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Histiocytic necrotizing lymphadenitis of the neck
Histiocytic Necrotizing Lymphadenitis of the Neck Serap Koybasi, MD,* Levent Saydam, MD,† and Yucel Gungen, MD‡ Histiocytic necrotizing lymphadenitis (HNL) also known as Kikuchi or Kikuchi-Fujimato disease is a benign and self-limiting disease. The entity was first described in 1972 by Kikuchi and Fujimato in Japan independently. HNL is prevalent in Asia, although it may be seen in a wide geographic distribution. It commonly affects young women. Cervical lymphadenopathy is the most prominent symptom and should be differentiated from lymphoproliferative, autoimmune, and postinfectious diseases. Apoptosis is the main process, taking role in pathogenesis of the disease. Although it is a well-known entity among pathologists, little is written in ear, nose, and throat literature. In this study, we report 2 male patients with HNL presenting with enlarged cervical lymph nodes with a brief review of literature. (Am J Otolaryngol 2003;24:344-347. © 2003 Elsevier Inc. All rights reserved.)
Kikuchi1 and Fujimato et al2 first described Kikuchi or Kikuchi-Fujimato disease in Japan in 1972 independently. The disease is also known as histiocytic necrotizing lymphadenitis (HNL). Although it is prominent in Asia, it is being increasingly reported in other areas. The disease usually affects women under 30 years of age but may also be diagnosed in men. The etiology of the disease is unclear. It is suggested to be an apoptotic process mediated mainly by CD8-positive T lymphocytes. Viral or autoimmune etiology is believed to be causative factors.3,4 HNL manifests itself as enlargement of the lymph nodes usually in posterior cervical region. Generalized lymphadenopathy may also be seen. Pyrexia and neutropenia may be the accompanying symptoms, which may lead to initial misdiagnosis of lymphoma.5 Laboratory usually gives nothing but sometimes slight neutropenia. The diagnosis is achieved by tissue biopsy. It can easily be confused with lymphoma and systemic lupus erythematosus both clinically and histologically.6,7 The disease has a benign course and good prognosis. It is a self-limiting disease; most
From the *Department of Otolaryngology, Abant Izzet Baysal University; †Department of Otolaryngology, Ankara Bayındır Hospital; and ‡Department of Pathology, Hacettepe University, Bolu, Turkey. Address correspondence to: Serap Ko¨ybas¸ı, Abant Izzet Baysal University, Izzet Baysal Medical Faculty Department of Otolaryngology, 14280, Bolu, Turkey. E-mail: [email protected]. © 2003 Elsevier Inc. All rights reserved. 0196-0709/03/2405-0000$30.00/0 doi:10.1016/S0196-0709(03)00061-9 344
patients recover spontaneously within a few weeks to months without any serious sequelae. Kikuchi disease is a well-known entity among pathologists; however, only a few reports are found in the otolaryngology literature. The first head and neck case was reported by Gleeson et al8 in 1985. Because many patients present to ear, nose, and throat surgeons for lymph node biopsy, it is important to heighten awareness of the disease among otolaryngologists also.9 CASE 1 A 31-year-old man has presented with a sole complaint of painless mass in the cervical region for 3 months. Ear, nose, and throat examination including endoscopic evaluations was normal other than a mobile nodal enlargement measuring 1.5 ⫻ 2 cm in the left posterior cervical region. Cervical ultrasonography (USG) revealed multiple nodal enlargements ovoid in shape in left posterior cervical (the biggest one to be 17 ⫻ 9 mm), submental, and right anterior cervical region. Hematologic investigations including erythrocyte sedimentation rate, biochemistry, antinuclear antibody titre, chest radiograph, and abdominal USG were totally normal. Excisional biopsy of the lymph node was performed under local anesthesia. The histopathologic evaluation was reported as Kikuchi’s disease. In the 2-year follow-up period, the patient had no recurrence or any complaint regarding the disease.
American Journal of Otolaryngology, Vol 24, No 5 (September-October), 2003: pp 344-347
HISTIOCYTIC NECROTIZING LYMPHADENITIS
Fig 1. A necrotic focus surrounded by lymphocytes is seen on the right side of the micrograph (hematoxylin and eosin, ⴛ100).
