Infantile Hemangioma: Clinical Guidelines

List of Abbreviations

AFP – alpha-fetoprotein

CG – congenital hemangioma

IH – infantile hemangioma

KHE – kaposiform hemangioendothelioma

CT – computed tomography

MRI – magnetic resonance imaging

RDS – respiratory distress syndrome

Ultrasound – ultrasound examination

CDCU – color duplex scanning

ECG – electrocardiography

EchoCG – echocardiography

GLUT1 (Glucose transporter 1) – glucose transporter protein

FGFa/FGFb (Fibroblast Growth Factors) – fibroblast growth factor a/b

HIF-1 (hypoxia-inducible factor) – hypoxia-inducible factor

IH-MAG (Infantile Hemangioma – Minimal or Arrested Growth Hemangioma) – abortive IH or reticular IH

ISSVA (International Society for the Study of Vascular Anomalies) – International Society for the Study of Vascular Anomalies

LUMBAR (Lower Body hemangioma, Urogenital anomalies, Ulceration, Myelopathy, Bony deformities, Anorectal malformations, Arterial anomalies, and Renal anomalies)

MMPs (Matrix Metalloproteinases) – matrix metalloproteinases

NICH (Non-Involuting Congenital Hemangioma) – non-involuting congenital hemangioma

PCNA (proliferating cell nuclear antigen) – proliferating cell nuclear antigen

PHACE (Posterior fosse abnormalities/Hemangioma/Arteries anomalies/Coarctation aortic/Eyes troubles/Sternal malformations)

PICH (Partially Involuting Congenital Hemangioma) – partially involuting congenital hemangioma

PELVIS (Perineal angioma, External genital malformation, Lipomyelomeningocel, Vesicorenal abnormalities, Imperforate anus, Skin tag)

PP (propranolol) – propranolol in the dosage form "oral solution"

RICH (Rapidly Involuting Congenital Hemangioma) – rapidly involuting congenital hemangioma

SACRAL (Spinal dysraphism, Anogenital, Cutaneous, Renal and urologic malformation, Angioma Lombosacral)

TGFα/β (transforming growth factor α/β) – transforming growth factor α/β

TIMP (Tissue inhibitor of metalloproteinase) – tissue inhibitor of metalloproteinases

TNF (tumor necrosis factor) – tumor necrosis factor

TSH-like factor (Thyroid-stimulating hormone-like factor) – thyroid-stimulating hormone-like factor

tPA (tissue plasminogen activator) – tissue plasminogen activator

uPA (urokinase plasminogen activator) – urokinase plasminogen activator

VEGF (Vascular Endothelial Growth Factor) – vascular endothelial growth factor

VEGFR1/R2 (Vascular Endothelial Growth Factor Receptor) – vascular endothelial growth factor receptor 1/2

WT1 (Wilms tumor gene 1) – Wilms tumor suppressor protein

Terms and Definitions

New and highly specific professional terms are not used in these clinical guidelines

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Infantile hemangioma (IH) is a benign vascular neoplasm characterized by abnormal proliferation of endothelial cells with impaired blood vessel angioarchitecture [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Etiology

The etiology remains incompletely understood. Several hypotheses are currently discussed (placental theory, mutation of a gene involved in endothelial cell proliferation), but it is evident that hypoxia, both antenatal and perinatal, is a fundamental factor in the development of IH [2]. This is also supported by the majority of predisposing factors [3–5]:

- antenatal hypoxia;

- multiple pregnancy;

- complicated pregnancy (preeclampsia, placental pathology/placental abruption);

- birth weight less than 1500 grams / prematurity (incidence of IH is 25%) [6];

- amniocentesis/chorionic villus sampling;

- female sex;

- Caucasian race;

- advanced maternal age [6].

Pathophysiology

IH is believed to be of embryonic origin, developing from the mesoderm. Normally, the formation of the skin vascular system is completed during the final weeks of gestation. If this maturation is not complete by birth, certain vessels remain exposed to stimulating factors, leading to their excessive proliferation and the formation of a vascular lesion.

The formation of IH is based on impaired angiogenesis caused by an imbalance between angiogenic and antiangiogenic factors.

Angiogenesis is a complex regulated process consisting of the remodeling (sprouting, fusion, regression of immature vessels) of the primary vascular plexus into new capillaries from precursor cells both under physiological conditions and in pathological processes driven by numerous stimulating and inhibiting factors [7].

Three successive barriers lie in the path of new vessel formation: the basement membrane, pericytes, connective tissue cells surrounding the vessel, and the extracellular matrix. The formation of a new vessel requires the breakdown of these barriers through the activation of the fibrinolysis system enzymes and the stimulation of endothelial cells by circulating or locally active factors: uPA (urokinase plasminogen activator) and tPA (tissue plasminogen activator). These enzymes, in turn, activate matrix metalloproteinases (MMPs), which degrade the extracellular matrix. MMPs facilitate the "detachment" of pericytes, lysis of the basement membrane, and creation of space within the extracellular matrix for the expansion of the new vessel. Activated endothelial cells migrate from the "parent" vessel and proliferate within the established niche of the extracellular matrix (Figure 1).

Figure 1. Schematic representation of the various stages of angiogenesis

1, 2, 3: activation of endothelial cells by stimulating factors, degradation of the basement membrane followed by protrusion of endothelial cells

4: endothelial cell migration, proliferation, and formation of a capillary "bud"

5: maturation of endothelial cells with lumen formation in the capillary "bud", restoration of the basement membrane. Formation of the vascular network.

The two main factors stimulating angiogenesis can be distinguished as follows:

VEGF (Vascular Endothelial Growth Factor) is a potent, specific endothelial cell growth factor with mitogenic and angiogenic activity, capable of stimulating capillary formation. It binds to specific receptors (VEGFR-1, VEGFR-2) located on endothelial cells and their precursors, leading to the proliferation and phenotypic transformation of endothelial cells and the production of proteolytic enzymes, which collectively promote the formation of new vessels [8]. Under hypoxic conditions, the concentration and expression of VEGF increase due to the Upregulation of HIF-1 (hypoxia-inducible factor) transcription. The active form of the latter induces VEGF gene transcription. Furthermore, under hypoxia, VEGF secretion is enhanced by interleukins and TGF (Transforming Growth Factor). All these factors promote endothelial cell proliferation, secretion of proteinases (metalloproteinases) necessary for extracellular matrix reorganization, and coordination of vascular cell differentiation and angiogenesis [8].

FGFa/FGFb (Fibroblast Growth Factors) are autocrine growth factors. They exhibit high mitogenic activity across a wide spectrum of cells of mesodermal and neuroectodermal origin, including endothelial cells, smooth muscle cells, and fibroblasts. bFGF is involved in all stages of neoangiogenesis (Figure 2), including the embryonic period of vascular formation, promoting the differentiation of mesodermal angioblasts into endothelial cells. Additionally, FGF has been isolated from numerous tissues, including tumors [8] and endothelial cells of proliferating vascular neoplasms.

Figure 2. FGF regulation of angiogenesis [9]

A hemangioma formed in this manner undergoes three stages: proliferation, stabilization, and involution, which are regulated by angiogenic factors and angiogenesis inhibitors (interferon beta, angiostatin, thrombospondin; TIMP [Tissue Inhibitor of Metalloproteinases] – an inhibitor of neovasculogenesis) [10]. The involution phase is characterized by increased expression of the endothelial cell maturity marker ICAM-1 (expressed in proliferating endothelial cells and acting as an intercellular adhesion molecule). Regression is achieved via apoptosis (endothelial and stromal cells express apoptosis markers – proteolytic enzymes such as caspase-3).

1.3 Epidemiology of the Disease or Condition

The most frequent of all forms of vascular pathology is IH.

