History

A thorough history is necessary to assess the lesion and correctly diagnose it. Particular importance should be placed on birth history, growth of the lesion, and any associated symptoms. Stridor, feeding or swallowing problems, bleeding, ulceration, and chronologic history should be elicited.

Exam

A complete head and neck exam should be performed to determine the superficial or deep extent of the vascular anomaly. Changes to oral mucosa coloration may indicate their presence. Flexible fiber-optic laryngoscopy in the clinic is often necessary to visualize the upper aerodigestive tract and evaluate laryngopharyngeal disease involvement.

Management of Infantile Hemangioma

Of particular importance in the head and neck are the functions of speech, swallowing, airway patency, and facial cosmesis. Infantile hemangiomas that bleed, cause functional limitation, or affect vision should be treated and are labeled as problematic (Fig. 29.6). Since the discovery of successful treatment of infantile hemangioma in 2009 with oral beta-blockade (propranolol), this has been the medication of choice for large or symptomatic infantile hemangiomas. However, multimodal management with cutaneous flash pump dye laser, intralesional steroid therapy (triamcinolone), and propranolol is often required in larger or more complex disease to achieve complete resolution. Typically, an EKG is obtained prior to initiation of propranolol therapy. In a 2013 consensus conference, guidelines were released that patients older than 8 weeks are safe to start therapy on an outpatient basis, while younger infants should be admitted for observation [12]. Propranolol is generally safe with low rates of hypoglycemia, bronchospasm, or cardiac events. Topical beta-blocker use in the form of timolol 0.5% has been an alternative treatment for superficial, localized, small infantile hemangiomas and has a 91% resolution rate [13]. With topical therapy, treatment during the proliferative phase typically gives the best outcome.

Special considerations apply to the treatment of subglottic hemangiomas . These typically present in an infant with new-onset, progressive stridor during the proliferative phase and are diagnosed with airway endoscopy in the operating room. Systemic propranolol is the mainstay of treatment and has success rates reported at 90% [14]. Of utmost consideration in these patients is airway patency, and endotracheal intubation may be necessary as a temporizing measure until the hemangioma responds to therapy. Intralesional steroid injection may also provide some benefit. If either medical modality fails, open resection with laryngotracheoplasty is appropriate.

Parotid hemangiomas have similar response rates of 90% with propranolol but may require prolonged treatment [15]. If started early in the proliferative phase, propranolol may be an adequate therapy alone. If disease persists superficially in the skin, this can be treated with flash pump dye laser therapy (585–595 nm), but surgical intervention may be necessary to remove residual soft tissue bulk through a parotidectomy approach with facial nerve identification and preservation.

Other hemangiomas with a significant vertical growth pattern may also leave undesirable fibrofatty residuum, which can be treated with elliptical surgical excision (Fig. 29.7). This is particularly common in scalp hemangiomas which develop alopecia during the involution phase, so these are typically excised [16].

Management of Vascular Malformations

Multiple treatment options exist for vascular malformations including surgery, laser photothermolysis, sclerotherapy, and systemic targeted drugs. While small, focal vascular malformations may be successfully treated with a single modality, deep or infiltrative lesions benefit from a multidisciplinary, staged, multimodal treatment plan to achieve optimal outcomes.

Lasers

Laser therapy is a valuable treatment option for the superficial, pigmented component of vascular anomalies due to selective photothermolysis. Laser therapy treats specific vessel sizes and chromophores, typically oxygenated or deoxygenated hemoglobin, to selectively absorb energy which injures tissue in a targeted fashion. This allows for treatment of the anomaly without damage to surrounding normal structures. Superficial, slow-flow lesions respond better to laser therapy due to higher concentration of thermal injury [17]. This makes lasers a particularly appealing modality for superficial hemangiomas, capillary malformations, and mucosal or skin venous and arteriovenous malformations. Laser treatments are not beneficial for purely lymphatic malformations. The risks of laser treatment include local pain, blistering, ulceration, scarring, and pigmentation changes.

