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Angiolymphoid hyperplasia with eosinophila and kimura disease: Dupilumab beckons

DII small banner By Warren R. Heymann, MD
April 10, 2017

Kimura Disease
Histopathologic features of Kimura's disease. A, Scanning view shows prominent germinal center formation. B, Higher magnification of a germinal center with abundant number of eosinophils. C, Focally, blood vessels may show prominent endothelial cells with vacuolated cytoplasm. (A-C, Hematoxylin-eosin stain; original magnifications: A, ¥10; B, ¥100; C, ¥400.)
Credit: JAAD

Controversy should be the middle name for angiolymphoid hyperplasia with eosinophilia (ALHE) and Kimura disease (KD). Throughout my career, I have read about these diseases, wondering why they were initially considered related entities but now viewed as distinct.

ALHE commonly presents in young to middle-aged adults as single or multiple, flesh-to-plum colored papules or nodules, predominantly on the head and neck. Lesions are usually asymptomatic, although tenderness, pulsations, pruritus, or bleeding may be noted. Histologically, histiocytoid endothelial cells, with prominent lymphocytic and eosinophilic infiltration, are observed. Peripheral eosinophilia and regional lymphadenopathy may be present (1).

KD is endemic in Asia, although cases have also been reported in Europe and America. It is a benign rare chronic inflammatory disorder characterized by generalized lymphadenopathy in the head and neck region. The nodes appear as one or several deep, non-tender and poorly circumscribed masses. Patients are usually young Asian men, and sometimes present with pruritic skin lesions; kidney involvement is often observed, and some patients may have albuminuria. Peripheral eosinophilia and elevated serum IgE are characteristic (2). Histologically florid lymphoid follicles with germinal center formation and eosinophilic infiltrates are appreciated. KD does not display the histiocytoid endothelial cells characteristic of ALHE (1).
The pathogenesis of both disorders is unknown. A long-standing question regarding ALHE is whether it is a neoplastic or reactive process (to arteriovenous shunts, infection, or trauma). The latest literature favors the latter. Fernandez-Flores and Cassarino detail 3 unusual cases of ALHE associated with chronic lymphocytic leukemia, syringocystedenoma papilliferum, and IgG4-related disease, respectively (3). Trauma may certainly incite ALHE, an example being those of earlobe lesions in a 15-year-old girl who had her ears pierced (4). KD is presumably a manifestation of immunodysregulation with excess IL-4, IL-5, IgE, and eosinophilia. It is speculated that this may be due to an anti-parasitic response (2).

I understand the broad differences, but I still suspect that ALHE and KD are fundamentally related, and exist as part of a spectrum. Of interest is the case of a 40-year-old Chinese woman who presented with a right postauricular subcutaneous swelling and subsequently developed multiple erythematous facial papules and nodules. Histopathological examinations of these lesions helped to confirm the diagnosis of KD and ALHE, respectively (5).

How many misdiagnosed cases of either AHLE or KD exist? I had been following a woman for years with a presumptive diagnosis of KD for years; this was manifested by persistent eosinophilia and eosinophil-infiltrating nodules of the skin, throat, and lymph nodes.  Only systemic steroids and surgical excision of large nodules would benefit her. She was found to have a somatic gain-of-function mutation in STAT3 (p.Y640F, c.1919A>T) in the CD3−CD4+ T cell, confirming the diagnosis of the lymphocytic variant of the hypereosinophilic syndrome (6). (I take no credit for this diagnosis. Years ago, I referred her to Dr. Eric Vonderheid to make sure she did not have a lymphoma. One day, I received a call from Eric, who I assumed was happily retired on a golf course in Arizona, informing me that he gave his patients’ samples to Dr. Jaehyuk Choi, who was then at Yale, but has since moved to Northwestern. Dr. Choi came to my office, met with my patient, drew her blood, and the rest is hypereosinophilic syndrome history).

Therapeutic options for both conditions are suboptimal. Adler et al, in a systematic review of 416 studies of ALHE concluded that surgical excision appears to be the most effective treatment, despite a 40% recurrence rate; pulsed dye and other lasers may be options (7). The list of treatments reported is long, including bevacizumab, methotrexate, and propranolol (8) among others. For KD, surgery and steroids are first-line, although radiation and cytotoxic agents have been utilized (2).

Dupilumab (Dupixent), the anti-IL-4/IL-13 antibody has just been released for atopic dermatitis. From my perspective, it makes perfect sense to try it for KD and recalcitrant cases of ALHE. To date there are no such reports utilizing dupilumab for these entities. It beckons – you heard it here first.

1. Guo R, Gavino ACP. Angiolymphoid hyperplasia with eosinophilia. Arch Pathol Lab Med; 2015; 139: 683-6.
2. Carretero RG, et al. Eosinophilia and multiple lymphadenopathy: Kimura disease, a rare, but benign condition. BMJ Case Reports 2016; doi:10.1136/bcr-2015-214211.
3. Fernandez-Flores A, Cassarino DS. Three unusual histopathological presentations of angiolymphoid hyperplasia with eosinophilia. J Cutan Pathol 2017; 44: 300-6.
4. Okman JS, et al. Angiolymphoid hyperplasia with eosinophilia: A previously unreported complication of ear piercing. Pediatr Dermatol 2014; 31: 738-41.
5. Chong WS, et al. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: two disease entities in the same patient: Case report and review of the literature. Int J Dermatol 2006; 45: 139-45.
6. Walker S, et al. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Blood 2016; 127: 948-51.
7. Adler BA, et al. Epidemiology and treatment of angiolymphoid hyperplasia with eosinophilia (ALHE): A systematic review. J Am Acad Dermatol 2016; 74: 506-12.
8. McClintic EA, et al. Oral propranolol as an alternative for orbital angiolymphoid hyperplasia with eosinophilia. Ophthal Plast Reconstr Surg 2016; 32: e139-40.

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