Kikuchi Fujimoto Disease (KFD) Definition, Symptoms,, Diagnosis and Treatment

Histiocytic Necrotizing Lymphadenitis (Kikuchi Disease) 

Kikuchi Fujimoto Disease Definition, Symptoms,, Diagnosis and Treatment

Kikuchi Fujimoto's Disease (KFD - histiocytic necrotizing lymphadenitis) causes symptoms of fever, weakness, joint pain, night sweats and neck swelling; is a self-limiting disease that typically involves len nodes in the head and neck region. It is more common in women and lymph nodes in the posterior triangle of the neck are more frequently involved. The reason is unclear. In the left photograph, the patient with a swollen lymph node in the posterior triangle of the neck and in the right photograph the incision mark of the right neck region, which allows the diagnosis of the same disease previously, is seen.

Kikuchi-Fujimoto Disease (KFD) Definition and Summary Information

Kikuchi-Fujimoto Disease (KFD) is a very rare, unknown etiology, characterized by fever, neutropenia, histiocytic necrotizing lymphadenitis and is self-limiting. Kikuchi-Fujimoto Disease (KFD), which has a benign course, was defined by Kikuchi and Fujimoto in Japan in 1972 and is also called histiocytic necrotizing lymphadenitis. The etiology is not fully explained. The disease is self-limiting. It is mostly seen in Asian young women and the ratio of women to men is 4: 1. Characteristics of KFD; Lymphadenopathy, fever, weakness, headache, sore throat, diarrhea and weight loss can be observed. Skin lesions may also be observed in patients. It has been reported infrequently in other parts of the world. The disease is rare in our country. The exact frequency is not known. There is no diagnostic laboratory test. Differential diagnosis is only possible by histopathological examination of the lymph node. Histopathological examination of the lymph node; It is characterized by lymphocytic and histiocytic cell populations surrounding the necrosis areas, including karyorectic nuclear residues. The association of KFD with Systemic Lupus Erythematosus (SLE), Sweet's syndrome, Still's disease, toxoplasma and various viral pathogens has been reported. Follow-up of KFD patients in terms of SLE is recommended. Recurrence is seen in approximately 3% of cases. Severe complications and mortality are very low.

Pathogenesis of Kikuchi-Fujimoto Disease

Although the pathogenesis of Kikuchi-Fujimoto disease is not fully understood, it has been suggested that viral agents, hyperimmune or autoimmune mechanisms triggered by different antigens and apoptosis play a role in its etiology. Viral etiology has been frequently discussed and the Herpes virus family has been extensively studied. However, viral etiology could not be proven in both serological and molecular studies. The fact that the disease does not benefit from antibiotherapy, self-limitation, symptoms of upper respiratory tract infection and fever of the character seen in viral diseases are still on the agenda of viral etiology. In some immunohistopathological and molecular studies, lymphoblastic cell infiltration in lymph nodes is predominantly T-lymphocytes (especially CD8 positive T lymphocytes). and in some rare cases of HTLV-1 positive KFDdisease has been identified, and also the presence of Parvovirus B-19 infection in a KFDcase has led to the questioning of viral etiology, although controversial.

Ultrastructural studies for cause of KFD

Ultrastructural studies emphasize the presence of similar tubular reticular structures in lymphocytes, histiocytes and endothelial cells of SLE and KFDpatients. Some authors have developed the hypothesis that KFD is an autoimmune disease triggered by virus-infected transformed lymphocytes. Cell death mechanisms in KFDhave not been widely studied. In their study, Oshima et al. Reported that proliferating CD8 + T lymphocytes act as necrosis-causing and necrosis cells in the process of Fas and perforin-mediated apoptosis and that apoptosis may be involved in the pathogenesis of KFD. Although the disease is more common in females than in males, it is reported in recent publications that the ratio of males to females is close to 1/1. The disease, which has an acute or subacute influenza-like onset, develops over a period of 2-3 weeks. Fever is associated with lymphadenopathy in 30-50% of cases. Night sweats, vomiting, diarrhea, loss of appetite, sore throat, weight loss, and muscle pain are other findings. The most common and characteristic finding is localized lymphadenopathy, especially in the posterior cervical triangle, and in most of the cases lymphadenopathy is detected in a single region, although rare lymphadenopathy has been reported. Hepatomegaly is common but extranodal involvement is rare. In laboratory examination; leukopenia, increased transaminases, and increased erythrocyte sedimentation rate. The increase in sedimentation is generally mild or moderate. Atypical lymphocytes may be found in peripheral blood. Blood and tissue cultures do not produce any microorganisms and do not respond to antibiotics. Although the disease is self-limiting in a few months, rare cases with progressive or even fatal progression have been reported. Relapse rate is 3-4%.

Kikuchi- Fujimoto Disease (KFD) Symptoms and Laboratory Tests

KFD may present with exanthem and neurological symptoms such as fatigue, headache, weight loss, night sweats, arthralgia, nausea and vomiting, fever, oral ulcers, aseptic meningitis, cerebellar ataxia. All clinical signs of KFD can also be observed in SLE. Our patient had all findings except neurological involvement.

In the literature, the skin findings of KFD have been reported as morbiliform 31%, photosensitivity 8%, oral ulcers 23%. and butterfly-like eruptions, edema of the lips and eyelids, erythema multiforme-like lesions, gingival erosion-ulcer and leukocytoclastic vasculitis. Oral ulcers and SLE-like lesions are present on the face, and histopathological examination of facial lesions may be consistent with SLE.

In the laboratory findings of Kikuchi-Fujimoto patients, leukopenia is present in approximately 50% and leukocytosis in 5%. Leukocytosis may be accompanied by atypical lymphocytes at a rate of 25%. Impaired liver function tests and an increase in sedimentation rate may also be observed.

