3 Pathology of Congenital Vascular Lesions



10.1055/b-0034-101159

3 Pathology of Congenital Vascular Lesions

Chad J. Jessup, Megan K. Dishop, Linda Rozell-Shannon, Thuy L. Phung, and Martin C. Mihm Jr.

3.1 Introduction


This chapter includes a discussion of many of the common and complex vascular tumors and malformations that are generally present at birth or shortly thereafter. In 1996, the International Society for the Study of Vascular Anomalies (ISSVA) revised the classification system initially proposed by Mulliken and Glowacki. 1 Given the inherent complexity and numerous changes of nomenclature describing vascular tumors and malformations over the past few decades, our effort strictly involves classifying vascular lesions according to their hemodynamic nature [i.e., fast-flow or slow-flow by Doppler ultrasound or magnetic resonance imaging (MRI) ( Table 3.1 ). In this chapter, for each vascular anomaly, we address the clinical presentation, pathogenesis (if known), and histologic findings ( Table 3.2 ).




























Table 3.1 Distribution of vascular tumors and malformations according to hemodynamics

Character of flow


Vascular tumors


Vascular malformations


Fast-flow


Infantile hemangioma


Rapidly involuting congenital hemangioma


Noninvoluting congenital hemangioma


PHACES


Kaposiform hemangioendothelioma


Tufted angioma


Kasabach Merritt phenomena


Arteriovenous malformation


Slow-flow



Port-wine stain


Venous malformation


Lymphatic malformation


Telangiectases


Combined


Parkes Weber syndrome*


Cutis marmorata telangiectatica congenital**


Klippel-Trenaunay syndrome*


*Parkes Weber syndrome and Klippel-Trenaunay syndrome must be distinguished from each other. Parkes Weber syndrome is a fast-flow complex combined lesion with AVMs. **Cutis marmorata telangiectatica congenital is a slow-flow lesion with both capillaries and venous vessels.



































































































Table 3.2 General clinical, pathogenesis, and histologic information of the lesions

Lesion


Clinical


Histology


GLUT1 marker


Fast-flow


IH


Initial


Well-circumscribed, erythematous, telangiectactic macule


Usually develops by 2nd wk of life


Proliferative phase


Growth into erythematous plaque or tumor. Growth phase complete by age 9 mo


Involuted phase


Involution occurs slowly up to 10 yr. No clinical lesion or residual scar; telangiectasias and redundant skin


Proliferative phase


Plump lobules of capillaries, mitotically active endothelial cells and stromal elements


Involution phase


Decreased mitotic rate, increased mast cells and endothelial cell apoptosis


Involuted phase


Fibrofatty replacement of capillaries


Positive


RICH


Infiltrating violaceous plaque/nodule with pale halo and large radiating vessels Present at birth, rapid regression by 12–14 mo


Small lobules of endothelial cells (smaller than IH, NICH), zonation effect


Negative


NICH


Similar to RICH with coarse telangectasias with admixed pallor and halo


Present at birth, grows proportionally with child


Large lobules of thin-walled endothelium with central dominant stellate vessel, hobnailing present, eosinophilic inclusions


Negative


PHACES syndrome


Posterior fossa malformation, cervicofacial hemangioma, arterial anomalies, cardiac defect/coarctation of the aorta, eye anomalies, sternal defect


See IH


?unclear, no reports


KHE


Single red or violaceous plaque or tumor


Can be associated with Kasabach Merritt phenomenon with rapidly growing tumor with advancing purpuric border


Ill-defined nodules of endothelial cells, minimal atypia, platelet-rich microthrombi


Negative


TA


Mottled firm plaque or nodule, extend/grow laterally


Usually persist. Can be associated with Kasabach Merritt phenomenon


“Cannonball” distribution in dermis, lymphatic spaces, poorly defined borders


Negative


Kasabach Merritt phenomenon


Life-threatening, rapidly enlarging erythematous to violaceous tumor with thrombocytopenia associated with TA and more frequently KHE


First few months of life


See KHE or TA


Negative


AVM


Stage I: Red, warm macular lesion


Stage II: Warm, pulsatile


Stage III: Destructive phase of necrosis, ulceration, hemorrhage, lytic bone lesions


Stage IV: additional high-output cardiac failure


Communicating blood vessels with irregularly thickened walls and lobular architecture and branching capillaries, randomly distributed in dermis


Negative


Slow-flow


Port-wine stain


Well-demarcated red macular stain, grows proportionally with child


Tends to involve trigeminal distribution of head/neck


Numerous ectatic capillaries along papillary and reticular dermis.