CASE 2 A 42-year-old man presented with a painless, slow-growing, left-sided neck lump for 2 years. On physical examination, a hard, mobile mass of 3 ⫻ 4 cm in diameter was found just medial to the left submandibular gland. The rest of the examination including endoscopic evaluation was unremarkable. Ultrasonography of the neck revealed a heterogenous, hypoechoic solid nodular mass of left submandibular fossa measuring 3 ⫻ 1.5 cm with a lymph node–like appearance. There was an adjacent lymphadenopathy 1 cm in diameter just inferior to the mass. Bilateral multiple very small lymph node enlargements were also noted. Hematologic parameters were normal except for hepatitis B virus surface antigen positivity, and hepatitis B virus
345
Fig 3. Higher magnification of a necrotic area composed of nuclear debris (hematoxylin and eosin, ⴛ400).
DNA was (⫹) on polymerase chain reaction. The liver functions and abdominal USG findings were all within normal limits. An excisional biopsy of the mass was performed along with the left submandibular gland removal under general anesthesia. The mass and the adjacent lymph node were reported as Kikuchi’s disease. The histopathologic evaluation of submandibular gland revealed normal glandular parenchyma. In the 1.5-year follow-up period, the patient has been observed to be disease free. HISTOPATHOLOGY Both biopsy materials were lymph nodes measuring 0.5 to 3 cm in diameter. Their cut surfaces were homogeneous with no specific macroscopic finding. The histologic sections of both cases were also similar. The normal structure of the lymph nodes were partially maintained, but in some portions sharply demarcated areas of necrosis surrounded by a diffuse infiltration of lymphocytes, proliferating immunoblasts, and histiocytic cells were observed. Abundant nuclear debris was present among the proliferating cells (Figs 1-3). DISCUSSION
Fig 2. The cells surrounding the areas of necrosis were a combination of lymphocytes, histiocytes, and proliferating immunoblasts (hematoxylin and eosin, ⴛ200).
Kikuchi disease or Kikuchi-Fujimato disease was first described by Kikuchi1 and Fujimato et al2 independently in Japan in 1972. It is also and more commonly known as HNL. HNL is most commonly seen in eastern Asia; however, it has a wide geographic dis-
346
tribution throughout the world. Despite the fact that the disease usually affects young women between 20 and 30 years of age, it also shows a wide range of age from 8 to 57.10 Despite an expressed female-to-male ratio in the literature as 4:1 or 3:2,7,10,11 both of our cases are male patients. Patients with HNL usually present with enlarged lymph nodes, intermittent fever, mild tenderness, slight neutropenia, and very rarely cutaneous manifestations. Although there may be generalized lymphadenopathies in 80% of the patients, the disease is more frequently localized in the neck and especially the posterior cervical region with an incidence of 65% to 70%. Axillary lymph node involvement comes next in frequency. The lymph nodes are usually painless, but the patients may note slight tenderness on pressure.7,9,11 Definitive etiology has not been identified yet. Recent studies have indicated that cellular apoptosis induced by perforin- or Fasbased mechanisms is the main process in HNL.12-14 This particular finding is shown both in lymphocytes and histiocytes in the diseased lymph nodes. Viral agents especially human herpes virus 6, cytomegalovirus, and Epstein Barr virus are the most strongly accused viral factors that may cause apoptosis. The apoptotic process seems to be responsible for the necrotic appearance of the lymph nodes.12,13,15-17 In our second case, probably a coincidental hepatitis B virus surface antigen positivity was present. Perforin, a cytolytic protein specific to killer cells essential for inducing apoptosis was found to be expressed abundantly by the infiltrating cells. Takakuwa et al14 in their study of 34 patients with HNL have found perforin expressing cells to be 82.4%, and they thought them to be CD8-positive cytotoxic T cells. Kato et al18 found that soluble Fas ligand was elevated, and they suggest soluble Fas ligan plays an important role in the symptoms and pathogenesis; furthermore, it may act as a surrogate marker of the disease. Some authors suggest that Fas-induced or perforin-induced apoptosis in lymph nodes of HNL is led by CD8-positive cells as the effector and target cells and histiocytes could play a role as enhancers.3,19,20
KOYBASI, SAYDAM, AND GUNGEN