The incidence is 5–10% [11] in infants during the 1st year of life and 30% in preterm infants weighing less than 1,800 grams. IHs are more common in Caucasian females (2.5–4:1) [12]. In preterm infants, the female-to-male ratio is lower at 1.4:1, but this ratio significantly increases in complicated and segmental forms of IH, reaching 9:1 [13].

1.4 Features of Coding the Disease or Condition

D18.0 – hemangioma of any site

1.5 Classification of the disease or condition

Currently, the International Society for the Study of Vascular Anomalies (ISSVA) has introduced the concept of "vascular anomalies." All vascular anomalies are divided into two major groups: vascular tumors and vascular malformations [14] (Table 1).

Table 1. Vascular anomalies, ISSVA classification

From a histological standpoint, vascular tumors are characterized by endothelial cell proliferation. Based on biological behavior, vascular tumors are classified into benign (hemangiomas), locally aggressive / borderline malignancy (hemangioendotheliomas, with the exception of epithelioid and others), and malignant (epithelioid hemangioendothelioma, angiosarcoma, etc.) (Table 2).

Table 2. Vascular tumors, ISSVA classification

According to the modern classification, IH belongs to benign tumors.

Three histological phases (Figure 3 A, B, C, D) follow one another, corresponding to the "life" cycle of the hemangioma [15].

Phase 1. Histologically, the tumor is highly cellular, corresponding to the clinical proliferation phase. Immature vascular tissue is identified, consisting predominantly of tightly packed endothelial cells occupying almost the entire area of the tumor, forming barely distinguishable vascular spaces that may require additional diagnostic methods for visualization (Figure 3 A, B). Stromal cells always contain a voluminous nucleus, and high mitotic activity is determined. A large number of mast cells are found. Perineural invasion may be detected.

Phase 2. The tumor becomes more differentiated and corresponds to the clinical stabilization stage. Histologically, the tumor has a lobular structure, consisting of clearly differentiated capillaries with well-defined lumens lined by flattened endothelium (Figure 3 C). The lobules are centered by arterioles and draining venules. Stromal cells are not identified at this stage.

Phase 3. Corresponds to regression. The volume of vascular proliferation progressively decreases, and the tumor tissue is replaced by fibrous connective and adipose tissue (Figure 3 D), among which rare, isolated capillaries are identified [13].

Figure 3 (A, B, C, D). Histological picture at different stages of IH development

A: Proliferative phase. Tightly packed small vessels without lumens, composed of endothelial and other differentiation-lineage cells (hematoxylin and eosin [H&E] stain, microscope magnification ×100)

B: GLUT1 expression in the endothelium (immunohistochemical study with antibodies against GLUT1, mag. ×100)

C: Onset of involution (plateau phase). Thin-walled capillaries with clearly visible vessel lumens (H&E, mag. ×100)

D: Changes after completion of involution. Rare structures of mature residual vessels among fibrous connective and adipose tissue (H&E, mag. ×100)

Immunohistochemical examination

Endothelial cells constitute the overwhelming majority and have a phenotype shared with placental endothelial cells (Fc gamma, merosin, Ag Lewis Y, GLUT1). The most reliable specific marker allowing differential diagnosis from any other vascular anomaly is GLUT1 (Glucose transporter 1) (Figure 3B), which is expressed in 100% of IH cases at any stage of evolution and is not detected in other vascular pathologies [10]. At the same time, as with any capillary proliferation, IH is WT1 (Wilms tumor gene 1) positive.

1.6 Clinical presentation of the disease or condition

IH has a firm-elastic consistency, is non-pulsatile, and is painless (except for cases accompanied by ulceration or perineural infiltration). Skin color at the tumor site varies depending on the type of IH.

Clinical forms:

• Focal form, the most frequent. Presented as a single focus

• Segmental form corresponds to a specific anatomical segment/dermatome. Syndromic variants of IH are most frequently associated with this form

• Multifocal forms are rare. The presence of more than 1 but fewer than 5 lesions is referred to as hemangiomatosis; the presence of multiple small (a few millimeters in diameter) hemangiomas is referred to as miliary hemangiomatosis, which is associated with visceral involvement (most commonly hepatic involvement)

Types of IH depending on the depth of skin and underlying tissue involvement:

1. Superficial (cutaneous) IH (50–60%). The angioma is tuberous, bright red, with clear margins, protruding above healthy skin, with a rough (granular) surface (referred to in literature as a tuberous angioma or "strawberry" angioma). In shape, it can be localized (focal or segmental) or diffuse.

2. Subcutaneous IH (15%) presents as a tumor-like formation with distinct borders. The skin over the tumor ranges from normal color to varying degrees of cyanosis, and it may be surrounded by a superficial dilated venous network. The subcutaneous hemangioma is located in the deep layers of the dermis and the hypodermis. The hemangioma has a firm-elastic consistency, is slightly warm to the touch, but painless and non-pulsatile.

3. Mixed hemangioma (25–35%) has two components: a superficial tuberous component and a deeper subcutaneous component that extends beyond the boundaries of the first, forming a cyanotic halo [16]. It occupies the entire dermis and hypodermis. As a rule, mixed IH presents as a single focus, but multiple foci can occur. In the latter case, they may be combined with visceral involvement [17].

4. In addition to the 3 described classical types of IH, there is a 4th type, atypical IH. This refers to the presence from birth of a skin "lesion" that resembles changes preceding the development of IH, the so-called initial changes: a slightly elevated erythematous patch with tiny telangiectاساتectasias (telangiectasias). A characteristic feature is the practically complete absence of the proliferative phase (less than 25% of the total lesion surface area undergoes proliferation). These hemangiomas are termed IH-MAG (Minimal or Arrested Growth Hemangioma), abortive IH, or reticular IH (ISSVA Classification 2014). The majority of such IHs are localized on the skin of the lower extremities. The affected limb is edematous with infiltration of underlying tissues. This type of IH is more frequently accompanied by local complications in the form of ulceration and may be associated with genitourinary system anomalies as well as heart failure [18].

Dimensions

Sizes are highly variable: from pinpoint to giant. 80% of IHs are small, less than 3 cm in diameter, and isolated in nature [19]. As for giant forms, 2 types are distinguished: those located superficially or proliferating both on the surface and in volume. Sizes can be so significant that they lead to alterations in anatomical boundaries, especially when localized in the zygomatic region and the parotid salivary gland area.

Localization

The topography is most diverse, but most frequently IHs are localized in the head and neck region: 40% and 20%, respectively [5]. 76% of facial focal forms are located on prominent areas, 60% of which are along the midline of the face [20]. The most frequent are localized forms, with only 24% being segmental. Four location zones are distinguished according to conventional segments (S1–S4) (Figure 4).

Figure 4. Segmental division of the head [21]

Certain types of localizations may indicate the presence of complications, with segmental forms being 11 times more likely to be associated with complications, specifically ulceration and the development of malformations [13,22]:

• S1/S4 – risk of cerebral malformations in approximately ¾ of cases [23];

• S2/S3 – risk of cardiovascular anomalies and upper airway involvement [23].

Evolution

IH is a "dynamic tumor," meaning it has specific kinetics, undergoing three phases of development: growth, stabilization, and regression, which correspond to analogous histological phases.

Usually in 70% of cases, IHs are absent at birth and begin to appear only a few days/weeks after birth [24,25]. It should be noted that subcutaneous forms may only be clinically detected by 2–3 months of age [24]. Initial manifestations may present in 1/3 of cases as local skin changes in the form of a pale spot resembling a hamartoma, or as a pale pink patch/capillary network, which progressively grows over the subsequent few weeks/months (the early and rapid proliferation phase is replaced by the late and slow proliferation phase), taking on the appearance of a classical hemangioma.

The proliferation phase usually ends by 6–8 months for superficial forms, or may last up to 9–12 months for subcutaneous and mixed IH forms [25]. In 80% of cases, IH doubles in size, typically reaching its final volume by 5 months of age [25], and in 5% of cases, the size triples. In very rare cases (less than 5%), mixed IHs reach giant proportions, and the proliferative phase can last up to 24 months [22].

