- Email: [email protected]
Kikuchi’s disease: a review and analysis of 61 cases
Kikuchi’s disease: A review and analysis of 61 cases HSIN-CHING LIN,
MD,
CHIH-YING SU,
MD,
CHAO-CHENG HUANG,
MD,
CHUNG-FENG HWANG,
MD,
and CHIH-YEN CHIEN,
MD,
Kaohsiung, Taiwan, Republic of China OBJECTIVE: Kikuchi’s disease (KD), or histiocytic necrotizing lymphadenitis, is a rare self-limiting disorder that typically affects the cervical lymph nodes. It has occasionally been misdiagnosed as malignant lymphoma or another serious diseases; hence, clinicians should be made more aware of this disease. METHODS: From January 1986 to January 2001, a series of 61 patients who underwent a biopsy of a cervical lymph node and proved histologically to have KD were enrolled in this study. We retrospectively reviewed the clinical records and pathologic parameters of each patient. The patients were followed up from 6 months to 14.3 years (mean, 6.9 years). RESULTS: There were 34 women and 27 men (1.26:1 ratio; age range, 6 to 46 years; mean age, 21 years). The affected cervical lymph nodes were commonly located in the posterior cervical triangle (54 of 61, or 88.5%). Unilateral and bilateral cervical lymph nodes were affected in 54 and 7 patients, respectively. The dimensions of affected lymph nodes were commonly in the range of 0.5 to 4 cm (57 of 61, or 93.4%). In 2 patients, the size of the enlarged lymph nodes was greater than 6 cm. Leukopenia was observed in 14 patients (23%); fever, in 18 patients (29.5%). Five patients had a past history of tuberculosis. Two patients developed systemic lupus erythematosus, 1 month and 5 years later, respectively. The cervical lymphadenopathy usually resolved without any medical treatment within 6 months after definite diagnosis was made. In 3 patients, the enlarged lymph nodes eventually disappeared after more than 1 year. No recurrence has since been noted.
From the Departments of Otolaryngology (Drs Lin, Su, Hwang, and Chien) and Pathology (Dr Huang), Chang Gung University, Chang Gung Memorial Hospital, Kaohsiung Medical Center. Reprint requests: Chih-Ying Su, MD, Department of Otolaryngology, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Naio-Sung Hsiang, 833, Kaohsiung Hsien, Taiwan; e-mail, [email protected]. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/S0194-5998(02)23291-X 650
CONCLUSION: The results of this study support the theory that KD is a self-limiting disorder that does not require any specific management. The female predominance was not as striking as in the studies performed in Western countries. We suggest that the patients with KD require a systemic survey and regular follow-up for several years; 2 of our patients developed systemic lupus erythematosus. An effective communication between the otolaryngologist and pathologist is needed because the clinical and pathologic characteristics of KD are essential in making an accurate diagnosis. (Otolaryngol Head Neck Surg 2003;128:650-3.)
K
ikuchi’s disease (KD), also known as KikuchiFujimoto disease or histiocytic necrotizing lymphadenitis, was first described in 1972 independently by Kikuchi1 and Fujimoto et al.2 More recently, descriptions of KD have appeared in the English pathologic literature, but the disorder has received little attention in otolaryngologic publications. This rare and unusual form of lymphadenitis preferentially affects young females, with a majority of patients under the age of 30 years, in a 3 to 4:1 ratio.3,4 Clinically, the most common presentation of this disorder is cervical lymphadenitis, although it may also be generalized. Other complaints include low-grade fever, malaise, fatigue, and diarrhea, and sometimes the condition is accompanied by weight loss, nausea, and vomiting. There are no specific laboratory tests available for the diagnosis of KD. Leukopenia and atypical lymphocytes were observed in the peripheral blood of 25% to 58.3% and 25% to 31.1% of patients, respectively.5 The definite diagnosis of KD can be made only through histopathologic examination, by means of lymph node excision biopsy. These findings may vary but often have the following criteria3,6: (1) patchy irregular areas of eosinophilic necrosis in the paracortex and/or cortex, (2) pronounced fragments of nuclear dust distributed in an irregular fashion through the area of necrosis, (3) absence of granulocytes and paucity of plasma cells, (4)
Otolaryngology– Head and Neck Surgery Volume 128 Number 5
