13An unusual reason for neck masses

Tuberculin (TB) skin test and TB polymerase chain reaction (TB-PCR) were al l negative. Computed tomography (CT) imaging of his neck was performed and multiple homogeneous enlarged lymph nodes with nodal necrosis and perinodal infiltration were found (Fig. 1, 2). Despite empiric antibiotics treatment with Amoxicillin/clavulanate (Augmentin), his fever persisted. He underwent a cervical lymph node biopsy on the fifth day of hospitalization. Microscopic examination showed lymph nodes with neutrophil-poor necrosis and karyorrhectic nuclear debris surrounded by foamy histiocytes without malignant cell. No microorganism was found either by acid-fast stain or by immunohistochemistry with anti-Bartonella

henselae antibody. The histology was consistent with histiocytic necrotizing lymphadenitis, or KFD. His symptoms subsided spontaneously after 10 days of supportive treatment and he was discharged.

Discussion

Cervical lymphadenopathy is a common finding on physical examination that physicians encounter in the emergency depar tment. I t could be divided into inflammatory/reactive and neoplastic etiologies. Inflammatory/reactive lymphadenopathy can be the result of infectious lymphadenitis, Kawasaki disease, or KFD. Viral, staphylococcal, mycobacterial, and Bartonella

Fig. 1 Transverse CT scan with contrast media shows lymph nodes (arrows) with necrosis and perinodal infiltration

J Emerg Crit Care Med. Vol. 25, No. 1, 201414

henselae infection are common etiologies of infectious lymphadenitis(1,2). Although it is rare in children, malignancies such as lymphoma or leukemia are also contributed to lymphadenopathy. Constitutional type B symptoms such as fever, malaise, weight loss, and night sweats suggest a possible malignancy(2). Due to wide varieties of differential diagnosis and associated treatment, cervical lymphadenopathy is definitely a diagnostic challenge for physicians.

KFD, or histiocytic necrotizing lymphadenitis, is a benign and self-limited disorder, characterized by regional cervical lymphadenopathy with tenderness and fever. KFD was first described in 1972 independently by two Japanese pathologists, Dr. Masahiro Kikuchi(9) and Dr. Fujimoto(10) and affects predominantly young adult Asian females(3,5,11). However, male predilection was reported in some pediatric studies with a 1.4 to 3:1 male to female ratio(4,6,11,12). Although KFD is primarily considered as a rare disease, the true incidence may be higher while KFD is increasingly recognized around the world(6). The pathogenesis

is unconfirmed currently. However viral etiology, inclusive of EBV, cytomegalovirus, parvovirus B19, human herpesvirus 6, human herpesvirus 7 and human herpesvirus 8, was suggested by previous studies(13,14).

Imaging studies such as sonography, CT and positron emission tomography (PET) may contribute to differentiation between KFD and other etiologies of cervical lymphadenopathy. Sonography may find elongated or oval hypoechoic lymph nodes with increased perinodal echogenicity and possess a smaller size, less round, less micronodular reticular echotexture and more signs of matting and cortical widening than those with lymphoma(15,16). On CT of KFD, mild-to-moderate multiple necrotic foci with indistinct margins and higher necrosis attenuation indices without calcification within the nodes are the characteristic patterns from tuberculous lymphadenitis(12,17). Tsujikawa et al reported that the affected nodes of KFD show high 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) uptake for their relative smaller size than lymphoma on PET and noncervical lesions of KFD

Fig. 2 Sagittal view of the same CT scan from figure 1 shows an inflammatory area measured around 4×5cm with multiple lymph nodes (arrows) with necrosis

15An unusual reason for neck masses

can also be detected by PET(18).The definite diagnosis of KFD relies on

histological examination of a lymph node excision biopsy. The affected lymph nodes reveal focal necrosis with perinodal lymphocytes and histiocytes infiltration along with abundant karyorrhectic debris in the paracortical region(11,20,21). KFD can be classified into three histological subtypes from proliferative type (>50%) to necrotizing type (~30%) and end up into xanthomatous type (<20%)(19-21). Moreover, the extent of the infiltration is highlighted by the expression of CD68 antigen. CD68 is used as a marker of histiocyte. Therefore, KFD may be a hyperimmune reaction of the histiocyte lineage to viral infections(11,20). However, several previous reports suggest that KFD may associate with autoimmune diseases such as systemic lupus erythematosus (SLE), hemophagocytic lymphohistiocytosis (HLH) and thyroiditis especially among patients with positive anti-nuclear antibody (ANA)(3-6,12,20,22-25).