The stabilization phase begins at approximately 8–9 months of age and lasts from 12 to 36 months. During this period, IH growth ceases and slow spontaneous involution begins, which clinically manifests as central lightening in cutaneous hemangiomas and soft tissue "settling" in subcutaneous forms. Sometimes the growth and regression phases may occur in parallel. In 60% of cases, IH completely regresses by 4 years of age, and in 76%, by 7 years of age [24], leaving behind a residual "slack pocket" (Figure 5).

Figure 5. Stereotypic stages of evolution.

The mean age of completion for the involution phase is 3.5 years [26]. It should be noted that subcutaneous forms have a slower involution than superficial (cutaneous) ones. They may not regress completely, leaving behind fibro-fatty tissue. Sometimes the skin may become lax due to the loss of elastic fibers or develop telangiectasia-like changes.

These features of hemangioma progression justify a watchful waiting approach, provided that the hemangioma is not accompanied by complications.

Complications

Despite spontaneous regression, which is observed in 90% of cases, certain types of locations can lead to complications and require medical intervention, or may indicate the possibility of systemic manifestations [24] (Figure 6 a, b, c).

Figure 6. Schematic representation of IHs associated with potential complications [27].

1. IHs leading to local complications (necrosis/ulceration/secondary infection/bleeding)/functional disorders

Local complications are the most frequent according to a major study [5] and occur during the proliferative phase [24].

Spontaneous ulceration (with potential secondary infection) is the most common complication of IH. Its incidence is 16% [28] and it usually occurs in the growth/proliferation phase (mean age 2–4 months) [29]. Ulceration can lead to bleeding and secondary infection, as well as functional disorders. Ulceration is always accompanied by severe pain syndrome. Subsequently, ulcerated areas may leave scarring changes behind. Subcutaneous forms are not prone to ulceration.

Necrosis may develop in superficial and mixed types of IH, which can be spontaneous or treatment-induced (cryotherapy, sclerotherapy, radiotherapy—these treatment modalities are currently not prioritized). Necrosis manifests with the appearance of a black crust, accelerates the involution process, and leaves behind a noticeable scar. The cause of spontaneously occurring necrosis is not fully understood, but some authors suggest that large hemangiomas in the proliferation stage may experience inadequate blood flow required to nourish the tumor. Certain cytokines may be involved, such as tumor necrosis factor (TNF).

Risk factors for local complications include large size of the vascular tumor, its cutaneous characteristics and topography (natural folds, upper lip, neck) (Figure 6 a), as well as localization at the mucocutaneous junction.

Hemangiomas of special locations [13]:

• Palpebral. Occlusion of the eye with the risk of strabismus (in 1/3 of cases), astigmatism, or amblyopia of the affected eye. The latter complication is the most severe and develops in 43–60% of cases [30]. Intraorbital and retroorbital extension of IH can lead to ocular globe dislocation, extraocular muscle infiltration, and optic nerve compression with secondary atrophy. In rare cases, periorbital location of IH may be combined with iris IH.

• Labial. Upper lip involvement is most commonly noted (70%), as well as perioral localization. Ulcerations, sialorrhea, sucking disorders, and structural abnormalities of jaw and dental development can be observed, especially in widespread forms [13]. When localized in the lower lip area (25%), IH can lead to decreased lower lip muscle strength and ulcer development in 30% [31], and subglottic involvement may develop in 30% of cases. Such locations require mandatory examination by an ENT specialist, as well as additional studies.

• Nasal. Threat of damage and deformation of underlying cartilaginous structures as a result of necrosis, secondary infection; airway obstruction. "Cyrano" angioma—hemangioma of the nasal tip—is distinguished separately. This is a subcutaneous form. If the hemangioma is mixed, it can cause cartilage necrosis (of the nasal tip and alae), leading to irreversible deformation.

• Auricular. Closure of the external auditory canal, necrosis of the auricular cartilage, secondary infection, auricular deformity, hearing loss.

• Parotid region. Clinically presented as a unilateral lesion in the form of a small tumor mass at birth, which increases very rapidly in size. The tumor is fluctuant, mobile, and painless. It is located inside the gland, without extending beyond the capsule and without affecting either the underlying tissues or the skin. This localization can lead to facial nerve damage. Involution begins later than usual, starting at 18 months of age with complete disappearance by 6–8 years.

• Perineal. Involvement of this area is rare, in less than 10% of cases, but is characterized by a very high risk of necrosis, ulceration, and superinfection. Ulceration is noted in 80% of cases when IH reaches more than 5 cm² and in only 10% if the lesion area does not exceed 2 cm². Clinically, they can be represented by two main forms: as a clearly demarcated tumor, or superficial but widespread. In addition, this location can be accompanied by various malformations (anogenital, urological, cutaneous), including labia minora agenesis, labia majora atrophy, anal atresia, and lipomas. Developmental anomalies of the perineal organs may be accompanied by micturition and defecation disorders. These anomalies may require surgical correction after the resolution of hemangioma manifestations.

• Sacral. May be associated with intraspinal extension, which manifests as decreased leg muscle strength, vesico-urinary disorders, and is also frequently associated with spina bifida.

• Areolar region. IH localized in the mammary gland area leads to impaired breast development, chest and breast asymmetry.

• Foot/hand area. Gait disturbance/impaired grasping movements of the hands.

2. IHs accompanied by vital function impairment

These complications are rare, but it is essential to remember them!

• Respiratory distress syndrome (RDS). Can be observed when the vascular tumor is localized in the upper respiratory tract, particularly in the subglottic space. Such localization must be ruled out if a hemangioma is present in the head and neck region (anterior neck, lower lip, chin), in the S3 segment area. The complication is observed in 1/3 of cases [32,33].

• Heart failure. Can develop in extensive forms of IH, as well as with liver involvement. Liver involvement in the pathological process can be either isolated or combined with skin lesions [34]. All these forms of IH increase venous return of blood, increasing preload on the right heart chambers.

• Gastrointestinal bleeding. In rare cases, massive gastrointestinal bleeding may complicate the course of IH when it is localized on the gastrointestinal mucosa [35].

3. IHs accompanied by structural and visceral anomalies.

Structural and visceral anomalies occur in so-called segmental IHs, which require special attention because they represent not only an aesthetic problem but can also conceal severe functional changes in other organs and systems.

Two major recently described syndromes are associated with various visceral anomalies (Table 3).

Table 3. Syndromes associated with segmental hemangiomas

LUMBAR/PELVIS/SACRAL syndromes are associated with the presence of a huge lumbosacral and/or perineal hemangioma with anogenito-vesico-renal and spinal anomalies [36].

• PHACE/PHACES syndrome is associated with a giant facial hemangioma, neurological, cardiovascular, and ocular anomalies [4] (Figure 7). The incidence is 2.3% of all hemangiomas and 20% of hemangiomas localized in the facial region, with a significant female predominance (9:1). About 300 cases have been described in the literature [37].

Figure 7. Main loci of internal organ and system involvement in PHACE syndrome

Certain clinical manifestations are classified as major or minor criteria of the disease (see Appendix B, Table 5) [38]. Their combination allows for the diagnosis of PHACE/PHACES syndrome (Table 6) [38].

Table 6. Diagnostic criteria for PHACE syndrome [38]

4. IH accompanied by visceral lesions.

The combination of IH with visceral involvement is possible in three scenarios:

• in the presence of multiple hemangiomas (more than 5)

• in the presence of IH localized in the perineal region

• in the presence of IH localized in the sacral region

The liver is the most frequent visceral organ involved in the pathological process. Liver involvement must be ruled out in cases of:

• presence of more than 5 cutaneous hemangiomas, or

• disseminated, miliary hemangiomatosis

Hepatic lesions in IH present either as multifocal forms or diffuse forms [34].

