20 Vascular Birthmarks and Other Abnormalities of Blood Vessels and Lymphatics

Transcription

Vascular Birthmarks and Other Abnormalities
of Blood Vessels and Lymphatics
CHAPTER
20
Ilona Frieden, Odile Enjolras and Nancy Esterly
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Vascular lesions are common in infants and children, but their precise classification can be confusing. In 1996, the International Society for the Study
of Vascular Anomalies (ISSVA) approved a classification system modified from
the schema originally proposed by Mulliken and Glowacki.1 Their aim was
to establish a common language for the many different medical specialists
involved in the management of these lesions.Two groups of vascular anomaly
are delineated: vascular tumors (of which hemangioma of infancy is the most
common) and vascular malformations (Table 20.1).2 The classification, as
TABLE 20.1 Examples of clinically significant vascular tumors
and malformations occurring in children
Tumors
Hemangioma of infancy
Lobular capillary hemangioma (pyogenic granuloma)
Rapidly involuting congenital hemangioma (RICH)
Non-involuting congenital hemangioma (NICH)
Tufted angioma (angioblastoma of Nakagawa)
Kaposiform hemangioendothelioma
Congenital eccrine angiomatous hamartoma
Spindle-cell hemangioendothelioma
Malformations
originally conceived, was based on differences in the cellular kinetics and
natural history of these lesions.Vascular tumors demonstrate endothelial cell
hyperplasia, and the most common of these in children, hemangioma of
infancy, spontaneously involutes. In contrast, malformations, such as portwine stains, have flattened endothelial cells with normal endothelial cell
turnover and do not involute spontaneously.
Although there are uncommon examples of either clinical or histologic
coexistence of vascular malformations and tumors (Fig. 20.1),3 this classification has stood the test of time, because of its simplicity and clinical
relevance. Most of the entities discussed in this chapter are congenital or
arise during infancy; however, some are acquired later in life. During the
1990s, there were exciting new developments in our understanding of
angiogenesis, in the appreciation of new clinical associations, and in our
therapeutic armamentarium for treating vascular anomalies. Despite this
expansion of knowledge, the precise etiology of most of these conditions is
not yet known.
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THE CLASSIFICATION OF VASCULAR
BIRTHMARKS
Capillary malformation (port-wine stain)
Venous malformation, including blue rubber bleb nevus (Bean) syndrome
Lymphatic malformation (lymphangioma; cystic hygroma)
Arteriovenous malformation (including Bonnet–Dechaume–Blanc,
Wyburn–Mason, and Cobb syndromes)
Capillary–lymphatic–venous malformation (most common type seen in
limbs with Klippel–Trenaunay syndrome)
Parkes–Weber syndrome (combined malformation with arteriovenous
fistulae)
Cutis marmorata telangiectatica congenita
Glomuvenous malformation (glomangioma–venous malformation,
including glomus tumor)
VASCULAR TUMORS
HEMANGIOMAS OF INFANCY
Hemangiomas of infancy are the most common benign tumors in children
and have a distinctive life-cycle, characterized by a proliferative phase
in early infancy followed by an involutional phase, leading to complete,
spontaneous regression in most patients. A wide variety of vascular
anomalies are referred to as “hemangiomas” in the medical literature, so it
is preferable to distinguish the specific vascular anomaly being discussed
with adjectives and modifiers, i.e., “hemangioma of infancy.” For the
purposes of this chapter, however, the term hemangioma, unless otherwise
Fig. 20.1 Salmon patch.
Coexistence of a salmon
patch (nevus simplex) and
a hemangioma of infancy
on the scalp of this young
infant.
Adapted from International Society for the Study of Vascular Anomalies classification
1. Mulliken JB, Glowacki J (1982) Hemangiomas and vascular malformations in infants and children.
A classification based on endothelial characteristics. Plast Reconstr Surg 69:412–422.
2. Enjolras O, Mulliken JB (1997) Vascular tumors and vascular malformations, new issues. Adv
Dermatol 13:375–423.
3. Garzon MC, Enjolras O, Frieden IJ (2000) Vascular tumors and vascular malformations: evidence
for an association. J Am Acad Dermatol 42:275–279.
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Chapter 20 Vascular birthmarks and other abnormalities of blood vessels and lymphatics
designated, refers specifically to “hemangioma of infancy.” Several excellent
review articles on vascular anomalies including hemangiomas of infancy have
been written.4–8
These common vascular tumors occur in approximately 2.5% of all
neonates and are seen in up to 5 to 10% of Caucasian infants by 1 year of
age. Although hemangiomas appear to be most common in fair-skinned
infants, they can occur in any race. Girls are affected three times as often as
boys, but the reason for this gender difference remains unclear.9 It is estimated
that 10% of patients have a history of affected family members; however, this
feature may be under-reported. Although monozygotic twins do not show
consistent concordance nor is there an obvious Mendelian pattern of
inheritance in most families, rare families do show an autosomal dominant
inheritance pattern for hemangiomas and other vascular anomalies, with a
putative localization to 5q.10 Hemangiomas are also more common in
preterm infants weighing less than 1500g, and in infants whose mothers have
undergone chorionic villus sampling.11,12
Fig. 20.2 Hemangioma
precursors. (A) Area of
blanching with
superimposed
telangiectasias.
(B) Extensive stain and
telangiectasias resembling
a port-wine stain.
(C) Bruise-like area.
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Although the precise events leading to the formation of hemangiomas are
not known, research in angiogenesis and blood vessel development have
provided some clues. During their proliferative phase, hemangiomas are
composed of densely packed endothelial cells, forming small sinusoidal
channels. Cellular markers of angiogenesis, such as basic fibroblast growth
factor, vascular endothelial growth factor (VEGF), proliferating-cell nuclear
antigen, and E-selectin, are increased. Immunohistochemical stains confirm
blood vessel markers such as CD31 von Willebrand factor and VE-cadherin.
Additional studies have shown that hemangiomas of infancy have a unique
vascular phenotype which most closely resembles that of placental microvasculature, rather than ordinary cutaneous vasculature, demonstrated by
staining markers such as glucose transporter 1 (GLUT-1), merosin, and
Lewis Y antigen.13 Other studies have demonstrated that hemangioma cells
cultured in vitro behave more like fetal than neonatal endothelial cells,
including more readily attaining a spindle-shaped rather than epithelioid
morphology, lower levels of expression of platelet–endothelial cell adhesion
molecule-1 and von Willebrand factor, and production of interstitial type
I collagen rather than epithelium-specific type IV collagen.14 Clonality has
been demonstrated in at least some hemangiomas.15 Taken together, these
observations have led some authors to propose that hemangiomas of
infancy represent either placentally derived vasculature or, at the very least,
immature vasculature expressing a placental phenotype.13 In this paradigm,
the rapid proliferation of a hemangioma developing in early infancy could
be explained by a loss of inhibitors of angiogenesis derived from the
placenta or mother. GLUT-1 is present in all phases of hemangiomas.
Regression causes histologic changes in hemangiomas with dilatation
of vascular lumina, flattening of endothelial cells, and the presence of
fibrous tissue. Programmed cell death, also known as apoptosis, is believed
to be the mechanism of hemangioma involution. Markers of apoptosis
become evident before 1 year of age and reach highest levels by 2 years
of age.16
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Etiology/pathogenesis
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Clinical characteristics
Approximately 30 to 50% of hemangiomas are heralded by a premonitory
mark, or so-called precursor lesion.The varied appearances of precursor
lesions include a focal or large area of pallor, often with fine thread-like
telangiectases (Fig. 20.2A), a telangiectatic or macular erythematous stain
(Fig. 20.2B), a bruise-like area (often erroneously attributed to perinatal
4. Metry DW, Hebert AA (2000) Benign cutaneous vascular tumors of infancy: when to worry, what
to do. Arch Dermatol 136:905–914.
5. Garzon MC, Frieden IJ (2000) Hemangiomas: when to worry. Pediatr Ann 29:58–67.
6. Drolet BA, Esterly NB, Frieden IJ (1999) Hemangiomas in children. N Engl J Med 341:173–181.
7. Esterly NB (1995) Cutaneous hemangiomas, vascular stains and malformations, and associated
syndromes. Probl Dermatol 7:67–108.
8. Mulliken JB, Fishman SJ, Burrows PE (2000) Vascular anomalies. Curr Probl Surg 37:519–584.
9. Mulliken JB, Young AE (1988) Vascular Birthmarks: Hemangiomas and Malformations.
Philadelphia, PA: WB Saunders.
10. Berg JN, Walter JW, Thisanagayam U et al. (2001) Evidence for loss of heterozygosity of 5q in
sporadic haemangiomas: are somatic mutations involved in haemangioma formation? J Clin
Pathol 54:249–252.
C
11. Powell TG, West CR, Pharoah PO et al. (1987) Epidemiology of strawberry haemangioma in low
birthweight infants. Br J Dermatol 116:635–641.
12. Burton BK, Schulz CJ, Angle B et al. (1995) An increased incidence of haemangiomas in infants
born following chorionic villus sampling (CVS). Prenat Diagn 15:209–214.
13. North PE, Waner M, Mizeracki A et al. (2001) A unique microvascular phenotype shared by
juvenile hemangiomas and human placenta. Arch Dermatol 137:559–570.
14. Dosanjh A, Chang J, Bresnick S et al. (2000) In vitro characteristics of neonatal hemangioma
endothelial cells: similarities and differences between normal neonatal and fetal endothelial cells.
J Cutan Pathol 27:441–450.
15. Boye E, Yu Y, Paranya G et al. (2001) Clonality and altered behavior of endothelial cells from
hemangiomas. J Clin Invest 107:745–752.
16. Razon MJ, Kraling BM, Mulliken JB et al. (1998) Increased apoptosis coincides with onset of
involution in infantile hemangioma. Microcirculation 5:189–195.
Vascular tumors
Fig. 20.3 Superficial
hemangioma of infancy.
Note the resemblance to
an upside-down
strawberry.
should be avoided since it has been used to refer to several disparate vascular
anomalies, rather than one single disease. Superficial and deep hemangiomas
are also referred to as “mixed hemangiomas.” They involve both the dermis
and subcutis and demonstrate clinical features of both the types described
above. All hemangiomas of infancy, regardless of their location, are benign
neoplasms of capillaries; terms such as combined capillary–cavernous
hemangiomas, which imply otherwise, are confusing and should be avoided.9
Hemangiomas are rarely painful, unless they have ulcerated. Many, especially
large ones, are warm to palpation and occasionally have enough blood flow
to produce a bruit.This warmth and high blood flow subsides as the tumor
begins to undergo involution. Although rapid growth is a common characteristic during the proliferative phase, some fluctuation of size may be
observed even once the tumor growth has ceased; consequently, some parents
report a temporary increase in size after the child has a crying episode or an
upper respiratory infection.
Specific morphologic patterns of hemangiomas can be recognized, and
their clinical implications are now beginning to be appreciated. In addition
to marked variations in size and location, some present as discrete papules or
nodules whereas others are small or large plaques. Some plaque-type
hemangiomas appear as numerous small papules coalescing into a plaque of
involvement. Larger plaques may involve broader segments of the skin.The
concept of localized (Fig. 20.5) and segmental (Fig. 20.6) hemangiomas has
demonstrable clinical correlates. Large segmental hemangiomas have been
associated with structural anomalies, such as Dandy–Walker malformation,
arterial anomalies, spinal cord tethering, genitourinary anomalies, as well as
subglottic hemangiomas (see discussion below). Large preauricular segmental
hemangiomas often have an associated hemangioma within the parotid gland
but do not compromise facial nerve function. Based on the known timing of
some of their associated structural defects, segmental hemangiomas appear to
have their origin as early as 6 to 8 weeks of gestation.20 Multiple focal
hemangiomas have a higher risk of visceral hemangiomas (Fig. 20.7) (see
“hemangiomatosis” below). Most hemangiomas are solitary, but a significant
percentage of patients (up to 15%) have multiple lesions.
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Fig. 20.4 Deep
hemangioma. Many deep
hemangiomas in the
preauricular area involve
the parotid gland.
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Sites of involvement
trauma) (Fig. 20.2C), or a small “scratch” or ulceration.17 Most precursor
lesions go on to develop fully, but occasionally only a small amount of proliferation occurs at the periphery. Uncommonly, fully formed hemangiomas
are present at the time of birth; in rare instances, these are diagnosed in utero.
These have a different clinical appearance, involute very rapidly, and, recently,
their relationship to hemangioma of infancy has been questioned.18,19 (See
the discussion below.)
The appearance of the proliferative phase of cutaneous hemangiomas
depends on which level(s) of the skin are affected. Superficial hemangiomas (Fig. 20.3) (also called “strawberry” marks) involve the superficial
dermis and appear as lobulated, bright red lesions with a thin, delicate surface
epithelium. Deep hemangiomas (Fig. 20.4) involve the deep dermis and
subcutis. In these cases, the epidermis retains its normal thickness and, instead
of a superficial red color, the surface of the tumor has a bluish cast or normal
skin color.Telangiectases, tortuous vessels, or a few vascular papules may be
visible on the surface, and draining veins are noted at the periphery. Deep
hemangiomas were formerly called “cavernous hemangiomas,” a term that
17. Hidano A, Nakajima S (1972) Earliest features of the strawberry mark in the newborn. Br J
18. Boon LM, Enjolras O, Mulliken JB (1996) Congenital hemangioma: evidence of accelerated
involution. J Pediatr 128:329–335.
19. North PE, Waner M, James CA et al. (2001) Congenital non-progressive hemangioma. A distinct
clinicopathologic entity unlike infantile hemangioma. Arch Dermatol 137:1607–1620.
20. Hersh JH, Waterfill D, Rutledge J et al. (1985) Sternal malformation/vascular dysplasia
association. Am J Med Genet 21:177–186, 201–202.
Anatomic location plays a critical role in determining whether complications
could occur, and if extra concern and vigilance during the growth phase is
necessary.Although any area of the body may be affected, approximately 60%
occur on the head and neck. Moreover, the distribution of facial hemangiomas
does not seem to be random but appears to have a predilection for embryologic fusion lines and facial developmental subunits.21 Less common anatomic
sites include the trunk (25%) and extremities (15%).7 Hemangiomas can also
develop in almost any internal organ.Table 20.2 outlines the risks associated
with hemangiomas in several anatomic locations.
Natural history
The natural history of hemangiomas has been well documented.9,22,23 During
the first 6 months, particularly in the first 3 to 4 months, superficial hemangiomas proliferate at a rapid rate. Between 6 and 10 months of age, the
lesion may continue to grow, albeit often at a slower rate, usually reaching
a maximum size by 9 to 12 months. Despite this generalization, the growth
characteristics of a hemangioma in an individual infant are extremely difficult
to predict, because some hemangiomas barely proliferate beyond their nascent
phase whereas others, particularly large hemangiomas with both a superficial
and deep component, continue to grow for longer than expected, occasionally
up to 1–2 years.24,25 Deep hemangiomas are often noted somewhat later than
superficial lesions and may also proliferate for somewhat longer periods of
time.
21. Waner M, Waner A, North P et al. (2000) Identification of two distinct types of hemangioma. In:
13th International Workshop on Vascular Anomalies, Montreal, 2000.
22. Jacobs AH (1957) Strawberry hemangiomas. The natural history of the untreated lesion. Cal Med
86:8–10.
23. Bivings L (1954) Spontaneous regression of angiomas in children. J Pediatr 45:643–647.
24. Blei F, Isakoff M, Deb G (1997) The response of parotid hemangiomas to the use of systemic
interferon alfa-2a or corticosteroids. Arch Otolaryngol Head Neck Surg 123:841–844.
25. Williams EF, III, Stanislaw P, Dupree M et al. (2000) Hemangiomas in infants and children. An
algorithm for intervention. Arch Facial Plast Surg 2:103–111.
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Fig. 20.6 Segmental
hemangioma. This
hemangioma was
extensive (A) and required
several modalities of
treatment, including
prednisolone (which was
unsuccessful) and then
interferon alfa (which was
very effective). The final
result at 5 years of age (B),
after surgical correction of
the eyelid and lip as well
as Erbium laser resurfacing
was good.
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A
B
B
Fig. 20.5 Localized hemangioma. (A) Appearance at 11 months of age.
(B) Appearance after spontaneous involution at 2.5 years of age.
The involution phase of hemangiomas is usually much slower than the proliferation phase. Involution of superficial lesions typically begins by about
1 year of age, occasionally sooner, and its onset is heralded by a color change
from bright cherry red to dull red-purple, beginning at the central portion
of the tumor and eventually developing a grayish-white color that extends
peripherally (Fig. 20.8). In some cases, hemangioma growth actually continues
at the margins of the lesion or in deeper components despite signs of
Vascular tumors
TABLE 20.2 Location and morphology of hemangioma of infancy
and associated risks
Anatomic location, morphology
Associated risk
Large segmental facial
PHACE syndrome (see text)
Nasal tip, ear, large facial (especially
with prominent dermal component)
Permanent scarring and
disfigurement
Periorbital and retrobulbar
Ocular axis occlusion, astigmatism,
amblyopia, tear-duct occlusion
Segmental “beard area” and
central neck
Airway hemangioma
Perioral, lips
Ulceration, disfigurement
Lumbosacral spine
Tethered spinal cord, genitourinary
anomalies
Perianal, axilla, neck
Ulceration
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Multiple hemangiomas
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Fig. 20.7 Multiple
disseminated
hemangiomas. These may
be associated with visceral
involvement, particularly
hepatic hemangiomas.
B
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Visceral involvement (especially
liver, gastrointestinal tract) with
high risk of congestive heart failure
Fig. 20.8 Plaque-type hemangioma.
Natural involution of a large plaque-type
hemangioma of the leg at ages 2 (A),
4 (B), and 5 (C) years. Although some
pigmentary and texture remains, the
overall result is satisfactory.
C
regression in the superficial central portions of the hemangioma. As the
hemangioma involutes and is replaced by fibrofatty tissue, its volume decreases
and it becomes softer and more easily compressible. Similarly, deeper lesions
become less blue, softer, and less warm.
Disappearance occurs at a rate of approximately 10% per year, so that
approximately 50% have involuted by 5 years of age, 70% by 7 years, and 90%
by 9 years.22,26 Involution, however, should not necessarily be equated with
resolution with completely normal skin. Exact estimates of the percentage of
hemangiomas that leave significant residual skin changes is a matter of great
controversy, with estimates varying widely, from less than 20% to 50%.8,27
Even when present, the residua in mild cases can be fairly inconspicuous,
characterized by focal telangiectases, atrophic wrinkling, slight hypopigmentation, and subtle textural changes. In more severe cases, anetoderma-like
scarring or fibrofatty swelling with marked distortion of anatomic structures
may be evident. Most small hemangiomas do not result in significant disfigurement, but in certain locations such as the glabella, nose, lips, and ears,
the risk of scarring is greater. Large facial hemangiomas, particularly those
with a significant superficial dermal component, also have an increased risk
of scarring (Fig. 20.9). Ulceration always causes some degree of scarring, with
the severity depending on the size and depth of the antecedent ulcer as well
as other prognostic factors such as the location and thickness of the
hemangioma itself.5
26. Bowers RE, Graham EA, Tomlinson KM (1960) The natural history of the strawberry nevus. Arch
27. Waner M, Suen JY (1999) Hemangiomas and vascular malformations of the head and neck. In:
The Natural History of Hemangiomas, Waner M, Suen JY, eds. New York: Wiley-Liss, pp. 13–46.
Diagnosis and differential diagnosis
In most cases, the diagnosis of hemangioma is a clinical one, based on
appearance and typical growth characteristics. In a small minority of patients,
diagnosis is less obvious and ancillary tests are necessary. Deep hemangiomas,
in particular, can be difficult to differentiate from other soft-tissue tumors.
Table 20.3 lists some of the diagnoses that can resemble hemangioma of
infancy. Imaging studies such as magnetic resonance (MR), computed tomography (CT), and ultrasound can be helpful in differentiating hemangiomas
from many of these conditions, but biopsy may be necessary in very atypical
cases. In the proliferative phase, CT and MR both demonstrate wellcircumscribed densely lobulated uniformly enhancing lesions with dilated
feeding and draining vessels either at the center or periphery. On MR, the
lesions are isointense or hypointense to muscle on T1-weighted images, and
hyperintense on T2-weighted images. Flow voids are seen within and around
the mass. Sonography with Doppler interrogation usually demonstrates a
A
B
TABLE 20.3 Differential diagnoses of hemangioma of infancy
Other vascular anomalies and tumors
capillary malformations
venous malformations
lymphatic malformations
arteriovenous malformation
noninvoluting congenital hemangioma
nonprogressive congenital hemangioma
rapidly involuting hemangioma
lobular capillary hemangioma (pyogenic granuloma)
tufted angioma
spindle cell hemangioendothelioma
Fibrosarcoma
Rhabdomyosarcoma
Myofibromatosis (including hemangiopericytoma)
Nasal glioma
Lipoblastoma
Fig. 20.10 Ulcerated hemangioma involving the oral commisure. Pain is a major
problem with ulcerations, particularly those in perioral and perianal sites, which are
very common locations for ulceration.
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Fig. 20.9 Large postauricular hemangioma. The hemangioma is shown at
1 (A) and 6 (B) years of age. No treatment was given; because the scar is in the
postauricular area, it is inconspicuous. In another site (such as the central face) the
resultant scar might be much more disfiguring.
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838
Dermatofibrosarcoma protuberans (and giant-cell fibroblastoma)
Neurofibroma
well-circumscribed parenchymal mass, often containing anechoic channels.28
Although true arteriovenous shunting is usually absent (except in hepatic
hemangiomas), hemangiomas are fast-flow lesions with numerous highflow vessels around and within the soft tissue mass; decreased arterial
resistance is evident during both the proliferating and the involuting
28. Paltiel HJ, Burrows PE, Kozakewich HP et al. (2000) Soft-tissue vascular anomalies: utility of US for
diagnosis. Radiology 214:747–754.
29. Burrows PE, Laor T, Paltiel H et al. (1998) Diagnostic imaging in the evaluation of vascular
birthmarks. Dermatol Clin 16:455–488.
30. Dubois J, Garel L, Grignon A et al. (1998) Imaging of hemangiomas and vascular malformations in
children. Acad Radiol 5:390–400.
31. North PE, Mihm MC (1999) The surgical pathology approach to pediatric vascular tumors and
anomalies. In: Hemangiomas and Vascular Malformations of the Head and Neck, Waner M, Suen
JY, eds. New York: Wiley-Liss, pp. 93–170.
phases.29 During the proliferative phase, ultrasound demonstrates nonspecific
echogenicity and numerous vessels with high Doppler shift (>2kHz) and
low resistance.30
The histopathology of hemangioma of infancy in the early proliferative
phase is characterized by well-defined unencapsulated aggregates of plump
endothelial cells with closely associated pericytes. Granulated mast cells are
numerous. Normal mitotic figures are often present and may be numerous.
