The precise pathogenesis of IHs remains unknown but is thought to occur due to dysregulation of both vasculogenesis and angiogenesis. IHs are composed of multipotent stem cells that have the potential for endothelial, hematopoietic, mesenchymal, and neuronal differentiation. These stem cells (expressing CD133) can proliferate and differentiate into neuroglial stem cells, endothelial progenitor cells (capable of differentiating into endothelial cells), hematopoietic stem cells (capable of differentiating into erythrocytes and myeloid cells), and mesenchymal stem cells (capable of differentiating into pericytes and adipocytes). ^,

The expression of various placental markers, including Glucose transporter 1 (GLUT-1), gFC receptor, merosin, Lewis-Y antigen, and type 3 iodothyronine deiodinase, by hemangioma endothelial cells suggests a placental origin. GLUT-1, an erythrocyte-type glucose transporter, is a specific marker for endothelial cells of IHs and is not found in other vascular anomalies. The placental cells may arrive at fetal tissue following local placental disruption as an embolic nidus through the permissive right-to-left shunt of fetal circulation. This can occur during chorionic villus sampling or placental complications, which have shown to be predisposing factors for hemangiomas. ^{, , ,}

Hypoxic stress has been proposed as the triggering signal to induce overexpression of angiogenic factors such as vascular endothelial growth factor-A (VEGF-A), insulin-like growth factor-2 (IGF-2), and GLUT-1, through increased expression of the hypoxia-inducible factor-1α (HIF-1α) pathway. ^{, ,} This is supported by epidemiologic factors and the clinical features of IH. Further, osteoprotegerin, a death receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), has been implicated in antiapoptosis during the proliferative phase of IH. More recent studies propose that the renin–angiotensin system (RAS) is a driver of IH proliferation: angiotensin II (ATII) may promote cellular proliferation through secretion of VEGF and osteoprotegerin. ^{, ,}

IHs are not fully developed at birth and first appear in the neonatal period, with a median age at onset of 2 weeks. A premonitory cutaneous sign (a pale area of vasoconstriction or a telangiectatic red macule) may be present at birth in 30%–50% of cases. ^, They are most often single (80%) lesions located in the skin and soft tissue and have an anatomic predilection for the head and neck region (60%), trunk (25%), and extremities (15%). ^, Internal and visceral lesions are uncommon. Up to 20% of patients can have multiple lesions, and these cases are more likely to have internal involvement affecting organs such as the liver, mucosal lining of the gastrointestinal (GI) tract, and the central nervous system. ^, These lesions can be classified by their depth (superficial, deep, mixed) as well as their distribution (localized, segmental, indeterminate, multifocal). Morphological characteristics and anatomic location assist in stratifying the risk of complications.

The proliferative phase of IH is marked by a period of rapid growth, reaching 80% of its final size at a mean of 5 months and completing growth by 9 months of age. Tumors that involve the superficial dermis present as a bright red, macule, papule, or plaque ( Fig. 68.1A ). Superficial tumors that are larger or that exhibit more rapid growth can occasionally cause ulceration of the skin with bleeding. Tumors in the lower dermis, subcutaneous tissue, or muscle may appear pale bluish in color with slightly raised overlying skin (previously incorrectly termed “cavernous” hemangiomas). The onset and growth period of deeper lesions are delayed by approximately 1 month compared to superficial IHs. ^, With experience, history and physical examination can establish an accurate diagnosis for most of these tumors.

(A) This infant has an infantile hemangioma that is in the proliferative phase. This hemangioma was not present at birth but was noted at several weeks of age. (B) This hemangioma is in its involuting phase.

The involuting phase of IHs occurs from age 1–7 years, during which time the tumor slowly regresses, although it may grow in proportion with the child. This phase is notable for fading color of the tumor from crimson to a dull purple, accompanied by a deflation of the tumor mass ( Fig. 68.1B ). The skin may become pale, usually in the center of the tumor first, spreading outward. Over 90% of IHs complete involution by 48 months of age, with most cases expected to show no significant change after 3.5 years of age. Deeper lesions may demonstrate slowed involution, continuing until 7–8 years of age. Up to 70% of patients can have residual skin changes following involution, including telangiectasia, excessive fibrofatty tissue, and skin laxity due to the destruction of elastic tissue. ^, Scars will persist if parts of the tumor were previously ulcerated.

The differential diagnosis of cutaneous hemangiomas consists primarily of other vascular anomalies. Capillary malformation (CM) that involves the skin can be mistaken for superficial hemangiomas, or vice versa. Deeper hemangiomas can be confused for a venous malformation (VM) or lymphatic malformation (LM) as all can appear as bluish masses through the skin. Hemangiomas with fast-flow vascularity of the parenchyma could be confused for arteriovenous malformation (AVM), but the age at onset and clinical history generally distinguishes the two. Congenital hemangiomas, discussed in a later section, may be misdiagnosed as vascular malformations, which are congenital by definition. Pyogenic granulomas, typically a solitary mucocutaneous lesion, rarely appear before 6 months of age (mean age is 6–7 years) ( Fig. 68.2 ). ^, However, the recently described congenital disseminated pyogenic granuloma consists of congenital multifocal cutaneous vascular tumors with frequent organ involvement and is briefly described in a later section. Other conditions such as reticulohistiocytoma, pilomatricoma, dermoid cyst, teratoma, neuroblastoma, and infantile fibrosarcoma can be diagnostically confused.

