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Kikuchi's disease is a rare self‐limiting lymphoproliferative condition of unknown aetiology, characterised by acute or subacute necrotising lymphadenitis. It is a benign condition that can mimic malignant lymphoma. In this report, a case of Kikuchi's disease associated with a chromosomal abnormality is described. This is the first report in the literature of such a case and it highlights an important learning point; benign lymphoproliferative conditions can be associated with chromosomal abnormalities that are more typically associated with malignant lymphoproliferative conditions such as malignant lymphoma. The report illustrates the necessity for interpreting cytogenetic data in the relevant clinical and histopathological context in a multidisciplinary setting to avoid misdiagnosis and inappropriate treatment.
Kikuchi's disease (KD) is a rare, benign, self‐limiting lymphoproliferative condition of unknown aetiology, characterised by acute or subacute necrotising lymphadenitis. It was first described in 1972 by Kikuchi1 and Fujimoto,2 and is synonymous with Kikuchi–Fujimoto disease, Kikuchi's necrotising lymphadenitis, Kikuchi's syndrome and necrotising lymphadenopathy without granulocytic infiltrations. The disease primarily affects the cervical lymph nodes in young women (female:male sex ratio is 3:1, with a mean age of around 30 years), and in approximately 50% of cases, the patient experiences a fever and a flu‐like illness. Extranodal manifestations such as cutaneous erruptions, hepatosplenomegaly and neurological involvement are rare. The disease process is self‐limiting, full resolution is usually seen within 2–3 months of diagnosis and relapses are rare.3,4,5 In this paper, we present what we believe to be the first reported case of KD associated with a cytogenetic abnormality, illustrating the importance of interpreting cytogenetic data from lymph node biopsies in the relevant clinical and histopathological context to avoid misdiagnosis.
A 20‐year‐old woman presented with painless axillary lymphadenopathy, weight loss and anorexia. On examination, she seemed clinically well, but had two firm, mobile, non‐tender lumps measuring 1.0 cm in the roof of her right axilla. No breast masses or evidence of infection in areas drained by the axillary nodes were detected. Supraclavicular/cervical lymphadenopathy and extranodal involvement were absent. Blood biochemistry and haematology were within the normal range. Fine‐needle aspiration cytology showed only reactive lymphoid hyperplasia. A review at 5 weeks detected an increase in the lymphadenopathy and a lymph node biopsy was carried out.
Histological examination showed a largely intact architecture with reactive lymphoid follicles in the cortical areas. Expansion of paracortical foci by large irregular aggregates of lymphoid cells was noted. Centrally, the aggregates contained abundant karyhorrhectic and apoptotic debris with foci of frank necrosis surrounded by a mixed population of histiocytes, immunoblast‐like cells and plasmacytoid monocytes (fig 1A1A).
Immunohistochemical examination showed the immunoblast‐like cells to be of T lineage (CD3 positive; fig 1B1B)) with expression of pan‐T cell antigens CD2, CD5 and CD7. Expression of CD8 was greater than that of CD4. Expression of CD30, CD56, EMA and ALK1 was absent. Epstein–Barr virus immunohistochemistry and in situ hybridisation for Epstein–Barr virus‐encoded RNA were negative. Histiocytes in the abnormal paracortical foci expressed CD68, MAC387 and were strongly positive for myeloperoxidase (fig 1C1C).). Polymerase chain reaction performed on DNA extracted from a sample of fresh nodal tissue showed polyclonal patterns of immunoglobulin heavy chain and T cell receptor γ gene rearrangement. Conventional cytogenetic analysis was performed on G‐banded preparations of cells mechanically disaggregated from the same fresh tissue. The resulting cell suspension was cultured overnight in the presence of colcemid (0.06 μg/ml) before harvesting by routine laboratory methods (30 min exposure to 0.075 M potassium chloride followed by fixation in 3:1 methanol:acetic acid). G‐banded preparations were analysed according to the International System of Cytogenetic Nomenclature (1995). The following abnormal karyotype was observed: 46,XX, t(2;16) (p11.2;p11.2)/46, XX (fig 22).). This was the sole abnormality detected. Subsequent cytogenetic analysis of a peripheral blood sample from the patient showed a normal female karyotype, ruling out the possibility of a constitutional abnormality.