Multiple lasers are used in the treatment of vascular anomalies depending on the depth and vessel size of the lesion. Pulsed dye laser (PDL), with wavelength of 585 nm, targets superficial, small-diameter vessels. This is used commonly for the treatment of cutaneous lesions, especially capillary malformations [17]. Multiple treatments are typically needed. When PDL was used in infancy on capillary malformations of the skin, 75% lightening was achieved after four treatments [18]. The Nd:YAG laser has a wavelength of 1064 nm and targets larger vessels, typically in venous malformations. This laser can be delivered through a fiber, which lends itself to the treatment of upper aerodigestive tract lesions during operative laryngoscopy or to interstitial treatment of a lesion. The Gentle YAG laser uses the same wavelength but comes with a coolant spray to treat darkly pigmented skin and penetrates up to 8 mm for deep venous lesions [17]. The carbon dioxide (CO₂) laser has been used for mucosal vesicles of microcystic lymphatic malformations with success but requires repeated treatments. It has also been used for infantile hemangiomas of the subglottis but is associated with high rates of scarring and airway stenosis, so alternative treatments are now preferred [19].

Surgical Resection

Surgical resection remains a valuable tool for the treatment of vascular malformations (Figs. 29.8 and 29.9). For focal, small lesions, excellent cure rates can be achieved with wide local excision. Larger, diffuse lesions present difficulty due to tissue infiltration and high recurrence rates. However, macrocystic malformations are amenable to surgical resection with a high rate of cure as they expand around soft tissue rather than within.

For more vascular lesions, preoperative sclerotherapy/embolization can induce thrombosis in the malformation and helps reduce blood loss. In particular, NCBA glue can be used in either venous malformations or arteriovenous malformations to define the lesion and provide borders for resection. Resection in previously treated areas is prone to distortion of anatomy and tissue planes, which makes the identification of critical structures more difficult. Ideally, surgical resection is performed in conjunction with preoperative embolization to targeted areas in a staged fashion, treating one area at a time at 3-month intervals. Complete resection of large lesions often leads to unacceptable functional and aesthetic results and so is often not feasible. Maintaining a global perspective and selectively targeting symptoms are key to a good outcome.

History

Vascular anomalies are comprised of malformed arteries, veins, capillaries, lymphatics, or a combination of two or more of those vessels. They are further divided into vascular tumors and vascular malformations (VM) [20]. Large VM can be debilitating and lead to significant complications. As with any complex disease, a detailed history, specifically focused on the evolution of the vascular malformation, is crucial. Eliciting the following information is important: time of onset, growth over time, initial color and change of color, and exacerbating symptoms (i.e., illnesses, onset of puberty, pregnancy, menopause). Patients may even express a feeling of warmth, throbbing, and compressibility or an increase in size with change in extremity position.

Because a simple or complex VM can be associated with other syndromes (e.g., PHACE {posterior fossa, hemangioma, arterial, cardiac, eye abnormalities} syndrome or LUMBAR {lower body hemangioma, urogenital anomalies, myelopathy, bone deformities, anorectal/arterial malformations, renal anomalies} syndrome), it is prudent to do a full review of systems. A patient’s past medical history may also elucidate associated syndromes (history of renal anomalies, eye anomalies, etc.). Family history is needed due to the hereditary nature of certain vascular malformations.

VM can further be delineated into low-flow and high-flow entities. High-flow malformations include arterial malformations, arteriovenous fistulas, and arteriovenous malformations. Low-flow VM include capillary, lymphatic, and venous malformations. There are several complications seen in patients with low-flow VM which include a disturbance in the hemostatic system. Therefore, it is important to elicit a history of episodic or persistent pain associated with “knots” within their malformation indicating thrombosis. Previous surgical history with an emphasis on complications with bleeding requiring blood products or thromboembolism is important as well.

Exam

Examination from head to toe is needed since vascular anomalies can be focal or diffuse and superficial or deep. The color of the malformation is dependent on the type of vessel that is involved. Superficial lesions that appear a reddish-maroon color may be capillary malformations. Bluish lesions may be deeper and signify a venous malformation.

Valsalva maneuvers may enlarge venous malformations due to the weakened vessel walls. Change in position of the involved lesion (lowering the extremity or placing a child in the supine position) below the level of the heart can enlarge the vessel due to filling and decreased venous return. Limb length and size discrepancies should be measured. A genitourinary exam can reveal pelvic and rectal involvement. Some lesions may have no color and present as a protruding mass. Warmth, pulsations, and/or an audible bruit will favor a high-flow lesion and can help differentiate from a low-flow VM. Evaluating the skin for ulceration, leakage of fluid, swelling, or hard well-circumscribed masses (indicating thrombi) is also important.

