|Ahead of print publication
Necrotizing lymphadenitis with generalized adenopathy: A diagnostic dilemma – Kikuchi–Fujimoto disease
Gaurav P S Gahlot1, Ravindra Dubey2, Tathagata Chatterjee1, Manu Chopra3
1 Department of Lab Sciences and Mol Med Army Hospital (R & R) Delhi, India
2 Department of Otorhinolaryngology, Military Hospital, Jaipur, Rajasthan, India
3 Department of Respiratory Medicine, Army Hospital (R & R) Delhi, India
|Date of Submission||28-Jan-2020|
|Date of Decision||06-Feb-2020|
|Date of Acceptance||09-Apr-2020|
|Date of Web Publication||22-Mar-2021|
Gaurav P S Gahlot,
Department of Lab Sciences and Mol Med, Army Hospital (R and R), Delhi
Source of Support: None, Conflict of Interest: None
Kikuchi–Fujimoto disease (KFD) is a rare, self-limiting, benign disorder of lymphoreticular system that commonly occurs in young Asian women predominantly under <30 years of age. Clinically, it presents as cervical lymphadenopathy, fever, and weight loss; therefore, it is a disease of exclusion in countries such as India, which are endemic for tuberculosis. Here, we are describing a case of a young female who again presented with low-grade fever and arthralgia; 1 month after the completion of 6-month antitubercular treatment. In view of generalized lymphadenopathy, raised erythrocyte sedimentation rate; clinical, radiological, and fluorodeoxyglucose positron emission tomography-computed tomography scan findings; and the differentials diagnoses of disseminated tuberculosis, lymphoma, or sarcoidosis were considered. Histopathology of the right axillary lymph node showed paracortical expansion by histiocytes, necrosis, numerous apoptotic debris, and paucity of plasma cells with the absence of neutrophils, thus confirming the diagnosis of KFD. The correct diagnosis thus helped to relieve the anxiety of the patient and prevented unnecessary medication.
Keywords: Disseminated tuberculosis, generalized lymphadenopathy, histiocytic necrotizing lymphadenitis, Kikuchi–Fujimoto disease
| Introduction|| |
Kikuchi–Fujimoto disease (KFD) or phagocytic necrotizing lymphadenitis is an uncommon, idiopathic disease with female dominance (M: F = 1:4) that occurs in second/third decades. As it is characterized by the triad of regional cervical lymphadenopathy, fever, and night sweats, the differential diagnosis of tuberculosis, lymphoproliferative disorders, systemic lupus erythematosus, infectious mononucleosis, or sarcoidosis are considered. Histomorphological features show distorted lymph node architecture with irregular cortical expansion by the areas of coagulative necrosis, abundant karyorrhectic debris, transformed lymphocytes (immunoblasts), and C-shaped histiocytes at the periphery of the necrosis. Management includes symptomatic care, analgesics-antipyretics, or corticosteroids with spontaneous recovery in 1–6 months, however recurrence rate of 3%–13% has been observed.
This case broadens the differentials of necrotizing lymphadenitis and highlights the importance of timely histomorphological diagnosis, so as to prevent the anxiety surrounding a misdiagnosis and administration of unnecessary medication.
