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Understanding vascular anomalies: a common language for doctors
VASCULAR I
Understanding vascular anomalies: a common language for doctors
Vascular anomalies are benign vascular lesions of childhood (although presentation may be delayed) that result from abnormal cell proliferation (tumours) or abnormal cell architecture (malformations) of vascular endothelia. They do not respect tissue planes. Assessment is based on the knowledge of their natural history, but sometimes requires special investigation such as gadoliniumenhanced MRI, Doppler ultrasound and histology. MRI also delineates the extent of the lesion. Angiography is only needed during embolization. Complex lesions should be managed by a multidisciplinary team that includes surgeons (craniofacial, otolaryngological, ophthalmic, orthopaedic, paediatric, plastic and vascular), dermatologists, paediatricians, interventional radiologists and histopathologists. Specialist nurses are invaluable in supporting the often confused and distressed parents. Links to parent support groups are also important. Understanding of vascular anomalies has been poor owing to lack of a common nomenclature among the various medical specialties. In the past, terms such as strawberry naevus, cavernous or capillary haemangioma, cystic hygroma and salmon patch, have added to the confusion. Dr John Mulliken (Boston, USA) and Mr Anthony Young (London, UK) founded the International Society for the Study of Vascular Anomalies (ISSVA) in 1976. Initially a workshop of enthusiasts, it subsequently became a society to debate research and management in this field. The classification of vascular anomalies was first proposed in the seminal work by Mulliken and Glowacki in 1982 into either infantile haemangiomas or vascular malformations based on their clinical and histological characteristics.1 This classification was adopted and expanded by ISSVA in 1996 (Table 1).2 However, it is a generation since the original paper, and the topic remains ignored in undergraduate and postgraduate courses. Although interested clinicians have adopted the ISSVA classification, the previous terminology is still seen in doctor’s letters as well as radiology and histopathology reports.
Jorge Leon-Villapalos Loshan Kangesu
Abstract Vascular anomalies are benign vascular lesions of childhood and complex lesions should be managed within a specialized multidisciplinary team. They have been poorly understood owing to a lack of a common nomenclature among the various medical specialties as the subject remains neglected in undergraduate and postgraduate courses. The seminal work of Mulliken and Glowacki in 1982 established the foundations of the understanding of vascular anomalies by classifying them according to their histopathological and clinical features. Based on these findings, in 1996 the International Society for the Study of Vascular Anomalies classified vascular anomalies into vascular tumours (haemangiomas and others) and vascular malformations (capillary, lymphatic, venous, arteriovenous or a combination). Their characteristics and management differ greatly. Haemangiomas are the most frequent tumours of infancy. They are benign, transitory and self-limiting vascular lesions that exhibit cellular proliferation. Usually not present at birth, haemangiomas undergo transformation through a cycle of rapid proliferation over 6 months, to a variable period of involution and spontaneous regression over years. Their management is usually conservative, with active treatment reserved for the presence of functional or cosmetic complications (ulceration, obstruction and distortion of vital structures). Vascular malformations are structural anomalies of vascular morphogenesis without cellular proliferation. They present at birth, do not regress spontaneously and are subclassified as low-flow (capillary, lymphatic and venous) and high-flow (arteriovenous) lesions. Their effects may be those of a space-occupying lesion: infection, bleeding, pain or coagulopathy. Treatment options include dye laser (capillary), percutaneous sclerotherapy and surgery (venous and lymphatic) and embolization and surgery (arteriovenous).
Classification of vascular anomalies
Keywords arteriovenous malformations; capillary malformations; haemangiomas; lymphatic malformations; multidisciplinary team; vascular anomalies; vascular malformations; venous malformations
Vascular tumours
Vascular malformations
Haemangiomas Others C Rapidly involuting congenital haemangioma (RICH) C Non-involuting congenital haemangioma (NICH) C Kaposiform haemangioendothelioma (KHE)
Low flow C Capillary (CM) C Venous (VM) C Lymphatic (LM) High flow C Arteriovenous (AVM) C Combined lesions/ syndromes*
Based on the International Society for the Study of Vascular Anomalies classification.
Jorge Leon-Villapalos FRCS (Plast) is a Consultant Plastic Surgeon at the St Andrews Centre for Plastic Surgery and Burns, Mid Essex Hospitals NHS Trust. Conflicts of interest: none declared.
*
Loshan Kangesu FRCS (Plast) is a Consultant Plastic Surgeon at the St Andrews Centre for Plastic Surgery and Burns, Mid Essex Hospitals NHS Trust, and Great Ormond Street Hospital, London, UK. Conflicts of interest: none declared.
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Slow-flow complexecombined types with overgrowth and gigantism of the affected limb: capillaryelymphaticevenous malformation (CLVM), as in the originally described KlippeleTrenaunay syndrome; high-flow complexe combined types with overgrowth of the affected limb: capillaryearteriovenous malformation (CAVM), as described in ParkeseWeber syndrome; facial capillary malformations associated with neurological disorder as in Sturgee Weber syndrome.
Table 1
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Vascular tumours
presence of plump endothelial cells with multilaminated basement membranes. Active, aberrant angiogenesis is present with up-regulation of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor.
