Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease)
 

A study of 14 cases from Qatar

Al Soub H.,*Al Bosom I., El Deeb Y., Al Maslamani M., Al KHuwaiter J.
Internal Medicine Section, Department of Medicine and*Department of Laboratory
Medicine & Pathology
 Hamad Medical Corporation, Doha, Qatar

Abstract:

      To define the demographic, clinical and laboratory features, and outcome of patients with Kikuchi-Fujimoto disease in Qatar and to compare it with those reported by others, fourteen cases of Kikuchi-Fujimoto disease seen at Hamad Medical Corporation between 1995 and 2004 were reviewed retrospectively. Unusually there was an unexplained male predominance amongst the ten males and four females even amongst the Qatari nationals who comprised 57% of the cases.

      All had lymphadenopathy, mostly cervical, and less commonly fever, anorexia, chills, weight loss, hepatome-galy, and skin rash. The diagnosis was made by lymph node biopsy, with no indication of any etiologic agent. All patients survived although symptomatic treat-ment with non-steroidal anti-inflammatory drugs and steroids was required in five patients. There was recurrence in two patients.

       It seems that Kikuchi-Fujimoto disease is rare in Qatar although the incidence might be increasing possibly due to greater awareness amongst clinicians. The clinical features are similar to those reported by others but certain diagnosis requires lymph node biopsy. The outcome is good.

Keywords: Kikuchi-Fujimoto disease, lymphadenopathy, fever of unknown origin.

Introduction:

    Kikuchi’s disease (KD) also known as Kikuchi-Fujimoto-Fujimoto disease or histiocytic necrotizing lymphadenitis was first described in 1972 independently by Kikuchi and Fujimoto et al(1,2). Initially all reports of Kikuchi-Fujimoto disease came from Japan but subsequently it has been reported from Europe, America, Asia and from the Middle East (3-7). Kikuchi-Fujimoto disease is a benign self-limited condition of unknown etiology which usually presents with cervical lymphadenopathy or fever of unknown origi (8). The disease is rare and so is frequently not included in the differential diagnosis at presentation. There are no specific laboratory tests available for the diagnosis of Kikuchi-Fujimoto disease and diagnosis can be made only after histologic examination of lymph node biopsy. Despite the self-limited nature of this disease, biopsy should be performed to exclude more serious conditions such as lymphoma, tuberculous adenitis, and systemic lupus erythematosis(4). We report fourteen patients with Kikuchi-Fujimoto disease seen at Hamad Medical Corporation over a period of ten years and we review the pertinent literature.

Methods

     A retrospective review of histopathologic records at Hamad Medical Corporation showed that there were 900 lymph node biopsies during the period from January 1995 to December 2004 from which 14 cases of Kikuchi-Fujimoto disease were identified. Diagnosis was established on the basis of consistent clinical features and characteristic histopathologic findings. The medical records of these patients were reviewed for age, sex, nationality, clinical characteristics, affected lymph nodes, laboratory results, diagnosis, treatment, complications and outcome.
 

Histological findings:

     All lymph nodes showed partially effaced architecture, the residual lymphoid follicles had reactive germinal centers. Patchy areas of necrosis were randomly distributed and occasionally confluent (Figure 1).

   The necrosis consisted of brightly eosinophilic fibrinoid deposits including nuclear fragments
(Figure 2) .

    surrounded by large accumulations of pale-staining histiocytes. Occasional cases showed only scattered cells with pyknosis or karyorrhexis and nuclear dust. The cellular debris was phagocytosed by numerous histiocytes mixed with mature lymphocytes and plasma cells . No neutrophils or eosinophils could be seen. At the periphery of necrotic areas there were groups of plasmacytoid monocytes (Figure 3).

    which varied in number from case to case. Immu-nohistochemistry highlighted the histiocytes by using antibodies against CD68 and for the lymphocytes, which proved to be T- cells, by antibodies against CD3 and CD45RO. The time for defervescence in those who had fever ranged from two to eighteen days (mean 8.7 days). Antibiotics were given empirically in eight patients but were discontinued either when there was no response or when the diagnosis was made. Non-steroidal anti-inflammatory drugs were used in five patients to control the fever, and in two patients steroids were necessary for its control. Follow-up for varying periods of one month to seven years was possible in nine patients. One patient was readmitted one month after discharge with aseptic meningitis which resolved spontaneously. Another patient had repeated hospital admissions with fever and lymphadenopathy; lymph node biopsy showed reactive changes. She needed steroids to control her fever and in one admission she developed pericarditis with tamponade that necessitated urgent pericardial drainage.

