INTRODUCTION — Kikuchi disease, also called Kikuchi-Fujimoto disease or Kikuchi histiocytic necrotizing lymphadenitis, was originally described in young women and is a rare, benign condition of unknown cause usually characterized by cervical lymphadenopathy and fever. Histopathology of the involved lymph nodes differentiates Kikuchi disease from several more serious conditions that it may mimic.
PATHOGENESIS — While the pathogenesis of Kikuchi disease is unknown, the clinical presentation, course, and histologic changes suggest an immune response of T cells and histiocytes to an infectious agent. Numerous inciting agents have been proposed, including Epstein-Barr virus (EBV) [1,2], human herpesvirus 6, human herpesvirus 8 [3], human immunodeficiency virus (HIV), parvovirus B19 [4], paramyxoviruses, parainfluenza virus, Yersinia enterocolitica, and Toxoplasma. In one report, EBV was detected by in situ hybridization in tissue in all of 10 patients examined [5,6], but immunohistochemistry detected EBV-encoded protein in only one of these patients. A torque teno/torque teno-like minivirus, which closely resembles the circovirus that causes necrotizing lymphadenitis in pigs, was found in three Korean patients [7]. An observation that is consistent with a viral etiology is increased levels of interferon-alpha and of other proteins stimulated by interferon-alpha including 2',5'-oligoadenylate synthetase and tubuloreticular structures in the cytoplasm of stimulated lymphocytes, histiocytes, and vascular endothelium [8].
Apoptotic cell death mediated by cytotoxic CD8-positive T lymphocytes is the principal mechanism of cellular destruction [9-11]. Histiocytes may act as enhancers. The apoptosis appears to be induced by the Fas-Fas ligand system. Morphologic characteristics of apoptotic cells including nuclear chromatin condensation and fragmentation along the nuclear membrane with intact organelles and histiocytes phagocytosing karyorrhectic debris (apoptotic bodies) are found on transmission electron microscopy.
A possible role for interferon-gamma and interleukin (IL-)6 in the pathogenesis of this syndrome is suggested by one study of four men with biopsy-proven Kikuchi disease [12]. During the acute phase of illness, these patients had elevated serum levels of interferon-gamma and IL-6 but not interferon-alpha, tumor necrosis factor, or IL-2. The interferon-gamma and IL-6 levels returned to normal during convalescence. Subsequent reports support this role [13]. Analysis of lymph node biopsies in patients with Kikuchi disease show T-bet-expressing CD4 cells accompanied by T-bet-positive CD8 and B cells [14]. Using high-throughput nucleotide sequencing of lymph node tissue to identify exomes and transcriptomes, candidate single-nucleotide polymorphisms for markers of Kikuchi disease markers have been identified, and the altered gene expression found may lead to better understanding of the disease, diagnosis, and treatment [15].
Kikuchi syndrome shares sex and age predisposition as well as histologic features with systemic lupus erythematosus (SLE). Tubuloreticular structures in the lymphocytes and endothelial cells in patients with SLE have been observed to be similar to those seen in Kikuchi disease. One ultrastructural study proposed that Kikuchi syndrome reflects a self-limited, SLE-like autoimmune condition caused by virus-infected transformed lymphocytes [16]. (See "Epidemiology and pathogenesis of systemic lupus erythematosus".)
EPIDEMIOLOGY — While initially described in young women, Kikuchi disease clearly also occurs in men. The ratio of affected males to females in three series was 1:4, 1:1.6, and 1:1.26, respectively [17-19]. In a report of 20 individuals younger than 18 years of age with Kikuchi disease in Korea, the sex distribution was equal [20]. Others have suggested that, in children, boys are slightly more frequently affected than girls, in contrast with older patients [21,22].
Most patients are younger than 40 years of age, but this condition has been reported in patients ranging in age from 6 to 80 years, most of whom were previously well [23-26]. The mean age at presentation in a United States series was 30 years [17].
Ethnic distribution — Although initially described in two separate cases from Japan, Kikuchi disease has since been found in all racial and ethnic groups and in many countries, including the United States [17,27]. In a study of 88 patients with Kikuchi disease in the United States, 75 percent were White individuals [17]. The frequency of this condition varies widely in different groups, but it has been most frequently reported from Asia. In a series of 920 lymph node biopsies from Saudi Arabia, only 5 (0.5 percent) had changes characteristic of Kikuchi disease [28] compared with 5.7 percent in a report from Taiwan [29]. In a Korean study of 147 patients presenting to an outpatient clinic, Kikuchi disease (34.7 percent) and tuberculous adenitis (22.4 percent) were the most common causes of cervical adenitis [30].
