22 Chapter 147 :: Vascular Malformations
:: Laurence M. Boon, Fanny Ballieux,
& Miikka Vikkula
VASCULAR
MALFORMATIONS
Part 22
AT-A-GLANCE
■
The worldwide prevalence is roughly 0.3%, mostly
accounted for by capillary malformations.
::
■ Congenital, localized (although sometimes
Vascular Diseases
extensive or multifocal), and well-demarcated
lesions of malformed vessels of various types:
capillary, venous, lymphatic, arteriovenous, and
combined
■ Histologically consist of enlarged, tortuous vessels
of various types.
■ Caused by inherited or somatic mutations in
various gene
■ Can be isolated, combined, or part of a syndrome
■ Management: multidisciplinary approach
INTRODUCTION
DEFINITION
Vascular malformations are believed to arise because
of errors in the development of vessels that occur dur-
ing the 4th to 10th weeks of intrauterine life. Most
vascular malformations are sporadic, although several
families with inherited forms have been identified.
They are very heterogeneous.1
CLASSIFICATION
For many years, vascular anomalies were grouped
under the term angioma, hampering precise classifica-
tion and leading to incorrect diagnosis and improper
management. For example, the term hemangioma has
been used both for vascular malformations, often
venous (cavernous hemangioma), as well as for vas-
cular tumors (strawberry hemangioma). This nomen-
clature changed in 1982 with the development of a
biologic classification by Mulliken and Glowacki.2,3
This classification system organized vascular anoma-
lies based on clinical, hemodynamic, radiologic, and
histologic features. It divided vascular anomalies
into two major categories: (1) vascular tumors (with
cellular proliferation, hemangioma being the most
Kang_CH147_p2636-2668.indd 2636
common; see Chap. 118), and (2) vascular malforma-
tions (structural anomalies of blood vessels) that are
subsequently subdivided, depending on the affected
vessel type, into arterial, capillary, lymphatic, or
venous malformations (VMs). In 1996, this classifica-
tion was adopted and further developed by the Inter-
national Society for the Study of Vascular Anomalies
(ISSVA; Table 147-1).4
Vascular malformations mostly affect a single ves-
sel type (Fig. 147-1), yet combined malformations
also exist. They are named according to the affected
vessel types, capillary-venous or venolymphatic
malformation, for instance. In addition to isolated
forms, vascular malformations occur in syndromes
such as Klippel-Trenaunay syndrome (KTS, capillary-
lymphatic-VM with limb hypertrophy), Maffucci
syndrome (multiple enchondromas associated with
multiple venous anomalies and high incidence of
malignancy), CLOVES (congenital lipomatous over-
growth with vascular malformations, epidermal nevi,
and spinal or skeletal anomalies or scoliosis) syn-
drome, or Parkes Weber syndrome (high-flow vas-
cular malformation of the extremity with soft tissue
hypertrophy).4
EPIDEMIOLOGY
Vascular malformations affect about 0.3% of the
population with most of these being capillary malfor-
mations (CMs). Vascular malformations are mostly
congenital, even though they may be diagnosed later
in life.5
CLINICAL FEATURES
Vascular malformations grow proportionately with
the patient. Usually they do not regress. Most fre-
quently, they are well-demarcated and localized.
They can affect any part of the body, including the
viscera. In rare instances, they can be the stigmata
of deep lesions or the first sign of a syndrome. Vas-
cular malformations are rheologically divided into
slow flow (capillary, lymphatic, venous, and com-
bined) and fast flow (arterial, arteriovenous, and
combined) (Table 147-2).4 They can lead to esthetic
or functional impairment or even threaten life in
rare instances.6
08/12/18 3:08 pm
 TABLE 147-1 DIAGNOSIS
22
Classification of Vascular Anomalies
The diagnosis is usually based on clinical features in
VASCULAR TUMORS VASCULAR MALFORMATIONS 90% of superficial malformations.
Hemangiomas Capillary
Infantile hemangioma Capillary malformation (CM, also called
port-wine stain)
SUPPORTIVE STUDIES
Congenital hemangioma Telangiectasia (hereditary benign telan- Pathology: Histologically, vascular malforma-
giectasia, essential telangiectasia) tions consist of enlarged, tortuous vessels with quies-
Rapidly-involuting Hereditary hemorrhagic telangiectasia cent endothelium. In contrast to hemangioma, there
congenital (HHT) is neither a parenchymal mass nor overt cellular
hemangioma (RICH) proliferation.
Noninvoluting congenital Capillary malformation–arteriovenous
Imaging: Radiologic investigation is needed to delin-

Chapter 147 :: Vascular Malformations

hemangioma (NICH) malformation (CM-AVM)
eate the extent of a malformation but rarely for diagno-
  Sturge-Weber syndrome
sis unless the malformation is deeply located. Doppler
Hemangioendothe- Venous ultrasonography is a very useful noninvasive radiologic
liomas examination that provides clues for differentiating the
Kaposiform hemangioen- Venous malformation (VM) various types. Magnetic resonance imaging (MRI) details
dothelioma the extension and precise location of the lesion.16
Tufted angioma Familial form: cutaneo-mucosal venous
  malformation (VMCM)
Genetic Testing: Because a germline or somatic
  genetic cause is known for a large number of vascular
Glomuvenous malformation (GVM)
anomalies, genetic testing can be used to confirm or
Blue rubber bleb nevus or Bean help make the precise diagnosis. For somatic mutations,
syndrome (BRBN)
a biopsy of the affected tissue is needed. For inherited
Angiosarcoma Lymphatic mutations, a blood test is sufficient to make the diagnosis.
  Lymphatic malformation (LM)
 
  Primary Lymphedemas
 
 
Arterial
MANAGEMENT
Arteriovenous malformation (AVM)
 
 
Capillary malformation–arteriovenous Treatment of vascular malformations depends on the
 
malformation (CM-AVM) affected vessel type, the location of the lesion, the
  Arteriovenous fistula (AVF) age of the patient, and the symptoms. Because many
  Syndromic Malformations lesions are extensive, patients should be aware that a
  complete cure is often not possible and that recurrence
Slow flow
occurs. Treatment can be difficult and with severe com-
Klippel-Trenaunay syndrome (capillary– plications. Extensive or complex lesions should always
lymphatic–venous malformation with
be managed by a multidisciplinary team.
limb hypertrophy)
Maffucci syndrome
CLOVES (congenital lipomatous over-
growth with vascular malformations, CAPILLARY
epidermal nevi, and spinal or skeletal
anomalies or scoliosis) syndrome MALFORMATIONS
Fast flow
  Parkes Weber syndrome AT-A-GLANCE
■ Worldwide occurrence. Prevalence is roughly 0.3%.
■ Congenital, slow-flow malformations of the capil-
lary bed
ETIOLOGY AND ■ Pinkish-red to purple in color; tend to darken and
thicken with time
PATHOGENESIS ■ Can be part of a sporadic syndrome, such as
Sturge-Weber syndrome or KTS
Several genes have been identified to be mutated ■ Can be part of the inherited capillary malformation-
in the inherited forms of vascular malformations arteriovenous malformation phenotype
(Table 147-3). Somatic genetic mutations have also
■ Pathology: capillaries that are increased in size and
been unraveled as the cause of many common spo- 2637
number with abnormal innervation.
radic lesions.7-15

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22

A
B
Part 22
::
Vascular Diseases

C E

Figure 147-1 Vascular malformations of various vessel types. A, Capillary malformation of left lower extremity and genita-
lia. B, Subcutaneous lymphatic malformation invading the cubital nerve. C, Extensive venous malformation of right lower
extremity, causing pain, swelling, and coagulopathy. D, Arteriovenous malformation of the sole. E, Nidus of the lesion on
arteriography.

Capillary malformations mainly occur sporadically,
although there are well-documented pedigrees show-
ing autosomal dominant inheritance.17 When inherited,
they are usually multiple and part of the capillary mal-
formation–arteriovenous malformation (CM-AVM)
phenotype, which associates atypical CMs with arte-
riovenous malformation (AVM, see Arteriovenous
Malformations later).18-23
EPIDEMIOLOGY
CMs, commonly called port-wine stain, is a slow-flow
2638 vascular malformation with a prevalence of 0.3%.5
There is no sex preponderance.
Although most often an isolated finding, in rare
instances, CM can be the cutaneous hallmark of occult
spinal dysraphism, especially if located in the lumbo-
sacral area.24 Other blanchable, pink patches, known
as stork bite, angel’s kiss, salmon patch, nevus simplex, or
nevus flammeus neonatorum, are often confused with
CM. They are located on the nape of the neck (81%),
the eyelids (45%), or the glabella (33%).25 When located
on the occiput, the moniker Unna nevus may be used
(Fig. 147-2). These patches have a much higher inci-
dence (42%) in white infants than in black infants
(31%).26 They are also present in various syndromes,
such as Beckwith-Wiedemann and Rubinstein-Taybi
syndromes. These lesions (with the exception of the
Unna nevus) disappear spontaneously around the age
of 1 to 4 years. In contrast, true CMs persist lifelong.