Interleukin 2, interleukin 6, and interferon gamma are also found to be mediators in the apoptotic process, and these data support the hypothesis of a viral or autoimmune pathology in HNL.3,4 Diagnosis of HNL depends solely on excisional biopsy.6,7,9 Fine-needle aspiration biopsy may be only suggestive but not accepted as diagnostic. Differential diagnosis is very important especially to avoid excessive and expensive investigations and to avoid overtreatment. Symptomatology is nonspecific. HNL usually presents itself as cervical lymphadenopathy with or without symptoms like fever and malaise. From the laboratory standpoint, only neutropenia can be shown in some cases. HNL is characterized by collection of histiocytes and lymphocytes surrounding areas of necrosis. Polymorphonuclear leukocytes are usually absent. Overlapping histological features require differential diagnosis between HNL and a number of infectious diseases such as tuberculosis, sarcoidosis, autoimmune, and lymphoproliferative diseases.7,21,22 The relation between systemic lupus erythematosis (SLE) and HNL remains to be a matter of debate because of rare cutaneous manifestations of HNL-like facial rash and erythema multiforme. Some authors advocate that the disease is an early presentation of SLE.23,24 Differential diagnosis is made by only histopathological study; in SLE, enlarged lymph nodes show follicular hyperplasia with granulocytes and plasma cells that are not found in HNL. Both pathologists and clinicians should be aware of the similar presentations of the lymph nodes in HNL and SLE. Another important disease is lymphoma and because of the resemblance of these 2 diseases, there are some reports in the literature describing HNL cases treated as lymphoma.9,10 HNL is a self-limiting disease and has a benign course. Clinical symptoms mostly resolve within a few weeks or 4 to 6 months without any given treatment. There are only very few reports of recurrence in the literature.11,22 With regards of complications, only 4 cases of meningitis were found as the most serious complication of the disease in the literature review.25 Mortality is very unusual, and only in 2 cases death was attributed to the disease since its first description.7
HISTIOCYTIC NECROTIZING LYMPHADENITIS
CONCLUSION HNL is a benign and self-limiting disease that usually affects cervical lymph nodes. Although it is well known among pathologists, otolaryngologists should also be aware of this disease and consider it in patients complaining enlarged cervical lymph nodes. Because of its self-limiting character, prevalence of HNL may be much more than mentioned in the clinical experience. REFERENCES 1. Kikuchi M: Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytosis. Nippon Ketsueki Gakkai Zasshi 35:379-380, 1972 2. Fujimato Y, Kozima Y, Yamaguchi K: Cervical subacute necrotizing lymphadenitis. A new clinicopathological entity. Naika 376:247-253, 1972 3. Felgar RE, Furth EE, Wasik MA, et al: Histiocytic necrotizing lymphadenopathy (Kikuchi disease): In situ endlabeling, immunohistochemical, and serologic evidencesuppoting cytotoxic lymphocyte mediated apoptotic cell death. Mod Pathol 10 3:231-241, 1997 4. Kubota M, Tsukamoto R, Kurukawa K, et al: Elevated serum interferon gamma and interleukin-6 in patients with necrotizing lymphadenitis. Br J Hematol 95:613-615, 1996 5. Wurm P, Towson G, Lauder I, et al: An unusual case of pyrexia of unknown origin with cervical lymphadenopathy. Postgrad Med J 76:655-656, 2000 6. Bhat MA, Hock YL, Turner NO, et al: Kikuchi’s disease of the neck (histiocytic necrotizing lymphadenopathy). J Laryngol Otol 112:898-900, 1998 7. Baumgartner BJ, Helling ER: Kikuchi disease: A case report and review of the literature. ENT J 81:331-335, 2002 8. Gleeson MJ, Siodlak MZ, Barbatis C, et al: Kikuchi’s disease—A new cause of cervical lymphadenopathy. J Laryngol Otol 99:935-939, 1985 9. Louis N, Hanly M, Davidson MCD: Kikuchi-Fufimato disease: A report of two cases and an overview. J Laryngol Otol 108:1001-1004, 1994 10. Thongsuksai P, Kayasut K: Histiocytic necrotizing lymphadenitis. J Med Assoc Thai 82:812-818, 1999 11. Kosch M, Hausberg M, Barenbrock M, et al: Histiocytic necrotizing lymphadenitis as a rare cause of cervi-
347