Diagnostic Evaluation

Localized intravascular coagulopathy (LIC) occurs mainly in low-flow VM but can be devastating if it progresses to disseminated intravascular coagulopathy (DIC). Obtaining a complete blood count (specifically looking at hemoglobin/hematocrit and platelet count), D-dimer, and fibrinogen at baseline and prior to any surgical/invasive procedures is critical. If there are abnormalities in the values, further management is needed.

Other coagulopathies such as Kasabach-Merritt phenomenon (KMP) can be seen in kaposiform hemangioendothelioma (KHE) and tufted angioma (TA), which are locally aggressive vascular tumors. KMP is a consumptive coagulopathy classically involving severe thrombocytopenia and hypofibrinogenemia due to platelet activation within the rapidly growing tumor. This can be life-threatening; thus, early recognition by evaluating a complete blood count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen is essential [21].

Medical Management

Due to the complexity and uniqueness of each individual VM, proper diagnosis is essential. Current treatment strategies require a multidisciplinary approach. There is a multitude of treatments available, but those that will be discussed in this section require the expertise of a hematologist-oncologist.

Sclerotherapy, a process in which intralesional injection causes vessel injury, has been shown to be effective [22]. Bleomycin, an antitumor antibiotic, leads to an inflammatory and fibrotic effect on endothelial cells when injected into an affected vessel [23]. Although there is no gold standard sclerosant, our institutional experience with bleomycin has shown a less painful inflammatory response.

With the increasing use of bleomycin in VM , there needs to be close monitoring for cumulative doses and long-term side effects. Bleomycin has been used in malignancies such as Hodgkin lymphoma (HL) and germ cell tumors and is associated with several side effects, the most concerning of which is pulmonary dysfunction [24, 25]. Our institution has a specific protocol in place and includes obtaining chemotherapy informed consent for every patient receiving bleomycin. Consent is obtained by an oncology physician or a treating member of the vascular anomaly team. The treatment and side effects are discussed thoroughly. The oncology faculty is required to provide a second signature prior to a patient receiving bleomycin. Four to 15 units of bleomycin is used in patients in one setting, depending on the size of the lesion being treated and age of patient. Prior to the first dose, a baseline physical exam is warranted with focus on the pulmonary history and exam. If the patient is >7 years of age, pulmonary function tests (PFTs) are obtained with specific focus on the diffusing capacity of the lung for carbon monoxide (DLCO). We no longer monitor chest x-rays since evidence of pulmonary fibrosis would be a late finding. Oxygen saturation is obtained immediately prior to each procedure to be certain there is no hypoxia. It is important to avoid high concentrations of oxygen during any general anesthetic. A complete blood count is obtained 2 weeks following each bleomycin treatment to monitor for cytopenia as seen in patients with malignancies. PFTs are repeated after the patient has received 60 units/m² to evaluate for pulmonary dysfunction. The maximum cumulative dose of bleomycin sclerotherapy is 100 units/m² at our institution.

It is difficult to make a direct comparison for systemic absorption between intralesional and intravenous bleomycin, but the intralesional bleomycin systemic distribution is likely lower than intravenous doses. Adults who received intravenous bleomycin showed evidence of pulmonary fibrosis in about 10% of adult patients after being exposed to a cumulative dose of 400 international units (~200 units/m² in an average size adult) [24, 25]. Four hundred units is the lifetime dose maximum recommended for oncologic processes. Thirty-four asymptomatic childhood HL survivors received a maximum of 60 units/m² of intravenous bleomycin with 40% showing evidence of restrictive or obstructive lung disease at a median follow-up of about 2 years [26].

Another drug that requires the expertise of a hematologist-oncologist is sirolimus (rapamycin). Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to be effective and safe in patients with complex vascular anomalies [27]. Several VM genetic mutations have since been identified along the PI3K pathway. The mTOR serine/threonine protein kinase is involved in the PI3K pathway and therefore is a fruitful target in preventing cellular growth and survival [28, 29].

