A Challenging Case of Kikuchi-Fujimoto Disease Associated with Systemic Lupus Erythematosus and Review of the Literature

Kikuchi–Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is a rare disease that is frequently underdiagnosed due to clinical features that are similar to those of non-Hodgkin lymphomas, systemic lupus erythematosus (SLE), or infectious reactive lymphadenopathy. An excisional biopsy is required. We report a young Caucasian female diagnosed with KFD with skin lesions, complicating with SLE. The clinical course, laboratory, and CT findings are described, as are histopathologic features, for a better recognition of this rare disorder in clinical practice.


Introduction
Kikuchi-Fujimoto disease (KFD) is a self-limiting disease that is characterized by cervical adenopathies and fever [1,2]. Although KFD is reported in various ethnic groups and geographical areas, young Asian females are frequently a ected. e onset is acute or subacute, with painful cervical nodes and fever in previously young individuals who were previously healthy. Extranodal manifestations are rare [3]. e skin is commonly a ected (16-40% of patients), with nonspeci c lesions [4]. e diagnosis represents a challenge due to similar features to non-Hodgkin lymphoma (NHL), systemic lupus erythematosus (SLE), and reactive lymphadenopathy; however, examination by an experienced morphopathologist o ers a correct diagnosis. KFD lymphadenitis presents coagulative necrosis and karyorrhectic debris [3].
Several reports have emphasized the importance of KFD and SLE association. KFD can precede or coexist with SLE [4]. Some authors recommend antinuclear antibody (ANA) screening at diagnosis and close follow-up, especially in patients with cutaneous lesions for the early detection of an autoimmune disease [5][6][7][8]. A 26-year-old Caucasian female was admitted to the hospital with fever, chills, and malaise. e patient reported fever of up to 39°C for the past 4 weeks, intermittent arthralgia of bilateral proximal and distal interphalangeal joints of the hands. One year prior to this, she presented with a similar episode of fever and tender cervical lymph node. She underwent a biopsy with a diagnosis of reactive lymphadenitis. e symptoms resolved spontaneously. No tests to exclude an autoimmune disease were performed. Her medical history included insulin-dependent type 1 diabetes.

Case Report
Clinical examination revealed a febrile patient with enlarged and tender bilateral cervical and axillary lymph nodes as well as hepatomegaly. Scattered erythematous macules were noted on the neck, trunk, and upper extremities.
Laboratory studies are presented in Table 1. She had a high erythrocyte sedimentation rate, moderate anemia, leukopenia with marked lymphopenia, negative in ammatory markers, increased hepatic enzymes, hypoalbuminemia, and albuminuria (1815 mg/24 h). Blood cultures were negative. Serologic tests for hepatitis B and C, HIV, Epstein-Barr virus, cytomegalovirus, and toxoplasmosis were negative. She had a positive ANA titer (1/3200) and positive double-strand DNA antibodies (2628 UI/mL), negative rheumatoid factor, C3 complement, and smooth muscle antibodies. Normocellular marrow with no tumor cells was found on bone marrow biopsy.
CT scan revealed generalized lymphadenopathy involving the submandibular, cervical, supraclavicular, and axillary areas, the mediastinum, and the intra-abdominal and inguinal regions ranging in size from 0.9 cm to 2.5 cm. CT also revealed hepatomegaly (right lobe 21 cm craniocaudal diameter) and pleural e usion (2.3 cm right side and 0.5 cm left side).
Excisional biopsy of axillary lymphadenopathy was diagnostic for KFD ( Figure 1). ere was an e aced architecture with foci of necrosis containing karyorrhectic debris, a polymorphic in ltration pattern with abundant histiocytes, large transformed lymphocytes with immunoblast morphology, and rare tangible macrophages. No polymorphonuclear leukocytes or plasma cells were identi ed. Immunohistochemical staining showed abundant CD3 dim positive immunoblastic activated cytotoxic T-cells that outnumbered CD20 immunoblastic B-cells, scattered CD56 NK cells, rare CD30 cells, and a large number of CD68/KP1 histiocytes. Pankeratin and ALK were negative.
Antipyretics and nonsteroidal anti-in ammatory drugs were started with slow clinical improvement. e patient was treated with prednisone 1 mg/kg/day × 2 weeks, which was then tapered. e arthralgias improved, fever did not reappear, and a gradual attenuation of skin lesions was noted. Soon after hospitalization in the Hematology Department, she was referred to the rheumatologist for evaluation and closer follow-up of her autoimmune disease.