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 TABLE 147-2
22
Clinical Characteristics of Vascular Malformations
CAPILLARY VENOUS LYMPHATIC ARTERIOVENOUS

Skin color Red Normal-bluish-purple Normal to yellowish-purple Normal to red

Aspect Flat Flat to raised Raised to vesicular Flat to raised
Temperature Normal Normal Normal Warm
Palpation Normal Compressible Firm, noncompressible Thrill, bruit
Associations — Phleboliths, deformation — Ulceration, deformation
Radiology No flow Slow flow Slow flow, cyst Fast flow
Histology Dilated capillaries Thin-walled venous channels Cystic lymphatic channels Arterialized veins
D2-40 negative D2-40 negative D2-40 positive D2-40 negative

Chapter 147 :: Vascular Malformations

Etiology See Table 147-3
Treatment Pulsed-dye laser Sclerotherapy, surgery, Surgery, sclerotherapy, Embolization followed by surgical resection
sirolimus medication sirolimus medication of nidus

SYNDROMIC DISORDERS DIFFUSE CAPILLARY

CMs can be part of a syndrome, such as phako-
matosis pigmentovascularis (PPV), Sturge-Weber
syndrome (SWS), KTS, Parkes Weber syndrome,
CLOVES syndrome, PTEN (phosphatase and ten-
sin homolog) Hamartoma tumor syndrome, diffuse
capillary malformation with overgrowth (DCMO),
and macrocephaly–capillary malformation (M-CM,
also called megalencephaly–capillary malformation–
polymicrogyria syndrome). None of these syndromes
is inherited.
PHAKOMATOSIS
PIGMENTOVASCULARIS
PPV is thought to be an embryogenic anomaly affect-
ing the vasomotor nerves and the melanocytes, both
derived from neural crest. It manifests as a large, meta-
meric CMs, usually located on the trunk or the extrem-
ities, in association with pigmented cutaneous lesions,
such as a pigmented nevus, a nevus spilus, a café-
au-lait patch, or an atypical Mongolian spot (see
Chap. 77) that is not located on the sacrum (Fig. 147-3).27
Nevus anemicus can also be seen in the vicinity as a
twin spot.28
STURGE-WEBER SYNDROME
When located in the frontopalpebral area, CM can be
part of SWS (Fig. 147-4A). This neuro-oculo-cutaneous
syndrome associates a cutaneous CM of the ophthal-
mic branch of the trigeminal nerve (V1) with a homo-
lateral leptomeningeal capillary-venous malformation
(CVM) and a choroid CVM. Glaucoma is often pres-
ent (Fig. 147-4B). SWS is associated with a high risk of
epilepsy and mental retardation because of anomalies
of the venous drainage of the encephalon, as well as
with glaucoma, buphthalmos, and sometimes retinal
detachment.29
MALFORMATION WITH
OVERGROWTH
Patients with DCMO have hemihypertrophy, which
can be total, regional, or contralateral. CM can be dif-
fuse over the entire body. This entity is characterized
by a reticulated, ill-defined CM.30 The lesions do not
follow the lines of Blaschko (Fig. 147-5A).
MACROCEPHALY–CAPILLARY
MALFORMATION
A well-delineated, dark CM of the vermillion bor-
der, the tip of the nose, or both associated with mac-
rocephaly is often pathognomonic of M-CM. These
patients have megalencephaly and are at risk of mental
retardation.31 There are two reports of M-CM associ-
ated with Wilms tumor in the literature.32
CLINICAL FEATURES
CUTANEOUS FINDINGS
CM is a red, homogenous, congenital lesion that is
often unilateral, sometimes bilateral, but usually not
median. CMs involve skin and subcutis and sometimes
mucosa (see Fig. 147-5). Their color varies from pink-
ish-red to deep purple with a geographic contour or a
dermatomal distribution. Lesions are flat and painless,
do not bleed spontaneously, and are never warm on
palpation in contrast to AVM (see later). Acquired CM
can be seen after trauma.33
Fifty percent of CMs are located on the face, where
they follow the distribution of the trigeminal nerve:
ophthalmic branch V1 (front and upper eyelid), max-
illary branch V2 (lower eyelid, cheek, and upper 2639
lip) (see Figs. 147-4A and 147-5B), or mandibular V3

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22 TABLE 147-3
The Genetic Causes of Vascular Anomalies
SPORADIC MALFORMATIONS INHERITED MALFORMATIONS
DIAGNOSIS MUTATED GENE DIAGNOSIS MUTATED GENE

Capillary Malformations (CMs)

CM GNAQ CM-AVM1 RASA1
Sturge-Weber syndrome   CM-AVM2 EPHB4
Phakomatosis pigmentovascularis (PPV) GNAQ or GNA11    
Macrocephaly–capillary malformation (M-CM) AKT3, PIK3CA, PIK3R2    
Venous Malformations (VMs)
VM TIE2 (60%) Mucocutaneous venous malformations TIE2
Part 22

PIK3CA (20%) (VMCM)

Blue rubber bleb nevus (BRBN) TIE2 Glomuvenous malformation (GVM) GLOMULIN
Multifocal venous malformation (MVM)      
::

Verrucous venous malformation (VVM) MAP3K3    

Vascular Diseases

Maffucci syndrome IDH1, IDH2    

Lymphatic Malformations (LMs)
LM PIK3CA Nonne-Milroy lymphedema VEGFR3
CLOVES (congenital lipomatous overgrowth with   Nonne-Milroy–like lymphedema VEGF-C
vascular malformations, epidermal nevi, and spinal or
skeletal anomalies or scoliosis)
Klippel-Trenaunay syndrome (KTS)   Lymphedema distichiasis FOXC2
    Microcephaly, chorioretinopathy, lymph- KIF11
  edema, mental retardation
 
    Hypotrichosis–lymphedema–telangiectasia SOX18
    Hennekam lymphedema–lymphangiectasia 1 CCBE1
    Hennekam lymphedema–lymphangiectasia 2 FAT4
 
  Hennekam lymphedema–lymphangiectasia 3 ADAMTS3
 
    Emberger syndrome GATA2
  Fetal chylothorax ITGA9
  Lymphedema–choanal atresia PTPN14
  Four-limb lymphedema GJC2 (CX47)
Arteriovenous Malformations (AVMs)
Extracranial AVM MAP2K1 Hereditary hemorrhagic telangiectasia (HHT)1 ENG
Brain AVM KRAS HHT2 ACVRL1 (ALK1)
    HHT3 SMAD4, GDF2
    Phosphatase and tensin (PTEN) homolog PTEN
(protein encoded by PTEN gene)

(lower lip, chin, and mandible). CM can be diffuse
over the entire body, often with associated hemi-
hypertrophy (see Fig. 147-5A). This entity is called
diffuse capillary malformation with overgrowth (see ear-
lier discussion).
When inherited, CMs are usually small and multifo-
cal, such as in CM-AVM1 and 2. These small CMs vary
in size from a couple mm to several centimeters in
size. They are often round-to-oval, pink, red, or brown
in color and are often surrounded with a pale halo
(Fig. 147-6).18,34 The lesions are well-circumscribed and
2640 blanch on pressure with a diascopy. Some of them are
present at birth, but others appear later. They grow
with the child and are asymptomatic. Bier spots,
white cutaneous spots surrounded by a pale halo of
redness, are seen in both entities. In contract to CM-
AVM1, CMs in CM-AVM2 can be more telangiectatic
in appearance, especially periorally and on the upper
thorax.23 CM-AVM1 is characterized by the presence
of CMs in 97%, AVMs or arteriovenous fistulas (AVFs)
in 24% (10% intra–central nervous system [CNS], 13%
extra-CNS), and Parkes Weber phenotype in 8% of
patients.21,35 In CM-AVM2, the risk of a fast-flow lesion
seems to be less frequent because the respective pen-
etrances are 93% (CM), 19% (AVM), and 7% (Parkes
Weber).

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A B
Figure 147-2 Nevus flammeus neonatorum (also called nevus simplex) on the glabella, upper eyelids, and upper lip (A)
of a 6-week-old neonate who also has an Unna nevus on the occiput (B).
NONCUTANEOUS FINDINGS
In rare instances, CM can be the stigmata of an under-
lying anomaly such as lumbar dysraphism underneath
a sacral CM. Cutaneous lesions of PPV can be associ-
ated with systemic, visceral (hypoplasia of the larynx,
intestinal polyposis), muscular (scoliosis), or neuro-
logic (mental retardation, epilepsy, intracranial) signs
and symptoms in 60% of cases.36
Figure 147-3 Clinical characteristics of phakomatosis pig-
mentovascularis. A large metameric capillary malforma-
tion with atypical extensive dermal melanocytosis located
on the back.
Kang_CH147_p2636-2668.indd 2641
22
Chapter 147 :: Vascular Malformations
SWS is associated with a high risk of epilepsy and
mental retardation because of anomalies of the venous
drainage of the encephalon, as well as with glaucoma,
buphthalmos, and sometimes retinal detachment.29
Patients with DCMO have hemihypertrophy, which
can be total, regional, or contralateral. They have also
associated toe anomalies (in 30%) and prominent
veins.30 In CM-AVM1 or 2, there is a 20% to 30% risk
of an associated AVM located on the skin, the brain,
or the spine.21,35 A well-delineated dark CM of the ver-
million border or the tip of the nose associated with
macrocephaly is often pathognomonic of M-CM, and
these patients have megalencephaly and are at risk of
mental retardation.31
COMPLICATIONS
The major concern for a patient with a CM is cosmetic
because of the visible discoloration. Hypertrophy of
soft (often lips and gums) and underlying hard tis-
sues can occur with time, especially when the CM
affects the V2 and V3 dermatomes or the extremities
(Fig. 147-7D and 147-7). Overgrowth of the maxilla or
mandible leads to skeletal asymmetry, occlusal tilt, and
open-bite deformity. When the child has atopic derma-
titis, psoriasis, or acne, lesions are worse in the area of
CM, a finding known as the Meyerson phenomenon.37
Evenly thickened skin, purple nodules, and pyogenic
granulomas can develop by adolescence (Fig. 147-7B
and 147-7C).38,39
ETIOLOGY AND
PATHOGENESIS
Facial CM is thought to be caused by clonal expansion 2641
of abnormal cells originating from the neural crest.40
08/12/18 3:08 pm
22 Part 22

A B

Figure 147-4 Extensive right facial capillary malformation. A, Involving the ophthalmic and maxillary branches of the
::

trigeminal nerve in a 6-month-old girl with Sturge-Weber syndrome. B, Choroid capillary–venous malformation causing
Vascular Diseases

vision loss in a 50-year-old man with Sturge-Weber syndrome.

