Modern Pediatrics.Ukraine.2019.8(104):71-82; doi 10.15574/SP.2019.104.71
Dorosh O. I.^1,2,3, Stignitsky M. V.^1,4, Petronchak O. A.^2,6, Seleznyov A. A.⁷, Mykh A. M.^1,8, Melko I. P.^1,9, Skaletska N. M.², Seredych L. P. ^1,10
1Сommunal noncommercial enterprise of Lviv regional council «Western Ukrainian Specialized Children's Medical Centre», Ukraine
²Lviv National Medical University named after Danylo Halytskyy, Ukraine
³«Doctor Smart» Hematology Clinic, Lviv, Ukraine
⁴Anna Mazurenko Children's Health Center, Lviv, Ukraine
⁵Municipal institution of Lviv regional council «Lviv regional pathoanatomical bureau», Ukraine
⁶Private limited company «Western Histology Laboratory», Lviv, Ukraine
⁷Pathomorphological Laboratory «CSD Health Care», Kyiv, Ukraine
⁸Center of Medical Innovations «NOVO», Lviv, Ukraine
⁹Medical Center of St. Paraskeva, Lviv, Ukraine
¹⁰Private Medical Center «Minipoliklinika», Lviv, Ukraine

For citation: Dorosh OI, Stignitsky MV, Petronchak OA, Seleznyov AA et al. (2019). Kikuchi-Fujimoto disease: features of diagnosis and clinical course. Modern Pediatrics. Ukraine. 8(104): 7-82. doi 10.15574/SP.2019.104.71
Article received: Aug 13, 2019. Accepted for publication: Nov 24, 2019.

This article describes a case of Kikuchi–Fujimoto disease (KFD) in Ukraine induced by Virus Epstein–Barr (VEB) in a one year old girl with lymphoproliferative syndrome (LPS), enteropathy, inflammatory manifestations of ENT organs, hyperthermia, leukopenia with neutropenia and thrombocytopenia, high levels of inflammatory markers, secondary hemophagocytic lymphohistiocytosis (SHLH). Empiric antibiotic therapy had no effect. Differentiation diagnosis was used to eliminate acute leukemia (AL), Myelodysplastic syndrome (MDS), infectious process and lymphoma. Bone marrow biopsy and bone marrow aspiration as well as genetic and molecular tests on bone marrow and blood were performed. The diagnosis of KFD was verified by two independent histological laboratories after histology and immunohistochemical testing on LN. A moderate amount of lymphoid cells mostly of a larger size with intensely basophilic vacuolated cytoplasm and large polymorph nucleus similar to Hodgkin cells, binucleate cell similar to Reed–Sternberg cells, macrophages, crescent shaped histiocytes were detected in the LN smears. Histology slides of LN showed a high amount of macrophages, signs of karyorrhexis and severe necrosis with absence of neutrocytes, which are common in cases of necrotizing lymphadenitis. Immunohistochemical testing showed that cells with immunoblast morphology were CD20, PAX-5 positive. Between the cells of the tumor a large amount of T-lymphocytes (CD3+) and macrophages (CD163, CD68) was detected. These cells were heterogeneously CD30-, bcl-2-positive and CD15-, CD10-, tdt-, CD38-, CD246-, bcl-6-, c-myc-negative. Expression of CD44, MUM1 та CD43 was detected in the cells of the tumor. Molecular analysis detected that most of the immunoblast cells, especially large atypical ones, were EBER EBV positive. Ki67 test showed the positivity of most of these cells and almost all of the large atypical ones. The p53 test showed the wild-type expression. The CT detected hotbeds of necrosis in a part of a lymph node and in the parenchyma of the spleen. Positive clinical effect (regression of lymphoproliferative syndrome, normalization of the hemogram, absence of laboratory sins of inflammation) was achieved after 1 month of corticosteroid treatment.
The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institution. The informed consent of the child's parents was obtained from the studies.
No conflict of interest was declared by the authors.
Key words: Kikuchi-Fujimoto Disease, Viral infection Epstein-Barr, hemophagocytic lymphohistiocytosis, children.

REFERENCES

1. Ade AS, Soares JM, de Sа Santos MH, Martins MP, Salles JM. (2010). Kikuchi-Fujimoto disease: three case reports. Sao Paulo Med J. 128(4): 232—235. https://doi.org/10.1590/S1516-31802010000400011; PMid:21120436

2. Adhikari RC, Sayami G, Lee MC, Basnet RB, Shrestha PK, Shrestha HG. (2003). Kikuchi-Fujimoto disease in Nepal: a study of 6 cases. Arch Pathol Lab Med. 127: 1345—1348.