This child has a pyogenic granuloma. These lesions bleed easily and often have a crusted appearance.

The primary local complications of cutaneous hemangiomas are ulceration, bleeding, and pain. Hemangiomas are rarely life-threatening, but complications can be anticipated by recognition of the anatomic distribution of the lesion. ^, Lesions in the cervicofacial region can lead to airway obstruction as they grow during the proliferative phase. Very large hemangiomas, notably in the liver, can lead to high-output congestive heart failure (secondary to fast-flow and vascular shunting within the tumor), hypothyroidism, and abdominal compartment syndrome (hepatic infantile hemangiomas are discussed in further detail in a later section). Facial lesions involving the eyelid, nose, lip, or ear can result in tissue destruction with cosmetic consequences. Periorbital and eyelid hemangiomas can cause deformation of the cornea leading to astigmatism, visual axis obstruction leading to deprivation amblyopia, proptosis, and strabismus ( Fig. 68.3 ). Perianal IHs complicated by ulceration can result in damage to the anal sphincter and subsequent fecal incontinence. GI hemangiomas are very rare but may manifest with GI bleeding.

Periorbital and eyelid hemangiomas, such as seen in this photograph, can cause visual axis obstruction and can lead to deprivation amblyopia.

A subset of IHs are associated with structural abnormalities involving multiple organ systems and are more frequently seen in infants with larger and segmental hemangiomas. PHACE(S) (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies, and sternal nonunion or supraumbilical raphe) syndrome is characterized by a large IH of the face, neck, and/or scalp with structural anomalies of the brain, eye, heart, and arteries. Females are affected in 90% of cases. Facial hemangiomas in these patients usually start as a small red macule and progress rapidly to a plaque-like or reticular pattern, though deeper hemangiomas can also occur. Hypoplasia or absence of carotid and vertebral vessels, as well as malformation of the aortic arch are described ( Fig. 68.4 ). These patients are at risk for neurologic complications ranging from developmental delays and cognitive impairment to stroke. Consensus guidelines for screening at-risk infants and for risk-adjusted ongoing health surveillance of patients with PHACE(S) were recently published.

This infant has the PHACE(S) association with congenital ocular abnormalities as well as vascular anomalies.

Structural abnormalities can also be associated with lower body IHs. LUMBAR (lower body IHs, urogenital anomalies and ulceration, myelopathy, bony deformities, anorectal malformations and arterial anomalies, and renal anomalies) are characterized by a large, usually segmental IH in the lumbosacral area and/or perineum, often extending toward one lower limb. ^{, ,} In a prospective study, half of patients with a lumbosacral IH were found to have intraspinal abnormalities by magnetic resonance imaging (MRI); ultrasonography (US) sensitivity for these spinal anomalies was found to be quite low at 50%.

The presence of multiple disseminated hemangiomas is termed hemangiomatosis. The cutaneous tumors are usually tiny (<5 mm) and dome-like. When five or more lesions are present, occult visceral lesions, most commonly in the liver, may also be present ( Fig. 68.5 ). Screening patients with US and/or MRI may be indicated for these patients.

This baby has hemangiomatosis. When multiple cutaneous lesions are found, occult visceral lesions, most commonly in the liver, may also be present. Screening for visceral hemangiomas with ultrasound may be indicated in these patients.

Proper radiologic diagnosis of vascular anomalies is dependent on specific expertise and clinical experience with the radiologic features of these lesions. US and MRI are the most useful imaging modalities. US of proliferative phase hemangiomas demonstrates a mass with dense parenchyma exhibiting fast-flow vascularity. ^, This distinguishes deep IHs from VMs, which exhibit slow-flow vascularity and larger blood-filled spaces. MRI of proliferating hemangiomas shows a lobulated solid mass of intermediate intensity with T1 spin-echo sequences and moderate hyperintensity on T2 spin-echo. Flow voids that represent fast flow and shunting are seen in and around the tumor. During the involuting phase, MRI demonstrates decreased flow voids and vascularity, with the mass taking on a more lobular and fatty appearance.

The majority of IHs do not require any specific treatment other than observation and reassurance of the parents. ^, Even tumors that exhibit rapid growth or fiery red skin will spontaneously regress and leave behind little to no evidence of their presence. However, regular follow-up is important as the potential complications have few clinical indicators. Serial photographs are very helpful in documenting progression and subsequent improvement. Reasons for treatment or referral to a vascular anomalies specialist or center include dangerous locations (impinging on a vital structure such as the airway or eye); unusually large size or rapid growth; and local or endangering complications (skin ulceration or high-output heart failure).