They can be accompanied not only by cardiovascular insufficiency (see above) and abdominal compartment syndrome, which are more common in diffuse forms [39], but also by severe acquired hypothyroidism associated with increased activity of type 3 iodothyronine deiodinase (an enzyme that degrades thyroxine) and/or secretion of a TSH-like factor [40]. Hypothyroidism is always observed in diffuse forms and in 21.4% of cases with multifocal involvement [39]. Thyroid hypofunction regresses in parallel with the involution of hepatic hemangiomas [41]. A combination of hepatic IH with severe thrombocytopenia is also observed, which likewise resolves in parallel with the regression of hemangiomas. Involution of hepatic hemangiomas occurs in parallel with the involution of cutaneous hemangiomas.

V. Residual manifestations of IH

As an outcome, IH can lead to significant local soft tissue changes in 55–65% of cases [26,42]:

• telangiectasias (84.3%)

• fibrofatty changes (47.1%)

• skin atrophy (32.6%)

• scarring changes

Secondary scarring changes are most often observed in mixed forms of IH. Risk factors also include the volume of the superficial part of the IH (facial IH measuring > 2 cm or > 1 cm in a patient under 3 months of age; scalp IH measuring > 2 cm) [27], the characteristics of its surface relief (cobblestone-like bumpy surface) [24,26], and localization (facial IH localized in the nasal and labial regions).

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of IH in most cases does not require additional diagnostic tests, but is established primarily based on anamnestic data and the clinical characteristics of the tumor [43]. Additional diagnostic methods (CT/MRI, etc.), including examinations by subspecialists (cardiologist, otorhinolaryngologist, ophthalmologist, neurologist, pediatric surgeon), are necessary when suspecting:

- involvement of internal organs in the pathological process;

- compression of vital organs;

- segmental forms of IH.

In doubtful cases, a biopsy of the lesion with mandatory immunohistochemical examination is indicated to confirm the diagnosis, allowing a reliable diagnosis to be established in 100% of cases [43].

2.1 Complaints and Anamnesis

• In all patients with suspected IH, it is recommended to take a history of present illness and complaints [27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: When establishing a diagnosis of IH, the medical history and the nature of complaints are among the most important components. When taking the history, it is necessary to pay attention to the features of pregnancy and childbirth, determine the time of appearance of the vascular lesion and its growth rate. Attention should be paid to the presence of complaints indicating pain, infant distress, or functional disorders (respiratory failure, feeding difficulties, neurological abnormalities).

2.2 Physical Examination

• In all patients with suspected IH, it is recommended to perform a general physical examination [27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: when examining the patient, it is necessary to provide a clear description of the nature of the vascular lesion, as well as to perform a full clinical examination of the child, assessing all organs and systems.

The description of the vascular lesion takes into account the following parameters:

• size

• color

• consistency

• pain

• clarity of borders and adherence to surrounding tissues

• presence of an inflammatory component

• determination of local temperature

Special attention should be paid to the number of lesions, their localization, and prevalence: certain localizations and distribution patterns require additional laboratory and instrumental diagnostic methods.

The detection of any pathology during a general clinical examination of organs and systems requires additional consultation with subspecialists, as well as additional instrumental diagnostic methods.

2.3 Laboratory Diagnostics

• In patients with suspected and diagnosed IH, prior to the initiation of metronomic therapy and after its completion, it is recommended to perform a complete blood count (CBC) to assess the patient's general condition and the feasibility of medical treatment [44,45].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In patients with IH with liver involvement, it is recommended to perform a general routine biochemical blood test determining the following parameters: ALT, AST, creatinine (once a month), blood potassium level (twice a month) to assess the patient's general condition and the feasibility of medical treatment [44,45].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In patients with IH prior to initiating propranolol therapy in the oral solution (OS) pharmaceutical form, it is recommended to perform a general routine biochemical blood test determining the following parameters: ALT, AST, total bilirubin/direct bilirubin to assess the patient's general condition and the feasibility of medical treatment [44,46,47].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In patients with IH with low body weight, prematurity, feeding difficulties, a history of hypoglycemia episodes prior to initiating OS therapy, as well as patients receiving combination therapy with #prednisolone** and OS, it is recommended to test fasting blood glucose levels [48,49].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In patients with multifocal/diffuse hepatic hemangiomatosis or PHACE syndrome, it is recommended to test blood levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) to detect thyroid dysfunction [37,50].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

• In patients with suspected IH localized on the mucous membranes of the gastrointestinal tract, it is recommended to perform a fecal occult blood test to rule out latent gastrointestinal bleeding [35,51–53].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In patients with LUMBAR/PELVIS/SACRAL syndrome, it is recommended to perform a urinalysis to clarify urinary system involvement in the pathological process [27,54].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In patients with ulcerated IH, it is recommended to perform a microbiological (culture) examination of wound discharge for aerobic and facultative anaerobic microorganisms to select relevant antibiotic therapy [27,29,55].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

2.4 Instrumental Diagnostics

Instrumental studies, such as ultrasound/duplex ultrasonography, contrast-enhanced MRI (CE-MRI)/contrast-enhanced CT (CE-CT) of the affected area, are supplementary and are used to confirm the diagnosis or serve as a follow-up assessment in complicated forms, in particular those accompanied by impaired vital functions; hemangiomatosis; or IH associated with potential structural and visceral anomalies (segmental forms).

• In patients with IH, it is recommended to perform an ultrasound examination (US) in the following situations:

• for focal subcutaneous IH – soft tissue ultrasound (one anatomical region) [56,57];

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• for PHACE syndrome – thyroid and parathyroid ultrasound [37,58–60];

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• in the presence of multiple cutaneous hemangiomas (5 or more) – liver ultrasound [61,62];

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

• for disseminated/miliary hemangiomatosis: ultrasound of the liver [63,64];

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

• for LUMBAR/PELVIS/SACRAL syndrome: comprehensive abdominal ultrasound, comprehensive pelvic ultrasound [27,54,65].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with IH are recommended to undergo electrocardiography before prescribing oral propranolol solution (OPS) therapy, as well as after reaching the therapeutic dose and during OPS treatment (once a month) [49,66,67].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Patients with IH are recommended to undergo echocardiography before prescribing beta-blockers, as well as during therapy every 3 months, to rule out organic heart pathology and determine myocardial contractility [13,27,37,67–70].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Patients with PHACE syndrome are recommended to undergo targeted chest radiography to rule out median chest anomalies (sternal defects) [37,38,67].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Patients with IH are recommended to undergo contrast-enhanced magnetic resonance imaging (CE-MRI) or contrast-enhanced computed tomography (CE-CT) of the affected area in the following situations [71–73]:

• in focal subcutaneous IH in doubtful clinical situations (not confirmed by ultrasound/duplex ultrasound) to verify the diagnosis [61,71];

• in focal subcutaneous IH located in the soft tissues of the head and neck to determine the extent of potential spread of the pathological process deep into the soft tissues of the neck/mediastinum and, accordingly, potential narrowing/obstruction of the upper respiratory tract [61,71];

• in focal IH of "special" locations, namely palpebral, labial, nasal, auricular, parotid, perineal, and sacral, to determine the extent and depth of the lesion [13];

• in segmental forms of IH [61,71];

• in multifocal and diffuse forms of liver involvement [63];

• in the presence of large bulky lesions/foci of visceral involvement 6 months after starting beta-blocker therapy, and 12 months later if necessary [27];

• in patients receiving metronomic therapy: after 2–3 courses of metronomic therapy to determine its efficacy and decide whether it can be discontinued. If it is decided to continue therapy due to insufficient reduction in tumor volume, repeat imaging is performed after two additional courses of MT [74,75].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with syndromic forms of IH are recommended to undergo CE-MRI and/or CE-CT [76]:

• in PHACE syndrome [76] (see Table 4; Section 7.3);