3. Atwater AR, Longley BJ, Aughenbaugh WD. (2008). Kikuchi's disease: case report and systematic review of cutaneous and histopathologic presentations. J Am Acad Dermatol. 59(1): 130—136. https://doi.org/10.1016/j.jaad.2008.03.012; PMid:18462833

4. Bagri PK, Beniwal S, Jakhar SL, Kapoor A. (2014). Kikuchi-Fujimoto disease: a diagnostic and therapeutic challenge. Clin Cancer Investig J. 3: 254—256. https://doi.org/10.4103/2278-0513.132125

5. Bakhshi GD, Shenoy SS, Jadhav KV, Tayade MB, Pawar DS, Tejaswini D, Singh AK. (2014). Kikuchi's disease: a case report. IJMAS. 3(1): 10—15.

6. Baskota DK. (2006). Kikuchi-Fujimoto disease: a rare cause of cervical lymphadenopathy. Nepal Med Coll J. 8(1): 63—64.

7. Bosch X, Guilabert A, Miquel R, Campo E. (2004). Enigmatic Kikuchi-Fujimoto disease: a comprehensive review. Am J Clin Pathol. 122: 141—152. https://doi.org/10.1309/YF081L4TKYWVYVPQ; PMid:15272543

8. Bosch X, Guilabert A. Kikuchi-Fujimoto disease. (2006). Orphanet J Rare Dis. 1:18. https://doi.org/10.1186/1750-1172-1-18; PMid:16722618 PMCid:PMC1481509

9. Dalugama C, Gawarammana IB. (2017). Fever with lymphadenopathy — Kikuchi Fujimoto disease, a great masquerader: a case report J Med Case Rep. 11: 349. https://doi.org/10.1186/s13256-017-1521-y; PMid:29246252 PMCid:PMC5732422

10. Chatterjee SS, Sengupta K, Mukhopadhyay P, Bandyopadhyay D, Chaudhury SR. (2014). A case of Kikuchi-Fujimoto disease. JIACM. 15(3—4): 224—226.

11. Chen JS, Chang KC, Cheng CN. (2000). Childhood hemophagocytic syndrome associated with Kikuchi's disease. Haematologica. 85: 998—1000.

12. Cheng CY, Sheng WH, Lo YC, Chung CS, Chen YC, Chang SC. (2010). 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. 43(5): 366—371. https://doi.org/10.1016/S1684-1182(10)60058-8

13. Dumas G, Prendki V, Haroche J, Amoura Z, Cacoub P, Galicier L et al. (2014). Kikuchi-Fujimoto disease: retrospective study of 91 cases and review of the literature. Medicine (Baltimore). 93: 372—382. https://doi.org/10.1097/MD.0000000000000220; PMid:25500707 PMCid:PMC4602439

14. Fahmi YK, Morad NA, Fawzy Z. (2007). Kikuchi's disease associated with hemophagocytosis. Chang Gung Med J. 30: 370—373.

15. Famularo G, Giustiniani MC, Marasco A, Minisola G, Nicotra GC, Simone CD. (2003). Kikuchi Fujimoto lymphadenitis: case report and literature review. Am J Hematol. 74: 60—63. https://doi.org/10.1002/ajh.10335; PMid:12949892

16. Graham LE. (2002). Kikuchi-Fujimoto disease and peripheral arthritis: a first! Ann Rheum Dis. 61(5): 475. https://doi.org/10.1136/ard.61.5.475; PMid:11959780 PMCid:PMC1754101

17. Hutchinson CB, Wang E. (2010). Kikuchi-Fujimoto disease. Arch Pathol Lab Med. 134 (2): 289—293.

18. Imamura M, Ueno H, Matsuura A, et al. (1982). An ultrastructural study of subacute necrotizing lymphadenitis. Am J Pathol. 107(3): 292—299.

19. Ingle SB, Hinge CR, Chopra S. (2012). A rare case of Kikuchi's disease — case report. Indian J Med Case Rep. 1(1): 1—3.

20. Jamal AB. (2012). Kikuchi-Fujimoto disease. Clin Med Insights Arthritis Musculoskelet Disord. 5: 63—66. https://doi.org/10.4137/CMAMD.S9895; PMid:22837646 PMCid:PMC3399407

21. Kang HM, Kim JY, Choi EH, Lee HJ, Yun KW, Lee H. (2016). Clinical Characteristics of Severe Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease) in Children. J Pediatr. 171: 208—212.e1. https://doi.org/10.1016/j.jpeds.2015.12.064; PMid:26852178

22. Kaur S, Mahajan R, Jain NP, Sood N, Chhabra S. (2014). Kikuchi's Disease — A Rare Cause of Lymphadenopathy and Fever. J Assoc Physicians India. 62(1): 54—57.