Discussion:

      Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a clinico-pathologic entity of unknown cause. Although Kikuchi-Fujimoto disease (KFD) has been reported from different parts of the world, it has been most frequently reported from Asia(5-7). The exact incidence is unknown although most reports indicate that this is a rare condition. The frequency varies in different areas. In a series of 920 lymph node biopsies from Saudi Arabia(9), only five (0.5%) had changes characteristic of KFD compared to 5.7% in a report from Taiwan(10). The fact that the condition is benign, self limiting and requires lymph node biopsy to make the diagnosis, suggests that the true incidence is probably more than that reported in the literature and that many cases are probably missed or overlooked. Because reports of KFD are predo-minantly published in the pathology literature, many clinicians are probably unaware of this condition and do not consider it in the differential diagnosis of patients presenting with lymphadenopathy.

     This series of 14 cases of KFD represents approximately 1.6 % of 900 lymph node biopsies performed at our institution during a ten-year period, confirming that KFD, or at least its clinical diagnosis, is rare. In a previous study at our institution between 1982 and 1992, KFD accounted for 0.68% of 735 lymph node biopsies(7). Comparing the two studies, the frequency of KFD almost doubled in the current study compared with the previous one. Only three of our patients were diagnosed in the first half of the study period, and 11 patients in the second half, suggesting that there has been an increased incidence in recent years; whether this represents a true increase or just increased awareness needs further study.

     The male to female ratio in our series is 2.5:1., unlike those reported by others which indicated a female predominance with ratios ranging from 4:1 to 1:6(4,11). A lower female predo-minance in Asian populations has been reported by others(12). Males outnumber females in the expatriate population of Qatar which might partly explain the male predominance in our patients but, even in Qataris, more males than females were affected.

     Eight Qatari nationals comprised 57% of the cases. Qatari nationals represent about one quarter of the total population in Qatar, suggesting that more cases of KFD are seen amongst them than amongst other nationalities; this might be due to genetic, environmental, or socioeconomic factors. In other studies the majority of patients were aged less than 40 years (mean 25.5-30 years)(4) whereas ages of our patients ranged from 15 to 45 years ( mean 32 years).

    The exact etiology of KFD is unknown and several infectious etiologies have been postulated as the cause; Toxoplasma, Yersinia enterocolitica, Epstein-Barr virus, paramyxovirus, cytomegalovirus, human herpes virus 6, human herpes virus 8, parvovirus, and parainfluenza virus (13-15) but no definite relationship has been established. Many authorities believe KFD to be the result of an immune response to multiple non-specific stimuli that are usually associated with infection (16-18). The investigations in our patients did not point to any possible etiologic agent.

    The most common presenting manifestation in patients with KFD is lymphadenopathy which was present in all our patients(4). The affected lymph nodes vary in size and may be painful. Cervical lymph nodes are the most commonly affected and were involved in 93% of cases in our series(12). Fever is the second most common presenting symptom, as in 71% of our cases(4). Other less common manifestations include anorexia, chills, weight loss, hepatomegaly, and skin rash(19). One of our patients developed aseptic meningitis, an unusual manifestation of KFD that has been reported twice before(20,21).

    There are no definitive laboratory tests available for the diagnosis of KFD but negative tests are important to exclude other diseases. Abnormal laboratory findings that have been reported in patients with KFD (and also were seen in our patients) include leucopenia, atypical lymphocytes, elevated erythrocyte sedimentation rate, and elevation of liver transa-minases(12). Autoimmune studies are usually negative. The possibility of systemic lupus erythematosus (SLE) must be kept in mind as some patients have been reported developing SLE later on (22). Often bone marrow examination is done as a means of investigating pyrexia of unknown origin, or for the evaluation of leukopenia; although this is usually normal it may show an increased number of macrophages or evidence of hemophagocytosis. Bone marrow examination revealed hemophagocytosis in two of our patients. Such a finding reported previously in two patients led to a misdiagnosis of virus-associated hemophagocytic syndrome(12).

