Dermatology Online Journal

Angiolymphoid hyperplasia with eosinophilia: A study of 7 cases
I Zaraa¹, M Mlika², S Chouk¹, I Chelly², M Mokni¹, M Zitouna², A Ben Osman¹
Dermatology Online Journal 17 (2): 1

1. Department of Dermatology
2. Department of Pathology
La Rabta Hospital, Tunis, Tunisia. inesrania@myway.com

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Abstract

INTRODUCTION: Angiolymphoid hyperplasia with eosinophilia (ALHE) is a benign vasoproliferative disease of undetermined origin. It is characterized by the presence of nodular pseudo-tumors corresponding microscopically to a vascular proliferation within an inflammatory infiltrate made up of lymphocytes, macrophages, and eosinophils. The authors describe 7 cases of ALHE.

METHODS: The 7 cases were diagnosed over a period of 19 years (1990–2008). Clinical data and histological slides were brought from the departments of dermatology and pathology of the Rabta Hospital.

RESULTS: The 7 patients were 4 women and 3 men with an average age of 34.5 years. The cephalic localization was the most frequent. Lesions were solitary or multiple and formed papules or plaques of variable color. The diagnosis was based in all cases on histological findings.

DISCUSSION: The main disease in the differential diagnosis of ALHE is Kimura disease, but the 2 entities have several clinical and histological differences. The pathogenesis remains unclear and there is no consensus on the best treatment.

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Introduction

Angiolymphoid hyperplasia with eosinophilia (ALHE) was initially described by Wells and Whimster in 1969 [1]. It is a benign vasoproliferative entity with an undetermined pathogenesis. ALHE and Kimura disease were initially described as 2 forms of a single disease but they are now considered as 2 distinct entities belonging to the group of eosinophilic dermatoses [2, 3, 4, 5, 6]. The aim of this work is to describe the clinical and histological characteristics of ALHE.

Methods

The authors present 7 cases of ALHE diagnosed over a 19 year period (1990–2008). For all patients, clinical data, histological findings, therapeutic modalities and evolution of the lesions were specified.

Results

Seven cases with ALHE were studied; the different findings are summarized in Table 1.

Figure 1	Figure 2
Figure 1. Angiomatous papules and nodules of the vertex Figure 2. Multiple retro-auricular angiomatous nodules with a regular surface

We present 4 women and 3 men with an average age of 34.5 years (10–75 years). The median period of duration of the symptoms was 3.65 years (3 weeks–10 years). Cranial localization was the most frequent, found in 5 cases (Figure 1). The lesions were multiple in 5 patients (Figure 2). Pruritus was the most frequent presenting symptom. No lymph node enlargement was found.

Figure 3	Figure 4
Figure 3. Angiolymphoid hyperplasia with vascular proliferation (H&E, x40) Figure 4. Angiolymphoid hyperplasia with lymphoid follicles (H&E, x60)

Microscopic examination showed a circumscribed proliferation in the dermis and hypodermis with a combined vascular and inflammatory component. This proliferation was surrounded by an inflammatory infiltrate forming lymphoid follicles (in 3 cases), histiocytes, mastocytes, and eosinophils (Figure 3). There were arborizing small blood vessels lined by endothelial cells with a distinct eosinophilic or epithelioid cytoplasm (Figure 4). No fibrosis was noted. Immunohistochemical study was performed in one case and showed a strong expression of CD34 by the tumor cells, confirming their vascular nature.

Peripheral eosinophilia was not noted in any patient. Serum immunoglobulin E level was normal.

Treatment modalities were specified in 3 patients: the first one received a topical corticosteroids (clobetasol propionate) and produced flattening and decrease in the lesions (Case Number 1). A surgical excision was performed in the second case. Finally, the third case was treated by cryotherapy; there was significant improvement of the symptoms and appearance within 10 cycles of treatment (Case Number 7). A spontaneous improvement of the lesions was observed in patient Number 4. The median of the follow up period was 9 months. The improvements achieved by the various treatments were maintained over this time. Three patients were lost to follow-up.

Discussion

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a benign inflammatory vascular disease characterized by endothelial abnormalities. It occurs in many countries, with an undetermined frequency [2, 3, 4, 5, 6]. The seven cases described in this study were diagnosed over a 19 year period, putting emphasis on the rarity of the disease. Young patients are most frequently involved with a median age varying from the second to the fourth decade. Cases described in children and elderly patients are rare. A female predominance was noted [3, 4, 5, 6]. In this study, a mild female predominance was also noted. According to the previous reports the median age of the patients was 34.5 years (10–75 years). Two cases were described in children aged 10 and 16 years.

