Itraconazole Oral Solution for Infantile Complicated Hemangioma with Double Lesions on the Skin and One Inside the Liver

Introduction

Infantile hemangioma (IH) is a congenital benign tumor formed by the proliferation of vascular cells during embryonic stages, affecting 1% to 2.6% of newborns and up to 10% of children by the first one year of age.¹ It is more common in the skin but can occur in the mucous membranes, liver, brain, and muscle.¹ Infantile hepatic hemangioma (IHH) is a benign tumor that originates from endothelial cells and is usually slowly progressive during childhood. Although most infants are asymptomatic and often overlooked by the parents and doctors, 15% may develop high-output cardiac failure, resulting in considerable mortality.^2–4 Current treatment methods for hepatic hemangioma include oral propranolol, systemic glucocorticosteroids, interferon, vincristine, cyclophosphamide, embolization, hepatic artery ligation, hepatectomy and liver transplantation.^5–10 However, many treatments have low success rates and a high risk of side effects. Kassarjian et al¹¹ reported that pharmacologic therapy fails in about one-third of patients, with an associated mortality rate of 11%. Oral propranolol is the first-line treatment for cutaneous hemangioma with hepatic complications, occasionally, its potential side effects, including drowsiness, bradycardia, low blood pressure, and hypoglycemia, are clinical concerns that needs attention.¹²

Itraconazole (ICZ), a key member of the triazole antifungal family, is widely used in clinical antifungal drugs and has recently been found to possess antiangiogenic and inhibition of mTOR pathway and hedgehog activity. Our team has previously reported cases in which ICZ was used in infants with hemangioma.^13,14 Herein, we report a case of infantile cutaneous hemangioma complicated with hepatic hemangioma treated by oral ICZ solution. Dermoscopy and color ultrasound images play a vital role in the diagnosis and in the therapeutic efficacy monitoring.

Case Presentation

A full-term fraternal twin male infant presented at 1 week of age with irregular erythema on the left anterior chest and left upper abdomen. The lesions gradually bulged, enlarged, brightened, and developed progressively into elevated erythema plaques (Figure 1). The patient was treated with topical 0.5% timolol maleate eye drops for one month in other hospital before the current treatment, but it did not stop the IH from growing. Physical examination revealed two irregular erythematous plaques of approximately 3.0 × 1.8 cm in size on the left anterior chest and 2.6 × 1.4 cm in size on the left upper abdomen (Figure 1). Dermoscopy revealed an intensive vascular network (Figure 2). The multiple lesions prompt us screening for liver hemangioma.¹⁵ Indeed, abdominal ultrasound revealed an approximately 1.3 × 0.9 × 1.5 cm hemangiomatoid solid mass in the patient’s right liver (Figure 3), and the hemogram showed an abundant blood flow signal in the mass (Figure 4), the diagnosis was consistent with Infantile hepatic hemangioma (IHH). After fully communicating with the mother and informing her of the benefits and risks of itraconazole and propranolol, the mother gave her consent and chose to be treated with itraconazole. Then, the patient was administered ICZ oral solution (Sporanox, Janssen Pharmaceutica N.V., Belgium) at 5.0 mg/kg/day. After 6 months of treatment, the skin lesion became flat and was significantly reduced in size (Figure 5); dermoscopic features showed a distinct vascular network and fewer capillary branches (Figure 6). Two repeat ultrasounds of the patient’s abdomen (4 and 7 months after starting the ICZ oral solution) revealed a progressive decrease in the size of the IHH, and the internal blood flow signal disappeared (Figures 7-9); therefore, the treatment was terminated at 9 months. The total dosage of oral solution is 10,500 mg ICZ. A follow-up 2 months later showed that the lesions had almost disappeared, with only residual skin erythema remaining (Figures 10 and 11), and ultrasounds showed that the IHH had completely disappeared (Figure 12). During the whole course of treatment, the child occasionally had mild diarrhea which spontaneous remission without stop of ICZ, his liver function and blood routine examination are within the normal range, without any other problems. Until the age of 40 months, no recurrence of hemangioma was observed.

Figure 1 Two irregular erythematous plaques hemangioma on the left anterior chest and on the left upper abdomen. The black arrow indicates the observation area for the dermoscope.

Figure 2 Dermoscopy (amplification ×33) revealed an intensive vascular network. The black arrow indicates the same landmark for comparative dermoscopic observations.

Figure 3 A two-dimensional grayscale diagram before treatment revealed an approximately 1.3×0.9×1.5 cm hemangiomatoid solid mass in the patient’s right liver. The white circle indicates the location of the hepatic hemangioma.

Figure 4 The hemogram showed an abundant blood flow signal in the mass before treatment. The white circle indicates the location of the hepatic hemangioma.

Figure 5 After 3 months of treatment, the two-hemangioma lesion became flat. The black arrow indicates the observation area for the dermoscope.

Figure 6 After 3 months of treatment, the intensive vascular network gradually disappeared. The black arrow indicates the same landmark for comparative dermoscopic observations.

Figure 7 After 4 months of treatment, the solid mass in the right liver shrank to approximately 0.9×0.9 cm. The white circle indicates the location of the hepatic hemangioma.

