Refractory Ulcerated Infantile Hemangioma Successfully Treated With Bleomycin Sclerotherapy: A Case Report

Introduction

Infantile hemangiomas (IH) are the most common benign vascular tumors found in infancy, occurring in approximately 4% to 5% of infants, and they are more common in females, premature infants, and those with low birth weight [1,2]. These lesions typically appear within the first few weeks of life, undergo a proliferative phase during early infancy, and then gradually regress spontaneously throughout childhood [2]. While most IHs resolve without intervention, some can exhibit rapid enlargement, develop ulcers, or cause functional problems, posing significant treatment challenges [3]. Ulceration is the most common complication, occurring in up to 15% of cases, and is associated with pain, infection, and potential scarring [4].

Diagnosis of infantile hemangiomas is primarily clinical, based on their characteristic appearance and typical pattern of proliferation and involution [1]. Imaging modalities such as ultrasound or magnetic resonance imaging (MRI) can be utilized in selected cases to assess lesion depth, evaluate internal involvement, or exclude associated structural anomalies [1,3]. Because infantile hemangioma is typically diagnosed clinically, histopathology is rarely required and is usually reserved for diagnostically uncertain cases [1,3].

It is important to distinguish infantile hemangiomas from congenital hemangiomas, which are a distinct vascular entity. Congenital hemangiomas are fully developed at birth and do not undergo the typical proliferative phase seen in infantile hemangiomas. They are classified into rapidly involuting congenital hemangiomas (RICH), which regress during the first months of life, and non-involuting congenital hemangiomas (NICH), which persist without spontaneous regression. In contrast, infantile hemangiomas usually appear within the first weeks of life, undergo a characteristic proliferative phase during infancy, and subsequently involute over several years [1,2]. This distinction is clinically important, as infantile hemangiomas typically exhibit a postnatal proliferative phase followed by involution, whereas congenital hemangiomas are fully formed at birth and do not undergo a postnatal proliferative phase [1,2].

Propranolol has revolutionized the management of infantile hemangiomas since its introduction as the first-line therapy due to its vasoconstrictive, anti-angiogenic, and pro-apoptotic effects on endothelial cells [5]. Despite being effective and generally safe, some ulcerated IHs exhibit paradoxical deterioration or show minimal improvement, particularly in lesions with rapid proliferation or compromised perfusion [6,7]. The proposed mechanism involves excessive vasoconstriction that can lead to ischemic necrosis and subsequent ulceration, highlighting the importance of careful monitoring during dose escalation [6]. In such cases, adjunctive or alternative therapies, including corticosteroids, sirolimus, or sclerotherapy, may be required to achieve adequate control [8,9].

While most infantile hemangiomas respond well to propranolol, a small number of cases do not improve or continue to develop ulcerations despite standard treatment, requiring a tailored and multifaceted approach [3]. Recently, sirolimus has gained attention as an effective alternative treatment inhibiting the PI3K/Akt/mTOR pathway, which suppresses endothelial proliferation and angiogenesis in complex vascular tumors [8,10]. In severe or treatment-resistant cases, sclerotherapy has been reported to provide substantial benefit by inducing endothelial damage and vascular thrombosis, leading to durable regression [9]. This report presents the case of a 6-month-old girl with multiple cutaneous and hepatic infantile hemangiomas, including a refractory ulcerated facial lesion, who had a dramatic clinical response to bleomycin sclerotherapy.

Case Report

OUTCOME AND FOLLOW-UP:

The ulceration healed rapidly following the sclerotherapy session, with marked improvement in the lesion’s color and resolution of the necrotic areas. Over the subsequent weeks, the hemangioma continued to stabilize, and the patient was discharged home on oral steroid and sirolimus approximately 3 weeks after the procedure, in good condition. The hepatic hemangiomas also remained radiologically stable (Figure 7).