Somatic activating mutations in GNAQ have been

identified as the cause of facial CM with hypertrophy
as well as of SWS.13 GNAG is a q class of G-protein
α subunits that mediates signals between G protein–
coupled receptors and their downstream effectors.
Mutations in GNAQ and GNA11 have also been identi-
fied in pigmented lesions such as blue nevi, nevus of
Ota, uveal melanoma, and PPV.41,42
The inherited CM-AVM1 is caused by inactivating
mutations in RASA1.21 This gene encodes a GTPase-
activating protein, which negatively regulates Ras
activity. CM-AVM2 is caused by inactivating muta-
tions in EPHB4.23 EPHB4 is usually expressed in
venous endothelial cells and its ligand EPHINB2 on
arterial endothelial cells. They regulate arteriovenous
identity. EPHB4 interacts with RASA1 to regulate RAS-
MAPK signaling, and loss of EPHB4 or RASA1 in CM-
AVM likely activates this signaling pathway. M-CM is
caused by activating mutations in AKT3, PIK3CA, and
PIK3R2.43
DIAGNOSIS
SUPPORTIVE STUDIES
Pathology: Histologically, CM is characterized by
dilated capillaries of the papillary and upper reticular
dermis combined with areas of increased number of
normal-looking capillaries (Fig. 147-8).44 Endothelial
cells are flat. Factor VIII, fibronectin, and basement
membrane protein are normal, but S100 staining shows
abnormal innervation.45,46
Imaging: No imaging studies are mandatory for
a CM except in rare situations. If a so-called “CM”
is painful, warm, or spontaneously bleeds, Doppler
ultrasound is indicated to exclude the diagnosis of a
fast-flow malformation, such as an AVM, Parkes Weber
syndrome, or a proliferating hemangioma.

A B C

2642 Figure 147-5 Several aspects of capillary malformations. A, Light red lesions involving half of the body. B, Dark red lesions
on the face with mucosal involvement and soft tissue hypertrophy. C, More localized on the shoulder and arm.

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 22

A B

Chapter 147 :: Vascular Malformations

C D

Figure 147-6 A–D, Examples of small atypical capillary malformations which belong to CM-AVM (capillary malformation-
arteriovenous malformation). D, Note the pale halo surrounding the lesion.

CM located in the frontopalpebral area, especially
if the inner part of the upper eyelid is involved, can
be part of SWS. Therefore, for these CMs, an ophthal-
mologic and neurologic examination is mandatory.
They need to be done during the first months of life
and repeated once a year until puberty, even if normal
at younger age.47 A brain MRI should also be done
to evaluate the occurrence of associated leptomen-
ingeal CVM. In patients with PPV, ophthalmologic,
neurologic, and orthopedic follow-up is mandatory
because of the common association of CM with sys-
temic lesions. In patients with extensive CMs of the
lower extremity, such as in DCMO, a scaniometry
study (leg length films) is needed to evaluate pos-
sible progressive growth discrepancy around the age
of 4 to 6 years and needs to be repeated until the end
of growth to allow the orthopedist to correct the
discrepancy at the adequate time. Serial renal ultra-
sound examinations are also indicated to rule out
the appearance of a Wilms tumor. MRI of the spinal
cord is indicated in the presence of a lumbosacral
CM. Brain and spinal MRI should be considered in
patients with CM-AVM.
Genetic Testing: Genetic testing is indicated,
especially in patients with multifocal lesions (CM-
AVM1 and 2) because of increased risk for intracerebral
fast-flow lesions. These patients should be screened for
RASA1 and EPHB4. Pale, uncharacteristic, and incon-
spicuous CMs can be sign of PHTS, especially if these
vascular lesions are associated with macrocephaly (see
AVM later). Because of increased cancer risk, such
patients should be screened for PTEN mutations. Iden-
tification of a germline mutation would enable precise
counseling and surveillance.
DIFFERENTIAL DIAGNOSIS
See Table 147-4.
CLINICAL COURSE
AND PROGNOSIS
CM is present at birth and never regresses spon-
taneously. During the first weeks of life, they can
slightly fade, as the hemoglobin level of the newborn
decreases. Subsequently, the red hue stabilizes, and
the lesion grows in proportion to the rest of the body.
Around puberty, as well as later in life, CM slowly
thickens and darkens with time. It often becomes 2643
raised and nodular (see Fig. 147-7).38 Pyogenic

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22 Part 22

A B C
::
Vascular Diseases

D E

Figure 147-7 Clinical evolution of capillary malformation: darkening and thickening with time. A, At age 6 months. B, At
age 33 years. C, Development of pyogenic granuloma. D, Soft tissue hypertrophy. E, Mucosal hypertrophy.

granuloma can occur with time, as well as soft tissue
or bony hypertrophy.39
MANAGEMENT
The goal of management is to monitor for associated
complications and minimize the impact of the CM
on self-esteem and quality of life. Camouflage using
a foundation such as Covermark is still an effectively
approach (Fig. 147-9)
INTERVENTIONS
Orthopedic Considerations: In the presence
of leg-length discrepancy, an early-adapted shoe lift
is needed if leg-length discrepancy is over 1.5 cm to
prevent compensatory tilting of the pelvis. Epiphysio-
2644 desis is sometimes necessary when the child is approx-
imately 11 to 13 years old.
Procedures: Laser treatment is the gold standard
therapy for most CM. Pulsed-dye laser with its specific
wavelength (585 or 595 nm) and a short pulse duration
(400–1500 ms) currently gives the best results in infants
and children by lightening the red color of the CM.
There are few complications. Multiple sessions (6–12) are
needed, and general anesthesia may be necessary as the
procedure is painful. Laser treatment is more efficient on
the cervicofacial and trunk area than on the extremities.
Early treatment during childhood does not reduce the
number of laser sessions.48 The use of a dynamic cool-
ing system to avoid heating the epidermis allows higher
laser fluencies, resulting in optimal lightening of the
lesion. Recurrence can occur after cessation of therapy.49
Laser has no impact on associated hypertrophy.6,50
Contour resection is considered to treat complications
such as pyogenic granuloma or lip hypertrophy.6
Counseling: Genetic and psychological counsel-
ing for the patients and their families are part of mul-
tidisciplinary management. Patient organizations
dedicated to vascular anomalies also have an impor-
tant role in supporting patients and their families.

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 22

Chapter 147 :: Vascular Malformations

A B

Figure 147-8 A, Extensive capillary malformation of upper extremity. B, Histologically, capillary malformation is charac-
terized by dilated capillaries of normal number in the papillary and upper reticular dermis in combination with areas of
increased number of normal-looking capillaries (hematoxylin and eosin staining).

reducing visual impairment will depend on the

PREVENTION promptness of treatment. Prophylactic antiepileptic
medication to prevent neural cell death has also been
In patients with SWS, ophthalmologic follow-up, advocated, although randomized prospective studies
started immediately after birth is essential because to support efficacy are lacking at this time.51,52

A B
2645
Figure 147-9 Efficient noninvasive management of facial capillary malformation using cosmetic makeup.

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22 TABLE 147-4 ■ Congenital slow-flow malformation of the venous
Differential Diagnosis of Capillary bed
Malformation ■ Bluish in color, localized or extensive, solitary or
multifocal
Based on Morphology
■ Compressible on palpation; presence of phleboliths
Most Likely
Faint pink median patch ■ Associated with consumptive coagulation abnor-
■ Unna nevus malities in about 40% of cases
■ Nevus flammeus neonatorum (nevus simplex) ■ Histologically consists of ectatic venous-like chan-
Multiple, inherited
nels with anomalies in mural cells
■ CM of CM-AVM
Telangiectatic patch ■ Mainly sporadic but can be inherited as an autoso-
■ CMTC mal dominant trait
■ HHT ■ Inherited venous anomalies: cutaneomucosal
■ CM-AVM2
Part 22

venous malformation (1%), glomuvenous malfor-

■ Essential telangiectasia mation (>5%)
■ Unilateral nevoid telangiectasia
■ Syndromic venous malformation: KTS, blue rubber
Warm on palpation
■ Proliferating hemangioma bleb nevus, Maffucci syndrome.
::

■ AVM
Vascular Diseases

■ AVF
Ulcerated or painful
■ AVM
■ AVF INTRODUCTION
Rule Out
Small, multiple
A VM is a congenital lesion made up of venous-type
■ Mastocytosis
vessels of the skin or mucosa but can involve any
■ CM of CM-AVM
structure (subcutis, muscles, bones, and nerves) and
Based on Location
any organ (CNS, gastrointestinal [GI] tract). Fifty per-
Most Likely
cent of VMs are located in the cervicofacial area, and
Occiput
37% are on the extremities. VMs are mainly isolated
■ Unna nevus
Glabella, upper eyelid, nape of neck but can be part of complex vascular disorders, such as
■ Stork bite, angel’s kiss, salmon patch the KTS, Maffucci, and blue rubber bleb nevus (BRBN)
Consider syndromes.53,54
Extremity
■ CMTC
■ Klippel-Trenaunay syndrome
■ Parkes Weber syndrome
Faint on trunk EPIDEMIOLOGY
■ M-CM
Rule Out Venous anomalies are the most common VMs
Scalp referred to specialized center with an overall inci-
■ Adams-Oliver syndrome dence of 1 in 10,000 in the population.54 They mainly
■ Multiple telangiectasia near canthus occur sporadically, although 1% are inherited muco-
■ Ataxia telangiectasia
cutaneous venous malformations (VMCMs) and 5%
AVF, arteriovenous fistula; AVM, arteriovenous malformation; CM, cap- are inherited glomuvenous malformations (GVMs).
illary malformation; CM-AVM, capillary malformation-arteriovenous No sex preponderance is reported.55 Both VMCM
malformation; CMTC, cutis marmorata telangiectatica congenita; HHT, and GVM have an age-dependant variation in pen-
hereditary hemorrhagic telangiectasia; M-CM, macrocephaly capillary
etrance, which reaches its maximum by 20 years of
malformation.
age (87% for VMCM and 92.7% for GVM).56 Large
VMCMs and GVMs are present at birth. However,
17% of affected individuals develop new small
lesions over time.55 BRBN syndrome is rare and

VENOUS ANOMALIES
occurs sporadically with about 200 cases reported in
the literature.

AT-A-GLANCE
■ Most common referral to specialized centers for
SYNDROMIC DISORDERS
vascular anomalies; incidence unknown but is
substantially lower than for CM and estimated at Syndromes with a venous anomaly include BRBN syn-
2646 1 in 10,000 drome, KTS (see Lymphatic Malformations later), and
Maffucci syndrome.

