Introduction

Vascular anomalies are divided into tumors and vascular malformations (VaMs)¹-³. Tumors originate from vascular proliferation; infantile hemangiomas are the most common and well-known¹. VaMs arise from errors in embryonic vasculogenesis, are present at birth (although not always evident), and do not involute. They can affect capillary, venous, arterial, and lymphatic vessels. VaMs have a variable clinical spectrum, ranging from skin spots to complex lesions with significant symptoms and impact on quality of life².

The International Society for the Study of Vascular Anomalies (ISSVA) classification³ divides VaMs into four groups: (1) Simple: A single type of vessel affected, (2) Combined: ≥ 2 types of vessels affected, (3) Large vessel or truncal, and (4) Associated with other anomalies or syndromic (Table 1).

The incidence of VaMs is 0.3-1.5% in the general population and 5-10% in the pediatric population⁴. There is no sex predilection, and they occur sporadically. VaMs can affect localized areas or might involve extensive or segmental body surfaces². Treatment varies depending on the affected vessel, location, size, and associated affected structures and can be conservative or interventional. In recent years, signaling pathways involved in the pathophysiology of VaMs have been identified, which has led to new therapeutic modalities such as sirolimus⁵.

The vascular anomalies clinic (VAC) at our referral institution was established in 2012 to provide comprehensive medical care to a specific patient population referred between institutions and internal services due to the complexity of their conditions. This study aimed to describe the demographic and clinical characteristics of the patients treated, the type of VaMs they presented with, the treatment received, and their response to treatment.

Methods

The study design was descriptive, observational, retrospective, and cross-sectional. The institutional committees approved the study protocol with registration number INP2021/022.

Records of patients with VaMs treated at the institutional VAC from January 01, 2012, to February 28, 2022, were reviewed. The variables studied were sex, age, final diagnosis according to ISSVA, date of symptom onset, type, size, distribution, depth, topography, symptomatology of the VaMs, number of visits to the VAC, treatment received, response, and treatment-associated complications. Patients whose records had < 80% of the analyzed variables were excluded from the study. As VaMs have heterogeneous involvement, for their study, we divided the patients into three categories according to distribution: (1) localized, affecting a single circumscribed body area; (2) segmental, affecting a body segment; and (3) extensive, affecting > 1 body segment. The depth of the VaMs was categorized into three groups based on physical examination and imaging studies: (1) superficial in skin and soft tissues, (2) deep in muscle, joints, and/or bone, and (3) mixed if they affected both of the above. Treatment response was evaluated according to three parameters: (1) clinical: comparison of clinical photographs before and after treatment, (2) radiological: comparison of radiological studies, and (3) functional: semi-quantitative evaluation by the patient and/or caregivers regarding volume reduction, pain reduction, and other symptoms, increased mobility or functionality, among others. These three types of response were quantified in a range of 0-100%, and the result was classified according to the following parameters: excellent (75-100%), good (50-74%), moderate (25-49%), and poor/no response (0-24%).

Descriptive statistics were used for continuous quantitative variables using measures of central tendency, as well as dispersion measures and proportions were used for qualitative variables.

Results

A total of 435 patients from 23 states were included in the study. The most frequent distribution was localized (351, 80.6%) and superficial involvement (195, 44.8%). The predominant topography was head and neck (212, 48.7%) (Figs. 1-3), followed by extremities (182, 41.8%) (Figs. 4 and 5). In general, the main signs and symptoms were increased volume (425, 97.2%), change in skin color (285, 65.5%), and pain (189, 43.4%) (Table 2). The age at which the signs and symptoms initially manifested varied widely from birth to 15 years (median of 1 month); it was not reported in 9 (2%) patients.

Figure 1 A: a 3-year-old patient with lymphatic malformation in the glabellar, periocular, cheek, and right auricular regions. B: after treatment with bleomycin sclerotherapy and sirolimus treatment. 

Figure 2 A: a 12-year-old patient with periorbital and intraconal lymphatic malformation. B: after treatment with sirolimus. 

Figure 3 A: a 6-year-old patient with venolymphatic malformation in the tongue and neck. B: after treatment with alcohol sclerotherapy. 

Figure 4 A: a 3-year-old patient with venolymphatic and capillary malformation in the right hemibody and arm. B: after treatment with surgery and sirolimus. 