By adulthood some increased dermal fibrosis


Negative


Venous malformation


Painless, diffuse bluish lesion, soft, compressible, grows proportionally with child


Can result in limb atrophy or hypertrophy


Poorly circumscribed, thin-walled, dilated vascular channels of varying sizes, thrombosis and calcification may be present


Negative


Lymphatic malformation


Clear or purplish vesicles that can mimic warts or frog spawn


Poorly circumscribed and may expand over time


Microcystic and macrocystic types, enlarged distorted irregular thin-walled endothelium


Negative


Telangiectases


Pink to erythematous in color and blanch with pressure. Presentation is variable, can appear as numerous speckled lesions or individual punctate, linear, or reticulate forms


Generally appear as dilated capillaries in the upper dermis ± mild perivascular lymphocytic infiltrate


Negative


Combined


Parkes Weber syndrome (fast-flow)


Overgrowth of limb, with associated capillary stain and multiple AVMs


Ectatic capillary malformation in papillary/reticular dermis, AVMs present


Negative


Klippel-Trenaunay syndrome (slow-flow)


Superficial vascular stain, limb hypertrophy, varicosities, favor lower extremities


Numerous ectatic capillaries along papillary and reticular dermis, dilated venous channels, distorted irregular lymphatics


Negative


Cutis marmorata telangiectatica congenita


Distinct, deeply erythematous to violaceous, reticulate vascular network that is either localized (predominantly) or generalized. Typically lesions are both segmental and unilateral, occurring most frequently on the limbs, trunk and rarely the face or scalp


Dilated capillaries and veins, with admixed vascular fibrosis. Other findings that may or may not be present include dilated lymphatics, venous thrombosis, epidermal atrophy, acanthosis, parakeratosis, hyperkeratosis, erosion, papillomatosis, sparse dermal perivascular lymphocytic infiltrates, and swelling of endothelial cells


Negative


Abbreviations: AVM, arteriovenous malformation; IH, Infantile hemangioma; KHE, akposiform hemangioendothelioma; NICH, noninvoluting congenital hemangioma; RICH, rapidly involuting congenital hemangioma; TA, tufted angioma.



3.2 Fast-Flow Lesions


Fast-flow lesions are those that, on Doppler ultrasound or MRI, display fast, dynamic blood flow characteristics. These lesions are typically arterial in origin (e.g., hemangiomas) or contain some arterial component (e.g., arteriovenous malformations [AVMs]). This section describes the clinical presentation, pathogenesis, and histology of the following fast-flow lesions: infantile hemangiomas (IHs), congenital hemangiomas, PHACES syndrome, tufted angioma (TA), kaposiform hemangioendothelioma (KHE) and the associated Kasabach Merritt phenomenon (KMP), AVMs, and Parkes-Weber syndrome.



3.2.1 Infantile Hemangioma



Clinical Characteristics

Hemangioma of infancy is a benign proliferation of blood vessels that occurs in approximately 5% of the newborn population, with a reported incidence as high as 10% in the first year of life, making it one of the most common tumors of infancy. 2 ,​ 3 ,​ 4 This discrete and generally well-circumscribed tumor predominantly affects females, persons of fairer skin types, and premature infants (particularly those weighing < 1,500 g) ( Fig. 3.1 ). 5 The clinical presentation is variable, depending largely on the anatomical site and the level of cutaneous involvement. More than half of these lesions tend to involve the head, neck, and trunk, and lesions can occur either singly or in multiple anatomical sites.