In recent years, propranolol, a nonselective beta blocker, has become the first-line pharmacotherapy for complicated IH, replacing oral corticosteroids. The efficacy of propranolol for IH was a serendipitous discovery in an infant with a nasal IH treated with propranolol for steroid-induced cardiomyopathy. Large studies have shown a mean response rate of 96%–98% to 6 months of oral propranolol therapy (2–3 mg/kg per day) with nearly complete regression in 60% of cases. Recommended dosing is 1–3 mg/kg/day divided into two or three daily doses until 1 year of age with the goal of preventing rebound growth. Treatment often leads to a consistent, rapid, therapeutic effect with softening of the lesion on palpation and color shift from intense red to purple ( Fig. 68.6 ). Rebound growth following discontinuation of propranolol occurs in 18%–19% of cases with facial and deep IH at a higher risk. ^, Propranolol is generally well tolerated with the most common side effects including sleep disorders, somnolence, and irritability. Other, less common, side effects include gastroesophageal reflux, bronchospasm or bronchiolitis, asymptomatic hypotension, bradycardia, exposure of an undiagnosed atrioventricular block, and hypoglycemia. ^, Several mechanisms of action have been proposed. ^, These include vasoconstriction, inhibition of angiogenesis, induction of apoptosis, inhibition of nitric oxide production, and diminution of the renin-angiotensin axis.

(A) This child was treated with propranolol for the hemangioma seen in this picture. With treatment, his hemangioma involuted more rapidly than expected (B).

Systemic corticosteroids, which inhibit the expression of VEGF-A by hemangioma-derived stem cells and thus angiogenesis, were first-line therapy for decades. However, propranolol has largely replaced corticosteroid therapy for IH due to its superior efficacy and more favorable side effect profile. ^, Oral prednisone may still have a role in IH treatment in cases where propranolol is contraindicated or leads to an inadequate response. It is given at a dose of 2–3 mg/kg/day, though doses up to 5 mg/kg/day have been used for life-threatening complications of large hemangiomas causing airway obstruction or heart failure. Combination therapy with propranolol can also be considered. Hemangiomas will have rebound growth if steroids are tapered or stopped too quickly. Potential complications of steroid use in infants and children include impaired growth and weight gain in about one-third of cases, cushingoid facies, fungal infection, personality changes, and gastric irritation. In rare circumstances, steroids may induce hypertension or hypertrophic cardiomyopathy, both of which are indications to wean or change therapy.

Topical timolol maleate 0.5%, a nonselective beta blocker, offers a well-tolerated and safe treatment option with moderate-to-good effectiveness for thin, superficial IH. Topical timolol may offer similar efficacy in the correct patient population and has lower systemic adverse effects. ^, Proliferating IH can demonstrate some response to ultrapotent topical corticosteroids and intralesional triamcinolone injection, but this carries risks of skin atrophy as well as adrenal suppression and even accidental embolization if administered systemically. ^,

Although attractive in concept, laser therapy is not often beneficial for IHs, except for a few specific indications. The flash lamp pulse-dye laser penetrates the dermis to a depth of only 0.75–1.2 mm. Most cutaneous hemangiomas are deeper than this and therefore not affected by laser treatment. In addition, laser therapy carries risks of scarring, skin hypopigmentation, and ulceration, which may lead to a poor result compared with observation alone. One instance in which the laser is advantageous is the treatment of telangiectasias that often remain in the involuted phase of hemangioma. The use of endoscopic continuous wave carbon dioxide laser has been shown to be a good strategy for controlling proliferative phase hemangiomas in the unilateral subglottic location. ^, Lastly, intralesional photocoagulation with bare fiber Nd:YAG laser can be useful for hemangiomas in certain locations, such as the upper eyelid where visual obstruction is a concern.

Indications for resection of IHs vary with patient age. During the proliferative phase in infancy, well-localized or pedunculated tumors can be expeditiously resected with linear closure, especially for tumors complicated by bleeding and ulceration. Sites that are most amenable to resection are the scalp, trunk, and extremities. Other modalities to treat ulceration include analgesia, bland emollients such as petrolatum, wound care with dressing changes, topical antibiotics, and topical steroids, which can accelerate healing. Tumors of the upper eyelid that obstruct vision and that do not respond to pharmacologic therapy may also require excision or debulking. Focal lesions of the GI tract with bleeding that fail medical management may require enterotomy and resection or endoscopic band ligation. Diffuse, patchy involvement is the more common presentation of GI hemangiomas. Management is difficult, but most lesions eventually involute and stop bleeding. ^{, ,} Preoperative localization with capsule endoscopy and/or intraoperative endoscopy may be necessary to identify lesions in the small bowel. ^,

During the involuting phase, resection may be needed for hemangiomas that are large and protuberant and therefore likely to create excess and lax overlying skin. Indications for proceeding with resection include (1) resection will be necessary sooner or later; (2) the scar will be identical regardless of timing of operation; and (3) the scar can easily be hidden. Lesions of the nose, eyelids, lips, and ears require special expertise. It is often preferable to perform the operation for the foregoing indications during the preschool years before children become aware of and focus on body image differences that may lead to low self-esteem.

