Enigmatic Kikuchi-Fujimoto Disease: A Comprehensive Review

Xavier Bosch, MD; Antonio Guilabert, MD; Rosa Miquel, MD; Elias Campo, MD


Am J Clin Pathol. 2004;122(1) 

In This Article

Differential Diagnosis

Although KFD is considered uncommon, at least in Western countries, this disorder must be included in the differential diagnosis of "lymph node enlargement" because its course and treatment differ dramatically from those of lymphoma, tuberculosis, and SLE. The histologic differential diagnosis of KFD includes mainly reactive lesions such as lymphadenitis associated with SLE, lymphadenitis associated with herpes simplex and other microorganisms, non-Hodgkin lymphoma, plasmacytoid T-cell leukemia, Kawasaki disease, nodal colonization by acute myeloid leukemia, and even metastatic adenocarcinoma. ( Table 2 ) provides clues to the differential diagnosis of KFD.[1,2,16,17,18,20,49,102,103]

SLE can be associated with lymphadenitis characterized by prominent foci of necrosis, mimicking the necrotizing type of KFD. Features that can be seen in SLE-associated lymphadenitis but not in KFD include hematoxylin-bodies, believed to represent degenerated nuclei that have reacted with antinuclear antibodies, and the Azzopardi phenomenon (ie, encrustation of blood vessel walls with nuclear material). Moreover, the finding of sparse cytotoxic T cells seems to tip the balance in favor of SLE-associated lymphadenitis, in contrast with the CD8+ lymphocyte abundance seen in lymph nodes in KFD.[78] These striking features might not be identified in every case of SLE-associated lymphadenitis, however, and the diagnosis cannot always be ruled out on histologic grounds alone.[16,17,18] Nevertheless, even though there is little information in the literature about lupus-associated lymphadenitis, its immunophenotype seems to be virtually identical to that of KFD, including the CD68+/MPO+ histiocytic pattern.[18,49] Finally, the presence of a large number of plasma cells in a given lymph node with features resembling those of KFD favors SLE-associated lymphadenitis over KFD.[20]

Herpes simplex-associated lymphadenitis can be characterized by histiocytic infiltrates and necrotic debris, findings that otherwise are characteristic of KFD. Yet, the histiocytic infiltrate usually is less striking than that in KFD, neutrophils often are observed, and the finding of viral inclusions confirms the diagnosis of herpes simplex-associated lymphadenitis. The immunophenotype of KFD might be similar to that of a viral lymphadenitis, but the findings in the latter are not specific.[18] Histiocytes from herpes simplex-associated lymphadenopathy and other nonspecific reactive or granulomatous lymphadenopathies are MPO-, in contrast with the histiocytes in KFD, which are MPO+.[49]

Recognition of KFD is crucial, especially because it can be mistaken for malignant lymphoma.[1,16,17,18] The case of a patient misdiagnosed as having large-cell lymphoma and subjected to 1 course of cytotoxic therapy before histologic sections were submitted to an expert pathologist in consultation was mentioned in an editorial in 1987.[1] In fact, numerous immunoblasts can be found in tissue specimens from patients with KFD, raising the question of diffuse large-cell lymphoma. The common presence of atypia in the immunoblasts and their occasional occurrence in clusters and sheets might lead the unwary to an erroneous diagnosis of malignant lymphoma. This impression might be reinforced further by the admixed histiocytes with twisted nuclei, which can be misinterpreted as atypical lymphoid cells. The histiocytes, however, can be distinguished from lymphoid cells by their delicate nuclear membrane. In addition, polymerase chain reaction for T-cell gene rearrangement might be useful for differentiating KFD from peripheral T-cell lymphoma. In any case, the polymorphous background and mixture of histiocytes (which, peculiarly, are MPO+/CD68+,[49] in contrast with the MPO- staining of the histiocytes from malignant lymphoma) would be exceptional findings in this hematologic neoplasm. In countries in the Western hemisphere, most lymphomas are of B-cell lineage, and among T-cell lymphomas, CD4 expression is more common than CD8, whereas a predominance of CD8 positivity is characteristic of KFD.[18] Plasmacytoid cells also can facilitate a clear distinction of KFD, especially in the early stages of the disease, from a large cell or high-grade lymphoma.[47] Likewise, histologic findings of skin lesions from patients with KFD can mimic cutaneous malignant T-cell lymphoma.

Plasmacytoid T-cell leukemia-the so-called plasmacytoid monocyte tumor-is a rare clinicopathologic entity, mostly described in elderly men, which is characterized clinically by lymphadenopathy, hepatosplenomegaly, and weight loss. Affected lymph nodes display T-zone expansion by plasmacytoid-like cells, later developing acute or chronic myelomonocytic leukemia. Ruling out this condition can be straightforward because proliferative plasmacytoid cells do not express MPO, in contrast with the varied KFD histiocytic component that is strikingly MPO+.[49,51,104]

Because KFD might be associated with histiocytes resembling signet-ring cells, the so-called signet-ring histiocytes, the diagnosis of metastatic adenocarcinoma occasionally, although rarely, is considered.[16,18] Distinguishing these cells from signet-ring carcinoma cells can be a diagnostic challenge. However, metastatic adenocarcinoma is composed of cells with atypical nuclei and that contain mucin rather than cellular debris.

The histologic and immunohistochemical diagnostic challenges of KFD have been evidenced in a series of 25 patients studied initially by referring pathologists in the United Kingdom.[105] The diagnosis of KFD was suspected by the referring pathologist in only 3 cases. The most common suggested diagnosis was non-Hodgkin lymphoma.


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