Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia/EH most commonly presents in young to middle-aged adults as single or multiple, nondescript, flesh- to plum-colored papules or nodules, ranging in size from a few to several centimeters.^1,3,4  This entity is a dermal and/or subcutaneous process. Although the head and neck region is most commonly involved, the trunk, extremities, hands, penis, oral mucosa, and colon may rarely be affected.^1,3–7  There appears to be a predilection for women, although some have reported a male preponderance.^1,3,4  However, the male sex bias in 2 of the studies from the former Armed Forces Institute of Pathology^2,3  is attributable to the large number of cases from military and Veterans Health Administration hospitals, where the patient population is predominantly male. Indeed, Olsen and Helwig³  found that 62% of the civilian cases in their study involved females. The length of time from onset of lesions to initial medical consultation has ranged from a few months to many years. There are usually no associated symptoms. However, owing mainly to the vascular nature of the lesions, tenderness, pulsation, pruritus, or bleeding, either spontaneously or after minor trauma, may occur in some patients.^1,3,4  Peripheral blood eosinophilia and regional lymphadenopathy may also be present.^1,3,4 

The etiology of ALHE/EH is currently unknown. Various hypotheses have been put forth, including a reactive process,^3,4,8,9  a neoplastic process,^7,10,11  and infectious mechanisms with possible association with human immunodeficiency virus¹² ; however, none have proven to be conclusive or definitive.

The characteristic inflammatory infiltrate in ALHE/EH appears to be a key component of this disease; however, its role in the etiology of ALHE/EH needs further clarification. Response of the endothelial cells to proliferative stimuli generated by the accompanying inflammatory cells and immunologic allergic reaction may account for the vascular proliferation.^3,9  Arteriovenous shunting,^3,8  local trauma,^4,9  and elevated serum estrogen levels^3,13  are probably important contributing factors in ALHE/EH as well.

Interestingly, a case of dermal ALHE/EH was found to harbor a mutation in the TEK gene, which encodes the endothelial cell tyrosine kinase receptor Tie-2, indicating that certain molecular alterations might be contributory to the pathogenesis of this entity.¹⁴  A larger-scale study will be necessary to further elucidate the molecular pathomechanisms underlying ALHE/EH.

Although considered a benign tumefaction, ALHE/HE has been associated with various lymphoproliferative conditions, supporting the contention made by some that ALHE/EH, in some cases, may represent a monoclonal T-cell process.^10,11  A few cases of ALHE/EH were found to have concurrent follicular mucinosis.¹⁵  However, this association is rather nonspecific, and a definitive association between ALHE/EH and mycosis fungoides has yet to be reported. Interestingly, peripheral T-cell lymphoma has been reported to develop in a patient with ALHE/EH.¹⁶  There are also cases of ALHE/EH in which T-cell receptor gene (TCR) rearrangement and monoclonality have been detected.^10,11  For example, in 1 of the aforementioned case reports, the patient had both peripheral T-cell lymphoma (axillary node) and ALHE/HE (temporal nodule), and the same monoclonal TCR gene rearrangement was detected in both lesions.¹¹ 

Central to the histology of ALHE/EH is the proliferation of blood vessels of varying sizes lined by plump endothelial cells.^1,3,4  These histiocytoid endothelial cells are enlarged, with abundant eosinophilic or clear cytoplasm and large vesicular nuclei (Figure 1). The cells are mostly cuboidal with occasional “hobnailing” (Figure 2, a), which is related to the presence of cytoplasmic vacuoles in these cells, causing cytoplasmic protrusion into lumina (Figure 2, b). The endothelial and inflammatory cells in ALHE/EH are typically bland. Mitoses are rare, if at all present. A case that contained multinucleated giant cells has been reported but the significance of this finding is not known.¹⁷ 

Inflammation is the second defining characteristic of ALHE/EH.^1,3,4  Lymphocytes and varying amounts of eosinophils diffusely surround and may infiltrate the blood vessels (Figures 1 and 2). The lymphocytes may be diffusely present or may form distinct follicles with germinal centers. It should be noted that approximately 20% of the patients have blood eosinophilia without elevation of immunoglobulin E (IgE) levels.³  An accompanying fibrous stromal reaction is generally present.