clusters of plasmacytoid T cells, or plasmacytoid monocytes, and (5) numerous immunoblasts (transformed lymphocytes, predominantly of T cell phenotype). Although the morphologic hallmarks of this disease have been described by numerous authors, this benign disease has been misdiagnosed as tuberculosis, systemic lupus erythematosus (SLE), or malignant lymphoma. That confusion has resulted in some patients having undergone extensive diagnostic evaluation and even chemotherapy.6,7 We reviewed the charts and histopathologic records of the patients with KD who were treated at our hospital during the past 15 years. Clinical features of this disease, specific characteristics of our patients, and long-term follow-up results are discussed. METHODS A retrospective chart review and a histopathologic characteristic review were completed for the patients with KD diagnosed at Chang Gung Memorial Hospital, Kaohsiung Medical Center, Taiwan, from January 1986 to January 2001. Clinical characteristics, affected lymph node status, associated symptoms, and laboratory study results were collected from the medical records when available, and follow-up information was traced from the outpatient department and by contacting the patients. The follow-up period averaged 6.9 years (range, 0.5 to 14.3 years). RESULTS The clinical features of the 61 patients with KD are summarized in Table 1. The patients, consisting of 27 men and 34 women at a ratio of 1:1.26, were entered into the database. The mean age was 20.9 years (range, 6 to 46 years). Twenty-one cases (34.4%) involved pediatric patients younger than 16 years. Fifty patients (86.9%) were under the age of 30. Single or multiple cervical lymph nodes were affected in 16 and 45 cases, respectively. Right cervical lymph node enlargement was found in 28 patients, left in 26 patients, and bilateral in 7 patients. The affected lymph nodes appearing in anterior only, posterior only, and combined anterior and posterior cervical triangles accounted for 2 (3.3%), 54 (88.5%), and 5 patients (8.2%), respectively. The greatest dimension of
LIN et al
651
Table 1. Clinical features of Kikuchi’s disease in Chang Gung Memorial Hospital, Kaohsiung No. of cases Male:female Age (y) Range Mean Site of lymphadenopathy (n) Posterior cervical only Anterior cervical only Combined anterior and posterior cervical Laterality of lymphadenopathy (n) Bilateral neck Right neck Left neck Fever (⬎37.5° C) (n) White blood cell count (n) Leukopenia Leukocytosis Associated with SLE (n)
61 27:34 (1:1.26) 6-46 20.9 54 (88.52%) 2 (3.3%) 5 (8.2%)
7 (11.5%) 28 (45.9%) 26 (42.6%) 18 (29.5%) 14 (23.0%) 1 (1.6%) 2 (3.3%)
SLE, Systemic lupus erythematosus.
the enlarged cervical lymph nodes ranged from 0.5 to 9 cm, ⬍2 cm in 41 patients (67.2%), and ⬎6 cm in 2 patients (3.3%). The duration between the patient’s noticing a cervical mass and seeking clinical help is measurable in days for 18 patients, weeks for 11 patients, months for 29 patients, and ⬎1 year for 3 patients. Elevated body temperature (⬎37.5°C) was observed in 18 patients (29.5%). Leukopenia with a white blood cell count of ⬍3900/mm3 in males and ⬍3500/mm3 in females was noted in 14 patients (23.0%). White blood cell count of ⬎10,600/mm3 was found in only 1 patient (1.6%). Among the patients who had leukopenia, 2 patients (3.3%) also were observed with atypical lymphocytes in the peripheral blood. Under the presumptive diagnosis of lymphoma, these 2 patients underwent a bone marrow study, which produced no remarkable findings. Both patients then underwent excision of the enlarged cervical lymph nodes, which resulted in the definite diagnosis of KD. Five patients had a past history of tuberculosis and received a complete antituberculous therapy. Two patients (3.3%) developed SLE 1 month and 5 years later, respectively. One patient was also the victim of advanced cancer of the buccal mucosa; he underwent a composite resection of the tumor. The histopathologic findings confirmed
652 LIN et al
the diagnosis of KD and metastasis of buccal cancer to the cervical lymph nodes. Unfortunately, the patient died of lung metastasis 6 months later. The affected lymphadenopathy generally resolved within 1 to 6 months (51 patients, 85%) or in ⬎1 year (3 patients, 5%). All patients except one were alive and well with complete resolution of the remaining lymph nodes at follow-up of 6 months to 14.3 years. Neither recurrence nor persisting KD has since been noted. DISCUSSION Kikuchi’s disease, or Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis, was first described in Japanese literature independently by Kikuchi1 and Fujimoto et al2 in 1972. The first report in English was published in 1977, and the first case in otolaryngologic literature was reported by Gleeson et al in 1985.8 Because the reports of KD are predominantly published in the pathology literature, many clinicians are probably unaware of this condition. That disease preferentially affects women in a 3-4:1 ratio is mentioned in most English publications3,4,9; however, our current series showed a ratio of only 1.26:1. Less female predominance in an Asian series was reported by Kuo in his pathologic report.5 