Isotretinoin as a promising treatment for angiolymphoid hyperplasia with eosinophilia

Dear Editor,

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare benign vascular neoplasm. It is potentially disfiguring since it presents as dermal and subcutaneous nodules, mainly in the head and neck region, with a predilection to the periauricular area, forehead, and scalp. The lesions are persistent with a high recurrence rate after treatment. Although spontaneous regression is possible, recurrent lesions require repeated treatment.¹ Management is challenging due to the absence of standard treatment guidelines. Multiple reports of therapeutic options are available, but none with consistent results.

A 39-year-old woman presented with a one-year history of spontaneously appearing, slowly progressive, asymptomatic, grouped, dome-shaped firm dull-red nodules about 0.5 to 2.5 cm in size on the left ear [Figure 1]. An excisional biopsy from one of the nodules revealed a dermal vascular lesion extending into subcutaneous tissue, formed of proliferating vascular channels lined by plump endothelial cells with abundant cytoplasm imparting a hobnail appearance. The surrounding stroma showed a mononuclear cell infiltrate of diffuse lymphocytes and lymphoid follicles, admixed with plasma cells and abundant eosinophils [Figure 2a]. Endothelial cells showed positive staining for CD31 and CD34. Ki-67 positive nuclear staining was noted in the germinal centres of proliferating lymphoid follicles and to a lesser extent in blood vessels. Lymphocytic infiltrate was predominately of reactive CD20⁺ B-cells, admixed with a lesser number of reactive CD3⁺ T-cells [Figures 2b-f]. History, examination, and histopathology were consistent with the ALHE diagnosis.

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Figure 1:

Auricular dome-shaped nodules of ALHE at the time of presentation.

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Figure 2:

a) Haematoxylin and eosin-stained section of the tumour showing proliferating blood vessels surrounded by lymphocytes, plasma cells, and eosinophils (Haematoxylin & eosin, 200x), b) CD31 positivity in blood vessels (CD31, 100x), c) CD34 positivity in blood vessels (CD34, 100x), d) CD20 positive staining of B-lymphocytes (CD20, 100x), e) CD3 positive staining of T-lymphocytes (CD3, 100x), f) Ki-67 positivity in actively proliferating germinal centres (Ki-67, 100x).

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Blood count showed no eosinophilia, while serum IgE level was high (329 IU/mL). A computed tomography (CT) scan showed submandibular, left deep cervical, and intraparotid discrete small lymph nodes showing benign features suggestive of reactive lymph nodes.

Differential diagnoses of ALHE include cutaneous lymphoma, pseudolymphoma (lymphocytic infiltrate of Jessner, lymphocytoma cutis), sarcoidosis, granuloma faciale, angiomatous lymphoid hamartoma, bacillary angiomatosis, pyogenic granuloma, and Kimura’s disease.²

Whether ALHE is a vascular lesion with a rich inflammatory component or a lymphoproliferative process with a reactive angiogenic pattern, developing as a response to trauma, infectons, increased renin, or oestrogen (pregnancy or oral contraception) level is still to be identified. Thus, regional lymphadenopathy may be present in 5-20% of cases, as in our case.¹

The patient was prescribed imiquimod (5%) cream every other day. Although the nodules decreased in size after 2 weeks, she suffered severe irritation. Tacrolimus (0.1%) was added once daily for another 2 weeks, after which mild improvement was seen. However, the patient didn’t tolerate the topical medications. After signing an informed consent regarding teratogenicity, systemic isotretinoin was prescribed at a dose of 20 mg/d (0.3 mg/kg/d) for 1 month, followed by 30 mg/d (0.5 mg/kg/d) for 5 months, with regular haematological and biochemical monitoring. Lesions showed progressive improvement over time [Figure 3a] till complete resolution at 6-months [Figure 3b]. The dose was maintained for the next 3-months and then reduced to 10 mg daily for 3 months to prevent recurrence. Post treatment follow-up at 6-months showed no recurrence.

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Figure 3a:

Regressing lesions after 3 months of isotretinoin.

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Figure 3b:

Complete remission at 6 months of isotretinoin.

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Surgery is considered the treatment of choice for ALHE with the lowest failure rate; however, it doesn’t prevent recurrence. However, it is sometimes difficult and disfiguring, particularly in the periauricular area. Laser therapies such as Nd:YAG, pulsed dye, argon, and carbon dioxide are good alternatives for surgery in patients with multiple lesions. Other interventions include photodynamic therapy, cryotherapy, electrodessication, and radiotherapy. Systemic therapy with corticosteroids, dapsone, and pentoxifylline and, intralesional corticosteroid have been tried with high failure rates. Topical options include imiquimod (5%), tacrolimus (0.1%), and intralesional IFNα-2b with variable outcomes.¹

Few previous reports of systemic retinoids as a treatment for ALHE are available in the literature, with variable outcomes [Table 1].^1-6 However, a longer duration of isotretinoin showed promising results even for recurrent lesions.^2,5 Our case adds to the available literature and emphasises the success of longer duration with isotretinoin to manage multiple ALHE lesions.

This effect may be due to the retinoid’s induced reduction of keratinocytes’ vascular endothelial growth factor (VEGF) production. Since retinoids inhibit the anti-activator protein 1 (AP1) pathway, they downregulate the expression of VEGF genes, which in turn inhibits angiogenesis.⁷ Since the successful use of isotretinoin for ALHE is limited to a few case reports, large-scale studies are needed to confirm its efficacy and to identify its recommended dose and duration.

In conclusion, isotretinoin for a long duration (1 year) could be a promising treatment for ALHE, particularly when lesions are multiple and in difficult-to-treat surgical areas. However, a longer follow-up is needed to prove non-recurrence.