Sirolimus is an immunosuppressive medication that has historically been used in solid organ transplantation to prevent graft rejection. Therefore, a lot of the information of side effects has been reported in the transplantation literature. No live vaccinations should be given during treatment. Because of its immunosuppressive properties, patients are susceptible to opportunistic infections, specifically Pneumocystis jirovecii pneumonia (formerly Pneumocystis carinii). Prophylaxis with trimethoprim/sulfamethoxazole is the recommended first drug of choice. Patients need to be evaluated for significant illnesses and/or fever of 101 °F or more. Blood work should be considered including a complete blood count and blood culture.

Dosing of sirolimus can be started at once to twice a day (1.6 mg/m²/day), and trough levels must be obtained after 2 weeks from the start and then every 1–3 months while on the medication. Sirolimus dosing is titrated for response and trough level between 10 and 15 ng/mL [30]. Sirolimus should be held for serious infections such as pneumonia, bacteremia, mononucleosis, etc. Likely, but usually reversible, side effects include high blood pressure, loss of appetite, swelling, mouth sores, increase in cholesterol and/or triglycerides, anemia, and skin rashes. Less likely but severe side effects include severe infections, low white blood cell count, poor wound healing especially after surgery, hypotension, fluid accumulation around organs (heart, lungs, kidneys), kidney failure, cancers (lymphoma, skin), and infertility [29].

Use of topical sirolimus has little to no systemic absorption; therefore no level monitoring is needed. It has been used in port-wine stains (PWS) and has shown some efficacy with the use in conjunction with laser therapies [31].

As discussed earlier, slow-flow VM have a unique complication of LIC due to the slow blood flow through the abnormal and sometimes ectatic vessels. LIC occurs due to stagnant blood flow which can lead to alteration in the coagulation system causing bleeding and/or localized thrombosis [32]. This can further lead to disseminated intravascular coagulopathy (DIC) which can be life-threatening and result in severe bleeding. A significantly elevated D-dimer with or without hypofibrinogenemia, in addition to a history of pain and “knots,” and evidence of phleboliths on imaging can confirm LIC and may warrant anticoagulation, especially periprocedurally. These low-flow lesions can be treated with compression garments and antithrombotic therapy with aspirin or low-molecular-weight heparin (LMWH) to treat pain [33]. Direct oral anticoagulants can also be utilized for treatment or prevention of thrombosis in adults but are not currently FDA approved in children [34].

Emerging Treatment

The phosphoinositide 3-kinase (PI3K) pathway is a signaling network that involves the cell cycle and is frequently altered in human tumors [35]. Through advancements in understanding the molecular pathways that are involved in vascular anomalies, several disorders have been associated with mutations in the PI3K pathway. The pathway involves several proteins including PI3K/AKT/mTOR for which development of targeted inhibitors is promising [35, 36]. Several genetic mutations in complex, disfiguring, and debilitating VM have been discovered. The following mutations have been associated with the following syndromes: AKT1 in Proteus syndrome, PIK3CA in Klippel-Trenaunay syndrome (KTS), CLOVES (congenital, lipomatous, overgrowth, VM, epidermal nevi, spinal/skeletal) syndrome, and FAVA (fibro-adipose vascular anomaly) [37]. Recently, Canaud et al. evaluated 19 patients with PROS after using BYL719, an inhibitor of PIK3CA inhibitor, which showed improvement in disease symptoms in all patients [38]. We have entered the era of molecular classification, and novel targeted therapies are quickly being developed which will advance the treatment of VM.

Venous Malformations

Venous malformations range from isolated large varicosities to more diffuse and infiltrative disease. The location and characteristics of the venous malformation will tend to favor treatment with either surgical resection or sclerotherapy.

Venous malformations with well-defined margins which are reasonably isolated from critical structures are effectively treated with surgical resection, often requiring only one hospitalization. Glue embolization of the venous malformation can be extremely beneficial to the surgeon, both by making the malformation firmer and more easily resectable and also by limiting intraoperative blood loss [39].