There may be no such obvious gender difference in the Asian population compared with Western populations. This difference might have a certain correlation with genetic, environmental, socioeconomic, and even dietary factors. This hypothesis, however, should have a greater series and further investigation to confirm it. The majority of patients in other studies are under the age of 30 years, with a mean of 25.5 to 30.0 years.5,9 Our patients’ ages ranged from 6 to 46 years, with a younger mean of 20.9 years. The etiology of the disease remains unclear; various infections have been postulated to be the cause: Toxoplasma, Yersina, enterocolitica, Epstein-Barr virus, rubella, paramyxovirus, and parainfluenzavirus.6 Some findings indicate that interferon ␥, interleukin-6, or apoptotic cell death may play a role in the pathogenesis of KD.10,11 In the relatively numerous cases reported from Japan, some authors suggested the possibility of an usual animal food source, such as raw fish.4 The sites of cervical lymphadenopathy are common in the pos-
Otolaryngology– Head and Neck Surgery May 2003
terior cervical triangle and jugular carotid chain, rarely in diffuse distributions.6 Our series of cases also show the same frequently affected sites as those of previous literature: the unilateral neck (88.5%) and posterior cervical triangle (88.5%) are dominant. Bilateral cervical lymph node enlargement occurred in only 7 cases (11.5%). The nodal diameters of 1 to 4 cm are common but may reach 5 to 6 cm,12 as was also true in our results. There are no definite laboratory tests available for the diagnosis of KD, but negative tests are important to exclude other disorders. White blood cell counts in the normal range occur commonly, but the presence of leukopenia is frequently mentioned and still consistent with KD, ranging from 25.5% to 58.3%.5,12 Our data showed no significant difference; leukopenia with white blood cell counts of ⬍3900/mm3 in males and ⬍3500/mm3 in females was observed in 14 of 61 patients (23.0%). However, there were 2 patients in the leukopenic subgroup who also had associated fever and atypical lymphocytes in the peripheral blood. Owing to the presumptive diagnosis of lymphoma, they both underwent aggressive diagnostic evaluation, but the definite diagnosis of KD was made only after excision biopsy of the enlarged cervical nodes. Dorfman and Berry’s13 study emphasized the differential diagnosis of KD, including malignant lymphoma, SLE, Hodgkin’s disease, toxoplasmosis, metastatic carcinoma, cat scratch disease, acquired immunodeficiency syndrome, angioimmunoblastic lymphadenopathy, and infectious mononucleosis. Lerosy et al6 particularly mentioned the consideration of the differential diagnosis between KD and Still’s disease in children. Because the microscopic characteristics alone may lead to an erroneous diagnosis, effective communication between the head and neck surgeon and expert pathologist is necessary for the accurate diagnosis of KD. Most authors do not recommend special treatment for KD; only in complicated cases or in coincidence with SLE was the use of a drug (corticosteroid) suggested.14,15 The cervical lymphadenopathy runs a benign course and appears to resolve spontaneously 1 to 6 months after definite diagnosis.3,12 In the current series, more than 80%
Otolaryngology– Head and Neck Surgery Volume 128 Number 5
of the affected lymph nodes subsided within 6 months without specific treatment. There have only been 3 reported fatal cases of KD.13,16,17 Recurrent KD has also been reported in some studies; its incidence ranges from 3% to 4%.3,5 The diagnosis of KD can precede, postdate, or coincide with the diagnosis of SLE.5,15 In our series, 2 patients developed SLE. One patient was found to have SLE at 1 month and the other at 5 years after the diagnosis of KD. It is important for patients with KD to undergo long-term follow-up to check for the development of the SLE. Associated disorders in other reports included meningitis, ruptured silicone breast implants, breast carcinoma, and gastric adenocarcinoma.18-20 In the current series, 1 patient with KD was also diagnosed with advanced cancer of the buccal mucosa with metastasis to the neck and lung, and 5 patients with a past history of tuberculosis were noted. We therefore presume that transient immune reaction may have some relation with KD. A clinical suspicion of KD and strict collaboration between the head and neck surgeon and pathologist are key for the accurate diagnosis of KD, especially in young persons with posterior cervical triangle mass in their first 3 decades of life. There may not be a female predisposition in the Asian population. Patients with KD should be kept under close observation for several years to survey the possibility of the development of SLE.