23. Kelly J, Kelleher K, Khan MK. (2000). A case of haemophagocytic syndrome and Kikuchi-Fujimoto disease occurring concurrently in a 17-year-old female. Int J Clin Pract. 54: 547—549.

24. Khishfe BF, Krass LM, Nordquist EK. (2014). Kikuchi disease presen0 ting with aseptic meningitis. Am J Emerg Med. 32(10): 1298.e10e2. https://doi.org/10.1016/j.ajem.2014.03.029; PMid:24746858

25. Kikuchi M. (1972). Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytosis. Nippon Ketsueki Gakkai Zasshi. 35: 379—380.

26. Kim YM, Lee YJ, Nam SO. (2003). Hemophagocytic syndrome associated with Kikuchi's disease. J Korean Med Sci. 18: 592—594. https://doi.org/10.3346/jkms.2003.18.4.592; PMid:12923340 PMCid:PMC3055072

27. Kucukardali Y, Solmazgul E, Kunter E et al. (2007). Kikuchi-Fujimoto Disease: analysis of 244 cases. Clin Rheumatol. 26(1): 50—54. https://doi.org/10.1007/s10067-006-0230-5; PMid:16538388

28. Kuo TT. (1990). Cutaneous manifestation of Kikuchi's histiocytic necrotizing lymphadenitis. Am J Surg Pathol. 14(9): 872—876. https://doi.org/10.1097/00000478-199009000-00009; PMid:2389817

29. Kuo TT. (1995). Kikuchi's disease (histiocytic necrotizing lymphadenitis): a clinicopathologic study of 79 cases with an analysis of histologic subtypes, immunohistology, and DNA ploidy. Am J Surg Pathol. 19(7): 798—809. https://doi.org/10.1097/00000478-199507000-00008; PMid:7793478

30. Kwon SY, Kim TK, Kim YS, Lee KY, Lee NJ et al. (2004). CT findings in Kikuchi disease: analysis of 96 cases. AJNR Am J Neuroradiol. 25: 1099—1102.

31. Lee HY, Huang YC, Lin TY, Huang JL, Yang CP, Hsueh T, Wu CT, Hsia SH. (2010). Primary Epstein-Barr virus infection associated with Kikuchi's disease and hemophagocytic lymphohistiocytosis: a case report and review of the literature. J Microbiol Immunol Infect. 43(3): 253—257. https://doi.org/10.1016/S1684-1182(10)60040-0

32. Lin HC, Su CY, Huang CC, Hwang CF, Chien CY. (2003). Kikuchi's disease: a review and analysis of 61 cases. Otolaryngol Head Neck Surg. 128(5): 650—653. https://doi.org/10.1016/S0194-5998(02)23291-X

33. Mahadeva U, Allport T, Bain B. (2000). Haemophagocytic syndrome and histiocytic necrotising lymphadenitis (Kikuchi's disease). J Clin Pathol. 53: 636—638. https://doi.org/10.1136/jcp.53.8.636; PMid:11002771 PMCid:PMC1762914

34. Martins SS, Buscatti IM, Freire PS, Cavalcante EG, Sallum AM, Campos LM, Silva CA. (2014). Kikuchi-Fujimoto disease prior to childhood-systemic lupus erythematosus diagnosis. Rev Bras Reumatol. 54(5): 400—403. https://doi.org/10.1016/j.rbre.2013.03.003

35. Masab M, Farooq H. (2017). Kikuchi Disease. Clin Rheumatol. 27(8): 1073—1075.

36. Palazzi DL, McClain KL, Kaplan SL. (2003). Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis. 36: 306—312. https://doi.org/10.1086/345903; PMid:12539072

37. Pepe F, Disma S, Teodoro C, Pepe P, Magro G. (2016). Kikuchi-Fujimoto disease: a clinicopathologic update. Pathologica. 108(3): 120—129.