Kang_CH147_p2636-2668.indd 2646 08/12/18 3:08 pm


Figure 147-10 Blue rubber bleb nevus syndrome. Pathog-
nomonic multiple small, dark blue, nipple-like lesions on
the toe.
BLUE RUBBER BLEB NEVUS
SYNDROME
BRBN is characterized by numerous malformations
of the venous system that involve the skin and vis-
ceral organs. It is commonly characterized by one
large “dominant” VM lesion associated with multiple
small, dark blue, nipple-like lesions, the latter being
typically located on the palm and soles (Fig. 147-10).15
These cutaneous lesions are associated with mul-
tiple small GI VMs, often responsible for chronic
anemia.15,57
MAFFUCCI SYNDROME
Maffucci syndrome is a rare disorder characterized
by multiple enchondromas associated with subcu-
taneous VMs of the distal extremities (Fig. 147-11).
The disease starts during childhood with the devel-
opment of enchondromas of the bones of hands and
feet, as well as of the long bones. Deformities and
shortening of extremities often occur. Subcutane-
ous vascular nodules appear later, around puberty,
on the fingers and the toes. Phleboliths may become
present.58
A B
Figure 147-11 Clinical (A) and radiologic (B) aspects of Maffucci syndrome. Multiple venous malformations and enchon-
dromas deforming the hand and fingers.
Kang_CH147_p2636-2668.indd 2647
CLINICAL FEATURES
22
The features of venous anomalies are summarized in
Table 147-5.
CUTANEOUS FINDINGS
VMs are usually solitary but can be multifocal, the
latter suggesting an inheritable disorder in most
instances.54 They may be relatively localized or
extensive within an anatomic region. The most com-
mon location is the head and neck area (Fig. 147-12A
and 147-12D–F). VMs can affect any tissue or organ
Chapter 147 :: Vascular Malformations
(Figs. 147-12 to 147-14).
VMs are congenital, light to dark bluish lesions. Deep
VM has a normal overlying skin color and is often diag-
nosed only at puberty or later in life with the onset of
pain. Size varies from small spongy blebs to large lesions
of several centimeters in diameter. Skin temperature is
normal. There is no thrill or bruit. VMs are larger when
in a dependent position and can easily be emptied by
compression or facilitating venous drainage. Palpation
is not painful unless thrombosis occurs.54,59
VM lesions in VMCM are small and multifocal. They
are more reminiscent of small sporadically occurring
VMs than BRBNs. They can enlarge with time and
are often asymptomatic. The VMs are generally small
(<5 cm), and more than 80% of patients have more than
two lesions. Some are present at birth; most lesions
appear by puberty. Mucosal lesions involve the lips,
tongue, and buccal mucosa.60,61
In rare instances, VM can be sporadic yet multiple.
These multifocal venous malformations (MVMs) are
very similar to the VMCM lesions, yet there is no fam-
ily history of the same findings.15
GVM is a bluish to purple, raised venous anomaly
characterized by multifocality, hyperkeratosis, and nod-
ularity with a cobblestone surface (see Fig. 147-13C). In
rare cases (especially in newborns), the lesions may be
flat and purple in color, mimicking CM62; this plaque-
like GVM usually darkens with time. GVMs are usually
present at birth and slowly expand during childhood.
2647
08/12/18 3:09 pm
22 TABLE 147-5
Characteristics of Venous Anomalies
VENOUS MALFORMATION GLOMUVENOUS
VENOUS MALFORMATION CUTANEOMUCOSAL MALFORMATION BLUE RUBBER BLEB NEVUS SYNDROME

Location 50% head and neck Extremities, mucosa 70% extremities Especially palms and soles
Skin color Normal to bluish-purple Bluish Bluish-red-purple Bluish-dark-blue
Aspect Flat to raised Raised, dome shaped Raised, cobblestone Dome shaped, nipple-like
Plaquelike, hyperkeratotic
  Single, large Multiple, small Multiple Multiple, small, often + 1 large lesion
Palpation Phleboliths Compressible Noncompressible, painful Firm, rubbery, spongy
Associated Coagulopathy — — Visceral venous malformation,
Part 22

coagulopathy
Radiologic Phleboliths Venous channels No phlebolith Venous channels
Tissue involved Often deep location Cutis, subcutis Cutis, subcutis Often deep component
::

Histology Thin-walled venous Thin-walled venous Glomus cells Thin-walled venous channels
channels channels
Vascular Diseases

Inheritance Sporadic Autosomal dominant Autosomal dominant Sporadic

New small lesions appear with time. In contrast to VM,
GVM is often painful on palpation and cannot be com-
pletely emptied by compression. GVMs are usually mul-
tifocal and located on the extremities, involving the skin
and subcutis. They are rarely encountered in mucosae,
and intestinal hemorrhage is not present. Patients with
GVMs have normal mental and physical development.
Diagnosis of GVM is based on clinical and histologic
evaluation of the cutaneous lesions. Genetic testing can
differentiate small multifocal GVMs from VMCMs.55

A B C

D E F

Figure 147-12 Various venous malformations. A. Of the soft palate, causing sleeping apnea. B and C, Of the knee, causing
2648 hemarthroses; confirmed by T2-weighted images. D. Of the mucosal eyelid. E and F, Of the cheek, causing facial asym-
metry and pain.

Kang_CH147_p2636-2668.indd 2648 08/12/18 3:09 pm

 22

Chapter 147 :: Vascular Malformations

A B

C D

Figure 147-13 Venous malformations (VMs). A, Extensive hemifacial VM causing soft tissue hypertrophy and lip defor-
mation in a 6-month-old boy. B, Histologically, VM consists of ectatic venous-like channels with anomalies in mural cells
(hematoxylin and eosin). C, Superficial glomuvenous malformation of the inner thigh. Note the presence of mural glomus
cells on histology (hematoxylin and eosin). D, Mucosal VM involving the lower lip and floor of the mouth.

Verrucous Venous Malformation: vascular anomaly. Although VVM expresses an

Verrucous venous malformation (VVM), previously
known as verrucous hemangioma, is a rare congenital
immunohistochemical profile similar to vascular
neoplasms (Wilms tumor 1 and GLUT-1 positive), it
is distinct from infantile hemangioma because it is
usually noted at birth and never spontaneously invo-
lutes. Mainly located on the legs, VVM can also be
found on the head and the trunk. It initially appears
as a bluish macule that later becomes erythematous-
violaceous in color and after trauma and secondary
infections often evolves into a verrucous nodule
(see Fig. 147-14). It never involves muscles or deep
tissues.63

Figure 147-14 Verrucous venous malformation (previ- NONCUTANEOUS FINDINGS

ously known as verrucous hemangioma) on the lower
extremity, causing oozing. It is purple-red in color and Patients with VMCM, like those with sporadically 2649
slightly raised, with hyperkeratosis. occurring MVM, seldom have VMs located in internal

Kang_CH147_p2636-2668.indd 2649 08/12/18 3:09 pm

22 organs, such as the lungs, kidneys, brain, or GI tract.15
Extracutaneous manifestations of BRBN include GI tract
involvement. The small bowel is the predominant region;
however, VMs can occur in any site from the oral cavity to
the anal mucosa. In rare instances, VMs can also be seen
in brain, lungs, and kidneys, as well as other organs.57
COMPLICATIONS
VM is usually unilateral, causing asymmetry and pro-
gressive, slowly worsening distortion (see Figs. 147-12
and 147-13). Depending on their size and location, VMs
can cause pain, particularly in the morning on awaken-
ing, and anatomic distortion and can even threaten life
Part 22
because of bleeding, expansion, or obstruction of vital
structures. Migraine is a common feature when VM is
located in the temporal muscle. Whereas oropharyngeal
VM can impair speech and cause difficulties in swallow-
::
ing, pharyngeal or laryngeal lesions can compromise
Vascular Diseases
the airway and cause snoring and sleeping apnea.54
On the extremities, VMs often involve muscles and
joints. They cause muscle weakness, hypotrophy, and
sometimes hypertrophy, resulting in leg-length dis-
crepancy, which is less severe than in KTS. Intraarticu-
lar bleeding, if the malformation is located in the knee
joint, leads to early-onset arthrosis.64 Genital VM often
occurs with limb VM and can cause dyspareunia. GI
VM may lead to chronic anemia.
Local thrombosis is usually responsible for acute
pain that lasts for several days and resolves as phlebo-
liths, which can be identified by palpation or by radi-
ography. VM rarely causes pulmonary embolism,
although this complication can occur when large
draining veins exist.65,66
Chronic localized intravascular coagulopathy
(LIC) is associated with solitary or syndromic spongy
VMs. It is characterized by elevated D-dimer level
(>500 ng/mL) in 40% of patients. Severe LIC with
low fibrinogen levels is common in large VMs of the
extremities and rare in the cervicofacial area. A num-
ber of events, such as surgery, sclerotherapy, and hor-
monal influences, can trigger the conversion of LIC to
disseminated intravascular coagulopathy (DIC).67
In contrast to skin lesions, GI lesions, as seen in
patients with BRBN, have a tendency to bleed. They
may spontaneously rupture, causing acute hemorrhage
and even death. However, most of the bleeding tends to
progress slowly, resulting in chronic and occult blood
loss that can lead to iron-deficiency anemia. Other com-
plications include intussusception, volvulus, and bowel
infarction, which are to be considered in patients with
BRBN and abdominal pain. Morbidity depends on the
extent of GI involvement.57 VVM often ulcerates.63
ETIOLOGY AND
PATHOGENESIS
2650 VMCM is inherited as an autosomal dominant disor-
der caused by germline mutations in the TEK gene,
Kang_CH147_p2636-2668.indd 2650
which encodes the angiopoietin receptor, TIE2.68,69 The
inherited mutations cause hyperphosphorylation of
the receptor even in the absence of a ligand. Somatic
second hits have been found in VMCM tissues of two
patients: one caused loss of membranous expression
of the second, wild-type, allele; two others occurred
on the allele with the inherited mutation, causing an
increase in hyperphosphorylation.15,70 These mutations
activate the PI3K/AKT signaling pathway in endothe-
lial cells.71,72
GVM is caused by dominant, loss-of-function muta-
tions in the glomulin gene.73 In addition, a somatic
second hit is required for lesions to form, leading
to complete loss of function of glomulin. The most
common second hit is acquired uniparental isodi-
somy, which leads to homozygosity of the inherited
mutation.73,74 This explains the variable expressivity
regarding penetrance, the extent of the lesions, and the
number of lesions within family members.75 So far, a
mutation in glomulin has been found in almost all GVM
families tested, demonstrating locus homogeneity.75-77
Glomulin seems to be expressed in vascular smooth
muscle cells, but its exact function remains unknown.
Sporadic VMs are also caused by genetic mutations.
Sixty percent are caused by activating somatic muta-
tions in TIE2.70 The mutations differ from the inher-
ited ones seen in VMCM. The most common mutation
in VMs (L914F) has not been identified in VMCM,
and the most common inherited mutation in VMCM
(R849W) has not been identified in single somatic
VM. This suggests that whereas the recurrent somatic
mutations have effects too detrimental to be supported
in the germline and probably cause lethality, the inher-
ited ones have weaker effects that require additional
changes (somatic second hits).70-72
Another 20% of sporadically occurring VMs are
caused by somatic mutations in the PIK3CA gene.10
The same mutations are seen in cancers. They activate
the PI3K/AKT signaling pathway, as do the mutations
in TIE2, underscoring perturbations in this signaling
activity to underlie pathogenesis of VMs.10,11
MVM is also caused by TIE2 mutations. Similar
to VMCM, these patients often have two TIE2 muta-
tions. Most frequently, a R915C mutation is present
as a mosaic change, and a somatic Y897C mutation
occurs on top of the R915C change on the same allele.
This explains the lack of family history (the first muta-
tion has appeared de novo in a mosaic fashion in the
patient), multifocality (the mosaic mutation is a pre-
disposing change, like the inherited mutations are
in VMCM), and the clinical similarity with VMCM
lesions (both have similar, albeit not the same, double
cis mutations).15 VVM is caused by somatic MAP3K3
mutations.78 BRBN syndrome, like VMCM, MVM,
and 60% of VMs, is also caused by mutations in TIE2.
BRBN mutations are not detectable in the blood; they
are somatic.15 Yet in distinct, distally located lesions of
the same patient with BRBN, the same double muta-
tions can be identified with equal allele frequencies.
The most common is a T1105N–T1106P double muta-
tion. This suggests that the separate and even newly
appearing lesions are formed by endothelial cells
08/12/18 3:09 pm
 that originate form a single common site, such as the
dominant lesion or bone marrow. The BRBN-causing
TIE2 mutations cause strong hyperphosphoryla-
tion of the receptor, and the endothelial cells acquire
increased colony-forming capacity, survival, and faster
migration.15
Maffucci syndrome is caused by somatic mutations
in IDH1 and 2.79-81
DIAGNOSIS
SUPPORTIVE STUDIES
location of the lesion (see Fig. 147-12).89 This will
highlight the more cellular component, as well as the
22
more superficial location of GVM compared with VM.
Atypical MRI findings require a biopsy to rule out a
sarcoma or neurofibroma.
In the presence of palmar-plantar multifocal lesions
typical of BRBN (see Fig. 147-10), an endoscopy, colo-
noscopy, or wireless capsule endoscopy should be per-
formed to detect GI lesions.
These radiologic examinations are mandatory for
pretherapeutic evaluation of any venous anomaly.
Genetic Testing: Consider genetic testing for
TIE2 and glomulin mutations in patients with multi-
focal lesions. This differentiates the conditions and

