Sjogren’s syndrome is a chronic autoimmune exocrinopathy associated with dry eyes and dry mouth as major clinical manifestations. It is characterized by lymphocytic infiltration of lacrimal and salivary glands and autoantibody production, especially anti-Ro (or SSA) and anti-La (or SSB). Lymphoproliferative disorders are a feature of Sjogren’s syndrome, and can be considered an extraglandular manifestation of the disease. Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare form of lymphadenitis. It is reported more often in young adult women with localized lymphadenopathy (usually cervical), fever, rashes, and leukopenia. It is a self-limiting disease with resolution within 1 - 4 months in almost all patients. Sjogren’s syndrome has been reported in patients with other systemic diseases including SLE and lymphomas. Here we present a patient with Kikuchi-Fujimoto disease who developed Sjogren’s Syndrome 8 years after her diagnosis of Kikuchi-Fujimoto disease.
Sjögren’s syndrome is a chronic autoimmune exocrinopathy associated with dry eyes and dry mouth as major clinical manifestations. It is characterized by lymphocytic infiltration of lacrimal and salivary glands and autoantibody production, especially anti-Ro (or SSA) and anti-La (or SSB). The etiology and pathophysiology underlying Sjögren’s syndrome are not clear. Chronic inflammation and persistent salivary gland enlargement in patients with SS are associated with impaired function [1,2].
The clinical features of SS can be divided into exocrine and extraglandular manifestations. All patients with SS have dry mouth and eyes. In a study of 80 patients followed over 7.5 years, Anaya et al. reported dry mouth and eyes in all patients, but only 31% of patients present with only dry mouth and eyes [
The lifetime risk of non-Hodgkin’s lymphoma in SS is 5% (16 - 44 times higher than normal population) [5,6]. Transition of SS to lymphoma is a slow process (rate of 6.5 - 7.5 years after diagnosis of SS). Primary SS patients can develop lymphoproliferative disease of the upper respiratory system or enlargement of the lymph nodes of the lung [
Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare form of lymphadenitis. It was described in 1972 in Japan by Kikuchi and Fujimoto independently [7,8]. Soon after the first report, cases were reported from other parts of the world [
Sjögren’s syndrome has been reported in patients with systemic lupus erythematosus [12-17], and lymphomas. [
A 44-year-old white woman presented to a dental office for right facial pain and temporomandibular joint (TMJ) pain of a few months duration. The pain was moderate, occasional and pain medications were helpful. Her past medical history was significant for Kikuchi-Fujimoto disease in 2007. In December 2006 she developed fever, red raised ring on her left forehead and right leg below the knee, cervical lymphadenopathy, arthralgia (bilateral knee pain), and skin rash. She received outpatient antibiotics for several courses and was subsequently admitted to the local hospital to receive IV antibiotics where she developed total body skin rash consisting of red raised, ulcerated lesions. She underwent an excisional biopsy of cervical lymph node which showed necrotizing lymphadenitis (Figures 1(A) and (B)). Thus, the diagnostic work up led to a diagnosis of Kikuchi-Fujimoto disease. Patient underwent a serological investigation that showed a positive ANA at 1:3240 along with positive anti-Ro and anti-La by immunodiffusion. However, there were no other clinical or laboratory features to further suggest either disease. In particular, there were no dry eyes or dry mouth. She was not diagnosed with either SLE or SS, and did not meet the classification criteria for either disease [21,22]. Otherwise, she did not have any other medical problem. She had no known drug allergies. She was a married with two healthy daughters. She was working full time in a medical office. Her family history was not contributory.
Examination revealed normal vital signs. She had bilateral moderate parotid enlargement which were tender to palpation (right more than left side), and only the right parotid gland was slightly red. Intraorally, saliva was expressed from Stensen’s and Whartin duct orifices. She did not complain of dry mouth or eyes. Temporomandibular joint examination was within normal limits. No other significant finding was noticed in intra/extra oral examination. Laboratory testing did not show any abnormality in the CBC, chemistries, liver profile, or blood glucose. Serology indicated significantly elevated ANA titer of more than 1:1280 (normal: <1:40), both anti-Ro and anti-La titers were more than 8.0 (normal: <1 by commercial ELISA). The erythrocyte sedimentation rate was 28 (normal: 20 mm/h or less). A biopsy of minor salivary gland was performed in the left inner lower lip under local anesthesia. The result indicated periductal lymphocytic infiltration with focus score of 12 (Figures 2(C) and (D)).