Figure 5 A: a 3-month-old patient with Klippel-Trenaunay syndrome in the right lower limb. B: after treatment with sirolimus. 

Manifestations in specific areas were reported. In patients with head and neck involvement, these were dysphagia, otalgia, odynophagia, loss of teeth, stridor, apnea, language disorders, and inability to eat (Fig. 1). In VaMs affecting the ocular area, eyelid edema, proptosis, visual field, or visual acuity alteration were found (Fig. 2). Localization in the extremities was accompanied by paresthesia, dysesthesia, soft-tissue hypertrophy, pruritus, cellulitis, infection, and pathological fractures (Figs. 4 and 5). Cavity involvement caused pleural effusion, airway compression, hematochezia, melena, and anemia.

The final diagnoses established in the VAC according to the ISSVA 2018 classification were 20 different ones (Table 3). Simple VaMs predominated in 300 patients (68.9%): lymphatic followed by venous and arteriovenous (Fig. 6). The next group was combined VaMs in 109 patients (25.0%), and of these, venolymphatic malformations were the most frequent (Fig. 3). Seven types of VaMs associated with other anomalies were identified; Klippel-Trenaunay syndrome was the most common in 15 (3.4%). Within the group of provisionally unclassified vascular anomalies, we found three patients diagnosed with fibroadipose vascular anomaly (FAVA). Regarding clinical follow-up, the patients had 931 consultations at the VAC, with a median of 2 per patient (range 1-12).

Figure 6 A 5-year-old patient with an arteriovenous malformation in the left hip. 

A total of 339 patients (77.9%) received treatment, with radiological interventions being the most frequent in 281 (82.8%), followed by medical or symptomatic treatment in 167 (49.2%), and surgical treatment in 63 (18.5%) (Table 4). One hundred and 25 patients (36.8%) received more than one therapeutic modality during the studied period, with a median of two modalities per patient (range 2-4).

Sclerotherapy was performed in 249 (73.4%) patients, with a median of 2 (range 1-15) procedures per patient, for a total of 698 procedures. The main conditions treated with this modality were lymphatic malformations (LMs) in 101 patients (40.5%), venolymphatic malformations in 51 patients (20.4%), and venous malformations in 50 patients (20.0%) (Fig. 3). According to the individual characteristics of each patient's VaMs and institutional availability, various drugs were used for sclerotherapy: bleomycin, polidocanol, absolute alcohol, 50% glucose solution, or OK-432. The functional therapeutic response was excellent in 59.6% of patients and good in 30.7% (Table 5). Complications were reported in 11 patients (4.4%) and were fibrosis (3), necrosis (2), unsightly scar (2), soft-tissue infection (1), facial paralysis (2), and rash (1).

Embolization was performed in 32 patients (9.4%), with a median of 1 (range 1-5) procedure per patient, for a total of 52 procedures. The agents used were hystoacril, polyvinyl alcohol, and coils. Seven patients were treated exclusively with embolization; the response was excellent in 25% of patients and good in 50% (Table 5). Complications occurred in 4 patients (12.5%): cerebrovascular disease, caudate nucleus infarction, left hemifacial paralysis, and retractile scar.

Surgical treatment was performed on 59 patients (17.4%), mainly with LM in 19 (32.3%). Of these, 14 patients received only surgical treatment, and an improvement classified as excellent was reported in 90-100% (Table 5). Six patients (10.1%) presented complications: nociceptive pain syndrome (1), functional incapacity (1), adhesions (1), soft-tissue infection (2), and esthetic alteration (1).

Medical treatment was given to 165 (48.6%) patients, with sirolimus being the most common in 63 (18.5%), and as adjuvant or symptomatic treatment, the use of compression stockings in 43 (12.6%) (Table 4). Sirolimus treatment was indicated in patients with VaMs related to mutations in the mTOR pathway, mainly simple (lymphatic) in 17 patients (26.9%), combined low-flow (venolymphatic) in 22 (34.9%), and associated with other anomalies such as Klippel-Trenaunay syndrome in 8 (12.6%) (Table 6 and Fig. 5). In four patients, it was discontinued due to adverse effects associated with the medication: mucositis (2), infection (2), and increased triglycerides (1), and in nine patients due to loss of follow-up. In patients who received sirolimus alone, the functional response was excellent in 31.8% and good in 54.5%. In 29 patients treated with sirolimus after receiving other therapeutic modalities, the functional therapeutic response was excellent in 41.6% and good in 37.5% (Table 5).

