Graft-versus-host Disease-associated Angiomatosis Treated With Topical Timolol Solution

Introduction. Scleroderma-like graft-versus-host disease (GVHD) is an uncommon subtype of chronic GVHD. Vascular lesions rarely arise within areas of scleroderma-like changes and until recently have not been considered to be related entities. Kaffenberg et al¹ have grouped this heterogeneous collection of vascular lesions under the term GVHD-associated angiomatosis. Treatment modalities thus far have been mostly ineffective. Topical timolol solution has been used in the treatment of superficial infantile hemangiomas with good success. Here the authors report the first case of GVHD-associated angiomatosis treated with topical timolol solution. Methods and Materials. Timolol 0.5% solution was applied daily to 3 lesions on the lower extremities of their patient for 3 months. Results. All lesions decreased in friability and frequency of spontaneous hemorrhage. Lesions remained stable in size throughout treatment duration, with no growth observed in any lesion. Granulation tissue surrounding all lesions was markedly reduced after the treatment period. Conclusion. Topical timolol remains a promising therapeutic option in the treatment of GVHD-associated angiomatosis.

Scleroderma-like graft-versus-host disease (GVHD) is an uncommon subtype of chronic GVHD that typically presents in patients several months to years after hematopoietic stem cell transplant. Vascular lesions rarely arise within areas of scleroderma-like changes and until recently have not been considered to be related entities. Kaffenberg et al¹ have grouped this heterogeneous collection of vascular lesions under the term GVHD-associated angiomatosis. After a thorough literature search in PubMed, the authors note timolol solution has been used in other vascular lesions but never in this particular entity. Here the authors report the first case of GVHD-associated angiomatosis treated with topical timolol solution.

A 35-year-old woman presented with a history of multiple bleeding lesions on her lower extremities. The patient reported that the lesions arose spontaneously over a year prior to presentation and bled easily with minor trauma. Past medical history was significant for acute myelogeneous leukemia (AML) with allogeneic hematopoietic stem cell transplant (HSCT) 4 years prior to presentation. The patient has been receiving chronic prednisone therapy, as well as prophylactic antibiotic and antiviral therapy with voriconazole, acyclovir, and trimethoprim/sulfamethoxazole since HSCT. The patient had previously failed therapy with vismodegib, rituximab, and etanercept. Tacrolimus was discontinued due to the development of posterior reversible encephalopathy syndrome. 

The patient had received extracorporeal photopheresis, which was stopped due to a prolonged illness approximately 1 year prior to presentation. 

Physical examination revealed multiple 1 cm to 4 cm friable, exophytic nodules with smooth pink rolled borders over the bilateral lower extremities (Figure 1). Depigmentation with sparing of the follicular ostia was present diffusely over the upper and lower extremities. 

Punch biopsies taken from the right lower extremity revealed a proliferation of large vessels with bland or fairly normal endothelial cells and focal valve formation throughout the dermis (Figure 2). Deep to the vascular structures, mild thickening of the deep dermal vessels and thickened horizontal collagen bundles were also present. Staining with human-herpes virus 8 (HHV-8) and Warthin-Starry were both negative. Biopsies were consistent with cavernous hemangioma on a background of scleroderma-like GVHD. 

The 3 lesions on the bilateral lower extremities were serially monitored during the patient’s hospital stay (Figures 3, 4, and 5). The lesions were noted to be extremely friable and hemorrhagic upon initial presentation. Initial measurements of each lesion were taken, measuring 4.0 cm, 1.8 cm, and 1.5 cm in diameter, respectively, at initial consultation (Figures 3, 4, and 5). The nursing staff applied topical 0.5% timolol opthalmic solution daily to all lesions during the patient’s inpatient stay from January 2015 to April 2015. The topical solution was only withheld during 1 week of treatment due to hypotension secondary to sepsis. 

All lesions decreased in friability and frequency of spontaneous hemorrhage. The lesions remained stable in size throughout treatment duration, with no growth observed in any lesion, but changed in color (more grey/skin colored as opposed to red/vascular) and bled less daily. (The patient specifically noted this at the end of her treatment.) Granulation tissue surrounding all lesions was markedly reduced after the treatment period. A thick fibrinous coating developed over all treated sites and friability was rapidly reduced during timolol treatment (Figures 3, 4, and 5). All lesions were removed by shave excision and electrocautery after 3 months of timolol treatment with minimal blood loss and no complications. The patient reported no side effects secondary to timolol application.  

