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Classification - Vascular lesions of the skin are divided into congenital and acquired lesions (Figure 1). Acquired vascular lesions – The most significant acquired vascular lesions of infancy are hemangiomas (1). The lesions are composed of proliferating blood vessels and although benign, they have a potentially destructive character. Hemangiomas undergo a proliferative and an involution stages. Pyogenic granuloma is another acquired vascular lesion that is frequently seen during childhood. It is of minor aesthetic significance compared to hemangiomas (2). After infancy, acquired vascular lesions are associated with aging (senile angiomas), trauma (arterio-venous fistulas), systemic conditions (spider angioma) and malignancy (Kaposi’s sarcoma). Congenital vascular lesions – The most common congenital vascular lesions are vascular malformations. Those lesions are the outcome of errors in vascular formation during embryonic life. They do not proliferate. The dilated blood vessels that build up those lesions gradually increase in size. Vascular malformations can be classified based on the type of their blood flow into slow flow lesions (capillary, venous or lymphatic), high flow lesions (arterial) and lesions with a combined slow and fast blood flow (Figure 2). The nomenclature of vascular lesions is confusing and one might find perplexing terms as “capillary hemangiomas” in some textbooks. Terms as “strawberry hemangiomas” for superficial lesions and “cavernous hemangiomas” for deep lesions are puzzling and should probably not be used. The classification presented in this paragraph is based on the type of blood vessel, type of flow and clinical presentation of the lesion (1). There are exceptions to this classification: some hemangiomas are congenital (3) and some vascular malformations are not present at birth. Congenital hemangiomas are discussed in section 7. Frequency - Approximately 80% of hemangiomas grow as a single tumor (4). Twenty percent proliferate in multiple sites. Hemangiomas are far more common in females than in males. The ratio is 3–5:1. The incidence in white infants is 10% to 12% and 22% in preterm infants who weigh less than 1,000 gm. The incidence is lower in dark-skinned infants (4). Etiology and Pathophysiology - Formation and remodeling of blood vessels are controlled generally by paracrine signals, many of which are protein ligands that bind and modulate transmembrane receptor tyrosine kinases (RTKs) (5). Negative regulators include angiostatin, endostatin, and thrombospondin. Among the positive regulators are vascular endothelial growth factor (VEGF), fibronectin, 5-integrin, VE cadherin, and TGF- 1 (5). Several studies indicate that hemangiomas are the outcome of an angiogenic growth factor effect (5,6,7). Basic fibroblast growth factor and vascular endothelial growth factor messenger RNAs are up-regulated in proliferative hemangiomas. Transforming growth factor-beta 1 messenger RNA remains low in both proliferative and involuted hemangiomas (6). Vascular endothelial growth factor is localized predominantly in pericytes and endothelial cells during the proliferative phase (7). Basic fibroblast growth factor is found in endothelial cells in both the proliferative and early involutional phases (7). Other studies indicate that the angiogenic peptide, basic fibroblast growth factor (bFGF) is elevated in the urine of infants with proliferating hemangiomas (4). It’s levels subsequently diminish and return to normal during natural involution or during accelerated regression induced by antiangiogenic therapy. In contrast, in patients with vascular malformations, normal urinary bFGF levels are found (4). Clinical presentation - Diagnosis of a vascular lesion is based on the medical history, physical examination and imaging. The type of lesion can usually be determined based on the first two. Imaging is mostly useful for confirming the clinical diagnosis, estimating the extent of the lesion and determining the feasibility of surgical resection. Medical history - When taking the medical history, four questions should be asked (Figure 3): 1. Was the lesion present at birth? 2. Was there proportional or un-proportional growth of the lesion after birth? 3. Was there a phase of involution? 4. Has an episodic increase in size occurred at any point? Physical examination - Physical examination of a vascular lesion includes inspection, palpation and trans-illumination (Figure 4). A complete body examination should be performed in order to rule out syndromes that include skin hemangiomas. One of them is neonetal hemangiomatosis, which refers to infants with multiple cutaneous hemangiomas. Such patients may have intrahepatic hemangiomas that can cause congestive heart failure, hepatomegaly, and anemia (4). Hemangiomas may be associated with other underlying conditions: lumbosacral hemangiomas may be overlying an occult spinal dysraphism as a tethered cord, lipomeningocele and diastematomyelia. Facial hemangioma may be associated with posterior fossa abnormality, malformations of great arteries and ocular abnormalities.
