Pediatric Dermatology Vol. 9 No. 4 356-357
A Biologic Approach to Cutaneous Vascular Anomalies John B. Mulliken, M.D. Children's Hospital, Boston, Massachusetts One decade ago a biologic classification of vascular anomalies was introduced, based on correlative studies of cellular features, physical examination, and natural history (1). The medical literature, however, continues to employ such nineteenthcentury misnomers as port-wine hemangioma, cavernous hemangioma, and cystic hygroma. Indeed, it is Nature's design that the majority of her cutaneous vascular birthmarks are either hemangiomas, characterized by increased endothelial turnover, or malformations, characterized by normal endothelial cell cycle (2). Hemangiomas grow rapidly in the postnatal period, followed invariably by slow involution. The sex ratio for these most common tumors of infancy is 3:1 female;male. Vascular malformations are, by definition, present at birth; however, they may not manifest until childhood, adolescence, or sometimes adulthood. Vascular malformations grow commensuratety or they may expand secondary to trauma, sepsis, or hormonal modulation. They have no predilection for either sex. The cellular characteristics of hemangioma include endothelial hyperplasia and increased numbers of mast cells. Once a hemangioma is completely involuted, the mast cell count returns to normal (3). Hemangiomas exhibit multitaminated basement membranes and capillary tubular formation in vitro. In contrast, vascular malformations exhibit flat endothelium with imperceptible cell turnover, normal mast celi levels, and thin basal lamina, and their endothelium is difficult to grow in tissue culture (4). Radiologic, skeletal, and hematologic characteristics also distinguish these two major categories of cutaneous vascular birthmarks. Primary platelet trapping, the Kasabach-Merritt phenomenon, is a life-threatening complication that occurs in a small number of infants with large or disseminated hemangiomas. In contrast, stasis in a venous malforma-
356
tion may cause localized or disseminated intravasculeir coagulopathy. It is clinically useful to labe! hemangiomas as occurring in either the proliferating phase or involuting phase (Table 1). Malformations cEin be subcategorized as either slow flow (capillary, lymphatic, venous) or fast flow (arterial malformations, including AVF and AVM). Many of the combinedcomplex vascular malformations (CLM, CVM, LVM, or CLVM) have eponyms, and feature a spectrum with abnormal neuroectodermal and mesodermal elements, and particularly with skeletal anomalies, for example, Sturge-Weber, KlippelTrenaunay, Maffucci, Solomon, and Proteus syndromes (5). A classification is justified only if it is diagnostically accurate, helps plan therapy, and guides studies of pathogenesis. For the majority of cutaneous vascular anomalies, an accurate dis^nosis is jxjssible based on physical examination and history (2). Not all hemangiomas look like strawberries, and not all strawberry-like lesions are hemangiomas. Superficial lesions are not "capillary," nor are deep lesions "cavernous." There is no cavernous hemangioma. Such a lesion is either a deep (subcutaneous) hemangioma or a venous malformation. If radiographic imaging is indicated, one should first consider ultrasonography with Doppler fiow. It is the least expensive examination, although highly operator dependent. Magnetic resonance imaging with gadolinium is now the standard (6). Computed tomography with contrast may be useful if there is a question of osseous involvement by vascular malformation. Angiography is used only to document or treat arteriovenous malformations and arteriovenous fistulae. Current management of hemangiomas includes observation, pharmacologic therapy, and surgical excision. Flashlamp-pumped pulsed dye laser may
Mulliken: Cutaneous Vascular Anomalies
TABLE 1. Biologic Classification of Cutaneous Vascular Anomalies Hemangioma
Malformation
Proliferating phase Involuting phase
Capillary (CM) Lymphatic (LM) Venous (VM) Arterial (AVF, AVM) Complex-combined (CLM, CVM, CLVM, LVM)
be useful for early, very small, and superficial lesions. Phannacologic therapy is indicated for endangering hemangiomas, those that obstruct vital structures, and lesions that cause distortion or deformation of soft tissues or life-threatening complications such as congestive heart failure or bleeding. Corticosteroid is the first-line drug, given either locally or systemically; response rates vary from 30% to 60%. A prospective study from our institution recently evaluated interferon-a2a for endangering hemangiomas. All patients entered into this study were unresponsive to corticosteroids. Fever occurred in all patients during the first week of therapy. Transient neutropenia was seen in two infants and epidermal sloughing occurred in one infant. There were no long-term toxicities in the follow-up period of two and one-half years. Eighteen of 20 patients experienced regression, with a mean regression time of seven to eight months. There was one death in an infant with Kasabach-Merritt syndrome. We believe that interferon-a should be the primary agent for platelet consumptive coagulopathy and for infants with endangering, corticosteroidunresponsive hemangioma (7). Surgical excision of proliferating hemangiomas may be indicated, in rare instances, during infancy. Lesions in the involuting phase can be contoured in early childhood, prior to attending school, or excision postponed to school ^ e . Capillary malformation (port-wine stain) and many telangiectasias are ameliorated by laser photocoagulation. Soft tissue, and sometimes skeletal hypertrophy is a common
