Final Diagnosis -- Histiocytic Necrotizing Lymphadenitis




In 1972 Kikuchi described the clinical and histologic features of a lymph node disease which he termed "lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytosis" (1,23). Fujimoto et. al. simultaneously and independently described the same disorder which they termed " cervical subacute necrotizing lymphadenitis" (1,24).

Since then many designations have been applied to this benign clinicopathologic entity, that is most commonly referred to as 'histiocytic necrotizing lymphadenitis'(HNL), 'Kikuchi's disease' or 'Kikuchi-Fujimoto disease'(KFD).Approximately 10 years after the initial reports from Japan, KFD was also described in western countries (10) including the US. Since then it has been described worldwide.

KFD affects a wide age range from 9 (2) to 75 (1) years with a mean age in the third decade (1,2). Females are more commonly affected with a F:M ratio of 1.1-4:1(1,2,5). The disease appears to affect all races(1), but has been reported more commonly in Asians (2,5).

KFD most often presents as adenopathy at a single site, predominantly in the cervical region but may also affect other, and multiple, lymph node regions including axillary, supraclavicular, mediastinal, inguinal, intraparotid, iliac, celiac and peripancreatic groups (1). Tenderness may be present. Generalized lymphadenopathy has also been reported (2). KFD has also been described in the skin (6,11,15). Fever is present in 33% - 50% (1,10) of cases. Other symptoms may include diarrhea, chills, sweats , nausea, vomiting, chest pain, abdominal pain and skin rash (1). Time from onset of symptoms to diagnosis range from 1 to 24 months (1). Splenomegaly and hepatomegaly is found in a minority of cases (1,10). Leukopenia is seen in 25% - 43% (2,10), leukocytosis in 2.9% - 5% (2,10) and atypical lymphocytosis in 25% (2).

Excised lymph nodes range, in greatest dimension, from 0.5 to 7 cm. (2) but averaged 1 to 2 cm. (1,2). Some authors (5,18) have noted fragmentation of the biopsies on handling.

Low power histologic examination demonstrates solitary or multiple, round to irregular, patchy circumscribed but sometimes coalescing, pale nodular foci with karyorrhectic debris, predominantly in the paracortical areas. The degree of nodal involvement is variable, but 50% or greater is seen in a majority of cases (5). The pale nodules are composed of histiocytic cells; small lymphocytes and some immunoblasts intermixed with eosinophilic granular debris and basophilic karyorrhectic debris (5). The majority of cells is histiocytic and may be phagocytic or non-phagocytic. Phagocytic histiocytes with a peripheral, thin compressed nucleus have been designated 'crescentic histiocytes' by Tsang et. al. (5). Other histiocytes with central irregular nuclei are also present. Foamy histiocytes and signet ring histiocytes are also described (5). A characteristic, cellular component is the plasmacytoid monocytes. These are medium sized cells with a round eccentric nucleus, inconspicuous nucleolus and moderate amounts of amphophilic cytoplasm(5). They are intermixed with the small lymphocytes, immunoblasts, histiocytes and apoptotic cells(5). Larger foci may demonstrate zonation with central coagulative necrosis with karyorrhectic debris (1,5), an intermediate zone of immunoblasts, plasmacytoid monocytes, histiocytes and debris; and an outermost zone of lymphocyte, immunoblasts and rare histiocytes (5). Plasmacytoid monocytes may also be seen in the subcapsular and interfollicular regions (8). The plasmacytoid monocytes express CD38 ( distributed in plasma cells, thymocytes and activated lymphocytes), LN 1 ( seen in follicle centre cells and erythroid cells) and CD4 antigens in addition to regular monocyte/macrophage antigens (8). It is uncertain whether these cells may transform into the numerous histiocytes seen in KFD (5).

It is postulated that the plasmacytoid monocytes play a role in the pathogenesis of KFD via a cell mediated cytotoxic immune response. Immunoblasts are present in variable numbers and frequently demonstrate atypical nuclear features and occasionally occur in clusters or sheets(5). They have an almost exclusive T cell phenotype(5,8) as do the majority of small lymphoid cells within the necrotic foci. CD8 positive cells increase with duration of disease (2,14). Cytolytic T cell mediated apoptosis is a suggested mechanism of cellular destruction (16). TIA 1 (cytolytic granule protein) positive lymphocytes are numerous in areas of necrosis but rare in unaffected areas (16). TIA 1 positive granules are also present in the apoptotic cells (16). BCL 2 and p53 do not appear to play a significant role (16).

The necrotic foci contain few CD20 positive B cells and plasma cells are scanty or absent. Neutrophils are characteristically absent leading to the designation by Pileri et. al. of "histiocytic necrotizing lymphadenitis without granulocytic infiltration" (10). Reactive follicular hyperplasia may be seen (13). An organizing phase of KFD, after the karyorrhectic process wanes, has been postulated (5) but not described. Ultrastructural studies demonstrate the population of cells seen by light microscopy (17). Cytoplasmic tubuloreticular structures resembling viral particles or aberrant organelle structures have been identified, by electron microscopy, in small lymphocytes, transformed cells, macrophages, and endothelial cells (4,7,17).

A viral etiology [Epstein-Barr virus , human herpes virus 6 (3,12,16) and parvovirus B19 (21)]for KFD has been proposed but not proven. Other suggested viruses include cytomegalovirus , herpes simplex virus, human herpes virus type 8 and adenovirus (16). Yersinia and toxoplasma have also been considered as potential etiologic agents.

In a small number of cases systemic lupus erythematosus (SLE) is diagnosed either simultaneously or subsequently (1,9,19,20). This association suggests an autoimmune mechanism for KFD. Some authors have considered KFD to be a forme fruste for SLE. However this remains unproved, and the majority of patients with KFD do not develop SLE (16).

The distinction between SLE and KFD is important since they have differing treatments and prognosis; however they are sometimes indistinguishable. The presence of more numerous plasma cells, hematoxyphilic bodies, deposition of DNA on vessel walls and neutrophilic infiltration favor SLE lymphadenitis. Extensive acellular coagulative necrosis with nuclear dust also suggests SLE. Whenever a diagnosis of KFD is made it may be prudent to rule out the possibility of SLE (1).

Approximately 30 % of KFD are mistaken for malignant lymphoma (1), an obviously important distinction. Karyorrhexis can be seen in high grade lymphomas, and the presence of immunoblastic cells and atypical histiocytes with irregular nuclei may confuse the picture, adding to the diagnostic difficulty. However, the monotonous population of cells seen in high-grade lymphomas, such as Burkitt lymphoma, is never seen in KFD. Kawasaki's disease, Hodgkin's lymphoma, Yersinia infection, cat scratch disease, toxoplasma lymphadenitis, infectious mononucleosis, metastatic carcinoma and lymph node infarction are all included in the differential diagnosis.

KFD is a benign self-limited disease with no specific treatment (22), however, patients should be followed for recurrence which occurs in approximately 3% of cases (2,5). The development of SLE should also be considered.


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Contributed by Rajendra Persad, MBBS, Lydia C. Contis, MD and Steven H. Swerdlow, MD


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