CLINICAL FEATURES — The most common clinical presentation of Kikuchi disease is fever and cervical lymphadenopathy in a previously well young woman. Fever is a primary symptom in 30 to 50 percent of patients. It is typically low grade and persists for about one week [17], rarely for up to one month. In one study of 86 children with Kikuchi disease, the median duration of fever was nine days but was more prolonged in those with higher fever (≥39.0°C), leukopenia, and larger lymph nodes [31].
In a retrospective literature review that described 244 patients with Kikuchi disease, the most common signs and symptoms were [32]:
●Lymphadenopathy (100 percent)
●Fever (35 percent)
●Rash (10 percent)
●Arthritis (7 percent)
●Fatigue (7 percent)
●Hepatosplenomegaly (3 percent)
A variety of other symptoms and physical findings occur sporadically in patients with Kikuchi disease. These include rigors, myalgia, arthralgia, and chest and abdominal pain [17]. Night sweats, nausea, vomiting, diarrhea, and weight loss have also been reported and appear to be more prominent in patients with extranodal disease [33]. There have been several reports of disease limited to the mediastinum, with no cervical involvement [34,35]. Mesenteric lymphadenitis may mimic appendicitis [36].
The clinical presentation in pediatric and adult patients is generally similar [37]. In one study, fever and rash were more common and generalized lymphadenopathy was less common in children compared with adults [38]. In children <6 years old, the presentation may be atypical. Leukocytosis may be more common than leukopenia and complications in multiple organ systems may occur (eg, interstitial pneumonia, hepatosplenomegaly) [39]. Weight loss may be more common in adults [22].
The risk of evolution into an autoimmune syndrome may be higher than in adult patients [40]. Several reports of hemophagocytic lymphohistiocytosis (HLH) in patients with Kikuchi disease have led to the recognition of macrophage activation syndrome, a secondary form of HLH, in these patients. The patients have generally been older, required glucocorticoid treatment, with some needing intensive care support and leading to in-hospital mortality [41]. Occasional reports describe Kikuchi disease associated with other conditions, such as Still's disease [42], cryptogenic organizing pneumonia [43], systemic lupus erythematosus (SLE) [44-46], and following B cell lymphoma [47].
Recurrent disease occurs but is uncommon, approximately 3 percent in pediatric cases [32]. In a Korean case series, with patients of mean age 24 years, recurrence was seen in 11.3 percent of patients and 2.7 percent of patients developed autoimmune diseases after an initial diagnosis of Kikuchi disease [48]. In children, recurrence has been reported more often in boys, but in adults recurrence has been more frequently reported in women [22].
Malignant lymphoma often is considered in the differential diagnosis. Misdiagnosis leads to extensive investigations and, in some cases, inappropriate treatment. Early reports suggested misdiagnosis is not uncommon [49].
Rash — Transient skin rashes similar to rubella or drug-induced eruptions may be seen in sicker patients [50]. Rash is more common in children [22] than adults. Occasionally, the rash is pruritic [51]. Some reports describe skin manifestations in up to 40 percent of patients, including facial erythema; erythematous macules, patches, papules, or plaques; lichen planus [52]; scattered indurated lesions; ulcers; polymorphous light eruptions; leukocytoclastic vasculitis; scales; pruritus; alopecia; conjunctival injection; and oral ulceration [1,53,54]. The presence of a malar "butterfly rash" should raise the diagnosis of SLE that, as noted above, has been associated with Kikuchi disease.
Lymph node involvement — Lymph node involvement is usually cervical and localized in Kikuchi disease. As an example, all 79 patients in a Chinese report had cervical node involvement [55]. In the United States series of 108 patients, 83 had lymphadenopathy localized to one site, usually cervical and particularly posterior cervical; only three patients had bilateral cervical adenopathy [17]. There may be more extensive node involvement or involvement of other sites. These sites include the axillary, epitrochlear, mediastinal, mesenteric, inguinal, intraparotid, iliac, retrocrural, celiac, retroperitoneal, and peripancreatic nodes. In a review of 60 patients with confirmed Kikuchi disease, and a mean age of 21years, extracervical disease was not uncommon, especially with bilateral cervical disease and leukopenia (abdominal 52 percent, pelvic 47 percent, inguinal 41 percent, and axillary 30 percent) [56].
The nodes are usually only moderately enlarged (1 to 2 cm in diameter) but occasionally are much larger (≤7 cm) [55]. They are typically firm, smooth, discrete, and mobile. The nodal enlargement is often associated with dull or acute pain.