| Case Report|| |
A 25-year-old young female doctor who presented in August 2016 with a history of 7 kg weight loss over 5 months and low-grade intermittent fever with anorexia for 1 month. On investigation, bilateral hilar prominence on chest X-ray and positive Mantoux test were noted. Computed tomography (CT) of the chest and abdomen revealed enlarged mediastinal, hilar, mesenteric, and retroperitoneal lymph nodes with central necrosis and peripheral enhancement [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. Antitubercular treatment (ATT) was started, and she responded well to 6 months ATT course in the form of recovery from arthralgia, gain of weight with normal appetite. One month later, she again developed intermittent fever with polyarthralgia and referred to our hospital for further evaluation. Whole-body CT scan showed right axillary, mediastinal necrotic lymphadenopathy, scant pulmonary nodule, granuloma, retroperitoneal lymphadenopathy, minimal ascites, splenomegaly, and small subcapsular necrotic lesion in the liver. Transbronchial needle aspiration cytology showed predominantly necrosis and was negative for GeneXpert. Serum angiotensin-converting enzyme level was slightly raised 73 U/L. Complete fluorodeoxyglucose (FDG)-positron emission tomography/CT scan showed FDG avid lymphadenopathy on both sides of the diaphragm, two mildly FDG avid nodular lesions adjacent to the lower pole of the spleen, reversal of liver-spleen metabolic ratio, focal isodense, and an ill-defined area of FDG avidity in segment III of the liver [Figure 1]e, [Figure 1]f, [Figure 1]g, [Figure 1]h. On the basis of clinical presentation and investigations, differential diagnosis of lymphoproliferative disorder, disseminated tuberculosis, or sarcoidosis was considered. Histopathology of dissected right axillary lymph node showed paracortical expansion with necrotizing lymphadenitis, numerous apoptotic bodies, fibrin deposits, histiocytes, sparse plasma cells, and absent neutrophils [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e. Ziehl–Neelsen stain was negative for acid-fast bacilli. The background cells show immunopositivity for histiocytes CD68 [Figure 2]f and mixed population of reactive T cells; CD3 [Figure 2]g, B cells;CD20 [Figure 2]h. Thus, histomorphological diagnosis of KFD was offered. All medications were stopped, and the patient was reassured with advice of follow-up to look for possible relapse. At present, the disease has resolved, and the patient is well with advice of 6-month follow-up.
|Figure 1: (a-d) Computed tomography chest shows right axillary and mediastinal necrotic lymphadenopathy with minimal ascites and splenomegaly. (e-h) Positron emission tomography computed tomography shows fluorodeoxyglucose avid lymphadenopathy on both sides of the diaphragm|
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|Figure 2: H and E photomicrographs from the lymph node show partially effaced architecture with paracortical expansion and necrotizing lymphadenitis (a; ×20, b; ×40, c; ×100 arrow head). Apoptotic bodies (d; ×200, e; ×400 star) present while neutrophils absent. Immunohistochemical positivity of histiocytes CD68 (f; ×200) and negativity for T-cells (CD3: g; ×200) or B-cells (CD20: h; ×200)|
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| Discussion|| |
KFD or histiocytic necrotizing lymphadenitis with granulocytic infiltration or subacute necrotizing lymphadenitis was first reported independently by Japanese pathologists Dr. Masahiro Kikuchi and Fujimoto in 1972 as “lymphadenitis showing focal reticulum hyperplasia with nuclear debris, phagocytosis, and “cervical subacute necrotizing lymphadenitis,” respectively. It is more common in Asian countries, however, now also recognized in North America, South America, Australia, Africa, and Europe. Usual clinical presentations include fever, night sweats, and lymphadenopathy, with rare symptoms comprising weight loss, rash, joint pain, diarrhea, and fatigue, thus mimicking tuberculosis, lymphoma, systemic lupus erythematosus (SLE), cat-scratch disease, toxoplasmosis, and infectious mononucleosis. In 83% of cases, painless/painful unilateral cervical lymph node is affected, while cases with generalized adenopathy involving axillary, inguinal, and mesenteric are uncommon. A raised erythrocyte sedimentation rate in 40%, leukopenia in 43%, and anemia in 23% cases with