Infantile haemangiomas Haemangiomas are benign, self-limiting vascular tumours that were previously called ‘strawberry naevae’. They are more common in Caucasians and are the most frequent tumours of infancy, affecting 10% of full-term babies with an increased incidence in prematurity.3 There is a female predominance of 2 : 1 but higher rates have been reported. There appears to be a predilection for the head and neck, but this may be due to referral bias, as this is a more sensitive area cosmetically. Haemangiomas are usually not present at birth, although a subtle premonitory red mark (herald patch) may be present. They are first noticed at about 2 weeks of life and undergo a three-stage cycle with characteristic histological features (Figure 1).4
A prolonged involuting phase lasts until the age of 7e9 years. During this phase the lesions initially become darker with a grey hue, then slowly lose their colour and have fine capillary telangiectasia. There is an increased inflow of mast cells and fibroblasts with apoptosis of, and gradual substitution of, the endothelial cells by fibrofatty tissue. The angiogenesis suppression factor tissue inhibitor metalloproteinase is characteristic in this phase. A final involuted phase is characterized by the presence of a soft lump that is visible in the case of superficial lesions and less so in deeper lesions. The lesion regresses by the age of 7 years in 70% of cases and by 9 years in 90%. Histologically, the cellular parenchyma has been substituted almost completely with a fibrofatty residue.
A rapid proliferating phase during the first 5e8 months of life is characterized by rapid, distressing and potentially disfiguring growth of the haemangioma. They are soft and warm with a high Doppler signal. If on the surface they are a bright strawberry red; however, if subcutaneous they may have a blue tinge or no colour. There may be ulceration with bleeding or obstruction of vital structures. Studies show increased cellular turnover and the
b
a
d
Features: infantile haemangiomas may be localized or diffuse. Histopathologically they share features with placental tissue and
c
e
f
g
Haemangioma of the cheek. a Initial presentation at 2 weeks; b,c in proliferative phase at 2 months; d,e in involuting phase at 18 months; f,g in involuted phase at 6 years. Steroid treatment was used in infancy and surgery has been avoided. Figure 1
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finding by a French group8 that the non selective beta-blocker propranolol can inhibit the vascular proliferation of infantile haemangiomas during their proliferating phase has opened a new and exciting option for management. The theoretical reasons why propranolol works include vasoconstriction and possibly decreased expression of pro-angiogenic factors of the hemangioma growth phase causing apoptosis of capillary endothelial cells. The enthusiasm for this treatment has catapulted other groups to design treatment protocols for the use of propanolol in proliferating hemangiomas9. As a result of this research, Great Ormond Street Hospital (Francesca Manunza, Samira Syed, Mary Glover, Alessandro Giardini and John Harper, 2009) designed the following treatment protocol for selected patients after full clinical radiological, hematological and biochemistry investigations have been performed. Propanolol dosage regime: Week 1: 1mg/kg/day divided into three doses. Week 2: Increase the dose up to 2mg/kg/day divided into three doses with a monthly dose adjustment according to the weight of the child up to 9 months of age if there is no clinical improvement. From month 9: Keep the patient on the same dose without weight adjustment until month 12 unless there is a need to continue. The propranolol should be stopped by tailing off the dose over 2 weeks, halving the dose each week. Full monitoring and adequate follow-up are mandatory to exclude and manage potential complications of this treatment.
both have positive expression for very specific tissue markers such as the glucose transporter protein GLUT-15 and others.6 They may be associated with other abnormalities in PHACE syndrome (posterior fossa malformations, haemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities). Management: treatment is mostly expectant, with an explanation to the parents of the natural history and availability to deal with complications. After the anxious proliferative phase, patients are seen yearly or every few years; if the child and family accept the final appearance of the lesion, they are discharged. If the diagnosis is uncertain or a differential diagnosis with malignant lesions is required, a biopsy is indicated with a request for GLUT-1 immunostaining.7 Similarly, a full blood count is done to exclude thrombocytopenia (see below). MRI or ultrasound is indicated to look for internal lesions if there are eight or more skin lesions in order to predict the likelihood of cardiac failure. Active intervention is necessary in the presence of complications such as: large size multiple lesions causing high-output cardiac failure obstruction of vital structures (vision, airway) persistent ulceration (Figure 2). Several active treatments are used. Steroids e given intralesionally for localized lesions (triamcinolone 2 mg/kg) every 4e6 weeks depending on response, or systemically (prednisone 2e3 mg/kg/day) over a minimum of 2 weeks, and often for 3 months with gradual dose reduction. Rebound growth is a recognized phenomenon. A third of patients have a good response, another third a moderate response and a further third are not responsive to steroids. Propanolol Until recently, steroids constituted the preferred therapy for problematic and endangering haemangiomas, with doses of oral prednisolone of 2-3mg/kg per day having been used until 6 months of age or longer depending on response. The recent
a
Pulsed-dye laser may help coagulate the surface of ulcerated lesions, but dressings are the main form of wound care. There is no evidence that laser treatment alters the natural history of haemangioma. Patching of the non-involved eye may be required for lesions obstructing vision and threatening amblyopia. Embolization is useful in high-output cardiac failure and for treating troublesome, bleeding lesions.