2. INDICATIONS FOR TREATMENT Most hemangiomas do not require treatment. They will regress spontaneously by the age of 10 to 12 years (4) (Figures 5-7). Indications for early intervention are primarily functional such as obscuration of vision or breathing difficulties (Figure 8). Uncontrolled bleeding and pain caused by an ulcerated hemangioma may be an indication for intervention as well (Figure 9-10). Facial hemangiomas, especially aggressive, rapidly spreading hemangiomas may necessitate early pharmacological or surgical intervention to decrease the long-term aesthetic deformity (Figure 9). Very large hemangiomas may be associated with platelet trapping and therefore require early intervention. Parental concerns and psychosocial effects of the deformity on the growing child should also be taken into consideration and may warrant earlier treatment. The indications for treatment and a regional approach to the management of facial hemangiomas are presented in the surgical therapy section.
3. ANATOMY and CONTRAINDICATIONS Hemangiomas are composed of abnormal vessels located at the skin and/or subcutaneous tissue. The lesion can extend far beyond the skin and invade adjacent structure such as the floor of the mouth and the cheek muscles. Figure 11 shows a lower lip hemangioma at age six months (upper left) and following proliferation, at 16 months of age (lower left). MRI shows extension of the lesion into the floor of the mouth and cheek.
4. WORKUP Imaging studies - The most important imaging tool is contrast enhanced MRI (8). This diagnostic test, which requires sedation or general anesthesia for children under 6 years of age, demonstrates the extent of the lesion and helps differentiate between hemangiomas, venous, lymphatic and arterial lesions. It may also help differentiate between a vascular lesion and non-vascular lesions such as found in neurofibromatosis. MRI scans have three basic images: T1-weighted spin-echo image, T2-weighted spin-echo image and contrast enhanced (Gadolinium) T1-weighted spin-echo image. T refers to the relaxation time (usually marked as TR value on the CT scan printout). TR refers to the time, which takes to the protons to discontinue spinning (Figure 12). T1 refers to a value around 600 milliseconds and T2 refer to a value around 4000 milliseconds. The typical findings in the three image modes are presented in figure 13. Hemangiomas have a typical solid appearance with intermediate intensity on a T1-weighted spin-echo image, which is more intense compared with venous or lymphatic malformations (8). During the proliferative stage, hemangiomas show a relatively low intensity in a T2-weighted spin-echo image while in the involution phase they have a very low intensity. Contrast enhanced T1-weighted MRI shows moderate intensity with prominent flow voids during the proliferative stage due to the high flow at this stage. In constrast, hemangiomas show low intensity during involution due to the low flow at that stage. Figure 14 shows a 5-year-old boy with a left intraorbital hemangioma which had caused vertical dystopia of the left globe. Figure 15 shows the contrast enhanced T1-weighted image with visible flow voids and intensity, typical for hemangiomas at the proliferative phase. U/S Doppler can assess the flow of hemangiomas. Generally, they are characterized by a shunt pattern with decreased arterial resistance and increased venous velocity. Arteriography is rarely used for diagnosis or treatment of hemangiomas. Superselective embolization may be used in selected bleeding hemangiomas with a detectable regional nourishing vessel. Histology - Proliferating hemangiomas are composed of clusters of rapidly dividing endothelial cells (Figure 16). With regression, endothelial activity gradually diminishes and the cells flatten and mature. Mast cells appear in the late proliferating phase and early involuting phase and interact with macrophages, fibroblasts, and other cell types (2,9). Light microscopy demonstrates during involution progressive deposition of perivascular and interlobular/intralobular fibrous tissue. Multilaminated basement membranes, an ultrastructural hallmark of a proliferative phase hemangioma, persist in the involuted phase (2,9). Proliferating cell nuclear antigen is expressed by the majority of endothelial cells and pericytes in the proliferative and early involuting phases (7). Its expression is negligible in the involuted phase (7). The total number of mast cells is highest in the involuting phase and the proportion of chymase-positive mast cells decreases with the progression of involution (7). Type IV collagen and the 2 chain of laminin and perlecan are detected in the basement membranes in all phases (7). Differential diagnosis - Hemangiomas may be confused with deep lymphatic or venous vascular malformations. The presence of the lesion at birth supports a diagnosis of a vascular malformation although congenital hemangiomas are seen at birth. MRI can help distinguish between a vascular malformation and a hemangioma. The differential diagnosis also includes gliomas and other benign and malignant tumors. Figure 17 shows a 1-year-old girl that presented with a 3-month history of a right facial lump. The lesion was initially managed as a hemangioma. However, MRI indicated that this was not a vascular lesion and excisional biopsy through an upper buccal incision disclosed nodular fasciitis. Figure 18 shows the differential diagnosis of orbital hemangioma. Pyogenic granuloma, which is also one of the most common acquired vascular lesions of childhood, has a typical history of a non-healing and occasionally bleeding wound. It does have a growth phase similar to that of hemangiomas but are usually much smaller (2).