cal lymphadenopathy and fever—A case of biopsy proven recurrence over 19 years. Eur J Haematol 62:282-283, 1999 12. Kruger GR, Huetter ML, Rojo J, et al: Human herpes viruses HHV-4 (EBV) and HHV-6 in Hodkin’s and Kikuchi’S diseases and their relation to proliferation and apoptosis. Anticancer Res 21:2155-2161, 2001 13. Ura H, Yamada N, Torii H, et al: Histiocytic necrotizing lymphadenitis (Kikuchi’s disease): The necrotic appearance of the lymph node cells is caused by apoptosis. J Dermatol 26:385-389, 1999 14. Takakuwa T, Ohnuma S, Koike J, et al: Involvement of cell-mediated killing in apoptosis in histiocytic necrotizing lymphadenitis (Kikuchi-Fujimato Disease). Histopathology 28:41-48, 1996 15. Stephan LJ, Jeannoel P, Chanoz J, et al: Epstein Barr virus associated Kikuchi Disease in two children. J Ped Hematol Oncol 23:240-243, 2001 16. Iguchi H, Sunami K, Yamane H, et al: Apoptotic cell death in Kikuchi’s disease: A TEM study. Acta Otolaryngol Suppl 538:250-253, 1998 17. Lopez C, Oliver M, Olavarria R, et al: KikuchiFujimato necrotizing lymphadenitis associated with cutaneous lupus erythematosis. Am. J Dermapathol 22:328333, 2000 18. Kato K, Ohsima K, Anzai K, et al: Elevated serum soluble Fas ligand in histiocytic necrotizing lymphadenitis. Int J Hematol 73:84-86, 2001 19. Ohsima K, Shimazaki K, et al: Perforin and Fas pathways of cytotoxic T cells in histiocytic necrotizing lymphadenitis. Histopathology 33:471-478, 1998 20. Ohsima K, Shimazaki K, et al: Apoptosis of cytotoxic T-cells in histiocytic necrotizing lymphadenitis. Virchows Arch 433:131-134, 1998 21. Jayaraj SM, Llyod J, Frosh AC, et al: Kikuchi-Fujimato’s syndrome masquerading as tuberculosis. J Laryngol Otol 133:82-84, 1999 22. Yoshino T, Mannami T, Ichiura K, et al: Two cases of histiocytic necrotizing lymphadenitis following diffuse large B-cell lymphoma. Human Pathol 31:1328-1331, 2000 23. Kaur S, Thami GP, Mohan H, et al: Kikuchi disease with facial rash and erythema multiforme. Pediatr Dermatol 18:403-405, 2001 24. Rakic L, Arrese JE, Thiry A, et al: Kikuchi Fujimato lymphadenitis with cutaneous involvement. J Eur Acad Dermatol Venereol 13:118-122, 1999 25. Sato Y, Kuno H, Oizumi K: Histiocytic necrotizing lymphadenitis (Kikuchi’s disease) with aseptic meningitis. J Neurol Sci 163:187-191, 1999
Kikuchi1 and Fujimato et al2 first described Kikuchi or Kikuchi-Fujimato disease in Japan in 1972 independently. The disease is also known as histiocytic necrotizing lymphadenitis (HNL). Although it is prominent in Asia, it is being increasingly reported in other areas. The disease usually affects women under 30 years of age but may also be diagnosed in men. The etiology of the disease is unclear. It is suggested to be an apoptotic process mediated mainly by CD8-positive T lymphocytes. Viral or autoimmune etiology is believed to be causative factors.3,4 HNL manifests itself as enlargement of the lymph nodes usually in posterior cervical region. Generalized lymphadenopathy may also be seen. Pyrexia and neutropenia may be the accompanying symptoms, which may lead to initial misdiagnosis of lymphoma.5 Laboratory usually gives nothing but sometimes slight neutropenia. The diagnosis is achieved by tissue biopsy. It can easily be confused with lymphoma and systemic lupus erythematosus both clinically and histologically.6,7 The disease has a benign course and good prognosis. It is a self-limiting disease; most
From the *Department of Otolaryngology, Abant Izzet Baysal University; †Department of Otolaryngology, Ankara Bayındır Hospital; and ‡Department of Pathology, Hacettepe University, Bolu, Turkey. Address correspondence to: Serap Ko¨ybas¸ı, Abant Izzet Baysal University, Izzet Baysal Medical Faculty Department of Otolaryngology, 14280, Bolu, Turkey. E-mail: [email protected]. © 2003 Elsevier Inc. All rights reserved. 0196-0709/03/2405-0000$30.00/0 doi:10.1016/S0196-0709(03)00061-9 344
patients recover spontaneously within a few weeks to months without any serious sequelae. Kikuchi disease is a well-known entity among pathologists; however, only a few reports are found in the otolaryngology literature. The first head and neck case was reported by Gleeson et al8 in 1985. Because many patients present to ear, nose, and throat surgeons for lymph node biopsy, it is important to heighten awareness of the disease among otolaryngologists also.9 CASE 1 A 31-year-old man has presented with a sole complaint of painless mass in the cervical region for 3 months. Ear, nose, and throat examination including endoscopic evaluations was normal other than a mobile nodal enlargement measuring 1.5 ⫻ 2 cm in the left posterior cervical region. Cervical ultrasonography (USG) revealed multiple nodal enlargements ovoid in shape in left posterior cervical (the biggest one to be 17 ⫻ 9 mm), submental, and right anterior cervical region. Hematologic investigations including erythrocyte sedimentation rate, biochemistry, antinuclear antibody titre, chest radiograph, and abdominal USG were totally normal. Excisional biopsy of the lymph node was performed under local anesthesia. The histopathologic evaluation was reported as Kikuchi’s disease. In the 2-year follow-up period, the patient had no recurrence or any complaint regarding the disease.