According to the type of VaMs, we found that patients with simple and combined VaMs received sclerotherapy more frequently (239, 58.4%), while those with VaMs associated with other anomalies received mainly medical treatment (16, 69.5%) and symptomatic treatment (16, 69.5%) (Table 6).

Discussion

VaMs can present with a variable clinical spectrum depending on the type of vessel affected, location, size, and depth. Due to the complexity of VaMs, the initial diagnosis is sometimes difficult, and they can be confused or misnamed, which delays appropriate treatment and does not allow for an accurate prognosis for patients⁶-⁸. Primary care physicians must know each VaMs type's correct classification and clinical characteristics to allow for a correct diagnostic approach and timely referral⁸. Non-invasive diagnostic tests (doppler ultrasound, magnetic resonance imaging) and sometimes invasive tests (arteriography or biopsy) are generally required to classify VaMs correctly. Once an accurate diagnosis is established, the required management can range from expectant observation to multidisciplinary interventional treatment, depending on the VaMs type⁶. For these reasons, it is recommended that a step-by-step diagnostic approach and comprehensive management to be established, ideally by a collaborative multidisciplinary team such as VACs⁶,⁷,⁹. The VAC in our institution was established in 2012 in response to institutional needs as a referral center for patients with complex VaMs. It holds weekly sessions with a fixed multidisciplinary team and support specialists.

Referred patients are assessed by one of the services, usually dermatology, and are scheduled with initial radiological studies (ultrasound or magnetic resonance imaging) at the VAC. Once there, a complete physical examination is performed again, and radiological studies are analyzed (new studies are indicated if necessary). A diagnosis is made according to the ISSVA criteria, and a treatment is proposed to the patient and their parents. Follow-up is done again at the VAC to assess the response to radiological or surgical treatment. In the outpatient clinic, the relevant services are provided depending on each case and the type of treatment.

Ten years after the start of the VAC, we conducted this study seeking to describe the clinical characteristics of the Mexican pediatric population with VaMs treated so far, as well as their clinical evolution and response to the treatments employed.

We found that simple VaMs were the most frequent, including LMs, followed by combined venolymphatic, venous, and arteriovenous malformations. This is similar to what has been previously reported in the literature, where simple malformations are the most common; however, in other studies, venous malformations predominate⁶,⁷, which may be because the population treated in our VAC is pediatric, and LMs frequently become evident after infectious processes, unlike venous malformations, whose clinical course is more chronic and slower.

The most frequent location in our study was the head and neck, followed by the extremities (mainly lower), which is consistent with the literature⁷. Airway involvement was infrequent; however, early identification is vital to avoid complications. All patients studied manifested symptoms or signs (100%), specifically increased volume, change in color, and pain, coinciding with the clinical presentation described in the literature⁷,¹⁰.

At the VAC, the most commonly used interventional radiology treatment was sclerotherapy in 56.6%, mainly for LMs, followed by venolymphatic and venous malformations. In similar studies, the most frequently used treatment was also sclerotherapy in 36-49%, coinciding with the type of VaMs treated with this modality⁷,¹¹. Sclerotherapy sessions were performed every 1-2 months, with two sessions per patient. In similar studies, an average of 2-3.7 procedures per patient is reported. In our study, approximately 90% of patients who received this therapeutic modality had an excellent and good response, similar to previous reports. Sclerotherapy is considered a useful procedure to improve the symptoms and size of VaMs with a lymphatic and/or venous component in those who undergo it before reaching puberty¹². Possible side effects of sclerotherapy include allergic reactions to sclerosants, pain, neurological alterations derived from the procedure, embolic complications, necrosis, pigmentation at the puncture site, or induration¹²,¹³. In our patients, complications associated with sclerotherapy occurred in 8.0% and were mainly fibrosis, esthetic alteration, and infection, coinciding with the literature⁷.