Chapter 147 :: Vascular Malformations

Laboratory Testing: A coagulation profile with enables genetic counseling.
platelet count, fibrinogen, and D-dimer level should
be done in any patients with a pure VM or complex
malformation with a venous component because the
D-dimer level is elevated in about 40% of VMs. This DIFFERENTIAL DIAGNOSIS
blood test, done at the first consultation, should be
repeated around puberty and whenever the malfor- See Table 147-6.
mation becomes painful. This is never the case in a
patient with GVM or other simple vascular anomalies.
Associated low fibrinogen is pathognomonic of severe
LIC. Severe LIC can easily decompensate to DIC with
TABLE 147-6
severe bleeding during interventional or surgical Differential Diagnosis of Venous Malformation
procedures.67,82-84 Based on Morphology
Most Likely
Pathology: VMs are histologically composed Bluish subcutaneous mass, noncompressible
of ectatic vascular channels of venous type with flat ■ Infantile hemangioma (deep)
endothelium. The vascular walls are thin and lined ■ Lymphatic malformation
by a discontinuous layer of mural smooth muscle With multiple enchondromas
cells positive for smooth muscle-α-actin.85 Basement ■ Maffucci syndrome
membranes are also thin. In contrast, GVM is histo- Consider
logically characterized by distended venous channels Hyperkeratotic
surrounded by mural “glomus cells,” which are aber- ■ GVM, if on extremity
■ Cutaneous lesions of CCM
rantly differentiated smooth muscle cells. Glomus cells
■ VVM
are round or polygonal, instead of being elongated, Rule Out
like the normal vascular smooth muscle cells.86 By Superficial, collateral normal veins
immunohistochemistry, glomus cells stain positively ■ Deep venous insufficiency, iatrogenic stenosis, or congenital
for smooth muscle-α-actin and vimentin, but they are agenesis 
negative for desmin, von Willebrand factor, and S100.87 Bluish nonvascular lesion
By in situ hybridization, they are also negative for Based on Location
glomulin.76 Consider
Consider 
VVM is characterized by hyperkeratotic epidermis Base of the nose
on top of small blood vessels with a multilaminated ■ Normal prominent veins
membrane located in the dermis and the subcutis. Scalp or forehead
Focal positive staining for GLUT-1 is seen.63 Histopath- ■ Sinus pericranii
ologic examination of patients with Maffucci syndrome ■ Underlying Galen malformation
Subungual
shows features of spindle cell hemangioendothelioma.
■ Solitary glomus tumor
Cheek
Imaging: Plain radiography can identify the calci- ■ Blue nevus
fication of phleboliths, which are pathognomonic of Brain
LIC in a VM. It can also show the presence of multiple ■ Developmental venous anomaly
enchondromas in patients with Maffucci syndrome ■ CCM
(see Fig. 147-11). Doppler ultrasonography is nonin- Rule Out
vasive and can confirm the slow-flow nature of the Neck; deep mass
lesion. In contrast to lymphatic malformations (LMs), ■ Thyroglossal duct
the venous channels are compressible with the probe.88 ■ Bronchogenic cyst
MRI imaging with spin-echo T1- and T2-weighted and CCM, cerebral cavernous malformation; GVM, glomuvenous malforma- 2651
fat-saturation sequences depicts the exact anatomic tion; VVM, verrucous venous malformation

Kang_CH147_p2636-2668.indd 2651 08/12/18 3:09 pm

22 An unusual pathway of cerebral drainage, a cere-
bral developmental venous anomaly that consists of
dilated intramedullary veins converging into a larger
draining vein, can be seen in 0.5% of the population. In
contrast, it is present in 20% of patients with extensive
head and neck VMs. Although usually asymptomatic,
this anomaly can cause headache.
CLINICAL COURSE
AND PROGNOSIS
VMs grow proportionately with the patient. They
Part 22
never regress spontaneously. Initially, asymptomatic
lesions often become painful in response to trauma
or in altered hormonal states (puberty or pregnancy).
::
They may also expand following thrombosis. No
oncogenic transformation of this condition has been
Vascular Diseases
described. The major complications are life-threat-
ening GI hemorrhage and airway compression.
Patients with inherited venous anomalies, as well as
BRBN and MVM, tend to develop additional small
lesions with time.15 Patients with Maffucci syndrome
have a high incidence of malignancies (40%), mainly
chondrosarcoma but also glioma, fibrosarcoma, and
angiosarcoma.58
MANAGEMENT
Treatment of venous anomalies is warranted when
lesions are symptomatic or for cosmetic purposes. The
most common indications for treatment are pain and
functional impairment.54 Their management is often
multidisciplinary, involving hematologists, surgeons,
and interventional radiologists.
INTERVENTIONS
Medical Management: Compression garments
can be helpful to decrease swelling and pain in VMs of
the extremity by decreasing venous pressure. In con-
trast, compression increases pain in GVM patients and
is not indicated in this situation.
Low-molecular-weight heparin (LMWH; LMWH,
100 IU anti-Xa/kg/day) is usually given to patients
with signs of LIC 24 hours before and for another 5
days after surgical procedures to minimize hemor-
rhagic risk. The same treatment is given to patients
with painful episodes of local thrombosis. In this
circumstance, the duration of treatment is usually
2 weeks.54,67,84
Bleeding from GI BRBN lesions can be managed
conservatively with iron supplementation and blood
transfusions.
With the understanding of the underlying patho-
physiologic mechanisms (activation of the PI3K-AKT
2652 signaling), targeted molecular therapies are becom-
ing possible. Rapamycin (sirolimus) was promising in
Kang_CH147_p2636-2668.indd 2652
a preclinical VM-mouse model trial.90 A phase II clini-
cal trial for difficult-to-treat extensive VMs or complex
slow-flow vascular anomalies not amenable to conven-
tional management also gave encouraging results.90,91
Patients experienced almost complete relief of pain
and symptoms, reduced coagulopathy when present,
improved function, and increased self-perceived qual-
ity of life. Bleeding in sporadic VM as well as in BRBN
stopped within 24 hours. Side effects were minor and
included mucositis, mild headache, fatigue, and diar-
rhea. Moreover, a statistically significant reduction in
volume was observed with MRIs in most patients that
reached 1-year follow-up. A multicentric European
Study (VASE; NCT 02638389) is ongoing to determine
which subtypes of VMs are best suited for rapamycin
treatment and for how long the treatment should be
continued. Rapamycin should not be considered as
treatment for small, localized, and asymptomatic slow-
flow vascular malformations that respond to standard
of care.92
Procedures: Percutaneous intralesional sclero-
therapy is the primary treatment for VM, in contrast
to GVM. Absolute ethanol is the most efficient scleros-
ing agent.93 Local compression or intralesional coils are
used to prevent dissemination of ethanol into the sys-
temic circulation. Local complications include inflam-
mation, edema, blistering, necrosis, chronic drainage,
and temporary or permanent nerve deficit. Systemic
complications, such as renal or pulmonary toxicity,
myocardial depression, and cardiac arrest, have been
reported. Multiple sclerotherapy sessions are often
needed because VMs have a propensity to recanalize
and recur. Alternatives to ethanol sclerotherapy are
sodium tetradecyl-sulphate foam or lauromacrogol
that are effective for small VMs and cause fewer local
adverse effects. Positive response was seen in 49.5%
(for pain) and 52.7% (for mass reduction), within the
86 patients (91 VMs) involved in one study.94 Detergent
sclerosants have been used as microfoams, using air
bubbles or carbon dioxide to increase volume and sur-
face contact with endothelium. However, neurologic
complications have been described in 2% of cases.
A modified radiopaque ethanol sclerosing agent was
therefore developed. It traps ethanol within a mesh of
ethylcellulose to increase viscosity.95,96
Surgical resection is often performed after
sclerotherapy.53 In patients with BRBN, endoscopic
coagulation with Nd:YAG (neodymium-doped yttrium
aluminum garnet)laser, bipolar or argon plasma coag-
ulation, and band-ligation are useful. An open sur-
gery allowing surgical resection of all GI lesions can
eradicate the need for blood transfusion as well as
the common intermittent abdominal pain caused by
intussuception.97,98 In patients with GVM, skin graft is
often needed if excision is undertaken. VVM is also best
treated with surgical resection. Closure often necessi-
tates a skin graft.
Counseling: In patients with VMCM or GVM,
genetic counseling should be provided for affected
families, informing patients of a 50% risk of inheriting
08/12/18 3:09 pm
 the disease-causing mutation and of the variability
in clinical expression. Psychosocial counseling and
patient organizations dedicated to vascular anoma-
lies are also an important asset for patients and their
families.
LYMPHATIC ANOMALIES
AT-A-GLANCE
■ Worldwide occurrence of LM is unknown, but it is
part of a syndrome, such as in Turner and Noonan
syndromes.100
22
SYNDROMIC DISORDERS
KLIPPEL-TRENAUNAY SYNDROME
Klippel-Trenaunay syndrome is a combined capillary–
lymphatic–venous malformation associated with
hypertrophy of the affected limb. Lower limbs are
affected in 70% of cases. It is characterized by a geo-
graphic, widespread CM associated with lymphatic