b
c
a Severe ulceration of the lip and nose in haemangioma; b appearance at age 4 years after spontaneous healing; c 6 months later after the first reconstructive surgical procedure. Figure 2
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during infancy, but there are few indications and the practice is deplored. Between the ages of 2 and 4 years there are occasions when plastic surgery is appropriate to minimize deformity from attenuation of vital structures such as the eyelids, nasal margin and lips. Late excision of the fibrofatty residue in the involuted face is the usual time for plastic surgery of haemangiomas. Traditionally this was performed after the age of 7 years, but there are few concerns when operating after the age of 4 years (Figure 2). Topical agents e there is interest in the use of topical agents such as steroid creams or imidazolquinilone, but results from studies are awaited. Rapidly involuting congenital haemangiomas These are uncommon entities that, unlike infantile haemangiomas, are present and fully developed at birth but exhibit a much faster involution with full regression by 1 year of age.10,11 They present as large masses, often on the legs. They are firmer than infantile haemangiomas, with or without telangiectatic changes, and sometimes surrounded by a pale halo (Figure 3).12 They leave a plaque-like residuum which may regress further to leave an atrophic patch of skin. They do not express GLUT-1. Non-involuting congenital haemangiomas These are rare tumours that mimic infantile haemangiomas and are of similar texture. They are present as round or oval masses, with flat shape or moderately bossed and accompanying telangiectasia, and may have a halo. They do not express GLUT-1, do not exhibit further growth and do not regress.13 Treatment is by surgical excision and often the diagnosis is retrospective. Kaposiform haemangioendotheliomas Kaposiform haemangioendotheliomas (KHEs) are locally aggressive vascular tumours characterized by rapid growth and extension before final regression. They appear in early infancy (although later presentation is possible) as purple or pink bulging masses. They are sometimes painful, ulcerated and infiltrative, and are hard with a diffuse edge (Figure 4). They are related to the tufted angioma that may be a localized type of KHE. The are complicated by dangerous thrombocytopenia and a risk of systemic bleeding (Kasabache
a A rapidly involuting congenital haemangioma of the knee at 1 month, with ulceration; b significant regression is evident at 3 months. Further flattening occurred and surgery was avoided. Figure 3
Surgery e early surgery such as a tracheostomy is sometimes needed in the neonatal period for airway lesions. This may be combined with endoscopic excision of the lesion. During infancy, if there is a threat to vision as indicated by decreasing visual revoked response, excision of intra-orbital lesions may be indicated. There may be parental pressure to excise facial lesions
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Figure 4 A Kaposiform haemangioendothelioma of the neck in infancy associated with KasabacheMerritt phenomenon. Complete resolution occurred after treatment.
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usually steroid resistant and, in severe instances, chemotherapeutic agents or embolization are required. The diagnosis can be confirmed by histology; the tissue does not express GLUT-1.
Vascular malformations Vascular malformations are vascular anomalies that, in contrast to haemangiomas, are present at birth, although some present late. They do not regress, and show normal endothelial cell mitotic rate unless stimulated, but abnormal vascular morphology.1 The different types of vascular malformation are classified according to their flow characteristics and vessel type: capillary, venous, lymphatic and arterial components, or a combination of these (Table 1). Ectatic vessels enlarge from pressure and flow changes. They are stimulated by hormonal changes, as seen during puberty and pregnancy. Vascular malformations cause symptoms by their appearance, including long-term soft issue and skeletal hypertrophy, as space-occupying lesions, or from secondary effects such as infection, bleeding and blood dyscrasia. Capillary malformations This commonest type is often known as ‘port-wine stains’ that affect the skin and occur in 0.3% of newborns.16 They present as a macular patch that is pink in infants, later becoming red and eventually purple in adults The skin temperature and Doppler signal are largely normal. There is secondary tissue hypertrophy, skin nodules and an increased incidence of pyogenic granuloma. On the face the distribution may correspond to the dermatomes of the trigeminal nerve branches (V1, V2, V3) (Figure 5). Histologically, there are ectatic capillaries to venule-sized dermal channels. They may be associated with syndromes such as KlippeleTrenaunay, SturgeeWeber and ParkeseWeber. Recent research has shown that the familial association between capillary malformations and arteriovenous malformations is caused by mutations in the RASA-1 gene.17 Less common capillary malformations include telangiectatic lesions (as in cutis marmorata telangiectatica congenita) and angiokeratoma.
Figure 5 A capillary malformation (port-wine stain) of the right side of the face on a 19-year-old boy. Note the skeletal and soft tissue hypertrophy of the affected area. He had two operations to reduce the lips in early teenagehood and a further procedure is planned.
Merritt phenomenon). The rate of systemic complications is high, with an associated mortality rate. The thrombocytopenia of KHE was for many years wrongly documented in medical textbooks as a complication of infantile haemangioma.14,15 The lesions are
a A woman with a venous malformation of the right side of the tongue, which had been treated once with sclerotherapy. b In extensive venous malformations, as on the trunk of this man, there may be consumptive intravascular coagulopathy. Figure 6
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a A macrocystic lymphatic malformation (formerly known as cystic hygroma) on the neck of a 2-year-old girl who had surgery for episodes of infection; b appearance at age 6 years. Results are also good with sclerotherapy. Figure 7
Management: the mainstay of treatment is pulsed-dye laser. Surgery is reserved for correcting deformity from secondary hypertrophy to the soft tissue and skeleton.
clots. In larger lesions, there is a localized intravascular coagulopathy detected by an increase in D-dimer levels. Extensive lesions have disseminated intravascular coagulopathy detected by elevated D-dimer levels as well as low serum fibrinogen (<1.5 g/l). Maintenance may paradoxically require anticoagulation to interrupt the clotting cascade. Rarely, these lesions are familial and associated with TIE-2 mutation.18 Glomangiomas are a variant that are tender, nodular, dark lesions characterized by the presence of smooth muscle-like glomus cells, and are often associated with a glomulin gene mutation.19
Venous malformations These low-flow lesions are blue, compressible soft tissue masses that empty on elevation (Figure 6). They can affect most tissues. Histologically, they are composed of abnormal venous channels with flat endothelium and normal cellular turnover. They cause disfigurement and aching, which is thought to be due to release of mediators from formation and dissolution of
a A woman with an arteriovenous malformation involving the extraconal portion of the orbit; b appearance following embolization and surgery. Figure 8
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Management: The symptomatic stages (III and IV) warrant aggressive treatment with combined embolization, excisional surgery and reconstruction. Some lesions can be controlled with repeated embolization. The nidus must be treated. Embolization agents include ethanol, cyanoacrylate (glue), coils and polyvinyl particles.