Fig. 3.1 Infantile hemangioma (clinical). Classic presentations of a well-circumscribed infantile hemangioma on the (a) forehead and the (b) neck and preauricular region of two infants. Infantile hemangioma (histologic): Histology (c,d) (hematoxylin and eosin [H&E] ×100 and ×200 magnification, respectively) of an infantile hemangioma demonstrating the numerous lobules of compact capillaries that are lined by plump, mitotically active, endothelial cells with intervening stromal elements. The glucose transporter-1 (GLUT1) immunohistochemical stain (e) (×200 magnification) is strongly positive in the lobules of the infantile hemangioma. Note: The immunostain highlights the internal controls by positively staining the GLUT1-positive red blood cells (within the luminal spaces) and negatively staining the nonhemangioma medium-sized artery, respectively.

Based on these clinical features and the level of soft tissue involvement, these lesions have traditionally been described as superficial, deep, or combined. Further efforts to better characterize these lesions have involved using anatomical spatial configurations (i.e., localized, segmental, indeterminate, or multifocal). There is some debate as to whether hemangiomas that are called “segmental type” are a misnomer because, instead of being limited to a particular anatomical location, they may in fact be derived embryologically from a soft tissue segment. 6 Despite greater than approximately 50% of hemangiomas having good outcomes, it appears the segmental type of hemangiomas have higher rates of complications, usually resulting in ulceration. 5 Additionally, segmental hemangiomas and hemangiomas with a deep component tend to have an unusually prolonged growth phase. 7 Other epidemiologic studies have found that, in addition to gender, ethnicity, and early gestational age, certain prenatal associations also exist, including older maternal age, placenta previa, and pre-eclampsia. 8


Although the pathogenesis is not completely understood, the natural history of these tumors is well established. IHs can be present at birth or develop postnatally, typically manifesting at a median age of 2 weeks. Approximately a third of these lesions will manifest as precursor or nascent lesions, either as an erythematous macule or blanched lesion, with or without telangiectasias. 9 Over a span of months during the initial period of rapid growth, these lesions continue to develop and enlarge, reaching their maximum size after 3 to 6 months. 2 ,​ 3 A recent prospective study of the growth characteristics of IHs found that the early proliferative part of the growth phase was essentially complete by 5 months of age and the overall growth was complete by 9 months of age. 10 Most of the time, this period of growth is followed by a slower period of total or partial regression of the lesion, occurring at as late as 5 to 10 years of age. 2 ,​ 4 Finally, the end stage of this lesion occurs when the involution of the lesion is replaced, either entirely or partially, by a fibrofatty residuum. 11


In addition to the previously classified types of hemangiomas, several atypical presentations of hemangiomas can occur, including deep subcutaneous, telangiectatic, AVM-like, multiple cutaneous, and congenital hemangiomas. 12 In addition, it is important for treating clinicians to keep in mind that mimics of hemangiomas do exist. The differential diagnosis includes capillary malformations (CMs) or telangiectasias, venous and lymphatic vascular malformations, KHE, TAs, pyogenic granulomas, infantile hemangiopericytomas, spindle cell hemangioendotheliomas, congenital eccrine angiomatous hamartomas, congenital fibrosarcomas, and other deep soft tissue masses. 12



Pathogenesis

Historically, the pathogenesis of IHs has been difficult to elucidate. Fortunately, attempts at understanding vasculogenesis and angiogenesis of normal and malignant vascular development has contributed to much of what we now know about hemangiomas. 13 Also, recent investigations of hemangiomas during different phases of the growth cycle and during involution have revealed some useful information regarding cellular markers ( Table 3.3 ).