38. Perry AM, Choi SM. (2018). Kikuchi-Fujimoto Disease: A Review. Arch Pathol Lab Med. 142(11): 1341—1346. https://doi.org/10.5858/arpa.2018-0219-RA; PMid:30407860

39. Ramanan AV, Wynn RF, Kelsey A. (2003). Systemic juvenile idiopathic arthritis, Kikuchi's disease and haemophagocytic lymphohistiocytosisis there a link? Case report and literature review. Rheumatology. 42: 596—598. https://doi.org/10.1093/rheumatology/keg167; PMid:12649409

40. Ruaro B, Sulli A, Alessandri E, Fraternali-Orcioni G, Cutolo M. (2014). Kikuchi-Fujimoto's disease associated with systemic lupus erythematous: difficult case report and literature review. Lupus. 23(9): 939—944. https://doi.org/10.1177/0961203314530794; PMid:24739458

41. Shim EJ, Lee KM, Kim EJ, Kim HG, Jang JH. (2017). CT pattern analysis of necrotizing and nonnecrotizing lymph nodes in Kikuchi disease. PLoS One. 12(7): e0181169. https://doi.org/10.1371/journal.pone.0181169; PMid:28742156 PMCid:PMC5524397

42. Singh YP, Agarwal V, Krishnani N, Misra R. (2008). Enthesitis-related arthritis in Kikuchi-Fujimoto disease. Mod Rheumatol. 18(5): 492—495. https://doi.org/10.3109/s10165-008-0076-6; PMid:18470474

43. Sopena B, Rivera A, Chamorro A et al. (2017). Clinical association between Kikuchi's disease and systemic lupus erythematosus: a systematic literature review. Semin Arthritis Rheum. 47(1): 46—52. https://doi.org/10.1016/j.semarthrit.2017.01.011; PMid:28233572

44. Spies J, Foucar K, Thompson CT, LeBoit PE. (1999). The histopathology of cutaneous lesions of Kikuchi's disease (necrotizing lymphadenitis): a report of five cases. Am J Surg Pathol. 23(9): 1040—1047. https://doi.org/10.1097/00000478-199909000-00006; PMid:10478663

45. Sudhakar MK, Sathyamurthy P, Indhumathi E, Rajendran A, Vivek B. (2011). Kikuchi's disease: a case report from South India. IJCRI. 2(2): 15—18. https://doi.org/10.5348/ijcri-2011-02-20-CR-4

46. Sumiyoshi Y, Kikuchi M, Takeshita M, et al. (1992). Immunohistological study of skin involvement in Kikuchi's disease. Virchows Arch B Cell Pathol Incl Mol Pathol. 62 (4): 263—269. https://doi.org/10.1007/BF02899691; PMid:1359699

47. Tsai MK, Huang HF, Hu RH et al. (1998). Fatal Kikuchi-Fujimoto disease in transplant recipients: a case report. Transplant Proc. 30(7): 3137—3138. https://doi.org/10.1016/S0041-1345(98)01292-5

48. Tyczynska A, Giza A, Kalicka A, Pikiel P, Kowalski J, Lesniewski-Kmak K et al. (2014). Kikuchi-Fujimoto disease: report of two new Polish cases and review of the current literature. Acta Haematol Pol. 45: 101—106. https://doi.org/10.1016/j.achaem.2013.11.003

49. Viallard JF, Parrens M, Lazaro E, Caubet O, Pellegrin JL. (2007). Subacute necrotizing lymphadenitis or Kikuchi-Fujimoto disease. Presse Med. 36(11:2): 1683—1693. https://doi.org/10.1016/j.lpm.2007.06.004; PMid:17611068

50. Wano Y, Ebata K, Masaki Y. (2000). Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto's disease) accompanied by hemo-phagocytosis and salivary gland swelling in a patient with systemic lupus erythematosus. Japan J Clin Hematol. 41: 54—60.

51. Yasukawa K, Matsumura T, Sato-Matsumura KC et al. (2001). Kikuchi's disease and the skin: case report and review of the literature. Br J Dermatol. 144(4): 885—889. https://doi.org/10.1046/j.1365-2133.2001.04151.x; PMid:11298555

52. Yen HR, Lin PY, Chuang WY, Chang ML, Chiu CH. (2004). Skin manifestations of Kikuchi-Fujimoto disease: case report and review. Eur J Pediatr. 163(4—5): 210—213. https://doi.org/10.1007/s00431-003-1364-y; PMid:14986121

53. Yufu Y, Matsumoto M, Miyamura T. (1997). Parvovirus B19-associated haemophagocytic syndrome with lymphadenopathy resembling histiocytic necrotizing lymphadenitis (Kikuchi's disease). Br J Haematol. 96: 868—871. https://doi.org/10.1046/j.1365-2141.1997.d01-2099.x; PMid:9074434

54. Zou CC, Zhao ZY, Liang L. (2009). Childhood Kikuchi-Fujimoto disease. Indian J Pediatr. 76(9): 959—962. https://doi.org/10.1007/s12098-009-0194-y; PMid:19904514