Graft-versus-host disease is the primary complication of HSCT. Graft-versus-host disease is characterized by a reaction of donor immune cells against host tissues, affecting up to 50% of allogeneic HSCT recipients.² It typically develops 3-5 months after HSCT and most frequently involves the distal extremities and mucous membranes.³ 

Scleroderma-like chronic GVHD is characterized by shiny, wrinkled, atrophic white plaques with sparing of the follicular ostia.⁴ The lesions have a predilection for the upper back and extremities, with morphea-like lesions favoring sites of previous trauma and areas of friction.⁵ 

Vascular proliferations rarely arise within existing scleroderma-like chronic GVHD. These lesions clinically and histologically represent a heterogeneous mix of vascular tumors including cavernous hemangioma, pyogenic granuloma, lymphangioma, angiokeratoma, acquired tufted angioma, diffuse dermal angiomatosis and acroangiodermatitis.¹ It recently has been proposed by Kaffenberger et al¹ that these lesions should be considered within the spectrum of reactive angiomatoses, termed GVHD-associated angiomatosis. Clinial appearance is that of asymptomatic vascular nodule(s) within areas of skin fibrosis, most frequently on extremities, with a tendency to bleed and ulcerate.¹ Histologically, proliferations of pericytes, histiocytes, and endothelial cells are present within and surrounding vascular structures. Lesions are postulated to develop due to long-standing fibrosis and edema and activation of donor-derived endothelial cells, appearing almost exclusively in late-stage scleroderma-like chronic GVHD.¹ 

Development occurs on average 44 months post HSCT and after the use of multiple chronic GVHD therapies, most commonly photopheresis and tacrolimus.¹ Treatment of GVHD-associated angiomatosis remains difficult. Multiple modalities, including thalidomide, external-beam radiation, shave biopsy with electrodessication, and sirolimus in combination with propranolol, have been used with little success.¹ 

Timolol is a non-selective beta-blocker that has been used in the treatment of glaucoma and recently for cutaneous vascular lesions. Although the exact mechanism is unknown, it is theorized that beta-blockers inhibit growth of vascular lesions by induction of apoptosis, inhibition of angiogenesis, vasoconstriction and recruitment of endothelial progenitor cells.^6-7 Timolol has shown efficacy in the reduction of volume, clinical appearance and growth in superficial infantile hemangiomas, when used during the proliferative phase.⁸ Deeper lesions have shown decreased response thought to be secondary to limited penetration by topical timolol application.⁹ No studies currently in the literature investigate the effects of topical timolol on other cutaneous vascular lesions. 

The patient’s lesions in this case report measured 4.0 cm, 1.8 cm, and 1.5 cm in diameter, respectively, at initial consultation (Figures 3-5). All lesions were extremely friable and bled with minor trauma and served as a portal of infection in an immunocompromised patient. All treated lesions stabilized in size and were noted to have an induction of superficial necrotic fibrin. The frequency of spontaneous hemorrhage and friability decreased throughout therapy. Lesions were easily removed after 3 months of therapy with minimal blood loss and no complications. 

As previously mentioned, GVHD-associated angiomatosis remains a rare complication of end-stage scleroderma-like chronic GVHD. Treatment remains difficult with many modalities failing to achieve resolution of lesions. This case represents the first documented trial of topical timolol for the treatment of GVHD-associated angiomatosis. Although lesions did not completely resolve, no growth was noted and all lesions decreased significantly in both frequency of spontaneous hemorrhage and friability. Lesions likely did not fully involute due to limited infiltration of the topical solution, as was seen in studies with deeper infantile hemangiomas.⁹ Topical timolol remains a promising therapeutic option in the treatment of GVHD-associated angiomatosis. 

From the Department of Dermatology, St. Joseph Mercy Hospital; and Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, MI

Address correspondence to:
Benjamin R. Bashline, DO
St. Joseph Mercy Health System Dermatology Clinic  
Reichert Health Center
5333 McAuley Drive
Suite-5003
Ypsilanti, MI 48197
Benjamin.bashline@gmail.com 

Disclosure: The authors disclose no financial or other conflicts of interest.