Embolization is used more frequently in high-flow malformations; it is considered helpful to reduce bleeding in case of severe symptoms or before a surgical procedure. To achieve therapeutic success, it is necessary to completely embolize the central vascular nidus¹⁴. In this study, 78.1% of patients treated with embolization had an arteriovenous malformation¹⁴,¹⁵. Only one intervention per patient was required, in general, and complications occurred in 12.5%: cerebrovascular disease, caudate nucleus infarction, left hemifacial paralysis, and retractile scar. Various complications have been described in the literature, including those reported in our patients. However, because the drugs and techniques are different, it is difficult to assess their actual frequency¹⁵.

Surgical interventions were the least frequent treatment in our clinic (17.4%); however, surgery is the most frequent therapeutic modality in centers where debulking and amputations are performed⁶.

Some VaMs are caused by mutations in the PIK3CA, RAS, and GNA gene families. Mutations in PIK3CA are involved in some syndromes with overgrowth and various types of simple or combined low-flow malformations. Mutations in genes in the RAS pathway (KRAS, MAP2K1, BRAF) are mainly associated with high-flow or arteriovenous malformations (Fig. 6)⁵. All these genes encode membrane-associated proteins that control endothelial cells' proliferation, differentiation, and organization and are closely linked to the mTOR pathway. Identifying these mutations and affected pathways has allowed the repositioning of therapeutic options. One of them is sirolimus, a specific mTOR inhibitor that has shown efficacy in VaMs and has become the first-line treatment, alone or as an adjuvant, in patients with extensive LM, VM, or combined low-flow malformations and those associated with overgrowth⁵,¹⁶. The recommended dose is 0.8 mg/m² until 10-15 ng/mL levels are reached¹⁷. Adverse effects reported with the use of this medication include mucositis, gastrointestinal problems, soft-tissue infections, alteration of laboratory parameters of liver and lipid profiles, pneumonia, and, to a lesser extent, bone marrow suppression and recurrence of basal cell carcinoma⁶,¹⁸. Currently, in our VAC, we have treated 56 patients with sirolimus, showing an excellent and good response in > 75%, and only 4 patients have had to discontinue treatment due to mild adverse effects.

Pulsed dye laser and intravascular lasers are other therapeutic options that can be used to treat VaMs⁶; however, our institution does not have other modalities.

The benefits of specialized multidisciplinary clinics have been well described, including enhancing the patient experience, improving population health, and reducing per capita costs⁹. We have observed these benefits throughout the years that VAC has been operating. First, patients can be evaluated by multiple specialists simultaneously, which streamlines time and costs for the institution and the patients themselves⁶,⁹. Moreover, this space allows for the discussion of each patient's case by the group of specialists together, taking into account previous diagnostic studies and clinical characteristics, aided by existing literature, instead of each specialist evaluating and concluding an opinion on their own. This allows for an accurate diagnosis and an appropriate treatment plan for the patient and their family. In addition, the latter have the opportunity to ask questions and resolve their doubts before the entire group of specialists⁶. Since the VAC was initiated in our institution, we have become a national referral center and a support center for specialists in other regions. We have had internal challenges, such as logistical issues for scheduling appointments, administrative support, and a lack of human and financial resources. However, our biggest challenge is that there is no VAC in our country to provide care for adult patients with VaMs, so on reaching the majority age, patients are referred to various tertiary-level care institutions. However, in many cases, follow-up is lost.

This study has limitations, such as loss of information in the medical record or lack of patient follow-up. In addition, the VAC does not treat patients with isolated capillary malformations or vascular tumors, so we did not include these conditions. Finally, there are no validated measures or tools to assess treatment response or effectiveness in patients with VaMs due to their wide range of clinical manifestations and inter-individual variability⁶, so we used semi-quantitative categories to describe the therapeutic response.

However, this study of 435 pediatric patients with VaMs is the largest in our country and one of the largest in the global literature. We describe the frequency of VaMs, associated clinical manifestations, treatment, and clinical evolution of a cohort of patients with follow-up over 10 years, generating relevant information to guide medical care of these patients. We confirm the importance of comprehensive and multidisciplinary care for patients with VaMs and hope that more institutions will use this experience to form multidisciplinary clinics to diagnose and treat patients with these complex conditions that significantly affect their quality of life.

Conclusion

The most common VaMs in this retrospective study in a multidisciplinary clinic for the care of children were lymphatic, venolymphatic, and venous malformations; the age at presentation is very early. The most frequent associated symptoms were increased volume, change in skin color, and pain. Sclerotherapy and sirolimus were the main treatments, with a good and excellent response.