Deeper hemangiomas may involve skeletal muscle, salivary gland tissue, and
even nerves, not by aggressive invasion but by insinuating themselves between
individual cells.When hemangiomas begin to involute, proliferating vessels
decrease in number and loose fibrous or fibrofatty tissue begins to separate
the vessels.31 As mentioned above, GLUT-1 is found at all phases in
hemangiomas of infancy and can be extremely helpful in their differentiation
from other vascular tumors.13
Complications
Most complications of hemangiomas of infancy develop during the first 6
months, when growth is most rapid.These complications include ulceration,
bleeding, infection, compromise of vital functions, and, in rare instances,
congestive heart failure. Cutaneous ulceration is the most common complication, occurring in 5 to 10% (Fig. 20.10). Rarely it may actually precede
the development of a hemangioma.32 If ulceration is mild in degree, it can
often be managed with topical therapies, including antibiotics such as
metronidazole gel33 or polymyxin/bacitracin ointment, and covered with an
occlusive dressing such as a thin hydrocolloid dressing or petrolatumimpregnated gauze.33 Pain, which is often a major feature of ulcerated
hemangiomas, is usually diminished with the use of occlusive dressings; if the
pain is severe, it can be helped by the oral administration of acetaminophen
(paracetamol) or acetaminophen with codeine.33 Flashlamp pumped pulsed
dye laser (PDL) can also be helpful in relieving the pain of ulcerated
hemangiomas.34
32. Liang MG, Frieden IJ (1997) Perineal and lip ulcerations as the presenting manifestation of
hemangioma of infancy. Pediatrics 99:256–259.
33. Kim HJ, Colombo M, Frieden IJ (2001) Ulcerated hemangiomas: clinical characteristics and
response to therapy. J Am Acad Dermatol 44:962–972.
34. Morelli JG, Tan OT, Yohn JJ et al. (1994) Treatment of ulcerated hemangiomas of infancy. Arch
Pediatr Adolesc Med 148:1104–1105.
Vascular tumors
839
EXTRACUTANEOUS COMPLICATIONS
ASSOCIATION WITH HYPOTHYROIDISM
The most common extracutaneous site of involvement is the liver. Liver
hemangiomas are sometimes referred to as hemangioendotheliomas, although
the reason for this distinction appears to be based less on true histologic
Severe hypothyroidism is a potential complication of hepatic hemangiomatosis
and, possibly, hemangiomas in other sites.The mechanism is believed to be
tumoral production of type 3 iodothyronine deiodinase, causing peripheral
35. Yagupsky P, Giladi Y (1987) Group A beta-hemolytic streptococcal septicemia complicating
infected hemangioma in children. Pediatr Dermatol 4:24–26.
36. Haik BG, Karcioglu ZA, Gordon RA et al. (1994) Capillary hemangioma (infantile periocular
hemangioma). Surv Ophthalmol 38:399–426.
37. Orlow SJ, Isakoff MS, Blei F (1997) Increased risk of symptomatic hemangiomas of the airway in
association with cutaneous hemangiomas in a “beard” distribution. J Pediatr 131:643–646.
38. Sie KC, Tampakopoulou DA (2000) Hemangiomas and vascular malformations of the airway.
Otolaryngol Clin North Am 33:209–220.
39. Blei F, Orlow SJ, Geronemus R (1997) Multimodal management of diffuse neonatal
hemangiomatosis. J Am Acad Dermatol 37:1019–1021.
40. Held JL, Haber RS, Silvers DN et al. (1990) Benign neonatal hemangiomatosis: review and
description of a patient with unusually persistent lesions. Pediatr Dermatol 7:63–66.
41. Boon LM, Burrows PE, Paltiel HJ et al. (1996) Hepatic vascular anomalies in infancy: a twentyseven-year experience. J Pediatr 129:346–354.
42. Holden KR, Alexander F (1970) Diffuse neonatal hemangiomatosis. Pediatrics 46:411–421.
43. Keller L, Bluhm JF, III (1979) Diffuse neonatal hemangiomatosis. A case with heart failure and
thrombocytopenia. Cutis 23:295–297.
44. Pereyra R, Andrassy RJ, Mahour GH (1982) Management of massive hepatic hemangiomas in
infants and children: a review of 13 cases. Pediatrics 70:254–258.
45. Moore J, Lee M, Garzon M et al. (2001) Effective therapy of a vascular tumor of infancy with
vincristine. Pediatr Surg 36:1273–1276.
46. Daller JA, Bueno J, Gutierrez J et al. (1999) Hepatic hemangioendothelioma: clinical experience
and management strategy. J Pediatr Surg 34:98–105.
Significant bleeding is a very uncommon complication of hemangiomas.
When it does occur, it is virtually always as a sequela of deep ulceration or
in scalp lesions. In most cases, local pressure is usually sufficient to control
bleeding. In difficult situations, powdered gel-foam or topical thrombin may
be used. In recurrent bleeding, an enuresis blanket can be useful, triggering
an alarm if bleeding develops during the night. Infection can occur in
ulcerated hemangiomas but has probably been overdiagnosed in the past. If
infection is suspected, a bacterial culture should be obtained and the patient’s
antibiotic regimen should be chosen for the organism(s) recovered. Sepsis
complicating infected hemangiomas has rarely been reported.35
AMBLYOPIA
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Amblyopia is a complication of periocular hemangiomas. Closure of
the eye can lead to occlusion of the visual axis, which will prevent light
stimulation and result in loss of vision (amblyopia). However, even if the
hemangioma does not completely occlude the eye, the presence of the
mass in the periorbital area can cause pressure on the globe and result in
astigmatism, which, if uncorrected, can lead to amblyopia.The risk of pressure
on the orbit is somewhat greater but not limited to hemangiomas with upper
lid involvement. Retro-orbital hemangiomas may cause proptosis.36 Infants
with periocular hemangiomas should have frequent eye examinations during
the first few months of life, when most rapid growth is likely to occur.
AL
Diffuse neonatal hemangiomatosis is a rare form of hemangioma characterized by multiple cutaneous hemangiomas with visceral involvement.
Although some infants with visceral hemangiomatosis have no cutaneous
involvement, most have multiple small, cherry-red superficial hemangiomas
that are present at birth or develop during the first few weeks of life
(Fig. 20.7).39 An innocuous variant, the so-called benign neonatal hemangiomatosis, has identical cutaneous hemangiomas without visceral involvement.40 The distinction between the two can only be made after careful serial
examinations and appropriate investigations (see below). In contrast to other
hemangiomas, the hemangiomas in neonatal hemangiomatosis often involute
by 2 years of age.
differences than on historical nomenclature. Hepatic hemangiomas can be
entirely asymptomatic, but they often lead to hepatomegaly, high-output
congestive heart failure, anemia, and, occasionally, thrombocytopenia.
Although some authors have defined diffuse neonatal hemangiomatosis
as occurring in those who have three or more organ systems involved, a more
rational approach is to recognize that these infants represent a continuum
along a disease spectrum, with tremendous variability.Therefore, thorough
evaluation and close follow-up rather than numerical assignation of the
absolute number of organ systems involved is central in patient management.
After the liver, the most commonly involved organs are the lungs, gastrointestinal tract, and central nervous system (CNS). Complications include
hemorrhage, seizures, biliary obstruction with jaundice, and respiratory tract
obstruction. Mortality rates in widely disseminated hemangiomatosis are high,
reportedly as high as 95%, but a recent review of hepatic hemangiomatosis
found a mortality rate of approximately 20% using more current modalities
of treatment.41 Most infants who die from disseminated hemangiomatosis do
so because of high-output cardiac failure; however, some have succumbed to
CNS or pulmonary complications.42,43
Because of the serious consequences of visceral involvement, early
diagnostic studies are essential in young infants with multiple (five or more)
hemangiomas. Hepatic ultrasound should be performed in all such infants.
Other studies should include a complete blood count with platelet count,
fibrinogen level, urinalysis, liver function tests (if hepatic involvement is
found), and stool examination for blood. Electrocardiogram and chest
X-ray should be performed in patients with signs of congestive heart failure.
Liver and spleen scans, MR imaging or ultrasonography of the head, ophthalmologic examination, angiography, and gastrointestinal series or endoscopy
should be carried out if clinically indicated.44 Occasionally, asymptomatic
small hepatic lesions are detected with imaging studies, and in some cases
these hemangiomas will remain small without causing organ dysfunction.
Such infants always require close follow-up; while there are no clear guidelines
for managing this situation, decision making about whether to treat will
depend on evaluating the extent of disease and looking for more subtle signs
of organ dysfunction. For example, hepatic hemangio-mas may cause
increased hepatic arterial and venous flow (detectable by ultrasound) or cardiomegaly and tachycardia before frank congestive heart failure is evident. In
this case, therapy should be initiated as soon as possible.
If symptomatic visceral involvement is present, early aggressive therapy is
indicated. Systemic corticosteroids (prednisone 2 to 4mg/kg daily) have been
helpful in some patients, with digoxin and diuretics added when indicated
for congestive heart failure.41 The response rate of hepatic hemangiomas to
systemic corticosteroids seems to be lower than for cutaneous hemangiomas.41
Other therapies such as interferon alfa in doses of 3 × 106 IU/m2 per day or
vincristine (standard dosage not established but generally in the range
1–1.5mg/m2 or 0.05 to 0.65mg/kg intravenously weekly45 may be helpful if
corticosteroid therapy is not effective.When these measures fail to control
liver disease, partial hepatectomy, or hepatic artery ligation or embolization,
may also be helpful.44 Liver transplantation has also been used in severe
conditions that are unresponsive to other modalities of treatment.46
SIGNIFICANT BLEEDING
HEMANGIOMAS OF THE AIRWAY
Hemangiomas of the airway, which are usually subglottic in location, may
occur either with or without cutaneous hemangiomas. Large segmental
hemangiomas involving the mandibular area and neck have a risk as high as
60% of associated airway hemangiomas, and infants with this anatomic
distribution should be followed extremely closely, particularly during the
first 12 to 16 weeks of life.37 These hemangiomas often present with “noisy
breathing” or biphasic stridor.Airway involvement can be life threatening; if
symptoms are present, direct endoscopic visualization of the airway should
be performed. Prompt medical and/or surgical intervention is necessary if
symptomatic airway hemangioma is present.38 Temporary tracheostomy may
be necessary to manage rapidly growing airway hemangiomas.
DIFFUSE NEONATAL HEMANGIOMATOSIS
inactivation of thyroid hormone.47 A lingual thryoid, which can lead to
hypothyroidism, has also been reported in hemangiomas in association with
PHACE (posterior fossa, hemangioma, arterial anomalies, cardiac defects and
coarctation of the aorta, and eye) syndrome.48 Although the incidence of
hypothyroidism in association with hemangiomas is unknown, some authors
recommend performing thyroid function studies (including thyroidstimulating hormone) in all infants with hepatic and large cutaneous
hemangiomas.47
Association of hemangiomas with structural malformations
TABLE 20.4
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Although most hemangiomas occur without associated anomalies, at least two
well-defined hemangioma–malformation complexes have been described.
PHACE syndrome describes the association of large segmental hemangiomas
with a variety of structural anomalies.47,48 Affected patients (nearly always girls)
usually have one or two of the associated features rather than all components.49
In the past, PHACE syndrome has sometimes been confused with
Sturge–Weber syndrome (SWS), but careful examination reveals more differences than similarities (Table 20.4). In a small number of patients, the neurovascular abnormalities have led to progressive neurologic deterioration.50
Patients with large segmental facial hemangiomas should be examined
thoroughly for signs and symptoms of PHACE syndrome, including a careful
cardiac evaluation, cardiac ultrasound and/or measurement of blood pressure
in all four extremities (to exclude coarctation of the aorta), and careful periodic
developmental and neurologic assessments. If any neurologic symptoms arise,
patients should have MR imaging and angiography of the brain and cranial
circulation. In neurologically asymptomatic individuals, recommendations for
imaging are less straightforward, but cranial MR imaging and angiography
should probably be performed at some point to determine whether aneurysms
or other potentially worrisome arterial anomalies are present.49
A second constellation of structural malformations is seen in association
with hemangiomas overlying the lumbosacral spine (with or without a
segmental hemangioma of the lower extremity) (Fig. 20.11). The most
common malformation in this setting is a tethered spinal cord, often
accompanied by an occult lipomeningocele. Genitourinary anomalies, which
are less common, include imperforate anus, abnormal external genitalia, and
renal anomalies. Infants with a hemangioma overlying the lumbosacral area
and those with perianal hemangioma extending into the gluteal cleft should
have MR imaging performed to exclude possible tethered cord.51,52
AL
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Comparative differences between Sturge–Weber and PHACE syndromes
Sturge–Weber Syndrome
PHACE syndrome
Gender difference; inheritance
M = F; sporadic
F > M; sporadic
Type, character, and distribution of
cutaneous lesion; age of presentation
Port-wine stain (nevus flammeus),
V1 ± V2 and V3;usually unilateral
but can be bilateral; present at
birth; occasionally leptomeningeal
and eye findings can occur without
cutaneous stain
Hemangioma of the face, with segmental distribution,
usually plaque-type morphology (rarely nodular); most
commonly involves upper face and forehead but can
be any segment of face, unilateral or bilateral;
appearance within the first month of life usually with
precursor lesion present at birth;
Mucocutaneous complications
May have progressive soft tissue and
skeletal hypertrophy beneath the
malformation; gingival hypertrophy, epulis,
macrochelia (if also involves V2 or V3)
Commonly complicated by ulceration and soft-tissue
loss, especially if hemangioma involves the
nose and/or lip
Ocular abnormalities
Glaucoma (most common; 42%),
increased choroidal vascularity,
buphthalmos, homonymous
hemianopia, retinal detachment
Increased retinal vascularity, microphthalmia, optic
nerve hypoplasia, exophthalmos, choroidal
hemangiomas, strabismus, colobomas, congenital
cataracts, glaucoma (rare)
Central nervous system (CNS)
involvement
Vascular anomaly of the pia mater, often
with occipital distribution, over the entire
hemisphere or localized to temporal or
frontal areas; calcification of the temporal
and occipital cortex and/or within or
beneath abnormal vessels; cerebral atrophy
Posterior fossa malformations (especially of the
Dandy–Walker type) most common; also agenesis of the
corpus callosum, cerebellar atrophy, and arachnoid
cysts; cervicocranial arterial anomalies also common,
may be further complicated by aneurysm development
Association of CNS findings to
skin changes
Usually ipsilateral, occasionally contralateral,
and may be bilateral (in which bilateral
CNS involvement is more likely)
Not directly correlated, although “V1” distribution
may have somewhat greater risk of CNS disease
Neurologic findings
Seizures usually begin prior to age 2 but
may be delayed until later in childhood;
mental retardation and hemiplegia are
fairly common; CNS involvement may be
progressive, with worsening of seizures
and deterioration of intellect; migraine
headaches are also common
Structural or cerebrovascular anomalies of the brain may
manifest as acute neurologic symptoms (severe
headaches and/or seizures) or developmental delay;
acute neurologic symptoms, which may be delayed in
onset, may be a sign of aneurysm formation within the
affected vasculature; many patients are neurologically
asymptomatic
47. Huang SA, Tu HM, Harney JW et al. (2000) Severe hypothyroidism caused by type 3
iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 343:185–189.
48. Frieden IJ, Reese V, Cohen D (1996) PHACE syndrome. The association of posterior fossa brain
malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects,
and eye abnormalities. Arch Dermatol 132:317–311.
49. Metry DW, Dowd CF, Barkovich AJ et al. (2001) The many faces of PHACE syndrome. J Pediatr
139:117–23.
50. Burrows PE, Robertson RL, Mulliken JB et al. (1998) Cerebral vasculopathy and neurologic
sequelae in infants with cervicofacial hemangioma: report of eight patients. Radiology
207:601–607.
51. Goldberg NS, Hebert AA, Esterly NB (1986) Sacral hemangiomas and multiple congenital
abnormalities. Arch Dermatol 122:684–687.
52. Albright AL, Gartner JC, Wiener ES (1989) Lumbar cutaneous hemangiomas as indicators of
tethered spinal cords. Pediatrics 83:977–980.
Vascular tumors
Management of hemangiomas of infancy
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The management of hemangiomas continues to be an area of considerable
controversy.53 Estimates of what percentage of hemangiomas require active
treatment and which can be allowed to involute spontaneously without
intervention vary widely, at least in part because of ascertainment bias.
Hemangiomas are extremely heterogeneous in location, size, and growth characteristics. In the primary care setting, most hemangiomas seen are small and
innocuous, and, in many cases, the results of spontaneous involution are
superior to those obtained with excisional or laser surgery. For these patients,
observation, reassurance, and frequent visits every few weeks during the
period of rapid growth are the mainstays of management.54 Unfortunately,
when the hemangioma is in a visible location, families are frequently
bombarded with stares, rude comments, accusations of child abuse, and
unsolicited advice.55 The natural history of hemangiomas should be described
in detail to the parents, with photographs of other patients (if possible) to
illustrate the involutional process.To varying degrees, all families of children
with hemangiomas need emotional support and information. For those not
receiving a specific treatment, extra support may be needed to bolster the
rationale for not actively treating, such as photographs and discussions
emphasizing that, for some hemangiomas, the final result in an untreated
lesion may be superior to that obtained with aggressive therapeutic intervention. A multidisciplinary approach, with dermatologists, surgeons, and
other health professionals, may also be helpful.25
Even once a decision to treat has been made, the specific treatment(s) used
depends on the age of the patient, location and depth of the lesion within
the skin (superficial or deep), expertise of the treating physician, and parental
preferences.The most commonly used treatments for hemangiomas include
corticosteroids (systemic, intralesional, and topical), pulsed dye laser (PDL),
interferon alfa, and surgical excision. Other less-common treatment modalities
include cryotherapy, other forms of laser surgery, embolization, and chemotherapeutic agents such as vincristine and cyclophosphamide.56
prednisone, in doses of 2 to 4mg/kg per day as a single morning dose, is the
most common regimen used57, although some investigators have recommended even higher doses.58–60 Response is usually seen within 2 to
4 weeks, but often within days of initiating therapy. Once the hemangioma
has stabilized, the medication may be tapered, but the duration of treatment
needed varies from a few weeks to many months depending on the age of
the child, the indications for treatment, and the growth characteristics of the
hemangioma being treated. Rapid tapering can lead to rebound growth.57
Some experts favor switching to alternate-day therapy when the dosage
reaches approximately 1mg/kg per day, in order to minimize effects on
somatic growth and to help adrenal recovery. In addition, the degree of
observed fluctuation of the hemangioma (i.e., whether there is an apparent
increase in size on the “off ” day) can sometimes be helpful in gauging how
quickly to taper the medication.
Corticosteroids are most effective when initiated during the first 6 months
of life, when the hemangioma is in its most rapid proliferative stage, but in
some cases they can be effective later in infancy.As a corollary, discontinuation
is more likely to result in rebound growth in younger patients.A recent metaanalysis of the efficacy of corticosteroids for the treatment of cutaneous
hemangiomas found that nearly 90% responded (defined as the cessation
of growth and/or shrinkage of the hemangioma) to treatment,57 and that a
daily dosage of 3mg/kg seemed more optimal than 2mg/kg. For unknown
reasons, hemangiomas involving the liver and other extracutaneous sites,
and those associated with the Kasabach–Merritt phenomenon (KMP; now
known to be caused by vascular tumors other than hemangioma of infancy),
appear to have a lower rate of response.41,61
There are many potential side effects of systemic corticosteroids.The most
common are irritability and gastrointestinal upset, which can sometimes be
helped by the concomitant administration of a histamine H2 blocker such as
ranitidine. Other reported side effects include hypertension, growth retardation, rapid weight gain, and immunosuppression.62 Less-commonly reported
adverse effects include decreased head growth, delayed motor milestones,
hirsutism, and premature thelarche.63 Despite the risks of administering high
doses of corticosteroids to young infants, most treated infants do very well,
and catch-up growth nearly always occurs after cessation of therapy.62
AL
Fig. 20.11 Perianal and
lumbosacral hemangioma.
This infant had an
associated tethered spinal
cord.
841
SYSTEMIC CORTICOSTEROIDS
Systemic corticosteroids have been a mainstay of therapy of hemangiomas
since the 1960s, when their efficacy was first recognized.Their mechanism
of action in treating hemangiomas is poorly understood. Prednisolone or
53. Special (1997) Symposia. Management of hemangiomas. Pediatr Dermatol 14:57–83.
54. Frieden IJ (1997) Which hemangiomas to treat – and how? Arch Dermatol 133:1593–1595.
55. Tanner JL, Dechert MP, Frieden IJ (1998) Growing up with a facial hemangioma: parent and child
coping and adaptation. Pediatrics 101:446–452.
56. Frieden IJ, Eichenfield LF, Esterly NB et al. (1997) Guidelines of care for hemangiomas of infancy.
American Academy of Dermatology Guidelines/Outcomes Committee. J Am Acad Dermatol
37:631–637.
57. Bennett ML, Fleischer AB, Chamlin SL et al. (2001) Oral corticosteroids are effective for
cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol 137:1208–1213.
58. Akyuz C, Yaris N, Kutluk MT et al. (2001) Management of cutaneous hemangiomas: a
retrospective analysis of 1109 cases and comparison of conventional dose prednisolone with
high-dose methylprednisolone therapy. Pediatr Hematol Oncol 18:47–55.
INTRALESIONAL CORTICOSTEROIDS
Most reports of intralesional corticosteroids were initially seen in the ophthalmologic literature, but this treatment has received growing recognition
for well-localized hemangiomas. Paradoxically, the injections have become
less popular among ophthalmologists because of the small risk of retinal
embolization of particulate matter, which in rare cases has resulted in blindness
(either ipsilateral or contralateral).This embolization is likely to be caused
by injection pressures exceeding the level of systemic blood pressure.64
Intralesional corticosteroid usage in other sites can be effective for hemangiomas, especially those that are actively growing and that are small enough
to distribute the medication relatively evenly throughout the hemangioma.
Doses should not exceed a maximum of 3–5mg/kg triamcinolone per treatment session (to a maximum of 20mg). Several treatments, spaced at monthly
intervals, may be necessary, but response rates as high as 85% have been
reported.65 Potential adverse reactions include cutaneous atrophy, anaphylaxis,
bleeding, infection, cutaneous necrosis, and adrenal suppression, but the
injections are usually well tolerated.
59. Ozsoylu S (1996) Megadose methylprednisolone therapy for Kasabach–Merritt syndrome.
J Pediatr 129:947–948.
