Clinical Characteristics and Treatment Options of Infantile Vascular Anomalies.

To analyze the clinical characteristics and treatment outcomes of vascular anomalies, and determine which therapy is safe and effective. The data of vascular anomalies pediatric patients who arrived at Beijing children's Hospital from January 2001 to December 2014 were analyzed retrospectively, including the influence of gender, age, clinical manifestation, diagnosis, treatment options, and outcomes. As to infantile hemangiomas, the outcomes of different treatments and their adverse reactions were compared. As to spider angioma and cutaneous capillary malformation, the treatment effect of 595 nm pulsed dye laser (PDL) is analyzed. A total number of 6459 cases of vascular anomalies were reclassified according to the 2014 ISSVA classification system. Among them, the gender ratio is 1:1.69, head-and-neck involved is 53.3%, the onset age within the first month is 72.4%, the age of initial encounter that younger than 6 months is 60.1%. The most common anomalies were infantile hemangiomas (42.6%), congenital hemangiomas (14.1%), and capillary malformations (29.9%). In treating infantile hemangiomas, laser shows the lowest adverse reactions rate significantly. Propranolol shows a higher improvement rate than laser, glucocorticoids, glucocorticoids plus laser, and shows no significant difference with propranolol plus laser both in improvement rate and adverse reactions rate. The total improvement rate of 595 nm PDL is 89.8% in treating spider angioma and 46.7% in treating cutaneous capillary malformation. The improvement rate and excellent rate of laser in treating cutaneous capillary malformation are growing synchronously by increasing the treatment times, and shows no significant difference among different parts of lesion that located in a body. Vascular anomalies possess a female predominance, and are mostly occurred in faces. Definite diagnosis is very important before treatment. In treating infantile hemangioma, propranolol is recommended as the first-line agent, and systemic use glucocorticoids should be considered when associated with serious complications. The 595 nm PDL is effective in managing superficial vascular malformations in childhood, and could attempt to increase the treatment times to improve the outcomes.

INTRODUCTION

Congenital lesions of abnormal vascular development are fairly common soft-tissue disorder in pediatric clinics. Traditionally, those anomalies were all considered as tumors until 1982, when a new classification system was created.[1] According to the classification system, vascular anomalies were divided into tumors and malformations based on their histology, biological behavior, and clinical presentation. This classification was soon adopted by the International Society for the Study of Vascular Anomalies (ISSVA).[2] The main distinction between vascular tumors and vascular malformations is that vascular tumors grew with cellular hyperplasia, but vascular malformations only represented a localized defect in vascular morphogenesis. At the 2014 ISSVA workshop in Melbourne, vascular anomalies were still divided into tumors and malformations as before. Furthermore, the new version was expanded, provided much greater details, and incorporated clinical associations.[3] Vascular tumors are subdivided into benign, locally aggressive or borderline, and malignant entities. The classic representatives of vascular tumors are infantile hemangiomas, which are further subdivided into patterns and different types. Noninvoluting (NICH) and partially involuting (PICH) were included in the congenital hemangioma. Pyogenic granulomas and other rare vascular tumors are also included in this category. Vascular malformations are subdivided into 4 main categories (simple, combined, of major named vessels, associated with other anomalies), based on the vessel types that are involved and the morphology of the affected area of the vascular system.[4] The lesions of vascular malformations usually present at birth, continue to expand over time, and sometimes, accompanied with other anomalies, such as soft tissue overgrowth, mucosal or ocular anomalies, etc.[5] The most common seen vascular malformations manifested as cutaneous capillary malformation (also known as port-wine stain) or telangiectasia. New data including causal genetic findings linked to the etiology of some identified vascular anomalies and syndromes were updated.