Rarely, nodal enlargement may be minimal or only mediastinal, or retroperitoneal nodes may be involved [57,58]. The diagnosis is unlikely to be considered prior to biopsy in such patients who may present as a fever of unknown origin.
Neurologic symptoms — Neurologic symptoms are increasingly reported, including aseptic meningitis [59-62], meningoencephalitis [63], acute cerebellar symptoms with tremor and ataxia [64], and optic neuritis [65]. Aseptic meningitis is the most common neurological complication, usually at the time of the lymphadenopathy. Low cerebrospinal fluid (CSF)/serum glucose ratios may be seen. Recurrent meningitis is more likely to occur in males. Very high levels of intracranial pressure were reported in one adolescent with aseptic meningitis [66], and recurrent subdural effusions requiring intervention in another patient [67]. Encephalopathy may occur in children 10 days to 3 months, and is characterized very high CSF protein levels, and extensive magnetic resonance imaging changes. Early immunomodulatory therapy is recommended.
Other manifestations — Thyroiditis and parotid enlargement [68], pleural effusions [69], pulmonary infiltrates [70], nodules [71], symmetrical polyarthritis [72], acute renal failure [73], polymyositis [74], hemophagocytosis [75-78], panuveitis [79], bilateral papillary conjunctivitis [80], autoimmune hepatitis [81], brachial neuritis [82], and peripheral neuropathy [83] have all been reported. In addition, there are reports of antiphospholipid syndrome with multiorgan failure [84].
Coronavirus disease 2019 (COVID-19) infection and vaccination have been associated with Kikuchi disease in rare reports; however, it is uncertain whether the association is causal. In most reports, disease was being and recovery was rapid and complete [85-89]. One individual developed Kikuchi disease 10 days postvaccination [90] and another developed Kikuchi disease complicated by hemophagocytic reticulosis following vaccination. [91].
LABORATORY STUDIES — The majority of patients with Kikuchi disease have a normal complete blood count [17], although leukopenia has been reported in up to 43 percent [18,30,32]. Atypical lymphocytes have been reported in up to 25 percent of patients [55]. Other reported findings include thrombocytopenia, pancytopenia, and, in those with severe disease, anemia of chronic disease [1,32,92].
The erythrocyte sedimentation rate can be normal but was elevated to more than 60 mm/hour in 70 percent of patients in one series [57]. Other nonspecific findings can include mildly abnormal liver function tests and elevated serum lactate dehydrogenase [58]. Macrophage activation syndrome was described in 30 percent of a series of hospitalized patients, associated with longer hospital stays and increased late glucocorticoid use [41].
Bone marrow examination — An increase in macrophages without atypical cells is the most frequent bone marrow finding [18]. In two patients, increased numbers of mature hemophagocytic histiocytes in the bone marrow led to the misdiagnosis of virus-associated hemophagocytic syndrome [55].
Serologic studies — Antinuclear antibodies (ANA), rheumatoid factor, and lupus erythematosus preparations are generally negative. Some patients initially diagnosed with Kikuchi disease have subsequently developed systemic lupus erythematosus (SLE) [17,93], and an ANA test should be performed in patients with suspected Kikuchi syndrome who have features suggestive of SLE in order to exclude this diagnosis. One report describes a transient rise in anti-deoxyribonucleic acid (DNA) and antiribonuclear protein antibody levels [18]. Adult onset Still’s disease has also been described simultaneously with Kikuchi disease [94].
Serology for Epstein-Barr virus, cytomegalovirus, HIV, toxoplasmosis, Y. enterocolitica, cat scratch disease, and other infectious agents is often performed since these infections are considered in the differential diagnosis of fever and lymphadenopathy.
DIAGNOSIS — The diagnosis of Kikuchi disease is made by lymph node biopsy. Biopsy should be performed, despite the self-limited nature of this syndrome, in order to exclude more serious conditions requiring aggressive therapy such as lymphoma. Patients with Kikuchi disease have been misdiagnosed as having lymphoma and treated with cytotoxic agents when physicians and pathologists are unfamiliar with this entity [17]. Other conditions that have been confused with Kikuchi disease are tuberculous adenitis, lymphogranuloma venereum [95], and Kawasaki disease [96,97].
Excisional biopsy has previously been most often recommended. However, ultrasound-guided fine needle aspiration in the hands of experienced cytopathologists is now well established as an alternative diagnostic method, using smears and cell block preparations designed to preserve lymph node architecture [98-100]. However, the diagnostic accuracy of ultrasound-guided core needle biopsy (95.6 percent) has been compared with aspiration (44.7 percent) in a retrospective analysis and is now suggested as the primary diagnostic modality for this condition [101].