5. TREATMENT Observation is indicated in most hemangiomas. Presentation of pictures showing the natural course of hemangiomas is very useful when discussing with the parents the natural course of the disease (10). Non surgical therapy – Local wound care – Local antibiotic ointment or wet to dry dressing is useful to clear the debris and decrease the likelihood of local infection during the involution stage. Parents need to be informed about the possibility of acute bleeding and how to apply local pressure. Local pressure – Wearing a pressure garment for at least 20 hours every day may be helpful in suitable anatomical sites. Figure 19 shows the effect of a pressure garment on a large chest hemangioma. The lesion decreased in size following treatment of this one-year-old girl with a compression garment 20 hours every day for 4 months. Local excision was deferred to avoid injury to the breast bud. Steroids – Systemic or local injection of steroids is indicated in certain cases (11). The usual dose is up to 2-3 mg/kg/day for 4 to 6 weeks with gradual tapering of the dosage afterwards. The dose may be increased up to 5 mg/kg/day in severe cases. The treatment is indicated when major functional complications arise. Figure 8 shows the effect of local and systemic steroid treatment on orbital hemangioma. The 9-month-old baby girl in the picture was able to open her eye again following 3 months of treatment. There may be short-term side effects that are minor and transient. It is uncommon to have long-term complications (12). Recombinant interferon alfa-2a (IFN) – May be indicated in cases where steroids are contraindicated or not effective (13). Treatment is associated with complications such as transient elevation of liver enzymes levels, neutropenia and anemia. A concerning complication is the possibility of long-term spastic diplegia (4). Flash lamp pulsed dye laser – Moderate lightening effect on the capillary discoloration of hemangiomas. Pulsed dye laser does not have effect on the volume of the lesions (14). Intra-lesional laser - Intralesional fiber with the KTP laser was shown to induce involution of voluminous hemangiomas of the face and neck regions (15). Intralesional photocoagulation treatment with the KTP and Nd:YAG lasers was also found to be effective and safe for the treatment of periorbital hemangiomas (16). Superselective catheterization and embolization – Infrequently used to treat hemangiomas with a defined nourishing artery. Embolization may be useful to decrease high-output cardiac failure in infants with liver hemangiomas. Surgical therapy – Surgical therapy may be considered in several circumstances: When intra operative and postoperative bleeding could be controlled. When surgery will not put an organ at risk (e.g. injury to the eye or facial nerve). When the expected aesthetic and/or functional outcome of the procedure is similar to or superior to the aesthetic outcome of spontaneous involution. When the aesthetic and/or functional outcome of the procedure is inferior to the predicted outcome of spontaneous involution and the psychosocial effect on the child having to live through childhood with a disfiguring deformity is significant. A regional approach to the management of facial hemangiomas – Facial hemangiomas are a challenge. They are associated with significant parental concerns and psychosocial effect on the developing child. A regional approach to the management of those often very disfiguring lesions is presented. Periorbital hemangiomas (Figures 8, 15 and 16) – Most hemangiomas in this area are managed by a conservative approach. Treatment with local injections and/or systemic steroids is indicated when the vision is impaired and this might cause astigmatisim or deprivation amblyopia (Figure 8). Late excision may be indicated for residual fibrous fatty tissue. MRI is mandatory to rule out other benign or malignant causes of periorbital fullness, proptosis and dystopia. The differential diagnosis (Figure 18) includes lymphatic lesions, neurofibromatosis, meningioma, lacrimal epithelial tumors and fibrous dysplasia. Forehead hemangiomas (Figures 10, 20) – The combination of a relatively thin skin, subcutaneous tissue and muscle makes most forehead hemangiomas to become exophytic. Those lesions, especially when located close to or within the hairline tend to bleed profusely. This may require early resection (Figure 10). Lower forehead hemangiomas may cause secondary ptosis. The lesions can be excised through a direct incision. A bicoronal approach provides excellent exposure and allows wide resection of the lesion without visible scars. Figure 20 demonstrates resection of a lower forehead hemangioma at the fibrous-fatty stage through a bicoronal approach. The lesion (upper left and middle pictures) was exposed through a bicoronal incision (upper right) and excised (lower left). The nasal bridge was exposed and excess fibro-fatty was resected as