Most vascular tumors and malformations can be diagnosed clinically based on the lesion appearance. As to complicated cases, biopsy pathology and imaging examination such as magnetic resonance imaging (MRI) and ultrasound can be helpful to differentiate and confirmed the diagnosed. Though most cases are benign process and some of them have a spontaneous involution over their lifecycle, vascular anomalies can cause many functional complications. So, infants with vascular anomalies usually grow up with morbidity, cosmetic disfigurement or psychological disorder, such as social impairment, communication deficits, and social disability. Therefore, parents usually search for therapeutic methods anxiously. In serious cases, vascular anomalies may cause difficulty in feeding, ulceration, vision loss, airway compromise, disabled, or even death. Various therapeutic approaches had been described, proposed and applied to treat vascular anomalies,[6] including wait-and-see principle, laser therapy,[7] drug therapy (glucocorticoid, interferon, vincristine, imiquimod),[8] sclerotherapy (corticosteroid, bleomycin), radiotherapy, plastic surgery,[9] constraint treatment, etc., or a combination of these modalities. The 595 nm pulsed dye laser (PDL) was once commonly considered as the primary choice for vascular anomalies in pediatric patients,[10] and had performed for a long period.[11] In 2008, a serendipitous discovery was reported that propranolol can inhibit the growth of severe hemangiomas.[12] Since then, application of propranolol in treating infantile hemangiomas has rapidly spread across the world, and has greatly improved the cosmetic outcomes of hemangiomas.[13] However, an ideal option for all vascular anomalies was not exist.

The aim of this study was to analyze and compare retrospectively the clinical characteristics and treatment options of vascular anomalies, and determine which therapy is safe and effective.

METHODS

Patients and Clinical Characteristics

The study was conducted in accordance with the principles of the Declaration of Helsinki, and the study protocol was approved by the ethics committee of our hospital. Because of the retrospective nature of the study, patients consent for inclusion in this study was waived.

Children with vascular anomalies who arrived at Beijing children's Hospital from January 2001 to December 2014 were reclassified according to the 2014 new ISSVA classification. The clinical data of those pediatric patients were analyzed retrospectively, including their clinical characteristics, laboratory examinations, diagnoses, treatments, etc., in order to investigate the influence of gender, age, presence, and treatment options. As a general pediatric dermatology clinical, we do not treat acquired immunodeficiency syndrome (AIDS), so children infected with human immunodeficiency virus (HIV) and manifested as Kaposi sarcomas were not included in this study.

Treatment Protocols

For infantile hemangiomas, doses of glucocorticoids (prednisone) were 1 to 3 mg/(kg day), and doses of propranolol were 1 to 2 mg/(kg day), which is gradually increased or decreased according to the change of baby weights and outcomes of follow-up. For full-term infants, the optimum time of start to prescribe propranolol is after the first month. Preterm and low birth weight infants should start a little later, at least after baby weight reached 2500 g. The full course of oral propranolol should cover the whole rapid growth stage, last at least 6 months, until the lesion shrank or showed good cosmetic result.

The treatment parameter of PDL (Vbeam, Candela, USA) was set as follows: wavelength 595 nm, pulse width 0.45 to 40 milliseconds, fluence density 7 to 40 J/cm2, spot size 7 mm, frequency 1.5 Hz. Parameters were adjusted based on age, conditions of lesion (color, size, thickness, texture, volume), outcomes of the previous treatment, demands of parents, and other influencing factors. The commonly used parameters are: pulse width 3 to 20 milliseconds, fluence density 9 to 13 J/cm2. The optimum time of start treatment is after the first month, no matter preterm or not. The treatment-free interval was at least 4 weeks, and within this time frame, moisturizer, and sunscreen cream should be used all through.

Treatment Outcomes

Patients were divided into separate groups according to their treatment methods. As to infantile hemangiomas, the outcomes of each patient were evaluated based on improvement of volume, color, and texture, judged by the following scale[14]: poor (proliferated, or no further growth, or intolerable adverse effects, or 0 to 25% reduction in volume); fair (26–50% reduction in volume); good (51–75% reduction in volume); and excellent (76–100% reduction in volume). Reduction more than 51% in volume (good and excellent) is considered improved, and the improvement rates were calculated and compared. Besides, the thickness of hemangioma was rechecked by color Doppler ultrasound, and these changes were also considered and included in the evaluation system. As to cutaneous capillary malformation, similar evaluation system was implemented, and the outcomes of each patient were evaluated based on improvement of erythema faded rates, judged by the following scale: poor (continued expanded, or no further expanded, or intolerable adverse effects, or 0–25% fading in size); fair (26–50% fading in size); good (51–75% fading in size); and excellent (76–100% fading in size). Reduction more than 51% in size (good and excellent) is considered improved, and the improvement rates were calculated and compared. The satisfaction and approval of parents was also an essential factor to be considered. The evaluation of efficacy was performed by 2 unrelated dermatologists who did not involve in the treatment process. Adverse reactions of each different therapy methods were also recorded and compared.