Arteriovenous malformation stages (Schobinger’s classification) Stage
Features
I II III IV
Quiescent, stable lesions Expansion with enlargement and tortuous veins Destruction, with pain, bleeding and ulceration Decompensation with cardiac failure
Conclusion The management of vascular anomalies poses a constant challenge stimulated by the emergence of basic science data that give hope for the future, the opportunity to work with colleagues and the pleasure of long-term care of our patients. A
Table 2
REFERENCES 1 Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982; 69: 412e22. 2 Enjolras O. Classification and management of the various superficial vascular anomalies: hemangiomas and vascular malformations. J Dermatol 1996; 24: 701e10. 3 Mueller BU, Mulliken JB. The infant with a vascular tumour. Semin Perinatol 1999; 23: 332e40. 4 Tan ST, Velickovic M, Ruger BM, Davis PF. Cellular and extracellular markers of hemangioma. Plast Reconstr Surg 2000; 106: 529e38. 5 North PE, Waner M, Mizeracki A, Mihm Jr MC. GLUT-1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000; 31: 11e22. 6 North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 2001; 137: 559e70. 7 Leon-Villapalos J, Kangesu L, Wolfe K. GLUT-1: an extra diagnostic tool to differentiate between hemangiomas and vascular malformations. Br J Plast Surg 2005; 58: 361e5. 8 Le´aute´-Labre`ze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo J-B, Ta€ıeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008; 358: 2649e51. 9 Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med 2008; 359: 2846. 10 Boon LM, Enjolras O, Mulliken JB. Congenital hemangioma: evidence of accelerated involution. J Pediatr 1996; 128: 329e35. 11 Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Dev Pathol 2003; 6: 495e510. 12 Soupre V, Enjolras O. Management of RICH and NICH. Milan: International Society for Study of Vascular Anomalies, 2006. 13 Enjolras O, Mulliken JB, Boon LM, Wassef M, Kozakewich HP, Burrows PE. Non-involuting congenital hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg 2001; 107: 1647e54. 14 Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabache Merritt Syndrome do not have ‘true’ hemangiomas. J Pediatr 1997; 130: 631e40. 15 Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (KasabacheMerritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997; 100: 1377e86. 16 Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics 1976; 58: 218e22.
Management: compression garments and non-steroidal antiinflammatory drugs such as ibuprofen provide good pain relief. For more symptomatic situations, the first line of treatment is sclerotherapy using ethanol, Ethibloc (a viscous mixture of propylene glycol, corn protein and other agents) and sodium tetradecyl sulphate; there is interest in polydocanol microfoam but concern has been expressed about emboli. Surgery is ideal for small localized lesions. Recurrence is common. Lymphatic malformations Classically these may be microcystic (previously known as lymphangioma circumscriptum) or macrocystic (previously known as cystic hygroma), but combined types also exist (Figure 7). Microcystic lesions appear as small raised cutaneous vesicles full of lymphatic fluid. Macrocystic lesions are larger, soft subcutaneous swellings that easily transilluminate. They may be complicated by infection or intralesional haemorrhage. Histologically they are composed of abnormal dilated lymphatic channels without connection to the normal lymphatic system. Management: sclerotherapy or surgery is effective for treatment of macrocystic lesions. Sclerosants used include sodium tetradecyl sulphate, picibanil (lyophilized Streptococcus also known as OK-432)20 and doxycycline. Surgery is more effective for microcystic lesions. Arteriovenous malformations These are the most aggressive vascular malformations, causing progressive deformity and posing a systemic risk (Figure 8). They are high-flow malformations that have a characteristic nidus with arterial feeders, arteriovenous fistulas and enlarged veins. Unlike the other malformations, which are largely structural malformations alone, arteriovenous malformations continue to recruit new vessels and are seldom cured. They may be quiescent at birth, mimicking innocent lesions such as capillary malformations or haemangiomas of infancy, but their behaviour is usually aggressive in later life sometimes triggered by pubertal changes, pregnancy or trauma. They may present with throbbing pain or ulceration with bleeding, and may cause cardiac failure. The lesions are warm with a loud Doppler signal; later stages have a pulsatile mass with a bruit, overlying purple discolouration and engorged, tortuous veins. Cure is seldom achieved. The progressive stages have been classified by Schobinger (Table 2).
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17 Eerola I, Boon LM, Mulliken JB, et al. Capillary malformatione arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 2003; 73: 1240e9. 18 Vikkula M, Boon LM, Carraway 3rd KL, et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996; 87: 1181e90. 19 Brouillard P, Boon LM, Mulliken JB, et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (‘glomangiomas’). Am J Hum Genet 2002; 70: 866e74. 20 Ogita S, Tsuto T, Tokiwa K, Takahashi T. Intracystic injection of OK-432: a new sclerosing therapy for cystic hygroma in children. Br J Surg 1997; 74: 690e1.
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Acknowledgements The care of the patients illustrated would not have been possible without the expertise of Jane Linward, Hilary Kennedy (clinical nurse specialists), Katheryn Hobbs, Peri Davis and other ward nurses, Dr Derek Roebuck, Dr Alex Barnacle, Dr Mohammed Badran, Dr Peter Butler, Dr James Jackson (interventional radiologists), Prof. John Harper (dermatologist) and Dr Samira Sayed (paediatrician).