Chapter 147 :: Vascular Malformations

less frequent than that of VM.
■ Congenital, sporadic, slow-flow malformations of
lymphatic vessels
■ LMs consist of micro- or macrocysts filled with
lymphatic fluid.
■ Histologically consist of dilated lymphatic
channels with flat endothelium that expresses
D2-40.
■ Primary lymphedema can be inherited as an
autosomal trait.
■ Infection is the most common complication that
can lead to septicemia.
vesicles. The persistence of a persistent embry-
onic vein located on the lateral side of the thigh is
pathognomonic.101,102
CLOVES SYNDROME
CLOVES syndrome is an eponym for congenital lipo-
matous overgrowth with vascular malformations,
epidermal nevi, and skeletal anomalies.103 This non-
hereditary disorder is characterized by progressive
asymmetric hypertrophy, multiple truncal lipomatous
masses with paraspinal fast-flow or slow-flow vascu-
lar anomalies (or both), epidermal nevus or nevi, acral
lesions, and skeletal or spinal anomalies (Fig. 147-15).

INTRODUCTION
LMs are localized morphogenic errors of the lym-
phatic vessels. They consist of small vesicles or large
cysts filled with lymphatic fluid. Macrocystic LM can
be diagnosed in utero as early as the first trimester of
pregnancy.99 However, most LMs are diagnosed dur-
ing infancy, before the age of 2 years. Some can mani-
fest only at puberty or during adulthood. They can be
isolated, combined with other vascular anomalies, or
be part of a syndrome.
Primary lymphedema is not a localized lesion but a
more generalized condition, in which the lymph fluid
accumulates in the interstitial tissue. Lower extremities
are most commonly affected. It can be uni- or bilateral.
Primary lymphedema can be an isolated condition or
part of a syndrome, and it can occur sporadically or as
an inherited disorder.

EPIDEMIOLOGY
LM is a congenital disorder of unknown incidence.
It occurs sporadically in contrast to primary lymph-
edema, which can be inherited, usually as an auto-
somal dominant trait, in up to 20% of cases. Primary
lymphedema is divided into congenital (Milroy dis-
ease, Online Mendelian Inheritance in Man [OMIM] Figure 147-15 Capillary–lymphatic–venous malforma-
#153100) and late onset (presenting at puberty, tion of right lower extremity with soft tissue hypertrophy 2653
Meige disease, OMIM #153200). It can be isolated or (CLOVES syndrome).

Kang_CH147_p2636-2668.indd 2653 08/12/18 3:09 pm

22 The most important differential diagnoses are other
overgrowth syndromes, such as the Proteus syndrome CLINICAL FEATURES
and Proteus-like syndrome.104
CUTANEOUS FINDINGS
GENERALIZED LYMPHATIC LMs are composed of microcysts (Figs. 147-16 and
ANOMALY 147-17), previously termed lymphangioma circumscrip-
tum) or macrocysts (>1 cm in diameter, previously
Generalized lymphatic anomaly (GLA) is a rare condition known as cystic hygroma) that grow proportionally
in which LMs can invade several organs such as the medi- with the child (see Figs. 147-1B, 147-16, and 147-17).
astinum, lungs, pleura, GI tract, bones, and soft tissue.105 They are filled with clear or serosanguineous fluid
(see Fig. 147-17B). Whereas macrocystic LM manifests
as a soft, multilobulated, well-defined mass, micro-
GORHAM-STOUT SYNDROME cystic LMs are ill-defined and often invade adjacent
Part 22

Gorham-Stout syndrome, or “vanishing bone disease,”
is an aggressive rare lymphatic disorder characterized
by progressive demineralization and destruction of
bones, which are replaced by lymphatic vessels and
::
structures. Dermal LMs can manifest as small, mil-
limeter-sized vesicles, clear (see Figs. 147-16D and
147-17A) or dark red in color (when there is intracys-
tic bleeding), that can bleed and become purple and

capillaries.106 nodular.
Vascular Diseases

A B C

2654 Figure 147-16 Various aspects of lymphatic malformation (LM). Bluish discoloration (A) of extensive LM of cheek, as seen
on computed tomography scan (B and C). Small clear vesicles of dermal LM (D).

Kang_CH147_p2636-2668.indd 2654 08/12/18 3:09 pm


A B
Figure 147-17 A, Microcystic, dermal lymphatic malformation (LM) consisting of clear and dark-red vesicles. B, Intraopera-
tive view of a macrocystic LM of axilla showing a well-delineated cyst filled with clear lymph fluid. C, Histologically, LM
consists of dilated lymphatic channels with flat endothelium (hematoxylin and eosin).
Angiokeratoma Circumscriptum: Angio-
keratoma circumscriptum, or capillary-lymphatic
malformation (CLM), is a combined, well-demarcated
lesion often located on an extremity. The lesion is pink
to bluish-red in color, slightly raised, and usually
hyperkeratotic. Clinically, angiokeratoma circumscrip-
tum, angiokeratoma of Mibelli (circumscribed, dark-
red, hyperkeratotic plaques on distal extremities),
and angiokeratoma of Fordyce (very common hyper-
keratotic, blue-black papules on the scrotum of elderly
men) are recognized. They are to be differentiated from
angiokeratomas of Fabry disease (see Chap. 127) and
from VVM (previously known as verrucous heman-
gioma; see earlier VM section).
Lymphedema: Lymphedema is characterized
by swelling of the affected body part, usually a lower
extremity, and caused by accumulation of lymphatic
fluid into the extracellular space caused by intrinsic
lymphatic dysfunction (Fig. 147-18). Various pheno-
types exist depending on the age of onset, location,
and associated anomalies.107,108
Congenital Lymphedema: Milroy disease is
suspected in the presence of swelling of the dorsum of
the feet with a family history of lymphedema. Lymph-
edema is present at birth, often bilateral, and affects
the lower limbs below the knees.109 Other features
can be associated with congenital lymphedema, such
as hydrocele (37% of males), prominent veins (23%),
upslanting toenails (14%), papillomatosis (10%), or
urethral abnormalities in males (4%).
NONCUTANEOUS FINDINGS
Pulmonary embolism can occur in patients with KTS
or CLOVES syndrome.110 Depending on the affected
organ, symptoms such as pleural effusion, ascites, and
malabsorption can occur in patients with GLA.105 Pain-
ful pathological fractures are common in patients with
Gorham-Stout syndrome.106
Kang_CH147_p2636-2668.indd 2655
22
C
Chapter 147 :: Vascular Malformations
COMPLICATIONS
LM can suddenly enlarge in response to cough, inflam-
mation, fever, viral or bacterial infection, or intral-
esional bleeding (Fig. 147-19). Recurrent cellulitis is
the major complication, especially in patients with
KTS, and it can evolve into septicemia if not promptly
treated. Local redness and warmth appear, and the
lesion becomes painful.
Facial asymmetry, especially of the mandible,
is commonly associated with microcystic LM (see
Fig. 147-16). Intraorbital LM is responsible for ocular
dystopia and exophthalmia, as well as orbital enlarge-
ment. LM on the tongue impairs speech and produces
oozing and halitosis. Airway obstruction is common
when the base of the tongue or the cervicofacial area is
affected.111 Extensive limb LM can cause elephantiasis.
Extension into the pleura can occur and cause chylo-
thorax. Visceral LM can cause protein-losing enteropa-
thy and hypoalbuminemia. Patients with KTS as well
as patients with CLOVES are at high risk of pulmonary
embolism because of the persistent embryonic vein and
the presence of ectatic thoracic veins, respectively.110
Lymphedema is complicated by cellulitis in
20% of cases. More rarely, pleural effusion, even in
utero; hydrops fetalis; and chylous ascites can be
observed.108,112,113
ETIOLOGY AND
PATHOGENESIS
LMs, as well as KTS and CLOVES syndrome, are caused
by mosaic or somatic mutations in PIK3CA that acti-
vate the PI3K/AKT/mTor signaling pathway.11,12,114,115
More than 20 genes have been identified to be
mutated in various forms primary lymphedema.108
Milroy disease is caused by inherited loss-of-function
mutations in vascular endothelial growth factor recep- 2655
tor 3 (VEGFR3).116-118 Mutations in the same gene
08/12/18 3:09 pm
22

A B
Part 22
::
Vascular Diseases

C D

Figure 147-18 Various types of congenital primary lymphedema characterized by lymphedema of lower limb, below the
knees (A); with papillomatosis (B); with upslanting toenails (C); that can evolve into elephantiasis (D).

are also responsible for sporadic hydrops fetalis and in the FOXC2 transcription factor.120 Lymphedema
generalized subcutaneous edema.119 Lymphedema- associated with microcephaly, with or without cho-
distichiasis is caused by loss-of-function mutations rioretinopathy or developmental delay, is caused

A B

2656 Figure 147-19 Intraoperative view of an axillary lymphatic malformation that had suddenly increased in size because of
intracystic bleeding.

