Vitorino Modesto Santos • Kikuchi-Fujimoto’s disease and SLE

ESTUDO DE CASO

BM • Brasília Med 2015;52(2):87-92

ABSTRACT

The case study of Kikuchi-Fujimoto’s disease or his-tiocytic necrotizing lymphadenitis is described in a previously healthy 20-year-old man with concomitant diagnosis of systemic lupus erythematosus and hemo-phagocytosis. Kikuchi-Fujimoto’s disease is a rare idio-pathic condition, more often found in young women with weight loss, fever and lymphadenopathy. The diagnosis is established with base on the histopathology and immu-nohistochemistry data. The association with lupus may be incidental and the coexistence of infections or hemo-phagocytosis might be considered a risk factor of poor prognosis. Nevertheless, in the case herein reported, the patient was successfully managed with prednisone and azathioprine. Case studies may enhance the suspicion in-dex about rare conditions in primary health care.

Descriptors. Kikuchi-Fujimoto’s disease; histiocytic ne-crotizing lymphadenitis; immunohistochemistry; syste-mic lupus erythematosus.

Kikuchi-Fujimoto's disease and systemic lupus erythematosus

Os autores declaram inexistência de conflitos de interesses.

Correspondência: Vitorino Modesto Santos.

Hospital das Forças Armadas.

Estrada do Contorno do Bosque s/n, Cruzeiro Novo, 70.658-900, Brasília-DF, Brasil.

Internet: vitorinomodesto@gmail.com

vitorinomodestos@gmail.com

Vitorino Modesto Santos, David Lima Pedrosa, Camila Azevedo Silva, Layssa Melo Feitosa

Vitorino Modesto Santos – Hospital das Forças Armadas e Universidade Católica de Brasília, Medicina Interna - Brasília DF - Brasil .

David Lima Pedrosa – Hospital das Forças Armadas, Medicina Interna - Brasília - DF - Brasil .

Camila Azevedo Silva – Hospital das Forças Armadas, Medicina Interna - Brasília - DF - Brasil .

Layssa Melo Feitosa – Hospital das Forças Armadas, Medicina Interna - Brasília - DF - Brasil.

DOI - 10.14242/2236-5117.2015v52n2a08

RESUMO

Doença de Kikuchi-Fujimoto e lupus eritematoso sistêmico

Estudo de caso de doença de Kikuchi-Fujimoto ou linfadenite necrosante histiocítica é descrito em um homem com 20 anos de idade previamente saudável, que teve diagnóstico concomi-tante de lúpus eritematoso sistêmico e hemofagocitose. A do-ença de Kikuchi-Fujimoto é uma condição idiopática rara, mais comum em mulheres jovens com perda de peso, febre e linfade-nopatia. O diagnóstico é firmado com base em achados histopa-tológicos e imunoistoquímicos. A associação com o lúpus pode ser incidental e a coexistência de infecções ou hemofagocitose é considerada risco de mau prognóstico. Entretanto, o paciente desse relato foi tratado com sucesso com prednisona e azatio-prina. Estudos de caso podem aumentar o índice de suspeita sobre condições raras na atenção primária à saúde.

Descriptors. Doença de Kikuchi-Fujimoto; linfadenite necrosan-te histiocítica; imunoistoquímica; lupus eritematoso sistêmico.