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Understanding vascular anomalies: a common language for doctors
Vascular anomalies are benign vascular lesions of childhood (although presentation may be delayed) that result from abnormal cell proliferation (tumours) or abnormal cell architecture (malformations) of vascular endothelia. They do not respect tissue planes. Assessment is based on the knowledge of their natural history, but sometimes requires special investigation such as gadoliniumenhanced MRI, Doppler ultrasound and histology. MRI also delineates the extent of the lesion. Angiography is only needed during embolization. Complex lesions should be managed by a multidisciplinary team that includes surgeons (craniofacial, otolaryngological, ophthalmic, orthopaedic, paediatric, plastic and vascular), dermatologists, paediatricians, interventional radiologists and histopathologists. Specialist nurses are invaluable in supporting the often confused and distressed parents. Links to parent support groups are also important. Understanding of vascular anomalies has been poor owing to lack of a common nomenclature among the various medical specialties. In the past, terms such as strawberry naevus, cavernous or capillary haemangioma, cystic hygroma and salmon patch, have added to the confusion. Dr John Mulliken (Boston, USA) and Mr Anthony Young (London, UK) founded the International Society for the Study of Vascular Anomalies (ISSVA) in 1976. Initially a workshop of enthusiasts, it subsequently became a society to debate research and management in this field. The classification of vascular anomalies was first proposed in the seminal work by Mulliken and Glowacki in 1982 into either infantile haemangiomas or vascular malformations based on their clinical and histological characteristics.1 This classification was adopted and expanded by ISSVA in 1996 (Table 1).2 However, it is a generation since the original paper, and the topic remains ignored in undergraduate and postgraduate courses. Although interested clinicians have adopted the ISSVA classification, the previous terminology is still seen in doctor’s letters as well as radiology and histopathology reports.
Jorge Leon-Villapalos Loshan Kangesu
Abstract Vascular anomalies are benign vascular lesions of childhood and complex lesions should be managed within a specialized multidisciplinary team. They have been poorly understood owing to a lack of a common nomenclature among the various medical specialties as the subject remains neglected in undergraduate and postgraduate courses. The seminal work of Mulliken and Glowacki in 1982 established the foundations of the understanding of vascular anomalies by classifying them according to their histopathological and clinical features. Based on these findings, in 1996 the International Society for the Study of Vascular Anomalies classified vascular anomalies into vascular tumours (haemangiomas and others) and vascular malformations (capillary, lymphatic, venous, arteriovenous or a combination). Their characteristics and management differ greatly. Haemangiomas are the most frequent tumours of infancy. They are benign, transitory and self-limiting vascular lesions that exhibit cellular proliferation. Usually not present at birth, haemangiomas undergo transformation through a cycle of rapid proliferation over 6 months, to a variable period of involution and spontaneous regression over years. Their management is usually conservative, with active treatment reserved for the presence of functional or cosmetic complications (ulceration, obstruction and distortion of vital structures). Vascular malformations are structural anomalies of vascular morphogenesis without cellular proliferation. They present at birth, do not regress spontaneously and are subclassified as low-flow (capillary, lymphatic and venous) and high-flow (arteriovenous) lesions. Their effects may be those of a space-occupying lesion: infection, bleeding, pain or coagulopathy. Treatment options include dye laser (capillary), percutaneous sclerotherapy and surgery (venous and lymphatic) and embolization and surgery (arteriovenous).
Classification of vascular anomalies
Keywords arteriovenous malformations; capillary malformations; haemangiomas; lymphatic malformations; multidisciplinary team; vascular anomalies; vascular malformations; venous malformations
Vascular tumours
Vascular malformations
Haemangiomas Others C Rapidly involuting congenital haemangioma (RICH) C Non-involuting congenital haemangioma (NICH) C Kaposiform haemangioendothelioma (KHE)
Low flow C Capillary (CM) C Venous (VM) C Lymphatic (LM) High flow C Arteriovenous (AVM) C Combined lesions/ syndromes*
Based on the International Society for the Study of Vascular Anomalies classification.
Jorge Leon-Villapalos FRCS (Plast) is a Consultant Plastic Surgeon at the St Andrews Centre for Plastic Surgery and Burns, Mid Essex Hospitals NHS Trust. Conflicts of interest: none declared.
*
Loshan Kangesu FRCS (Plast) is a Consultant Plastic Surgeon at the St Andrews Centre for Plastic Surgery and Burns, Mid Essex Hospitals NHS Trust, and Great Ormond Street Hospital, London, UK. Conflicts of interest: none declared.
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Slow-flow complexecombined types with overgrowth and gigantism of the affected limb: capillaryelymphaticevenous malformation (CLVM), as in the originally described KlippeleTrenaunay syndrome; high-flow complexe combined types with overgrowth of the affected limb: capillaryearteriovenous malformation (CAVM), as described in ParkeseWeber syndrome; facial capillary malformations associated with neurological disorder as in Sturgee Weber syndrome.
Table 1
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Vascular tumours
presence of plump endothelial cells with multilaminated basement membranes. Active, aberrant angiogenesis is present with up-regulation of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor.