Kang_CH147_p2636-2668.indd 2656 08/12/18 3:09 pm

 by dominantly inherited mutations in KIF11.121,122
Hypotrichosis–lymphedema–telangiectasia, which has
an autosomal-dominant or -recessive pattern of inheri-
tance, is caused by mutations in SOX18.118 Hennekam
syndrome (OMIM #235510) is an autosomal recessive
generalized lymphatic dysplasia characterized by
intestinal lymphangiectasia with severe and progres-
sive lymphedema of the limbs, genitalia, and face, as
well as severe mental retardation.123 Mutations have
been identified in CCBE1 (collagen and calcium-
binding EGF domains 1).107,124 Lymphedema is asso-
ciated with hematologic malignancies in Emberger
syndrome caused by GATA2 mutations.125 In about
35% to 40% of patients with familial primary lymph-
edema, a germline mutation can be identified.108,126
DIAGNOSIS
SUPPORTIVE STUDIES
Pathology: LMs are characterized by dilated, flat-
endothelium-lined channels of variable wall thick-
ness (see Fig. 147-8C). No blood cells are seen in these
spaces, except after intracystic bleeding or in the pres-
ence of a combined lymphatic-venous malformation.
Macrocystic LM consists of a single or multiple lym-
phatic cysts surrounded by a thick fibrous membrane.
The cysts do not communicate with each other. Endo-
thelial cells express specific lymphatic markers, such as
podoplanin, D2-40, and VEGFR-3.44,127 Lymphedema is
characterized by abnormalities in the primary periph-
eral lymphatic capillaries, collecting lymphatic vessels,
or lymphatic valves and lymphovenous valves. This is
pronounced in the affected limb but is sometimes also
seen on the contralateral side. Extensive dermal fibro-
sis is often present.44
Imaging: Doppler ultrasound shows microcysts,
macrocysts, or both separated by thin septa. In con-
trast to VMs, they are not compressible by the probe.
MRI also demonstrates the cystic nature of the lesion,
with often discernable fluid-fluid levels.128,129 Com-
puted tomography (CT) is the best study to show bony
involvement.
Doppler ultrasonography of the deep venous sys-
tem of the affected lower limb and the pelvic area is
needed in patients with KTS and CLOVES. Moreover,
because CLOVES syndrome is characterized by pro-
gressive overgrowth during infancy, careful follow-
up every 6 months is recommended until the end of
puberty. Follow-up consists of clinical examination,
scaniometry (leg length films), and abdominal ultra-
sonography because of the increased risk of cryptor-
chidism, hydrocele, renal atrophy, and Wilms tumor.130
Additional investigations should be done according to
symptoms.
Genetic Testing: Genetic panel–based testing is
available in accredited diagnostic laboratories. Such
screens help identify germline mutations and can aid
Kang_CH147_p2636-2668.indd 2657
TABLE 147-7
22
Differential Diagnosis of Lymphatic
Malformation
Most Likely
■ Infantile hemangioma
Consider
■ Venous malformation
■ Teratoma
■ Fibrosarcoma or rhabdomyosarcoma
Rule Out
Vulvar
■ Acquired lymphangiectasia caused by radiotherapy
■ Acquired lymphangiectasia caused by Crohn disease
Chapter 147 :: Vascular Malformations
management. For example, identification of a germ-
line GATA2 mutation indicates specific cancer sur-
veillance programs, and a KIF11 mutation implies a
need for detailed ophthalmologic and developmental
examination.
DIFFERENTIAL DIAGNOSIS
See Table 147-7.
CLINICAL COURSE
AND PROGNOSIS
LM usually grows with the child. It can cause asym-
metry with bony overgrowth. Increases in size can be
seen during infection or intralesional bleeding. Epi-
sodic reports of spontaneous involution exist. Because
regression is commonly seen after local infection, it
may be caused by postinflammatory autosclerosis.
Patients with Gorham-Stout syndrome have a poor
prognosis; it is lethal in 16% of cases.
MANAGEMENT
INTERVENTIONS
Medical Management: Systemic antibiotics
should be used to treat intralesional bacterial infec-
tion as well as early cellulitis in both isolated and syn-
dromic LM. Antiinflammatory drugs may be required
to alleviate pain. Patients with CLOVES or KTS syn-
drome need to receive LMWH at prophylactic dosages
of 100 anti-Xa/kg/day before any surgical procedure;
this should be continued for another 10 to 20 days post-
operatively to avoid perioperative decompensation of
their coagulation abnormalities, and more importantly,
to reduce the risk of life-threatening postoperative pul- 2657
monary embolism.110 Rapamycin has been effectively
08/12/18 3:09 pm
22 Part 22
::
Vascular Diseases
A B
Figure 147-20 Dermal lymphatic malformation (A) efficiently treated with carbon dioxide laser (B).
used for extensive LMs resistant to standard treatment,
as well as for patients with KTS and GLA. Although
none had complete resolution, several patients experi-
enced cessation of lymphatic leakage and infection and
reduction of volume of the malformation. Side effects
were minor.131,132
Lymphedema is best treated with elastic stock-
ings, massage, and pneumatic compression devices.
Sildenafil was suggested as effective in the treatment
of LM,133 but further studies have not confirmed its
efficacy and highlighted potential side effects, such as
infections and bleeding.134,135
Procedures: Nd:YAG laser or carbon dioxide laser
photocoagulation has been used to treat dermal LM
vesicles that cause oozing (Fig. 147-20). Macrocystic
LM is treated with fluid aspiration followed by per-
cutaneous, intralesional injection of sclerosing agents
performed by an interventional radiologist. Scleros-
ing agents include sodium tetradecyl sulfate, pure
ethanol, OK432 (extract from a killed strain of group
A Streptococcus pyogenes: picibanil), doxycycline, and
bleomycin. Side effects vary from fever and erythema
to edema.136,137
Surgical resection is another alternative for LM,
CLOVES, and KTS syndrome.138,139 Results depend on
the anatomical site and extension of the lesion. Recur-
rence is frequent because it is difficult to differentiate
microcystic LM from adjacent normal tissue. This leads
to either incomplete resection or unnecessary sacrifice
of normal structures.
Counseling: Family and patient education
regarding the cause and treatment is necessary for
2658 primary lymphedema because it can be inherited
and associated with other important medical
Kang_CH147_p2636-2668.indd 2658
problems, necessitating inclusion in special surveil-
lance programs. Psychosocial counseling and patient
organizations dedicated to vascular anomalies are also
an important help for patients and their families.
ARTERIOVENOUS
MALFORMATIONS
AT-A-GLANCE
■ Worldwide occurrence; rare but exact frequency
unknown
■ Congenital, fast-flow malformations that can be
occult until puberty
■ Histologically consist of direct communications
between arteries and veins
■ Usually sporadic but can have a genetic predis-
position as in CM-AVM, hereditary hemorrhagic
telangiectasia, or PHTS
■ Most difficult vascular malformation to treat; need
a multidisciplinary approach
INTRODUCTION
Fast-flow vascular malformations, namely AVM and
AVF, are the most severe and devastating malforma-
tions. AVF is usually the result of trauma. AVM is char-
acterized by the presence of a “nidus,” the epicenter of
the lesion that is composed of direct communications
between multiple feeding arteries and draining veins
08/12/18 3:09 pm
 without an intervening normal capillary bed. AVMs
are present at birth, although they are not always
visible. They can be localized or extensive and evolve
with age.
EPIDEMIOLOGY
The incidence of AVM is unknown. No sex preponder-
ance has been identified. It is a rare, usually sporadic,
fast-flow vascular malformation. Hereditary hemor-
rhagic telangiectasia (HHT) is an autosomal inherited
disorder with a prevalence of 1 in 5000 individuals.140
CM-AVM is another familial form with autoso-
mal dominant inheritance and a similar prevalence
estimate.19-23
SYNDROMIC DISORDERS
BONNET-DECHAUME-BLANC OR
WYBURN-MASON SYNDROME
Bonnet-Dechaume-Blanc or Wyburn-Mason syndrome
is a sporadic, syndromic AVM located in the centrofa-
cial or hemifacial area (or both), with oculo-orbital and
cerebral involvement.141 It rarely follows a trigeminal
distribution like SWS. Intracerebral AVMs are common
in Bonnet-Dechaume syndrome and can cause epi-
staxis, exophthalmos, and hemianopia. Mental retar-
dation can also occur.
COBB SYNDROME
Cobb syndrome is another sporadic, syndromic AVM
that associates cutaneous and spinal cord AVMs of the
same metamere.142 The cutaneous lesion masquerades
as a CM, although it is warm on palpation. Cobb syn-
drome manifests in childhood with a sudden onset of
back or lower extremity pain associated with sensory
disturbance. Other neurologic complications (pain,
sensory and motor disturbances, and neurogenic blad-
der) can occur depending on the location and exten-
sion of the AVM.
HEREDITARY HEMORRHAGIC
TELANGIECTASIA
Individuals with HHT demonstrate combinations of
the following triad: multiple cutaneous and mucosal
telangiectasias, often located on the mucosal lip; epi-
staxis; and a positive family history.143 The diagnosis
is clinical, in accordance with the Curaçao criteria.
The estimated frequencies of manifestations in HHT
patients are spontaneous, recurrent epistaxis, 90%;
skin telangiectasia, 75%; hepatic or pulmonary AVMs,
30%; and GI bleeding, 15%.144 In 30% of patients with
HHT, a hepatic, pulmonary, or cerebral AVM (or a
Kang_CH147_p2636-2668.indd 2659
combination of any of these AVMs) can be seen.144 In
contrast, in 23% of patients with CM-AVM1 and 13%
22
of patients with CM-AVM2, an intracerebral or intra-
spinal AVM is present.18,19,22,23,35], but there is no risk for
visceral AVM as in HHT. Vein of Galen aneurysmal
malformation is also part of the phenotype. Recur-
rent epistaxis is typically the initial manifestation of
HHT. The nosebleeds can be severe enough to require
blood transfusions. Pulmonary AVMs affect approxi-
mately 30% of patients with HHT and are particularly
common in HHT1. These patients are at higher risk of
stroke and brain abscess than in the healthy popula-
tion because the normal filtering function of the lung is
lost. Migraine headaches occur in 13% to 50% of cases.
Chapter 147 :: Vascular Malformations
Recurrent painless GI bleeding occurs in 10% to 40%
of patients. Symptoms may include abdominal pain,
jaundice, symptoms of high-output cardiac failure,
and bleeding from esophageal varices.145
PARKES WEBER SYNDROME
Parkes Weber syndrome is characterized by a large,
congenital, cutaneous, red vascular stain on an extrem-
ity in association with soft tissue and skeletal hyper-
trophy of the affected limb and underlying multiple
arteriolar-venular microfistulas.146 The affected extrem-
ity, often the lower one, is longer and larger than the
contralateral one. Although often sporadic, it can be
part of CM-AVM. In these cases, there are small, multi-
focal CMs located on other parts of the body. The signs
and symptoms worsen with age. Affected patients can
develop congestive heart failure.
PHOSPHATASE AND TENSIN
HOMOLOG HAMARTOMA
TUMOR SYNDROME
PHTS is an autosomal-dominant disorder that includes
patients with Bannayan-Riley-Ruvalcaba syndrome
and Cowden syndrome because 60% and 81% of them,
respectively, have a mutation in PTEN.147 These patients
typically have macrocephaly, penile freckling, multiple
developmental venous anomalies in the brain, fast-
flow VMs (54%), and an increased risk of malignancy.
The VMs are often multifocal (57%) and musculoskel-
etal and associated with ectopic fat deposition and dis-
ruption of the normal tissue architecture.147,148
CLINICAL FEATURES
CUTANEOUS FINDINGS
AVMs usually manifest as cutaneous, faint, red to
purple, ill-defined masses with a thrill, a bruit, or
a pulsation of increased amplitude (Figs. 147-21 to
147-23; see also Figs. 147-1D and 147-1E). About one
third of AVMs are present at birth, another -third 2659
appear during childhood or at puberty, and the rest
08/12/18 3:09 pm
22 Part 22
::
Vascular Diseases