Discussion

This case highlights the clinical challenge of managing severe ulcerated infantile hemangiomas refractory to medical therapy and illustrates the potential role of bleomycin sclerotherapy as rescue therapy.

Infantile hemangiomas (IH) are the most common benign vascular tumors of infancy. They typically appear within the first few weeks of life, undergo a rapid proliferative phase, and then gradually involute over several years [1].

While most lesions are uncomplicated and respond favorably to oral propranolol, a subset of cases have atypical progression, including rapid growth, ulceration, or resistance to standard therapy, leading to considerable morbidity and potential complications such as bleeding, infection, or scarring [4]. Ulceration is the most common complication of infantile hemangioma, typically occurring during the proliferative phase, and is associated with severe pain, delayed healing, and risk of secondary infection [4,11]. Early identification and timely management are essential, as complicated or refractory hemangiomas often require multidisciplinary evaluation and individualized therapy beyond beta-blockers [3,12].

Ulceration in infantile hemangiomas is believed to result from ischemic injury secondary to rapid endothelial proliferation, tissue hypoxia, or mechanical friction over prominent areas such as the lips, nose, or perineum [1].

While propranolol has become the first-line therapy due to its vasoconstrictive, anti-angiogenic, and pro-apoptotic effects on capillary endothelial cells, paradoxical worsening of ulceration following propranolol initiation or dose escalation has been reported in rare cases [7]. This paradoxical deterioration is hypothesized to be caused by excessive vasoconstriction leading to reduced local blood flow and tissue ischemia, especially in lesions with already compromised perfusion [6].

These cases show that ulceration during propranolol therapy may not necessarily indicate treatment failure, but rather a potential adverse response requiring dose reassessment, adjunctive therapy, or temporary discontinuation, depending on the clinical context [11]. In the present case, reducing the dose and adding systemic corticosteroids were tried to manage potential ischemic ulceration related to propranolol; however, progressive tissue breakdown persisted, necessitating escalation of therapy.

Management of complicated or refractory infantile hemangiomas requires an individualized and often multimodal approach, particularly in cases presenting with deep components, ulceration, or poor response to standard therapy [3]. Although propranolol remains the primary treatment, delayed initiation, large lesion size, and mixed morphology have been associated with reduced effectiveness [12]. Additional therapies such as systemic corticosteroids have been used to suppress the inflammatory and angiogenic activity that contributes to rapid lesion growth and ulceration. In recalcitrant cases, short courses of oral prednisolone can provide transient improvement, particularly when combined with propranolol during the acute proliferative phase [1,3]. However, corticosteroid use is often limited by adverse effects and the possibility for relapse after discontinuation, highlighting the importance of timely reassessment and transition to alternative agents when no sustained response is observed [5]. In complex or treatment-resistant hemangiomas, multidisciplinary team management involving dermatology, infectious disease, hematology, and interventional radiology has been shown to improve outcomes and minimize complications [3,14].

Sirolimus, which acts as an inhibitor of the mammalian target of rapamycin [mTOR], has become a therapeutic option for patients with complicated or propranolol-resistant infantile hemangiomas [10]. Its mechanism involves suppression of the PI3K/Akt/mTOR signaling pathway, leading to reduced endothelial proliferation, angiogenesis, and inflammation processes central to hemangioma growth [8]. Its effectiveness has been demonstrated across a spectrum of vascular tumors and malformations, particularly in lesions refractory to standard beta-blocker therapy [8,10]. Clinical reports have shown notable regression in propranolol-resistant hemangiomas when sirolimus was introduced either as monotherapy or in combination with propranolol, with only mild and reversible side effects such as oral ulcers and hypertriglyceridemia [10]. Systematic reviews further support its role, reporting symptomatic improvement and lesion stabilization in the majority of treated patients, while emphasizing the importance of close hematologic and metabolic monitoring [8]. Overall, sirolimus is an effective and safe second-line option in select cases of propranolol-resistant infantile hemangioma. In the present case, sirolimus was initiated as part of rescue therapy; although ulcer progression persisted initially, subsequent stabilization following bleomycin sclerotherapy may have been facilitated by its anti-angiogenic effects [8,10].