LIN et al
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
REFERENCES
1. Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytes: a clinicopathological study. Nippon Ketsueki Gakkai Zassho 1972;35:379-80. 2. Fujimoto Y, Kojima Y, Yamaguchi K. Cervical subacute necrotizing lymphadenitis. Naika 1972;30:920-7. 3. Garcı´a CE, Girdhar-Gopal HV, Dorfman DM. KikuchiFujimoto disease of the neck. Update. Ann Otol Rhinol Laryngol 1993;102:11-5. 4. Louis N, Hanley M, Davidson NM. Kikuchi-Fujimoto disease: a report of two cases and an overview. J Laryngol Otol 1994;108:1001-4. 5. Kuo TT. Kikuchi’s disease. A clinicopathologic study of 79 cases with an analysis of histologic subtypes, immu-
17.
18.
19.
20.
653
nohistology, and DNA ploidy. Am J Surg Pathol 1995; 19:798-809. Lerosy Y, Lecler-Scarcella V, Francois A, et al. A pseudo-tumoral form of Kikuchi’s disease in children: a case report and review of the literature. Int J Pediatr Otorhinolaryngol 1998;45:1-6. Dylewski J, Berry G, Pham-Dang H. An unusual cause of cervical lymphadenitis: Kikuchi-Fujimoto disease. Rev Infect Dis 1991;13:823-5. Gleeson MJ, Siodlak MZ, Barbatis C, et al. Kikuchi’s: a new cause of cervical lymphadenopathy. J Laryngol Otol 1985;99:935-9. Tsang WYW, Chan JKC, Ng CS. Kikuchi’s lymphadenitis. A morphologic analysis of 75 cases with special reference to unusual features. Am J Surg Pathol 1994; 18:219-31 Kubota M, Tsukamoto R, Kurokawa K, et al. Elevated serum interferon␥and interleukin-6 in patients with necrotizing lymphadenitis (Kikuchi’s disease). Br J Haematol 1996;95:613-5. Iguchi H, Sunami K, Yamane H, et al. Apoptotic cell death in Kikuchi’s disease: a TEM study. Acta Otolaryngol. 1998;Suppl 538:250-3. Sterman BM, Benninger MS, Eliachar I. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease). Head Neck 1989;11:349-52. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin Diagn Pathol 1988;5:32945. Bhat NA, Hock YL, Turner NO, et al. Kikuchi’s disease of the neck (histiocytic necrotizing lymphadenitis). J Laryngol Otol 1998;112:898-900. Martı´nez-Va´ zquez C, Hughes G, Bordon J, et al. Histiocytic necrotizing lymphadenitis, Kikuchi-Fujimoto’s disease, associated with systemic lupus erythematosus. Q J Med 1997;90:531-3. Chan JKC, Wong K-C, Ng C-S. A fatal case of multicentric Kikuchi’s histiocytic necrotizing lymphadenitis. Cancer 1989;63:1856-62. O’Neill D, O’Grady J, Variend S. Child fatality associated with pathological features of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease). Pediatr Pathol Lab Med 1998;18:79-88. Sato Y, Kuno H, Oizumi K. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease) with aseptic meningitis. J Neurol Sci 1999;163:187-91. Sever CE, Leith CP, Appenzeller J, et al. Kikuchi’s histiocytic necrotizing lymphadenitis associated with ruptured silicone breast implant. Arch Pathol Lab Med 1996;120:380-5. Aqel NM, Peters EE. Kikuchi’s disease in axillary lymph nodes draining breast carcinoma. Histopathology 2000; 36:280-1.