Table 3.3 Cellular markers and immunostains associated with the different stages of the life cycle of the hemangioma 11 ,​ 13 ,​ 20


Proliferation


Involuting


Involuted


Cellular markers/


immunostains


GLUT1


PCNA


VEGF


FGF-2


Matrix metalloproteinases


type IV collagenase


CD31


CD34


Factor VIII–related antigen


Ulex europaeus lectin I


VE-cadherin


HLA-DR


Vimentin


Ki-67


vWf


SMC-actin


GLUT1


TIMP


Mast cells


FGF-2


CD31


vWf


SMC-actin


GLUT1


CD31


vWf


FGF-2


SMC-actin


Abbreviations: CD31/34, cluster of differentiation; FGF-2, fibroblast growth factor-2; GLUT1, erythrocyte-type glucose transporter protein 1; HLA-DR, human leukocyte antigen DR; Ki-67, monoclonal antigen to antibody KI-67, a marker of cell proliferation; PCNA, proliferating cell nuclear antigen; SMC-actin, smooth muscle cell actin; TIMP, tissue inhibitor of metalloproteinase; VE, vascular endothelial; VEGF, vascular endothelial growth factor; vWF, Von Willebrand factor.


Studies have shown that during the proliferative phase, expression of type IV collagenase, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) increase, in contrast to the markedly decreased expression of VEGF observed during involution of the hemangiomas. During involution, a persistently high expression of bFGF exists despite the decreased expression of VEGF. Other studies have revealed that during the proliferative phase, VEGF increases proangiogenic factors (e.g., B-cell lymphoma-2, interleukin-8) while decreasing levels of the apoptotic enzyme (caspase-3), 14 whereas expression of apoptotic proteins increases in involuting hemangiomas. 15 In addition, gene-expression analysis has shown that insulin-like growth factor 2 follows an expression pattern similar to that of VEGF, increasing during proliferation and significantly decreasing during involution. Recent studies have shown that IH endothelial cells have low VEGF receptor (FEGFR)1 expression but constitutive VEGFR2 signaling caused by reduced activity of a pathway involving β1 integrin, the integrin-like receptor tumor endothelial marker-8 (TEM-8), VEGFR2, and nuclear factor of activated T-cells (NFAT). 16 Mutations in VEGFR2 and TEM-8 genes have also been found in some patients with IHs and caused reduced NFAT activity and VEGFR1 expression.


Other efforts toward examining messenger RNA expression patterns of genes necessary for angiogenesis in hemangiomas have shown that the angiopoietin-Tie-2 system is also a molecular regulator of IHs. 17 Numerous studies evaluating immune-mediated processes and their roles in IH involution have been fruitful. For instance, one study showed how treatment with imiquimod for proliferating hemangiomas accelerated their regression. 18 This finding was further examined in murine studies assessing the effects of imiquimod and the expression of tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), 19 which is significant because this inhibitor (i.e., TIMP-1) is known to be increased in involuting hemangiomas. 20 Continuing this effort to understand more fully the involvement of the immune system with IHs, another group investigated the role of indoleamine 2,3 dioxygenase (IDO). 21 IDO is an enzyme that is involved in the degradation of the amino acid tryptophan. Tryptophan’s availability is critical to normal T-cell functioning. When tryptophan is depleted or decreased, T-cell proliferation and activity decrease and T-cell apoptosis increases. Ritter et al proposed that the extended involution period of IHs is secondary to the early inhibition of T-cell function by way of increased levels of IDO. They found that IDO levels were highest during the proliferative phase of IHs and lowest during involution. 21


More recently, several distinct and shared markers between IH and placental fetal microvessels have been demonstrated. These cellular markers include glucose transporter 1 (GLUT1), Lewis Y antigen, Fc (Fragment, crystallizable region of heavy chain regions of immunoglobins) gamma receptor II, and merosin. 11 ,​ 22 These findings raise the possibility that angioblasts (vascular precursor cells) might undergo aberrant differentiation into a placental vascular phenotype during development. 23 Another consideration is that placental vascular cells shed, secondary to local trauma, and embolize to locations (via right-to-left shunting) within the fetus and then undergo maturation to become a hemangioma. This notion is further supported, but yet to be proven, by the observed increased incidence of infants born with hemangiomas of mothers who have undergone chorionic villous sampling during pregnancy. 24 Additionally, an immunohistochemical evaluation of the expression of vascular lineage-specific markers revealed ( Fig. 3.2 ) that IHs express the same markers [specifically, CD34 and lymphatic vessel endothelial hyaluronan-1 (LYVE-1)] as the cardinal vein during early normal embryogenesis, suggesting that IHs display the immature immunophenotype of a vessel arrested early in vascular differentiation. 25