well (lower middle). A satisfactory result is seen 3 months after surgery (lower right). Cheek hemangiomas (Figures 5,6) – Most hemangiomas in this area are managed by a conservative approach. Systemic and/or local treatment with steroids is indicated when vision is impaired. The aesthetic outcome of deep lesions is excellent. Figure 5 demostrates two patients with deep cheek hemangioma at the age of one year and 8 years. This shows excellent outcome with conservative treatment. When the hemangioma includes a superficial skin involvement a future intervention to address excess skin and skin texture is anticipated. Figure 6 shows two patients that had cheek hemangiomas with a superficial component. The patient at the upper part of the figure is seen at the age of 9 months and 9 years. The patient at the lower part of the picture is seen at the age of 4 months and 5 years. Nasal hemangiomas – Hemangiomas can be classified (Figure 21) based on their location into nasal tip lesions, nasal bridge lesions and lateral nasal lesions. Lateral nasal lesions are managed in the same way cheek lesions are treated and early treatment of those lesions with steroids is indicated when vision is obstructed. Early surgery has proved, in our experience, to be beneficial for nasal bridge and nasal tip lesions. The feasibility of the surgical intervention depends on the size of the lesion and the likelihood of aesthetically pleasing primary skin closure. The surgical excision can be preceded with local steroid injections. Nasal bridge lesions can be excised and the skin primarily closed in many cases (Figure 22). Nasal tip (“Pinocchio”) lesions can be addressed at the age of 3-4 years by open rhinoplasty. The vascular lesion is excised from the inner side of the nasal skin. The tip is redrapped and the excess skin is excised. Figure 23 shows the outcome of early excision of a nasal tip hemangioma (upper left). The nose is seen (lower left and upper and lower right) 10 years following open rhinoplasty done at the age of 2.5 years. Upper lip hemangiomas – Upper lip hemangiomas are usually not associated with functional problems. They are associated with aesthetic concerns and cause discoloration, protrusion and lip ptosis on the affected side due to their mass effect. In our experience, lesions that do not involve the skin can be excised through an intraoral approach with good aesthetic outcome. Lesions that involve the skin are best managed conservatively until the lesion decreases in size. Waiting allows reconstruction of the entire aesthetic unit or sub unit of the upper lip. This usually makes an almost impossible reconstruction a feasible one. Figure 7 shows the natural course of upper lip lesions that involve the skin. The upper and lower left pictures show upper lip hemangiomas at the age of 9 months and 2 years respectively. The upper and lower right pictures show upper lip hemangioma at the age of 6 and 11 years respectively. Observation facilitates lip reconstruction but may be associated with severe psychosocial effect on the child. This should always be taken into consideration when surgery is planned. The girl seen at the lower left and right pictures was frequently teased by her peers because of the “worm” on her upper lip. Lower lip hemangiomas - Lower lip lesions have aesthetic as well as functional consequences. Lip protrusion and ptosis may cause drooling and speech impairment (Figure 24). The lesions may extend into the floor of the mouth. The visible lip lesion in those cases is usually the “tip of an iceberg”. Figure 11 shows a lower lip hemangioma at the age of six months (upper left) following proliferation at the age of 16 months (lower left). MRI shows involvement of the floor of the mouth and cheek. Lip reduction is advised in such cases at the end of the proliferation phase. This can be done by a fusiform mucosal excision with lip debulking. Tumescence is a valuable adjunct for the excision of such lesions (17). Rapidly spreading pan facial hemangiomas – Rapidly spreading “malignant” type hemangiomas are defined by us as lesions that rapidly extend from its original aesthetic unit. Those lesions are frequently associated with significant aesthetic deformity. They require early detection and treatment with steroids. The healing process may be associated with necrosis and soft tissue loss that produce severe facial deformities. Figure 9 (upper left) shows a 4-month-old baby girl with rapidly spreading hemangioma that started as a small cheek nodule and ended up invading the forehead, eyelids, cheek, and lip aesthetic units. Part of the lip underwent necrosis and caused a cleft of the lip (lower left). The right side pictures are of a 6 month old (upper right) and a 4-month-old (lower right) infants with aggressive rapidly spreading hemangioma. Parents need to be informed that administration of steroids may induce repulsive necrosis of the lesion (Figure 9, lower right).