60. Sadan N, Wolach B (1996) Treatment of hemangiomas of infants with high doses of prednisone.
J Pediatr 128:141–146.
61. Enjolras O, Riche MC, Merland JJ et al. (1990) Management of alarming hemangiomas in infancy:
a review of 25 cases. Pediatrics 85:491–498.
62. Boon LM, MacDonald DM, Mulliken JB (1999) Complications of systemic corticosteroid therapy
for problematic hemangioma. Plast Reconstr Surg 104:1616–1623.
63. Blei F, Chianese J (1999) Corticosteroid toxicity in infants treated for endangering hemangiomas:
experience and guidelines for monitoring. Int Pediatr 14:146–153.
64. Egbert JE, Paul S, Engel WK et al. (2001) High injection pressure during intralesional injection of
corticosteroids into capillary hemangiomas. Arch Ophthalmol 119:677–683.
65. Chen MT, Yeong EK, Horng SY (2000) Intralesional corticosteroid therapy in proliferating head
and neck hemangiomas: a review of 155 cases. J Pediatr Surg 35:420–423.
TOPICAL CORTICOSTEROIDS
Superpotent, topical corticosteroids have anecdotally been reported as
being effective in relatively small, superficial hemangiomas.66,67 They may be
considered for treatment of very early hemangiomas that are not causing
overt functional impairment and are small and superficial enough to allow
adequate percutaneous penetration of the medication. Potential risks of this
treatment include cutaneous atrophy and systemic absorption affecting the
hypothalamic–pituitary axis.
RECOMBINANT INTERFERON ALFA
SURGERY
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Recombinant interferon alfa, an inhibitor of angiogenesis, has been used
successfully in the treatment of endangering hemangiomas. Both the 2a and
2b forms have been used with apparently equal success.68,69 The usual dosage
is 3 × 106 IU/m2 per day as a subcutaneous injection, although lower dosages
at less frequent intervals have also been reported.70 Interferon alfa often
improves severe hemangiomas that have not responded to high doses of corticosteroids, but unfortunately, the discovery of serious neurotoxicity has
limited its use. In one report, as many as 20% of infants developed spastic
diplegia, which was irreversible in several of those treated.71 Others have
reported less frequent neurotoxicity, but regular monitoring is advised, not
only for neurotoxicity but also for the relatively common side effects, which
include irritability, neutropenia, and liver enzyme abnormalities.72 Because
of the risk of neurotoxicity, this medication should be used only in severe
hemangiomas causing functional impairment or serious soft tissue damage
where high-dose corticosteroids have failed or cannot be tolerated.
necessary for larger defects. A purse-string type closure has recently been
shown to minimize scar length and give improved results for exophytic focal
hemangiomas.74 Laser surgery (see below) may be helpful for removing
residual erythema and superficial telangiectases.
Several kinds of laser have been used to treat hemangiomas.The PDL has
been used since the early 1990s and several case series have emphasized its
use in the treatment of superficial hemangiomas as well as for residual lesions
after involution.75,76 Treatment of an actively growing hemangioma is typically
performed every 2 to 3 weeks until control of proliferation has been achieved.
Although this modality has a low risk of scarring when used for treating portwine stains, there is anecdotal evidence that it may cause ulceration and
scarring when used for treating hemangiomas.77 Paradoxically, PDL has also
been used successfully for treating ulcerated hemangiomas, resulting in
decreased pain and possibly accelerating reepithelialization.34 Deep hemangiomas are not effectively treated with PDL because of its limited depth of
penetration. Other laser systems including intralesional bare-fiber Nd-YAG
(neodymium–yttrium aluminum garnet) have been used for this purpose
and appear to be effective, but with some risk of cutaneous ulceration and
scarring.78
Sclerosing agents and embolization may be helpful in serious, lifethreatening hemangiomas. They are not used for routine management.
Cryotherapy has been used successfully to treat hemangiomas and is popular
in some parts of Europe and South America.79,80 The risks of scarring,
hypopigmentation and epidermal atrophy have limited the popularity of this
modality in the USA. Radiation therapy, a treatment option of the past, is no
longer considered an acceptable therapeutic modality unless there are lifethreatening complications, because of the risk of effects on bone growth
and/or late complications such as carcinogenesis.
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Indications for surgical removal of hemangiomas can be divided into those
appropriate in early infancy and those to be considered later in the course
of the hemangioma, usually after 3 or 4 years of age. Early surgical intervention should be considered for sharply demarcated and localized exophytic
and pedunculated hemangiomas, which have such a prominent dermal
component that they are extremely likely to leave permanent skin changes
after involution. Other reasonable indications include those with ulceration
and bleeding that are unresponsive to other modalities of treatment and upper
eyelid hemangiomas that have not responded to pharmacologic therapy.8,73
Surgery can also be considered for children between the ages of 3 and
5 years who continue to have prominent and disfiguring hemangiomas. At
this age, enough involution has usually occurred to make the ultimate
outcome more predictable (although there are exceptions). Moreover, children
at this age are becoming aware of facial differences, and some begin to develop
low self-esteem because of their hemangioma.The potential surgical scar must
be weighed against the child’s emotional distress, as well as the likely outcome
if the lesion was left to involute spontaneously. Excision at this age should be
seriously considered if resection will be inevitable at some point, if the result
of surgery will ultimately be the same whether or not excision is postponed,
and in situations where the scar can be easily hidden.8 In cases with a high
degree of uncertainly, it may be best to postpone surgery until later in childhood, in order to allow maximal involution prior to determining how much
skin needs to be removed. A multidisciplinary vascular anomalies team can
be helpful in decision-making in these cases. Staged resections may be
66. Elsas FJ, Lewis AR (1994) Topical treatment of periocular capillary hemangioma. J Pediatr
Ophthalmol Strabismus 31:153–156.
67. Cruz OA, Zarnegar SR, Myers SE (1995) Treatment of periocular capillary hemangioma with
topical clobetasol propionate. Ophthalmology 102:2012–2015.
68. Ezekowitz RA, Mulliken JB, Folkman J (1992) Interferon alfa-2a therapy for life-threatening
hemangiomas of infancy. N Engl J Med 326:1456–1463.
69. Chang E, Boyd A, Nelson CC et al. (1997) Successful treatment of infantile hemangiomas with
interferon-alpha-2b. J Pediatr Hematol Oncol 19:237–244.
70. Rampini E, Rampini P, Occella C, Bleidl D (2000) Interferon alpha 2b for treatment of
complex cutaneous haemangiomas of infancy: a reduced dosage schedule. Br J Dermatol
142:189–191.
71. Barlow CF, Priebe CJ, Mulliken JB et al. (1998) Spastic diplegia as a complication of interferon
Alfa-2a treatment of hemangiomas of infancy. J Pediatr 132:527–530.
72. Dubois J, Hershon L, Carmant L et al. (1999) Toxicity profile of interferon alfa-2b in children: A
prospective evaluation. J Pediatr 135:782–785.
OTHER VASCULAR TUMORS
Congenital hemangiomas
At least two, possibly three types of fully formed congenital hemangioma have
been described; although their relationships to one another are not completely
understood, they appear to be distinct entities that are not part of the spectrum
of hemangiomas of infancy.
Rapidly involuting congenital hemangiomas
Rapidly involuting congenital hemangiomas, as described by Boon et al.,18
typically present as raised violaceous tumors with ectatic veins (Fig. 20.12),
raised grayish tumors with overlying telangiectasias surrounded by a pale rim
of vasoconstriction (Fig. 20.13), or as flat infiltrative tumors with violaceous
overlying skin.They vary in size but are often several centimeters in diameter,
sometimes even larger.They are frequently warm and occasionally have bruits
or even a palpable thrill. In addition to their distinctive appearance, their
behavior also differs from hemangiomas of infancy.They do not grow rapidly
after birth and many involute extremely rapidly, completing involution by
12–18 months of age.
North et al. have described the pathologic features of fully formed vascular
tumors, so-called congenital nonprogressive hemangiomas, which share
many of the clinical features of rapidly involuting congenital hemangiomas.19
73. Aldave AJ, Shields CL, Shields JA (1999) Surgical excision of selected amblyogenic periorbital
capillary hemangiomas. Ophthalmic Surg Lasers 30:754–757.
74. Mulliken JB, Rogers GF, Marler JJ (2001) Circular excision of hemangioma and purse-string
closure - the shortest possible scar. Plast Reconstr Surg in press.
75. Hohenleutner S, Badur-Ganter E, Landthaler M et al. (2001) Long-term results in the treatment of
childhood hemangioma with the flashlamp-pumped pulsed dye laser: an evaluation of 617 cases.
Lasers Surg Med 28:273–277.
76. Haywood RM, Monk BE, Mahaffey PJ (2000) The treatment of early cutaneous capillary
haemangiomata (strawberry naevi) with the tunable dye laser. Br J Plast Surg . 53:302–307.
77. Waner M, Adams D, North P et al. (2000) A rare complication of pulsed dye laser treatment of
hemangiomas. In: 13th International Workshop of Vascular Anomalies, Montreal 2000.
78. Achauer BM, Celikoz B, VanderKam VM (1998) Intralesional bare fiber laser treatment of
hemangioma of infancy. Plast Reconstr Surg 101:1212–1217.
79. Cremer H (1998) Cryosurgery for hemangiomas. Pediatr Dermatol 15:410–411.
80. Reischle S, Schuller-Petrovic S (2000) Treatment of capillary hemangiomas of early childhood with
a new method of cryosurgery. J Am Acad Dermatol 42:809–813.
Vascular tumors
843
Fig. 20.14 Noninvoluting congenital
hemangioma.
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Fig. 20.12 Rapidly
involuting congenital
hemangioma.
Fig. 20.13 Rapidly
involuting congenital
hemangioma.
dominantly dilated, often dysplastic, veins; arteries are also increased in
number.Tests for GLUT-1 are negative.These lesions do not involute over
time but are usually easily excised without risk of recurrence.
Lobular capillary hemangioma
The pathologic findings of these tumors include cellular lobules with
mitotically active capillaries set within a densely fibrotic stroma containing
deposits of hemosiderin; focal lobular thrombosis and sclerosis; and frequent
association of proliferating lobules with large, thin-walled vessels.The lack of
immunoreactivity to GLUT-1 and LeY antigens is also evidence that these
tumors are not hemangiomas of infancy.
Another recently described tumor is the noninvoluting congenital
hemangioma.81 These vascular tumors are also fully formed at birth,
occurring slightly more often in male patients, and always appearing as a
solitary tumor.Typical lesions are round-to-ovoid in shape, plaque-like or
bossed, with central or peripheral pallor as well as coarse, overlying telangiectases (Fig. 20.14). Lesions vary in size, from a few centimeters to 10–15cm,
with an average diameter of 5cm. Most have palpable warmth with a
component of fast arterial flow that can be demonstrated by Doppler ultrasonography. Pathology typically reveals lobular collections of small, thin-walled
vessels with a large, often stellate, central vessel. Interlobular areas contain pre-
Lobular capillary hemangioma (pyogenic granuloma) is one of the most
common vascular tumors in children, second in frequency to hemangioma
of infancy. Lesions can be seen at any age but the majority occur during
childhood.82,83 Pyogenic granulomas may be seen in the early weeks of life
though umbilical. Onset during the first year of life is less common but by
no means rare, and the tumor is sometimes misdiagnosed at this time as
hemangioma of infancy, with false reassurances of spontaneous involution.84
Pyogenic granulomas may be seen, in the early weeks of life, affecting the
umbilicus. Pyogenic granulomas usually present as rapidly growing, bright
red papules varying in size from a few millimeters up to 2cm (Fig. 20.15,16).
They may have an intact overlying epidermis but frequently become
ulcerated. Lesions may be pedunculated and often have a collarette of scale
at their periphery.The head and neck are the most common locations, but
lesions can occur at any site including mucosal surfaces.While the occurrence
of pyogenic granulomas seems to be more frequent in males, females have a
much higher frequency of mucosal pyogenic granulomas.82,83 In contrast to
hemangioma of infancy, pyogenic granulomas often bleed repeatedly and
profusely, even with very superficial ulceration, prompting this to be called
the “Band-Aid disease.”9 In a minority of patients, there is an antecedent
history of trauma prior to onset. Pyogenic granulomas usually arise de novo
but can develop on the surface of a preexisting vascular malformation.As the
revised nomenclature suggests, the pathology of pyogenic granuloma is neither
pyogenic nor granulomatous but rather consists of a lobular capillary
hemangioma.82 So-called umbilical granulomas, seen commonly in neonates,
are similar in clinical appearance to pyogenic granulomas.Their histology is
not well described but their response to silver nitrate treatment suggests that
they are probably more similar to granulation tissue rather than a true lobular
capillary hemangioma. More persistent “umbilical granulomas” are the result
of omphalomesenteric duct cysts and other remnants of the umbilicus.
The management of pyogenic granuloma depends on the location and size.
Most small pyogenic granulomas can be removed by shave excision with
curettage and light electrodesiccation to the base of the lesion. If the base of
the lesion is small, this usually leaves an acceptable scar. PDL has been reported
81. Enjolras O, Mulliken JB, Boon LM et al. (2001) Noninvoluting congenital hemangioma: a rare
cutaneous vascular anomaly. Plast Reconstr Surg 107:1647–1654.
82. Harris MN, Desai R, Chuang TY et al. (2000) Lobular capillary hemangiomas: An epidemiologic
report, with emphasis on cutaneous lesions. J Am Acad Dermatol 42:1012–1016.
83. Patrice SJ, Wiss K, Mulliken JB (1991) Pyogenic granuloma (lobular capillary hemangioma): a
clinicopathologic study of 178 cases. Pediatr Dermatol 8:267–276.
84. Frieden IJ, Esterly NB (1992) Pyogenic granulomas of infancy masquerading as strawberry
hemangiomas. Pediatrics 90:989–991.
844
Fig. 20.15 Pyogenic
granuloma (lobular
capillary hemangioma).
Fig. 20.17
angioma.
Tufted
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including solitary tumors, large infiltrated plaques (Fig. 20.17), sometimes
having increased lanugo hair, and “port-wine stain-like” areas with a cobblestone surface.87 The characteristic histology is of vascular tufts of tightly
packed capillaries dispersed throughout the dermis in a cannonball pattern.
Cleft-like lumina are often present at the periphery of the vascular lobules.88
Some patients with onset of tufted angioma in early infancy develop the
Kasabach–Meritt phenomenon (KMP) (see below), and the histology can
also be evident in patients with residual tumor following resolution of the
KMP.The natural history of tufted angioma is less predictable than that of
hemangioma of infancy. Some cases resolve, leaving only minor cutaneous
changes whereas others persist and expand over time.
Fig. 20.16 Pyogenic
granuloma (lobular
capillary hemangioma).
Kaposiform hemangioendothelioma (KHE) is a rare, distinctive neoplasm that
can occur in the skin but has also been reported as a retroperitoneal tumor.89
It is frequently associated with the KMP (Fig. 20.18). Affected infants have
either a congenital tumor or develop a lesion soon after birth and 75% of
KHE occurs in early infancy. In rare cases, the tumor arises within a preexisting lymphatic malformation.89,90 Histologic examination reveals densely
infiltrating nodules composed of spindled cells with minimal atypia and
infrequent mitoses, as well as slit-like vessels containing hemosiderin.91 Rare
cases of KHE without a consumption coagulopathy have also been reported.92
Kasabach–Merritt phenomenon
to be effective in many patients,85 but other authors have found this modality
to be disappointing.83 Excisional surgery, carbon dioxide laser, and cryotherapy
have also been used to treat pyogenic granulomas. Estimates of recurrence
after removal vary, but recurrence is probably greater with larger lesions. A
more worrisome, but rare, complication is the development of multiple
satellite lesions after initial removal.
Tufted angioma
Tufted angioma, also known as angioblastoma of Nakagawa, is an uncommon
vascular tumor that usually has its onset during infancy or early childhood
but rarely can be congenital.86 Various presentations have been described,
85. Tay YK, Weston WL, Morelli JG (1997) Treatment of pyogenic granuloma in children with the
flashlamp-pumped pulsed dye laser. Pediatrics 99:368–370.
86. Igarashi M, Oh-i T, Koga M (2000) The relationship between angioblastoma (Nakagawa) and
tufted angioma: report of four cases with angioblastoma and a literature-based comparison of
the two conditions. J Dermatol 27:537–542.
87. Okada E, Tamura A, Ishikawa O et al. (2000) Tufted angioma (angioblastoma): case report and
review of 41 cases in the Japanese literature. Clin Exp Dermatol 25:627–630.
88. Weiss SW, Goldblum JR (2001) Benign tumors and tumor-like lesions of blood vessels. In: Soft
Tissue Tumors, Weiss EA, ed. St Louis: Mosby, pp. 837–890.
89. Zukerberg LR, Nickoloff BJ, Weiss SW (1993) Kaposiform hemangioendothelioma of infancy and
childhood. An aggressive neoplasm associated with Kasabach–Merritt syndrome and
lymphangiomatosis. Am J Surg Pathol 17:321–328.
KMP was first described in 1940.Although originally believed to be a complication of hemangioma of infancy, it is virtually always a complication of
other vascular tumors, particularly tufted angioma and KHE.91,93,94 The
clinical features, which can occasionally be present at birth, more commonly
appear in the first few months of life, with the development of tenderness,
rapid growth, and bruising in a growing soft-tissue tumor (Fig. 20.18A).The
central features are a consumption coagulopathy with very low platelet counts
and low fibrinogen levels. Other hematologic abnormalities may also be
present including elevated D-dimers, prothrombin time and partial thromboplastin time, as well as hemolytic anemia.95 KMP should not be confused
with the coagulopathy that may occur in the setting of a large venous or
mixed malformation.The coagulopathy associated with malformations usually
has a later onset and is characterized by consumption of clotting factors and
elevated D-dimers, but the platelet count and fibrinogen level are generally
not as low as seen in KMP (Table 20.5).
90. Vin-Christian K, McCalmont TH, Frieden IJ (1997) Kaposiform hemangioendothelioma. An
aggressive, locally invasive vascular tumor that can mimic hemangioma of infancy. Arch Derm
133:1573–1578.
91. Alvarez-Mendoza A, Lourdes TS, Ridaura-Sanz C et al. (2000) Histopathology of vascular lesions
found in Kasabach–Merritt syndrome: review based on 13 cases. Pediatr Dev Pathol 3:556–560.
92. Weiss SW, Goldblum JR (2001) Hemangioendothelioma: vascular tumors of intermediate
malignancy. In: Soft Tissue Tumors, Weiss EA, ed. St Louis: Mosby, pp. 891–915.
93. Enjolras O, Wassef M, Mazoyer E et al. (1997) Infants with Kasabach–Merritt syndrome do not
have “true” hemangiomas. J Pediatr 130:631–640.
94. Sarkar M, Mulliken JB, Kozakewich HP et al. (1997) Thrombocytopenic coagulopathy
(Kasabach–Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not
with common infantile hemangioma. Plast Reconstr Surg 100:1377–1386.
95. Hall GW (2001) Kasabach–Merritt syndrome: pathogenesis and management. Br J Haematol
112:851–862.
Vascular malformations
Fig. 20.18 Kaposiform
hemangioendothelioma.
(A) The
hemangioendothelioma
with associated
Kasabach–Merritt
phenomenon.
(B) At age 7 residual tumor
and lymphedema is still
present.
A
845
X-ray irradiation is reserved for truly life-threatening disease but should
be avoided if possible because of its effects on growth and future risk of
malignancy.95,100 Although supportive therapies such as transfusions and
infusions of fibrinogen and fresh-frozen plasma may be helpful, platelet
transfusions should be avoided except before surgical procedures or if active
bleeding is occurring, since the platelets are consumed extremely rapidly and
can cause enlargement of the tumor and worsening of the condition.101
Heparin therapy, which can be helpful in the consumption coagulopathy
seen with vascular malformations, is ineffective and can worsen bleeding. Even
with current management, the mortality of KMP may be as high as 20%.
Residual lesions after resolution of the coagulopathy are relatively common
(Fig. 20.18B).They include areas of vascular staining resembling port-wine
stains, fibrotic areas of skin, actual tumor mass, or areas of swelling.102
Spindle-cell hemangioendothelioma
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Spindle-cell hemangioendothelioma is a rare vascular tumor that is most often
found on the extremities. It can be associated with Maffucci syndrome103 (see
below) or may arise in conjunction with a preexisting vascular malformation.
Although originally believed to be a low-grade angiosarcoma, it is now
thought to represent a reactive vascular tumor arising in conjunction with
malformed vasculature.104,105 Surgical excision is the only known effective
therapy.
Congenital eccrine angiomatous hamartoma
Congenital eccrine angiomatous hamartoma (sudoriparous angioma) is a rare
entity that can present at birth, during infancy, or in early childhood; it is a
large, ill-defined vascular plaque, with increased hairs and sweating at the
site of the lesion.106,107 The extremities and abdomen are the usual sites
of involvement. Pain may be present. The diagnosis is established by the
characteristic histologic findings of closely packed eccrine sweat glands in
association with dilated capillaries and venous channels within a dense
collagenous matrix.
Infantile hemangiopericytoma is a rare tumor that is now considered to be
a form of infantile myofibromatosis rather than a true vascular tumor.
VASCULAR MALFORMATIONS
B
The management of KMP must include a multidisciplinary approach,
involving pediatricians, hematologists, dermatologists, and, where appropriate,
surgeons and interventional radiologists.96,97 In contrast to hemangioma of
infancy, corticosteroids alone are rarely effective as a sole treatment modality,
but they are still often used as a first-line therapy. Surgical excision of
the tumor is an effective treatment but is rarely feasible.98 The addition of
interferon alfa has been helpful in some patients, but it is by no means
uniformly effective. Recently, vincristine 1–1.5mg/m2 or 0.05–0.65mg/kg
intravenously weekly has been demonstrated to be a highly effective treatment, although relapses may require repeat treatment.99 Other reportedly
effective treatments include aspirin with either ticlopidine or dipyramidole,
ε-aminocaproic acid, pentoxifylline (oxpentifylline), and arterial embolization.
96. Shin HY, Ryu KH, Ahn HS (2000) Stepwise multimodal approach in the treatment of
Kasabach–Merritt syndrome. Pediatr Int 42:620–624.
97. Blei F, Karp N, Rofsky N et al. (1998) Successful multimodal therapy for kaposiform
hemangioendothelioma complicated by Kasabach–Merritt phenomenon: case report and review
of the literature. Pediatr Hematol Oncol 15:295–305.
98. Drolet BA, Scott LA, Esterly NB et al. (2001) Early surgical intervention in a patient with
Kasabach–Merritt phenomenon. J Pediatr 138:756–758.