• in LUMBAR/PELVIS/SACRAL syndrome [6,76]: abdomen/pelvis/spinal cord.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with IH with PHACE syndrome and suspected involvement of the posterior cranial fossa or other CNS anomalies are recommended to undergo computed tomography angiography of the cerebral vessels [77,78].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Patients with IH with PHACE syndrome and suspected cardiovascular anomalies are recommended to undergo computed tomography angiography of the aorta [79].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Patients with IH with PHACE syndrome are recommended to undergo electroencephalography to clarify/rule out neurological complications [38,78].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with IH and suspected upper airway narrowing are recommended to undergo laryngoscopy under general anesthesia [76,80,81].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Patients with IH and suspected gastrointestinal bleeding are recommended to undergo esophagogastroduodenoscopy under general anesthesia [27,82].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.5 Other Procedures

• In exceptional cases where a diagnosis cannot be established based on clinical and instrumental findings, patients with suspected IH are recommended to undergo a biopsy of the lesion and pathological examination of the biopsy (surgical) material, including immunohistochemical methods to verify the diagnosis [27,83].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• Patients with IH with PHACE syndrome, visceral forms of IH with liver involvement (to rule out heart failure), and in all cases before prescribing beta-blockers (to rule out contraindications) are recommended a cardiologist consultation [13,27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with IH located in the orbital area are recommended an ophthalmologist consultation and ophthalmoscopy [13,27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with IH located on the anterior neck, lower lip, or chin are recommended an otolaryngologist consultation [76].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with segmental IH and those with neurological symptoms are recommended a neurologist consultation [13,27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with IH with LUMBAR/PELVIS/SACRAL syndrome are recommended a urologist consultation and (for female patients) an obstetrician-gynecologist consultation [13,27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with IH who develop secondary hypothyroidism, as well as all patients with PHACE syndrome, are recommended an endocrinologist consultation [13,27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Pharmacotherapy

• Patients with IH are recommended to initiate drug therapy in the following situations [12,13,27,84]:

- IH accompanied by / at risk of vital function impairment:

• subglottic IH

• giant IH / hepatic IH (risk of heart failure)

• CNS IH (risk of compression)

• gastrointestinal IH (risk of bleeding)

• segmental forms

- IH accompanied by / at risk of functional impairment / cosmetic defects:

• orbital or eyelid IH (risk of amblyopia)

• ear canal IH (hearing loss)

• lip IH

• nasal IH

• perineal IH near natural orifices;

- IH accompanied by ulceration, secondary infection, bleeding, and pain.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: most patients with IH do not require active intervention, and in 85% of cases the tumor undergoes spontaneous regression.

• Patients with IH indicated for drug therapy are recommended propranolol in the oral solution formulation as first-line therapy [85–87].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: for the principles, rules, and dosing regimen of oral propranolol solution, see Appendix A3.1 of these guidelines.

• Patients with IH who require the fastest possible reduction in tumor volume (IH accompanied by or at risk of vital complications) are recommended second-line therapy using one of the following combinations:

• oral solution + #vincristine** 0.05 mg/kg (1 mg/m2) once a week (duration 6–10 weeks until safe tumor size is achieved) [13,63,84,88]

• oral solution + metronomic therapy with #vinblastine** (IV bolus 1 mg/m2 3 times a week, total 6 injections) and #cyclophosphamide** (IV bolus or oral 50 mg/m2/day in two daily doses for 14 days), 2–6 cycles depending on tumor volume and rate of reduction [74,75,84,89]

• oral solution + oral #prednisolone** [90] at a dose of 2–3 mg/kg/day for 2 months, followed by a gradual taper taking into account the duration of the proliferative phase of the disease [13,84,91]

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: some forms and locations (as mentioned above) can lead to severe complications, sometimes with impaired vital functions (heart failure, compartment syndrome, upper airway compression, extension into the spinal canal with development/risk of myelopathy), as well as severe cosmetic defects requiring subsequent corrective treatment (plastic surgery, laser therapy). To prevent these complications, immediate and sufficiently intensive therapy is necessary to achieve the fastest possible reduction in tumor volume. These situations include [13]:

• IH associated with vital function impairment;

• IH involving internal organs (liver, GI tract);

• IH complicated by destruction of underlying tissues;

• IH complicated by necrosis, ulceration, or secondary infection;

• IH accompanied by structural and visceral anomalies (PHACE or LUMBAR/PELVIS/SACRAL syndromes).

Beta-blocker monotherapy cannot achieve rapid tumor reduction, especially in giant forms with a high proliferation rate. The time spent reaching the therapeutic dose and the appearance of the first signs of tumor shrinkage can be significant—4–6 weeks (dose titration 7–14 days + 2–5 weeks until the first significant signs of tumor reduction appear)—and lead to severe, life-threatening, or serious local complications (e.g., the need for tracheostomy).

In addition, there are resistant forms of IH, defined as continued tumor growth or lack of reduction during therapy with oral propranolol solution at a dose of 3 mg/kg/day for 5 weeks.

Combination therapy with #prednisolone** and oral propranolol solution may increase the risk of hypoglycemia [92].

• For patients with IH who have contraindications to BB therapy, including severe cerebral vascular pathology in PHACE syndrome, it is recommended to use one of the following treatment regimens:

• #vincristine** 0.05 mg/kg (1 mg/m2) once a week (duration 6–10 weeks until safe tumor size is achieved) [13,63,84,88]

• metronomic therapy with #vinblastine** (IV bolus 1 mg/m2 3 times a week, total of 6 injections) and #cyclophosphamide** (IV bolus or orally 50 mg/m2/day in two divided doses daily for 14 days), 2–6 cycles depending on tumor volume and rate of regression [74,75,84].

• #prednisolone** orally at a dose of 2–3 mg/kg/day; duration of therapy is at least 2 months (determined by the rate of lesion reduction until a size safe from vital complications is reached), followed by gradual tapering taking into account the duration of the proliferative phase of the disease [84].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: long-term #prednisolone** therapy is associated with the development of severe complications, such as secondary arterial hypertension, metabolic disorders of all types, growth retardation, gastroesophageal reflux, obstructive hypertrophic cardiomyopathy, adrenal insufficiency, and the risk of severe infections, including Pneumocystis jirovecii pneumonia (co-trimoxazole [sulfamethoxazole+trimethoprim]** is indicated for the prevention of this complication), and CMV infection.

3.2 Surgical methods of treatment

• For patients with IH, surgical methods are recommended in the following situations [63,84]:

• early onset soft tissue necrosis;

• severe functional disorders (vision and hearing organs);

• persistence of residual volume after spontaneous involution;

• deformity of anatomical structures;

• surgical correction of internal organ malformations in syndromic forms of IH

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3.3 Other treatment methods

• For patients with bronchial obstruction syndrome or severe sleep disorders, it is recommended to prescribe #atenolol** at a dose of 1 mg/kg once daily (starting dose 0.5 mg/kg/day) [93–96].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: rules for prescribing the drug are similar to those for non-selective beta-blockers. Currently, there are no large randomized trials confirming the efficacy of #atenolol**, comparable to BBs, in the treatment of IH.

• For patients with single superficial IH measuring no more than 2 cm in diameter, it is recommended to prescribe #timolol** eye drops at a dose of no more than 2 drops twice daily topically [49,97–99].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: topical #timolol** therapy may have systemic effects. The drug is absorbed through the skin. Only 15–20% of the dose is metabolized during first-pass hepatic metabolism (mainly via the P450 enzyme), which may lead to certain serum concentrations of the drug, and its bioavailability cannot always be reliably determined. The drug has proven effective in treating IH at a dose of less than 0.2 mg/kg/day, divided into two applications. However, topical beta-blocker therapy in full-term infants requires additional randomized trials (frequency of administration? duration of therapy?). This therapy should not be prescribed in premature infants due to the inability to predict adverse effects. The drug is contraindicated in the presence of local complications (ulcers, necrosis, secondary infection).