6. COMPLICATIONS Vision – Obstruction of vision during the first six months of life by a periorbital, cheek, forehead or nasal hemangioma may cause long-term visual damage. Early treatment with steroids and / or surgery is indicated in such cases (Figure 8). Breathing – Hemangiomas, which invade the neck, may compress the soft tracheal rings of the infant and present as stridor. Steroids are indicated in those cases. Direct external excision of the lesions is impossible in most cases due to close proximity to vital structures. Localized subglottic lesions can be reopened with CO2 laser. Tracheostomy should be considered in cases of failed pharmacological treatment. Bleeding – Hemangiomas have a high flow during the proliferative phase and when extensive lesions become ulcerated anemia may be caused. This is especially common in the scalp. Parents are instructed to apply pressure over the bleeding area. Parmacological treatment and/or surgery are indicated in symptomatic cases. Figure 10 shows a small but repeatedly bleeding forehead hemangioma before and after surgical excision. Thrombocytopenia - Large hemangiomas with a high flow may be associated with platelet trapping and thrombocytopenia (Kasabach-Merritt phenomenon). Pharmacological treatment is indicated in such cases. Psychosocial complications – Many facial hemangiomas cause a significant facial deformity during the proliferative and early involution phases. Facial appearance usually improves after age 10 (4). Children with facial hemangiomas are often teased by their peers. Early surgery may be indicated in such cases.
7. OUTCOME and PROGNOSIS Most hemangiomas appear during the first months of life, undergo proliferation with a peak at the age of one year and then undergo gradual involution. Involution is 50% complete by age 5 years and 70% complete by the age of 7 years with continued improvement up to the age 10 to 12 years (4). An exception is congenital hemangioma, which is present at birth and usually undergoes regression around the age of one year (4). Noninvoluting congenital hemangioma is a variant of the common hemangioma of infancy with persistent fast-flow (18). Unlike vascular malformations, hemangiomas rarely cause bony distortion and overgrowth except huge facial hemangiomas, which may affect the underlying bone and cartilage (4). Various associated medical conditions are discussed in the physical examination section of paragraph 1.
8. FUTURE and CONTROVERSIES A significant contribution to the understanding of vascular lesions was the introduction of a classification method by Mulliken and his associates (1). This made diagnosis and treatment more accurate and predictable. However, one still finds confusing and occasionally wrong terms used by different subspecialties. Improvement in patient monitoring and anesthesia during and after surgery made early excisions safer and more acceptable. Other contributions included the introduction of the pulsed dye laser, which helps fade away the capillary component of hemangiomas (14) and intra-lesional fiber laser (15, 16). A major controversy is whether to wait until involution is complete or to operate early on children with a disfiguring lesion. There is no clear-cut answer to this question. We believe that decisions should be made according to the individual case. The psychosocial consequences of growing up with a facial deformity should always be taken into consideration. Future genetic research including angiogenic growth factor products will contribute to the understanding of the mechanism underlying the formation of hemangiomas and may provide new modalities for treatment (5). Because basic fibroblast growth factor and vascular endothelial growth factor messenger RNA have been implicated in the pathobiology of human hemangioma formation, biochemical modulation of these angiogenic cytokines may eventually help inhibit proliferation and promote regression of hemangiomas (6).
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