American Journal of Otolaryngology, Vol 24, No 5 (September-October), 2003: pp 344-347
HISTIOCYTIC NECROTIZING LYMPHADENITIS
Fig 1. A necrotic focus surrounded by lymphocytes is seen on the right side of the micrograph (hematoxylin and eosin, ⴛ100).
CASE 2 A 42-year-old man presented with a painless, slow-growing, left-sided neck lump for 2 years. On physical examination, a hard, mobile mass of 3 ⫻ 4 cm in diameter was found just medial to the left submandibular gland. The rest of the examination including endoscopic evaluation was unremarkable. Ultrasonography of the neck revealed a heterogenous, hypoechoic solid nodular mass of left submandibular fossa measuring 3 ⫻ 1.5 cm with a lymph node–like appearance. There was an adjacent lymphadenopathy 1 cm in diameter just inferior to the mass. Bilateral multiple very small lymph node enlargements were also noted. Hematologic parameters were normal except for hepatitis B virus surface antigen positivity, and hepatitis B virus
345
Fig 3. Higher magnification of a necrotic area composed of nuclear debris (hematoxylin and eosin, ⴛ400).
DNA was (⫹) on polymerase chain reaction. The liver functions and abdominal USG findings were all within normal limits. An excisional biopsy of the mass was performed along with the left submandibular gland removal under general anesthesia. The mass and the adjacent lymph node were reported as Kikuchi’s disease. The histopathologic evaluation of submandibular gland revealed normal glandular parenchyma. In the 1.5-year follow-up period, the patient has been observed to be disease free. HISTOPATHOLOGY Both biopsy materials were lymph nodes measuring 0.5 to 3 cm in diameter. Their cut surfaces were homogeneous with no specific macroscopic finding. The histologic sections of both cases were also similar. The normal structure of the lymph nodes were partially maintained, but in some portions sharply demarcated areas of necrosis surrounded by a diffuse infiltration of lymphocytes, proliferating immunoblasts, and histiocytic cells were observed. Abundant nuclear debris was present among the proliferating cells (Figs 1-3). DISCUSSION
Fig 2. The cells surrounding the areas of necrosis were a combination of lymphocytes, histiocytes, and proliferating immunoblasts (hematoxylin and eosin, ⴛ200).