On the basis of the histological and immunohistochemical findings alone, we were confident of the diagnosis of KD. However, the presence of a cytogenetic abnormality led us to seek a second opinion from an expert in the field, Dr John KC Chan, Queen Elizabeth Hospital, Hong Kong, who concurred with our diagnosis.
The patient received no specific treatment. The lymphadenopathy resolved spontaneously and she remains well 4 years after her initial presentation.
Histologically, Kikuchi's lymphadenitis is characterised by infiltration of the cortex or paracortex by numerous proliferating crescentic histiocytes, T immunoblasts, small lymphocytes and plasmacytoid monocytes, associated with total or partial necrosis of the affected node.4,5 The differential diagnosis is wide and varied, including systemic lupus erythematosus‐associated lymphadenopathy, herpes simplex‐associated lymphadenopathy, non‐Hodgkin's lymphoma, plasmacytoid T cell leukaemia, Kawasaki disease, nodal colonisation by acute myeloid leukaemia and infectious lymphadenitis.4,5
One of the most frequently reported misdiagnoses is that of malignant lymphoma.6 Pathological features that help in discriminating Kikuchi's lymphadenitis from lymphoma include the partial maintenance of lymph node architecture, the presence of small and large atypical lymphocytes, phagocytic histiocytes, extracellular debris and the absence of plasma cells, multinucleated giant cells and Reed–Sternberg cells.4,5,6 Myeloperoxidase expression in the histiocytic component of the infiltrate is also said to favour a diagnosis of KD.7 Conversely, chromosomal aberrations, particularly translocations, are often observed in malignant lymphoma but, to the best of our knowledge, have not been previously reported in Kikuchi's disease. Nevertheless, despite finding a t(2;16) in our case, we remain convinced that it represents a bona fide example of Kikuchi's disease in view of the typical pathological findings, the spontaneous resolution of symptoms and the fact that the patient remains free from disease 4 years after diagnosis. Moreover, although the presence of a cytogenetic aberration may be used to support the diagnosis of lymphoma, it should not be used as the sole determinant of malignancy as clonal cytogenetic abnormalities may also occur in reactive lymphoid hyperplasias.8
The aetiology of KD remains unknown, although infective and/or autoimmune causes have been postulated.4,5 The current case raises the additional intriguing possibility that some examples may be associated with a chromosomal translocation, and the lack of previous similar reports in the literature may simply reflect the fact that KD is a relatively rare condition, and that cytogenetic analysis is not routinely performed on lymph node biopsies in most laboratories. It is possible that the cytogenetic abnormality identified here is coincidental and not linked to the pathogenesis of the disease, perhaps occurring as a secondary phenomenon in rapidly proliferating cells within the necrotic foci. Alternatively, the chromosomal translocation may be linked to the pathogenesis of the disease. A search of the Mitleman database (http://cgap.nci.nih.gov/Chromosomes/Mitelman) shows only rare reports of balanced translocations involving the 2p11 and/or 16p11 loci, predominantly in cases of acute lymphoblastic leukaemia/lymphoma, incuding three cases with a t(2;16)(p11;p11), as well as occasional cases of B cell non‐Hodgkin's lymphoma and myeloid leukaemia, suggesting a role in the development of haematological neoplasms.9,10 Candidate genes at these loci include the immunoglobulin κ joining region, immunoglobulin κ variable region, granulysin (T lymphocyte activation gene 519) and latent transforming growth factor β binding protein 1 on chromosome 2p, and integrin α‐D, integrin α‐L, B cell chronic lymphocytic leukaemia/lymphoma 7C and interleukin 21 receptor on chromosome 16p. However, there are no reports of these genes being associated with KD, and further studies will be required to ascertain their significance in this disease.
In summary, this case report illustrates that Kikuchi's lymphadenitis can be associated with chromosomal abnormalities and great care should be taken when diagnosing malignant lymphoma on the basis of cytogenetics when the lymph node morphology and clinical features might also suggest Kikuchi's disease.
We thank Dr John KC Chan, Queen Elizabeth Hospital, Kowloon, Hong Kong, for reviewing the case. Dr Goodlad holds a part time Senior Clinical Research Fellowship in the Division of Pathology and Neuroscience, University of Dundee, funded by the Leng Charitable Trust at the Ninewells Cancer Campaign, Dundee, UK.
KD - Kikuchi's disease
Competing interests: None.