Most previous reports advise no specific treatment despite nonsteroidal anti-inflammatory agents to control the symptoms. A few reports suggest that the essence of KFD is the activation of histiocytes, which produces excessive inflammatory cytokines. In order to interrupt the cytokines, it is important to occupy the corticosteroid receptor completely for a certain period. No standardized therapeutic regimen for KFD is available. Oral prednisolone and methylprednisolone pulse therapy (MPT) are used empirically and Katsunobu et al reports that MPT may prevent KFD from progression to fatal HLH(26,27). Immunomodulator such as hydroxychloroquine is reported as an alternative for the treatment of KFD(28). The recurrence rate is around 4% in most reports. However, Cheng et al found a 14.6% recurrence rate in Taiwan and Song et al reported an over 20% recurrence rate in Korea, especially in patients with high ANA(5,22).

In conclusion, cervical lymphadenopathy though is a common finding that frequently be found in emergency department. Physicians should keep in mind that KFD may be the possible differential diagnosis for cervical lymphadenopathy after excluding other relative prevalent diagnosis such as bacterial or viral infection, Kawasaki disease and malignancy. Imaging exams and biopsy should be considered when empiric antibiotics are unresponsive and the diagnosis is uncertain. Most cases of KFD take very benign and self-limiting courses without special management, however, long-term follow-up is necessary at least every 6 months to monitor for the possible later recurrence and development of autoimmune disease.

References

1. Karthik R, Paul K. Enlarged neck lymph nodes in children. Pediatr Clin North Am 2013;60:923-36.

2. Jeremy DM, Johannes FG. Evaluation and management of neck masses in children. Am Fam Physician 2014;89:353-8.

3. Bosch X, Guilabert A. Kikuchi-Fujimoto disease. Orphanet J Rare Dis 2006;1:18.

4. Lin HC, Su CY, Huang SC. Kikuchi’s disease in Asian children. Pediatrics 2005;115:92-6.

5. Cheng CY, Sheng WH, Lo YC, et al. Clinical presentations, laboratory results and outcomes of patients with Kikuchi’s disease: emphasis on the association between recurrent Kikuchi’s disease and autoimmune diseases. J Microbiol Immunol Infect 2010;43:366-71.

6. Kim TY, Ha KS, Kim Y, et al. Characteristics of Kikuchi-Fujimoto disease on children c o m p a r e d w i t h a d u l t s . E u r J P e d i a t r 2014;173:111-6.

7. Kurahara Y, Tachibana K, Tezuka K, et al. Kikuchi-Fujimoto disease mimicking tuberculous lymphadeni t i s. In tern Med

J Emerg Crit Care Med. Vol. 25, No. 1, 201416

2012;51:1927-30.8. Gupta P, Lau K, West K, et al. Kikuchi-

Fujimoto disease masquerading as tuberculosis. Gen Thorac Cardiovasc Surg 2014;62:125-7.

9. Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytes: a clinicopathological study. Acta Hematol Jpn 1972;35:379-80.

10. Fujimoto Y, Kozima Y, Yamaguchi K. Cervical subacute necrotizing lymphadenitis: a new chinicopathologic entity. Naika 1972;20:920-7.

11. Seo JH, Kang JM, Lee HJ, et al. Histiocytic necrotizing lymphadenitis in children: a clinical and immunohistochemical comparative s tudy with adul t pat ients. Int J Pediatr Otorhinolaryngol 2013;77:429-33.

12. Han HJ, Lim GY, Yeo DM, et al. Kikuchi’s disease in children: clinical manifestations and imaging features. J Korean Med Sci 2009;24:1105-9.

13. Bhargava P, Matthew P. Kikuchi’s disease with systemic manifestations: a link to the Epstein-Barr virus. Singapore Med J 2009;50:e110.

14. Labrador J, Aparicio MA, Santos-Briz A, et al. Kikuchi-Fujimoto disease: a case supporting a role for human herpesvirus 7 involvement in the pathogenesis. Rheumatol Int 2013;33:3065-8.

15. Yoo JL, Suh S, Lee YH, et al. Gray scale and power Doppler study of biopsy-proven Kikuchi disease. J Ultrasound Med 2011;30:957-63.