Fig. 3.2 Lymphatic vessel endothelial hyaluronan-1 (LYVE-1). Schematic demonstrating that infantile hemangiomas express the same markers (specifically CD34 and LYVE-1) as the cardinal vein during normal embryogenesis, suggesting that infantile hemangiomas are arrested in early vascular differentiation. Prox-1, prospero homeobox 1; SLC, solute carrier family; VEGFR, vascular endothelial growth factor receptor. (Used with permission from Dadras SS, North PE, Bertoncini J, et al. Modern Pathology. 2004;17:1068-1079.)

Lastly, the significance of mast cells and their proangiogenic role in hemangiomas has yet to be fully understood. Recent efforts have found that the number of mast cells is highest during the involuting phase, second highest once the hemangioma has completely involuted, and lowest during proliferation. 26 ,​ 27 Other studies have supported this relationship by studying how mast cell proliferation increases during the involuting stage of IH. 27 Subsequent investigations have revealed that, of the several mast cell mediators, VEGF and FGF-2 are the most potent of the angiogenic factors. 28



Histology

Both focal and segmental types of IHs have a characteristic histopathologic ( Fig. 3.1 c,d) evolution that correlates with the gross clinical appearance. During the proliferative phase, hemangiomas are composed of lobules of compact capillaries lined by plump, mitotically active endothelial cells with intervening stromal elements (fibroblasts, pericytes, and mast cells). Difficult to appreciate in early proliferation are small vascular lumens noted focally throughout the growing lesion. To illustrate more clearly the individual lobules, reticulin and periodic-acid Schiff stains can be used to highlight the reticulin fibers surrounding the endothelial cells and underlying endothelial cell basement membrane, respectively. As the proliferating lobules mature, the fibrous septae separating each lobule become more apparent. It is within these septae that large feeding and draining vessels can be found. The mitotic activity during this stage is reflective of the hyperplastic nature of IHs. Notably, increased numbers of mast cells are seen at this stage. Once the lesion has reached maturity, it then begins the next stage of involution.


At the beginning of involution, mitotic activity decreases and the numbers of mast cells increase somewhat; the ensuing apoptosis of the endothelium results in a flattened endothelial appearance. During this stage, the numbers of vessels begin to decrease and those that remain undergo separation and replacement by fibrofatty tissue. Toward the end stages of involution, the numbers of mast cells begin to decrease along with the numbers of persistent lobules. In addition to the morphologic findings, immunohistochemical stains can further assist in differentiating IHs from the other vascular lesions. Of these markers, GLUT1 is the most specific for IHs ( Fig. 3.1 e). In IHs, GLUT1 stains strongly positive but negative in congenital hemangiomas, vascular malformations, and other various reactive vascular lesions.



3.2.2 Congenital Hemangiomas


First recognized in 2001, congenital hemangiomas were initially thought to be a possible subset of IHs; however, more recently, their distinct clinicopathologic, radiologic, and histologic differences indicate that they may even be a completely distinct entity compared with IHs. 29 By definition, congenital hemangiomas proliferate in utero, and, unlike IHs, they are at their maximum size at birth. These lesions are less frequent (<3%) than IHs. Based on their natural history, congenital hemangiomas can be divided into two types of lesions: rapidly involuting congenital hemangiomas (RICHs) and noninvoluting congenital hemangiomas (NICHs). Sometimes RICHs and NICHs are referred to collectively as congenital nonprogressive hemangiomas. 12 Both RICHs and NICHs are high-flow lesions by Doppler evaluation, often showing arteriovenous microfistulas. Unlike IHs, these rare, solitary lesions are GLUT1 immunostain negative, have no gender predilection, and are distributed most commonly on the head and limbs, mostly near the joints. 9 ,​ 11 ,​ 30 These differences raise the question as to whether these lesions are in fact unique or related to IHs. As with any lesion, the challenge of recognizing these distinct entities falls on the clinician to elucidate their unique presentation, natural course, and histology. The following describes the differences in clinical presentation, pathogenesis, and histologic characteristics of both RICH and NICH lesions.