Statistical Analysis

The Statistical Package for the Social Science (SPSS, Inc., Chicago, IL), version 21, was used for descriptive statistics. Crossovers were evaluated for significance using Pearson's Chi-square (χ2) tests, or Fisher exact test if needed. Significance was set at P less than 0.05.

RESULTS

General Information

From January 2001 to December 2014, there were a total number of 6459 pediatric patients with vascular anomalies arrived at Beijing children's Hospital. The most common anomalies were infantile hemangioma (42.6%, 2752/6459), congenital hemangioma (14.1%, 910/6459), and capillary malformations (29.9%, 1933/6459), which included spider angioma (14.0%, 907/6459) and cutaneous capillary malformation (12.3%, 796/6459) (Table 1, Figure 1).

TABLE 1

General Information About All of the Vascular Anomalies Children

FIGURE 1

Components of vascular anomalies in 6459 patients. Vascular tumors 60.4%. Vascular malformations 39.4%. (1) Infantile hemangiomas 42.6%. (2) Congenital hemangiomas 14.1%. (3) Other vascular tumors 3.7%. (4) Cutaneous capillary malformations 12.3%. (5) Spider angiomas 14.0%. (6) Other vascular malformations 13.0%. (7) Provisionally unclassified vascular anomalies 0.2%.

The gender ratio was 1:1.69 in total, 1:1.86 in tumors, 1:1.47 in malformations, shows vascular anomalies with a female predominance.

Clinical Characteristics

Among 6459 pediatric patients, 53.3% involved head-and-neck (3443 cases), followed by multiple lesions, upper limbs, lower limbs, and chest. In infantile hemangioma alone, 57.7% involved head-and-neck (Table 2). The lesions in Kasabach–Merritt syndrome were mainly located in lower limbs, shared 45.6% (31/68, in Table 2, 38 limbs included 7 upper limbs).

TABLE 2

Characteristics About Children With Vascular Tumors

The onset age within the first month is 72.4% in total cases (4678/6459). The rate of born with anomalies is 100% (910/910) in congenital hemangioma, 77.9% (53/68) in Kasabach–Merritt syndrome, 88.0% (1702/1933) in capillary malformations, 51.5% (17/33) in lymphatic malformations, 62.4% (141/226) in venous malformations.

The age of initial encounter that younger than 6 months is 60.1% in total cases (3884/6459), 64.6% in infantile hemangioma (1778/2752), 97.9% in congenital hemangioma (891/910), 98.5% in Kasabach–Merritt syndrome (67/68), but broadly dispersed in vascular malformations.

Treatment Options

Before 2008, glucocorticoids and laser therapy was the most common management used for treating vascular anomalies. Interferon, vincristine, imoquimod, sclerotherapy, radiotherapy, plastic surgery, constraint treatment were also performed in some cases according to specific conditions. Since 2008, patients treated by propranolol increased year by year. Some cautious parents, concerned about side effects deeply, full of worries about continuous administrating, chose wait-and-see principle. Some parents suspected the effect of propranolol, and still prefer to traditional glucocorticoids and laser therapy. So, among 2752 infantile hemangiomas patients, 20.9% treated with glucocorticoids (including intralesional injection and systemic use), 34.2% with laser, 11.3% with glucocorticoids plus laser, 16.8% with propranolol (including topical application), 2.4% with propranolol plus laser, 7.6% with other treatments, and 6.8% untreated (Table 3).

TABLE 3

Effects of Different Treatments on Infantile Hemangioma (Total: 2752)

For congenital hemangiomas, especially those rapidly involuting congenital hemangiomas (RICH), wait-and-see principle was the first option. For noninvoluting congenital hemangiomas (NICH) and partially involuting congenital hemangiomas (PICH), laser and plastic surgery was usually performed. So among 910 congenital hemangiomas patients, 59.8% (544/910) was just followed up and waited, 35.4% (322/910) was treated with laser, 4.2% (38/910) with plastic surgery, and 0.7% (6/910) with other treatments.