The presenting appearance may be non-specific, leading to a delay in the diagnosis reaching 10 years in one case. Cutaneous lesions consist of red papules or persistent subcutaneous nodules, varying from 0.2 to 10 cm [2, 3, 4, 5, 6]. The main entities in the differential diagnosis are Kimura disease, Kaposi sarcoma, pyogenic granuloma, or cutaneous metastases [2, 3, 4, 5, 6].

Generally, cutaneous lesions are solitary, but multiple ones are reported in 20 percent of the cases [2, 3, 4, 5, 6]. In this study, 4 patients presented with more than 2 lesions. These lesions were mainly located in the head and neck [2, 3, 4, 5, 6]. Other rare locations were described such as the trunk or the distal extremities [2, 3, 4, 5, 6]. In this study, the growths were mainly located in the cephalic region. Exceptionally, extra-cutaneous locations have been described, including oral, genital, or colonic mucosa [7, 8]. Generally, cutaneous lesions are asymptomatic but they may be pruritic, painful, or hemorrhagic [3, 4]. Among our patients, 5 were asymptomatic, one noted itching, and one had pulsating lesions. Extra-cutaneous location is exceptional. Regional adenomegaly is noted in 5–10 percent of the cases (none in our cases).

Serum hypereosinophilia is inconstant (21%) and is not required to make the diagnosis [3, 4, 5, 6]. Radiologic examinations such as MRI or angiography may be required to determine the extension of the lesions [2, 3, 4, 5, 6]. Positive diagnosis is based upon histological findings consisting in a proliferation of small vessels lined by epithelioid endothelial cells and surrounded by inflammatory cells including lymphocytes, mastocytes, eosinophils, and sometimes lymphoid follicles [2, 3, 4, 5, 6]. Atypical mitoses, fibrinoid necrosis, and leukocytoclastic elements are generally absent [4]. Images of arteriovenous shunt and intravascular proliferation may be noted and seem to be correlated with a high rate of local recurrence [2]. The variety of the histological characteristics explains the initial terms that included atypical granuloma, angiomatous inflammatory nodule, histiocytoid hemangioma. Today, this disease is classified among the eosinophilic dermatoses. According to the histological findings, many diagnoses may be suspected, including angiosarcoma, Kaposi sarcoma, epithelioid hemangioendothelioma, and Kimura disease.

Kimura disease is the major item in the differential diagnosis. Clinically it presents as large deep nodules or subcutaneous plaques covered by normal skin associated with adenomegaly. Serum eosinophil and IgE levels are generally increased. Extra-cutaneous locations are more frequent than in ALHE. There is involvement of the salivary glands or renal location in 21 percent of the cases. In Kimura disease, microscopic findings generally exhibit a less predominant neoangiogenesis and show prominent lymphoid follicles. Histiocytoid endothelial cells aren’t noted. Eosinophil abscesses, fibrosis, and IgE deposit are generally present [2–9]. Currently, we consider that AHLE and Kimura disease are 2 different entities and many authors put emphasis on the different epidemiological, clinical, and microscopical differences between them (Table 2).

The diagnosis of angiosarcoma may be ruled out. These tumors show nuclear abnormalities and abnormal mitoses of the endothelial cells. Kaposi sarcoma is characterized by the presence of fusiform cells admixed with vascular channels. Epithelioid hemangioendothelioma may be excluded by the absence of a myxoid or sclerotic stroma in ALHE. Moreover, in epithelioid hemangioma, tumor cells are vacuolated and centered by red blood cells.

Immunohistochemical study could be useful in some cases. Endothelial cells are positive for CD31, CD34, and VWF; in addition, they are keratin negative. The proliferative index of the endothelial cells has been reported as 5 percent using Ki-67 with negative staining for Cyclin D1 and bcl-2 [9, 10]. The main lymphocytes are T helper, expressing CD3, CD4, CD43, and CD45RO [4, 5, 6, 9]. In our case series, despite that clinical and histological findings at first appeared equivocal in some cases, the diagnosis of ALHE was based on the rarity of Kimura disease in Mediterranean patients, the female predominance, the presence of superficial lesions without lymph node enlargement, eosinophilia, or high serum IgE levels. Also, microscopic features consisting in a predominant vascular proliferation, few lymphoid follicles, and moderate eosinophils without fibrosis lead to the diagnosis of ALHE. However, the distribution of the nodules wasn’t typical in all cases because we noticed a few lesions in the trunk and extremities.

In the absence of treatment, lesions may either increase progressively or decrease spontaneously like in one patient of this series [11]. Surgical treatment remains the treatment of choice. Recurrences, essentially after incomplete excision, are observed in 30 percent of the cases [6]. No metastatic cases have been reported [4, 5, 6]. Considering the possible spontaneous involution of the lesions, a simple follow up is recommended 3 to 6 months before surgical excision or other extensive therapeutic modalities are attempted. Many therapeutic procedures have been described in the literature including electro-dessication, cryotherapy, micrographic surgery, systemic corticoid treatment, intra-lesional injection of corticoids or sclerosing products, phototherapy, or alpha-2a interferon. Despite the multiplicity of therapeutic modalities, their real efficacy have not been well studied and frequent recurrences have been noted. Surgical excision may be efficient in limited lesions but recurrences remain frequent because surgical margins remain difficult to determine.