Infantile haemangiomas Haemangiomas are benign, self-limiting vascular tumours that were previously called ‘strawberry naevae’. They are more common in Caucasians and are the most frequent tumours of infancy, affecting 10% of full-term babies with an increased incidence in prematurity.3 There is a female predominance of 2 : 1 but higher rates have been reported. There appears to be a predilection for the head and neck, but this may be due to referral bias, as this is a more sensitive area cosmetically. Haemangiomas are usually not present at birth, although a subtle premonitory red mark (herald patch) may be present. They are first noticed at about 2 weeks of life and undergo a three-stage cycle with characteristic histological features (Figure 1).4
A prolonged involuting phase lasts until the age of 7e9 years. During this phase the lesions initially become darker with a grey hue, then slowly lose their colour and have fine capillary telangiectasia. There is an increased inflow of mast cells and fibroblasts with apoptosis of, and gradual substitution of, the endothelial cells by fibrofatty tissue. The angiogenesis suppression factor tissue inhibitor metalloproteinase is characteristic in this phase. A final involuted phase is characterized by the presence of a soft lump that is visible in the case of superficial lesions and less so in deeper lesions. The lesion regresses by the age of 7 years in 70% of cases and by 9 years in 90%. Histologically, the cellular parenchyma has been substituted almost completely with a fibrofatty residue.
A rapid proliferating phase during the first 5e8 months of life is characterized by rapid, distressing and potentially disfiguring growth of the haemangioma. They are soft and warm with a high Doppler signal. If on the surface they are a bright strawberry red; however, if subcutaneous they may have a blue tinge or no colour. There may be ulceration with bleeding or obstruction of vital structures. Studies show increased cellular turnover and the
b
a
d
Features: infantile haemangiomas may be localized or diffuse. Histopathologically they share features with placental tissue and
c
e
f
g
Haemangioma of the cheek. a Initial presentation at 2 weeks; b,c in proliferative phase at 2 months; d,e in involuting phase at 18 months; f,g in involuted phase at 6 years. Steroid treatment was used in infancy and surgery has been avoided. Figure 1
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finding by a French group8 that the non selective beta-blocker propranolol can inhibit the vascular proliferation of infantile haemangiomas during their proliferating phase has opened a new and exciting option for management. The theoretical reasons why propranolol works include vasoconstriction and possibly decreased expression of pro-angiogenic factors of the hemangioma growth phase causing apoptosis of capillary endothelial cells. The enthusiasm for this treatment has catapulted other groups to design treatment protocols for the use of propanolol in proliferating hemangiomas9. As a result of this research, Great Ormond Street Hospital (Francesca Manunza, Samira Syed, Mary Glover, Alessandro Giardini and John Harper, 2009) designed the following treatment protocol for selected patients after full clinical radiological, hematological and biochemistry investigations have been performed. Propanolol dosage regime: Week 1: 1mg/kg/day divided into three doses. Week 2: Increase the dose up to 2mg/kg/day divided into three doses with a monthly dose adjustment according to the weight of the child up to 9 months of age if there is no clinical improvement. From month 9: Keep the patient on the same dose without weight adjustment until month 12 unless there is a need to continue. The propranolol should be stopped by tailing off the dose over 2 weeks, halving the dose each week. Full monitoring and adequate follow-up are mandatory to exclude and manage potential complications of this treatment.
both have positive expression for very specific tissue markers such as the glucose transporter protein GLUT-15 and others.6 They may be associated with other abnormalities in PHACE syndrome (posterior fossa malformations, haemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities). Management: treatment is mostly expectant, with an explanation to the parents of the natural history and availability to deal with complications. After the anxious proliferative phase, patients are seen yearly or every few years; if the child and family accept the final appearance of the lesion, they are discharged. If the diagnosis is uncertain or a differential diagnosis with malignant lesions is required, a biopsy is indicated with a request for GLUT-1 immunostaining.7 Similarly, a full blood count is done to exclude thrombocytopenia (see below). MRI or ultrasound is indicated to look for internal lesions if there are eight or more skin lesions in order to predict the likelihood of cardiac failure. Active intervention is necessary in the presence of complications such as: large size multiple lesions causing high-output cardiac failure obstruction of vital structures (vision, airway) persistent ulceration (Figure 2). Several active treatments are used. Steroids e given intralesionally for localized lesions (triamcinolone 2 mg/kg) every 4e6 weeks depending on response, or systemically (prednisone 2e3 mg/kg/day) over a minimum of 2 weeks, and often for 3 months with gradual dose reduction. Rebound growth is a recognized phenomenon. A third of patients have a good response, another third a moderate response and a further third are not responsive to steroids. Propanolol Until recently, steroids constituted the preferred therapy for problematic and endangering haemangiomas, with doses of oral prednisolone of 2-3mg/kg per day having been used until 6 months of age or longer depending on response. The recent
a
Pulsed-dye laser may help coagulate the surface of ulcerated lesions, but dressings are the main form of wound care. There is no evidence that laser treatment alters the natural history of haemangioma. Patching of the non-involved eye may be required for lesions obstructing vision and threatening amblyopia. Embolization is useful in high-output cardiac failure and for treating troublesome, bleeding lesions.