Kikuchi disease or Kikuchi-Fujimato disease was first described by Kikuchi1 and Fujimato et al2 independently in Japan in 1972. It is also and more commonly known as HNL. HNL is most commonly seen in eastern Asia; however, it has a wide geographic dis-
346
tribution throughout the world. Despite the fact that the disease usually affects young women between 20 and 30 years of age, it also shows a wide range of age from 8 to 57.10 Despite an expressed female-to-male ratio in the literature as 4:1 or 3:2,7,10,11 both of our cases are male patients. Patients with HNL usually present with enlarged lymph nodes, intermittent fever, mild tenderness, slight neutropenia, and very rarely cutaneous manifestations. Although there may be generalized lymphadenopathies in 80% of the patients, the disease is more frequently localized in the neck and especially the posterior cervical region with an incidence of 65% to 70%. Axillary lymph node involvement comes next in frequency. The lymph nodes are usually painless, but the patients may note slight tenderness on pressure.7,9,11 Definitive etiology has not been identified yet. Recent studies have indicated that cellular apoptosis induced by perforin- or Fasbased mechanisms is the main process in HNL.12-14 This particular finding is shown both in lymphocytes and histiocytes in the diseased lymph nodes. Viral agents especially human herpes virus 6, cytomegalovirus, and Epstein Barr virus are the most strongly accused viral factors that may cause apoptosis. The apoptotic process seems to be responsible for the necrotic appearance of the lymph nodes.12,13,15-17 In our second case, probably a coincidental hepatitis B virus surface antigen positivity was present. Perforin, a cytolytic protein specific to killer cells essential for inducing apoptosis was found to be expressed abundantly by the infiltrating cells. Takakuwa et al14 in their study of 34 patients with HNL have found perforin expressing cells to be 82.4%, and they thought them to be CD8-positive cytotoxic T cells. Kato et al18 found that soluble Fas ligand was elevated, and they suggest soluble Fas ligan plays an important role in the symptoms and pathogenesis; furthermore, it may act as a surrogate marker of the disease. Some authors suggest that Fas-induced or perforin-induced apoptosis in lymph nodes of HNL is led by CD8-positive cells as the effector and target cells and histiocytes could play a role as enhancers.3,19,20
KOYBASI, SAYDAM, AND GUNGEN
Interleukin 2, interleukin 6, and interferon gamma are also found to be mediators in the apoptotic process, and these data support the hypothesis of a viral or autoimmune pathology in HNL.3,4 Diagnosis of HNL depends solely on excisional biopsy.6,7,9 Fine-needle aspiration biopsy may be only suggestive but not accepted as diagnostic. Differential diagnosis is very important especially to avoid excessive and expensive investigations and to avoid overtreatment. Symptomatology is nonspecific. HNL usually presents itself as cervical lymphadenopathy with or without symptoms like fever and malaise. From the laboratory standpoint, only neutropenia can be shown in some cases. HNL is characterized by collection of histiocytes and lymphocytes surrounding areas of necrosis. Polymorphonuclear leukocytes are usually absent. Overlapping histological features require differential diagnosis between HNL and a number of infectious diseases such as tuberculosis, sarcoidosis, autoimmune, and lymphoproliferative diseases.7,21,22 The relation between systemic lupus erythematosis (SLE) and HNL remains to be a matter of debate because of rare cutaneous manifestations of HNL-like facial rash and erythema multiforme. Some authors advocate that the disease is an early presentation of SLE.23,24 Differential diagnosis is made by only histopathological study; in SLE, enlarged lymph nodes show follicular hyperplasia with granulocytes and plasma cells that are not found in HNL. Both pathologists and clinicians should be aware of the similar presentations of the lymph nodes in HNL and SLE. Another important disease is lymphoma and because of the resemblance of these 2 diseases, there are some reports in the literature describing HNL cases treated as lymphoma.9,10 HNL is a self-limiting disease and has a benign course. Clinical symptoms mostly resolve within a few weeks or 4 to 6 months without any given treatment. There are only very few reports of recurrence in the literature.11,22 With regards of complications, only 4 cases of meningitis were found as the most serious complication of the disease in the literature review.25 Mortality is very unusual, and only in 2 cases death was attributed to the disease since its first description.7
