Angiolymphoid Hyperplasia With Eosinophilia

Article Author:
Imene Ben Lagha
Article Editor:
Asmahane Souissi
Updated:
3/5/2019 8:49:40 AM
PubMed Link:
Angiolymphoid Hyperplasia With Eosinophilia

Introduction

Angiolymphoid hyperplasia with eosinophilia (ALHE), aka epithelioid hemangioma, is an uncommon benign vasoproliferative disorder, first described in 1969 by Wells and Whimster. The pathogenesis of ALHE is not clearly understood. It usually presents with solitary or multiple papules or nodules involving mostly the head and neck region. More rarely, the lesions can appear in other sites of the body or affect extracutaneous tissues. The objective of the treatment is to attend to cosmetic issues and to allow symptomatic relief. Multiple treatment modalities have been tried, but none of them proved a reproducible success.[1][2]

Etiology

The etiology of ALHE is not fully understood, and it is not clear whether it consists of a vascular neoplasm or a lymphoproliferative process. 

The first hypothesis has support by the association with arteriovenous shunts in 43% of the cases as well as the frequency of preceding trauma (friction, surgery, frostbite, laceration, etc.), similarly to pyogenic granuloma.[2][3] Hyperestrogen state seems to contribute to the pathogenesis of this condition. This phenomenon is also observed with various vascular tumors during pregnancy.[4][5] Furthermore, a recent study described intracytoplasmic endothelial staining of Wilms tumor-1 in 19 of 20 ALHE specimens. Immunoreactivity for Wilms tumor-1 was also found previously in multiple vascular neoplasms such as infantile hemangiomas and pyogenic granulomas.[6] Moreover, a mutation of the endothelial cell tyrosine kinase receptor Tie-2 was present in both ALHE and other noninherited vascular anomalies.[7] It also has been suggested that renin, induced by associated arteriovenous shunts, might be a pathogenic factor for ALHE by stimulating new vessels formation and eosinophils activation and migration through angiotensin II production.[8]

The second hypothesis of ALHE as a lymphoproliferative disorder has support from the condition's progressive course and frequent recurrences. Interestingly, T-cell receptor gene rearrangement and monoclonality have been previously observed in ALHE cases, raising the possibility to consider this condition as a low-grade T-cell lymphoma.[9] Additionally, there were two previous reports of ALHE associated with peripheral T-cell lymphoma. In one case, the same monoclonal TCR gene rearrangement was present in both ALHE and T-cell lymphoma.[10][11] A few cases of ALHE showed evidence of follicular mucinosis, but no reports of association with mycosis fungoides exist so far.[12] Of note, some cases of ALHE correlated to human herpesvirus 8 and human T-cell lymphotropic virus.[9][13]

Finally, whether ALHE is a true vascular neoplasia with a rich inflammatory component or a lymphoproliferative process with a reactive angiogenic response is yet to be clarified. 

Epidemiology

Angiolymphoid hyperplasia with eosinophilia is uncommon but not rare. The exact prevalence is unknown, but it is mostly seen in Asians, followed by Whites and less frequently in Blacks. ALHE has a wide prevalence range varying from 0.7 months to 91 years. The mean age at presentation is 37 years, and it occurs in both males and females without significant difference.[14]

Histopathology

Histopathology displays specific histologic features. The tumors are mainly located in the dermis and less frequently in subcutaneous tissues.  A combination vascular-inflammatory component is present. The lesions show a proliferation of capillary-sized vessels lined by prominent, enlarged endothelial cells giving the typical cobblestone appearance. The cells are mostly cuboidal, with intracytoplasmic vacuoles and uniform ovoid nuclei. A dense vascular and interstitial infiltrate of lymphocytes and eosinophils is seen. Mitoses are rarely observed, but lack anaplasia and atypical figures. The vascular component predominates in early or actively growing ALHE, while the lymphoid infiltrate is more prominent in the late stages of the disease. Histological evidence of arteriovenous shunts is present in 42% of the cases.[2][15]

History and Physical

Angiolymphoid hyperplasia with eosinophilia is a benign, locally proliferating disease, that tends to arise in the skin of the head and neck, particularly in the periauricular area and the scalp. Nonetheless, lesions can occur on any site of the body including extremities, trunk, oral and genital mucosa, and orbit.[14][15] Internal organs may also be involved in a lesser frequency such as heart, colon, kidney, bone, and lung ALHE.[16][17][18][19][20] Several reports exist of a few cases of ALHE arising from arteries. They can present as pulsatile tumors mimicking vascular malformation.[21]