• For patients with superficial IH with persistent residual lesions in the involution phase, laser therapy is recommended [49,84,100–102].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: pulsed dye laser (PDL, wavelength 595 nm) is used to treat post-residual skin changes in the post-involutive stage of IH. The treatment is very painful and should be performed only under general anesthesia. Skin pigmentation or depigmentation may develop at the laser site.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

No rehabilitation measures have been developed for this disease.

5. Prevention and Dispensary Observation

• For patients with uncomplicated forms of IH, dynamic monitoring is recommended: repeat examinations at intervals in weeks equal to the patient's age in months (observation interval in weeks = age in months) [55].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: for such patients, an "active surveillance" tactic is indicated. The dynamics of all IH parameters (size and rate of growth, color, appearance of new elements, secondary changes) are evaluated, as well as potential risks of complications.

6. Organization of Medical Care

Indications for hospital admission:

1. Diagnosis of IH with a high risk of complications (see above)

2. At the onset of BB therapy (initiation of therapy, dose titration)

Indications for patient discharge from a medical organization:

1. In complicated forms – management of complications

2. Titration of systemic medical therapy and transition to outpatient care

Outpatient management of the patient:

During BB treatment, outpatient management is indicated for dose adjustment based on the child's target weight (once a month) with follow-up examinations.

7. Additional Information

7.1. Differential Diagnosis of IH

1. Other vascular tumors

Congenital hemangioma (CH) [103]

The term "congenital hemangiomas" encompasses vascular tumors that are classified as benign vascular neoplasms arising intrauterine and fully formed by the time of birth. Unlike IH, they do not undergo a proliferative process in the postnatal period. Three subtypes are distinguished based on the degree of tumor regression:

1. RICH - Rapidly involuting congenital hemangioma

2. NICH –Non  involuting congenital hemangioma

3. PICH – Partially involuting congenital hemangioma

Among all subtypes, RICH is the most common. The involution phase begins immediately after birth and usually completes by 6–18 months [104]. It is localized with equal frequency on the extremities (near large joints) and in the head/neck region (forehead, temporal region, cheek, scalp), predominantly in the parotid region; extremely rarely on the trunk. The tumor develops subcutaneously. It typically presents as a massive lesion protruding above the surface, measuring several centimeters in diameter. On palpation, it is usually multinodular, moderately dense, with varying consistency in places, and warm to the touch [105]. The skin over the lesion is thin and easily traumatized. The tumor may be pale or bluish-purple with a perifocal "halo" of normal-colored skin. Radiating telangiectasias may be visible on its surface, or it may be "dotted" with smooth red nodules in the center.

Kaposiform hemangioendothelioma (KHE)

A very rare vascular tumor (0.07 per 100,000) [106–108]. It may be present at birth or unnoticed, with gradual enlargement during the first months of life. It is a vascular lesion characterized by giant size with predominant localization on the extremities, upper shoulder girdle, and neck. It is classified as an intermediate malignancy tumor, meaning it exhibits locally infiltrative growth without metastatic potential. Regional lymphadenopathy is characteristic. Lesions present as a bright red, slightly elevated macule, hot and firm on palpation with a prominent infiltrative component, forming a single entity with underlying tissues. Hypertrichosis and hyperhidrosis are sometimes noted on the surface. The tumor may be accompanied by pain resulting from hemorrhage into the tumor tissue or compression of the neurovascular bundle. Currently, KHE is known to be the primary cause of Kasabach-Merritt phenomenon (syndrome): thrombocytopenia and consumption coagulopathy with a risk of bleeding and hemorrhage, leading to mortality in 30% of cases.

"Tufted" angioma (TA).

Congenital or acquired (always before 5 years of age) [109], having a more chronic course and slowly progressive. Clinically, the tumor presents either as an ill-defined red macule infiltrating underlying tissues, or as numerous red papules of varying intensity. It may be accompanied by tenderness on palpation, sometimes quite pronounced. Local hypertrichosis and/or hyperhidrosis may be observed. Cases of spontaneous regression have been described. Sometimes, when the tumor is localized on the extremities, infiltration and sclerosis of the skin occur. Sclerotic changes may affect underlying muscles and joints, leading to severe functional disorders. Histologically, TA is considered a "minor" form of KHE. Less frequently than KHE, it may be complicated by the development of KMP.

2. Vascular malformations

Venous malformations, in particular, Blue rubber bleb nevus syndrome (disseminated venous angiomatosis). In most cases, lesions are detected at birth or in infancy. They present as single or disseminated blue-to-violet or purple papular lesions with a firm-elastic consistency, easily compressible upon palpation. Pain syndrome may be present. Localization varies widely: skin (typically involving the finger- and toe-pads), muscles, gastrointestinal mucosa (typically involving the small intestine), and parenchymal organs. One of the main clinical symptoms of this disease is acute or chronic bleeding from multiple venous malformations localized in the gastrointestinal tract, which inevitably leads to anemia [110].

Lymphatic malformation.

Clinically presented as soft-tissue "mass(es)", usually with overlying unchanged skin, soft-elastic consistency, painless, easily compressible and mobile. Enlargement of regional lymph nodes is possible. Malformed lymphatic vessels forming micro- / macrocystic / mixed cavities can have a wide variety of locations with respect to both integumentary tissues and internal organs, sometimes growing into cavities and affecting the skeletal system. In subcutaneous localization, they may visually not differ from the subcutaneous type of IH.

Capillary malformation

The most common vascular malformation is a port-wine stain (nevus flammeus) found in 25–40% of newborns. Detected from birth as a red-purple patch, predominantly located on the face (especially the forehead area) and neck, although any areas can be affected, including mucous membranes. As a rule, they tend to regress in childhood. However, some may persist, sometimes with the formation of red nodular elements on their background. In specific locations, capillary malformation may indicate the presence of systemic pathology (Sturge-Weber syndrome, Klippel-Trenaunay syndrome, Parkes-Weber syndrome, certain types of phacomatosis).

1. Other diseases (differential diagnosis with miliary hemangiomatosis) [63]

Infantile myofibromatosis

This is a fibrovascular tumor. It can present as a single nodular lesion or have a multifocal form. The skin in the area of the nodes is red with a purple hue, sometimes with telangiectasias on the surface. In solitary forms, the lesion may spontaneously regress. In multifocal forms, which may resemble miliary hemangiomatosis, visceral organ involvement is possible.

Monocytic and myelomonocytic leukemia.

Rarely occurs in newborns. Skin changes are represented by dense papular-nodular elements localized in the dermis and hypodermis, sometimes with a hemorrhagic component and necrosis.

Neonatal Langerhans cell histiocytosis (Hashimoto-Pritzker disease).

The clinical picture is polymorphic: multiple dark red papular-nodular elements are detected from birth, predominantly localized on the skin of the upper trunk. Usually, these elements are combined with vesiculopustular ones. They undergo involution within a few weeks.

«Blueberry muffin baby» syndrome

Multiple dark blue nodular lesions detected from birth, usually associated with an infection (TORCH syndrome) or malignant diseases such as leukemia.

Pseudoangiomatosis

A rare disease that in most cases occurs in the context of an infectious episode. Skin elements are represented by monomorphic miliary maculopapular red lesions, asymptomatic, prone to complete resolution within 2 days to 3 weeks. Favored locations are the cheeks and extremities.

In doubtful cases, biopsy of the lesion is indicated. The main distinguishing criterion will be a positive reaction with GLUT-1 upon immunohistochemical examination.

7.2. Risk Factors

Risk factors include:

1. IH of special locations

2. segmental forms

3. visceral organ involvement

7.3 Clinical criteria and necessary examinations in PHACE/PHACES syndrome.

Table 4. Possible clinical manifestations and scope of examinations in PHACE syndrome [37].