After complete involution of hemangioma, cosmetic distortion often becomes the primary indication for resection. Fibrofatty residuum and redundant skin can be excised in staged operations if necessary. Occasionally, extensive scarring from tissue destruction may necessitate reconstructive techniques.

Finally, for the difficult-to-treat and life-threatening large hemangiomas, especially in the liver, angiographic embolization may be required to manage high-output cardiac failure. Arterial catheterization in infants carries significant risks and should generally be limited to those situations with cardiac compromise in which there is the capacity and intent to perform simultaneous embolization. In these rare cases, pharmacotherapy remains the first line of therapy and should continue along with angiographic procedures. Repeat embolization procedures may be required. Success with embolization is dependent on occlusion of macrovascular shunts within the tumor rather than occlusion of feeding vessels. ^,

Congenital HH are discrete, focal lesions and represent the hepatic equivalent of the cutaneous congenital hemangioma. ^, They proliferate in utero , are fully grown at birth, and regress much faster than IHs. Depending on the subtype, they can follow one of three patterns of natural evolution as a rapidly involuting congenital hemangioma (RICH), partially involuting congenital hemangioma (PICH), or noninvoluting congenital hemangioma (NICH). Many focal lesions are detected antenatally on prenatal US or are discovered as an abdominal mass in otherwise healthy infants. They are usually asymptomatic, found in equal numbers in both genders, and rarely associated with cutaneous hemangiomas. Transient anemia and moderate thrombocytopenia, due to intralesional bleeding and subsequent thrombosis, are observed in some infants and generally resolve spontaneously. ^, This is in contrast to the profound thrombocytopenia seen with Kasabach–Merritt phenomenon, which occurs specifically in kaposiform hemangioendothelioma and does not occur in the hepatic parenchyma. ^,

Diagnosis can typically be made based on clinical history and imaging findings. Consensus guidelines based on multidisciplinary expert opinion recommend a complete blood count, fibrinogen, and liver function tests at diagnosis and repeated based on clinical concern. AFP can help rule out hepatoblastoma. Although consumptive hypothyroidism is classically associated with infantile HH, thyroid function tests should be performed if there is diagnostic uncertainty. Liver US can demonstrate a well-circumscribed focal vascular mass with large feeding and draining vessels with cross-sectional imaging indicated in the setting of diagnostic uncertainty. If biopsy is obtained, congenital HH stains negative for GLUT-1. ^,

Most neonates with congenital HH will remain asymptomatic with serial US indicated for monitoring of involution. However, a subset of congenital HH will have macrovascular shunts from the hepatic arteries and/or portal veins to the hepatic veins. These shunts can cause a large steal, accounting for blood-flow demands above and beyond the hypervascular tumor parenchyma and can result in high-output cardiac failure. These shunts may close as the tumors involute and therefore patients should initially be managed with supportive care and medical management of cardiac failure. However, cardiac strain occasionally mandates interruption of the shunts via embolization. Steroids and propranolol have been utilized in the literature, but their benefit remains unproven and is doubtful. Resection is rarely indicated.

Multifocal and diffuse HH are true IHs, representing the visceral counterparts of the common cutaneous IH. Rarely is a singular hepatic IH seen. Multifocal HH presents as multiple discrete nodules with normal intervening hepatic parenchyma. Diffuse HH consists of innumerable hepatic tumors nearly completely replacing the hepatic parenchyma. ^, It is likely that these two diagnoses exist on a continuum. They undergo involution similar to cutaneous IH with a period of rapid postnatal growth and gradual spontaneous involution. They are more common in females and Caucasians, express GLUT-1, and are associated with the presence of cutaneous IH. Given this association, screening hepatic US is recommended for infants with five or more cutaneous IHs. ^,

Although many infants will remain asymptomatic, a subset of patients presents with severe, potentially life-threatening symptoms secondary to proliferation of the lesions, including abdominal distention, hepatomegaly, congestive heart failure, consumptive hypothyroidism, jaundice secondary to biliary obstruction, and hepatic failure. Acquired consumptive hypothyroidism, due to high expression of type 3 iodothyronine deiodinase in tumor tissues, is highly specific for infantile HH, with 21% of patients with multifocal HH and 100% of patients with diffuse HH experiencing this complication; this does not occur with congenital HH. Aggressive exogenous thyroid hormone replacement is essential to prevent hypothyroid complications such as mental retardation and cardiac failure. Involution of the lesions will usually result in amelioration of the hypothyroidism. ^{, ,}