99. Haisley-Royster CA, Enjolras O, Frieden IJ et al. (2002) Kasabach–Merritt phenomenon: a
retrospective study of treatment with vincristine. J Pediatr Hematol Oncol 24:459–462.
100. Ogino I, Torikai K, Kobayasi S et al. (2001) Radiation therapy for life- or function-threatening
infant hemangioma. Radiology 218:834–839.
101. Phillips WG, Marsden JR (1993) Kasabach–Merritt syndrome exacerbated by platelet transfusion.
J R Soc Med 86:231–232.
Vascular malformations are composed of anomalous blood vessels and/or
lymphatics lined by a quiescent endothelium without cellular hyperplasia.2
Although it is believed that all vascular malformations are present at birth,
most are evident in infancy. A minority appear in childhood or later, after a
dormant phase, as “acquired” vascular anomalies. Depending on their flow
characteristics, vascular malformations are defined as either slow flow or
fast flow.The slow-flow anomalies include capillary, venous, and lymphatic
malformations and combinations thereof. Arterial aneurysms or arteriovenous malformations (AVMs) with arteriovenous shunting are the fast-flow
anomalies.9 Vascular malformations persist lifelong, unchanged, growing proportionate to the child’s growth, or, in some cases, worsening and expanding.
They never regress spontaneously but only rarely go through a rapid growth
phase such as is seen with hemangiomas of infancy. Growth in vascular malformations may be stimulated by trauma, clotting, the effects of hormones
during puberty and/or pregnancy, or may occur in the absence of any known
triggering factor.
102. Enjolras O, Mulliken JB, Wassef M et al. (2000) Residual lesions after Kasabach–Merritt
phenomenon in 41 patients. J Am Acad Dermatol 42:225–235.
103. Pellegrini AE, Drake RD, Qualman SJ (1995) Spindle cell hemangioendothelioma: a neoplasm
associated with Maffucci’s syndrome. J Cutan Pathol 22:173–176.
104. Fletcher CD (1996) Vascular tumors: an update with emphasis on the diagnosis of angiosarcoma
and borderline vascular neoplasms. Monogr Pathol 38:181–206.
105. Perkins P, Weiss SW (1996) Spindle cell hemangioendothelioma. An analysis of 78 cases with
reassessment of its pathogenesis and biologic behavior. Am J Surg Pathol 20:1196–1204.
106. Nakatsui C, Schloss E, Krol A et al. (1999) Eccrine angiomatous hamartoma: report of a case and
literature review. J Am Acad Dermatol 41:109–111.
107. Requena L, Sangueza OP (1997) Cutaneous vascular anomalies. Part I. Hamartomas,
malformations, and dilation of preexisting vessels. J Am Acad Dermatol 37:523–549.
846
TABLE 20.5 Differences between Kasabach–Merritt syndrome and coagulopathy associated with vascular malformations (usually venous
malformation or lymphatic–venous malformation)
Kasabach–Merritt syndrome
Vascular malformations-associated local or disseminated intravascular coagulation
Ages
Birth and infancy: growth of the tumor;
onset of coagulopathy; childhood: cure of
coagulopathy, residual tumor
Lifelong biologic process of localized intravascular coagulopathy (LIC) with flares and
risk of disseminated intravascular coagulopathy (DIC)
Clinical features
Congenital or early-onset plaque or tumor
followed by a distinctive ecchymotic,
inflammatory, painful mass; purpura, bruises;
visceral hemorrhages are rare
Occurs mainly with extensive limb or trunk venous malformations and, very rarely,
with head-and-neck venous malformations; plaques, patches, masses of blue vascular
anomalies, soft, compressible; swelling when dependent, pain; normal temperature;
phleboliths
Hematology
Severe thrombocytopenia (often
< 5000 × 106 cells/l); low fibrinogen, elevated
D-dimers
Mild thrombocytopenia (> 80 000 × 106 cells/l); very high D-dimers; low fibrinogen;
von Willebrand deficiency in some patients
Course
Acute, sudden; involution of the tumor
occurs subsequently
Vascular malformation persists and slowly worsens lifelong; coagulopathy may also
worsen
Pathology
Vascular tumor: either kaposiform
hemangioendothelioma or tufted angioma
(occasionally associated with lymphatic
malformation)
Vascular malformation: usually venous malformation (sometimes lymphatic and
venous malformation)
Radiodiagnostic
Doppler: high-flow; MRI: parenchymal
tumoral signal and flow voids
Doppler: slow-flow; MRI: hypersignal on T2-weighted image; radiograph: phleboliths
Treatment
Heparin ineffective; a number of drugs have
been useful including: corticosteroids,
interferon alfa, vincristine and ticlopidine
plus aspirin (see text)
The most effective treatment is low-molecular-weight heparin; compressive stockings
for extremity lesions
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Differences
Although some progress in the understanding of the pathogenesis of vascular
malformations has been made, the precise origin of most is not known.They
are presumed to be errors in blood vessel development most likely caused by
localized dysfunction in pathways regulating vascular embryogenesis, especially
the molecular events responsible for vascular remodeling.108 The study of rare
families with Mendelian inheritance of their vascular malformations has
enhanced our understanding of molecular genetics in this field.109 Mutant
genes responsible for familial venous malformations, glomangiomas,
lymphedema, cerebral cavernomas, hereditary hemorrhagic telangiectasia
(HHT), and ataxia-telangiectasia have been identified.The functions of these
mutations, and how they affect signaling pathways between endothelial cells
and other mural cells, are currently being investigated. It is hoped that a better
understanding of pathogenesis as well as new treatment modalities may arise
from such research.
Cutaneous AVMs usually present as a faint stain in childhood, expanding
at or after puberty. Hormonal changes and trauma are known to trigger
growth. Many head and neck AVMs are located at so-called “choke zones,”
representing the anastomotic junction of two arterial blood supplies. It has
been hypothesized that their occurrence in these areas as well as their growth
in response to trauma may be a consequence of their vulnerability to
oxidative stress.110 The cells cultured from skin AVMs differ from normal
endothelial cells in culture, demonstrating higher rates of proliferation with
lack of inhibition by known angiogenic inhibitors, such as interleukin 1β,
tumor necrosis factor α, interferon-γ, and transforming growth factor β, and
a lack of expression of leukocyte adhesion molecules; they also express the
108. Chiller KG, Arbiser J, Frieden IJ (2001) Vasculogenesis and Angiogenesis in the Development of
Cutaneous Vascular Birthmarks. Submitted.
109. Vikkula M, Boon LM, Mulliken JB (1998) Molecular basis of vascular anomalies. Trends
Cardiovasc Med 8:281–292.
110. Mitchell EL, Taylor GI, Houseman ND et al. (2001) The angiosome concept applied to
arteriovenous malformations of the head and neck. Plast Reconstr Surg 107:633–646.
111. Wautier MP, Boval B, Chappey O et al. (1999) Cultured endothelial cells from human
arteriovenous malformations have a defective growth regulation. Blood 94:2020–2028.
proto-oncogene c-ets-1.111 Brain AVMs have been studied more extensively.
Cerebral AVMs express basic fibroblast growth factor in the endothelium and
subendothelium, as well as in the brain tissue intermingled within the
AVM.112 Capsase-3 immunoreactivity has been detected in the endothelium,
media, and perivascular tissue of CNS AVMs, indicating that apoptosis and
vascular remodeling play a role in their development.113 Childhood cerebral
AVMs that recur after surgery have a high degree of endothelial expression
of VEGF in the primary vascular lesion, while nonrecurring lesions have low
expression of VEGF.114 Upregulation of VEGF mRNA has been observed
in the parenchyma adjacent to brain AVMs, with elevated levels of Tie
endothelial cell-specific receptor tyrosine kinase in the AVM vessels and
VEGF protein in the AVM endothelia compared with those in normal brain
tissue and vasculature.115 The applicability of these findings to cutaneous
AVMs remains controversial as no comparable experimental data exist for
them, but the expression of angiogenic cytokines in the AVM environment
could explain their propensity to recur and recruit new vessels when the
overlying stained skin is left in place after embolization and excision of the
AVM nidus.
CAPILLARY MALFORMATIONS
Capillary malformations are the most common vascular malformations.They
involve vessels of the capillary network in skin and mucous membranes.
Capillary malformations may be isolated and innocuous, may cause disfigurement and stigmatization, and, in some cases, may herald the presence of
an extracutaneous disease.
112. Kilic T, Pamir MN, Kullu S et al. (2000) Expression of structural proteins and angiogenic factors in
cerebrovascular anomalies. Neurosurgery 46:1179–1191.
113. Takagi Y, Hattori I, Nozaki K et al. (2000) DNA fragmentation in central nervous system vascular
malformations. Acta Neurochir (Wien) 142:987–994.
114. Sonstein WJ, Kader A, Michelsen WJ et al. (1996) Expression of vascular endothelial growth
factor in pediatric and adult cerebral arteriovenous malformations. J Neurosurg 85:838–845.
115. Hatva E, Jaaskelainen J, Hirvonen H et al. (1996) Tie endothelial cell-specific receptor tyrosine
kinase is upregulated in the vasculature of arteriovenous malformations. J Neuropathol Exp
Neurol 55:1124–1133.
referred to as a midline facial nevus flammeus) has been described in the
Beckwith–Weidemann syndrome, a condition that has several other features
including omphalocele, macroglossia, dysmorphic facies, hemihypertrophy,
and neonatal hypoglycemia, as well as a risk of Wilm’s tumor and other
malignancies.120,121. In Nova syndrome, glabellar salmon patches are reported
as an autosomal dominant trait in association with posterior fossa brain
malformations.122
Usually no treatment of salmon patches is necessary, as most of those on
the face fade by 1 to 2 years of age.116 The nuchal lesions tend to be more
persistent and are present in many adults. If salmon patches do not fade
completely, they can be effectively treated with a PDL. Nuchal salmon patches
may occur in association with a hemangioma, as an overlap between vascular
malformation and vascular tumor.3 (Fig. 20.1) Predisposed infants may
develop a superimposed eczematous dermatitis.
Port-wine stains
The port-wine stain, or nevus flammeus, occurs in 0.3% of all newborns and
has an equal sex distribution.117 Port-wine stains are present at birth and do
not undergo spontaneous resolution.These well-demarcated vascular stains
grow in proportion to the growth of the child.They are usually unilateral and
segmental, generally (but not always) respecting the midline, although occasionally there is a contralateral component in the same or adjacent dermatome. The stain may appear on any area of the body. In a review of 310
patients with port-wine stains, 85% were unilateral, 15% were bilateral, and
68% had more than one dermatome involved. In this group, 8% of port-wine
stains involving the V1 dermatome were associated with ocular or CNS
involvement, but this increased to 25% if there was bilateral V1 or complete
involvement of all three trigeminal dermatomes (Figs 20.20 and 20.21).123
Port-wine stains are usually pink or red during infancy.They sometimes
appear to lighten somewhat in the first 1–6 months of life, probably because
of the marked drop in circulating blood hemoglobin concentration during
this time period.This lightening should not be interpreted as an indication
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The most common vascular lesion in infancy is the salmon patch, also known
as nevus simplex, erythema nuchae, angel’s kiss, and stork bite.The term nevus
flammeus is synonymous with port-wine stain and should not be used to
describe a salmon patch. The latter lesion is best classified as a superficial
vascular malformation, although its course is typically different from that of
the port-wine stain. Salmon patches consist of ectatic capillaries that have been
thought to represent the persistence of fetal circulatory patterns in the skin.
Their disappearance may be based on maturation of the autonomic innervation
of these vessels in early infancy, but this is hypothetical, not proven.
The salmon patch is present at birth in about 40% of infants and appears
as a pink to red macule on the nape, glabella, forehead, upper eyelids, nasolabial
region, and occasionally on the parietal and occipital scalp and overlying the
thoracic or lumbosacral spine (Fig. 20.19) In contrast to the port-wine stain,
the salmon patch tends to be located in the central portion of the face and
does not follow a dermatomal distribution. Occasionally, however, port-wine
stains occur in this more medial location (so-called “medial telangiectatic
nevus”); at times, these can be difficult to differentiate from salmon patches.
Many infants have salmon patches in several locations. Of those infants born
with salmon patches, 81% have lesions at the nape, 45% on the eyelids, and
33% on the glabella.116,117
A variant of the salmon patch termed the butterfly-shaped mark, a redviolet rhomboid-shaped macule, can occur in the sacral region.These lesions
are less common than salmon patches at other sites and tend to disappear
more slowly.Although some authors have concluded that radiographic studies
of the lumbosacral area are not indicated when the butterfly-shaped mark is
present, this premise remains controversial and many physicians continue to
suggest routine imaging studies of the lumbar spine in patients with a midline
cutaneous vascular malformation, because it can be a marker of occult spinal
dysraphism.118,119 Salmon patches of the face are, in rare instances, a manifestation of other diseases. Prominent and persistent salmon patch (often
AL
Salmon patches
Fig. 20.19 Salmon patch
(nevus simplex). Note that
in addition to the glabella
and upper eyelids – the
most common sites of
involvement – the nose
and upper lip are often
affected (Courtesy of
Howard Pride.)
116. Leung AK, Telmesani AM (1989) Salmon patches in Caucasian children. Pediatr Dermatol
6:185–187.
117. Jacobs AH, Walton RG (1976) The incidence of birthmarks in the neonate. Pediatrics 58:218–222.
118. Metzker A, Shamir R (1990) Butterfly-shaped mark: a variant form of nevus flammeus simplex.
Pediatrics 85:1069–1071.
119. Ben-Amitai D, Davidson S, Schwartz M et al. (2000) Sacral nevus flammeus simplex: the role of
imaging. Pediatr Dermatol 17:469–471.
120. Jonas R, Kimonis V (2001) Chest wall hamartoma with Wiedemann–Beckwith syndrome: clinical
report and brief review of chromosome 11p15.5-related tumors. Am J Med Genet 101:221–225.
847
Fig. 20.20 Port-wine
stain involving both V1
and V2 dermatomes. This
infant had Sturge–Weber
syndrome.
121. Lam W, Hatada I, Ohishi S et al. (1999) Analysis of germline CDKN1C (p57-KIP2) mutations in
familial and sporadic Beckwith–Wiedemann syndrome (BWS) provides a novel genotypephenotype correlation. J Med Genet 36:518–523.
122. Nova H (1979) Familial communicating hydrocephalus, posterior cerebellar agenesis, mega
cisterna magna, and port-wine nevi. Report on five members of one family. J Neurosurg
51:862–865.
123. Tallman B, Tan OT, Morelli JG et al. (1991) Location of port-wine stains and likelihood of
ophthalmic and or central nervous system complications. Pediatrics 87:323–327.
848
Sturge–Weber (SWS) and Klippel–Trenaunay (KT) and Proteus syndromes
typically feature port-wine stains as a clinical manifestation. Rarely, lesions
resembling port-wine stains occur overlying AVMs or in rare disorders such
as Cobb, Bonnet–Dechaume–Blanc, or Wyburn–Mason syndromes, but in
these cases it is not understood whether the port-wine stain is an associated
capillary malformation or if it is a true component of the AVM. In some
patients, it is the only indication of a dormant AVM for many years.
The development of lasers that selectively ablate vascular lesions has greatly
advanced our ability to treat these congenital anomalies, and the rationale for
treatment, including psychosocial and ethical issues have been well
documented.133 Port-wine stain, especially when located on visible skin such
as the face, can invoke teasing and stigmatization, causing significant emotional
distress in affected children. A British study examining psychological disabilities among patients with port-wine stains found a high level of psychological morbidity, resulting from a feeling of stigmatization, but these
morbidities were not evident in casual social interactions or with standard
psychological tests.134 Troilus,135 after quantifying the psychological disabilities
associated with port-wine stains, stressed the considerable emotional turmoil
encountered in 259 patients and their families and advised early treatment
with the aim of finishing prior to beginning school.Although as yet unproven,
treatment in childhood could potentially prevent the thickening and vascular
nodules that develop over time in many port-wine stains.The mainstay of
treatment of port-wine stains in children is the PDL with wavelengths
between 585 and 595nm and a pulse duration between 450 and 1500ms.The
latter duration is usually used together with a cooling device to minimize
thermal damage. Newer lasers using even longer pulse durations (up to 10ms)
have recently been introduced. PDLs have been used in children and adults
for more than 10 years and have a low risk of scarring and high percentage
of clinical response (Fig. 20.22).Although initial reports emphasized complete
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Fig. 20.21 Anatomic
drawing of trigeminal
dermatomes. Note the
blackened area – the
so-called V1–V2 watershed
area, which can be
ennervated by either V1 or
V2. (Reprinted with
permission Irom Enjolras O,
Garzon MC (2001) Vascular
stains, malformations, and
tumors. In Textbook of
Neenatal Dermatology,
Eichenfield LF, Frieden IJ,
Esterly NB, eds.
Philadelphia, PA: WB
Saunders, p. 332.)
of spontaneous resolution as this rarely if ever occurs. Port-wine stains often
darken to a dull erythrocyanotic or purple hue with advancing age.Although
most are initially macular, the surface may become irregular, thickened, and
nodular during adulthood.This feature is frequent in facial port-wine stains
but is less commonly observed in those located on the trunk and limbs.124
Bony and soft tissue hypertrophy can be associated with overlying port-wine
stains, particularly in the V2 facial distribution. Progressive ectasias manifest
by thickening and nodularity of the port-wine stains may develop over time.
In addition, pyogenic granulomas may arise within port-wine stains,
presenting as small papules or nodules.3
Histologically, the port-wine stain is composed of normal numbers of
ectatic mature capillaries in the superficial dermis with no evidence of cellular
proliferation.These vessels become more dilated over time and are found in
the deep dermis and subcutaneous tissue when the clinical lesion is raised or
nodular.9 Loosely arranged collagen fibers surround the ectatic vessels.125
Studies have demonstrated a decrease in the number of nerves surrounding
the abnormal blood vessels. Progressive vascular dilatation is thought to be a
result of impairment of neural control of the vascular elements.126 Additional
studies have documented impaired neural regulation of blood flow in portwine stains.127
Although almost all port-wine stains are present at birth, rare instances
of later onset have been documented. These “acquired” port-wine stains
sometimes develop after injury to the skin or in association with the use of
oral contraceptives. Perhaps acquired telangiectatic nevus would be a more
accurate term for these puzzling lesions.128–130 Differential diagnosis includes
mastocytosis (the telangiectasia macularis eruptiva perstans type) and telangiectasias occurring in aluminum workers.131
Port-wine stains can occur as isolated cutaneous lesions or in association
with other abnormalities.Although a midline port-wine stain alone, without
other associated hallmarks (e.g., fatty mass, dimple, tuft of hair), is very rarely
associated with dysraphism,132 some physicians still recommend the evaluation
of these areas with ultrasound (very early in infancy) or MR imaging.
Neurogenic bladder and accompanying voiding dysfunction may be the initial
symptom of tethered spinal cord and once established may be irreversible.
124. Klapman MH, Yao F (2001) Thickening and nodules in port-wine stains. J Am Acad Dermatol
44:300–302.
125. Lever W, Schaumburg-Lever G (1990) Histopathology of the Skin, 7th edn. Philadelphia, PA
Lippincott.
126. Smoller B, Rosen S (1986) Port wine stains. A disease of altered neural modulation of blood
vessels? Arch Dermatol 122:177–179.
127. Gaylarde PM, Dodd HJ, Sarkany I (1987) Port wine stains. Arch Dermatol 123:861.
128. Colver GB, Ryan TJ (1986) Acquired port wine stains. Arch Dermatol 122:1415–1416.
129. Goldman L (1970) Oral contraceptives and vascular anomalies. Lancet ii:108–109.
130. Tsuji T, Sawabe M (1988) A new type of telangiectasia following trauma. J Cutan Pathol 15:22.
Fig. 20.22 Telangiectactic
port-wine stain. (A) Before
laser treatment.
(B) Complete resolution
after three laser
treatments.
A
B
131. Theriault G, Cordier S, Harvey R (1980) Skin telangiectases in workers at an aluminum plant.
N Eng J Med 303:1278–1281.
132. Tavafoghi V, Ghandehi A, Hambrick G et al. (1978) Cutaneous signs of spinal dysraphism.
Arch Dermatol 114:573–577.
133. Strauss RP, Resnick SD (1993) Pulsed dye laser therapy for port wine stains in children:
psychosocial and ethical issues. J Pediatr 122:504–510.
134. Lanigan SW, Cotterill JA (1989) Psychological disabilities amongst patients with port wine stains.
Br J Dermatol 121:209–215.
135. Troilus A, Wrangsjö B, Ljunggren B (1998) Potential psychological benefits from early treatment
of port-wine stains in children. Br J Dermatol 139:59–65.
849
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Fig. 20.23 Port wine stain V2 dermatome. (A) Before
laser treatment. (B) After eight laser treatments the
lesion is considerably lighter but still persists.
B
Sturge–Weber syndrome
clearing,136 more recent studies have emphasized that this is the exception,
with most patients achieving lightening but not complete clearance. The
response to treatment is based on a number of factors including the size and
location of the port-wine stain.Very large port-wine stains and those located
in a V2 distribution or those involving the extremities do respond, but less
well than lesions in other sites (Fig. 20.23). Stains over bony prominences
require fewer treatments. Scarring is rare, but transient pigmentary changes
are sometimes seen. Although many authors have reported that earlier
treatment results in better clearance137,138 others disagree.139 Recurrences of
port-wine stains after completion of treatment can occur, but the incidence
of recurrence is uncertain. Michel et al.140 reported no recurrences in children
treated before 10 years of age, which might hint at a lower recurrence
frequency with early treatment. Laser treatments are typically performed every
2 to 3 months, allowing for maximal lightening of the lesion prior to
subsequent treatment. The type of anesthesia or sedation necessary for
treatment with PDL is controversial.With the introduction of EMLA (eutectic
mixture of local anesthesia) cream in 1993, many older children and those
with small, well-localized port-wine stain can be treated without general
anesthesia or sedation.The cream consists of a combination of prilocaine and
lidocaine. Its efficacy depends on the amount of cream applied, duration of
contact, and proper use of an occlusive covering.The cream should be applied
thickly, and the site must be completely occluded with a nonpermeable,
airtight patch. Duration of contact should be at least 1 hour, preferably 2.The
maximum action time is between 1.5 and 3 hours. The recommended
maximum application of EMLA to children weighing 5–10kg is 20cm2.
There have been reports of methemoglobinemia induced by topical
application of EMLA, particularly when used in infants less than 6 months
of age.
SWS, also known as encephalotrigeminal angiomatosis, is the triad of a facial
port-wine stain in a V1 distribution (Fig. 20.20), an ipsilateral leptomeningeal
vascular malformation, and a choroidal vascular malformation of the eye,
which can lead to ipsilateral glaucoma and buphthalmos.There is no clear
evidence of a genetic predisposition, and the etiology remains unknown.The
three tissues involved are all derivatives of the so-called mesoectoderm.