Sclerotherapy has re-emerged as a valuable adjunctive or rescue therapy for complicated infantile hemangiomas, particularly those unresponsive to beta-blockers or presenting with ulceration and infection. The therapeutic effect of sclerotherapy is mediated through direct endothelial injury, intravascular thrombosis, and subsequent obliteration of abnormal vascular channels, resulting in lesion regression and volume reduction [9]. Combination strategies integrating sclerotherapy with systemic propranolol or corticosteroids can provide better outcomes than monotherapy, especially for deep or mixed lesions [15]. In a retrospective analysis of 56 patients with lip hemangiomas, the combination of oral propranolol and intralesional sclerotherapy resulted in complete or nearly complete regression in most cases, without significant complications [15]. These findings show that multimodal therapy, tailored to lesion characteristics, can optimize recovery while reducing recurrence, provided procedures are performed with precision and post-intervention monitoring [9].

In the present case, the patient presented with early ulceration and progressive tissue necrosis despite propranolol therapy, with diagnosis supported by clinical findings, imaging, and GLUT-1-positive histopathology. The clinical course was marked by rapid deterioration despite multiple medical therapies before eventual improvement following bleomycin sclerotherapy.

Similar findings have been reported in previous studies evaluating sclerotherapy for complicated infantile hemangiomas. In a large retrospective analysis, Wang et al reported significant regression of lesions following low-dose sclerotherapy, with an acceptable safety profile [9]. Likewise, Ling et al demonstrated favorable outcomes using propranolol combined with intralesional sclerotherapy for lip hemangiomas, achieving substantial lesion regression in most patients [15]. However, our case was distinguished by the severity of early ulceration, failure of multiple medical therapies including propranolol and sirolimus, and the rapid response observed after a single session of bleomycin sclerotherapy.

Severe or refractory ulceration in infantile hemangiomas remains one of the most challenging clinical scenarios, often associated with rapid deterioration, infection, and potential life-threatening bleeding [4]. Published reports identify shared risk factors such as large or segmental morphology, mixed components, and facial or perioral involvement [16]. Ulceration can be followed by arterial erosion or vascular compromise, and early white discoloration is a warning sign of impending tissue breakdown [6]. Fulminant cases with rapid ulcer expansion after propranolol initiation suggest a possible ischemic effect related to excessive vasoconstriction in susceptible lesions [6]. Interestingly, some atypical cases have shown rapid healing with conservative topical regimens, such as timolol and mupirocin, emphasizing that treatment should be individualized [17]. These observations confirm that ulceration in IH is a varied and dynamic process influenced by vascular anatomy, timing, and therapy, underscoring the need for careful monitoring and adaptable treatment strategies [16].

The management of complicated or propranolol-resistant infantile hemangiomas underscores the importance of individualized, multidisciplinary care. Current guidelines recommend early referral to vascular anomaly specialists for ulcerated or treatment-resistant cases [3]. Evolving treatment strategies now combine propranolol with adjunctive corticosteroids, sirolimus, and interventional approaches such as sclerotherapy or laser therapy in a stepwise manner [2]. Future research should aim to standardize the dosing and safety protocols for sirolimus and sclerotherapy, as well as developing predictive tools for poor responses to beta-blockers. Ultimately, precision, multidisciplinary management offers the best opportunity to improve both survival and quality of life for infants with severe or refractory hemangiomas [3,4].

Conclusions

This case underscores the challenge in managing ulcerated infantile hemangiomas that are refractory to standard medical therapy. Bleomycin sclerotherapy may be an effective and safe therapeutic option. Early multidisciplinary evaluation and timely escalation to interventional treatment may help prevent progressive tissue destruction and improve functional and cosmetic outcomes.