Figure 8 The internal blood flow signal disappeared after 4 months of treatment. The white circle indicates the location of the hepatic hemangioma.

Figure 9 By the seventh month of treatment, the mass had shrunk to a 0.5 cm echogenic area. The white circle indicates the location of the hepatic hemangioma.

Figure 10 2 months after termination of treatment, the lesions had almost disappeared, with only residual skin erythema remaining. The black arrow indicates the observation area for the dermoscope.

Figure 11 2 months after termination of treatment, the vascular network has almost completely disappeared. The black arrow indicates the same landmark for comparative dermoscopic observations.

Figure 12 The last follow-up showed no significant liver abnormalities.

Discussion

IH is the most common benign soft tissue tumor in children, and it is usually formed within one week after birth. These lesions usually grow rapidly after birth and gradually degenerate in childhood. The first 3–6 months is known as the proliferating phase, but growth may also last for one year or even longer.^16–18 Although IH usually presents as isolated skin lesions, multiple IH lesions are not uncommon and may involve extracutaneous organs, most commonly, the liver.¹

IHH is the most common hepatic tumor in neonates,¹⁹ and it occurs in early infancy, as no clinical symptom it is always overlooked, and most tumors spontaneously resolving, similar to IH. In addition, some IHH lesions express the same glucose transporter (GLUT)-1, a glucose transport protein normally present in erythrocytes and endothelial blood-tissue barriers as IH,^20,21 which suggests that cutaneous and liver hemangiomas may originate from the same source. According to the imaging features, IHH can be classified into three categories: focal, multifocal, and diffuse.²² Clinical manifestations may include abdominal distention, abdominal mass, or a large liver, and there is occasional discovery without any clinical symptoms. Although focal IHH is a morphologically isolated and rapidly regressing hemangioma, jaundice, hepatomegaly, cardiac insufficiency and thyroid dysfunction are not uncommon conditions developed from this tumor type. In addition, multifocal and diffuse types are more harmful to infants. Among 91 IHH cases reported by Selby et al, 11% were complicated with cutaneous hemangioma, and 15% were complicated with congestive heart failure.²³ Thus, hepatic hemangioma, although histologically benign, may be associated with significant morbidity and mortality in affected infants and thus requires clinical intervention.²⁴

Oral propranolol is considered a first-line treatment for cutaneous hemangioma complicated with hepatic hemangioma. However, recent studies have found that multifocal and diffuse lesions are sensitive to propranolol with a good effect, but the efficacy of local lesions is still not clear.^25,26 In addition, there are still potential side effects to consider, which can manifest variably as lethargy, restlessness, cool skin, and decreased appetite.¹² ICZ is a key member of the triazole antifungal family, which has been widely used for more than 40 years,²⁷ the efficacy and safety in infants were approved.²⁸ It has been reported to inhibit angiogenesis.^29,30 In 2015, our team found that ICZ had a positive effect on the treatment of IH, which was further confirmed in later treatment practice.^13,14 Research also demonstrated that oral itraconazole can be an equivalent option for oral propranolol while safer and shorter treatment periods.³¹ We found that ICZ can induce IH regression by downregulating the platelet-derived growth factor-D/PI3K/Akt/mTOR pathway.³² Certainly, research on the use of itraconazole in the treatment of hemangioma is limited at present. Further studies are necessary to comprehensively determine its safety and efficacy, especially in comparison with propranolol.

In this case, IH showed significant improvement after 3 months of ICZ treatment; the abdominal ultrasound revealed a significant reduction in the volume of IHH 4 months later and showed that it had disappeared after nearly 9 months of treatment. During the whole treatment, hepatic and renal function remained normal, with only mild diarrhea. Timolol maleate eye drops were topically applied for 1 month before the current treatment, but it did not stop IH from growing, which suggests that the infant was in the proliferative period during treatment with ICZ and was unlikely to undergo spontaneous resolution alone. Liver function can be conveniently monitored before and after ICZ treatment, and the cherry flavor of the oral liquid preparation is conducive to infant acceptance. The infant in this case had no recurrence of skin or liver hemangioma during the nearly 6-month follow-up period. However, since this is the first case using ICZ oral solution for the treatment of infantile cutaneous hemangioma complicated with hepatic hemangioma, more clinical trials are needed for confirmation. Our case indicates, at least, ICZ can be used as one of the complementary therapy for the treatment of IHH.

As a noninvasive testing tool in dermatology, dermoscopy can be used to observe the changes in skin lesions more clearly by adjusting the magnification ratio. Moreover, apply color Doppler ultrasound to screen out IHH inside liver, and, dynamically monitor the imaging changes during treatment, is very important, especially in the baby with multiple cutaneous hemangioma.^15,33

Conclusion

ICZ oral solution for the treatment of infantile cutaneous hemangioma complicated with hepatic hemangioma shows good efficacy, safety, and enables good patient compliance in this case. Thus, it may be used as a complementary therapy for infantile cutaneous hemangioma and liver hemangiomas. Dermoscopy and the observation of abdominal color via ultrasound can be used as tools to monitor changes in disease progression before and after treatment of cutaneous and hepatic hemangiomas for effective treatment evaluation.