Diagnosis in pediatric patients using a scoring system and avoiding lymph node biopsy has been proposed [102]. Criteria used are temperature, maximum lymph node size, and serum B2 microglobulin. The report described 100 percent sensitivity and specificity with this system but further evaluation in other centers and larger patient numbers is desirable.
Pathology
Lymph nodes — The histology of the lymph node in Kikuchi disease can usually be easily differentiated from most known infectious conditions in the differential diagnosis of fever and lymphadenopathy but not from that seen in some patients with systemic lupus erythematosus (SLE) [17,23,54]. Yellowish necrotic foci may rarely be noted on the cut surface of the node. Microscopic examination usually shows paracortical foci often with necrosis and a histiocytic cellular infiltrate (picture 1 and picture 2). These foci may be single or multiple. The capsule may be infiltrated, and perinodal inflammation is common. The necrotizing process is often confined to circumscribed areas of eosinophilic fibrinoid material with irregular distribution of fragments of nuclear debris. Overt coagulative necrosis is not a prerequisite for the diagnosis of Kikuchi disease [23].
The histologic appearance changes as the disease progresses.
●Early biopsies in the "proliferative phase" show follicular hyperplasia and paracortical expansion by lymphocytes, T and B cell blasts, plasmacytoid monocytes, and histiocytes with numerous apoptoses in the background.
●In the "proliferative phase," the presence of numerous blast cells raises the differential diagnoses of lymphoma, Epstein-Barr virus infection, and herpes simplex infection. Preservation of the nodal architecture, the polyclonal infiltrate, and negative viral immunohistochemistry exclude these conditions.
●Later biopsies in the "necrotizing phase" show necrosis without a neutrophilic infiltrate associated with progressive dominance of histiocytes as the major cell type. The histiocytes often have crescentic nuclei and contain phagocytosed debris. Immunohistochemical stains show CD68-positive plasmacytoid monocytes and histiocytes with predominantly CD8-positive T lymphocytes [103]. The absence of neutrophils in the "necrotizing phase" is helpful in distinguishing this condition from SLE and drug-induced lymphadenopathy.
Xanthomatous appearance seems to be a distinct histologic variant [104].
The histologic differential diagnosis includes SLE, herpes simplex lymphadenitis, and lymphoma (non-Hodgkin and Hodgkin). In SLE, hematoxylin bodies and plasma cells are also seen. Differentiation from SLE may be particularly difficult, but C4D immunohistochemistry may be of some help, when taken in conjunction with clinicopathologic features [105]. Digital quantification of CD123 immunohistochemical staining may be useful in distinguishing Kikuchi disease from other necrotizing lymphadenitis [106]. In herpes simplex lymphadenitis, there are fewer surrounding mononuclear cells, and neutrophils are usually present. Necrosis associated with Hodgkin lymphoma usually includes neutrophils, and, in contrast with Kikuchi disease, the large atypical cells (Reed-Sternberg cell variants) are CD15, CD30, and CD45 positive. It has been suggested that plasmacytoid dendritic cells more frequently infiltrate the lymph nodes in Kikuchi disease than in either reactive lymphadenitis or T or B cell lymphoma, irrespective of the age of the Kikuchi lesion, and thus they may be useful indicators for the cytologic diagnosis of Kikuchi disease [107]. Necrotic lymph nodes have been misdiagnosed as metastatic disease from head and neck cancer [108].
CD8-positive cytotoxic T cells are abundant around necrotic areas and may be helpful in differentiating this from SLE and reactive lymphoid hyperplasia [109].
Skin — In contrast with the characteristic histopathologic changes seen in lymph nodes of patients with Kikuchi disease, the histologic features in skin biopsy samples are highly variable and nonspecific. Common histologic findings that may be present include epidermal change (most commonly with necrotic keratinocytes), nonneutrophilic karyorrhectic debris, basal vacuolar change, papillary dermal edema, and a lymphocytic infiltrate [54]. In a review of skin biopsies from 16 cases, features noted included vacuolar interface changes (in 75 percent), necrotic keratinocytes (in 68 percent), karyorrhexis (in 100 percent), superficial and deep lymphohistiocytic infiltration (in 100 and 56 percent, respectively), and panniculitis (in 60 percent) [110]. Infiltrating cells were predominantly CD68- and CD163-positive histiocytes and CD3-positive T lymphocytes. Neutrophil-predominant inflammation with superficial dermal edema, a Sweet syndrome-like morphology, has also been reported [111].