MD,
CHIH-YING SU,
MD,
CHAO-CHENG HUANG,
MD,
CHUNG-FENG HWANG,
MD,
and CHIH-YEN CHIEN,
MD,
Kaohsiung, Taiwan, Republic of China OBJECTIVE: Kikuchi’s disease (KD), or histiocytic necrotizing lymphadenitis, is a rare self-limiting disorder that typically affects the cervical lymph nodes. It has occasionally been misdiagnosed as malignant lymphoma or another serious diseases; hence, clinicians should be made more aware of this disease. METHODS: From January 1986 to January 2001, a series of 61 patients who underwent a biopsy of a cervical lymph node and proved histologically to have KD were enrolled in this study. We retrospectively reviewed the clinical records and pathologic parameters of each patient. The patients were followed up from 6 months to 14.3 years (mean, 6.9 years). RESULTS: There were 34 women and 27 men (1.26:1 ratio; age range, 6 to 46 years; mean age, 21 years). The affected cervical lymph nodes were commonly located in the posterior cervical triangle (54 of 61, or 88.5%). Unilateral and bilateral cervical lymph nodes were affected in 54 and 7 patients, respectively. The dimensions of affected lymph nodes were commonly in the range of 0.5 to 4 cm (57 of 61, or 93.4%). In 2 patients, the size of the enlarged lymph nodes was greater than 6 cm. Leukopenia was observed in 14 patients (23%); fever, in 18 patients (29.5%). Five patients had a past history of tuberculosis. Two patients developed systemic lupus erythematosus, 1 month and 5 years later, respectively. The cervical lymphadenopathy usually resolved without any medical treatment within 6 months after definite diagnosis was made. In 3 patients, the enlarged lymph nodes eventually disappeared after more than 1 year. No recurrence has since been noted.
From the Departments of Otolaryngology (Drs Lin, Su, Hwang, and Chien) and Pathology (Dr Huang), Chang Gung University, Chang Gung Memorial Hospital, Kaohsiung Medical Center. Reprint requests: Chih-Ying Su, MD, Department of Otolaryngology, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Naio-Sung Hsiang, 833, Kaohsiung Hsien, Taiwan; e-mail, [email protected]. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/S0194-5998(02)23291-X 650
CONCLUSION: The results of this study support the theory that KD is a self-limiting disorder that does not require any specific management. The female predominance was not as striking as in the studies performed in Western countries. We suggest that the patients with KD require a systemic survey and regular follow-up for several years; 2 of our patients developed systemic lupus erythematosus. An effective communication between the otolaryngologist and pathologist is needed because the clinical and pathologic characteristics of KD are essential in making an accurate diagnosis. (Otolaryngol Head Neck Surg 2003;128:650-3.)
K
ikuchi’s disease (KD), also known as KikuchiFujimoto disease or histiocytic necrotizing lymphadenitis, was first described in 1972 independently by Kikuchi1 and Fujimoto et al.2 More recently, descriptions of KD have appeared in the English pathologic literature, but the disorder has received little attention in otolaryngologic publications. This rare and unusual form of lymphadenitis preferentially affects young females, with a majority of patients under the age of 30 years, in a 3 to 4:1 ratio.3,4 Clinically, the most common presentation of this disorder is cervical lymphadenitis, although it may also be generalized. Other complaints include low-grade fever, malaise, fatigue, and diarrhea, and sometimes the condition is accompanied by weight loss, nausea, and vomiting. There are no specific laboratory tests available for the diagnosis of KD. Leukopenia and atypical lymphocytes were observed in the peripheral blood of 25% to 58.3% and 25% to 31.1% of patients, respectively.5 The definite diagnosis of KD can be made only through histopathologic examination, by means of lymph node excision biopsy. These findings may vary but often have the following criteria3,6: (1) patchy irregular areas of eosinophilic necrosis in the paracortex and/or cortex, (2) pronounced fragments of nuclear dust distributed in an irregular fashion through the area of necrosis, (3) absence of granulocytes and paucity of plasma cells, (4)
Otolaryngology– Head and Neck Surgery Volume 128 Number 5
