Early and Late Histological and Ultrastructural Findings in Resected Infantile Capillary Hemangiomas Following Treatment with Topical Beta-Blocker Timolol Maleate 0.5%

Abstract

Background: Infantile capillary hemangiomas (IHs) affect approximately 4-5% of infants. The systemic nonselective β-adrenergic antagonist, propranolol, has become the standard first-line treatment for severe IHs. The topical β-antagonist, timolol maleate, has also demonstrated efficacy and safety in treating superficial and some deep capillary hemangiomas. Despite their therapeutic success and prevalent use, the mechanism of action of β-adrenergic antagonists in the treatment of IHs is not well understood. Methods: Histopathological and electron microscopic evaluation of two periocular IHs excised at 1 week and 24 months following topical timolol treatment was performed. Results: Distinct morphological differences were observed between spontaneously regressed and β-antagonist-treated IHs. The former was characterized by diffuse collagen deposition and interstitial fibrosis, while the latter showed organized concentric collagen IV deposition within obliterated vessel lumen, suggestive of waves of endothelial cell apoptosis, leaving behind layers of basement membrane deposits as a stress response. Conclusions: Based on these observations, we hypothesize that, apart from their well-known cardiac and vasodilatory effects, β-antagonists could induce endothelial cell apoptosis in IH leading to endovascular occlusion and we present supporting evidence to explain why this response might be specific to hypoxic tissue.

Topical Timolol for Infantile Haemangioma of the Orbit

“…He was started on topical timolol 0.5 %, three drops applied to the skin overlying the haemangioma two to three times a day. An orbital biopsy performed a week after starting timolol confirmed the diagnosis of IH and histological analysis demonstrated evidence of early apoptosis among the endothelial cells, as previously reported [12]. Significant improvement in proptosis was noted by 4 months (▶ Fig.…”

“…Several mechanisms have been proposed to explain the betablocker effect on the regression of IH, including immediate capillary constriction, inhibition of angiogenesis, and initiation of apo-ptosis [11]. We have previously shown histopathological evidence of apoptosis of endothelial cells in treated periocular IH tissue 1 week after the initiation of topical timolol treatment [12]. With the application of three drops of timolol maleate 0.5 % two to three times daily to the skin overlying the IH, we estimate to deliver at least 1 mg timolol maleate to the lesion per day, comparable to an oral propranolol dosage of 2 mg/kg/day [17].…”

An infant with localized vasoconstriction following topical propranolol exposure for infantile hemangioma

“…1 However, the exact mechanism of action of systemic beta-blockers in IHs is not fully known and the question is whether the mechanism of action is the same when applied topically. 2 Moreover, IH involution is most likely induced by other mechanisms following beta-receptor blockade, such as decreasing local levels of growth factors including vascular endothelial growth factor, induction of apoptosis, and effects on the renin-angiotensin system. 1,[3][4][5] Topical timolol is commonly used for management of superficial IH.…”

Successful Late Treatment of Orbital Infantile Haemangiomas in Two Teenagers with Topical Transcutaneous Timolol Maleate 0.5% Alone

“…In support of this is that the repeat MRIs showed little (case 1) or no (case 2) remaining radiologically detectable IH residua. We have previously shown histological evidence for apoptosis using light and electron microscopy as early as 1 week after onset of topical treatment with TM 0.5 % and a different pattern of resolution between spontaneously resolved and transcutaneously timolol-treated IH in infants during the proliferative phase [25].…”