ALHE presents with dermal and/or subcutaneous, single or multiple, pink to red-brown papules and/or nodules of variable size ranging from a few to multiple centimeters. The lesions are most commonly symptomatic, accompanied by pruritus, bleeding and/or pain. Regional lymphadenopathy is rarely associated. The lesions tend to be persistent and recurrent. However, there are also reports of spontaneous remissions. Early age of onset disease characteristically has a longer duration and multiple bilateral lesions, more prone to bleeding, pain, and pruritus.[2][14] The association with nephrotic syndrome has been reported in a few cases, but it is not well-established.[22][23][2]

Dermoscopy of ALHE lesions reveals a polymorphous vascular pattern composed of regularly distributed dotted and linear vessels, over a concomitant pink to a red background.[24]

Evaluation

Laboratory analysis includes a complete blood count which reveals peripheral blood eosinophilia in approximately 20% of the cases.[2] Kidney function tests may be performed to assess eventually associated nephropathy.

A biopsy of the lesions is required to establish the diagnosis (see histopathology for findings). An immunohistochemical study reveals a strong reactivity for CD31 and lesser reactivity for CD34 and factor VIII-related antigen.[25] More recently, FOSB immunohistochemistry proved to be sensitive in the diagnosis of ALHE by allowing differentiation from its histological mimics.[26] Intracytoplasmic endothelial staining of Wilms Tumor 1 can also be useful for the diagnosis of ALHE.[6]

Adequate radiologic workup can be further performed to explore ALHE involving internal organs, arteries, orbit, bones, etc.

Treatment / Management

Although ALHE is a benign disease, its management is particularly challenging considering the frequency of recurrences and the absence of randomized controlled clinical trials. In fact, most of the available treatment evidence exists from case reports and retrospective analyses. There are reports of multiple therapeutic options but none with consistent results.

Surgical excision is considered the treatment of choice in ALHE. It is the most commonly used therapeutic intervention and has the lowest failure rate of 44.2%. Given this high recurrence rate, Mohs micrographic surgery was suggested as a treatment option for lesions with ill-defined margins and when tissue sparing is desirable. Lesions with large cutaneous vessels may respond better if a preoperative embolization is performed.[14][27][28]

Laser therapies are promising alternatives for surgery in patients with multiple lesions, in cosmetic sensitive sites and poor surgical candidates. Argon, Nd: YAG, pulsed dye and carbon-dioxide lasers were previous choices. But the recurrence rate remains high over 50%. Combination of pulsed dye laser and carbon-dioxide lasers also had consideration. The recurrence can be prevented by maintenance treatment.[14][29]

Other interventional treatment options include photodynamic therapy, cryotherapy, electrodesiccation, and radiotherapy.[14][30] One report noted no recurrence up to eight after brachytherapy.[31] Sclerotherapy with polidocanol or bleomycin were performed in three cases of multiple ALHE achieving complete healing and clinical remission at follow-up.[32][33] Radiofrequency ablation showed to be efficient in three case studies.[34][35][36] Combination of radiofrequency and sclerotherapy was also described in three patients and resulted in clinical remission for up to three years.[37]

Systemic treatments with systemic corticosteroids, oral isotretinoin, oral dapsone, and oral pentoxifylline were previously used but with high failure rates (80% to 100%).[14] Two cases with refractory orbital and multiple ALHE were successfully managed with methotrexate and thalidomide respectively.[38][39] Mepolizumab or anti-interleukin-5 antibody was administered in a patient with ALHE associated with blood eosinophilia. Local pruritus and hypereosinophilia disappeared, while the nodules regressed only slightly.[40][38]

Recent data suggested oral propranolol alone or before surgery to reduce the size or number of lesions.[41][42][43] 

Topical timolol also showed some success in the management of ALHE.[44] Topical and intralesional corticosteroids were the primary therapeutic agents, but high recurrence rates remained.[14] Other local treatment options are topical imiquimod 5%, topical tacrolimus 0.1%, and intralesional interferon alpha-2b. Variable outcomes have been the observed result.[45][46][47][48]