HISTIOCYTIC NECROTIZING LYMPHADENITIS
CONCLUSION HNL is a benign and self-limiting disease that usually affects cervical lymph nodes. Although it is well known among pathologists, otolaryngologists should also be aware of this disease and consider it in patients complaining enlarged cervical lymph nodes. Because of its self-limiting character, prevalence of HNL may be much more than mentioned in the clinical experience. REFERENCES 1. Kikuchi M: Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytosis. Nippon Ketsueki Gakkai Zasshi 35:379-380, 1972 2. Fujimato Y, Kozima Y, Yamaguchi K: Cervical subacute necrotizing lymphadenitis. A new clinicopathological entity. Naika 376:247-253, 1972 3. Felgar RE, Furth EE, Wasik MA, et al: Histiocytic necrotizing lymphadenopathy (Kikuchi disease): In situ endlabeling, immunohistochemical, and serologic evidencesuppoting cytotoxic lymphocyte mediated apoptotic cell death. Mod Pathol 10 3:231-241, 1997 4. Kubota M, Tsukamoto R, Kurukawa K, et al: Elevated serum interferon gamma and interleukin-6 in patients with necrotizing lymphadenitis. Br J Hematol 95:613-615, 1996 5. Wurm P, Towson G, Lauder I, et al: An unusual case of pyrexia of unknown origin with cervical lymphadenopathy. Postgrad Med J 76:655-656, 2000 6. Bhat MA, Hock YL, Turner NO, et al: Kikuchi’s disease of the neck (histiocytic necrotizing lymphadenopathy). J Laryngol Otol 112:898-900, 1998 7. Baumgartner BJ, Helling ER: Kikuchi disease: A case report and review of the literature. ENT J 81:331-335, 2002 8. Gleeson MJ, Siodlak MZ, Barbatis C, et al: Kikuchi’s disease—A new cause of cervical lymphadenopathy. J Laryngol Otol 99:935-939, 1985 9. Louis N, Hanly M, Davidson MCD: Kikuchi-Fufimato disease: A report of two cases and an overview. J Laryngol Otol 108:1001-1004, 1994 10. Thongsuksai P, Kayasut K: Histiocytic necrotizing lymphadenitis. J Med Assoc Thai 82:812-818, 1999 11. Kosch M, Hausberg M, Barenbrock M, et al: Histiocytic necrotizing lymphadenitis as a rare cause of cervi-
347
cal lymphadenopathy and fever—A case of biopsy proven recurrence over 19 years. Eur J Haematol 62:282-283, 1999 12. Kruger GR, Huetter ML, Rojo J, et al: Human herpes viruses HHV-4 (EBV) and HHV-6 in Hodkin’s and Kikuchi’S diseases and their relation to proliferation and apoptosis. Anticancer Res 21:2155-2161, 2001 13. Ura H, Yamada N, Torii H, et al: Histiocytic necrotizing lymphadenitis (Kikuchi’s disease): The necrotic appearance of the lymph node cells is caused by apoptosis. J Dermatol 26:385-389, 1999 14. Takakuwa T, Ohnuma S, Koike J, et al: Involvement of cell-mediated killing in apoptosis in histiocytic necrotizing lymphadenitis (Kikuchi-Fujimato Disease). Histopathology 28:41-48, 1996 15. Stephan LJ, Jeannoel P, Chanoz J, et al: Epstein Barr virus associated Kikuchi Disease in two children. J Ped Hematol Oncol 23:240-243, 2001 16. Iguchi H, Sunami K, Yamane H, et al: Apoptotic cell death in Kikuchi’s disease: A TEM study. Acta Otolaryngol Suppl 538:250-253, 1998 17. Lopez C, Oliver M, Olavarria R, et al: KikuchiFujimato necrotizing lymphadenitis associated with cutaneous lupus erythematosis. Am. J Dermapathol 22:328333, 2000 18. Kato K, Ohsima K, Anzai K, et al: Elevated serum soluble Fas ligand in histiocytic necrotizing lymphadenitis. Int J Hematol 73:84-86, 2001 19. Ohsima K, Shimazaki K, et al: Perforin and Fas pathways of cytotoxic T cells in histiocytic necrotizing lymphadenitis. Histopathology 33:471-478, 1998 20. Ohsima K, Shimazaki K, et al: Apoptosis of cytotoxic T-cells in histiocytic necrotizing lymphadenitis. Virchows Arch 433:131-134, 1998 21. Jayaraj SM, Llyod J, Frosh AC, et al: Kikuchi-Fujimato’s syndrome masquerading as tuberculosis. J Laryngol Otol 133:82-84, 1999 22. Yoshino T, Mannami T, Ichiura K, et al: Two cases of histiocytic necrotizing lymphadenitis following diffuse large B-cell lymphoma. Human Pathol 31:1328-1331, 2000 23. Kaur S, Thami GP, Mohan H, et al: Kikuchi disease with facial rash and erythema multiforme. Pediatr Dermatol 18:403-405, 2001 24. Rakic L, Arrese JE, Thiry A, et al: Kikuchi Fujimato lymphadenitis with cutaneous involvement. J Eur Acad Dermatol Venereol 13:118-122, 1999 25. Sato Y, Kuno H, Oizumi K: Histiocytic necrotizing lymphadenitis (Kikuchi’s disease) with aseptic meningitis. J Neurol Sci 163:187-191, 1999