Discussion
Kikuchi disease occurs in a wide age range of patients but usually a ects young adults. e age of diagnosis in our patient was similar to that in other published series (median age of 20 to 30 years), including mostly Asian females with a male : female ratio of 1 : 2 [9][10][11]. Kikuchi disease may be underdiagnosed due to similarities with other disorders. Recent data reported increasing incidence outside of Asia for all races [12][13][14], yet very rare cases of KFD are reported in Caucasian population and the exact incidence is unknown.
Pathogenesis remains unclear. Various infections have been proposed, such as Epstein-Barr virus, human herpes virus, herpes simplex virus, hepatitis B, parvovirus B19, human T-lymphotrophic virus 1, Yersinia enterocolitica, and toxoplasma [4,15]. is theory is based on the self-limited course, laboratory ndings (atypical morphologic lymphocytes on peripheral blood smear, as well as elevated in ammatory cytokines interferon α, and interleukin 6), and histological features (CD8 + T-lymphocytes that induce cell apoptosis). ese cells later undergo apoptosis themselves, resulting in a necrosis background [3,16,17]. However, the results are inconclusive, and it is not clear whether infections are responsible for pathogenesis. Other reports suggested an autoimmune origin because KFD has been reported to simultaneously occur or follow SLE. Our patient also associated with autoimmune features-SLE criteria in addition to a 17-year-history of diabetes type 1. Other autoimmune diseases (Still's disease, Sjogren's syndrome, polymyositis, and rheumatoid arthritis) have rarely been reported to be associated with KFD [4,[18][19][20].
Lymphadenopathies are the most relevant manifestations. e cervical area is a frequently involved site with severe pain or tenderness. KFD usually presents as solitary or multiple enlarged cervical lymph nodes and rarely with generalized lymphadenopathies, such as in our case [21][22][23].
Fever is another manifestation, which is present in 30-50% of reported cases. Less common clinical ndings include weight loss, malaise, chills, night sweats, or gastrointestinal symptoms [24].
Few reports noted hepatomegaly as presenting extranodular sites. Biopsies performed in published cases revealed that reactive changes and hepatic enzymes reverted to normal after a short period of time, as in our patient [11].
Nonspeci c cutaneous manifestations (such as erythematous macules, papules, plaques, facial malar erythema, erosions, patches, and nodules) have been observed in up to 40% of cases [25]. In our case, skin lesions preceded the appearance of adenopathies and resolved 3-4 weeks after initiating treatment. Unfortunately, a skin biopsy was not performed. It would have been of great value to distinguish KFD from SLE skin lesions, and we strongly recommend it to be performed whenever possible. Histological ndings such as perivascular and interstitial in ltration of CD68-and CD163-positive histiocytes, CD8-positive cytotoxic T-lymphocytes, nuclear debris, the absence of neutrophils, vacuolar degeneration, keratinocyte necrosis, and the presence of interface dermatitis have been described in KFD cutaneous lesions [26,27]. e KFD cutaneous lesions could resemble clinically and morphologically with skin manifestations observed in SLE: the presence of interface dermatitis, dermal mucin deposition, and panniculitis. e  [26]. Biological ndings such as leukopenia, neutropenia, atypical lymphocytes on peripheral blood smear, thrombocytopenia, and anemia have been classically reported in KFD. It is notable that our patient displayed lymphopenia which is not commonly seen in KFD and has rather been reported when SLE associated with KFD [18,28]. Reports also associate severe lymphopenia with more forms of KFD [28].
In addition to these, other biological abnormalities have also been reported: elevated in ammatory markers, elevated liver transaminases, increased LDH, ANA, and reduced C3 values [11,29].