Theoretical causes of this disorder include an error of morphogenesis within
the cephalic neural crest and lethal genes surviving by mosaicism.141,142
Port-wine stains in SWS follow the distribution of the first branch of the
trigeminal nerve. Consequently, the stain typically involves the forehead and
upper eyelid.The distribution of V1 varies somewhat, so V1 can involve the
skin below the eye and on the nose in some patients; however port-wine
stains that spare the upper face and eyelids are almost never associated with
an intracranial vascular malformation (Fig. 20.21).141 Approximately 10% of
patients with a port-wine stain in the V1 distribution have SWS. Extensive
and bilateral involvement including other trigeminal dermatomes may also
occur, but the midline is respected in most cases. Even in infants with bilateral
involvement of the V1 areas, often in association with other stains on face and
body, only one side of the brain and eye is usually affected. Bilateral brain
lesions, observed in about 15% of patients (including some patients with
hemifacial port-wine stains) carries a greater risk of neurologic impairment.142
Patients may have partial forms of SWS, including port-wine stain with
only eye or only CNS involvement. In addition, individuals with typical CNS
or eye findings of SWS without a facial port-wine stain have also been
reported.143 Common neurologic abnormalities include contralateral seizures,
episodes of contralateral hemiparesis or hemiplegia, headaches, and intellectual
impairment. Seizures are usually of the focal motor or generalized tonic-
136. Tan OT, Sherwood K, Gilchrest BA (1989) Treatment of children with port wine stains using the
flashlamp-pulsed tunable dye laser. N Engl J Med 320:416–421.
137. Ashinoff R, Geronemus RG (1991) Flashlamp-pumped pulsed dye laser for port wine stains in
infancy: earlier versus later treatment. J Am Acad Dermatol 24:467–472.
138. Nguyen CM, Yohn JJ, Huff C et al. (1998) Facial port-wine stains in childhood: prediction of rate
of improvement as a function of the age of the patient, size and location of the port-wine stain,
and the number of treatments with the pulsed dye (585 nm) laser. Br J Dermatol 138:821–825.
139. van der Horst CM, Koster PH, de Borgie CA et al. (1998) Effect of the timing of treatment of
port-wine stains with the flashlamp pumped pulsed dye laser. N Eng J Med 338:1028–1033.
140. Michel S, Landthaler M, Hohenleutner U (2000) Recurrence of port-wine stains after treatment
with the flash-lamp pumped pulsed dye laser. Br J Dermatol 143:1230–1234.
141. Enjolras O, Riche MC, Merland JJ (1985) Facial port wine stains and Sturge–Weber syndrome.
Pediatrics 76:48–51.
142. Happle R (1987) Lethal genes surviving by mosaicism: a possible explanation for sporadic birth
defects involving the skin. J Am Acad Dermatol 16:899–906.
143. Martinez-Bermejo A, Tendero A, Lopez-Martin V et al. (2000) Angiomatosis leptomeningea sin
angioma facial. Debe considerarse como variante del syndrome de Sturge Weber? Rev Neurol
30:837–841.
not contraindicated and can begin as soon as seizures are controlled by anticonvulsants. Gum hypertrophy, which is particularly common in patients
receiving phenytoin, can be resected with a photocoagulator. Because
the malformation is a low-flow one, there is no need for preoperative
embolization. Children with a V2 port-wine stain, in association with V1
location, frequently develop an enlarged maxilla. This bony hypertrophy
creates an occlusion deformity and crossbite and requires orthodontic evaluation and follow-up. A team approach is very important in managing these
patients, because many children need the expertise of neurologists, ophthalmologists, pediatricians, neurosurgeons, dermatologists, plastic surgeons, ear,
nose, and throat surgeons, and neuroradiologists.
Klippel–Trenaunay syndrome
KT syndrome (angio-osteohypertrophy) is characterized by a triad of portwine stain, varicose veins (venous malformation), and bony and/or soft tissue
hypertrophy.The cutaneous stains are the earliest sign and are typically limited
to a single extremity, although multiple extremities can be involved. A lymphatic component is common, evidenced either by lymphedema or by
lymphatic vesicles, usually intermingled with the port-wine stain in the lateral
or anterior aspect of the thigh and knee (Fig. 20.24). Osteohypertrophy is
rarely present at birth. Overgrowth of the affected limb appears either at birth
or within the first few months or years of life. In a review of 144 patients
with KT syndrome, 95% had a cutaneous vascular malformation, 93% had
soft tissue or bony hypertrophy, 76% had varicosities, and 71% had involvement limited to one leg.153 The etiology of KT syndrome is unknown.
Although it has been suggested that this syndrome may be inherited in a
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clonic types initially.They usually have their onset before two years of age.
Developmental delay in motor and cognitive skills is seen in about half of
affected children. Continued seizures predispose the child to severe mental
impairment. Extensive brain lesions contribute to poor intellectual development, behavioral abnormalities, and learning disabilities.The reason for the
developmental delay is not known but it may be because of the seizures or
atrophy of the affected areas of the brain.
Ocular abnormalities are included in the classic triad of SWS but need
not be present in order to make a definitive diagnosis. Glaucoma develops
in approximately half of patients whose port-wine stain is adjacent to the
eye and occurs independent of neurologic involvement.The precise cause
of elevated intraocular pressure is a matter of debate, and more than one
mechanism is probably responsible. Hyperemia of the ciliary body, anomalies
of the anterior chamber angle structures, and abnormal arteriovenous
communications in the episcleral vascular plexus may all play a role in the
pathogenesis of glaucoma in SWS.144 Ophthalmologic examination at
regular intervals (every six to 12 months) should be performed in all those
affected, as glaucoma can develop early and should be tested for as soon as
possible. Long-term follow-up is important because glaucoma can develop
later in life. Early detection of increased intraocular pressure is important
in order to prevent progressive disease. For 60% of patients with
SWS and glaucoma, onset is in infancy, when the eye may stretch because
of the increased intraocular pressure; these infants have an enlarged
cornea, buphthalmos (bull eye – large eye), and myopia. For the other
40%, glaucoma begins in childhood or adulthood and there is no eye
enlargement.145
Because most affected children are initially normal, neuroimaging studies
can be helpful in detecting brain involvement. Radiographic examination of
the brain in patients over 2 years of age reveals characteristic calcifications in
two-thirds of patients, but this finding has only rarely been detected in the
neonate,146 Calcifications follow the convolutions of the cerebral cortex and
are characterized by sinusoidal parallel lines simulating “railroad tracks,” most
often in the occipital region of the brain adjacent to the leptomeningeal
vascular lesions. They are best demonstrated by CT scan and are usually
evident by 1 year of age. MR imaging with gadolinium enhancement is the
most useful study for even earlier detection of SWS, because it provides clear
identification of increased blood vessels as well as any accompanying cortical
atrophy. MR occasionally fails initially to detect small areas of vascular malformation in infants less than 6 months of age, but advanced myelination or
an enlarged choroid plexus may be seen in the involved hemisphere.146,147
The use of functional cerebral imaging such as positron emission tomography
(evaluating the glucose metabolism in the brain) or single photon emission
computed tomography (SPECT: studying the regional cerebral blood flow)
may indicate increased metabolism and increased cerebral blood flow in the
abnormal hemisphere early in infancy. After the development of seizures,
however, rapid cerebral impairment with hypometabolism and hemispheric
hypoperfusion develops.148–150
The management of SWS depends on the clinical manifestations. Seizures
require anticonvulsant medications;151 in those with severe, intractable
seizures, surgical intervention, such as localized resection of the involved brain
tissue or hemispherectomy, is necessary.152 Glaucoma, when present, can be
treated medically but most cases of congenital glaucoma require surgery.
Argon laser photocoagulation of prominent conjunctival and episcleral vessels
in SWS has been reported to be successful and is accompanied by no apparent
vision-threatening complications. Laser treatment of the port-wine stains is
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144. Celebi S, Alagoz G, Aykan U (2000) Ocular findings in Sturge–Weber syndrome. Eur J
Ophthalmol 10:239–243.
145. Cheng KP (1999) Ophthalmologic manifestations of Sturge–Weber syndrome. In Sturge–Weber
Syndrome, Bodensteiner JB, Roach ES, eds. Mt Freedom: Sturge–Weber Foundation, pp. 17–26.
146. Griffiths PD (1996) Sturge–Weber syndrome revisited: the role of neuroradiology.
Neuropediatrics 27:284–294.
147. Adamsbaum C, Pinton F, Rolland Y et al. (1996) Accelerated myelination in early Sturge–Weber
syndrome: MR–SPECT correlations. Pediatr Radiol 26:759–762.
148. Maria BL, Hoang K, Robertson RL et al. (1999) Imaging brain structure and function in
Sturge–Weber syndrome. In Sturge–Weber Syndrome, Bodensteiner JB, Roach ES, eds. Mt
Freedom: Sturge–Weber Foundation, pp. 43–69.
Fig. 20.24
Klippel–Trenaunay
syndrome in association
with a capillary–
lymphatic–venous
malformation. The
geographic stain and
multiple eclasias are
common when a lymphatic
component is present.
149. Pinton F, Chiron C, Enjolras O et al. (1997) Early single photon emission computed tomography
in Sturge–Weber syndrome. J Neurol Neurosurg Psychiatry 63:616–621.
150. Maria BL, Neufeld JA, Rosainz LC et al. (1998) Central nervous system structure and function in
Sturge–Weber syndrome: evidence of neurologic and radiologic progression. J Child Neurol
13:606–618.
151. Kramer U, Kahana E, Shorer Z et al. (2000) Outcome of infants with unilateral Sturge–Weber
syndrome and early onset seizures. Dev Med Child Neurol 42:756–759.
152. Bruce DA (1999) Neurosurgical aspects of Sturge–Weber syndrome. In Sturge^=Weber
Syndrome, Bodensteiner JB, Roach ES, eds. Mt Freedom: Sturge–Weber Foundation, pp. 39–42.
153. Gloviczki P, Stanson AW, Stickler GB et al. (1991) Klippel–Trenaunay syndrome: the risks and
benefits of vascular interventions. Surgery 110:469.
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Fig. 20.25 Phakomatosis
pigmentovascularis type
IIB. This patient also had
facial involvement and
glaucoma.
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multifactorial fashion, it is generally a sporadic disorder.154 It affects males
more often than females.
There is no known cure for KT syndrome. Management includes regular
visits, with clinical and radiographic measurements of affected limbs at regular
intervals. Scanograms should be obtained to evaluate limb length discrepancy
more accurately in any children with more than 1–2cm difference in limb
length. Those with significant differences in length should be referred
for orthopedic evaluation. Non-invasive arterial/venous evaluation with
ultrasonography/Doppler is preferred to conventional contrast angiography
and contrast venography during childhood. MR imaging155 is the single best
method for evaluation and delineation of the extent of the disorder. In
addition, MR angiography and venography will demonstrate the anomalous
vessels, located in the skin and subcutis, and indicate whether muscle
involvement is present, although, in contrast to venous malformations, muscle
involvement is actually very uncommon. MR lymphography, a new noninvasive tool, is useful for differentiating veins from lymphatics as enlarged
axial and extra-axial lymphatic channels may be seen in children with KT
syndrome.155 Pelvic, intestinal, and/or bladder vascular anomalies may be
associated.
Treatment of this condition is usually aimed at controlling specific
symptoms and is, in general, conservative.156,157 Compression stockings are a
mainstay of treatment, but accurate fitting for these stockings is not usually
practical until the child is 2 or 3 years of age. Compressive wraps may be used
in younger infants with significant venous congestion. Intermittent pneumatic
compression devices can reduce limb size and control varicosities. This
modality can be combined with use of elastic garments to provide continuous
compression. Surgical correction of varicose veins is controversial. Some feel
it is contraindicated and others feel it may be beneficial as long as the deep
venous system is intact.153 Most patients do relatively well with compression
alone. Debulking of soft tissue may be indicated to restore function of the
affected extremities; however, it carries a high risk of long-term complications
(severe scarring, fibrosis, pedal edema). Orthopedic management is mandatory
during childhood to decide if epiphysiodesis will be necessary at early
puberty, as a means of equalizing the limbs if discrepancy in length is
significant.
Other abnormalities have been described in association with KT syndrome,
including the association with SWS, ocular anomalies, glaucoma, and retinal
exudative vascular masses. Lymphatic obstruction, lymphatic involvement of
the lungs,158 nonimmune hydrops fetalis, severe menorrhagia,159 cerebral
aneurysm, gastrointestinal hemorrhage,160 and pulmonary embolism161 have
also been reported. Many orthopedic abnormalities have been noted to occur
in these patients, including frequent polydactyly and syndactyly that may
also suggest possible Proteus syndrome. Patients frequently have a low-grade
coagulopathy similar to that seen with venous malformations (see discussion
below).
The differential diagnosis of KT syndrome includes extensive pure venous
malformations of the extremities,162 and the Parkes–Weber, and Maffucci
syndromes. Features of typical KT syndrome may also occur in Proteus
syndrome.
851
lesions may be persistent dermal melanocytosis (Fig. 20.25) or a speckled
lentiginous nevus.163,164 The macules of dermal melanocytosis resembles
Mongolian spots and are often present at sites other than the lumbosacral
region. In most cases, these lesions are extensive. Four distinct types of
phakomatosis pigmentovascularis, all characterized by a port-wine stain and
either a pigmented or an epidermal nevus, have been described.Type I has
an associated epidermal nevus; type II has dermal melanocytosis (ectopic
Mongolian spots) with or without nevus anemicus; type III has a speckled
lentiginous nevus with or without nevus anemicus; and type IV has dermal
melanocytosis and a speckled lentiginous nevus with or without nevus
anemicus. Additional subtypes further classify the disorder as to the absence
(type a) or presence (type b) of systemic manifestations. Happle has proposed
that phakomatosis pigmentovascularis is caused by so-called “twin spotting.”165
TELANGIECTASIA
Telangiectasias are dilated small vessels that may or may not blanch on
diascopy.They appear on the skin and mucous membranes as small, red, linear,
stellate or punctate markings.There are many causes of secondary telangiectasia, such as rosacea, actinic or radiologic damage; various connective tissue
diseases; mastocytosis; poikiloderma; prolonged application of topical corticosteroids; and miscellaneous genodermatoses. Primary telangiectases include
spider angioma, angioma serpiginosum, HHT, ataxia telangiectasia, generalized
essential telangiectasia, hereditary benign telangiectasia, unilateral nevoid
telangiectasia, and cutis marmorata telangiectatica congenita.
Spider angioma
Phakomatosis pigmentovascularis
Phakomatosis pigmentovascularis consists of an extensive port-wine stain
accompanied by either melanocytic or epidermal lesions.The melanocytic
154. Aelvoet GE, Jorens PG, Roelen LM (1992) Genetic aspects of the Klippel–Trenaunay syndrome.
155. Laor T, Hoffer FA, Burrows PE et al. (1998) MR lymphangiography in infants, children and adults.
Am J Roentgenol 171:1111–1117.
156. Rogalski R, Hensinger R, Loder R (1993) Vascular abnormalities of the extremities: clinical
findings and management. J Pediatr Orthopaed 13:9–14.
157. Berry SA, Peterson C, Mize W et al. (1998) Klippel Trenaunay syndrome. Am J Med Genet
79:319–326.
158. Joshi M, Cole S, Knibbs D et al. (1992) Pulmonary abnormalities in Klippel–Trenaunay syndrome.
Chest 102:1274.
159. Markos AR (1987) Klippel–Trenaunay syndrome-a rare cause of severe menorrhagia. Br J Obstet
Gynaecol 94:1105.
The spider angioma (nevus araneus) is the most common of the telangiectases.
In adults, spider angiomas frequently develop in large numbers during
pregnancy and are also characteristically associated with liver disease. In
160. Azizkhan RG (1991) Life-threatening hematochezia from a rectosigmoid vascular malformation
in Klippel–Trenaunay syndrome: long term palliation using an argon laser. J Pediatr Surg
26:1125.
161. Gianlupi A, Harper R, Dwyre D et al. (1999) Recurrent pulmonary embolism associated with
Klippel–Trenaunay-Weber syndrome. Chest 115:1199–1201.
162. Enjolras O, Ciabrini D, Mazoyer E et al. (1997) Extensive pure venous malformations in the
upper or lower limb, a review of 27 cases. J Am Acad Dermatol 36:219–225.
163. Ruiz-Maldonado R, Tamayo L, Laterza AM et al. (1987) Phakomatosis pigmentovascularis: a new
syndrome? Report of 4 cases. Pediatr Dermatol 4:189–196.
164. Guiglia MC, Prendiville JS (1991) Multiple granular cell tumors associated with giant speckled
lentiginous nevus and nevus flammeus in a child. J Am Acad Dermatol 24:359–362.
165. Happle R (1991) Allelic somatic mutations may explain vascular twin nevi. Hum Genet
86:321–322.
childhood, however, these lesions are commonly found in the absence of
systemic disorders.
The spider angioma is composed of small telangiectases radiating from a
central point in fine hair-like branches.The central point or punctum is an
arteriole from which the superficial blood vessels radiate peripherally. Because
the central vessel is an arteriole and blood flow is centrifugal, gradually
increasing pressure over the central vessel will cause blanching of the lesion
in a centripetal fashion.This phenomenon will help to differentiate the spider
angioma from other telangiectases.
In childhood, spider angiomas appear most commonly on the face (malar
areas), upper trunk, arms, and hands.They are never present at birth but are
often detectable after 2 years of age, reaching a frequency of 30% of normal
children by age 4 and 40% by age 8.The prevalence figures start to decline
in the early teens to approximately 10–15% in the adult population.166 From
these data, it is clear that more than 50% of spider nevi disappear by adult life.
Therapy for the spider nevus, when desired for cosmetic reasons, consists
of gentle electrodesiccation of the central vessel or ablation of the lesion by
the PDL. Almost immediately after coagulating the central vessel, all the
branches disappear.
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Angioma serpiginosum
same mutation.168 Recurrent epistaxis from telangiectases over the nasal
septum and inferior turbinates is the presenting sign in over 50% of individuals
and occurs in approximately 80% of patients at some time during their
course.169,170 This manifestation is usually seen by puberty, in contrast to
hemorrhage from other sites such as the gastrointestinal and genitourinary
tracts, which occur later in life. Epistaxis may become severe, requiring
transfusions.Anemia is a common complication.
The mucocutaneous lesions are not commonly observed in childhood but
generally become evident during the third or fourth decade, occasionally
somewhat earlier.These vascular lesions develop primarily on the face, lips,
nasal mucosa, tongue, palms, and palate, but they can also be found in the nail
beds, on the soles of the feet, and even on the tympanic membrane.They are
dark red and tend to be slightly elevated, with an ill-defined border and one
or more legs radiating from an eccentrically placed punctum.
Gastrointestinal hemorrhage is the second most common complication,
occurring in about 40% of affected individuals; however, unlike epistaxis,
onset of this complication is rare before midlife. Bleeding may occur from
lesions in the upper and lower bowel, but despite careful evaluation by
endoscopy and radiologic studies, the bleeding site may remain undetermined.
The bleeding pattern is one of chronicity and recurrence and tends to be
progressive as new telangiectases appear.
Some patients have pulmonary AVMs, and one-third have multiple
pulmonary lesions. Patients may be asymptomatic or may exhibit dyspnea,
cyanosis, fingernail clubbing, and polycythemia; both ischemic and septic
neurologic complications may ensue as a result of these lesions.168–170 In
addition, a small number of affected individuals have cerebral telangiectases,
aneurysms, and AVMs of the brain and spinal cord, giving rise to focal and
generalized neurologic deficits. Hepatic AVMs can cause liver enlargement
and portal hypertension. Liver disease in HHT is rare but severe, combining
vascular anomalies, fibrosis, and cirrhosis;171 these patients may develop a
severe coagulopathic disorder as a result of the cirrhosis, complicating any
surgical procedure on their vascular lesions.
HHT involves capillaries, arteries, veins and arteriovenous fistulae, and the
combinations of vessels vary in different individuals. Cutaneous telangiectases
are composed of a subepidermal tortuous mass of dilated capillaries and postcapillary venules with markedly thinned walls comprising a single layer of
endothelium. Hemorrhage is thought to result from malformation of the
vessel walls or possibly defects in the surrounding perivascular tissue. No
specific hematologic defects have been consistently identified.
New advances in molecular genetics have helped to explain the previously
obscure heterogeneity of HHT. It is now clear that there are various phenotypes and genotypes. Identification of two genes endoglin (for HHT type 1)
and ALK-1 (for HHT type 2), both of which can be affected by differing
intragenic mutations, have brought new insights in the pathogenesis of HHT,
as well as the hope of new treatments.172 Genotype–phenotype correlations
are not yet completely defined; however, pulmonary AVMs seem more
common in HHT1 than in HHT2, and hepatic AVMs are more common in
HHT2.168 Other genes may be involved, as demonstrated by a family with
HHT and pulmonary AVMs173 when no genetic abnormality could be
established.
The vast majority of patients survive the disease and die of some other
cause, although frequent treatment for hemorrhages and anemia is a lifelong
necessity.Therapy is primarily directed at the control of hemorrhage and
blood replacement.The local therapy of the bleeding nasal telangiectases with
chemical cautery or electrocoagulation has temporary value, as does
tamponade. For severe recurrent epistaxis, laser coagulation, sclerotherapy by
means of direct puncture of the telangiectases, or septal dermoplasty are the
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852
Angioma serpiginosum is a distinctive rare entity involving the capillaries of
the dermis.The onset of this condition is usually in childhood, and 90% of
the reported cases have been in females.167
The primary lesion consists of an asymptomatic vascular ectasia that appears
clinically as a minute, partly compressible, red-to-purple punctum, which may
require slight magnification for visualization.These small puncta appear in
groups that fuse into patches and spread by forming new satellite puncta
at the periphery. This extension results in the formation of annular or
serpiginous patterns. Because of the confluence of capillary ectasias, there
may be an erythematous background.Angioma serpiginosum usually develops
on the lower extremities and the buttocks, but occasionally lesions occur
elsewhere. Although the lesions extend gradually, widespread cutaneous
involvement is infrequent.The condition is progressive despite periods of
relative stability; although areas of fading and involution are evident, complete
spontaneous resolution does not occur.
Angioma serpiginosum can be confused with the various pigmented
purpuric eruptions; however, it is not a capillaritis but rather a nevoid telangiectatic condition.There is no evidence of variegated pigmentation, scaling,
atrophy, or lichenification in angioma serpiginosum.These lesions must also
be distinguished from other localized telangiectases.