     The diagnosis of KFD is established by lymph node biopsy. The pathologic characteristic is the presence of well-defined necrosis without granulocytic cells. Karyorrhexis of the necrotic cells is prominent and is usually located in the paracortical area of the lymph node(1-2). Special stains for acid-fast bacilli and fungi are usually negative. Immunohistochemistry is also an important tool for diagnosing KFD and for distinguishing it from high grade B and T cell lymphoma(23). Biopsy is important not only to make the diagnosis of KFD but also to exclude other conditions that may mimic this condition. On morpho-logical basis the differential diagnosis of this entity includes: necrotizing granulomatous lymphadenitis particularly tuberculosis, SLE, infectious mononucleosis and Non-Hodgkin lymphoma; however the patchy necrosis, reactive lymphoid follicles and the mixture of lymphocytes and histiocytes with absence of neutrophils, eosinophils and giant cells make the diagnosis of Kikuchi-Fujimoto lymphadenitis feasible (4). The fact that 30% of 108 lymph nodes reviewed by Dorfman and Berry(4) were initially misdiagnosed as malignant lymphoma emphasizes the need for the histopathologist to be alert to the possibility of KFD in order to avoid subjecting patients to unnecessary treatment. The value of FNA in the diagnosis of KFD has been examined in few studies(24-26). The overall accuracy of FNA diagnosis of KFD was approximately 50% (25). In this series, FNA was performed in five patients and excisional biopsy in 13. In the five patients in whom FNA was done, the findings in two of them were sufficient to establish the diagnosis of KFD. Although the number of our patients in whom FNA was performed is small, our findings and those of others indicate that when the typical cytologic findings are present in an adequate clinical context a precise diagnosis is possible, avoiding unnecessary biopsy.

    Most authorities do not recommend special treatment for KFD. However non-steroidal anti-inflammatory drugs or corticosteroids are required occasionally to control the associated systemic manifestations(27). In this series non-steroidal anti-inflammatory drugs and steroids were needed to control systemic symptoms in 36% and 14% of cases respectively. The outcome of the disease is usually favorable with resolution of symptoms in most cases within one to four months(4). All our patients survived. The literature includes three reported fatal cases of KFD(4, 28,29). Recurrences are rare and have been reported in 3% of cases(12). Recurrences were observed in two of our patients. In the first one, it was in the form of aseptic meningitis and fever, and in the other in the form of recurrent hospital admission for fever, lymphadeno-pathy, and pericarditis. Follow up is necessary in these patients because SLE has been reported in some of these patients at a later time(22). In this series no such case had been seen.

    We conclude that Kikuchi-Fujimoto disease is rare in Qatar but the incidence might be increasing. The most common presenting symptoms were lymphadenopathy and fever. A male predominance has been found. Laboratory findings are nonspecific and diagnosis requires lymph node biopsy. In the presence of typical clinical features, FNA allows precise diagnosis avoiding biopsy. The outcome is good, and recur-rences are uncommon.

References::

1. Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytes: A clinico- pathologic study. Nippon Ketsueki Gakkhi Zazzhi 1972; 35: 378-80.

 2. Fujimoto Y, Korjiria Y, Yamaguchi K. Cervical subacute necrotizing lymphadenitis: a new clinicopathological entity. Naika 1972; 20: 920-7.

3. Turnner RR, Martin J, Dorfman RF. Necrotizing lymphade- nitis: A study of 30 cases. Am J Surg Pathol 1983; 7: 115-23.

4. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin Diagn Pathol 1988; 5: 329-45.

5. Pileri S, Kikuchi M, Helbron D, Lennort K. Histiocytic necrotizing lymphadenitis without granulocytic infiltration. Virchows Arch Abrol Anab 1982; 395: 257-71.

6. Abba AA, Afzal M, Al-Moharab FI, Baez-Gianreco A. Kikuchi disease: A clinicopathologic analysis of 13 cases from Riyadh Central Hospital. Annals of Saudi Medicine 1995; 15: 288-90.

7. Ejeckam GC, Azadeh B, Matar I, Aboud O. Kikuchi’s lympha- denitis in Qatar. East African Medical Journal 1993; 70: 575-77.

8. Unger P, Rappaport K, Strauchen J, et al. Necrotizing lymphadenitis (Kikuchi’s disease). Arch Pathol Lab Med 1987; 111: 1031.

9. Kutty MK, Anim JT, Sowayen S. Histiocytic necrotizing lymphadenitis in Saudi Arabia. Trop Geogr Med 1991; 43: 68.

10. Kuo T, Shi LY. Surgical pathology of lymph node biopsy specimens in Taiwan with an update on adult Tcell leukaemia/ lymphoma. In: Hanoaka M, Kadin ME, Mikata A, editors. Lymphoid malignancy: immunocytology and cytogenetics. New York: Field and Wood; 1990. p.109-15.