3.2.3 Rapidly Involuting Congenital Hemangioma



Clinical Characteristics

Clinically, RICHs ( Fig. 3.3 a,b,c) can manifest as infiltrating violaceous plaques or firm violaceous telangiectatic nodules with a surrounding pale halo and large peripheral radiating vessels. These lesions can also have a central depression, scar, or ulceration. Prenatal ultrasounds have detected them at as early as 12 weeks of gestation, and they typically spontaneously involute by the time the child is 14 months of age or sooner. 31 The early flow dynamics of these tumors by ultrasound or MRI is fast flow. It is important not to confuse RICHs with congenital fibrosarcomas on imaging. 32 Classically, RICHs demonstrate accelerated involution by 12 to 14 months of age. 9 The remaining skin overlying the regressed lesion is often depressed or atrophic. Subsequent Doppler imaging of the postregressional lesion reveals normal blood flow.

Fig. 3.3 Rapidly involuting congenital hemangioma (RICH) (clinical). Classic presentation of a firm, violaceous RICH lesion at birth (a), followed by its rapid partial involution at 2 (b) and 4 (c) weeks of life. RICH (histologic). The RICH lesion was a 3-cm atrophic violaceous plaque on the back of a 3-month-old female infant. The lesion shows regressive changes with ectatic venules and slitlike channels in the fibroconnective tissue between rounded aggregates of capillaries (d) (hematoxylin and eosin [H&E], ×40 original magnification). The cellular aggregates consist of compact capillaries surrounding a central ectatic venule (e), (H&E, ×200 original magnification). The congenital hemangiomas are negative for glucose transporter 1 (GLUT1), which aids in distinguishing them histologically from infantile hemangiomas (f) (GLUT1 immunohistochemistry, ×200 original magnification).


Pathogenesis

The pathogenesis of RICHs is still unclear and it is uncertain whether there is any similarity to that of IHs.



Histology

Compared with the lobular architecture of IHs and NICHs, RICHs tend to have the smallest lobules ( Fig. 3.3 d,e). The endothelial cells are moderately enlarged and occasionally may have cytoplasmic endothelial inclusions. Similar to NICH, RICHs have prominent draining channels; however, RICHs tend to have more perilobular fibrous tissue than NICHs and much more than IHs. In resected lesions, a zonation effect is observed. This effect is created by the central portion of the RICHs having more involution than the periphery. The zonation effect can also be seen in NICHs but not in IH. Unlike IHs, RICHs characteristically do not stain immunohistochemically ( Fig. 3.3 f) for GLUT1. 29



3.2.4 Noninvoluting Congenital Hemangioma



Clinical Characteristics

Clinically, NICHs can appear much like RICHs ( Fig. 3.4 a). Characteristically, NICHs have coarse, prominent, overlying telangiectasias with admixed areas of pallor and a pale peripheral halo. Usually, they are warm to palpation, are only slightly raised, and have a heterogeneous pink–purple color. These lesions tend to occur slightly more often in male infants, and they grow proportionally with the child. Hemodynamically, these lesions are quite similar to IHs during the proliferative phase, exhibiting fast-flow dynamics by Doppler examination. 29 ,​ 33 ,​ 34 Some propose that NICHs could be a variant of RICHs, as some RICHs have been observed to involute only partially, resembling an NICH. 12 ,​ 35

Fig. 3.4 Noninvoluting congenital hemangioma (NICH) (clinical). (a) A coarse, prominent supraorbital NICH with admixed areas of pallor and healing ulceration. The NICH lesions are histologically similar to RICH lesions but do not show regressive changes. This congenital lesion on the abdominal wall of a 9-month-old male infant was slowly enlarging with the growth of the child. Large interconnected lobules of capillaries have only a small amount of intervening connective tissue (b) (hematoxylin and eosin [H&E], ×20 original magnification). The lobules of capillaries have a central ectatic/stellate vessel (c) (H&E, ×100 original magnification), similar to that seen in the RICH lesions. Like RICH lesions, the endothelial cells lack glucose transporter 1 (GLUT1) expression. Not shown in this figure is one of the frequently found foci of extramedullary hematopoiesis.