Histopathologically, the fundamental lesion is a dilatation of the capillaries
of papillary and subpapillary regions of the dermis.The vessel walls may be
slightly thickened. Other dermal structures are normal. An inflammatory
infiltrate is not a significant feature, and no red cell diapedesis or hemosiderin
pigment is present.
Obliteration of angioma serpiginosum is probably best accomplished by
laser therapy.
Hereditary hemorrhagic telangiectasia
(Osler-Weber-Rendu disease)
This autosomal-dominant mucocutaneous and visceral vascular malformation
is characterized by the triad of telangiectasia, recurrent epistaxis, and a positive
family history of the disorder. Completely normal carriers are rare, but about
20% of patients are unaware of other affected family members. HHT is heterogeneous in terms of age of onset and clinical expression. In a given family,
symptoms and severity may vary considerably even in individuals with the
166. Wenzl JR, Burgert EO (1964) The spider nevus in infancy and childhood. Pediatrics 33:227–232.
167. Stevenson JR, Lincoln CS (1967) Angioma serpiginosum. Arch Dermatol 95:16–22.
168. Mc Donald JE, Miller FJ, Hallam SE et al. (2000) Clinical manifestations in a large hereditary
hemorrhagic telangiectasia (HHT) type 2 kindred. Am J Med Genet 93:320–327.
169. Porteous MEM, Burn J, Proctor SJ (1992) Hereditary hemorrhagic telangiectasia: a clinical
analysis. J Med Genet 29:527.
170. Reilly PJ, Nostrant TT (1984) Clinical manifestations of hereditary hemorrhagic telangiectasia. Am
J Gastroenterol 79:363.
171. Weik C, Johanns W, Janssen J et al. (2000) The liver and hereditary hemorrhagic telangiectasia.
Gastroenterology 38:31–37.
172. Azuma H (2000) Genetic and molecular pathogenesis of hereditary hemorrhagic telangiectasia.
J Med Invest 47:81–90.
173. Wallace GM, Shovlin CL (2000) A hereditary hemorrhagic telangiectasia family with pulmonary
involvement is unlinked to the known HHT genes, endoglin and ALK-1. Thorax 5:685–690.
Generalized essential telangiectasia
Cutis marmorata telangiectatica congenita
Cutis marmorata telangiectatica congenita (CMTC), also known as congenital generalized phlebectasia, is an unusual, clinically distinctive
cutaneous vascular anomaly. The variable presence of cutaneous atrophy
and/or coexistent port-wine stains are frequent.The condition is said to be
rare. However, one report of 13 cases, 10 of them seen by one physician in a
10-year period,179 and another of 22 patients seen by a single physician
in an 8-year period,180 suggest that many instances of CMTC remain
undiagnosed.The etiology is unclear, and there is no evidence of genetic
origin. It is usually stated that CMTC occurs predominantly in females, but
in four large series the male to female ratios were 7:6, 9:13, 5:5, and 5:3,
respectively.179–182
This disorder, which is present at birth, mimics the physiologic vascular
marbling effect (cutis marmorata) commonly seen in young infants,
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This uncommon disorder might more appropriately be called essential
progressive telangiectasia, because it does not become generalized until
many years after its onset.The condition occurs more frequently in females
and most commonly develops in late childhood or early adult life. It is not
familial. It usually begins on the legs and slowly spreads to involve the thighs,
lower abdomen, occasionally the arms, and rarely the face.The telangiectases
are macular, retiform, and linear and may coalesce to form confluent sheets
over large areas. Occasionally, patients experience sensations of numbness,
tingling, and burning in an involved limb.174
Essential telangiectasia must be differentiated from relangiectasia secondary
to underlying disease as well as from HHT. For some patients, it represents a
serious cosmetic problem, and lasers offer the best option for successful
treatment.
Lesions occur unilaterally on the face, neck, chest, and arms (trigeminal,
C3 and C4 or adjacent dermatomes) and only rarely elsewhere.They are
evident as macular telangiectatic mats, although elevated puncta and even
pulsatile spider angiomas may be found in some cases. Lesions fade on
pressure. Blanching or vasoconstriction surrounding individual lesions is
common and represents “vascular steal.” In the congenital type, the telangiectasia is permanent; the acquired form of the disorder (e.g., onset during
pregnancy) may resolve spontaneously in some patients. Lasers with selectivity
for cutaneous vascular structures are the best treatment for areas causing disfigurement.
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treatments of choice. Resection or, if possible, embolization of pulmonary
AVMs is mandatory in order to prevent the occurrence of pulmonary
insufficiency, high-output heart failure, or brain abscess (owing to loss of
pulmonary filtration of bacteria). Treatment of AVMs in other locations
depends on accessibility. Genetic counseling should be offered to all affected
individuals, and if both partners are affected, they should be warned that the
homozygous state might be lethal in childhood.
Hereditary benign telangiectasia
Hereditary benign telangiectasia has been described in several kindreds.
Affected persons were noted to have widespread asymptomatic telangiectases
unassociated with systemic disease.175,176 It is inherited as an autosomal
dominant trait.The telangiectases are not present at birth or during the first
year of life but begin to appear between 2 and 12 years of age. Predominantly
affected areas are the face, arms, and upper trunk, but lesions have been noted
on the vermilion border of the lips and palate in some individuals.Typical
lesions are macular, punctate or plaque-like, radiating, arborizing, or merely
a diffuse blush; they often have a halo of pallor. Capillary microscopy reveals
that the main feature is dilatation of the horizontal subpapillary venous plexus.
This is accompanied by loss of the more superficial capillaries that normally
stain with alkaline phosphatase and supply the papillae.The disorder is slowly
progressive, but in old age it becomes less obvious because of the normal skin
changes of aging.
Hereditary benign telangiectasia must be differentiated from other primary
telangiectases, the most important of which is HHT. Intervention is
unnecessary except for cosmetic reasons; as with other benign telangiectasias,
laser therapy or electrocautery may help to improve the lesions.
853
Fig. 20.26 Cutis
marmorata telangiectatica
congenita.
Unilateral nevoid telangiectasia
Unilateral nevoid telangiectasia (also known as unilateral dermatomal
superficial telangiectasia) is a relatively rare condition that occurs in both a
congenital and an acquired form.The acquired type has occurred mainly in
females, either at puberty or during pregnancy, and is thought to be estrogen
related; this disorder has also occurred in male alcoholics suffering from
cirrhosis of the liver.177 Some authors have proposed that this entity represents
a localized form of generalized essential telangiectasia.177
Congenital unilateral nevoid telangiectasia has been documented only
rarely and reportedly affects males predominantly.178 None of the children
reported have had evidence of endocrine abnormalities.178
174. Abrahamian LM, Rothe MJ, Grant-Kels JM (1992) Primary telangiectasia of childhood. Int J
Dermatol 31:307.
175. Ryan TJ, Wells RS (1971) Hereditary benign telangiectasia. St Johns Hosp Dermatol Soc Trans
57:148–156.
176. Gold MH, Eramo L, Prendiville JS (1989) Hereditary benign telangiectasia. Pediatr Dermatol
6:194–197.
177. Colver GB, Shrank AB, Ryan TJ (1985) Unilateral dermatomal superficial telangiectasia. Clin Exp
Dermatol 10:455.
178. Wilkin JK, Smith JG, Jr., Cullison DA et al. (1983) Unilateral dermatomal superficial
telangiectasia: 9 new cases and a review of unilateral dermatomal superficial telangiectasia.
J Am Acad Dermatol 8:468–77.
179. South DA, Jacobs AH (1993) Cutis marmorata telangiectatica congenita (congenital generalized
phlebectasia). J Pediatr 93:944–949.
180. Picascia DD, Esterly NB (1989) Cutis marmorata telangiectatica congenital; report of 22 cases.
J Am Acad Dermatol 20:1098–1104.
181. Kennedy C, Oranje AP, Keizer K et al. (1992) Cutis marmorata telangiectatica congenita.
Int J Dermatol 31:249–252.
182. Pehr K, Moroz B (1993) Cutis marmorata telangiectatica congenita: long-term follow-up, review
of the literature, and report of a case in conjunction with congenital hypothyroidism. Pediatr
Dermatol 10:6–11.
hyperkeratosis of the overlying epidermis.107 All present as asymptomatic,
firm, dark-red to black papules, with varying degrees of secondary hyperkeratosis, increasing with time. Classically, four types of localized
angiokeratoma are described, all of which are probably related but vary in
size, depth, and location. They are solitary papular angiokeratoma,
angiokeratoma circumscriptum, angiokeratoma of Mibelli, and angiokeratoma of the scrotum and vulva. Angiokeratoma corporis diffusum
represents a distinctive fifth group. In addition, angiokeratomas may occur
in the setting of KT syndrome.
Papular angiokeratoma
Papular angiokeratomas represent a response to trauma and can occur at any
age and at any site, although the legs are the favored location.They can be
solitary or multiple and consist of blue-black warty papules 2–10mm in
diameter.A single angiokeratoma may be mistaken for a viral wart, nevus, or
malignant melanoma, but it can be differentiated on the basis of histopathologic examination or dematoscopy. Microscopic features include
grouped dilated papillary blood vessels, acanthosis and hyperkeratosis of the
epidermis, and elongation of the rete ridges, which tend to enclose the
underlying capillary spaces.Treatment of a solitary angiokeratoma for cosmetic
reasons or because of undue anxiety can be accomplished by local excision,
electrodesiccation, or by laser ablation.
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particularly when they are chilled or exposed to low environmental temperatures. However, the pattern of CMTC is more vivid and darker in color,
with a coarser pattern of mottling (Fig. 20.26). Although it is always discernible at rest, it can be accentuated by cold exposure, vigorous movement,
or crying.The reticulated mottling of the skin is accompanied by varying
degrees of telangiectasia, phlebectasia, ulcerations with crusts, and
atrophy.179,183 The pattern of CMTC may be either generalized or localized,
often with a segmental distribution and a sharp midline demarcation.The
extremities are most commonly affected, followed by the torso, and only rarely
the face, palms, soles, and mucous membranes.
Most patients with CMTC experience definite improvement of their
mottled vascular pattern, with the most dramatic change occurring in the
first year and tapering thereafter. It has been theorized that this improvement
may be a result of the normal maturation process with thickening of the
epidermis and dermis. However persistence of a purple vascular reticulated
network is a common finding.184
Associated abnormalities occur in up to 50% of patients but may be
overstated through ascertainment bias.184 The following have been reported:
subcutaneous atrophy, deep ulceration, port-wine stain, body asymmetry (both
hemiatrophy and hemihypertrophy), dystrophic teeth, glaucoma, patent ductus
arteriosus, pulmonary hypertension, mental retardation, SWS, macrocephaly,
varicosities, hemangiomas, syndactyly, hypothyroidism, and delayed psychomotor development. CMTC has been described as an associated finding in a
large number of patients with the Adams–Oliver syndrome, which is characterized by distal transverse limb defects and aplasia cutis congenita.185
Decrease in the size of an affected limb is probably the most common finding
associated with CMTC,186 especially those with involvement of the lower
limb.187 A decrease in girth, rather than length, is obvious in some infants
with a single affected limb. Clinically, CMTC must be differentiated from
physiologic cutis marmorata and from genuine diffuse phlebectasia of
Bockenheimer. The latter is a deep venous malformation that begins in
childhood rather than being present at birth, with the gradual development
of multiple large venous sinusoids. It may be difficult to distinguish CMTC
from a reticulated port-wine stain. Persistent livedo and telangiectases
resembling CMTC have been described in neonates with Down syndrome,
Cornelia de Lange syndrome, homocystinuria, neonatal lupus erythematosus,
and other genetic, neurologic, and metabolic conditions.A distinct syndrome
(or phenotype?) of macrocenphaly and cutis marmorata, reminiscent of
CMTC, includes a high risk of growth disturbances and cardiac and neurologic complications.188
The microscopic findings in CMTC are not specific, and diagnosis is best
made on the basis of clinical criteria.The histologic appearance usually consists
of an increased number of dermal thin-walled dilated capillaries, occasionally
with venous lakes and large dilated veins in all layers of the dermis and subcutaneous tissue. Cutaneous atrophy, ulceration, and microthromboses may
also be evident histopathologically.
The management of CMTC involves careful examination for associated
disorders. Laser therapy may help those components with true capillary malformation. Occasionally, ulcerations may be severe enough to require specific
ulcer wound care regimens.They may also become secondarily infected and
may require topical or systemic antibiotics.
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854
ANGIOKERATOMAS
The term angiokeratoma is applied to a group of disorders characterized
by ectasia of the superficial dermal vessels (capillaries) and compact
183. Gerritsen MJ, Steijlen PM, Brunner HG et al. (2000) Cutis Marmorata telangiectatica congenita.
184. Enjolras O (2001) Cutis Marmorata telangiectatica congenita. Ann Dermatol Venereol
128:161–166.
185. Dyall-Smith D, Ramsden A, Laurie S (1994) Adams Oliver syndrome: aplasia cutis congenital,
terminal transverse limb defects and cutis marmorata telangiectatica congenital. Australas J
186. Devillers ACA, de Waard-van der Spek FB, Oranje AP (1999) Cutis marmorata telangiectatica
congenita. Clinical features in 35 cases. Arch Dermatol 135:34–38.
187. Ben Amitai A, Fichman S, Merlob P et al. (2000) Cutis marmorata telangiectatica congenital:
clinical findings in 85 patients. Pediatr Dermatol 17:100–104.
Angiokeratoma circumscriptum
Angiokeratoma circumscriptum is a rare disorder typically appearing as
a large, solitary, hyperkeratotic plaque on a lower extremity. The most
common sites of involvement are the extremities. These vascular malformations may be present at birth or develop during infancy or childhood.
They extend during adolescence.The aggregates of warty, keratotic, deep-red
to blue-black papules and nodules are often distributed in a band-like configuration. These angiokeratomas may enlarge to form a plaque several
centimeters in size; there are reports of lesions as large as one-quarter of
the body.
Microscopically, these lesions consist of dilated capillaries, some of which
may be thrombosed, in the papillary dermis. The closely approximated
epidermis is papillomatous, acanthotic, and hyperkeratotic.
Angiokeratoma circumscriptum may be confused with the so-called
verrucous hemangioma; however, in the latter, the abnormal vascular structures extend into the deep dermis and subcutaneous tissue.
Verrucous “hemangioma” is a misnomer107 for a vascular malformation with
hyperkeratosis and involvement of capillaries, veins, and, in some cases,
lymphatics.
Distinctive hyperkeratotic, cutaneous capillary–venous malformations
resembling angiokeratomas have been described in a small group of patients
with cerebral capillary malformations (also known as familial cerebral cavernomas). These patients may present with headaches and lifethreatening cerebral hemorrhages.189 In some families, the skin lesion
represented a hallmark for risk of brain involvement.190 The first mutated
gene, CCM1, detected is located on 7q21-22 and encodes the protein
KRIT-1.
Angiokeratoma circumscriptum has also been confused with lymphangioma circumscriptum, both clinically and histologically.Thrombosis within
a solitary angiokeratoma may cause changes in size and color simulating
melanoma.191 Small lesions can be removed by electrodesiccation and curettage, cryosurgery or laser ablation; for larger lesions surgical excision is the
treatment of choice.
188. Yano S, Watanabe Y (2001) Association of arrhytmia and sudden death in macrocephaly-cutis
marmorata telangiectatica congenita syndrome. Am J Med Genet 102:149–152.
189. Labauge P, Enjolras O, Bonerandi JJ et al. (1999) An association between autosomal dominant
cerebral cavernomas and a distinctive hyperkeratotic capillaro-venous cutaneous vascular
malformation in 4 families. Ann Neurol 45:250–254.
190. Eerola I, Plate KH, Spiegel R et al. (2000) KRIT 1 is mutated in hyperkeratotic cutaneous
capillaro-venous malformation associated with cerebral capillary malformation. Hum Mol Genet
9:1351–1355.
191. Goldman L, Gibson SH, Richfield DF (1981) Thrombotic angiokeratoma circumscriptum
simulating melanoma. Arch Dermatol 117:138.
Fig. 20.27 Fabry disease
with multiple
angiokeratomas in a
mother of an affected
male.
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Angiokeratoma of Mibelli
Angiokeratoma of Mibelli is a rare condition that occurs primarily in female
children and adolescents. It has been seen in siblings and in children with an
affected parent, suggesting a dominant mode of inheritance with variable
penetrance.192
The frequent association of lesions with acrocyanosis, chilblains, and
frostbite suggests that cold sensitivity is the precipitating factor of this disorder.
The lesions are most often seen on the dorsal and lateral aspects of the toes
and fingers, and the knees and elbows. Less frequently, they arise on the
knuckles, malleoli, palms, soles, and ears. Early lesions are minute bright-red
macules that fade somewhat on diascopic pressure.They slowly increase in
size and become elevated, warty, and darker in color, attaining a diameter of
5–10 mm. The papules are asymptomatic but bleed easily. There is no
tendency for spontaneous involution, although occasionally involution may
occur following trauma.
Microscopically, there are ectatic vessels in the papillary dermis. The
epidermis is hyperkeratotic and often acanthotic, with elongated rete ridges
that enclose the vascular lacunae. There may be some cellular infiltrates,
which are predominantly lymphocytic. Clinically these lesions may resemble
those of acral pseudolymphomatous angiokeratoma of children
(APACHE). However, pseudolymphomatous angiokeratoma is usually
unilateral, unassociated with cold exposure, and has histologic features of a
pseudolymphoma rather than true angiokeratoma.193,194 Treatment of angiokeratoma of Mibelli consists of cryosurgery, electrodesiccation, or laser
ablation.
855
Angiokeratoma of the scrotum and vulva (Fordyce)
Although relatively common, angiokeratomas of the scrotum and vulva are
primarily a phenomenon of aging.The lesions usually appear in middle to
later adult life and arise as multiple, small, bright-red vascular papules that
subsequently become keratotic.They are distributed along the superficial
veins of the scrotum and rarely over the penis, inguinal area, and upper thighs
in men and on the labia majora in women.With increasing age, they may
become quite numerous. On occasion, these angiokeratomas become bothersome and may itch or bleed when traumatized.
The diagnosis of angiokeratoma corporis diffusum must be considered in
any patient with these lesions, particularly if onset is early in life. Symptomatic
lesions can be removed with cryotherapy, electrodesiccation, or laser ablation.
Angiokeratoma corporis diffusum
In the past, angiokeratoma corporis diffusum has been used synonymously
with Fabry syndrome, but, currently, it can only be used as a descriptive term
because the characteristic clinical findings can be seen in patients with several
metabolic diseases as well as in some metabolically normal individuals.195
Anderson-Fabry disease (Fabry disease; angiokeratoma
corporis diffusum)
Fabry disease is a rare X-linked recessive lysosomal storage disorder caused
by an error in glycosphingolipid catabolism.The defect in α-galactosidase A
results in intracellular accumulation of globotriaosylceramide (ceramide trihexoside), which is responsible for the multisystemic involvement.Various
mutations have been described in the gene for α-galactosidase A.196 The
disorder exhibits complete penetrance but variable clinical expressivity in
hemizygous males. Heterozygous females generally have α-galactosidase A
activity and plasma globotriaosylceramide levels intermediate to that of
hemizygous males and normal individuals.Among female carriers, 15% have
192. Smith RBW, Prior IAM, Park RG (1968) Angiokeratoma of Mibelli: a family with nodular lesions of
the legs. Aust J Dermatol 9:329.
193. Ramsay B, Dahl MCG, Malcolm AJ et al. (1990) Acral pseudolymphomatous angiokeratoma of
children. Arch Dermatol 126:1524.
194. Hara M, Matsunaga J, Tagami H (1991) Acral pseudolymphomatous angiokeratoma of children
(APACHE): a case report and immunohistological study. Br J Dermatol 124:387.
195. Gasparini G, Sarchi G, Cavicchini S, Bertagnolio B (1992) Angiokeratoma corporis diffusum in a
patient with normal enzyme activities and Turner’s syndrome. Clin Exp Dermatol 17:56.
similar clinical findings in one or more organs, and approximately 70% show
evidence of the distinctive whorl-like corneal dystrophy.197
The first sign of Fabry syndrome is the onset of cutaneous vascular lesions,
usually between 5 and 10 years of age, although occasionally as late as age 20.
The lesions are small macules and papules, red, purple, or dark blue, usually
1–2mm in size (Fig. 20.27).They develop on the trunk predominantly, particularly on the periumbilical skin, genitalia, inguinal folds, upper thighs,
buttocks, and lumbosacral area, seldom occurring on the hands, feet, or face.
They are distributed symmetrically and do not blanch with pressure.These
angiokeratomas gradually increase in size and number with age and persist
indefinitely.The overlying hyperkeratosis is of a very mild degree.
The oral (and occasionally nasal) mucosa is involved in most of the patients
with Fabry disease.Typical lesions are small discrete blue papules, which on
the vermilion border of the lower lip resemble petechiae.These lesions have
also been identified in the gastrointestinal, genitourinary, and respiratory
mucosae.
A decrease in sweating is often noted by the time puberty begins. Sweating
may be entirely absent by the third decade, with the exception of the face
where sweating may be normal or increased. Bouts of severe, often excruciating, pain occur in association with fever of unknown origin and paresthesias in the hands and feet.The pain, caused by vasomotor disturbances,
usually occurs subsequent to changes in temperature, but it also may be
spontaneous or elicited by exertion or emotional stress. Pedal and ankle edema
is usually present and may result in stasis ulcers.These findings are believed
to be caused by impaired autonomic reflexes resulting from glycolipid deposits
in the autonomic and sensory ganglia.198
Involvement of the ocular tissues occurs early in the disease. The conjunctiva, cornea, lens, and retina can all be affected. Deposits of glycosphingolipid in the corneal epithelium produce a corneal opacity with a
characteristic whorled vortex configuration (corneal verticillata) that is
asymptomatic and visible only on slit-lamp examination.The opacities are
usually present during childhood and are found in all affected males as well
196. Ashton-Prolla P, Tong B, Shabbeer J et al. (2000) Fabry disease: twenty-two novel mutations in
the alpha-galactosidase A gene and genotype/phenotype correlations in severely and midly
affected hemizygotes and heterozygotes. J Invest Med 48:227–235.
197. Burda CD, Winder PR (1967) Angiokeratoma corporis diffusum universale in female subjects.
Am J Med 42:293.
198. Brady RO, Schiffmann R (2000) Clinical features and recent advances in therapy for Fabry
disease. J Am Med Assoc 284:2771–2775.
Fucosidosis
Clinical differences202 distinguish fucosidosis from other metabolic disorders
characterized by angiokeratomas.The diagnosis is firmly established by biochemical assay of fucosidase enzyme activity in fibroblasts or peripheral
leukocytes.The gene FUCA has been localized to chromosome 1. Fucosidase
assays of amniocytes and direct detection of the mutation by DNA analysis
should permit prenatal diagnosis.