On account of thrombocytopenia, 85.3% of Kasabach–Merritt syndrome (58/68) turned to glucocorticoids systemic use. For pyogenic granuloma, 42.1% (62/147) chose laser, and 37.1% (55/147) chose surgery.

As for vascular malformations, laser is effective in helping to fade the superficial erythema. So, in spider angioma (nevus araneus), the most common vascular malformations seen in outpatient, 82.0% (744/907) turn to laser treatment, and in cutaneous capillary malformation, the rate is 78.3% (623/796). As to other vascular malformations, treatment methods included sclerotherapy (corticosteroid, bleomycin), radiotherapy, plastic surgery, constraint treatment, etc., or a combination of these modalities (Table 4).

TABLE 4

The Treatment Options of Vascular Malformations (Total: 2544)

As to infantile hemangiomas, the effect of different treatments shows significant difference across the 5 groups (P < 0.05). Through multiple comparisons (significance was set at P′ less than 0.005 here, P′ = P/10), there is no significant difference between the propranolol group and the propranolol plus laser group (P′ = 0.148), no significant difference between the glucocorticoids group and the glucocorticoids plus laser group (P′ = 0.675). But there is significant differences between other multiple compared groups (P′ < 0.005). Briefly, propranolol (90.0%) and propranolol plus laser (95.5%) shows no significant difference, and the 2 methods each shows better effect compared with laser (64.6%), laser plus glucocorticoids (55.3%), glucocorticoids alone (53.8%) (Table 3, Table 5).

TABLE 5

Comparison of Different Treatments on Infantile Hemangioma (Total: 2752)

Adverse reactions of glucocorticoid included central obesity, hirsutism, blood glucose risen, muscle wasting, infection, hypertension, etc. Adverse reactions of laser included erythema, postinflammatory hyperpigmentation, infection, cicatrix, acneiform eruption, etc. Adverse reactions of propranolol included diastolic blood pressure fallen, sleep disorder, mild diarrhea, hypoglycemia, cold extremities, bronchial hyperreactivity, elevated alanine transaminase/aspartate aminotransferase or creatine kinase isoenzyme, etc.[15,16] The adverse reactions of different treatments shows significant difference across the 5 groups (P < 0.05). Through multiple comparisons, there is no significant difference between the glucocorticoids group and the glucocorticoids plus laser group (P′ = 0.08), no significant difference between the propranolol group and the propranolol plus laser group (P′ = 0.72). But there is significant differences between other multiple compared groups (P′ < 0.005). Briefly, laser (3.0%) shows significant the lowest adverse reactions than all the other 4 groups. Propranolol (11.9%) and propranolol plus laser (13.4%) show no significant difference, and each of them shows significant lower adverse reactions than the glucocorticoids group and laser plus glucocorticoids group. Glucocorticoids (56.6%) and laser plus glucocorticoids (50.5%) show no significant difference (Table 3, Table 5).

In treating spider angioma, the improvement rate of laser is 89.4% in a single time of treatment, and 91.0% in twice, 88.4% in 3 times of treatment (Table 6). By increasing of treatment times, the improvement rate shows no significant difference (χ2 = 0.515, P = 0.773). In treating cutaneous capillary malformation, according to the difference of treatment times, the curative effect of laser shows significant difference both in improvement rate (χ2 = 162.4, P < 0.001) and in excellent rate (χ2 = 70.985, P < 0.001), but the adverse reactions rate (χ2 = 9.000, P = 0.109) shows no significant difference (Table 7, patients who received more than 6 times of PDL treatments were merge into 1 group as their numbers are few). Through linear regression analysis and Spearman rank correlation analysis, there is a positive correlation relationship between treatment times and improvement rate (F = 70.253, P = 0.001), and also a positive correlation relationship between treatment times and excellent rate (F = 109.807, P < 0.001) (Figure 2). As to the lesion that located in different parts, the effect of PDL shows no significant difference in improvement rate (χ2 = 10.004, P = 0.075) and in excellent rate (χ2 = 8.607, P = 0.126), and the adverse reactions rate (χ2 = 1.862, P = 0.868) shows no significant difference either (Table 8).