Asymptomatic patients can be observed with serial US to document involution and final appearance of the hepatic parenchyma. ^, Medical therapy, with the goal of accelerating tumor involution, is first line for infants who develop hypothyroidism or symptoms of cardiac failure secondary to shunting. After recognition of the efficacy of propranolol for the treatment of cutaneous IH, propranolol has been increasingly used and now become the first-line medical therapy for infantile HH. Symptoms refractory to propranolol may be treated with the addition of corticosteroids. Embolization of arteriovenous and portohepatic shunts should be considered in patients with refractory symptoms and worsening clinical status. Hepatic transplantation is the last resort for critically ill infants. ^,

Lymphatic malformations (LMs) are usually noted at birth but can manifest at any age or even be identified on prenatal US. ^, Activating somatic mutations in PIK3CA , involving the catalytic subunit of the PIK3 enzyme, have been identified in some LMs. ^{, ,} LMs are classified as microcystic (diameter <1 cm), macrocystic (diameter >1 cm), or a combination thereof. These descriptions are also useful therapeutically, as size determines whether the cystic cavity can be aspirated or compressed. Clinical presentation varies across a wide spectrum, from focal masses to areas of diffuse infiltration, to chylous fluid accumulations in various body cavities. Lymphedema, a type of LM, does have heritable forms. ^,

The skin and soft tissues are most affected, but LM can also involve the subcutaneous tissues, muscle, bone, and more rarely, internal organs such as the GI tract and lungs. As with CMs, underlying localized soft tissue and skeletal hypertrophy is often associated with LMs. LMs appear as soft compressible masses, similarly to VMs, and may have a bluish hue, although not to the same extent as VMs ( Fig. 68.11A ). LMs appear histologically as thin-walled vascular channels lined by LECs, whose lumen can be empty or filled with a proteinaceous fluid containing macrophages and lymphocytes. These cells stain positive for podoplanin (D2-40) and LYVE-1. Involvement of the dermis may produce puckering of the skin or vesicles that weep clear yellowish fluid. Hair can be more prominent in skin with dermal involvement. Diffuse infiltration of the subcutaneous tissue can produce extensive lymphedema that also falls within the spectrum of LMs. One unique factor among the vascular anomalies is that LMs are at risk for infection that can lead to cellulitis or even severe systemic illness. Similarly, infections located elsewhere in the body, or viral illnesses, can cause increased size and tension in LMs. The cystic components of LMs are also subject to intralesional bleeding secondary to trauma or abnormal venous connections. The vesicles from cutaneous involvement can also leak thin sanguineous fluid or appear as red, purple, or black nodules.

This baby has a (A) large right axillary lymphatic malformation, which is seen on the CT scan (B). (C) This operative photograph shows the residual cavity after resection of the mass.

LMs at various anatomic locations are prone to unique associated anomalies. Periorbital LMs can lead to proptosis and visual disturbance. Facial LMs can cause the associated deformities of macrocheilia (enlarged lips), macroglossia (enlarged tongue), and macromala (enlarged cheeks). Overgrowth of the mandible, sometimes massive, can be seen with cervicofacial LMs. Congenital airway obstruction is rare but also possible ( Fig. 68.12 ). Lesions of the tongue and floor of the mouth, on the other hand, may more commonly produce obstruction of the oropharynx. LMs in the cervical and axillary regions can signal an associated LM in the mediastinum. Anomalies of the central conducting lymphatic channels, the thoracic duct and cisterna chyli, can lead to very problematic and recurrent chylous effusions that affect the pleural, pericardial, and/or peritoneal cavities. In addition, LMs in the GI tract can lead to loss of chyle and subsequent protein-losing enteropathy. In the pelvis, associated problems include recurrent infection and bladder outlet obstruction. LMs of the extremities are seen in conjunction with overgrowth and limb-length discrepancy.

This baby has undergone a tracheostomy due to oropharyngeal obstruction from this large cervicofacial lymphatic malformation.

Well-localized and cystic LMs are easily characterized by US and CT (see Fig. 68.11B ). However, MRI provides the most reliable diagnosis and is best for documenting the full extent of more complex LMs as well as their macrocystic and microcystic components ( Fig. 68.13 ). LMs are hyperintense on T2 sequences because of their high water content. Within the cysts, fluid-fluid levels denote layering of protein and/or blood. Cystic rims and intralesional septae are highlighted by contrast enhancement. Adjacent enlarged or anomalous venous channels may be apparent as well. The differential diagnosis of these cystic lesions in the infant includes teratoma, infantile fibrosarcoma, and infantile myofibroma. For lymphatic anomalies of the thoracic duct and chylous effusions, contrast lymphangiography, although technically difficult to perform, can be helpful to identify the abnormal lymphatic channels or site of leakage. Recently, magnetic resonance lymphangiography (MRL) has emerged as an alternative to traditional fluoroscopic lymphangiography.

This MRI shows a mixed micro- and macrocystic lymphatic malformation of the left upper arm and shoulder.

