Kikuchi-Fujimoto Disease: A Study Of 67 Cases From Coastal South India CURRENT

Background Kikuchi-Fujimoto disease is a rare, benign condition, of unknown etiology, presenting as cervical lymphadenitis, usually tender and maybe associated with systemic symptoms. Despite the extensive literature on this disease, it continues to be misdiagnosed owing to its misleading clinical presentation. Results The mean age in our study was 26.9 (±11.3) years with a female majority of 65.7%. The clinical presentation of most cases was, tender swelling over the side of the neck ( n =50, 74.6%). On local examination, the mean length and width were 2.3 (±1.0) cm and 2.2 (±0.7) cm respectively. Histopathological examination revealed that most patients presented in the proliferative stage ( n =40, 59.7%). In 83.6% of the patients lymphadenopathy resolved in less than 2 months. Follow up of these patients over 9 months revealed that a vast majority of the patients underwent full recovery with symptomatic treatment ( n =42, 62.7%). Conclusions The disease is prevalent in young, female patients of Asian descent and often presents as cervical lymphadenopathy. Early diagnosis with excisional lymph node biopsy is crucial to avoid unnecessary investigations and treatment. Treatment is only symptomatic unless complicated, where steroid therapy is considered. Kikuchi’s disease has an excellent prognosis with almost no risk of fatality.

Background Kikuchi-Fujimoto disease is a rare, benign condition, of unknown etiology, presenting as cervical lymphadenitis, usually tender and maybe associated with systemic symptoms. Despite the extensive literature on this disease, it continues to be misdiagnosed owing to its misleading clinical presentation. Results The mean age in our study was 26.9 (±11.3) years with a female majority of 65.7%. The clinical presentation of most cases was, tender swelling over the side of the neck ( n =50, 74.6%). On local examination, the mean length and width were 2.3 (±1.0) cm and 2.2 (±0.7) cm respectively. Histopathological examination revealed that most patients presented in the proliferative stage ( n =40, 59.7%). In 83.6% of the patients lymphadenopathy resolved in less than 2 months.
Follow up of these patients over 9 months revealed that a vast majority of the patients underwent full recovery with symptomatic treatment ( n =42, 62.7%). Conclusions The disease is prevalent in young, female patients of Asian descent and often presents as cervical lymphadenopathy. Early diagnosis with excisional lymph node biopsy is crucial to avoid unnecessary investigations and treatment.
Treatment is only symptomatic unless complicated, where steroid therapy is considered. Kikuchi's disease has an excellent prognosis with almost no risk of fatality.

Background
Kikuchi-Fujimoto disease (KFD), also known as "histiocytic necrotizing lymphadenitis" is a rare condition of unknown etiology. This benign condition presents as cervical lymphadenopathy, usually tender and is often associated with systemic symptoms like fever 1 .
Identified first by 2 Japanese pathologists, independent of each other in the year of 1972, KFD was noted to have a higher incidence in Asian patients 2 , Kikuchi disease continues to be misdiagnosed till date 1 . Therefore, the awareness of this condition amongst clinicians and pathologists alike would be fruitful as it would aid in the early detection and prevention of life threatening sequelae such as malignancies 3 .
Kikuchi's disease is seen more frequently in young adults, with a mean age between 20-30 years 4 but it can occur in any age group 1 . Even though a female predominance is reported in many previous cases, some studies done in Asia show a male to female ratio of 1:1 1 . The rare involvement of the heart, liver and lungs increases the fatality of an otherwise self-limiting disease 2 .
The most common clinical feature is cervical lymphadenopathy, with or without systemic features, such as fever, fatigue, headache and night sweats 5 . The lymphadenopathy is usually under 4 cm 6 , and in most cases can be tender or painful 2 . Hepatosplenomegaly has been reported in a few cases 1 .
Both the etiology and pathogenesis of this disease is still unknown 1 . Clinically and histologically, the disease is often misdiagnosed as tuberculosis, lymphoma or systemic lupus erythematosus (SLE) 4 .
KFD can be seen in patients with previous history of SLE, it can coexist with SLE or complicate into SLE 7 .This association with SLE was more common in Asian than European patients 6 . Meanwhile, a significant number of patients were found to have underlying viral infections 6 .
The gold standard investigation for diagnosis is by histopathological examination of an excisional biopsy obtained from the affected lymph node 7 . Histologically, altered lymph node architecture by nodules in the cortex, and apoptotic cells with areas of necrosis accumulation of crescentic histiocytic, and the absence of eosinophils and basophils are typical fine-needle aspiration cytology features seen in KFD 6,8 . Due to challenges faced in diagnosing KFD, three evolving histologic patterns have been proposed by pathologists based on key morphologic features. Namely, they are proliferative, necrotizing and xanthomatous 7 . Most patients have normal laboratory findings 1 . However, a few cases with mild anemia, elevated Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP), along with leucopenia, and elevated Lactate Dehydrogenase (LDH) have been reported rarely 3 .
Even though, this disease almost always runs a benign course and resolves in several weeks to months in most patients 6,9 , it is seen to increase the risk of SLE and lymphoma 7 . Treatment if necessary is symptomatic with analgesics and antipyretics 1 . Kikuchi's disease has a very low recurrence rate of and only a few fatalities have been reported 1 . The use of corticosteroid therapy is still under debate for the management of recurrent cases 1 .
Despite the extensive studies done on Kikuchi's disease, it continues to be misdiagnosed till date. The objective of this study was to promote awareness among clinicians and pathologists alike. Therefore, this study discusses the clinico-epidemiological presentations of the disease, the pathological morphology commonly found in these cases and the importance of follow up of these patients to ensure complete recovery and avoid possible sequelae and complications.