The patient was then seen in the Oklahoma Medical Research Foundation Sjögren’s Syndrome Clinic. Eye examination with Schirmer test and Lissamine green indicated dry eyes. She met international criteria for Sjögren’s syndrome [
There are only a few cases regarding Kikuchi-Fujimoto disease and SS is reported. Kikuchi-Fujimoto disease is a relatively new condition but is it known worldwide. The patients are usually young adults with a slight predilection for female (55/23 = F/M ratio), and mean age of 30 years with a range of 11 - 75 years and more Caucasian than others were reported (60/6 = W/B) [
common sign is localized unilateral cervical lymphadenopathy. Common locations include axilla, supraclavicular, mediastinal, inguinal, intraparotid, iliac, celiac, and peripancreatic areas. The enlarged lymph nodes may be associated with pain, and some patients manifest systemic symptoms, including fever, myalgias, and skin rashes. The clinical course is typically benign, with resolution of the adenopathy in a few weeks to months [
Duration of symptoms are reported to be 1 - 24 months with a mean of 3 months [
Histological examination is valuable for an accurate diagnosis of Kikuchi-Fujimoto disease. The histopathologic characteristic of a lymph node in Kikuchi-Fujimoto disease include patchy necrosis of paracortical area, and abundant extracellular apoptotic nuclear debris. A mixture of different types of histiocytes include nonphagocytic histiocytes known as crescentic-shaped histiocytes as well as plasmacytoid monocytes and small lymphocytes surrounding the necrotic areas [24,25]. Histiocytic immunophenotypes are positive for CD68, lysozyme, and myeloperoxidase. T cells within the lesions are more likely to be cytotoxic (CD8+). Granulocytes such as neutrophils are absent and plasma cells are rare or absent [23,24].
Kikuchi-Fujimoto disease has been reported in association with SLE. Histopathologic features of KikuchiFujimoto disease and SLE may be similar. In both SLE and Kikuchi-Fujimoto disease, cellular protein structures have been found in the cytoplasm of lymphocytes and histiocytes that emphasize the hypothesis that Kikuchi-Fujimoto disease is a self-limited SLE-like disorder [26,27], but these two diseases can be differentiated by the absence of the neutrophils, plasma cells, and hematoxylin bodies in Kikuchi disease. Plasma cells are a prominent feature of SLE. Some authorities believe that Kikuchi-Fujimoto disease could be a precursor for SLE, as both diseases have had coexisting patterns in the same patients [12-20,23]. Some percentage of Kikuchi-Fujimoto disease patients go on to develop SLE, about 3% in one series [
Sanpavat et al. [
A report in Chinese reported two patients, a 14-yearold boy with SLE and secondary Sjögren’s syndrome with 8 months disease duration, and a 9-year-old boy with primary Sjögren’s syndrome who was diagnosed after 3 years of disease duration. Both had multi-organ involvement and biopsy proven KFD [
Our patient had Kikuchi-Fujimoto disease followed a few years later with Sjögren’s syndrome. Given the known association of SLE to Kikuchi-Fujimoto disease, it is perhaps not surprising that Sjögren’s syndrome may also be associated. SLE and Sjögren’s syndrome are clearly related, both clinically and serologically. While dry eyes and dry mouth are the hallmark manifestations of Sjögren’s syndrome, these patients, similar to those with SLE may have non-deforming inflammatory arthritis, vasculitic skin rash, photosensitivity as well as lymphopenia and leukopenia [30,31]. Anti-Ro and anti-La are found in both diseases, albeit more commonly in those with Sjögren’s syndrome [
The differential diagnosis of patients presenting with KFD includes lymphoma. The presence of the large plasmacytoid monocytes in KFD may be mistaken for lymphoma cells. But, a mixture of lymphocytes and histiocytes and the presence of reactive follicles can help to separate these two diseases [9,24].
In summary, KFD is a rare, but perhaps under-recognized disease. It can easily be confused with lymphoma and lymphadenopathy in SLE. To date, only a few cases of KFD with Sjögren’s syndrome have been reported in English literature [33,34]. Although KFD is a self-limiting condition, patients should be followed for the possibility of developing autoimmune disease, including SS and SLE.