Many venous malformations are not candidates for surgical resection, often due to infiltration of important structures such as muscle and bone which would result in morbidity if resected. These lesions are frequently treated with sclerotherapy. Ethanol, sodium tetradecyl sulfate, doxycycline, and bleomycin are some of the more commonly used sclerosants. There is no consensus as to which sclerosant is best; however, ethanol is often considered the most potent sclerosant and ideal for lesions where adjacent injury is better tolerated (e.g., intramuscular) but should be used with caution near the skin and critical structures such as nerves. Bleomycin has shown promise to treat venous malformations with lower rates of inflammation and injury to adjacent structures and may be used for sensitive areas such as orbits, airways, and near nerves.

Additional technical considerations for treatment of venous malformations are the characteristics of the drainage of the malformation. Some venous malformations have no significant central drainage (sequestered) and can be treated by removing the venous blood and simply replacing it with sclerosant. For lesions with central drainage, the centrally draining veins must be blocked in order to allow the sclerosant to be effective. Techniques range from coil or glue embolization of the draining veins to simple pressure from a tourniquet.

Lymphatic Malformations

Lymphatic malformations broadly fall into two groups, macrocystic and microcystic. If the lymphatic cyst is large enough to puncture directly, near complete remission can often be accomplished with a few sessions of sclerotherapy. Percutaneous needle puncture with drainage of intraluminal contents is performed using a 1:1 replacement with sclerosant, frequently doxycycline, which is allowed to dwell for 30–60 min. Although doxycycline has been reported to cause tooth discoloration in pediatric patients when used as a systemic antibiotic, this side effect has not been reported for sclerotherapy of macrocystic lymphatic malformations, likely in part due to removal of the sclerosant at the end of the case.

Microcystic lymphatic malformations often come as a cluster of tens if not hundreds of tiny cysts, and treating each tiny cyst with intraluminal sclerosant is not possible. These lesions often benefit from adjacent, interstitial administration of sclerosant. Many sclerosants have been used, although bleomycin is one of the most common and effective for this indication.

Arteriovenous Malformations

Most interventionalists consider arteriovenous malformations the most difficult to treat. The high-flow nature of these lesions makes them difficult to treat intraluminally due to the rapid washout of sclerosant. In addition, partial treatment often results in increased angiogenesis which can worsen the disease over time. If possible, complete destruction of the malformation should be attempted. Unfortunately, the nature and location of many malformations make them incurable, and in these cases selective, incomplete treatment may be the only option.

There has been a great deal of literature detailing innumerable methods of treating arteriovenous malformations, and an entire book could be written detailing the different methods. For brevity, some of the more commonly used methods will be described here. However, to prevent vascular collateralization and recruitment, management of AVM should be staged and performed at periodic intervals (3–4 months). Although cure may not be possible in diffuse AVM, control can be maintained with gradually increasing treatment intervals.

If the AVM is amenable to surgical resection, preoperative glue embolization can aid the surgeon and minimize blood loss. The goal of glue embolization is both to inject as much glue into the nidus of the malformation as possible and also to embolize the feeding vessels and venous outflow tracts. Single large feeding vessels may be occluded intraoperatively; however, many malformations have numerous small feeders arising from different arteries. Focal AVM (one to two feeding arteries), though, can often be cured with a single intervention with embolization followed by surgical resection.

For nonsurgical lesions, intraluminal ethanol injection is often considered the best treatment. Small aliquots of ethanol can cause rapid protein denaturation and endothelial cell injury resulting in a marked inflammatory response. The end result is fibrosis of the malformation. The injection site is selected to maximize the amount of alcohol that will flow into the nidus of the malformation, and 1 mL/kg of ethanol up to 50 mL is often injected during each treatment. Depending on the exact anatomy of the lesion, it may be best approached with arterial access, venous access, or direct puncture. These are long, difficult cases and almost always require numerous treatments to achieve the desired result.

Intraprocedural and Postprocedural Care

With the exception of bleomycin, all forms of sclerosis cause moderate to intense inflammatory responses and result in pain and swelling to the site. Steroids are often given both during the procedure and for 5–7 days afterward to reduce discomfort. Hemolysis is common and can result in hemoglobinuria. For this reason, patients are hydrated during the procedure, and if there is evidence of hemoglobinuria (often cola-colored urine), fluids are switched to D5W with 75 mEq sodium bicarbonate per liter to cause alkalization of the urine. Pain control medications can range from NSAIDs to narcotics. Skin discoloration seen during the procedure often precedes blistering and rarely ulceration. Patients should be given antibiotic ointments and followed closely.