The indications for LM treatment vary with the extent, symptoms, and anatomic location of the lesions. ^, Focal and macrocystic LMs are amenable to ablation by both sclerotherapy and resection (see Fig. 68.11C ). In contrast, more diffuse and predominantly microcystic LMs are difficult to eradicate by any method. For local intralesional bleeding that causes sudden enlargement of LMs and pain, conservative management with rest and pain medications is sufficient. Similarly, the enlargement of LMs that coincides with systemic viral or bacterial infections can be managed expectantly, as it is usually harmless. On the other hand, bacterial infections presenting with cellulitis require timely treatment. Infected LMs become tense and swollen producing erythema, pain, and toxicity; the incidence of this complication is around 15%–20%. Treatment consists of systemic antibiotics, and hospitalization for intravenous antibiotics is often necessary.

Indications for ablation or resection include recurrent complications with infection, cosmesis, deformity, dysfunction, and leakage into body cavities or from the skin. Commonly used agents for injection sclerotherapy, such as ethanol, sodium tetradecyl sulfate, bleomycin, and doxycycline, produce scarring and collapse of the cysts. For a simple, well-localized macrocystic LM, sclerotherapy can ameliorate most lesions. For more diffuse and complex LMs, sclerotherapy procedures need to be staged and can lead to significant improvement. However, reexpansion of the lesions to some extent usually occurs. Weeping or bleeding from cutaneous vesicles can be controlled with local sclerotherapy or carbon dioxide laser, though leakage generally resumes in 6–24 months. Significant complications from sclerotherapy are related to the specific agent used and include injury to adjacent nerves, necrosis of overlying skin, skin pigmentation, hemoglobinuria, pulmonary fibrosis, and cardiotoxicity.

Resection for complex LM can also be of significant benefit (see Fig. 68.11C ), but staging is often needed. The operations can be long and tedious, and often require meticulous dissection to preserve vital structures. General guidelines for resection are (1) each operation should focus on a defined anatomic region, removing as much of the lesion as possible including neurovascular dissection, but without injuring vital structures; (2) limit blood loss to less than the patient’s blood volume; and (3) prolonged closed-suction drainage of the resulting cavity is important. The recurrence rate following “macroscopically complete excision” ranges from 15% to 40%. This recurrence is thought to be secondary to regrowth and reexpansion of unexcised lymphatic channels. Sclerotherapy of the residual cavity following excision may be helpful in this regard. Following resection, it is common for cutaneous vesicles to occur within the scar. These can be controlled to some extent by local intravesicular sclerotherapy or laser. Alternatively, additional staged excision, pulling uninvolved dermis over the resection bed, may prevent this bothersome result.

Some other caveats about operation for LMs are worthy of mention. Cervicofacial LMs will often require staged orthognathic procedures to improve bite and speech impediments related to maxillary and mandibular overgrowth. Tracheostomy may be needed in cases of oropharyngeal and airway obstruction (see Fig. 68.12 ) and should precede attempts at sclerotherapy for cervicofacial LMs. Reactive inflammatory swelling can be dramatic in the initial period following sclerotherapy and can exacerbate partial oropharyngeal obstruction. Lesions of the cervical and axillary regions often involve the brachial plexus. The use of nerve stimulators is a useful adjunct to help prevent injury in these cases. Resection of thoracic and mediastinal LMs to treat recurrent pleural and pericardial effusions involves dissection and skeletonization of the great vessels and vagus and phrenic nerves. For pelvic and anorectal LMs, detailed knowledge of the anatomy of the ischiorectal fossa and sciatic nerve are important. Preoperative sclerotherapy to shrink lesions is often useful as well, but discernment is necessary as scarring can impede the preservation of important nerves. Lastly, for the specific type of cutaneous LMs, “lymphangioma circumscriptum,” wide resection and closure, if necessary, with split-thickness skin grafts, can be curative. However, serial resections, allowing adjacent skin to grow, are generally preferable to grafting.

Recent identification of the pathogenic mutations in the RAS-MAPK-ERK and PI3K-AKT-mTOR signaling pathways in vascular malformations has permitted the use and development of drugs targeting these pathways. Sirolimus (rapamycin) inhibits mammalian target of rapamycin (mTOR), which is a serine/threonine kinase regulated by PI3K. mTOR regulates numerous cellular pathways including angiogenesis and cell growth. In patients with LMs, systemic sirolimus has been shown to lead to a reduction in size, number of lymphatic vesicles, infection, pain, and overall improvement in quality of life. ^, Side effects can include mouth sores, metabolic/laboratory alterations, headache, GI upset, and bone marrow suppression, though few patients have adverse effects severe enough to discontinue the medication. Close monitoring with serum drug levels and laboratories is indicated. Cutaneous LMs can also be treated with topical sirolimus, leading to an improvement in lymphatic blebbing, bleeding, and leaking. Alpelisib, a PI3K inhibitor recently FDA-approved for use in PIK3CA-related overgrowth spectrum (PROS), has shown promising results in small studies of severe and complicated LMs. ^,