Miscellaneous disorders with angiokeratomas
Several other rare metabolic disorders are associated with angiokeratomas.
These include β-galactosidase deficiency (GM1 gangliosidosis), sialidosis with
combined deficiency of β-galactosidase and neuraminidase, aspartyl glycosaminuria, mannosidosis, partial combined deficiency of fucosidase and
α-galactosidase, and α-N-acetylgalactosaminidase deficiency.202 Several wellstudied patients with angiokeratoma corporis diffusum with and without
systemic abnormalities but without demonstrable enzyme defects have also
been reported.
VENOUS MALFORMATIONS
Venous malformations are usually evident at birth and may occur either as
localized or segmental lesions with no associated abnormalities or as a part
of a complex syndrome. Lesions comprise anomalous dilated veins with
irregularly thickened walls, which often have focal regions lacking smooth
muscle cells.9,107,109 There are slit-like or open lumens. Interconnected
channels dissect through normal tissues.Thromboses give rise to calcifications,
which can become progressively more evident over time as phleboliths.
The clinical expression, sequelae, and management of venous malformation
differ, depending on the age of the patient, the severity, and the anatomic
location, but they share some common features.Venous malformations give
a blue hue to the involved skin and mucous membranes.They can be small
and well localized (Fig. 20.28) or large, crossing several anatomic planes
(Fig. 20.29).They swell and enlarge when dependent and with exertion or
activities (such as Valsalva maneuver or crying) that increase venous pressure.
Skin temperature is normal or minimally warm; neither thrill nor bruit is
present. Pain is variable but fairly common. Slow enlargement is commonly
observed over time. Radiologic imaging is helpful in delineating the extent
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as almost all female carriers and are thus highly diagnostic of the disease. A
pathognomonic posterior cortical cataract with narrow wavy spokes also
develops in the lens of about 50% of the hemizygotes but not in the
heterozygous females. Ectasia and tortuosity of the conjunctival and retinal
vessels are another early finding.
The onset of renal involvement during early adult life is indicated by
abnormal findings on urinalysis or renal biopsy. Renal failure, the most
common cause of death, usually ensues. Hypertension, angina pectoris, and
congestive heart failure are also frequent findings. Myocardial infarction may
occur as early as age 29, and cerebrovascular disease also may be evident in
early adult life. Death usually occurs by age 40 as a result of renal, cardiac, or
cerebrovascular disease.
The diagnosis of Fabry disease should be suspected in any individual with
the characteristic clinical findings, a positive family history, and a marked
decrease in activity of α-galactosidase A in white blood cells or cultured
fibroblasts. Early in the course of the disease, casts, red cells, fat-laden epithelial
cells (mulberry cells), and lipid inclusions with characteristic birefringent
“Maltese crosses” appear in the urinary sediment. Biopsy of the skin or kidney
is confirmatory if intracellular birefringent lipoid deposits can be demonstrated. Skin biopsy specimens contain deposits of glycosphingolipid in the
walls of the blood vessels, which stain positively with Sudan black and periodic
acid–Schiff reagent. Analysis of genomic DNA, isolated from patients and
related family members, allows the accurate detection of heterozygous
carriers, so that effective genetic counseling can be provided.196 Prenatal
diagnosis in a pregnant female carrier is possible by demonstration of deficient
α-galactosidase activity in cultured cells obtained by amniocentesis or biopsies
of chorionic villi, or by detecting mutations in the gene.197
Treatment of Fabry disease has traditionally been supportive, but recently
recombinant human α-galactosidase replacement therapy has been shown to
clear microvascular endothelial deposits of globotriaosylceramide from the
kidney, heart and skin in patients with Fabry’s disease, offering hope of a
specific biologic treatment.199 Protection from extremes of temperature is
advised. Phenytoin and carbamazepine have been found to provide relief from
the severe pain crises of Fabry syndrome, although the latter drug may
exacerbate autonomic dysfunction in some patients. Hemodialysis is indicated
for chronic renal failure; renal transplantation has restored renal function and
provided a source of functional enzyme in some individuals.
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856
Disseminated angiokeratomas may also be seen in patients with fucosidosis,200
an autosomal-recessive lysosomal storage disorder, caused by deficient α1fucosidase activity in all tissues.This very rare disorder is manifest by accumulation of fucose-containing glycolipids and glycoproteins in the skin and
other organs; various kinds of mutation of the gene FUCA 1 lead to nearly
absent enzyme function.201 Phenotypically, there is a spectrum of severity of
the disease. Patients dying at an early age usually lack the angiokeratomas that
develop later in the course.
Common clinical manifestations include progressive mental and motor
deterioration, coarse facies, growth retardation, recurrent infections, dysostosis
multiplex, visceromegaly, and seizures. Angiokeratoma corporis diffusum is
seen in more than 50% of patients.The skin lesions appear in the groin and
on the genitalia, rarely as early as 6 months of age but more often later in life,
and gradually spread over the trunk and limbs. Mats of telangiectases develop
on the palms and soles and occasionally on the trunk as well.The gingivae
may also be the site of vascular ectasia, and there is dilatation and tortuosity
of the conjunctival vessels in almost all affected individuals. Sweating abnormalities, both hypo- and hyperhidrosis, have been recorded in a number of
patients.
199. Eng CM, Guffon N, Wilcox WR et al. (2001) Safety and efficacy of recombinant human
α-Galactosidase A replacement therapy in Fabry’s disease. N Engl J Med 345:9–16.
200. Willems PJ, Seo HC, Coucke P et al. (1999) Spectrum of mutations in fucosidosis. Eur J Med
Genet 7:60–67.
Fig. 20.28
openbite.
Venous malformation of the lip and oral mucosa, resulting in an
201. Fleming C, Rennie A, Fallowfield M et al. (1997) Cutaneous manifestations of fucosidosis. Br J
Dermatol. 136:594–597.
202. Kodama K, Kobayashi R, Abe A et al. (2001) A new case of N-acetylgalactosaminidase deficiency
with angiokeratoma corporis diffusum, with Menière’s syndrome and without mental retardation.
Br J Dermatol. 144:363–368.
synovium of the joints may also be affected.162,206 In rare cases, the muscle is
affected without overlying skin involvement. Genitalia are commonly affected
in association with a lower extremity venous malformation. Limb length discrepancy is uncommon and generally mild. If there is synovial involvement,
the symptoms often manifest before 10 years of age and include pain, swelling,
and functional impairment, owing to effusion or hemarthrosis. Permanent
joint damage and severe muscle pain may follow. Chronic localized intravascular coagulopathy is common in patients with severe, extensive, or bulky
lesions.This coagulopathy causes pain, thromboses, and phlebolith formation
and may result in severe bleeding during surgical procedures. Low fibrinogen
and elevated D-dimers are the hallmarks of this disorder.This venous malformation-associated local and disseminatred intravascular coagulation is often
mislabeled in the literature as Kassabach–Merritt (KM) syndrome, but it is
not the same condition (see discussion of KMP and Table 20.5).162 The
platelet count may be slightly low, but not to the degree seen in the KMP.
Treatment with low-molecular-weight heparin is indicated in severe disease.
Conservative management with elastic stockings is always recommended, and
for localized lesions percutaneous sclerotherapy may be helpful.206 Excision
may be considered in some patients with symptomatic lesions.207 Staged
excisions are usually necessary and, in contrast to AVMs, this does not trigger
the growth of the residual venous malformation. Knee joint venous malformation embedded in the synovial membrane that causes repeated episodes
of hemarthrosis is an indication for resection to prevent joint degeneration,
similar to that observed in hemophiliacs.
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Fig. 20.29 Venous
malformation of the leg
involving the skin and
musculature.
857
The glomuvenous malformations: glomus tumors
(glomangiomas) and glomangiomatosis
of involvement and in differentiating venous malformations from other
vascular anomalies and soft tissue tumors. MR imaging is the best single
imaging modality: it gives a bright hypersignal on T2-weighed spin-echo
sequences, because of slow flow, and this clearly indicates the extent of the
lesions throughout the involved tissues.29 There is rarely a need for CT scans
to look for associated bony defects. Doppler ultrasound is a useful study for
limb venous malformations: as it is a rapid and easy method of portraying the
vascularization and low-flow velocity.203 Arteriography and venography are
usually not necessary.29
Cephalic venous malformations create a blue discoloration of the skin
and mouth, distortion of facial features, and pain when swelling occurs in
dependent positions or with straining. Involvement of the cheek and tongue
can cause dental malocclusion, crossbite and/or openbite deformity through
a mass effect on the developing jaws during childhood (Fig. 20.28). Deep
mucous membranes lesions, involving the palate, pharyngeal and laryngeal
areas, can cause snoring, progressive sleep apnea and respiratory difficulties.
Orbital involvement, in communication with cheek and infratemporal venous
malformations through the sphenomaxillary fissure, can cause enophthalmos
when standing, and exophthalmos when supine; dark-blue veins may be visible
on the inner surface of the conjunctiva or sclera. Usually there is no visual
impairment. Management of cephalic venous malformations combines percutaneous sclerotherapy and staged excisions. A multistep approach, through
multiple procedures over the years, will give the best results. In many patients,
“cure” is impossible; treatment will aim at improving appearance, maintaining
facial symmetry and muscle dynamics, and restoring lip competence. Soft tissue
venous lesions and bone deformities can be treated in parallel.204,205
Venous malformations of the limb can be well localized or diffuse. Deeper
venous malformations often involve the musculature and in some cases the
Glomus tumors (glomangiomas) are relatively uncommon hamartomas of the
glomus body, a special temperature-regulating arteriovenous shunt that
bypasses the usual capillary bed of the dermis. Solitary tumors are more likely
to occur in adults, whereas multiple lesions, more commonly have their onset
in childhood.Although some cases are sporadic, rather than familial, a recent
study carefully searching for small lesions in family members found familial
occurrence in more than 75% (LM Boon, personal communication 2001).
Although very rare in infancy, congenital glomus tumors have been
reported.208 In a review of 731 cases of glomus tumors occurring in children,
six were congenital and one of those was also multiple.209
Solitary glomus tumors usually occur on the upper extremities, particularly
in the nail beds, although occasionally they are found on the lower extremities, head, neck, or genitalia.These extremely tender purple nodules vary
in size from 1mm to several centimeters. In addition to marked tenderness,
there may be paroxysms of pain, either spontaneously or evoked by trauma.
The solitary tumors are not genetically transmitted. Multiple glomus tumors
are transmitted in an autosomal dominant fashion. In a given family, some
affected members have small lesions, sometimes only a solitary lesion, whereas
others have widely scattered (disseminated) lesions and still others have
grouped lesions, often in a segmental distribution (Fig. 20.30).These large
plaque-like lesions are usually congenital.They may be pink and macular at
birth, becoming thicker and more nodular during childhood or may already
be thick at the time of birth. Diagnosis can be particularly difficult in deeply
pigmented skin.The lesions are usually dark blue and multinodular; although
they resemble venous malformations superficially, they are firmer, less compressible and show less change with dependency or exercise.210
Familial glomangiomas have been linked to chromosome 1p21-22.211 The
gene VMGLOM is currently a poorly understood regulator of vasculogenesis
or angiogenesis.212
203. Trop I, Dubois J, Guibaud L et al. (1999) Soft-tissue venous malformations in pediatric and young
adult patients: diagnosis with Doppler. US Radiology. 212:841–845.
204. Enjolras O, Deffrennes D, Borsik M et al. (1998) Les “tumeurs vasculaires” et les règles de prise
en charge chirurgicale. Ann Chir Plast Esthet. 4:455–490.
205. Berenguer B, Burrows PE, Zurakowski D et al. (1999) Sclerotherapy of craniofacial venous
malformations. Plast Reconstr Surg. 104:1–15.
206. Yakes WF (1994) Extremity venous malformations. Semin Intervent Radiol. 11:322–329.
207. Upton J, Coombs CJ, Mulliken JB et al. (1999) Vascular malformations of the upper limb: a
review of 270 patients. J Hand Surg (US). 24:1019–1035.
208. Landthaler M, Braun-Falco O, Eckert F et al. (1990) Congenital multiple plaquelike glomus
tumors. Arch Dermatol 126:1203–1207.
209. Kohout E, Stout AP (1961) The glomus tumor in children. Cancer 14:555–566.
210. Mounayer C, Enjolras O, Wassef M et al. (2001) Facial glomangiomas masquerading as venous
malformations. J Am Acad Dermatol in press.
211. Boon LM, Brouillard P, Irrthum A et al. (1999) A gene for inherited cutaneous venous anomalies
(“glomangiomas”) localizes to chromosome 1p21-22. Am J Hum Genet 65:125–133.
212. Irrhum A, Brouillard P, Enjolras O et al. (2001) Linkage disiquilibrium narrows locus for venous
malformations with glomus cells (VMGLOM) to a single 1.48 Mbp YAC. Eur J Hum Genet 9:34–38.
858
Fig. 20.30
Glomangiomatosis. Family
history was positive in this
case.
Fig. 20.31 Maffucci
syndrome with
radiographic evidence of
bony involvement.
Maffucci syndrome
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On histopathologic examination, the large tortuous dysplastic venous
channels are reminiscent of a capillary–venous malformation. However in
many vessels, the walls contain one or several rows of poorly differentiated
cubical cells with eosinophilic or pale cytoplasm and a round nucleus; these
cells stain with stains specific for vimentin, and smooth-muscle cell α- actin,
a pattern consistent with glomus cells.210 The pattern has features of both a
vascular malformation and a tumor. Therefore the names venous malformation with glomus cells or glomuvenous malformation have been
proposed as more appropriate names than glomangioma.
Complete surgical excision is the only reliable treatment for these tumors,
although percutaneous sclerotherapy may improve some.
AL
A
Maffucci syndrome is a rare congenital disorder with no recognized genetic
basis. It is characterized by dyschondroplasia of one or more limbs, multiple
enchondromas, and vascular malformations that are often large and located
in the subcutaneous tissues.The lesions appear early in life, often in infancy.
There is no racial or sex predilection.The vascular malformations are blue or
purple, soft, compressible, and occasionally tender. Cutaneous lesions exhibit
clinical (blue color of the nodules), radiological (presence of phleboliths and
vascular tufts on the late phase of the angiogram), and pathologic features of
venous malformations (Fig. 20.31). However, on pathologic specimens there
is coexistence of anomalous venous channels and of a vascular tumor, the
spindle cell hemangioendothelioma.107,213 Although the vascular lesions may
develop anywhere on the body surface, the hands and feet are involved most
frequently. Localized forms involving a single extremity are observed.The site
of the vascular malformation does not necessarily correlate with that of
skeletal lesions, and lesions in bones may appear before the skin lesions.214
Skeletal changes consist of multiple enchondromas, exostoses, and recurrent
fractures. Bone lesions are usually bilateral but asymmetric (Fig. 20.31B).
Radiographic findings include oval defects in association with expansion and
thinning of the cortex of involved bones. Limb deformity and leg lengthening, as well as scoliosis, occur in approximately one-third of patients.
The diagnosis of Maffucci syndrome is usually based on clinical findings.
The differential diagnosis of the skeletal changes includes Ollier and Gorham
syndromes.The skin changes often resemble multiple venous malformations
clinically.
The most serious complications of Maffucci syndrome, aside from multiple
fractures in childhood, are the neurologic deficits, resulting from encroachment of cranial enchondromas on the cerebral cortex, and the development
of malignant tumors. Chondrosarcomas are the most common malignancy
and are estimated to occur in 15% of patients. Other malignancies such as
angiosarcomas, fibrosarcomas, lymphangiosarcomas, and intracranial tumors,215
have also been reported.
Treatment involves surgical extirpation of skeletal and vascular lesions
where possible. Diagnostic biopsy is mandatory to exclude malignancy in any
213. Hisaoka M, Aoki T, Kouho H et al. (1997) Maffucci’s syndrome associated with spindle cell
hemangioendothelioma. Skeletal Radiol 26:191–194.
214. Enjolras O, Wassef M, Merland JJ (1998) Syndrome de Maffucci; une fausse malformation
veineuse? Un cas avec hémangioendothéliome à cellules fusiformes. Ann Dermatol Venereol
125:512–515.
215. Balcer LJ, Galetta SL, Cornblath WT et al. (1999) Neuro-ophthalmologic manifestations of
Maffucci’s syndrome and Ollier’s disease. J Neuroophthalmol 19:62–66.
B
bony or soft tissue tumor that enlarges rapidly or becomes painful. Radiation
is of no therapeutic value.
Blue rubber bleb nevus syndrome
The blue rubber bleb nevus syndrome consists of multiple venous malformations in the skin and gastrointestinal tract associated with massive or
occult intestinal hemorrhage and anemia.This disorder is rare, without known
sexual predilection. Most cases are sporadic; some are inherited in an
autosomal dominant fashion.The etiology is unknown.The syndrome usually
is manifest at birth or during early childhood, but adult onset has been
reported.216
The cutaneous malformations may be solitary or may number in the
hundreds and can occur anywhere on the skin surface.The trunk and upper
extremities are involved most often. Oral mucosal lesions may be evident as
well. Skin lesions range in size from 1–2mm to several centimeters, vary in
color from purplish-red to blue or black, and may be flat or elevated.
According to the original description by Bean, they have “the feel and look
of rubber nipples, are compressible and refill fairly promptly from their
rumpled compressed state.” In some cases, they may contain thrombi and
phleboliths. These patients may also develop large combined venous and
lymphatic vascular malformations with blue nodules on their surface.The
vascular lesions tend to increase in size and number with age; spontaneous
involution does not occur.
Histologically, the cutaneous venous malformations have certain distinctive
features. In some areas, the vascular spaces, which are separated by a smooth
muscle or fibrous stroma, are lined by cuboidal cells and intimately associated
with sweat glands.
Gastrointestinal involvement can easily be detected by endoscopic
examination.The gastrointestinal vascular malformations are usually multiple
and submucosal, involving the small intestine and distal colon.217 The lesions
can be macular, polypoid, or, rarely, tumor-like masses. Each nodule has an
overlying central blue or purple cap.218 They vary in size and number, but
there is no correlation with extent of cutaneous involvement. MR imaging
is a useful noninvasive modality to detect gastrointestinal lesions. Selective
216. Oranje AP (1996) Blue rubber bleb nevus syndrome. Pediatr Dermatol 3:304–310.
217. Goraya JS, Marwaha RK, Vatve M et al. (1998) Blue rubber bleb nevus syndrome. Pediatr
Hematol 15:261–264.
218. Gallo S, McClave S (1992) Blue rubber bleb nevus syndrome: gastrointestinal involvement and
its endoscopic presentation. Gastrointest Endosc 38:72–76.
859
abdominal angiography performed during bleeding episodes can demonstrate
location and extent of vascular lesions.These vascular malformations can also
arise in other organs, including the liver, lung, pleura, urinary tract, brain and
muscle.
Management is directed toward control of chronic gastrointestinal bleeding
and correction of the resultant iron-deficiency anemia. Endoscopic electrocautery or surgical removal may be indicated if bleeding is severe.219
Cutaneous lesions do not need to be removed unless they are disabling or
disfiguring.The prognosis of this condition cannot be predicted.
Blue rubber bleb nevus syndrome, with its malformations of the venous
network, can easily be differentiated from Osler–Weber–Rendu syndrome,
which has malformations of the capillaries and arterioles.
Management
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AVMs are fast-flow vascular malformations with direct arteriovenous shunts
without an intervening capillary bed.They are among the most dangerous of
the vascular anomalies.There is no gender predominance.AVMs are noted at
birth in 40% of patients. Progression during childhood occurs in a majority.
Known trigger factors include puberty, pregnancy (25% in a group of 102
women),219 and trauma, including iatrogenic causes such as subtotal surgical
resection, proximal artery ligation, or arterial embolization that is too
proximal.AVMs can be classified according to the ISSVA–Schobinger staging2
into four clinical stages: 1, dormancy; 2, expansion; 3, destruction; and 4,
destruction plus congestive cardiac failure. In stage 1, AVMs mimic a portwine stain or an involuting hemangioma, or they create a small pulsatile mass
under normal skin (Fig. 20.32). In stage 2, the expansion creates plaques or
masses, which are red and warm, with local tenderness, pulsations, bruits, and
enlarged tortuous veins. In stage 3, skin necrosis, torpid ulcers, bleeding and
hemorrhage become evident and lytic bone lesions may develop. Stage 4 is
rare, occurring in approximately 2.5% and consists of increasing congestive
cardiac failure from increased arterial pressure.220,221
Once a diagnosis of AVM is considered, certain investigations are necessary.
Ultrasound/Doppler studies can help to confirm the high-flow nature of the
condition and will provide measurements of the comparative output between
arteries on the affected and unaffected sides of the body.This helps in serial
reevaluation. If the output is markedly increased on the affected side, cardiac
evaluation and follow-up become mandatory. MR imaging and arteriography
plus conventional arteriography are all helpful in characterizing the angioarchitecture and extent of the AVM. Effects on the bone are best evaluated with
CT scan, which can identify complications such as draining veins penetrating
the skull and draining into an intracranial sinus.
AL
ARTERIOVENOUS MALFORMATIONS
Treatment is often fraught with difficulty and no one treatment can be
guaranteed to provide total cure. Embolization alone may initially appear to
be successful, but good long-term results are rare, particularly for lesions on
the extremities or facial AVMs.220 Combining embolization and resection of
the AVM nidus and overlying skin may give good results for small AVMs,221
but the need for systematic excision of small AVMs (stage 1 or 2) in order to
prevent further extension is controversial. For larger lesions (stage 2 and 3),
embolization and excision are also performed, but covering the surgical
wound is not easy; in addition, the therapeutic outcome is uncertain. In
patients with pain, ulcers, and hemorrhages, particularly those with extensive
AVMs in limbs, distal amputation may be required, even years after a technically and clinically effective embolization.222 In some distal extremity AVMs
with local complications, one may stabilize the disease by covering the region
with a vascularized, anastomosed cutaneous and muscular flap transfer, after
wide excision or localized amputation.223 Similar flap transfer is used for severe
219. Ertem D, Acar Y, Kotoliglu E et al. (2001) Blue rubber bleb nevus syndrome. Pediatrics
107:418–420.
220. Enjolras O, Logeart I, Gelbert F et al. (2000) Malformations artérioveineuses. Etude de 200 cas.
Ann Dermatol Venereol 127:17–22.