Results
The baseline characteristics of the results are shown below in the in Table 1. The age of our study population ranges from 4 to 77 years. The mean age is 26.9 (± 11.3) years and a median age of 27 years (IQR: 18-32 years). As shown below Kikuchi's disease commonly affects younger adults between the ages of 21 to 40 years (n = 44, 65.7%). Kikuchi's disease was seen more in female patients (n = 44, 65.7%). When the occupation of the study population was analyzed, most of the patients were found to be homemakers (n = 27, 40.3%).  Table 2 demonstrates the distribution of chief complaints at presentation in Kikuchi's patients. A vast majority of the patients presented with tender swelling over the side of the neck (n = 50, 74.6%).
Local examination revealed, the length and width of the cervical lymph nodes ranged from 0.5 to 5 cm and 1 to 5 cm respectively, with mean length of 2.3 (± 1.0) cm and mean width of 2.2 (± 0.7) cm. Patients also presented with complaints of fever (n = 35, 52.2%) and hepatosplenomegaly (n = 10, 14.9%) due to the systemic involvement of the disease. The histopathological profile of all patients was analyzed after classifying the findings of excision biopsies to the three morphological stages are given in Table 3. As shown in the table given, most of the patients were in the proliferative stage (n = 40, 59.7%). The duration of lymphadenopathy in Kikuchi's disease patients ranged from a few days to 6 months.
In most patients, lymphadenopathy resolved in less than 2 months (n = 56, 83.6%). The patients were followed-up over a period of 9 months to observe the outcomes of kikuchi's disease as seen in Table 5.  On analysis of the gender prevalence in this study, a female predominance of 1.91:1 was observed.
Meanwhile, in a study done South India, there was a significant female majority of 2.4:1 9 . However, a gender comparison of 1:1 was observed in the results obtained from a study conducted in Italy, in September 2016 5 . A reversal of the gender ratio in our study was observed in a study carried out in Korea which showed a significant male majority of 2.8:1 16 , and another conducted in North India where the ratio was 2:1 15 .
Younger females were noted to be more predisposed to KFD in our study with ages ranging from 4-38 years, all considerably younger than their male counterpart in this study. A study of 9 patients was conducted in Sri Lanka by Abeysekara R A et al, where all the cases were female patients in the age group of 12-30 years 13 . A similar study was carried out by Adhikari R C et al, in Nepal where 5 of the 6 cases were females and the age range was 13-32 years 14 .
The most common clinical presentation of these patients was tender swelling on the side of the neck (74.6%). Similar results were obtained from a study done in Michigan, in May 2018 with 60-90% of the cases having posterior cervical lymphadenopathy 1 . Systemic symptoms such as fever (52.2% of the cases) and hepatosplenomegaly (14.9% of the cases) was found abundantly in this study. Fever was noted to be associated frequently with tender cervical lymphadenopathy (n = 30, 44.8%). This coexistence of symptoms was replicated in the Michigan study in 35-77% of the patients 1 . Tender cervical lymphadenopathy was the most common symptom in studies done in Italy 5 (60-98%), Saudi Arabia 2 (56-98%) and Michigan 1 (60-90%). The involvement of axillary lymph nodes was encountered in 9% of the cases in this study, while the same in a study conducted on 24 cases in Bangalore yielded, 13% 9 .
One 22 year old male patient in this study presented with symptoms of cervical lymphadenopathy for 15 days associated with systemic symptoms of fever, neck stiffness and meningitis, was treated with steroids, tapered over a period of 1 month. Follow-up over 2 years revealed that lymphadenopathy subsided in 3 months and the patient recovered fully with no recurrence reported. In a study done in Japan by Komagamine T et al, which reported 5 cases of recurrent aseptic meningitis associated with Kikuchi's Disease, all the cases resolved within several months with 3 requiring treatment with steroids 11 . Thus the use of steroids in patients with recurrence of Kikuchi Fujimoto disease with neurological involvement is considered beneficial following extensive investigation to ensure its safety 11 .
The histopathology findings of the excisional lymph node biopsy remains gold standard for confirming Kikuchi's disease. In this study, the findings were sub grouped into 3 morphological phases as done in previous studies 5,7,8 , and a vast majority of the confirmed cases presented in proliferative phase of KFD (n = 40, 59.7%).
In contrast to a study that was conducted in Bangalore, in 2013, where the lymphadenopathy lasted from 1 week to 3 months 9 , this study results suggested a longer duration of symptoms and varied from, 2 weeks to 6 months.
The follow up outcomes of the patients over a period of 9 months revealed that all recovered fully with no complications in this study.
A significant majority of our patients recovered after symptomatic management (62.7% of the cases), which was the choice of initial treatment in previous studies as well 1,11,15 . One fourth of the patients in this study were treated successfully with steroids (25.4%). A similar result was obtained in a study done by Guleria et al in 2019, where 2 of the 6 patients required steroid therapy 15 . In a study done in Florida, in 2014, the treatment with methylprednisolone showed a drastic response within 24 hours 6 .
Even though Kikuchi's disease is known to be a self-limiting condition, this study showed that only a small fraction of patients recovered completely without any treatment (9%). In contrast, in Florida, majority of the patients had self-limiting cases of KFD which typically lasted 1 to 4 months 6 , while in a study conducted in England, following the hospital visit for the lymph node biopsy, most of their symptoms resolved spontaneously within 6 months 7 .
There was minimal recurrence of 3% when patients were followed up for 9 months in this case study, occur as late as 8 years following the initial presentation and in this study the recurrence was reported as 15% 6 . Therefore, long-term follow-up is essential to determine the rate of recurrence of KFD.