Venous malformations (VMs), often mistermed “cavernous hemangiomas,” are slow-flow congenital lesions consisting of venous channels that can develop anywhere in the body, most commonly in the skin and soft tissues. VMs may be seen at birth or become apparent later, depending on the anatomic location. They occur at an estimated incidence of 1–5 in 10,000 births. A wide spectrum of presentations is possible, including simple varicosities and ectasias, discreet spongy masses, and complex channels that can permeate any tissue or organ system. They tend to slowly enlarge with normal growth of the patient but can dilate and become symptomatic at any time. As with other vascular malformations, the proportional growth that occurs may become exaggerated during puberty. On examination, these soft, bluish, compressible lesions can expand with dependent position and Valsalva maneuver ( Fig. 68.16 ). Episodes of phlebothrombosis secondary to stasis may lead to acute pain and swelling. Phleboliths can be palpated in many VMs. Associated local overgrowth and limb-length discrepancy are not uncommon. Involvement of bones and joints creates risk for pathologic fractures and hemarthroses, with subsequent arthritis.

This adolescent has a venous malformation in the subcutaneous tissues of his back. These soft, bluish, compressible lesions can expand with dependent position and during Valsalva maneuver.

VMs of the GI tract are often multiple as well and can affect every part from mouth to anus. They are more common in the left colon and rectum when associated with VM of the pelvis and perineum. GI bleeding, typically chronic in nature, can result. Blue rubber bleb nevus syndrome (BRBNS, or “Bean syndrome”) represents a specific rare disorder consisting of multifocal VMs that affect the skin and GI tract primarily ( Fig. 68.17 ). ^, The skin lesions are unique in that they are often quite numerous and resemble tiny “blue rubber nipples.” These skin lesions present diffusely and are classically seen on the palms and soles of the feet (see Fig. 68.17A ). As with other GI VMs, chronic bleeding and intussusception can result. Diagnosis of a GI VM is generally based on endoscopy. Patients with rectal VMs can have associated ectatic mesenteric veins and are at risk for developing portomesenteric venous thrombosis.

Blue rubber bleb nevus syndrome. (A) Classic cutaneous venous malformations are seen on the sole of the foot. (B) Venous malformations of the small intestine and colon were found at operation.

Large VMs can also be complicated by localized intravascular coagulopathy caused by stasis and stagnation of blood within the malformation, leading to consumption of coagulation factors. Phlebolith formation and increased risk of bleeding result. The clotting profile consists of prolonged prothrombin time, decreased fibrinogen, and elevated D -dimers. PTT is often normal. Thrombocytopenia can occur with a typical platelet range of less than 100,000/μL. The distinction between this coagulopathy and KMP is important, given the implications for treatment.

Histologically, VMs most often consist of sinusoidal vascular spaces with variable communication to adjacent veins. The dilated venous channels are thin walled, compared with normal veins, and smooth muscle actin staining reveals abnormal smooth muscle architecture that may be responsible for the gradual expansion seen over time with these lesions. Calcified phleboliths can be seen that provide evidence of prior clot formation within the VM. A variant of VM, glomuvenous malformation (GVM, also incorrectly called “glomangioma”), has the additional presence of ball-shaped glomus cells that line the vascular channels.

Approximately 90% of VMs are sporadic; half of those result from a mutation in the vascular endothelial cell-specific receptor tyrosine kinase TIE-2 and its associated TEK gene. ^, The TIE-2 signaling pathways play an important role in angiogenic remodeling and vessel stabilization during development. Approximately 20% of sporadic VMs have somatic activating mutations in PIK3CA .

BRBNS has been found to harbor a double (cis) mutation in TIE-2 . Cutaneomucosal VMs, inherited through autosomal dominant transmission, are caused by a gain-of-function mutation in TIE-2 and represent 1%–2% of VMs. ^, GVM, also autosomal dominant, represents 5% of VMs and results from loss-of-function mutations in glomulin , which affects vascular smooth muscle differentiation.

Radiologic modalities useful for the diagnosis of VMs include US, MRI, and venography. MRI is most informative in defining disease extent and demonstrates hyperintense lesions with T2 sequences. Contrast enhancement of the vascular spaces distinguishes VM from LM, as does the presence of pathognomonic phleboliths. Intralesional bleeding within LMs can represent an exception to this rule. In contrast to AVMs, VMs do not demonstrate evidence of arterial flow on MRI.

Indications for treatment include appearance, pain, functional impairment, and bleeding. Unfortunately, cure for VMs, as with LMs, is difficult to achieve for all but the most localized and therefore less problematic lesions. For extensive VMs of the extremities, conservative management with the use of graded compression stockings can achieve significant improvement in size and symptoms. Patient satisfaction with this treatment depends on a proper customized fit, but can be elusive, especially for children and teenagers. For more extensive VMs, multidisciplinary care with both medical and procedural interventions should be considered.