Differential Diagnosis

The major differential diagnosis of ALHE is Kimura disease. These two conditions were previously considered as manifestations of the same entity. Epidemiological, clinical and histopathological particularities subsequently distinguished them from each other. Kimura disease occurs in young Asian men. It presents with solitary or multiple large subcutaneous masses with deeper localization. The lesions typically involve the salivary glands in the periauricular or submandibular region. It is commonly accompanied by regional lymphadenopathy. Laboratory workup often finds peripheral blood eosinophilia and elevated IgE. Nephrotic syndrome is more associated with Kimura's disease than with ALHE. On histopathology, hyperplastic lymphoid follicles with prominent germinal centers and eosinophilic infiltrate are conspicuous features of Kimura's disease. Vascular proliferation is present, but it is less notable than in ALHE and lacks the characteristic plump epithelioid endothelial cells.[49][50]

ALHE should also be distinguished from pyogenic granuloma, which presents as an eruptive papule, sometimes eroded or ulcerated, with an epidermal collarette. Histologically, it consists of capillary-sized vessels separated by fibromyxoid stroma, contrasting with the immature blood vessels with hobnailing seen in ALHE.[51]

Clinically, ALHE can look very similar to nodular Kaposi sarcoma. However, the histopathological distinction is usually easy. Kaposi sarcoma is composed of spindle cell proliferation with stiltlike vascular spaces that stain positively with human herpesvirus 8.[51]

Another differential diagnosis is angiosarcoma, especially in its epithelioid variant. The latter has more rapid growth, an aggressive course, and histologically shows vigorous mitotic activity, polymorphism, and nuclear hyperchromasia.[15]

ALHE can also be confused with epithelioid hemangioendothelioma. The presence of myxohyaline stroma separating strand, cords, and nests of vacuolated endothelial cells, the lack of lymphoid or eosinophilic infiltrate and the presence of mitoses, and nuclear atypia can address the diagnosis.[52]

Granuloma faciale usually presents as a red-brown plaque located on the face and refractory to treatments. Eosinophil infiltrate may be present on histology, but chronic leukocytoclastic vasculitis, fibrin deposition, and fibrosis permit to differentiate the diagnosis.[51]

Prognosis

Angiolymphoid hyperplasia with eosinophilia tends to persist for years and to recur after treatment in more than 40% of the cases. Early age of onset, long disease duration, multiple lesions, and symptomatic disease seem to have a higher recurrence rate. Spontaneous regression can occur occasionally.[14]

ALHE is an entirely benign disease. Even though there were cases of T-cell receptor gene rearrangement and monoclonality, no reports of absolute evidence of malignant behavior in ALHE exist thus far.

Complications

Angiolymphoid hyperplasia with eosinophilia is a benign disease. Reports exist of concomitant nephropathy in a few cases, but the association is not all that common. According to the location of the lesions, complications may present. Rectal bleeding was reported in colonic ALHE. Orbital ALHE can present with proptosis, diplopia and blurred vision. Arterial ALHE can result in compressing proximal nerves: there are prior reports of entrapment of the ulnar nerve resulting in paresthesia and tactile dysesthesia of the involved area. Arterial ALHE can also cause complete occlusion of the vessel lumen leading to chronic ischemia. A case of cardiac ALHE presented with supraventricular arrhythmia.[18][53][54][55][56]

Deterrence and Patient Education

Patients with ALHE should be aware of the chronic course of the disease and the possibility of recurrence after treatment. But they should also be reassured about the benign nature of the condition.

It is as well advised to inform the patients of the different treatment options and to involve them in decision-making about their care.

Enhancing Healthcare Team Outcomes

The management of ALHE requires the efforts of a multidisciplinary team of physicians, pharmacists, and nurses. In most of the cases, patients present with unique or multiple cutaneous papules and/or nodules. Therefore primary care providers and nurse practitioners generally address them to a dermatologist. In many other cases, ALHE can present in any site of the body and present with several symptoms. Thus, different specialists such as ophthalmologists, cardiologists, gastroenterologists, neurologists, and otorhinolaryngologists can be involved in making the diagnosis and organizing a treatment plan. The role of the radiologist can also be vital in some cases where the lesions are not accessible, especially in ALHE with arterial involvement.  A biopsy is recommended to confirm the diagnosis and requires a trained pathologist. Many patients with disfiguring lesions develop depression and anxiety. Psychological counseling is useful for these individuals. 

Given the high rate of recurrence, the treatment of ALHE can be tricky and challenging. Hence, the need for meticulous discussion and planning between professionals such as surgeons, radiotherapists, and pharmacists is required — [ Level V]. 

Nurses are of course involved in every step of the management of ALHE by providing the necessary education, assisting the procedures and monitoring postoperative care.



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References

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