b
c
a Severe ulceration of the lip and nose in haemangioma; b appearance at age 4 years after spontaneous healing; c 6 months later after the first reconstructive surgical procedure. Figure 2
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during infancy, but there are few indications and the practice is deplored. Between the ages of 2 and 4 years there are occasions when plastic surgery is appropriate to minimize deformity from attenuation of vital structures such as the eyelids, nasal margin and lips. Late excision of the fibrofatty residue in the involuted face is the usual time for plastic surgery of haemangiomas. Traditionally this was performed after the age of 7 years, but there are few concerns when operating after the age of 4 years (Figure 2). Topical agents e there is interest in the use of topical agents such as steroid creams or imidazolquinilone, but results from studies are awaited. Rapidly involuting congenital haemangiomas These are uncommon entities that, unlike infantile haemangiomas, are present and fully developed at birth but exhibit a much faster involution with full regression by 1 year of age.10,11 They present as large masses, often on the legs. They are firmer than infantile haemangiomas, with or without telangiectatic changes, and sometimes surrounded by a pale halo (Figure 3).12 They leave a plaque-like residuum which may regress further to leave an atrophic patch of skin. They do not express GLUT-1. Non-involuting congenital haemangiomas These are rare tumours that mimic infantile haemangiomas and are of similar texture. They are present as round or oval masses, with flat shape or moderately bossed and accompanying telangiectasia, and may have a halo. They do not express GLUT-1, do not exhibit further growth and do not regress.13 Treatment is by surgical excision and often the diagnosis is retrospective. Kaposiform haemangioendotheliomas Kaposiform haemangioendotheliomas (KHEs) are locally aggressive vascular tumours characterized by rapid growth and extension before final regression. They appear in early infancy (although later presentation is possible) as purple or pink bulging masses. They are sometimes painful, ulcerated and infiltrative, and are hard with a diffuse edge (Figure 4). They are related to the tufted angioma that may be a localized type of KHE. The are complicated by dangerous thrombocytopenia and a risk of systemic bleeding (Kasabache
a A rapidly involuting congenital haemangioma of the knee at 1 month, with ulceration; b significant regression is evident at 3 months. Further flattening occurred and surgery was avoided. Figure 3
Surgery e early surgery such as a tracheostomy is sometimes needed in the neonatal period for airway lesions. This may be combined with endoscopic excision of the lesion. During infancy, if there is a threat to vision as indicated by decreasing visual revoked response, excision of intra-orbital lesions may be indicated. There may be parental pressure to excise facial lesions
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Figure 4 A Kaposiform haemangioendothelioma of the neck in infancy associated with KasabacheMerritt phenomenon. Complete resolution occurred after treatment.
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usually steroid resistant and, in severe instances, chemotherapeutic agents or embolization are required. The diagnosis can be confirmed by histology; the tissue does not express GLUT-1.
Vascular malformations Vascular malformations are vascular anomalies that, in contrast to haemangiomas, are present at birth, although some present late. They do not regress, and show normal endothelial cell mitotic rate unless stimulated, but abnormal vascular morphology.1 The different types of vascular malformation are classified according to their flow characteristics and vessel type: capillary, venous, lymphatic and arterial components, or a combination of these (Table 1). Ectatic vessels enlarge from pressure and flow changes. They are stimulated by hormonal changes, as seen during puberty and pregnancy. Vascular malformations cause symptoms by their appearance, including long-term soft issue and skeletal hypertrophy, as space-occupying lesions, or from secondary effects such as infection, bleeding and blood dyscrasia. Capillary malformations This commonest type is often known as ‘port-wine stains’ that affect the skin and occur in 0.3% of newborns.16 They present as a macular patch that is pink in infants, later becoming red and eventually purple in adults The skin temperature and Doppler signal are largely normal. There is secondary tissue hypertrophy, skin nodules and an increased incidence of pyogenic granuloma. On the face the distribution may correspond to the dermatomes of the trigeminal nerve branches (V1, V2, V3) (Figure 5). Histologically, there are ectatic capillaries to venule-sized dermal channels. They may be associated with syndromes such as KlippeleTrenaunay, SturgeeWeber and ParkeseWeber. Recent research has shown that the familial association between capillary malformations and arteriovenous malformations is caused by mutations in the RASA-1 gene.17 Less common capillary malformations include telangiectatic lesions (as in cutis marmorata telangiectatica congenita) and angiokeratoma.
Figure 5 A capillary malformation (port-wine stain) of the right side of the face on a 19-year-old boy. Note the skeletal and soft tissue hypertrophy of the affected area. He had two operations to reduce the lips in early teenagehood and a further procedure is planned.
Merritt phenomenon). The rate of systemic complications is high, with an associated mortality rate. The thrombocytopenia of KHE was for many years wrongly documented in medical textbooks as a complication of infantile haemangioma.14,15 The lesions are
a A woman with a venous malformation of the right side of the tongue, which had been treated once with sclerotherapy. b In extensive venous malformations, as on the trunk of this man, there may be consumptive intravascular coagulopathy. Figure 6
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a A macrocystic lymphatic malformation (formerly known as cystic hygroma) on the neck of a 2-year-old girl who had surgery for episodes of infection; b appearance at age 6 years. Results are also good with sclerotherapy. Figure 7
Management: the mainstay of treatment is pulsed-dye laser. Surgery is reserved for correcting deformity from secondary hypertrophy to the soft tissue and skeleton.
clots. In larger lesions, there is a localized intravascular coagulopathy detected by an increase in D-dimer levels. Extensive lesions have disseminated intravascular coagulopathy detected by elevated D-dimer levels as well as low serum fibrinogen (<1.5 g/l). Maintenance may paradoxically require anticoagulation to interrupt the clotting cascade. Rarely, these lesions are familial and associated with TIE-2 mutation.18 Glomangiomas are a variant that are tender, nodular, dark lesions characterized by the presence of smooth muscle-like glomus cells, and are often associated with a glomulin gene mutation.19
Venous malformations These low-flow lesions are blue, compressible soft tissue masses that empty on elevation (Figure 6). They can affect most tissues. Histologically, they are composed of abnormal venous channels with flat endothelium and normal cellular turnover. They cause disfigurement and aching, which is thought to be due to release of mediators from formation and dissolution of
a A woman with an arteriovenous malformation involving the extraconal portion of the orbit; b appearance following embolization and surgery. Figure 8
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Management: The symptomatic stages (III and IV) warrant aggressive treatment with combined embolization, excisional surgery and reconstruction. Some lesions can be controlled with repeated embolization. The nidus must be treated. Embolization agents include ethanol, cyanoacrylate (glue), coils and polyvinyl particles.