TABLE 6

Number of Treatment Times and the Effect of Pulsed Dye Laser in Treating Spider Angioma

TABLE 7

Number of Treatment Times and the Effect of Pulsed Dye Laser in Treating Cutaneous Capillary Malformation

FIGURE 2

Effect of pulsed dye laser in treating cutaneous capillary malformation, with different treatment times. With the increase of treatment times, improvement rate and excellent rate are growing synchronously. Through linear regression analysis and Spearman rank correlation analysis, there is a positive correlation relationship between treatment times and improvement rate (F = 70.253, P = 0.001), and also a positive correlation relationship between treatment times and excellent rate (F = 109.807, P < 0.001).

TABLE 8

Effect of Pulsed Dye Laser in Treating Different Areas of Cutaneous Capillary Malformation

DISCUSSION

Among all the vascular anomalies children, infantile hemangiomas, capillary malformations, and congenital hemangiomas were the most common anomalies, and show a female predominance. The gender ratio of infantile hemangiomas (1:1.82), congenital hemangiomas (1:1.51), vascular malformations (1:1.47) are all different from previous data (which showed the gender ratio of infantile hemangiomas is 1:3–6, congenital hemangiomas and vascular malformations occur with equal frequency in males and females).[17,18]

The lesions occurred on head-and-neck in more than half pediatric patients, displayed an interesting anatomical predilections.[3,19] From another point of view, head-and-neck involved spoiled appearances, so parents tempted to intensive or even aggressive medical treatment, but other parts of body involved usually be underappreciated by parents, and lead to a lower visitation rates. The lesions in Kasabach–Merritt syndrome were mainly located in lower limbs, maybe associated with a poor distal extremity and peripheral circulation.

In hemangiomas, no matter infantile, congenital, or Kasabach–Merritt syndrome, the age of initial encounter is focused on less than 6 months. But in vascular malformations, the age of initial encounter is very scattered. This may be because hemangiomas grow rapidly (infantile hemangiomas) or manifest fully developed at birth (congenital hemangiomas), but most vascular malformations grow slowly and steadily, or even unchanged at the initial stage.

In capillary malformations, the onset age is usually within the first month (88%), but in lymphatic malformations and venous malformations, the onset age is often after the first month. The reason may be partly because the lesions of capillary malformations is reddish or dark red patches on the surface of skin, and easy to noticed by scrupulous parents. As for other malformations, the lesions usually the same color as skin, and occurred deep under the skin, caused an overlook in early stages by those thoughtless parents.

Treatment Options and Outcomes

Unless accompanied with serious complications, vascular anomalies are usually benign disorder and not life-threatening. The biggest influence of them is just cosmetic problems. Therefore, it is very essential to strike a balance during the process of treatment, and to prevent performing excessively radical treatments. In some cases, the psychology of parents should also be considered.

The treatment of vascular tumors or vascular malformations is differently nowadays. So, before treatment, the first principle that should be followed is to differentiate and diagnostic the lesion clearly and definitely, especially in those infants with complex anomalies or syndromes.[20]

In treating infantile hemangiomas, numerous treatment options are available, but deciding which modality to pursue is dependent on a detailed and accurate assessment of the disease process. Historically, laser is once widespread used to treat various vascular anomalies, as a main approach or as an adjunctive therapy. In our study, PDL is effective in treating infantile hemangiomas indeed,[21] and even, its improvement rate (64.6%) is high than cutaneous capillary malformation (46.7%). But compared with propranolol, PDL has a lower improvement rate and excellent rate.[22] Thus the role of PDL could not be overstated. The improvement rate of PDL combination with propranolol, when compared with propranolol, shows no significant difference. Meanwhile, the adverse reactions rate shows no significant difference either. So, in our experience, oral propranolol should the first-line therapy in treating infantile hemangiomas, and PDL could be recommended to use in superficial lesion of hemangiomas as an adjuvant therapy in order to promote involution.[23,24] Besides, topical application of β-adrenoceptor blocker (β-adrenoceptor antagonist) is also a preferred option for some superficial lesions,[25,26] but the effect of topically external use of β-adrenoceptor blocker (different drugs, different preparation, and different dosage regimen, such as ointment, gel, membrane, sustained-release reagent, etc.) compare to oral propranolol in treating infantile hemangiomas with different types (superficial, deep, mixed) are still needed to be further discussed. The expectation of intensive treatment was associated with serious complications (such as thrombocytopenia in Kasabach–Merritt syndrome) or lesions located in particular region (such as eyelid, orbit, nasal cavity, pharynx, larynx, perineum), which could cause destructive dysfunction or even life-threatening symptoms. In such circumstances, systemic glucocorticoids should be considered.