The most common findings of KFD are; fever height and LAP. The first symptom is fever in 30-50% of the cases. Fever is typically low and persists for about one week (rarely one month). However, in our case, high fever lasted for more than three months, primarily. There is usually localized lymph node involvement in the cervical region, but more common nodal involvement (such as axillary, epitrochlear, mediastinal, inguinal, intraparotid, iliac, retrocrural, celiac and peripancreatic nodes). Systemic symptoms may accompany fever and LAP and are more prominent in cases with extranodal involvement. Systemic symptoms are mainly; night sweats, nausea, vomiting, weight loss and diarrhea. Transient maculopapular rash in the form of rubella-like or drug eruption is a common finding (especially in fever and severe cases). The clinical manifestations of the disease usually begin after flu-like symptoms, have a self-limiting benign course and resolve spontaneously. Rarely, recurrent episodes have been reported for several years.

Complete blood count is often normal in KFD. However, leukopenia has been reported in 20-32% of cases and atypical lymphocytes in 25% of cases. Other rare laboratory findings; thrombocytopenia, pancytopenia and chronic disease anemia in severe cases. ESR may be normal, but is higher than 60 mm / h in 70% of cases. Other non-specific laboratory findings; mild liver dysfunction and elevated serum lactate dehydrogenase (LDH) enzyme activity. ANA, rheumatoid factor and lupus anticoagulant activity are generally negative. Serological tests of EBV, CMV, HIV, toxoplasmosis, Y. enterocolitica, cat scratch disease, and other infectious agents, which are considered in the differential diagnosis of fever and LAP, were negative.

Diagnosis and Differential Diagnosis of Kikuchi-Fujimoto Disease

For the definitive diagnosis of Kikuchi-Fujimoto disease, lymph node biopsy is required. The sensitivity of lymph node aspiration cytology was reported as 56.25%. The rate of misdiagnosis was reported to be 40% and the highest risk of confusion with non-Hodgkin's lymphoma was reported. Histopathological characteristic of the disease; Geographic necrosis in the paracortical areas partially distorting the normal structure of the lymph node, cellular infiltration of histiocytes and immunoblasts without karyorectic debris and polymorphonuclear leukocytes. Mitosis is frequently observed. Frequent mitotic activity, especially in areas where immunoblasts and lymphoblasts are dense, may lead to misdiagnosis of non-Hodgkin's lymphoma. Distinguishing from lymphoma is possible with the absence of significant cellular atypia and monomorphic appearance. The majority of lymphocytes monitored are T lymphocytes. Especially CD8 + T lymphocytes were more dominant than CD4 + T lymphocytes. Although diffuse necrosis and karyorrhexis are present in SLE, plasma cell infiltration is intense and the presence of hematoxylin bodies are important findings for SLE. The diagnosis of lymphoma can be ruled out by the absence of T cell receptor rearrangement (TCR) as an auxiliary parameter in differentiation with lymphoma. Although tuberculous lymphadenitis manifests itself with epitheloid granulomas and Langhans type giant cells showing characteristic caseic necrosis, it is important to be careful in cases with diffuse necrosis and cellular debris. It has the potential to be confused with cat scratch disease. However, the presence of histiocytes around the necrosis and the presence of polymorphonuclear leukocytes in the necrosis areas are the findings supporting cat scratch disease.

Importance of histopathological examination of lymph node biopsy

Diagnosis is made by histopathological examination of lymph node biopsy. Despite the benign course of the disease, biopsy should be performed to exclude more serious conditions such as lymphoma.

Kikuchi- Fujimoto Disease (KFD) and Systemic Lupus Erythematosus (SLE) Similarity

It is also suggested that KFD is a self-limiting form of SLE due to its similar histopathological findings to SLE lymphadenitis. However, both diseases are known to have some histopathological differences. The histopathology of KFD is characterized by patchy focal necrotic foci accompanied by widespread karyorrhexis and nuclear residues, and histiocytes, immunoblasts, localized plasma cells and T lymphocytes proliferating around these areas. In the histopathology of SLE, although diffuse necrosis and karyorrhexis were found, it was stated that it can be differentiated from KFD by the presence of hematoxylin-eosin bodies and dense plasma cells and vascular fibrinoid necrosis especially in the paracortical region. In our patient's histopathology, many histiocyte and plasma cells were found, fibrinoid necrosis in the vessel walls, onion membrane appearance and hematoxylin bodies were observed in some of the patients. The relationship and association between KFD and SLE has not been fully explained.

Kikuchi-Fujimoto Disease Treatment

The treatment strategy is characterized by KFD, which is a supportive treatment, with a noisy clinical onset and cervical lymphadenopathy. Antibiotics do not benefit and may need antipyretics for fever. Systemic corticosteroids and nonsteroidal anti-inflammatory drugs can be used as a specific treatment for KFD, which is a spontaneous regression in about 4 months. Antimalarials were found to be more effective especially in patients with SLE.

Kikuchi-Fujimoto Disease - Follow-up

KFD cases should be followed up for several years after diagnosis. Because SLE may develop in some cases or recurrent attacks may last for years. Our patient showed spontaneous recovery despite no medical treatment. There was no recurrence or exacerbation in the 12-month period after discharge. Early diagnosis of KFD is very important. Otherwise, because the clinical and laboratory findings are similar to many diseases, long-term and costly examinations and interventions including invasive procedures have to be carried out unnecessarily.

Murat Enoz, MD, Otorhinolaryngology, Head and Neck Surgeon - ENT Doctor in Istanbul

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