Vitorino Modesto Santos • Kikuchi-Fujimoto’s disease and SLE

ESTUDO DE CASO

BM • Brasília Med 2015;52(2):87-92

INTRODUCTION

Kikuchi-Fujimoto disease (KFD) or histiocytic nec-rotizing lymphadenitis is a rare benign idiopathic condition more common in young women, mani-fested by weight loss, fever, cervical lymphadenop-athies, and leukopenia.1-22 The first description of this entity was made in 1972,5,9 and the differential diagnosis should involve lymphatic malignancies, connective tissue diseases, and infections by my-cobacteria, bacteria, protozoans, or virus.1-4,6,8,10,16-22 Systemic lupus erythematosus (SLE) may be as-sociated with KFD,1-4,6,8,10,20 and hemophagocytosis developing in this clinical scenery might lead to poor outcomes.4,6,8,10,17 The SLE diagnosis can be at-tained before, simultaneously, or after the diagno-sis of KFD.1-4,6,8,10,20 The KFD diagnosis must be based on histopathology and immunohistochemistry da-ta;1-22 whereas hemophagocytosis should be char-acterized by the presence of erythrocytes, plate-lets, leukocytes, or fragments of these cells inside the cytoplasm of the activated macrophages. The main challenges related to KFD diagnosis involve lymphomas and SLE lymphadenitis. KFD treatment includes AINEs, corticosteroids, and hydroxychlo-roquine.1-4,6,8,10,13-17,19,20 The purpose of the case study reported herein is to describe a previously healthy 20-year-old man with simultaneous diagnosis of KFD and SLE during his recent hospital admission. The authors believe that case reports may enhance the suspicion index about uncommon diseases, mainly in primary health care.

CASE REPORT

A previously healthy 20-year-old man had been presenting with asthenia, neck pain, and difficulty to perform lateral head movements for a month. In the last two weeks, he noticed morning stiff-ness, pain, edema and hyperemia in the distal phalanges of the hands. He also had lower-limb myalgia, nasal lesions with bleeding, and reddish and violet plaques on the extensor surface of the upper limbs, in addition to weight loss of six kilo-grams in 30 days. Hand plain radiographs showed no changes in soft tissue, bone or articular struc-tures. Laboratory tests revealed anemia, leukope-nia with lymphocytosis, microscopic hematuria, proteinuria, and increased myoglobin (table 1) levels. He was discharged to the outpatient clinic using NSAIDs. Three days after discharge he was hospitalized with headache, neck pain and vom-iting. He was pale (4+), dehydrated (2 +), febrile (38.2° C), and hypotensive (70/40 mmHg); BMI was 21.3 kg/m², and he showed movement restriction in the cervical spine, without signs of meningitis. The cerebrospinal fluid (CSF) evaluation revealed no abnormalities. The patient underwent volume expansion and ceftriaxone was administered; then, he was referred for control in the ICU. Computed tomography (CT) of the skull and cervical spine, with and without contrast, showed a retropharyn-geal abscess measuring 7cm (Figure 1A), which was drained. Biopsy was performed in the lymph nodes of the left jugular and carotid chains that showed

Table 1. Blood tests of a young man with Kikuchi-Fujimoto’s disease and SLE

D1: Day of hospital admission; ESR: Erythrocyte sedimentation rate. D1: Day of hospital admission; ESR: Erythrocyte sedimentation rate.

Parameters (normal ranges) D1 D30 D60

Red cells (4.5-6.1 x 1012/L) 3.64 4.33 4,20

Hemoglobin (13-18 g/dL) 9.5 11.9 11.6

Hematocrit (42-52%) 28.6 37.4 36.1

Leukocytes (4-10 x 109/L) 2673 6045 5806

Platelets (140-450 x 109/L) 155 243 224

Sodium (135-145 mmol/L) 142 143 144

Potassium (3.5-5.5 mmol/L) 3.8 4.2 3.7

Urea (10-50 mg/dL) 52.8 39.9 23.9

Creatinine (0.7-1.3 mg/dL) 1.49 0.94 0.95

ESR (<10mm/1ªh) 88 68 67

C-Reactive protein (<0.5mg/dL) 2.0 0.6 -

BM • Brasília Med 2015;52(2):87-92

ESTUDO DE CASO

Vitorino Modesto Santos • Kikuchi-Fujimoto’s disease and SLE

Figure 1. Computed tomography (CT) showing inflammatory changes in the right tonsil, extending to the retropharyngeal space (9.2 x 3.2 x 1.4 cm, and approximately 22 ml); the right posterolateral area of the neck had densification of soft tissues; the lymph nodes appeared enlarged with central necrosis (the largest one with 0.8 cm in the smallest diameter).