Vascular malformations are not unusual anomalies, shared nearly 40% in total cases. They are diverse variety disorders, and their clinical presentation is not only just vascular structural abnormalities, but also more frequently complicated with vascular function abnormalities, and sometimes associated with other anomalies. Treatment options are relatively few. As for spider angioma and cutaneous capillary malformation, the most common vascular malformations in pediatric clinic, laser is a less invasive approach, and could been used to handle the lesions.[27,28] For superficial lesions, 595 nm PDL is very sensitive and effective, and for deep lesions, 1064 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is available for alternative. Unlike adult, the lesions of infants are much shallower and smaller, so PDL is enough in handling most regular vascular malformations. Even so, the effect of laser with different wavelength (532, 577, 585, 595, 1064 nm, etc.) in treating various capillary malformations in children among different age groups are still needed to be further discussed.

The most common vascular malformation is spider angioma, a subclass of telangiectasia, which may be related to the infection of hepatitis B in some cases. So, child with spider angioma child are usually suggested to make an appointment with physicians and begin antiviral therapy if necessary. As to the superficial lesion, laser is effective in helping to fade the erythema and to make a cosmetic improvement.

As shown in our study, the improvement rate (46.7%) and excellent rate (14.9%) of PDL in treating cutaneous capillary malformation is relatively lower in infants than in older children or adults. The reason account for this discrepancy may be partly related to the treatment times. Nearly half of the infants (45.7%, 285 infants) received no more than twice treatments, shows a low improvement rate (23.2%), but with the increase of treatment times, improvement rate and excellent rate are growing synchronously (Figure 2). For those infants who received more than 5 times of treatment (21.7%, 135 infants), the improvement rate is 82.2%, which is much close to the datum of adult. So, if the PDL treatment remain acceptable and withstand in patients and their families, we suggest adopting a measures of increasing treatment times in order to improve outcomes. For some less efficacious hypertrophic or profundus cutaneous capillary malformation, long-pulsed 1064 nm ND:YAG laser[29] or topical application of rapamycin[30] can be try with cautious, but further research is needed to better understand the best treatment for these complicated presentations.

As to other vascular malformations, selective operation could be performed to correct complex deformities.[31] For lymphatic malformations, oral sildenafil may be a new approach.[32,33] Propranolol is not appropriate for venous malformations, arteriovenous malformations, and arteriovenous fistula, as it only achieved a light improvement initially in single cases. Further therapeutics, such as vincristin, marmistat, are still underway, as them either undertaking a significant risk with questionable success or only applied in older children before. In summary, it can be stated that small and unifocal malformations usually can be treated curatively, but combined, associated with other anomalies, diffuse, multifocal malformations are a major therapeutic challenge, and often bear the high risk of recurrence and progression.[20]

CONCLUSIONS

Infantile hemangiomas, capillary malformations, and congenital hemangiomas were the most common vascular anomalies, which possess a female predominance, and are more inclined to occur in head and neck areas. Before treatment, the first principle that should be followed is to diagnostic clear, especially in those infants with complex anomalies, mixed tumor, tumor accompanied malformations, or multisystem syndromes. Pathological examination can be helpful to differentiate and confirmed the diagnosed in those complicated cases. Propranolol is recommended as the first-line agent in treating infantile hemangiomas, when associated with serious complications, systemic use glucocorticoids should be considered. The 595 nm PDL is effective in managing superficial vascular malformations in childhood, and could attempt to increase the treatment times to improve the outcomes.