clusters of plasmacytoid T cells, or plasmacytoid monocytes, and (5) numerous immunoblasts (transformed lymphocytes, predominantly of T cell phenotype). Although the morphologic hallmarks of this disease have been described by numerous authors, this benign disease has been misdiagnosed as tuberculosis, systemic lupus erythematosus (SLE), or malignant lymphoma. That confusion has resulted in some patients having undergone extensive diagnostic evaluation and even chemotherapy.6,7 We reviewed the charts and histopathologic records of the patients with KD who were treated at our hospital during the past 15 years. Clinical features of this disease, specific characteristics of our patients, and long-term follow-up results are discussed. METHODS A retrospective chart review and a histopathologic characteristic review were completed for the patients with KD diagnosed at Chang Gung Memorial Hospital, Kaohsiung Medical Center, Taiwan, from January 1986 to January 2001. Clinical characteristics, affected lymph node status, associated symptoms, and laboratory study results were collected from the medical records when available, and follow-up information was traced from the outpatient department and by contacting the patients. The follow-up period averaged 6.9 years (range, 0.5 to 14.3 years). RESULTS The clinical features of the 61 patients with KD are summarized in Table 1. The patients, consisting of 27 men and 34 women at a ratio of 1:1.26, were entered into the database. The mean age was 20.9 years (range, 6 to 46 years). Twenty-one cases (34.4%) involved pediatric patients younger than 16 years. Fifty patients (86.9%) were under the age of 30. Single or multiple cervical lymph nodes were affected in 16 and 45 cases, respectively. Right cervical lymph node enlargement was found in 28 patients, left in 26 patients, and bilateral in 7 patients. The affected lymph nodes appearing in anterior only, posterior only, and combined anterior and posterior cervical triangles accounted for 2 (3.3%), 54 (88.5%), and 5 patients (8.2%), respectively. The greatest dimension of
LIN et al
651
Table 1. Clinical features of Kikuchi’s disease in Chang Gung Memorial Hospital, Kaohsiung No. of cases Male:female Age (y) Range Mean Site of lymphadenopathy (n) Posterior cervical only Anterior cervical only Combined anterior and posterior cervical Laterality of lymphadenopathy (n) Bilateral neck Right neck Left neck Fever (⬎37.5° C) (n) White blood cell count (n) Leukopenia Leukocytosis Associated with SLE (n)
61 27:34 (1:1.26) 6-46 20.9 54 (88.52%) 2 (3.3%) 5 (8.2%)
7 (11.5%) 28 (45.9%) 26 (42.6%) 18 (29.5%) 14 (23.0%) 1 (1.6%) 2 (3.3%)
SLE, Systemic lupus erythematosus.
the enlarged cervical lymph nodes ranged from 0.5 to 9 cm, ⬍2 cm in 41 patients (67.2%), and ⬎6 cm in 2 patients (3.3%). The duration between the patient’s noticing a cervical mass and seeking clinical help is measurable in days for 18 patients, weeks for 11 patients, months for 29 patients, and ⬎1 year for 3 patients. Elevated body temperature (⬎37.5°C) was observed in 18 patients (29.5%). Leukopenia with a white blood cell count of ⬍3900/mm3 in males and ⬍3500/mm3 in females was noted in 14 patients (23.0%). White blood cell count of ⬎10,600/mm3 was found in only 1 patient (1.6%). Among the patients who had leukopenia, 2 patients (3.3%) also were observed with atypical lymphocytes in the peripheral blood. Under the presumptive diagnosis of lymphoma, these 2 patients underwent a bone marrow study, which produced no remarkable findings. Both patients then underwent excision of the enlarged cervical lymph nodes, which resulted in the definite diagnosis of KD. Five patients had a past history of tuberculosis and received a complete antituberculous therapy. Two patients (3.3%) developed SLE 1 month and 5 years later, respectively. One patient was also the victim of advanced cancer of the buccal mucosa; he underwent a composite resection of the tumor. The histopathologic findings confirmed
652 LIN et al
the diagnosis of KD and metastasis of buccal cancer to the cervical lymph nodes. Unfortunately, the patient died of lung metastasis 6 months later. The affected lymphadenopathy generally resolved within 1 to 6 months (51 patients, 85%) or in ⬎1 year (3 patients, 5%). All patients except one were alive and well with complete resolution of the remaining lymph nodes at follow-up of 6 months to 14.3 years. Neither recurrence nor persisting KD has since been noted. DISCUSSION Kikuchi’s disease, or Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis, was first described in Japanese literature independently by Kikuchi1 and Fujimoto et al2 in 1972. The first report in English was published in 1977, and the first case in otolaryngologic literature was reported by Gleeson et al in 1985.8 Because the reports of KD are predominantly published in the pathology literature, many clinicians are probably unaware of this condition. That disease preferentially affects women in a 3-4:1 ratio is mentioned in most English publications3,4,9; however, our current series showed a ratio of only 1.26:1. Less female predominance in an Asian series was reported by Kuo in his pathologic report.5 There may be no such obvious gender difference