Medical therapy with antiinflammatory, anticoagulation, and targeted therapies can be used. NSAIDs, such as low-dose aspirin, may help with pain and swelling occurring from phlebothrombosis. Low-molecular-weight heparin and direct oral anticoagulants (DOACs) have shown efficacy in controlling localized intravascular coagulopathy, and thereby decreasing bleeding risk, as well as in alleviating pain. ^, Following recent breakthroughs in understanding the genetic causes of VMs, sirolimus (mTOR inhibitor) has become an option as a first-line medical therapy for VMs. Sirolimus has been shown to lead to improvement in pain, function of the affected body part, self-perceived quality of life, and coagulopathy, and may lead to reduction in size of the malformation. ^{, ,} Side effects are dose-dependent, and laboratory monitoring is indicated for identification of toxicities and assessment of drug levels.

Intralesional sclerotherapy is commonly employed and is the first-line interventional treatment for most VMs. Sclerosing agents, most commonly ethanol and sodium tetradecyl sulfate, cause direct endothelial damage, thrombosis, and scarring. For small VMs, the injection process is similar to that for simple varicosities. Larger lesions are accessed by direct puncture, and the therapeutic agents are injected under fluoroscopy, with the use of tourniquets and compression of venous drainage to prevent systemic administration of the sclerosants. General anesthesia is required in most instances. Staged therapy and occasional embolization of large venous channels are useful for more complex VMs. The more complex lesions are best treated by a skilled interventional radiologist who has experience with vascular anomalies.

VMs have a propensity for recanalization and reenlargement. Complete cure with sclerotherapy is rare, though symptom relief is often dramatic. Given that recurrence is quite common, results from treatment are often stated in terms of patient satisfaction, with decreased pain and an improved appearance. Resection is typically reserved for well-localized lesions or for symptoms persisting despite medical therapy and minimally invasive interventions. Procedural morbidity and recurrence must be considered, especially for complex VMs. Preoperative sclerotherapy or glue embolization can be considered preceding operations for extensive VMs to shrink the lesion and decrease bleeding during the resection.

Unifocal GI lesions can be excised. Diffuse colorectal malformations causing significant bleeding may be treated by colectomy, anorectal mucosectomy, and coloanal pullthrough. Although surgical resection of multifocal VMs in BRBNS provided a potential cure for GI bleeding, more recently many patients with BRBNS have had an excellent response to sirolimus, with improvement or resolution of their GI bleeding and subsequently have achieved transfusion independence. Patients with GI bleeding resistant to sirolimus can be managed with complete resection of all lesions. This can be done via wedge excision and polypectomy, by intussusception of successive lengths of intestine, combined with endoscopy of the entire GI tract at the time of operation.

Arteriovenous malformations (AVMs) are fast-flow vascular malformations characterized by abnormal connections or shunts between feeding arteries and draining veins, without an intervening capillary bed. These shunts define the nidus of the malformation. Lesions tend to be localized but can be extensive as well. AVMs are one of the most common vascular anomalies that occur in the CNS and are more frequent than extracranial AVM. A clinical staging system has been developed to describe the natural history of progression ( Table 68.2 ). At birth, they appear as a pink cutaneous blemish that can be confused with both a CM and the premonitory sign of an IH. The fast flow through the shunt becomes more evident in childhood and adolescence as the lesion expands and develops into a mass. Lesions will feel warm to the touch, often with a bruit or thrill. With continued expansion, they become more red/purple and prominent and develop telangiectasias. Puberty, pregnancy, or local trauma can trigger more rapid expansion. Skin ischemia can develop from expansion or local steal phenomenon, leading to pain, ulceration, and bleeding ( Fig. 68.18 ). Large AVMs can cause high-output cardiac failure.

A facial arteriovenous malformation (stage III) with ulceration of the skin is seen in this patient.

Most AVMs are sporadic, but heritable forms exist. Mutations in RASA1 and EPHB4 cause the autosomal dominant disorder CM-AVM. ^{, ,} The CMs are multifocal, small, round-to-oval, pinkish-to-red lesions and are usually randomly distributed. They can be associated with an AVM or arteriovenous fistula. Visceral AVMs are a hallmark of hereditary hemorrhagic telangiectasia (HHT or Osler-Rendu-Weber disease). Pathogenic autosomal dominant mutations in ENG , ACVRL1 , GDF2 , and SMAD4 , all of which are involved in the binding and signaling of TGF-β, have been identified in patients with HHT. ^, Recently, mutant MAP2K1 alleles were identified in a large proportion of extracranial AVM specimens studied. It is thought that somatic mutations in this gene cause dysfunction in endothelial cells due to increased MEK1 activity, therefore making MEK1 inhibitors a potential therapy for AVMs in the future.

US and Doppler imaging can elucidate the fast flow of these lesions and distinguish them from VMs. On CT, dilated feeding arteries and veins are seen as areas of contrast enhancement. MRI and MRA are the most useful modalities to demonstrate the full extent of these lesions. They appear as signal flow voids on MRI or areas of contrast enhancement on MRA ( Fig. 68.19 ). Superselective angiography can clearly identify the nidus when treatment is planned.

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