IMAGING STUDIES — Computed tomography (CT) imaging of the affected lymph nodes typically shows perinodal infiltration (81 percent) and homogenous nodal contrast enhancement (83 percent) [112]. Nodal cortical attenuation and its ratio to adjacent muscle on CT imaging may be used to differentiate Kikuchi disease from nodal reactive hyperplasia and tuberculous lymphadenopathy, if the lymphadenopathy is not necrotic. If the lymphadenopathy is necrotic, the pattern of necrosis may allow differentiation from tuberculosis [113]. Positron emission tomography scanning, including splenic activation, has been investigated in assessing disease severity [114]. Most patients are found to have multiple hypermetabolic lymph nodes with only a few enlarged [115].
On ultrasound, lymph nodes may appear suspicious for malignancy; 66 percent of a series of 29 lymph nodes evaluated sonographically showed features suggestive of malignancy [116]. Differentiating features on power Doppler ultrasonography between Kikuchi disease and tuberculous adenitis have been described [117]. In Kikuchi disease compared with tuberculous adenitis, lymph nodes are smaller, less rounded, more likely to have an echogenic hilum, more likely to be abnormal in the posterior cervical region, less likely to have internal calcifications (0 versus 36 percent), and less likely to be necrotic (9 versus 71 percent).
TREATMENT — No effective treatment has been established for Kikuchi disease. Signs and symptoms usually resolve within one to four months [118].
Patients with severe or persisting symptoms have been treated with glucocorticoids [119] or high-dose glucocorticoids with intravenous immune globulin [120] with apparent benefit. There have been reports of recurrent Kikuchi disease successfully treated with hydroxychloroquine monotherapy or combined with glucocorticoids [121-123]. One report describes a response to the interleukin 1 inhibitor, anakinra, in a patient unresponsive to steroid therapy [124]. Affected patients should be followed for some years because they can develop systemic lupus erythematosus, and recurrences of Kikuchi disease can occasionally continue for many years. One patient, for example, had four episodes of lymphadenopathy over 18 years and another had two episodes separated by 6 years [92,97].
OUTCOMES — Kikuchi disease is self-limited in the majority of patients, although recurrences have been reported [92,97,125,126]. In a series of 108 patients, 59 of 64 patients (92 percent) for whom data were available were alive and well at a median of 32 months of follow-up [17]. Among 102 patients in Korea between 2001 and 2006, 3 developed systemic lupus erythematosus, 8 experienced early relapse, and 13 had late recurrence [125]. Recurrent cases were symptomatic for longer than initial cases. A positive fluorescent antinuclear antibody test was associated with a higher risk of recurrent disease.
SUMMARY AND RECOMMENDATIONS
●Background − Kikuchi disease is a rare, benign condition of unknown cause usually characterized by cervical lymphadenopathy and fever. Histopathology of the involved lymph nodes differentiates Kikuchi disease from several more serious conditions that it may mimic. (See 'Introduction' above.)
●Pathogenesis − While the pathogenesis of Kikuchi disease is unknown, the clinical presentation, course, and histologic changes suggest an immune response of T cells and histiocytes to an infectious agent. (See 'Pathogenesis' above.)
●Age association − Although initially described in young women, Kikuchi disease also occurs in men. Most patients are younger than 40 years of age and were previously well. (See 'Epidemiology' above.)
●Ethnic distribution − Kikuchi disease has been most frequently reported from Asia but has been found in all racial and ethnic groups and in many countries. (See 'Ethnic distribution' above.)
●Clinical presentation − The most common clinical presentation is low-grade fever and cervical lymphadenopathy in a previously well young woman. Patients may also have fatigue, joint pain, rash, arthritis, hepatosplenomegaly, night sweats, nausea, vomiting, weight loss, and/or diarrhea. (See 'Clinical features' above.)
●Lymph node involvement − Lymph node involvement is usually cervical and localized. (See 'Lymph node involvement' above.)
●Diagnosis − The diagnosis of Kikuchi disease is made by lymph node biopsy. Microscopic examination usually shows paracortical foci often with necrosis and a histiocytic cellular infiltrate (picture 1 and picture 2). (See 'Diagnosis' above.)
●Other testing − Antinuclear antibodies should be performed in patients with suspected Kikuchi disease who have features suggestive of systemic lupus erythematosus (SLE) in order to exclude SLE. (See 'Serologic studies' above.)
●Management − No effective treatment has been established for Kikuchi disease. Signs and symptoms usually resolve within one to four months. (See 'Treatment' above.)