Fig. 20.32
Scalp arteriovenous malformation mimicking a port-wine stain.
facial AVMs in adolescents and adults, and this may also cure the lesion or
stabilize the progress of a residual AVM; nevertheless, the results are
cosmetically poor.204 Therapies that are known to be trigger factors of AVMs,
such as arterial ligation, partial excision, proximal or incomplete embolization,
PDL for the red staining of the skin overlying the arteriovenous nidus, and
cryosurgery, should be avoided whenever possible.
Parkes–Weber syndrome
The presence of arteriovenous fistulae distinguishes Parkes–Weber syndrome
from KT syndrome.9 Other features of Parkes–Weber syndrome include
warmth and tenderness overlying the malformation, dilated veins with a thrill
on palpation, lengthening of the affected limb, and hypertrophy in girth owing
to both lipomatosis and lymphatic hyperplasia. Patients with Parkes–Weber
syndrome may develop high-output congestive heart failure secondary to
the arteriovenous fistulae.The prognosis is not as good as in KT syndrome,
because there may be progressive worsening with pain and worsening functional outcome.
Treatment of Parkes–Weber syndrome should not be aggressive. Conservative management (such as compression stockings) is recommended.
Surgical orthopedic management is necessary when leg length discrepancy
is prominent. Epiphysiodesis may be considered, to achieve symmetric lower
extremities; in many patients, this surgical procedure in the knee area, where
arteriovenous fistulae are commonly located, induces worsening of the
fast-flow malformation. Embolization is usually unsatisfactory because of
multiple arteriovenous shunts along the limb. Surgical resection of the shunts
usually fails, as new vessels are recruited and complicate the anomalous
vascular network. Overaggressive surgical management can precipitate local
221. Kohout MP, Hansen M, Pribaz JJ et al. (1998) Arteriovenous malformations of the head and
neck: natural history and management. Plast Reconstr Surg 102:643–654.
222. White RI, Pollack J, Persing J et al. (2000) Long-term outcome of embolotherapy and surgery
for high-flow extremity vascular malformations. J Vasc Interv Radiol 11:1285–1295.
223. Toh S, Tsubo K, Arai H et al. (2000) Vascularized free-flaps for reconstruction after resection of
congenital arteriovenous malformations of the hand. J Reconstr Microsurg 16:511–517.
860
Wyburn–Mason syndrome is similar, combining a facial cutaneous AVM,
midbrain AVM and unilateral congenital anomalies of the retinal vessels.
Treatment of these unusual but severe syndromic neuro-ophthalmologic
and cutaneous AVMs is daunting; it is rarely possible to excise the whole facial
lesion, using either free-flap transfer or cutaneous expansion to cover the large
wound created, and arterial embolization is a palliative therapy that is usually
unable to change a frequently bad prognosis.
Cobb syndrome
LYMPHATIC MALFORMATIONS
Cutaneomeningospinal angiomatosis (Cobb syndrome) consists of a capillary
stain or a fast-flow skin mass on the posterior thorax (and sometimes on the
limb) in association with a contiguous or nearly contiguous fast-flow vascular
malformation of the spinal cord.224 A vertebral body is sometimes involved.
The location of the spinal cord lesion corresponds within a segment or two
with the involved dermatome of the skin lesion.The syndrome is very rare,
much rarer than isolated intraspinal AVMs.225
The neurologic problems, which usually develop during adolescence or
young adulthood, are the result of cord compression by the AVM or of spinal
subarachnoid hemorrhages (occurring in one-third of patients).They vary
with the level of spinal cord involvement and are thought to result from
physical cord compression and/or anoxia.The spinal AVM is intramedullary
in most patients; it may also be medullary and meningeal, or perimedullary.
The patient becomes symptomatic as the spinal AVM increases in size.The
onset of neurologic signs and symptoms can be gradual, episodic and progressive, or sudden and acute.They include pain in the areas supplied by the
involved segment of the spinal cord, radiculopathy, weakness and atrophy of
the limb muscles, loss of sensation, monoplegia, paraparesis and paraplegia.
Scoliosis is present in 20% of reported cases.
The diagnosis of Cobb syndrome is suggested by the presence of a posterior
thoracic vascular lesion in association with neural deficit.The vascular lesion
either mimics a port-wine stain or is evident as an AVM with a thrill and
bruit (with or without stained overlying skin); it is accompanied by neurologic
evidence of a vascular abnormality of the spinal cord. MR imaging and
angiography226 and spinal angiography will demonstrate the vascular fast-flow
lesion and pinpoint its precise location. Patients are generally not considered
at risk for Cobb metameric syndrome if the cutaneous vascular malformation
is venous, capillary–lymphatic–venous, or purely capillary, although on rare
occasions quiescent AVMs may appear as a macular “pseudo-port-wine stain,”
making this a relative, rather than absolute, rule.
Endovascular embolization of spinal AVM has greatly improved the
neurologic prognosis of Cobb syndrome; however, results may be temporary.
If there is also a symptomatic vertebral vascular lesion, it can be treated by
means of intralesional injections of ethanol or glue under CT guidance.
Intramedullary lesions can be resected in some patients when embolization
is impossible or too dangerous.227
Lymphatic malformations, or so-called lymphangiomas, are disorders of the
lymphatic system and of the circulation of lymphatic fluid. Several subcategories appear in the medical literature based on clinical features (e.g.,
lymphangioma simplex, lymphangioma circumscriptum, cavernous lymphangioma, cystic hygroma, acquired progressive lymphangioma, benign lymphangioendothelioma); there are also several severe diffuse, often lethal, visceral
types known as diffuse visceral lymphangiectasia or visceral lymphangiomatosis. It is probably more helpful to think of lymphatic malformations as microcystic (corresponding to lymphangioma circumscriptum
and cavernous lymphangioma) and macrocystic (previously called cystic
hygroma). Combined micro- and macrocystic types are common, particularly
in the head and neck area, as well as in other sites (Fig. 20.33). In a review of
186 patients, lymphatic malformations involved the head and neck in 48%,
the trunk and extremities in 42%, and were internal and visceral in 10%.228
Common complications of lymphatic malformations include disfigurement,
infection, and bleeding (superficial vesicles become hemorrhagic or there is
a sudden hemorrhage in a large cyst). Recurrent inflammation with swelling
can be particularly dangerous in some locations. For example, in orbital
locations it can cause proptosis and may impair vision. In the mouth and
perioral area it can create deformity of the maxilla and mandible; it may then
cause crossbite, openbite, and speech impairment. The diagnosis is often
clinical but is best confirmed with MR imaging, which often demonstrates
fluid levels to suggest cystic components and shows the extent of the malformation. The stagnant lymphatic lesions show a bright hypersignal on
T2-weighed sequences.
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complications, including pigmentary changes in skin, pseudo-Kaposi sarcoma
skin alterations, pain, ulcers, hemorrhage, and ischemic distal changes in toes
or digits necessitating amputation.These patients are evaluated initially with
Doppler studies, MR arteriography, and conventional arteriography. Isotopic
lymphography should be performed if lymphatic involvement is suspected.
Many patients with Parkes–Weber syndrome have been grouped with those
with KT syndrome under the rubric Klippel–Trenaumay–Weber syndrome,
as the distinction between the two entities has not always been clear.
Fig. 20.33 Lymphatic
malformation of the
cheek.
Bonnet–Dechaume–Blanc and Wyburn–Mason
syndromes
Bonnet-Dechaume-Blanc syndrome is the association of a pseudo-port-wine
vascular anomaly of the skin (which is actually an AVM in a quiescent stage)
with retinal and brain AVMs. Lesions tend to worsen progressively or become
evident during childhood in all three locations.The cutaneous lesion is either
hemifacial, involving the eyelids and cheek, or located in the central portion
of the face (nose, forehead and, upper lip). It worsens over many years, particularly when incomplete resection is performed.The intracranial lesions
occur predominantly around the thalamus and mesencephalon and are
clinically manifest after hemorrhage; vascular accidents may occur in
childhood or early adult life.
224. de Vera C, Peiro R, Gort. A et al. (1996) Cobb syndrome. Rev Neurol 24:720.
225. Aminoff MJ, Logue V (1974) Clinical features of spinal vascular malformations. Brain 97:197–210.
226. Binkert CA, Kollias SS, Valavanis A (1999) Spinal cord vascular disease: characterization with fast
three-dimensional contrast-enhanced MR angiography. Am J Neuroradiol 20:1785–1793.
227. Huffmann BC, Spetzger U, Reinges M et al. (1998) Treatment strategies and results in spinal
vascular malformations. Neurol Med Chir (Tokyo) 38:231–237.
228. Alqahtani A, Nguyen LT, Flageole H et al. (1999) 25 years’ experience with lymphangiomas in
children. J Pediatr Surg 34:1164–1168.
Macrocystic lymphatic malformations are uncommon lesions that most often
occur in the neck, axilla, groin, or chest wall.They are large, single or multiple
cysts that are usually present at birth or by the age of 2 years. Rare documented cases of sudden development in an adolescent or an adult have been
described. Large congenital forms are documented by ultrasound as early as
the fourth month of pregnancy; in some of these fetuses a chromosomal
abnormality is present (Down or Turner syndrome). In all cases, there is an
increase of amniotic fluid α-fetoprotein level.229 Usually macrocystic lymphatic malformations persist unchanged, if not treated, or they expand;
however, there are instances of spontaneous regression, usually after infection
of the cysts. Some lymphatic malformations of the neck extend into the
mediastinum; others involve the tongue and floor of the mouth. Infection
and hemorrhage into the lesion or close to it may lead to rapid enlargement,
with resultant respiratory compromise, dysphagia, infection, and death.
Radiologic assessment of the upper airway is essential for proper management
of patients with neck lesions, as acute obstruction may supervene at any time.
Management
Management
The treatment of microcystic and combined micro-macrocystic lymphatic
malformations is exceedingly difficult. If therapy is indicated, deep and
extensive surgery is necessary. If possible, this should be performed after tissue
expansion of adjacent normal skin to take a larger area and avoid recurrences.
A number of patients with extensive lesions of the head and neck undergo
multiple resections with a high rate of recurrence and persistent disease, and
poor cosmetic and functional results.236,238 Patients with jaw involvement and
overgrowth need orthodontic and orthognathic procedures after completion
of skeletal growth, but overgrowth may recur and is difficult to repair. Carbon
dioxide, diode and Nd–YAG lasers have been used successfully to obliterate
the vesicular component in some lymphatic malformations, while the PDLs
usually give only a temporary improvement after multiple procedures.
Acquired progressive lymphangioma
Acquired progressive lymphangioma (benign lymphangioendothelioma) is a
rare but distinctive form of lymphatic malformation that develops gradually
over a period of years.239 It may occur at any age but is often seen in young
individuals and takes the form of a well-defined solitary erythematous macule
or plaque that is usually asymptomatic.These lesions may become quite large,
in some instances measuring more than 30cm. The histologic findings of
anastomosing, often widely dilated, channels lined by a single flat layer of
endothelial cells dissecting through the collagen fibers in the dermis and
occasionally the fat make it difficult to distinguish from a well-differentiated
angiosarcoma or patch-stage Kaposi’s sarcoma. Excision is the treatment of
choice.
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Recommendations for the management of macrocystic lymphatic malformations have varied from early total excision to waiting for spontaneous
regression for several years. However, as resection often has considerable
morbidity, techniques of percutaneous sclerotherapy have been developed,
using a number of sclerosants with high irritant capabilities: the most widely
used have been killed bacteria, known as OK-432230 or Picibanil231,232 and
Ethibloc, a mixture of a corn protein and ethanol.233 Other sclerosants that
have been used include sodium morrhuate, dextrose, bleomycin, cyclophosphamide, and doxycycline.234 Shrinkage of the lesions after single or
multiple procedures is the result of the intense inflammatory reaction and
subsequent fibrosis. It occurs in more than 50% of patients and the technique
is now considered a first-line effective treatment.
lymphatic malformation. Leakage of lymphatic fluid may occur. Recurrent
cellulitis is common and can cause worsening lymphedema.
AL
Macrocystic lymphatic malformations
861
Microcystic lymphatic malformations
Microcystic lymphatic malformations are more common than macrocystic
lymphatic malformations.The lesions are sometimes present at birth or appear
in childhood.They may develop anywhere on the body surface, but the most
common sites are the axillary folds, shoulders, neck, proximal limbs, perineum,
tongue, and floor of the mouth, where they may encroach on parapharyngeal
spaces and the larynx, and create bony overgrowth.235,236 The lesions consist
of grouped small papules and translucent thin-walled vesicles resembling frog
spawn, occasionally with superimposed hyperkeratosis. Some of the vesicles
may contain varying amounts of blood, giving them a pink-red cast;
coagulation of blood will produce a purple to black color.237 Microcystic
lymphatic malformations range in size from small (1cm) plaques of vesicles
to exceedingly large lesions covering extensive areas.A deeper component is
almost always present and may be detectable as diffuse swelling or thickening
and a bluish hue of the underlying tissues. Massive lymphatic malformations,
deeply invading the dermis, subcutis, and underlying muscles, may involve an
entire limb and appear as spongy subcutaneous masses without overlying color
change or as multiple dark red vesicles, often with a hyperkeratotic or even
verrucous surface (sometimes labeled angiokeratomas).237 Very often, clusters
of vesicles develop in the vicinity of the scar from a previously excised
229. Musone R, Bonafiglia R, Menditto A et al. (2000) Fetuses with cystic hygroma. A retrospective
study. Panminerva Med 42:39–43.
230. Ogita S, Tsuto T, Deguchi et al. (1991) OK-432 therapy for unresectable lymphangiomas in
children. J Pediatr Surg 26:263–270.
231. Brewis C, Pracy JP, Albert DM (2000) Treatment of lymphangiomas of the head and neck in
children by intralesional injection of OK-432 (Picibanil). Clin Otolaryngol 25:130–135.
232. Luzzato C, Midrio P, Tchaprassian Z et al. (2000) Sclerosing treatment of lymphangiomas with
OK-6432. Arch Dis Child 82:316–318.
233. Brevière GM, Bonnevalle M, Pruvo JP et al. (1993) Use of Ethibloc in the treatment of cystic and
venous angiomas in children. Eur J Pediatr 3:166–170.
234. Molitch HI, Unger EC, White CL et al. (1995) Percutaneous sclerotherapy of lymphangiomas.
Radiology 194:343–347.
Lymphedema
Lymphedema is the result of inadequate lymphatic drainage. Lymphatic
obstruction from any cause produces a similar sequence of events.The protein
content of the extravascular tissue rises and, because of its osmotic effect,
additional water is retained.The newly established equilibrium permits the
lymphatics to remove a smaller volume of lymph that is richer in protein.
Unfortunately, an excess of extravascular protein often leads to proliferation
of fibroblasts and organization of the edema fluid. This gives rise to the
characteristic firm, nonpitting, and largely irreversible swelling of chronic
lymphedema. For this reason, it is important to institute treatment early.
Advances in diagnostic imaging studies and the development of improved
lymphotropic contrast agents allow more accurate assessment of lymphatic
function and lymphatic vascular morphology. Molecular genetic studies are
delineating the origins of congenital lymphedema.240
Lymphedema is divided into primary and secondary forms. Secondary
lymphedema is caused by lymphatic obstruction following surgery, by
recurrent lymphangitis or cellulitis, by an extralymphatic process (such as
compression by neoplastic invasion of lymphatics), or by fibrosis resulting
from radiation therapy or scar formation. Secondary lymphedema is rare in
childhood.
Patients with primary lymphedema are usually subdivided into clinical
groups according to the age of onset. In congenital lymphedema, the swelling
235. Padwa BL, Hayward PG, Ferraro NF et al. (1995) Cervicofacial lymphatic malformation: clinical
course, surgical intervention, and pathogenesis of skeletal hypertrophy. Plast Reconstr Surg
95:951–960.
236. Hartl DM, Roger C, Denoyelle F et al. (2000) Extensive lymphangioma presenting with upper
airway obstruction. Arch Otolaryngol Head Neck Surg 126:1378–1382.
237. Davies D, Rogers M (2000) Morphology of lymphatic malformations, a pictorial review.
Australas J Dermatol 41:1–7.
238. Orvidas LJ, Kasperbauer JL (2000) Pediatric lymphangiomas of the head and neck. Ann Otol
Laryngol 109:411–421.
239. Guillou L, Fletcher CD (2000) Benign lymphangioendothelioma (acquired progressive
lymphangioma): a lesion not to be confused with well-differentiated angiosarcoma and patchstage Kaposi’s sarcoma) clinicopathologic analysis of a series. Am J Surg Pathol 24:1047–1057.
240. Irrthum A, Karkkainen MJ, Devriendt K et al. (2000) Congenital hereditary lymphedema caused
by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 67:295–301.
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is firm and is characterized by pitting on pressure. In lymphedema praecox,
females are primarily affected, and the swelling appears spontaneously,
generally between the ages of 9 and 25 years. It is common to see patients
with one extremity involved for years and later have a second one become
affected. It is evident, using isotopic lymphography in patients with one limb
involved, that the lymphatic network of these patients is bilaterally impaired;
however, the clinical manifestations may occur at different periods of life.
About 20% of primary lymphedema is familial. Lymphedema occurring
distally and present at birth is referred to as Milroy disease; Meige disease
describes later onset. In these autosomal dominant disorders, the edema is
almost always confined to the legs and feet.The edema is at first pitting and
disappears completely with elevation. Subsequently, with the development of
fibrosis, the swelling becomes harder and more or less nonpitting. The
epidermis may become hyperkeratotic and warty (so-called pseudoverrucous
hyperplasia) and the skin is often chronically thickened. Fissures and secondary
infection often occur. Changes of elephantiasis, similar to that caused by
parasitic infection in the tropics, occurs in severe cases.Another familial form
is Hennekam disease, combining limb lymphedema, facial anomalies (flat
face, flat nasal bridge, tooth and ear anomalies), intestinal lymphangiectasia
with protein-losing enteropathy, mental retardation, and cerebral anomalies;
most reported patients were born from consanguineous parents.241,242
Several other syndromes have been described that combine congenital
primary lymphedema with various associated anomalies. Many are genetic
and of varied inheritance. Lymphedema has been associated with Turner and
Noonan syndromes. Opitz has proposed that the presence of generalized
congenital lymphedema can contribute to certain facial dysmorphisms as
well as minor abnormalities of the ears, hair patterns, nails, and palmar
prints.243
hood, often occurring in association with intravascular coagulopathy and
leading to severe visceral hemorrhages.
Management
Treatment of advanced lymphedema is very unsatisfactory, but early treatment
can often prevent further deterioration.This includes external pressure by
elastic stockings or bandages, active muscle exercises, and centripetal massage.
Diuretics may also be helpful. Systemic antibiotics may be necessary for the
recurrent inflammatory episodes and infections. Sequential pneumatic compression devices have been efficacious in many instances in preventing progression of the lymphedema. Operations to restore the damaged or absent
lymphatics are generally unsatisfactory, with only transient improvement.
Surgery, to remove the grossly thickened tissues, and liposuction are sometimes
performed. Lymphaticovenous shunts have given some improvement in
visceral forms with massive effusions. Visceral lymphangiomatosis in the
thoracic or abdominal area, or both, is a life-threatening situation in child-
Three autosomal dominant disorders, Riley–Smith syndrome, Bannayan–
Zonana syndrome and Ruvalcaba–Myrhe syndrome, have been demonstrated
to have clinical overlap and are now considered a part of the same disease
spectrum named Bannayan–Riley–Ruvalcaba syndrome (BRRS). Interestingly, families with BRRS share mutations of the same tumor suppressor gene,
PTEN, as families with Cowden syndrome.246,247 Mutations in PTEN have
also been seen in patients with features of Proteus syndrome. Symptoms in
BRRS include macrocephaly without hydrocephalus, lipomas, capillary
and/or venous malformations, lymphatic anomalies, pigmented macules
of the genitalia, intestinal polyps, macrodactyly, pseudopapilledema and
Hashimoto thyroiditis.248 There is normal CNS function and, therefore,
awareness of the benign nature of the macrocephaly should help to avoid
unnecessary intervention.
241. Hennekam RC, Geerdink RA, Hamel BC et al. (1989) Autosomal recessive intestinal
lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med
Genet 34:593–600.
242. Huppke P, Christen HJ, Sattler B et al. (2000) Two brothers with Hennekam syndrome and
cerebral abnormalities. Clin Dysmorphol 9:21–24.
243. Opitz J (1986) On congenital lymphedema. Am J Med Genet 24:127–129.
244. Moller G, Priemel M, Amling M et al. (1999) A report of six cases with histopathological findings.
J Bone Joint Surg Br 81:501–506.
245. Sato K, Sugiura H, Yamamura S et al. (1997) Gorham massive osteolysis. Arch Orthop Trauma
Surg 116:510–513.
246. Tok Celebi J, Chen FF, Zhang H et al. (1999) Identification of PTEN mutations in five families
with Bannayan–Zonana syndrome. Exp Dermatol 8:134–139.
247. Lowichik A, White FV, Timmons CF et al. (2000) Bannayan–Riley–Ruvalcaba syndrome: spectrum
of intestinal pathology including juvenile polyps. Pediatr Dev Pathol 3:155–161.
248. Gorlin RJ, Cohen MM, Condon LM et al. (1992) Bannayan–Riley–Ruvalcaba syndrome. Am J
Med Genet 44:307–314.
GORHAM SYNDROME (GORHAM–STOUT SYNDROME)
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Gorham syndrome (Gorham’s massive osteolysis, disappearing bone disease,
phantom bone disease) is an extremely rare sporadic disorder. It is characterized by massive osteolysis and partial or complete replacement of bone
by fibrous tissue.The translucent “phantom” bones develop in any part of the
skeleton. Bone loss may stop after a few years of progression but may create
local complications. When the spine is affected, neurologic deficits may
develop.Thoracic involvement may cause chylothorax.The associated vascular
lesions are usually venous, lymphatic, or capillary. Areas of osteolysis are
probably the result of intense osteoclastic activity.244 Similar lesions have been
observed in patients with an antecedent history of KMP in infancy and in
patients with AVMs, so they are not entirely specific to low-flow vascular
malformations. In addition, lesions have rarely been described in areas of the
skeleton remote from a cutaneous vascular anomaly. Rare cases are lethal: in
most patients, Gorham’s osteolysis is considered a benign, self-limited
condition. Multiple pathologic poorly healing fractures occur and require
orthopedic care. Because of increased osteoclastic activity, it has been suggested
that bisphosphonates and calcitonin be given to these patients. Implants of
bone in the osteolytic areas are usually absorbed in a few months; therefore,
artificial devices like titanium implants should be utilized to stabilize the
lesions or to replace the bone after curettage of the vascular lesion.245
Amputation may rarely be necessary.
BANNAYAN–RILEY–RUVALCABA SYNDROME

20 Vascular Birthmarks and Other Abnormalities of Blood Vessels and Lymphatics

Transcription

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