October 2009
Written by Angie Duong, M.D., 3rd year resident in Pathology at the Medical University of South Carolina, Charleston, South Carolina.

Submitting Pathologist
Jared Block, M.D., Carolinas Medical Center-University, Charlotte, North Carolina.

Diagnosis
Kimura Lymphadenopathy

Case History
The patient is an 8 year old Caucasian male who presented with bilateral postauricular masses.

Microscopy
Best appreciated at low power, the lymph node architecture is largely intact. Some hyperplastic follicles with prominent germinal centers are easily identified (see Figure 1).

Closer examination reveals an eosinophilic abscess (top left corner, Figure 2). Additionally, hyperplastic postcapillary venules (bottom right corner, Figure 2) and polykaryotic cells (arrow, Figure 2) are features that help to make this diagnosis. The inset in Figure 2 is a higher magnification view of a polykaryotic cell (Giemsa stain).

Ancillary Studies
Paraffin section immunohistochemistry (IHC) of the lymph node for CD35 and CD3 were used as confirmatory tests. The CD35 not only highlights the dendritic cell network of the follicle center, but also positively stains the polykaryotic cells (yellow arrows, Figure 3). The CD3 study identifies T-cells scattered throughout the germinal center. Note that the polykaryotic cells are themselves negative for CD3 (red arrow).

Discussion
Kimura disease is a localized chronic inflammatory disorder typically involving subcutaneous tissues of the head and neck, often with associated lymphadenopathy (2). While areas of the head and neck are most commonly affected (postauricular, preauricular, cervical, and salivary gland), case reports of Kimura disease have described involvement of several other sites, including the inguinal and axillary lymph nodes. Most cases are unilateral, but a significant number of cases (up to 40%) can be bilateral/multifocal. Although most frequently encountered in Asian regions, such as China and Taiwan, sporadic cases have been reported world-wide in diverse ethnicities. Kimura disease occurs more often in men. The age range for Kimura disease extends from childhood up to the late 60s, but most often patients are in their third or fourth decade (1). Peripheral blood eosinophilia and increased serum IgE is associated with the disease, with the latter causing nephrotic syndrome in some patients (3). In fact, in this case the patient has been found to have proteinuria and is being further evaluated for renal disease. The cause of this disorder is unknown. Several studies attempting to associate Kimura disease with a specific infectious agent have been unsuccessful (3).

Kimura lymphadenopathy has a unique histopathology. Overall, the lymph node architecture remains intact with large hyperplastic follicles. The lymph node capsule can be thickened. At higher magnification, an increase in the number of eosinophils is easily seen. Eosinophils accumulate in both the follicles and interfollicular areas and can form eosinophilic abscesses. Also, eosinophils can appear to "invade" the follicles, giving the appearance of folliculolysis. In a few cases, Charcot-Leyden-like crystals can be identified. Aside from the eosinophilia, the other characteristic finding in Kimura’s disease is proliferation of postcapillary venules. This is most easily identified in the mantle zone of the lymphoid follicles (1-3). The vessels can show some sclerotic change (2). T-cells and mast cells are increased in Kimura’s lymphadenopathy. The T-cells are concentrated in the paracortex but less densely populated follicle centers as well. The T-cells are usually polyclonal, but a single case has been reported with demonstrated T-cell clonality (3). The increased mast cells are associated with increased serum IgE (1-3). Polykaryotic cells of Warthin-Finkeldey type can be seen in some cases of Kimura's disease, located in the follicles and the interfollicular areas. These multinucleated cells have overlapping nuclei, resembling a bunch of grapes. The origin of these polykaryotic cells has earlier been the subject of debate, with some believing them to be of T-cell origin while others believed them to be polykaryotic forms of follicular dendritic cells (2, 3). In our case, we performed a CD35 immunohistochemical stain which highlighted the polykaryotic cells, supporting the hypothesis that these cells are of follicular dendritic cell origin. Interestingly, while these cells were negative for CD3 staining they showed a close relationship with surrounding T-cells.

Since Kimura disease has such a unique histological appearance, immunohistochemical stains are usually unnecessary for establishing the diagnosis. IgE immunofluorescence or immunohistochemical stain can be used to identify deposits of IgE in the germinal centers. A factor VIII immunohistochemical stain would highlight the vascular proliferation (2).

The major differential diagnosis in relation to Kimura disease concerns angiolymphoid hyperplasia with eosinophilia (ALHE). Due to their overlapping microscopic features, ALHE was considered at one time to be an early form of Kimura disease and for some time these two terms were interchangeable (1). However, AHLE is usually seen in Caucasian females and is histologically characterized by hypertrophic endothelial cells protruding into and occluding vessels. Additionally, no lymphadenopathy is associated with AHLE (2). Most authorities on the subject now consider ALHE to be a variant of epithelioid angioma (4).

Kimura disease is usually a self-limited event, but some cases can wax and wane over several years. While surgical removal of the lesion is the mainstay of treatment, corticosteroids, cytotoxic therapy, and radiation can also be used effectively. One reference reported that recurrence can be prevented with radiation therapy (1).

References

1. Chen H, Thompson LD, Aguilera NS, Abbondanzo SL.
   Kimura disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2004; 28: 505-513.
2. Ioachim H and Medeiros LJ.
   Kimura Lymphadenopathy. Pp. 190-192, in Ioachim’s Lymph Node Pathology. 4th ed. Baltimore, Ioachim H, Medeiros LJ, eds., Lippincott Williams & Wilkins, 2009
3. O'Malley DP, George TI, Orazi A, and Abbondanzo SL.
   Kimura disease. Pp. 145-148, in Atlas of Nontumor Pathology: Benign and Reactive Conditions of the Lymph Node and Spleen. 1st ed. Washington, DC: American Registry of Pathology, 2009.
4. Rosai J.
   Angiolymphoid hyperplasia with eosinophilia of the skin. Its nosological position in the spectrum of histiocytoid hemangioma. Am J Dermatopathol. 1982; 4: 175-184.

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