in the Asian population compared with Western populations. This difference might have a certain correlation with genetic, environmental, socioeconomic, and even dietary factors. This hypothesis, however, should have a greater series and further investigation to confirm it. The majority of patients in other studies are under the age of 30 years, with a mean of 25.5 to 30.0 years.5,9 Our patients’ ages ranged from 6 to 46 years, with a younger mean of 20.9 years. The etiology of the disease remains unclear; various infections have been postulated to be the cause: Toxoplasma, Yersina, enterocolitica, Epstein-Barr virus, rubella, paramyxovirus, and parainfluenzavirus.6 Some findings indicate that interferon ␥, interleukin-6, or apoptotic cell death may play a role in the pathogenesis of KD.10,11 In the relatively numerous cases reported from Japan, some authors suggested the possibility of an usual animal food source, such as raw fish.4 The sites of cervical lymphadenopathy are common in the pos-
Otolaryngology– Head and Neck Surgery May 2003
terior cervical triangle and jugular carotid chain, rarely in diffuse distributions.6 Our series of cases also show the same frequently affected sites as those of previous literature: the unilateral neck (88.5%) and posterior cervical triangle (88.5%) are dominant. Bilateral cervical lymph node enlargement occurred in only 7 cases (11.5%). The nodal diameters of 1 to 4 cm are common but may reach 5 to 6 cm,12 as was also true in our results. There are no definite laboratory tests available for the diagnosis of KD, but negative tests are important to exclude other disorders. White blood cell counts in the normal range occur commonly, but the presence of leukopenia is frequently mentioned and still consistent with KD, ranging from 25.5% to 58.3%.5,12 Our data showed no significant difference; leukopenia with white blood cell counts of ⬍3900/mm3 in males and ⬍3500/mm3 in females was observed in 14 of 61 patients (23.0%). However, there were 2 patients in the leukopenic subgroup who also had associated fever and atypical lymphocytes in the peripheral blood. Owing to the presumptive diagnosis of lymphoma, they both underwent aggressive diagnostic evaluation, but the definite diagnosis of KD was made only after excision biopsy of the enlarged cervical nodes. Dorfman and Berry’s13 study emphasized the differential diagnosis of KD, including malignant lymphoma, SLE, Hodgkin’s disease, toxoplasmosis, metastatic carcinoma, cat scratch disease, acquired immunodeficiency syndrome, angioimmunoblastic lymphadenopathy, and infectious mononucleosis. Lerosy et al6 particularly mentioned the consideration of the differential diagnosis between KD and Still’s disease in children. Because the microscopic characteristics alone may lead to an erroneous diagnosis, effective communication between the head and neck surgeon and expert pathologist is necessary for the accurate diagnosis of KD. Most authors do not recommend special treatment for KD; only in complicated cases or in coincidence with SLE was the use of a drug (corticosteroid) suggested.14,15 The cervical lymphadenopathy runs a benign course and appears to resolve spontaneously 1 to 6 months after definite diagnosis.3,12 In the current series, more than 80%
Otolaryngology– Head and Neck Surgery Volume 128 Number 5
of the affected lymph nodes subsided within 6 months without specific treatment. There have only been 3 reported fatal cases of KD.13,16,17 Recurrent KD has also been reported in some studies; its incidence ranges from 3% to 4%.3,5 The diagnosis of KD can precede, postdate, or coincide with the diagnosis of SLE.5,15 In our series, 2 patients developed SLE. One patient was found to have SLE at 1 month and the other at 5 years after the diagnosis of KD. It is important for patients with KD to undergo long-term follow-up to check for the development of the SLE. Associated disorders in other reports included meningitis, ruptured silicone breast implants, breast carcinoma, and gastric adenocarcinoma.18-20 In the current series, 1 patient with KD was also diagnosed with advanced cancer of the buccal mucosa with metastasis to the neck and lung, and 5 patients with a past history of tuberculosis were noted. We therefore presume that transient immune reaction may have some relation with KD. A clinical suspicion of KD and strict collaboration between the head and neck surgeon and pathologist are key for the accurate diagnosis of KD, especially in young persons with posterior cervical triangle mass in their first 3 decades of life. There may not be a female predisposition in the Asian population. Patients with KD should be kept under close observation for several years to survey the possibility of the development of SLE.