Our patient ful lled SLE diagnosis criteria according to both ACR and SLICC classi cation [30], respectively (a total of 6 criteria): serositis (pleural e usion), arthritis (tenderness in bilateral proximal and distal interphalangeal joints of hands), proteinuria greater than 500 mg/24 hours (1815 mg), leukopenia (2200/mmc) with signi cant lymphopenia (approx. 300/mmc), double-stranded DNA, and ANA positivity (immunologic criteria). Sopeña et al. reported an incidence of 23% SLE cases in 20 patients with Kikuchi disease and autoimmune manifestations. e incidence was similar to those in previous literature [18]. According to Kucukardali et al., SLE-associated Kikuchi's disease is more common in Asian patients than in European patients. 28 patients were studied: 18 had simultaneous SLE and KFD, 6 presented with SLE after KFD diagnosis, and 4 were previously diagnosed with SLE [11]. e association between these two disorders is not completely understood. e clinical features are similar, and di erentiation between them is based on lymph node histopathology [31]. e absence of hematoxylin bodies and neutrophils indicates KFD rather than SLE, and our patient showed de nite features of Kikuchi's disease. Histopathologic features that support SLE include an increased number of plasma cells, hematoxyphilic bodies, DNA deposits in the vascular walls, neutrophilic in ltration, and varying degrees of coagulative necrosis with Azzopardi phenomenon [3]. Given the number of published clinical cases, the association between KFD and SLE cannot be random. Some authors have postulated that KFD is prodromal for SLE and recommend follow-up for KFD patients with cutaneous lesions for detecting an autoimmune disease. Others recommend ANA screening at the time of KFD diagnosis [7,19,27].
Di erentiating KFD from other diseases such as lymphoma and reactive lymphadenopathies (e.g., sarcoidosis, tuberculosis, toxoplasmosis, and cat-scratch fever) is mandatory [22,32]. Our patient was referred to the hematologist with the clinical suspicion of NHL, particularly angioimmunoblastic T-cell lymphoma, as it may associate with rash, arthralgias, and ANA positivity [33]. e differential diagnosis of the two most clinical relevant ndings, fever and lymphadenopathy, is often challenging and requires an extensive work-up.
is is emphasized in a group of 244 KFD patients published by Kucukardali et al. [11]. Our patient had a normal bone marrow examination and negative virology serological tests. Even with adequate biopsy, appearances can be mistaken for NHL or reactive lymphadenopathies [22]. In our patient, an experienced morphopathologist con rmed KFD on the second biopsy. Coagulative necrosis with histiocytes proliferation and the absence of granulocytic in ltration is mandatory for diagnosis. Necrosis, karyorrhexis, and cellular debris are the hallmarks of the necrotizing type. Kuo proposed three histopathological stages: (a) a proliferative stage with histiocytes, plasmacytoid monocytes, lymphoid cells, karyorrhectic nuclear fragments, and eosinophilic apoptotic debris; (b) a necrotizing stage with coagulative necrosis; and (c) a xanthomatous stage with foamy histiocytes predominance [3]. In our case, the biopsy con rmed the necrotizing stage. A helpful histopathological feature is the absence of granulocytes in the necrotizing stage, which is used to distinguish KFD from SLE or reactive lymphadenopathy, especially given the coexistence of clinical or biological abnormalities that are similar to those of an autoimmune disease.
Recurrence is rarely reported (3-5%). Song et al. reported a higher incidence rate in ANA-positive cases and identi ed fever, fatigue, extranodal involvement, and positive uorescence antinuclear antibody as predictive factors for relapse [34]. Our patient had presented a previous episode of fever and enlarged lymph nodes. However, the excisional biopsy did not suggest KFD and unfortunately was not available for reexamination. at is why we emphasize again the need for an expert morphopathologic evaluation in any case with features resembling KFD. e outcome of these patients is generally favorable with a self-limited course. Treatment is symptomatic with NSAIDs and a short course of steroids. KFD coexisting with SLE can have a more aggressive course, and treatment is recommended to prevent relapse, as in our case. Rare cases with a fatal evolution have been reported; KFD was found to be complicated with hemophagocytic syndrome, heart failure, or recurrent aseptic meningitis that required intravenous immunoglobulin and corticosteroids [35][36][37][38].

Conclusions
Many of the symptoms, cutaneous manifestations, biological and histopathological features of KFD are similar to those of autoimmune diseases, particularly those of SLE, and differentiating between the two entities is challenging.
We present this case in order to highlight the rare clinical entity of Kikuchi's disease in Caucasian population, the need for an experienced pathologist and for long-term follow-up, especially for those cases with cutaneous manifestations, and high risk of associating autoimmune diseases such as SLE.

Consent
Informed consent from the patient was obtained prior to data collection.

Conflicts of Interest
e authors have no con icts of interest.