Table 5. Major and minor diagnostic criteria for PHACE syndrome [38].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Conflict of interest: all authors declare no conflict of interest.

1. Khachatryan L.A. – Cand. of Sci. (Med.), Head of the Boxed Hematology/Oncology Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health

2. Maschan A.A. – Dr. of Sci. (Med.), Professor, Deputy General Director - Director of the Institute of Hematology, Immunology and Cell Technologies, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health

3. Kletskaya I.S. – Pathologist at the Department of Pathology, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University

4. Petrushin A.V. – Cand. of Sci. (Med.), Endovascular Surgeon, Head of the Interventional Radiology Group, Radiology Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health

5. Garbuzov R.V. – Dr. of Sci. (Med.), Endovascular Surgeon, Department of Interventional Radiology, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University

6. Narbutov A.G. – Cand. of Sci. (Med.), Head of the Department of Reconstructive and Plastic Surgery, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University

7. Mylnikov A.A. – Cand. of Sci. (Med.), Endovascular Surgeon, Department of Interventional Radiology, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University

8. Kovalev I.A. – Dr. of Sci. (Med.), Professor, Deputy Director for Medical Work, Head of the Department of Pediatric Cardiology and Arrhythmology, Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University; President of the Association of Pediatric Cardiologists of Russia.

9. Kotlukova N.P. – Dr. of Sci. (Med.), Professor, Head of the Competence Center for the Treatment of Infantile Hemangiomas, Bashlyaeva Children's City Clinical Hospital of Moscow, Professor at the Department of Hospital Pediatrics named after Academician V.A. Tabolin, Pirogov Russian National Research Medical University; Member of the Association of Pediatric Cardiologists of Russia.

10. Konstantinova N.K. – Neonatologist, Pediatric Cardiologist (Moscow). Assistant at the Department of Hospital Pediatrics named after Academician V.A. Tabolin, Pirogov Russian National Research Medical University.

11. Trunina I.I. – Dr. of Sci. (Med.), Professor at the Department of Hospital Pediatrics named after Academician V.A. Tabolin, Pirogov Russian National Research Medical University; Freelance Pediatric Cardiologist, Moscow Healthcare Department; Member of the Association of Pediatric Cardiologists of Russia.

12. Shkolnikova M.A. – Dr. of Sci. (Med.), Professor, Scientific Director of the Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University; Honorary President of the Association of Pediatric Cardiologists of Russia.

13. Stefanov D.N. – Head of the Scientific and Organizational Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health

14. Polyaev Yu.A. – Dr. of Sci. (Med.), Professor, Head of the Department of Interventional Radiology, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University, Russian Ministry of Health, Moscow

15. Belysheva T.S. – Dr. of Sci. (Med.), Dermatovenereologist, Leading Researcher at the Outpatient Department, Research Institute of Pediatric Oncology and Hematology named after Academician of RAMS L.A. Durnov, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health, Moscow

16. Kirgizov K.I. – Cand. of Sci. (Med.), Deputy Director for Research, Head of the Department of Pediatric Bone Marrow Transplantation and Hematopoietic Stem Cells, Research Institute of Pediatric Oncology and Hematology named after Academician of RAMS L.A. Durnov, Associate Professor at the Department of Postgraduate Medical Education, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health, Executive Director of RODOG, Moscow

17. Polyakov V.G. – Vladimir G. Polyakov, Academician of the RAS, Dr. of Sci. (Med.), Professor, Advisor to the Director of the Research Institute of Pediatric Oncology and Hematology named after Academician of RAMS L.A. Durnov, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health, Head of the Department of Pediatric Oncology named after Academician L.A. Durnov, Russian Medical Academy of Continuous Professional Education, Russian Ministry of Health, Moscow

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Dermatovenerologists

2. Pediatricians

3. Pediatric oncologists.

4. Pediatric surgeons

5. Pediatric cardiologists

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Prescription principles, prescription rules, and dosing regimen of beta-blockers

I. Before starting beta-blocker therapy, the child must undergo a cardiological evaluation to identify contraindications to the drug:

1. detailed family history taking to rule out hereditary rhythm disorders;

2. ECG to rule out:

a. complete AV block (occurs in 1:20,000 newborns) [111],

b. bradycardia: heart rate less than 70 bpm in newborns, less than 80 bpm in children under 12 months, less than 70 bpm in children over 12 months; echocardiography;

3. monitoring of blood pressure, heart rate, and respiratory rate for 2 days;

4. fasting blood glucose level determination for 2 days.

II. Drug dose

The initial recommended dose is 1 mg/kg/day. For segmental forms, the initial dose should be 0.5 mg/kg/day. Dose escalation should occur gradually over 2–3 weeks in an inpatient setting with mandatory vital sign monitoring. After reaching the therapeutic dose (2.5–3 mg/kg/day), therapy is continued in an outpatient setting.

Week 1 – 1 mg/kg/day

Week 2 – 2 mg/kg/day

Week 3 – 2.5–3 mg/kg/day

In case of resistance – #beta-blockers 3.5–4 mg/kg/day (off-label) [84]

In case of relapse – resume therapy at the previous dose, following dose titration rules.

The daily dose should be divided into two or three doses, every 12 or 8 hours respectively (minimum interval between doses is 6 hours). Dose recalculation is performed once a month taking into account the child's weight, with mandatory clinical examination and follow-up cardiological evaluation. When increasing the drug dose (titration or dose recalculation period), respiratory rate, blood pressure, heart rate, and ECG are monitored 1–2 hours before the dose increase and 1–3 hours after taking the higher dose to detect potential rhythm disorders (maximum cardiovascular changes – heart rate and blood pressure – are achieved 1–3 hours after drug administration, which corresponds to the time of maximum blood concentration). At the same time, heart rate is the most reliable and easiest parameter to measure. Heart rate is measured during the first 3 hours after the dose increase.

III. Duration of therapy

According to international guidelines, the drug is prescribed within the age range of 35 days – 5 months (with corrected age for premature infants). The duration of therapy should be determined by the duration of the proliferative phase of the disease and be at least 6 months [1] for superficial hemangiomas and at least 12–24 months for subcutaneous/mixed and segmental forms of infantile hemangiomas. Drug discontinuation should be gradual (over 2–3 weeks).

IV. Beta-blocker administration rules

The drug must be taken either directly during a meal or immediately after. The drug is absorbed quickly and completely. If the child is not eating or vomiting occurs, therapy should be suspended until normal feeding rhythm is restored (Table 1).

Table 1. Normal feeding schedule [41].

If the child spits out the drug or does not receive the full dose (e.g., due to vomiting), it is not recommended to additionally give the 'missing' dose or increase the dose at the next feeding! If a scheduled beta-blocker dose is missed (for any reason), the next dose must not be increased either. Therapy should be continued in the previous regimen.

If intercurrent diseases develop, accompanied by a decrease in food intake, refusal to eat, or dyspeptic symptoms, beta-blocker therapy should be temporarily suspended [12, 112].

If procedures requiring prolonged fasting are necessary, adequate infusion therapy with dextrose solutions** should be prescribed [41].

V. Tolerability

The oral formulation of the drug is generally well tolerated at therapeutic doses. Nevertheless, monitoring of certain parameters is required:

1. Cardiovascular system. PP can cause cardiac rhythm disturbances. Therapy should be suspended if the HR drops below 60 beats per minute and BP falls below 60/40 mm Hg (Table 2).

Table 2. Minimum permissible blood pressure and heart rate values (BP/HR) [113].

This table shows the minimum HR and BP figures for each age group. Bradiarrhythmia is understood not only as a decrease in HR to the minimum figures specified in the table, but also as a decrease in HR by 30 units from baseline data. As a rule, the decrease in HR and BP (predominantly diastolic) is asymptomatic. If bradiarrhythmia or hypotension develops, PP therapy must be suspended. Administration of the drug may be resumed after the bradycardia/arterial hypotension is resolved.