357
problem in these patients. Surgical resection, particularly of the lip, is beneficial, and orthognathic procedures may be required to correct jaw malalignment. Lymphatic malformations are managed by staged surgical excision, limiting each procedure to a single anatomic area. Skeletal overgrowth is also a surgical problem. Venous malformations are managed by sclerotherapy, often followed by contour excision. The current agents are 95% alcohol and sodium tetradecyl suifate 1% and 3%. Arteriovenous fistulae and malformations are usually treated when the patients become symptomatic. The approach is preoperative embolization, wide surgical excision, and immediate reconstruction. Free-flap (microsurgical) transfer extends the limits of excision and improves the aesthetic results. Many patients with vascular anomalies are, in a sense, medical nomads, wandering from place to place, looking for someone who understands their problem. Vascular anomalies is an interfacial field, and these patients are best managed by interdisciplinary programs in referral centers. REFERENCES 1. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children; a classification based on endothelial characteristics. Plast Reconstr Surg 1982;69:4i2-420. 2. Mulliken JB, Young AE. Vascular birthmarks: hemangiomas and mEilformations. Philadelphia: WB Saunders, 1988:483. 3. Glowacki J, Mulliken JB. Mast cells in hemangiomas and vascular malformations. Surgery 1982;70:4&-51. 4. Mulliken JB, Zetter BR, FoUcman J. In vitro characteristics of endothelium from hemangiomas and vascular malformations. Surgery 1982;92:348-353. 5. Bums AJ, Kaplan LC, MuUiken JB. Is there an association between hemangioma and syndromes with dysmorphic features? Pediatrics t991;88:i257.-1267. 6. Meyer JS, Hoffer FA, Barnes PD, Mulliken JB. MRI correlation of the biological classification of soft tissue vascular anomalies. AJR 1991; 157:559-564. 7. Ezekowitz RAB, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992;326:1456-1463.
A Biologic Approach to Cutaneous Vascular Anomalies John B. Mulliken, M.D. Children's Hospital, Boston, Massachusetts One decade ago a biologic classification of vascular anomalies was introduced, based on correlative studies of cellular features, physical examination, and natural history (1). The medical literature, however, continues to employ such nineteenthcentury misnomers as port-wine hemangioma, cavernous hemangioma, and cystic hygroma. Indeed, it is Nature's design that the majority of her cutaneous vascular birthmarks are either hemangiomas, characterized by increased endothelial turnover, or malformations, characterized by normal endothelial cell cycle (2). Hemangiomas grow rapidly in the postnatal period, followed invariably by slow involution. The sex ratio for these most common tumors of infancy is 3:1 female;male. Vascular malformations are, by definition, present at birth; however, they may not manifest until childhood, adolescence, or sometimes adulthood. Vascular malformations grow commensuratety or they may expand secondary to trauma, sepsis, or hormonal modulation. They have no predilection for either sex. The cellular characteristics of hemangioma include endothelial hyperplasia and increased numbers of mast cells. Once a hemangioma is completely involuted, the mast cell count returns to normal (3). Hemangiomas exhibit multitaminated basement membranes and capillary tubular formation in vitro. In contrast, vascular malformations exhibit flat endothelium with imperceptible cell turnover, normal mast celi levels, and thin basal lamina, and their endothelium is difficult to grow in tissue culture (4). Radiologic, skeletal, and hematologic characteristics also distinguish these two major categories of cutaneous vascular birthmarks. Primary platelet trapping, the Kasabach-Merritt phenomenon, is a life-threatening complication that occurs in a small number of infants with large or disseminated hemangiomas. In contrast, stasis in a venous malforma-
356