Depending on the age of the lesion, the vascular or inflammatory component may predominate. In early or actively growing ALHE/EH, the vascular component predominates, whereas in late stages of the disease lymphocytes become more prominent. The vessels in early ALHE/EH are immature with prominent epithelioid endothelial cells, whereas in the later stage when the lymphoid infiltrate predominates, the endothelial cells lining the maturing vessels become smaller and less epithelioid.^3,4 

Angiolymphoid hyperplasia with eosinophilia/EH is typically an intradermal or subcutaneous process, with primary or secondary involvement of the latter being more common.^1,3,4  Peculiar to the subcutaneous form of ALHE/EH is the florid proliferation of large epithelioid endothelial cells that may become so exuberant as to form solid intraluminal nodules or clusters. Thus, subcutaneous ALHE/EH may be treacherous and challenging to diagnose in that these masses may obscure the vascular nature of the lesion. By contrast, dermal ALHE/EH tends to be less circumscribed, smaller, and composed of more mature open vessels lined by smaller, less epithelioid endothelial cells.^1,3,4 

The histologic features of ALHE/EH are relatively distinct. The major differential diagnosis lies between ALHE/EH and Kimura disease. In the past, ALHE/EH and Kimura disease were thought to be the same entity. It has been found, however, that ALHE/EH is actually clinically and pathologically distinct from Kimura disease. The typical presentation of Kimura disease is that of a large subcutaneous mass in the periauricular or submandibular region of a young Asian male.¹⁸  Moreover, Kimura disease is a systemic immune-mediated process that commonly presents with lymphadenopathy, eosinophilia, increased serum levels of IgE, and may be associated with renal disease.¹⁹  Histologically, florid lymphoid follicles with germinal center formation, eosinophilic infiltrates, eosinophilic microabscesses, and eosinophilic folliculolysis are salient features of Kimura disease. In addition, the process does not have the histiocytoid/epithelioid cells that are characteristic of ALHE/EH.^18,20 

Angiolymphoid hyperplasia with eosinophilia/EH must also be differentiated from angiosarcoma, particularly the latter's epithelioid variant, and from epithelioid hemangioendothelioma. Angiosarcoma is distinguished from ALHE/EH by its unmistakable atypical appearance with nuclear hyperchromasia, pleomorphism and brisk mitotic activity, and the prominent formation of anastomosing vascular channels.^3,21  Epithelioid hemangioendothelioma, on the other hand, is differentiated from ALHE/EH by the presence of vacuolated endothelial cells growing singly or in linear streaks or cords separated by a myxohyaline stroma, and lack of lymphoid or eosinophilic inflammatory infiltration.^1,3,4 

Clinically, the nodule of ALHE/EH can be very similar to that of Kaposi sarcoma and pyogenic granuloma. However, the distinctions of histopathologic features among the above entities are usually dramatic. Kaposi sarcoma is composed of fusiform cells and slitlike vascular spaces that stain positively with human herpes virus-8 (HHV-8).^3,22  Pyogenic granuloma consists of tight aggregates of capillary-sized vessels that grow in a lobulated fashion in a fibromyxoid (granulation tissue–like) stroma.^3,4,22,23 

Surgical excision is the treatment of choice and when completely excised, ALHE/EH rarely recurs.^3,4,22,24  One-third of cases that are incompletely excised do recur, either at the same site or distant from it, but still typically along the course of the affected vessel.^3,4,24  Other types of procedures, such as Mohs micrographic surgery,²⁵  pulsed-dye laser,²⁶  carbon dioxide laser,²⁷  and cryosurgery,²⁸  have been applied and reported. Medical treatment of ALHE/EH with conventional intralesional corticosteroids and irradiation is generally not very effective.^29,30  New regimens have been extensively investigated and have shown promising results, including topical imiquimod, tacrolimus, isotretinoin, and interferon α-2a.^31–34 

Concerning the prognosis of ALHE/EH, it tends to persist for years without regressing spontaneously except for occasional cases, which makes surgical or medical intervention necessary in most cases.^3,4,24 

Angiolymphoid hyperplasia with eosinophilia/EH is an uncommon idiopathic lesion characterized by proliferation of histiocytoid endothelial cells with lymphoid and eosinophilic inflammatory infiltration. Histologically, it shows some overlapping features with several other types of dermatologic vascular lesions, especially Kimura disease, and the pathologic differential diagnosis for this condition is important. Clinically, ALHE/EH follows a benign clinical course, with no metastases reported thus far, and with only one-third of cases recurring when incompletely excised. Multiple other treatments have been applied for ALHE/EH with undetermined effects.

We would like to sincerely thank Elizebeth Gillies, MD, for providing the sample case we used, and for helping with the critical revision of this manuscript.