areas of necrosis and abscesses; and the antibiotic therapy was changed to cover infection by anaer-obes. Control CT images showed reduction of the retropharyngeal abscess, and bilaterally enlarged lymph nodes with central areas of necrosis (Figure 1B). The patient developed episodes of chills and weight loss of 10 kg during the hospitalization. The hypothesis of lymphoproliferative disease (lymphoma) with B symptoms was then raised. A biopsy study of cervical lymph nodes showed re-active lymphoid hyperplasia, characterized by a predominant follicular pattern with enlarged fol-licles and prominent germinal centers and mantle

zones; lymph mononuclear infiltrate permeated by polymorphonuclear cells and leukocytoclasis; septal fibrosis around nodules and germinal cen-ters; in addition to numerous tingible body mac-rophages. Vasculitis, hematoxylin bodies, plasmo-cytes, atypical polylobated or lacunar cells, and parasites were absent. The immunohistochemistry evaluation evidenced CD20+, CD3+, CD10+, CD15+, and CD30+ in activated lymph nodes (Figure 2); in addition to BCL2- and TDT-, and absence of MUM-1 in histiocytes. The PET-CT images showed inflam-matory or infectious lymph nodes with low SUV and no lymph node larger than 2 cm. Malignant

Vitorino Modesto Santos • Kikuchi-Fujimoto’s disease and SLE

ESTUDO DE CASO

BM • Brasília Med 2015;52(2):87-92

Figure 2. Photomicrography of cervical lymph node biopsy showing features consistent with follicular lymphoid hyperplasia, al-though polymorphonuclear cells and leukocytoclasis are permeating the mononuclear infiltrates (Hematoxylin and eosin in low magnification); the immunohistochemistry study revealing CD30+ (Ki-1 antigen, Ber-H2 clone) in activated lymphocytes (showed in high magnification). In addition, CD15+ (granulocyte antigen and ReedSternberg cells, Carb-3 clone) in histiocytes, CD20+, CD10+, and CD3+ were found.

lymphoproliferative disease was then discarded. He was again hospitalized with head and cervical pains, without visual disturbances or meningeal signs; CSF analysis was normal. The serological tests revealed hepatitis B-HBsAg: negative; hepati-tis B-anti-HBs: positive; hepatitis B-anti-HBc IgM: negative; hepatitis C-anti-HCV: negative; HIV 1 and HIV 2: negative; cytomegalovirus IgM: nega-tive; toxoplasmosis IgM: negative; rubella IgM: negative; Epstein Barr (IgG): positive; Epstein-Barr (IgM): negative; antistreptolysin O: positive; VDRL: negative; anti-Treponema pallidum: negative; and FTA-ABS IgG: negative. The images of mag-netic resonance and angioresonance of the skull showed no abnormalities. The 24-hour proteinuria was normal; ANA titer was 1:640 (homogeneous nuclear pattern) and anti-dsDNA 1:320; protein electrophoresis showed high gamma globulin; the direct Coombs test was positive; C3: 62.92 (normal: 90-180) and C4: 9.76 (normal: 10-40); anti-Ro, anti-La, anti-Sm, anti-RNP, anti-cardiolipin IgA, IgG and IgM, lupus anticoagulant, LKM-1, and anti-mito-chondria were normal. His clinical course evolved with arthralgia, malar rash, serositis, leukopenia, lymphopenia, and immune hemolytic anemia; in addition to above mentioned positive rheumato-logic markers. Therefore, the definitive diagnosis of SLE could be established in accordance with the

ACR criteria; whereas the SLE-disease activity in-dex-2000 (SLEDAI-2K) was estimated at 13 on that occasion. Due to hydroxychloroquine contraindi-cation (flat macula with change in pigmentation, and brightness in fovea), the patient received pred-nisone (1mg/ kg daily) and azathioprine (2mg/ kg daily) with good clinical response. Asymptomatic, he has been under specialized outpatient follow-up to date.