2. Hypoglycemia

The pathophysiology of hypoglycemia is poorly understood, but it cannot be ruled out that it is associated with glycogenolysis due to the blockade of endogenous catecholamines by PP. Beta-blockers mask adrenergic symptoms of hypoglycemia: tachycardia, palpitations, increased sweating. The situation may be aggravated under conditions of fasting (prolonged intervals between meals), hyperthermia, vomiting, or drug overdose. It must be remembered that hypoglycemia associated with PP intake may present exclusively with seizures and coma! Therapy must be stopped if blood sugar drops below 40 mg/dL. Therapy may be resumed once glucose levels are restored. Hypoglycemia develops when relatively low doses are prescribed – 1.25–2 mg/kg/day, meaning that hypoglycemia is dose-independent in nature!

Patients receiving concurrent glucocorticoid therapy are at a higher risk of developing hypoglycemia, since adrenal insufficiency that develops with glucocorticoid use can lead to a lack of response to the regulatory hormone – cortisol, and accordingly increase the risk of hypoglycemia. Such a situation is also possible when glucocorticoids are taken by a breastfeeding mother!!! Risk factors for hypoglycemia also include prematurity, infectious processes, and feeding difficulties [114].

3. Bronchospasm

Therapy must be stopped if bronchiolitis or bronchitis develops, accompanied by shortness of breath and wheezing. In parallel, selective beta-2 agonists and inhaled glucocorticoids may be prescribed. Beta-blocker therapy is resumed after the resolution of the respiratory pathology. It is recommended to resume therapy at a dose of 1 mg/kg/day given for 2 days, followed by a gradual increase. If a second episode of bronchial obstruction develops, beta-blocker therapy must be discontinued.

VI. Potential risks of prescribing PP

1. PHACE syndrome.

There is very little data on prescribing PP in this syndrome. When prescribing this drug, one must remember the high risk of reduced cerebral perfusion given the presence of serious cerebrovascular anomalies accompanied by decreased blood flow or significant vascular stenosis, which can further aggravate ischemia. In addition, the presence of severe malformations of the main arteries in this syndrome may also be a reason to refuse prescribing the drug. The decision on therapy must be made collectively with the mandatory participation of a cardiologist.

2. Hypersensitivity

In patients prone to anaphylactic shock, especially to iodine-containing substances, treatment with beta-blockers may lead to an aggravation of the reaction and resistance to treatment with epinephrine** at standard doses.

3. General anesthesia

Beta-blockers lead to a decrease in reflex tachycardia and an increase in the risk of hypotension. The anesthesiologist must be warned about the intake of beta-blockers. If surgery/procedures under general anesthesia are elective, beta-blocker therapy must be suspended 48 hours before the procedure.

4. Hyperkalemia

Rare cases of hyperkalemia may occur during PP treatment of giant or ulcerated hemangiomas, which may be caused either by tumor lysis syndrome or directly as a manifestation of the adverse effects of PP. Patients in this category require routine blood electrolyte monitoring.

5. Psoriasis

Cases of worsening psoriasis during PP intake have been described. The prescription of beta-blockers in this situation must be very carefully weighed.

6. Hepatic or renal impairment

90% of the drug binds to blood proteins. 25% of PP is metabolized during first-pass hepatic metabolism involving cytochrome P450, and is excreted by the kidneys. The half-life is approximately 3 hours. PP and its metabolites are completely eliminated from the body within 48 hours. The drug is contraindicated in the presence of hepatic/renal impairment.

"Minor" side effects may occur during PP treatment: asymptomatic hypotension, a 10 bpm decrease in HR, acrocyanosis, sleep disturbances, diarrhea at the onset of treatment, which are not contraindications for withdrawing the drug. It should be noted that PP does not affect the development of the reproductive, nervous, and cardiovascular systems.

VII. Contraindications to prescribing PP

• Preterm infants with a corrected age of less than 5 weeks (the difference between the child's actual age in weeks and the missing weeks of gestation to reach full term)

• Breastfed newborns whose mothers are receiving medications incompatible with propranolol**

• History of asthma or bronchospasm

• Grade II–III atrioventricular block / sick sinus syndrome (including sinoatrial block), sinus bradycardia

• Raynaud's phenomenon and other peripheral circulation disorders

• Predisposition to hypoglycemia.

• Cardiogenic shock

• Heart failure

• Arterial Hypotension

• Pheochromocytoma

Virtually all of the listed contraindications are rare in children under 1 year of age.

Appendix B. Physician Action Algorithms

PP prescription algorithm

Appendix C. Patient Information

Having an infantile hemangioma in a child can raise many questions for parents.

1. What is an infantile hemangioma?

An infantile hemangioma is a benign vascular neoplasm consisting of proliferating vascular endothelial cells. The causes of its occurrence are currently not fully understood. Many factors implicated in its development are discussed, including decreased local tissue oxygenation (hypoxia). In 90% of cases, an infantile hemangioma appears/develops for the first time in the first two weeks of life.

2. How does it manifest clinically?

The most common form of IH is superficial: it appears as a red skin-elevated lesion (sometimes called a "strawberry hemangioma") ranging in size from a few millimeters to 10–12 cm. Subcutaneous forms are less common, leading to minimal changes in skin color over the lesion, being less noticeable and requiring differential diagnosis with other lesions. Mixed forms are occasionally found. Rarer forms also occur, so-called "segmental" ones, occupying a specific segment. In general, IH can occur on any part of the body.

3. How common is IH?

The incidence is 5–10%, with girls being affected 2–4 times more often. The incidence is higher in premature infants.

4. How do IHs "behave"?

Several clinical stages are distinguished in the development of IH (Fig.):

1. proliferation phase – appearance and growth of the lesion

2. stabilization phase – cessation of growth

3. regression phase – spontaneous involution of the lesion

Typically, in 70% of cases, IHs are absent at birth and begin to manifest only a few days/weeks after birth [31, 11].

4. The proliferation phase is usually preceded by a phase of minimal clinical changes on the skin in the form of a pale pink/red superficial patch. The proliferation phase usually ends by 6–8 months for superficial forms, or may last up to 9–12 months for subcutaneous and mixed forms of IH [31].

From approximately 8–9 months of age, the stabilization phase begins, lasting from 12 to 36 months. During this period, IH growth stops and slow spontaneous involution begins. In 60%, IH completely regresses by 4 years, and in 76% by 7 years [11], leaving behind a "baggy pocket" (an area of secondary skin atrophy), spider veins, and scars – the residual manifestation phase.

These features of hemangioma progression justify a watch-and-wait approach for most IHs, provided the hemangioma is not accompanied by complications, which are generally associated with the specifics of localization, size, and depth of the lesion.

5. When does IH need to be treated?

Indications for systemic therapy are determined by the physician based on a combination of clinical data characterizing the infantile hemangioma itself, as well as potential or existing complication risks.

6. How should IH be treated?

Currently, the "gold standard" and universally accepted treatment for IH is the administration of beta-blockers (propranolol in oral solution form). Therapy should be initiated as early as possible (between 5 weeks and 5 months of age), i.e., during the period of maximum IH growth (proliferative phase). Treatment should be initiated in an inpatient setting, followed by outpatient management. Before prescribing specific therapy, the physician rules out absolute contraindications. The drug dosage is gradually increased under the monitoring of key cardiovascular parameters (heart rate, blood pressure) and respiratory parameters (respiratory rate, O2 saturation). If the child tolerates the treatment well, the dose is increased to the therapeutic level (2–3 mg/kg/day). Side effects from beta-blocker therapy are minimal (the physician will provide detailed information) and occur quite rarely (in approximately 3% of cases).

Complicated forms may require more complex systemic therapy and consultation with specialists in other fields.

7. What are the treatment outcomes?

The response rate to beta-blocker therapy is over 90%.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Absent