Conclusion
Kikuchi-Fujimoto disease is a rare, idiopathic condition which presents as a diagnostic challenge to both pathologists and clinicians due to its misleading presentation. Demographically, the disease is prevalent in young, Asian, female patients and often presents as cervical lymphadenopathy. Early diagnosis with excisional lymph node biopsy is crucial to avoid unnecessary investigations and treatment for this self-limiting condition. Treatment is only symptomatic unless complicated, where steroid therapy is considered. KFD has an excellent prognosis with almost no risk of fatality. Long term follow up of patients is vital to prevent recurrence and complications of this condition.
Therefore, KFD patients should not only be diagnosed early, but long term follow-up with annual screening for SLE and blood ESR levels is advised to prevent misdiagnosis and complications 7 .
From a clinical standpoint, early diagnosis is essential to prevent extensive investigations, unnecessary treatment and to avoid rare complications. Kikuchi-Fujimoto disease should be considered in young females presenting with cervical lymphadenopathy with nodal biopsy showing necrosis and karyorrhexis.

Methods
The study was a record based retrospective study was carried out among all patients diagnosed with Histopathological examination of the excision biopsy of all suspected cases of KFD was carried out.
The results obtained were categorized into 3 phases. Namely, proliferative phase, xanthomatous phase and necrotizing phase. The classical presentation of the proliferative stage was histiocytes, dendritic cells, lymphocytes and nuclear fragments. In the xanthomatous phase the predominant feature was foamy histiocytes within the lesions. Necrotizing phase typically shows extensive necrosis with karyorrhectic nuclear debris and coagulative necrosis and complete loss of lymph node architecture. The diagnosis of KFD was confirmed based on these morphological findings.
The data collected was analyzed using Statistical Package for Social Sciences (SPSS) version 20 to analyse the clinico-epidemiological data, clinical presentation, local examination findings, histopathological presentation as well as outcomes on follow up. This data was expressed as proportions, mean, standard deviation, median and Inter Quartile Range (IQR). Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests

Funding
No Funding NVD, BA and JK contributed to the conception, design and analysis of the study and drafted the manuscript.
CH and BS contributed to the acquisition of data and have drafted the manuscript.
RH contributed to the analysis and interpretation of study data DM and SM contributed to the analysis and interpretation of study data.
All authors have read and approved the final manuscript