LIN et al
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
REFERENCES
1. Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytes: a clinicopathological study. Nippon Ketsueki Gakkai Zassho 1972;35:379-80. 2. Fujimoto Y, Kojima Y, Yamaguchi K. Cervical subacute necrotizing lymphadenitis. Naika 1972;30:920-7. 3. Garcı´a CE, Girdhar-Gopal HV, Dorfman DM. KikuchiFujimoto disease of the neck. Update. Ann Otol Rhinol Laryngol 1993;102:11-5. 4. Louis N, Hanley M, Davidson NM. Kikuchi-Fujimoto disease: a report of two cases and an overview. J Laryngol Otol 1994;108:1001-4. 5. Kuo TT. Kikuchi’s disease. A clinicopathologic study of 79 cases with an analysis of histologic subtypes, immu-
17.
18.
19.
20.
653
nohistology, and DNA ploidy. Am J Surg Pathol 1995; 19:798-809. Lerosy Y, Lecler-Scarcella V, Francois A, et al. A pseudo-tumoral form of Kikuchi’s disease in children: a case report and review of the literature. Int J Pediatr Otorhinolaryngol 1998;45:1-6. Dylewski J, Berry G, Pham-Dang H. An unusual cause of cervical lymphadenitis: Kikuchi-Fujimoto disease. Rev Infect Dis 1991;13:823-5. Gleeson MJ, Siodlak MZ, Barbatis C, et al. Kikuchi’s: a new cause of cervical lymphadenopathy. J Laryngol Otol 1985;99:935-9. Tsang WYW, Chan JKC, Ng CS. Kikuchi’s lymphadenitis. A morphologic analysis of 75 cases with special reference to unusual features. Am J Surg Pathol 1994; 18:219-31 Kubota M, Tsukamoto R, Kurokawa K, et al. Elevated serum interferon␥and interleukin-6 in patients with necrotizing lymphadenitis (Kikuchi’s disease). Br J Haematol 1996;95:613-5. Iguchi H, Sunami K, Yamane H, et al. Apoptotic cell death in Kikuchi’s disease: a TEM study. Acta Otolaryngol. 1998;Suppl 538:250-3. Sterman BM, Benninger MS, Eliachar I. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease). Head Neck 1989;11:349-52. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin Diagn Pathol 1988;5:32945. Bhat NA, Hock YL, Turner NO, et al. Kikuchi’s disease of the neck (histiocytic necrotizing lymphadenitis). J Laryngol Otol 1998;112:898-900. Martı´nez-Va´ zquez C, Hughes G, Bordon J, et al. Histiocytic necrotizing lymphadenitis, Kikuchi-Fujimoto’s disease, associated with systemic lupus erythematosus. Q J Med 1997;90:531-3. Chan JKC, Wong K-C, Ng C-S. A fatal case of multicentric Kikuchi’s histiocytic necrotizing lymphadenitis. Cancer 1989;63:1856-62. O’Neill D, O’Grady J, Variend S. Child fatality associated with pathological features of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease). Pediatr Pathol Lab Med 1998;18:79-88. Sato Y, Kuno H, Oizumi K. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease) with aseptic meningitis. J Neurol Sci 1999;163:187-91. Sever CE, Leith CP, Appenzeller J, et al. Kikuchi’s histiocytic necrotizing lymphadenitis associated with ruptured silicone breast implant. Arch Pathol Lab Med 1996;120:380-5. Aqel NM, Peters EE. Kikuchi’s disease in axillary lymph nodes draining breast carcinoma. Histopathology 2000; 36:280-1.