tion may cause localized or disseminated intravasculeir coagulopathy. It is clinically useful to labe! hemangiomas as occurring in either the proliferating phase or involuting phase (Table 1). Malformations cEin be subcategorized as either slow flow (capillary, lymphatic, venous) or fast flow (arterial malformations, including AVF and AVM). Many of the combinedcomplex vascular malformations (CLM, CVM, LVM, or CLVM) have eponyms, and feature a spectrum with abnormal neuroectodermal and mesodermal elements, and particularly with skeletal anomalies, for example, Sturge-Weber, KlippelTrenaunay, Maffucci, Solomon, and Proteus syndromes (5). A classification is justified only if it is diagnostically accurate, helps plan therapy, and guides studies of pathogenesis. For the majority of cutaneous vascular anomalies, an accurate dis^nosis is jxjssible based on physical examination and history (2). Not all hemangiomas look like strawberries, and not all strawberry-like lesions are hemangiomas. Superficial lesions are not "capillary," nor are deep lesions "cavernous." There is no cavernous hemangioma. Such a lesion is either a deep (subcutaneous) hemangioma or a venous malformation. If radiographic imaging is indicated, one should first consider ultrasonography with Doppler fiow. It is the least expensive examination, although highly operator dependent. Magnetic resonance imaging with gadolinium is now the standard (6). Computed tomography with contrast may be useful if there is a question of osseous involvement by vascular malformation. Angiography is used only to document or treat arteriovenous malformations and arteriovenous fistulae. Current management of hemangiomas includes observation, pharmacologic therapy, and surgical excision. Flashlamp-pumped pulsed dye laser may
Mulliken: Cutaneous Vascular Anomalies
TABLE 1. Biologic Classification of Cutaneous Vascular Anomalies Hemangioma
Malformation
Proliferating phase Involuting phase
Capillary (CM) Lymphatic (LM) Venous (VM) Arterial (AVF, AVM) Complex-combined (CLM, CVM, CLVM, LVM)
be useful for early, very small, and superficial lesions. Phannacologic therapy is indicated for endangering hemangiomas, those that obstruct vital structures, and lesions that cause distortion or deformation of soft tissues or life-threatening complications such as congestive heart failure or bleeding. Corticosteroid is the first-line drug, given either locally or systemically; response rates vary from 30% to 60%. A prospective study from our institution recently evaluated interferon-a2a for endangering hemangiomas. All patients entered into this study were unresponsive to corticosteroids. Fever occurred in all patients during the first week of therapy. Transient neutropenia was seen in two infants and epidermal sloughing occurred in one infant. There were no long-term toxicities in the follow-up period of two and one-half years. Eighteen of 20 patients experienced regression, with a mean regression time of seven to eight months. There was one death in an infant with Kasabach-Merritt syndrome. We believe that interferon-a should be the primary agent for platelet consumptive coagulopathy and for infants with endangering, corticosteroidunresponsive hemangioma (7). Surgical excision of proliferating hemangiomas may be indicated, in rare instances, during infancy. Lesions in the involuting phase can be contoured in early childhood, prior to attending school, or excision postponed to school ^ e . Capillary malformation (port-wine stain) and many telangiectasias are ameliorated by laser photocoagulation. Soft tissue, and sometimes skeletal hypertrophy is a common
357
problem in these patients. Surgical resection, particularly of the lip, is beneficial, and orthognathic procedures may be required to correct jaw malalignment. Lymphatic malformations are managed by staged surgical excision, limiting each procedure to a single anatomic area. Skeletal overgrowth is also a surgical problem. Venous malformations are managed by sclerotherapy, often followed by contour excision. The current agents are 95% alcohol and sodium tetradecyl suifate 1% and 3%. Arteriovenous fistulae and malformations are usually treated when the patients become symptomatic. The approach is preoperative embolization, wide surgical excision, and immediate reconstruction. Free-flap (microsurgical) transfer extends the limits of excision and improves the aesthetic results. Many patients with vascular anomalies are, in a sense, medical nomads, wandering from place to place, looking for someone who understands their problem. Vascular anomalies is an interfacial field, and these patients are best managed by interdisciplinary programs in referral centers. REFERENCES 1. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children; a classification based on endothelial characteristics. Plast Reconstr Surg 1982;69:4i2-420. 2. Mulliken JB, Young AE. Vascular birthmarks: hemangiomas and mEilformations. Philadelphia: WB Saunders, 1988:483. 3. Glowacki J, Mulliken JB. Mast cells in hemangiomas and vascular malformations. Surgery 1982;70:4&-51. 4. Mulliken JB, Zetter BR, FoUcman J. In vitro characteristics of endothelium from hemangiomas and vascular malformations. Surgery 1982;92:348-353. 5. Bums AJ, Kaplan LC, MuUiken JB. Is there an association between hemangioma and syndromes with dysmorphic features? Pediatrics t991;88:i257.-1267. 6. Meyer JS, Hoffer FA, Barnes PD, Mulliken JB. MRI correlation of the biological classification of soft tissue vascular anomalies. AJR 1991; 157:559-564. 7. Ezekowitz RAB, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992;326:1456-1463.