DISCUSSION

KFD is a rare benign condition of unclear etio-pathogenesis, limited clinical course and uncom-mon recurrences, and usually associated with in-fectious or autoimmune diseases.1-22 Because the clinical and pathological features of KFD can mimic diverse benign and malignant entities, it may con-stitute diagnostic challenges, mainly for primary health care workers. The diagnosis of KFD is based on lymph node histopathology showing necrotic areas surrounded by histiocytes and plasmocytes, with apoptotic bodies and nuclear dust, and ab-sence of neutrophils and eosinophils. Except for vasculitis and hematoxylin bodies, several mor-phological characteristics of KFD may be observed in the lymphadenitis of SLE.23 Possible diagnostic pitfalls should be always considered based on the

BM • Brasília Med 2015;52(2):87-92

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Vitorino Modesto Santos • Kikuchi-Fujimoto’s disease and SLE

high frequency of association with SLE, which may manifest before, concomitantly or after the diag-nosis of KFD.7 Therefore, immunohistochemistry evaluation is mandatory to establish the defini-tive diagnoses.7 In this patient with KFD and SLE, the immunohistochemistry evaluation performed in lymph node samples revealed the following findings: CD30+, CD20+, CD15+, CD10+, and CD3+. Interestingly, immunohistochemistry studies in lymph nodes of patients with KFD and SLE showed more frequently: CD68+, CD123+, CD4+, and CD8+ T predominance.2,4,8,17-19 Similar analysis revealed CD30+ and CD45+ in a patient with isolated lymph-adenitis due to SLE.18 Immunostaining often shows CD68+, CD45+; CD43+, and CD8+ T cells in KFD lymph nodes,7 but some studies suggest that CD30+ may be consistent with this diagnosis.6,21,22,24 As com-mented by Vassallo et al. about a patient with KFD and HIV+,22 damages to the immune system caused by SLE may play a role in the increased number of CD30+ macrophages. Worthy of note, this young woman had tonsillitis associated with lymphade-nopathies in the cervical region with areas of ne-crosis, in addition to the positive Epstein Barr IgG test. From a clinical standpoint, the main differen-tial diagnoses were lymphomas and SLE lymphade-nitis. The initial concern was Hodgkin’s lymphoma, which can be associated with CD30+, CD45+, CD43+, CD20+, CD15+, CD3+, as well as to previous EBV in-fection.24 Hudnall et al. compared the EBV DNA de-tection in lymph nodes between KFD (n = 30) and reactive lymphoid hyperplasia (RLH) either associ-ated (n = 2) or not (n = 10) with SLE. These authors found different rates of EBV DNA positivity among the groups, as follows: 18/30 (60%) in KFD; 9/10 (90%) in RLH without SLE; and 2/2 (100%) in RLH plus SLE.23 The immunohistochemistry pattern that was disclosed in KFD lymph nodes was CD68+, CD20+; CD3+.23 In this case, the evaluation showed mixed KFD and SLE features. Hydroxychloroquine is a good option for both diseases, but was contra-indicated in this case, and the patient was success-fully controlled with prednisone and azathioprine.

CONCLUSION

The differential diagnosis of cervical lymphadenitis should include KFD; and the possible association with

connective tissue diseases must be ruled out because of their role in outcomes. SLE lymphoma and lymph-adenitis are among the main alternative hypotheses to be ruled out. The earlier the correct diagnosis is established, the better the final prognosis will be. Despite of the inherent weaknesses of a single-case study, this report may increase the awareness about still unsuspected, misdiagnosed, underdiagnosed or underreported uncommon conditions.

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Vitorino Modesto Santos • Kikuchi-Fujimoto’s disease and SLE

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