16. L o W C, C h a n g W C, L i n Y C, e t a l . Ultrasonographic differentiation between Kikuchi’s disease and lymphoma in patients with cervical lymphadenopathy. Eur J Radiol 2012;81:1817-20.

17. Lee S, Yoo JH, Lee SW. Kikuchi disease: differentiation from tuberculous lymphadenitis based on patterns of nodal necrosis on CT. AM J Neuroradiol 2012;33:135-40.

18. Tsujikawa T, Tsuchida T, Imamura Y, et al.

Kikuchi-Fujimoto disease: PET/CT assessment of a rare cause of cervical lymphadenopathy. Clin Nucl Med 2011;36:661-4.

19. Kuo TT. Kikuchi’s d isease (h is t iocyt ic necrotizing lymphadenitis): a clinicopathologic study of 78 cases with an analysis of histologic subtypes, immunohistology, and DNA ploidy. AM J Surg Pathol 1995;19:798-809.

20. Kim JH, Kim YB, In SI, et al. The cutaneous lesions of Kikuchi’s disease: a comprehensive a n a l y s i s o f 1 6 c a s e s b a s e d o n t h e clinicopathologic, immunohistochemical, and immunofluorescence studies with an emphasis on the differential diagnosis. Hum Pathol 2010;41:1245-54.

21. Aminiafshar S, Namazi N, Farhad A. Kikuchi-Fujimoto disease in 21-year-old man. Int J Prev Med 2013;4:964-6.

22. Song JY, Lee J, Park DW, et al. Clinical outcome and predictive factors of recurrence among patients with Kikuchi’s disease. Int J Infect Dis 2009;13:322-6.

23. Go EJ, Jung YJ, Han SB, et al. A case of Kikuchi-Fujimoto disease with autoimmune thyroiditis. Korean J Pediatr 2012;55:445-8.

24. Zuo Y, Foshat M, Qian YW, et al. A rare case of Kikuchi Fujimoto’s disease with subsequent development of systemic lupus erythematosus. Case Rep Rheumatol volume 2012 (2012), Article ID 325062, 4 pages.

25. Lee BC, Patel R. Kikuchi-Fujimoto disease: a 15-year analysis at a children’s hospital in the United States. Clin Pediatr 2013;52:92-5.

26. Yoshioka K, Miyashi ta T, Nakamura T, et al. Treatment of histiocytic necrotizing lymphadeni t is (Kikuchi’s d isease) wi th p ro longed fever by a s ing le course o f methylprednisolone pulse therapy without maintenance therapy: experience with 13 cases. Inter Med 2010;49:2267-70.

27. Yalc in S, Toprak SK, Er ismis B, e t a l.

17An unusual reason for neck masses

Management of Kikuchi-Fujimoto disease using glucocorticoid: a case report. Case Rep Med volume 2011 (2011), Article ID 230840, 3 pages.

28. Chen PH, Huang YF, Tang CW, et al. Kikuchi-Fuj imoto disease: an amazing response t o h y d r o x y c h l o r o q u i n e. E u r J P e d i a t r 2010;169:1557-9.

J Emerg Crit Care Med. Vol. 25, No. 1, 201418 不尋常原因之頸部腫塊

收件：103年9月14日　接受刊載：103年12月15日1國軍桃園總醫院小兒科　2國防醫學院

通訊及抽印本索取：儲聖知醫師　桃園縣龍潭鄉大昌路1段94號10樓國軍桃園總醫院小兒科

電話：0937-511185E-mail: ndmchenry@msn.com

不尋常原因之頸部腫塊：病例報告

儲聖知1,2

菊地氏病，又稱組織球壞死性淋巴腺炎，是一個良性且自限性的疾病。常以頸部淋巴結腫大作為臨

床病徵。然而，此病的致病原因及處置目前尚未被確立，所以菊地氏病很容易被誤診或是被忽略掉。我

要提出一個8歲男孩的病例報告，起初在診所以抗生素治療2周，但由於持續高燒及頸部腫大疼痛被送至本院兒科急診處理。經過淋巴結病理切片後，診斷為菊地氏病，在支持療法下順利恢復健康。

關鍵詞： 菊地氏病，組織球壞死性淋巴腺炎，淋巴腺炎，罕見疾病，兒童