Pathogenesis

The pathogenesis of NICHs is still unclear, and it is uncertain whether there is any similarity to IHs or RICHs.



Histology

The architecture of NICHs ( Fig. 3.4 b,c) is generally dominated by large lobules of small, thin-walled vessels with curved lamina and a large, often stellate, central vessel. 29 They also have hobnailed endothelial cells and eosinophilic endothelial cytoplasmic inclusions with prominent lobular draining channels and a prominent interlobular vascular network. 34 Similar to the involuting or involuted phase of IHs, NICHs can have lobules of capillaries with multilamellated basement membranes. 29 However, extensive fibrosis separates the lobules. An interesting aspect is the presence of iron scattered apparently free and in siderophages diffusely throughout the tissue. Another characteristic feature is the presence of extramedullary hematopoiesis. Generally, there is no significant atypia. Like RICHs, these lesions are negative for GLUT1.



3.2.5 PHACES Syndrome



Clinical Characteristics

Despite a small number of cases of infants with facial hemangiomas and associated aortic or cerebrovascular malformations reported in the literature in the 1980s, Frieden et al were the first to describe the PHACES association or syndrome. 36 ,​ 37 The PHACES association ( Fig. 3.5 ) is a neurocutaneous syndrome associated with facial segmental IHs consisting of the following features: posterior fossa brain malformations, cervicofacial hemangiomas, arterial anomalies, cardiac defects or coarctation of the aorta, eye anomalies, and sternal clefting or supraumbilical raphe. 36 ,​ 38 Although up to 70% of the patients have only one extracutaneous defect, the most critical and important associations remain the cardiac and cerebrovascular anomalies.

Fig. 3.5 PHACES (clinical). Classic V1 dermatomal distribution of a PHACES hemangioma in two different infants (a,b). Although sometimes bilateral, they tend to be ipsilateral and more commonly on the left face. In (b), the lower lip involvement is focal. Some lesions affect the beard area.

It is likely that PHACES is an underrecognized syndrome given that nearly 20% of the infants who are referred for facial hemangiomas are eventually diagnosed with this disorder. 39 Most infants with PHACES have hemangiomas in the V1 distribution alone or in combination with V2, V3 dermatomes. They have a tendency to be ipsilateral and more commonly are on the left side of the face; however, bilateral lesions can occur. The more extensive the cutaneous disease, the more likely there seems to be structural or vascular central nervous system involvement, resulting in higher complication rates. 40 The most frequent cardiovascular anomaly associated with PHACES is aortic coarctation. These coarctations tend to have an absence of aortic valve pathology and a much more complex anatomical involvement than the classic aortic coarctation. 41


The noncutaneous associations of PHACES are described in order of most to least common. Beginning with the posterior fossa abnormalities, the different types of abnormalities include Dandy-Walker malformation, hypoplasia or absence of cerebellum, corpus callosum of cerebrum or the septum pellucidum, frontal lobe calcifications, microcephaly, and arachnoid cysts. Of the arterial malformations, arterial stenosis and intracranial aneurysmal dilations are most common. Arterial vessel absence, or hypoplasia, as well as anomalous or aberrant branches of carotid and vertebral arteries can occur. The persistence of embryonic arteries should also be considered. As previously mentioned, aortic coarctations are the most common of the aortic cardiac anomalies, followed by, aneurysms, hypoplasia, atresia, duplication, and aberrant locations. Aside from the aortic complications, pulmonary stenosis, patency of both ductus arteriosus and foramen ovales can occur, as well as ventricular or atrial septal defects and aortic and tricuspid atresia. Ophthalmologic abnormalities can include microphthalmos, exophthalmos, coloboma, optic nerve atrophy or hypoplasia, hemangiomas, congenital cataracts, congenital glaucoma, amblyopia, and strabismus. Sternal fusion defects, including supraumbilical raphes, sternal clefting and a sternal pit have been described. 42

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