otherwise normal hematological and biochemical parameters have been observed., The exact cause is unknown, however, possible postulated theory of autoimmune etiology with possible infectious triggers such as Mycobacterium szulgai, Yersinia More Details enterocolitica, toxoplasma, or viral agents Epstein–Barr virus, HHV6, HHV8, parvovirus B19, human immunodeficiency virus, or chemical, physical, and neoplastic agents has been considered. It may be associated with antiphospholipid syndrome, polymyositis, idiopathic arthritis, bilateral uveitis, or cutaneous necrotizing vasculitis. Apoptotic cell death is mediated by cytotoxic CD8 + T lymphocytes as the principal mechanism of cellular destruction. Histopathology comprises (a) initial phase, that is, follicular hyperplasia and paracortical expansion, (b) proliferative phase, that is, lymphocytes, T- and B-cell blasts, plasmacytoid monocytes, histiocytes, and numerous apoptosis in the background, and (c) necrotizing phase, that is, necrosis without a neutrophilic infiltrate with predominance of histiocytes having crescentic nuclei and phagocytosed debris., The proliferative phase mimics lymphoma, whereas the necrotic phase mimics SLE lymphadenitis. KFD can be distinguished from lymphoma due to partially distorted architecture with patent sinuses, numerous reactive histiocytes without a starry-sky pattern, low mitotic rate, absence of Reed–Sternberg cells, absence of neutrophils in the “necrotizing phase” paucity of plasma cells, presence of hematoxylin bodies, and thrombosed blood vessels favor SLE. The immunohistochemical profile of KFD shows the predominance of CD8+ cytotoxic T-cells, CD68+ histiocytes, and CD123+ plasmacytoid dendritic cells with immunonegativity for CD3 or CD20.,
Being a self-resolving disease, no specific treatment is available except the requirement of prednisolone, antibiotics intravenous immunoglobulins, and hydroxychloroquine in few cases for rapid recovery., A recurrence rate of 3%–13% with longer symptomatic duration and more extranodal involvement in such cases has been observed. A positive antinuclear antibody titer is associated with a high risk of recurrence., As <3% cases may develop SLE later on, these patients should be followed up for a few years.
In conclusion, KFD is an uncommon, self-limiting disease of unknown etiology with excellent prognosis. Its clinical features mimic with tuberculosis in endemic areas as noted in the index case, therefore, the clinician needs to be vigilant; because a timely histological diagnosis can prevent misdiagnosis and inappropriate use of antibiotics or immunomodulatory drugs.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We acknowledge the support of our patient, as with her support, the study had been feasible.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dalugama C, Gawarammana IB. Fever with lymphadenopathy – Kikuchi Fujimoto disease, a great masquerader: A case report. J Med Case Rep 2017;11:349.
Priya S, Ashish N. Kikuchi's disease presenting as pyrexia of unknown origin: A case report & literature review. J Med Sci Clin Res 2017;5:15737-40.
Lansky C, Sheikh H, Lazkani M, O'Malley C. Kikuchi-Fujimoto Necrotizing Lymphadenitis: A rare case of generalized lymphadenopathy. Integr Cancer Sci Therap. 2016;3:476-78. DOI: 10.15761/ICST.1000191.
Perry AM, Choi SM. Kikuchi–Fujimoto disease: A review. Arch Pathol Lab Med 2018;142:1341-6.
Ranabhat S, Tiwari M, Kshetri J, Maharjan S, Osti BP. An uncommon presentation of Kikuchi Fujimoto disease: A case report with literature review. BMC Res Notes 2015;8:478.
Joean O, Thiele T, Raap M, Schmidt RE, Stoll M. Take a second look: It's Kikuchi's disease! A case report and review of literature. Clin Pract 2018;8:1095.
Xu S, Sun W, Liu J. Kikuchi-Fujimoto disease: A case report and the evaluation of diagnostic procedures. BMC Oral Health 2019;19:223.
Youssef A, Ali R, Ali K, AlShehabi Z. Kikuchi-Fujimoto disease: A case report of a multi-drug resistant, grueling disease. Oxf Med Case Reports 2017;2017:omx 024.
Wong YK, Khan M. Kikuchi-Fujimoto disease: A rare cause of cervical lymphadenopathy and fever. BMJ Case Rep 2018;2018. pii: bcr-2018-225210.doi: 10.1136/bcr-2018-225210. PubMed PMID: 30097545.
Vivekanandarajah A, Krishnarasa B, Hurford M, Gupta S. Kikuchi's disease: A rare cause of fever and lymphadenopathy. Clin Med Insights Pathol 2012;5:7-10.
[Figure 1], [Figure 2]