Arteriovenous malformation stages (Schobinger’s classification) Stage
Features
I II III IV
Quiescent, stable lesions Expansion with enlargement and tortuous veins Destruction, with pain, bleeding and ulceration Decompensation with cardiac failure
Conclusion The management of vascular anomalies poses a constant challenge stimulated by the emergence of basic science data that give hope for the future, the opportunity to work with colleagues and the pleasure of long-term care of our patients. A
Table 2
REFERENCES 1 Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982; 69: 412e22. 2 Enjolras O. Classification and management of the various superficial vascular anomalies: hemangiomas and vascular malformations. J Dermatol 1996; 24: 701e10. 3 Mueller BU, Mulliken JB. The infant with a vascular tumour. Semin Perinatol 1999; 23: 332e40. 4 Tan ST, Velickovic M, Ruger BM, Davis PF. Cellular and extracellular markers of hemangioma. Plast Reconstr Surg 2000; 106: 529e38. 5 North PE, Waner M, Mizeracki A, Mihm Jr MC. GLUT-1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000; 31: 11e22. 6 North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 2001; 137: 559e70. 7 Leon-Villapalos J, Kangesu L, Wolfe K. GLUT-1: an extra diagnostic tool to differentiate between hemangiomas and vascular malformations. Br J Plast Surg 2005; 58: 361e5. 8 Le´aute´-Labre`ze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo J-B, Ta€ıeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008; 358: 2649e51. 9 Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med 2008; 359: 2846. 10 Boon LM, Enjolras O, Mulliken JB. Congenital hemangioma: evidence of accelerated involution. J Pediatr 1996; 128: 329e35. 11 Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Dev Pathol 2003; 6: 495e510. 12 Soupre V, Enjolras O. Management of RICH and NICH. Milan: International Society for Study of Vascular Anomalies, 2006. 13 Enjolras O, Mulliken JB, Boon LM, Wassef M, Kozakewich HP, Burrows PE. Non-involuting congenital hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg 2001; 107: 1647e54. 14 Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabache Merritt Syndrome do not have ‘true’ hemangiomas. J Pediatr 1997; 130: 631e40. 15 Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (KasabacheMerritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997; 100: 1377e86. 16 Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics 1976; 58: 218e22.
Management: compression garments and non-steroidal antiinflammatory drugs such as ibuprofen provide good pain relief. For more symptomatic situations, the first line of treatment is sclerotherapy using ethanol, Ethibloc (a viscous mixture of propylene glycol, corn protein and other agents) and sodium tetradecyl sulphate; there is interest in polydocanol microfoam but concern has been expressed about emboli. Surgery is ideal for small localized lesions. Recurrence is common. Lymphatic malformations Classically these may be microcystic (previously known as lymphangioma circumscriptum) or macrocystic (previously known as cystic hygroma), but combined types also exist (Figure 7). Microcystic lesions appear as small raised cutaneous vesicles full of lymphatic fluid. Macrocystic lesions are larger, soft subcutaneous swellings that easily transilluminate. They may be complicated by infection or intralesional haemorrhage. Histologically they are composed of abnormal dilated lymphatic channels without connection to the normal lymphatic system. Management: sclerotherapy or surgery is effective for treatment of macrocystic lesions. Sclerosants used include sodium tetradecyl sulphate, picibanil (lyophilized Streptococcus also known as OK-432)20 and doxycycline. Surgery is more effective for microcystic lesions. Arteriovenous malformations These are the most aggressive vascular malformations, causing progressive deformity and posing a systemic risk (Figure 8). They are high-flow malformations that have a characteristic nidus with arterial feeders, arteriovenous fistulas and enlarged veins. Unlike the other malformations, which are largely structural malformations alone, arteriovenous malformations continue to recruit new vessels and are seldom cured. They may be quiescent at birth, mimicking innocent lesions such as capillary malformations or haemangiomas of infancy, but their behaviour is usually aggressive in later life sometimes triggered by pubertal changes, pregnancy or trauma. They may present with throbbing pain or ulceration with bleeding, and may cause cardiac failure. The lesions are warm with a loud Doppler signal; later stages have a pulsatile mass with a bruit, overlying purple discolouration and engorged, tortuous veins. Cure is seldom achieved. The progressive stages have been classified by Schobinger (Table 2).
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17 Eerola I, Boon LM, Mulliken JB, et al. Capillary malformatione arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 2003; 73: 1240e9. 18 Vikkula M, Boon LM, Carraway 3rd KL, et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996; 87: 1181e90. 19 Brouillard P, Boon LM, Mulliken JB, et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (‘glomangiomas’). Am J Hum Genet 2002; 70: 866e74. 20 Ogita S, Tsuto T, Tokiwa K, Takahashi T. Intracystic injection of OK-432: a new sclerosing therapy for cystic hygroma in children. Br J Surg 1997; 74: 690e1.
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Acknowledgements The care of the patients illustrated would not have been possible without the expertise of Jane Linward, Hilary Kennedy (clinical nurse specialists), Katheryn Hobbs, Peri Davis and other ward nurses, Dr Derek Roebuck, Dr Alex Barnacle, Dr Mohammed Badran, Dr Peter Butler, Dr James Jackson (interventional radiologists), Prof. John Harper (dermatologist) and Dr Samira Sayed (paediatrician).
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