Interleukin-5 based treatment represents an interesting approach. This cytokine interferes with the production and activation of eosinophils, which are supposed to play a key role in the pathogenesis of ALHE. Imiquimod, which inhibits the production of interleukin 5, and mepolizumab, which inhibits the reaction of IL5 with its receptor, were reported to be effective [14]. In our series, surgical excision, cryotherapy, and application of topical corticosteroids were used in 3 patients.

The pathogenesis of ALHE remains unclear. Some authors consider ALHE as a neoplasm developing from endothelial cells; others suggest that it is secondary to an inflammatory vascular reaction secondary to complex immunologic mechanisms. Many other hypotheses have been reported implicating environmental factors such as insect bite, trauma, and infections. Some authors consider that arterio-venous shunt is the main etiopathogenetic mechanism observed in 42 percent of the cases [5, 6]. The predominance of T lymphocytes and a rearrangement of TCR receptor in some cases made some authors suppose that ALHE is a low-grade neoplastic disease secondary to various stimuli [2, 3, 4, 5, 6, 9].

Angiolymphoid hyperplasia with eosinophilia is a rare affliction with a challenging diagnosis and treatment. In spite of the benignity of this disease, it causes a therapeutic dilemma because of the cosmetic defects and frequent resistance to treatment.

References

1. Wells GC, Whimster IW. Subcutaneous angiolymphoid hyperplasia with eosinophilia. Br J Dermatol 1969; 81:1-14. [PubMed]

2. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia. J Am Acad Dermatol 1985; 12: 781-96. [PubMed]

3. Chun SI, Ji HG. Kimura's disease and angiolymphoid hyperplasia with eosinophilia: clinical and histopathologic differences. J Am Acad Dermatol 1992; 27: 954-8. [PubMed]

4. Chong WS, Thomas A, Goh CL. 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. [PubMed]

5. Demitsu T, Nagato H, Inoue T. Angiolymphoid hyperplasia with eosinophilia: its character and therapy. Skin Surg 2000; 9: 8-16.

6. Ramchandani PL, Sabesan T, Hussein K. Angiolymphoid hyperplasia with eosinophilia masquerading as Kimura disease. Br J Oral Maxillofac Surg 2005; 43: 249-52. [PubMed]

7. Acocella A, Catelani C, Nardi P. Angiolymphoid hyperplasia with eosinophilia: a case report of orbital involvement. J Oral Maxillofac Surg 2005; 63:140-4. [PubMed]

8. Park Y, Chung J, Cho CG. Angiolymphoid hyperplasia with eosinophilia of the tongue: report of a case and review of the literature. Oral Oncol 2002; 38: 103-6. [PubMed]

9. Kempf W, Haeffner AC, Zepter K, Sander CA, Flaig MJ, Mueller B, Panizzon RG, Hardmeier T, Adams V, Burg G. Angiolymphoid hyperplasia with eosinophilia: evidence for a T-cell lymphoproliferative origin. Hum Pathol 2002; 33: 1023-9. [PubMed]

10. Aoki M, Kimura Y, Kusunoki T, Tahara S, Kawanah S. Angiolymphoid hyperplasia with eosinophilia associated with anomalous dilatation of occipital artery: IL-5 and VEGF expression of lesional mast cells. Arch Dermatol 2002; 138: 982-4. [PubMed]

11. Satpathy A, Moss C, Raafat F, Slator R. Spontaneous regression of a rare tumour in a child: angiolymphoid hyperplasia with eosinophilia of the hand: case report and review of the literature. Br J Plast Surg 2005; 58: 865-8. [PubMed]

12. Papadavid E, Krausz T, Chu AC, Walker NP. Angiolymphoid hyperplasia with eosinophilia successfully treated with the flash-lamp pulsed-dye laser. Br J Dermatol 2000; 142: 192-4. [PubMed]

13. Shenefelt PD, Rinker M, Caradonna S. A case of angiolymphoid hyperplasia with eosinophilia treated with intralesional interferon alfa-2a. Arch Dermatol. 2000; 136: 837-9. [PubMed]

14. Braun-Falco M, Fischer S, Plötz SG, Ring J. Angiolymphoid hyperplasia with eosinophilia treated with anti-interleukin-5 antibody (mepolizumab). Br J Dermatol 2004; 151: 1103-4. [PubMed]

15. Redondo P, Del Olmo J, Idoate M. Angiolymphoid hyperplasia with eosinophilia successfully treated with imiquimod. Br J Dermatol 2004; 151: 1110-1. [PubMed]

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