11. Asano S, Akaike Y, Jinnouchi H, et al. Necrotizing lymphade- nitis: a review of clinicopathological, immunohistochemical and ultrastructural studies. Hematol Oncol 1990; 8: 251.

12. Kuo TT. Kikuchi’s disease. A clinicopathologic study of 79 cases with an analysis of histologic subtypes, immunohisto- logy, and DNA ploidy. Am J Surg Pathol 1995; 19: 798-809.

13. Yen A, Fearneyhough P, Raimer SS, Hudnall SD. EBV- associated Kikuchi’s histiocytic necrotizing lymphadenitis with cutaneous manifestation. J Am Acad Dermatol 1997; 36: 342.

 14. Huh J, Kang GH, Gong G, et al. Kaposi’s sarcoma- associated herpesvirus in Kikuchi’s disease. Hum Pathol 1998; 29: 1091.

 15. Yufu Y, Matsumoto M, Miyamura T, et al. Parvovirus B19- associated haemophagocytic syndrome with lymphadenopthy resembling histiocytic necrotizing lymphadenitis (Kikuchi’s disease). Br J Hematol 1997; 96: 868.

 16. Niedobitek G, Herbst H, Young LS, Brooks L, Masucci MG, Crocker J, et al. Patterns of Epstein-Barr Virus infection in non-neoplastic lymphoid tissue. Blood 1992; 79: 2520-26.

 17. Anagnostopoulos I, Hummel M, Korbjuhn P, Papadaki T, Anagnostou D, Stein H. Epstein-Barr virus in Kikuchi- Fujimoto disease. Lancet 1993; 341: 893.

 18. Sumiyoshi Y, Kikuchi M, Ohshima K, Yoneda S, Kobari S, Takeshita M, et al. Human herpes virus 6 genome in histio- cytic necrotizing lymphadenitis ( Kikuchi’s disease) and other forms of lymphadenitis. Am J Clin Pathol 1993; 99: 609-14.

19. Kuo T. Cutaneous manifestation of Kikuchi’s histiocytic necrotizing lymphadenitis. Am J Surg Pathol 1990; 420: 872.

20. Sato Y, Kuno H, Oizumi K. Histiocytic necrotizing lympha- denitis ( Kikuchi’s disease) with aseptic meningitis. J Neurol Sci 1999; 163: 187.

 21. Mathew LG, Cherian T, Srivastava VM, Raghupathy P. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease) with aseptic meningitis. Indian Pediatr 1998; 35: 775.

22. Litwin MD, Kirkham B, Henderson DR. Milazzo SC. Histiocytic necrotizing lymphadenitis in systemic lupus erythematosis. Ann Rheum Dis 1992; 51: 805-7.

23. Hansmann ML, Kikuchi M, Wacker HH, et al. Immunohisto- chemical monitoring of plasmcytoid cells in lymph node sections of Kikuchi-fujimoto disease by a new pan-macro- phage antibody Ki-MIP. Hum Pathol 1992; 23: 676-80.

24. Hsueh EJ, Ko WS, Hwang WS, Yam LT. Fine needle aspiration of histiocytic necrotizing lympadenitis ( Kikuchi’s disease). Diagn Cytopathol 1993; 9: 448-52.

25. Tong TR, Chan OW, Lee KC. Diagnosing Kikuchi disease on fine needle aspiration biopsy: a retrospective study of 44 cases diagnosed by cytology and 8 by histopathology. Acta Cytol 2001; 45: 953-7.

26. Tsang WY, Chan JK. Fine-needle aspiration cytologic diagnosis of Kikuchi’s lymphadenitis. A report of 27 cases. Am J Clin Pathol. 1994; 102: 454-8.

 27. Jang YJ, Park KH, Seok HJ. Management of Kikuchi’s disease using glucocorticoid. J Laryngol Otol 2000; 114: 709.

 28. Chan JKC, Wong KC, Ng CS. A fatal case of multicentric Kikuchi’s histiocytic necrotizing lymphadenitis. Cancer 1989; 63: 1856-62.

29. O’Neill D, O’Grady J, Variend S. Child fatality associated with pathological features of histiocytic necrotizing lympha- denitis (Kikuchi-Fujimoto disease). Pediatr Pathol Lab Med 1998; 18:79-88.n