A B

Figure 147-21 Stage 2 arteriovenous malformation of the left thigh mimicking an infantile hemangioma that did not
disappear at 8 years of age (A). Arteriography showing the nidus confirmed the diagnosis (B).

manifest in adulthood because hormonal changes and
trauma usually trigger the growth of an AVM. AVMs
can affect any tissue and organ. Seventy percent of
AVMs are located on the head and neck. They never
regress spontaneously and get worse with time.149
In 1985, Schobinger staged AVMs according to their
severity. Schobinger stage I is a red stain with bruit
and pulses of increased amplitude. With age, puberty,
or trauma, AVM can worsen, and veins become prom-
inent and tortuous (Schobinger stage II; Fig. 147-22)
and subsequently darker and painful, and they ulcer-
ate and bleed (Schobinger stage III; see Fig. 147-23).
The final stage of a large AVM is cardiac failure
(Schobinger stage IV; see Fig. 147-23).150 The patient
often reports hearing his or her cardiac pulse.
CM-AVM (see earlier discussion of CM-AVM) mani-
fests as multiple atypical CMs that are randomly dis-
tributed (see Fig. 147-6) and associated with fast-flow
lesions—AVM, AVF, or Parkes Weber syndrome—in
30% (CM-AVM1) or 20% (CM-AVM2) of patients. The
expressivity is highly variable within families, from
small, asymptomatic CMs to life-threatening AVMs.
The fast-flow lesions (AVM or AVF) are either cutane-
ous or subcutaneous, with or without intramuscular
and intraosseous involvement. About 10% to 15% of
patients with CM-AVM have a Parkes Weber pheno-
type affecting the lower (two thirds of such cases) or
the upper extremity. The AVMs can be asymptomatic,
but complications occur depending on the location
and size.19-21

A B C

Figure 147-22 A, Extensive arteriovenous malformation deforming the right buttock. B, Arteriography showing nidus of
2660 the malformation. C, Histology shows direct connection between artery and vein, with thrombotic material secondary to
embolization procedure.

Kang_CH147_p2636-2668.indd 2660 08/12/18 3:09 pm


A B
Figure 147-23 Stage 2 arteriovenous malformation (AVM; A) evolving into stage 4 AVM (B).
NONCUTANEOUS FINDINGS
In 30% of patients with HHT, a hepatic, pulmonary,
or cerebral AVM (or a combination of any of these
AVMs).144 In 23% of patients CM-AVM1 and 13% of
patients with CM-AVM2, an intracerebral or intraspi-
nal AVM (or both) is present.18,19,22,23,35
COMPLICATIONS
AVMs involving the face can as well destroy the bone
structure underneath and can cause gingival bleeding
or epistaxis as well as hypertrophic asymmetry. Bony
hypertrophy is a common feature of facial AVM, which
causes asymmetry. AVM of an extremity often causes
peripheral ischemia due to blood flow steel phenome-
non. Cardiac failure is rare (Schobinger stage IV), espe-
cially during childhood. Puberty and trauma as well as
hormonal influence can trigger appearance of AVMs.
Intracerebral AVM such as in Bonnet-Dechaume syn-
drome, can cause epistaxis, exophthalmos, and hemi-
anopia. Mental retardation can also occur.
Cobb syndrome manifests in childhood with a sud-
den onset of back or lower extremity pain associated
with sensory disturbance. Other neurologic complica-
tions (pain, sensory and motor disturbances, and neu-
rogenic bladder) can occur depending on the location
and extension of the AVM.
Recurrent epistaxis is typically the initial manifes-
tation of HHT. The nosebleeds can be severe enough
to require blood transfusions. The prevalence of brain
AVM is 1000-fold higher in patients with HHT1 than
in the general population (1 in 10,000) and 100-fold
Kang_CH147_p2636-2668.indd 2661
22
Chapter 147 :: Vascular Malformations
higher in patients with HHT2. A similar increased risk
is seen in CM-AVM1 and 2. Patients with HHT with
pulmonary AVMs and telangiectasia of the GI tract are
at risk for life-threatening hemorrhage. Other sites of
bleeding may include sites in the kidney, spleen, blad-
der, liver, meninges, and brain. Strokes may be either
hemorrhagic or ischemic.
These patients are at higher risk of stroke and brain
abscess than in the healthy population because the
normal filtering function of the lung is lost. Migraine
headaches occur in 13% to 50% of the cases. Recurrent
painless GI bleeding occurs in 10% to 40% of patients.
Symptoms may include abdominal pain, jaundice,
symptoms of high-output cardiac failure, and bleeding
from esophageal varices.145
Patients with CM-AVM can exhibit intrauterine life-
threatening intracerebral bleeding caused by vein of
Galen aneurysmal malformation.22,151 The brain and
medullary AVMs can also bleed postnatally.22,35,151
ETIOLOGY AND
PATHOGENESIS
Underlying genetic defects have been identified for
the fast-flow vascular malformations of CM-AVM
(OMIM #608354), HHT (OMIM #187300), and PHTS
(OMIM #153480 and 158350). These disorders are
inherited as an autosomal-dominant pattern with a
penetrance of about 95% for the cutaneous CMs or
telangiectasias.18,19,22,151
HHT is caused by alterations in the transforming 2661
growth factor-β signaling pathway. The genes implicated
08/12/18 3:09 pm
22 in HHT are ENG, encoding endoglin (HHT type 1), and
ACVRL1 (formerly called ALK1, HHT type 2); SMAD4,
and GDF2 are less frequently involved.152-155
Endoglin and ACVL1 are type III and type I trans-
forming growth factor-β receptors, and both are
well-expressed on vascular endothelial cells. Loss-
of-function of this signaling concomitantly increases
PI3K-AKT signaling.156
CM-AVM1 is caused by loss-of-function mutations in
RASA1.18,20 RASA1 encodes P120RASGAP, a GTPase reg-
ulating RAS activity. It converts the active GTP-bound
RAS into its inactive GDP-bound form.61,62,157 The high
intrafamilial phenotypic variability is explained by the
necessity of a somatic second-hit mutation to occur.21,158
Part 22
In 30% of patients with CM-AVM1, the mutation is de
novo. CM-AVM2 is caused by loss-of-function mutation
in EPHB4, which encodes an endothelial cell receptor
in venous vessels. The ligand EPHRINB2, in contrast
::
to EPHB4, is expressed in arterial endothelial cells. This
Vascular Diseases
bidirectional ligand–receptor system is important for
arteriovenous identity and separation. EPHB4 signals
using p120RASGAP, and the loss of function of either
gene causes increased RAS-MAPK signaling.18,159-162
AVM can also be caused by loss-of-function mutation
in PTEN, a tumor suppressor gene, as seen in patients
with PHTS.163 PTEN regulates PI3K-AKT activity, and
this seems to be regulated at least in part by the HHT
receptor complex (see earlier). Loss of function of one
of the partners of this complex or of PTEN itself leads
to activation of PI3K.
Sporadic extracranial AVMs are caused by somatic
activating MAP2K1 (MEK) mutations.14 Brain AVM
are caused by another activating mutation in KRAS,
which is also involved in the RAS-MAPK signaling
pathway.164
DIAGNOSIS
SUPPORTIVE STUDIES
Pathology: Histologically, AVMs are poorly
demarcated and consist of distorted arteries and veins
with thickened muscle walls caused by arteriovenous
shunting and fibrosis (see Fig. 147-22C).
Imaging: Ultrasonography and color Doppler
show no mass but an aggregation of high-velocity
arterial and pulsatile venous flow with low resistance.
Vessels are tortuous. On the extremities, noninvasive
follow-up is performed by comparing the arterial out-
flow of the affected limb with the unaffected one. MRI
is preferred over CT to delineate the extent of an AVM
and differentiate AVM from hemangiomas and other
VMs. Flow voids, corresponding to fast-flow vessels,
are pathognomonic of AVM. Arteriography is needed
before any treatment to determine feeding arteries and
the nidus (see Figs. 147-1E and 147-22B).
2662 Genetic Testing: Genetic testing is indicated in
patients with an AVM that is associated with multifocal
Kang_CH147_p2636-2668.indd 2662
cutaneous CMs (CM-AVM) or telangiectasias (HHT).
Molecular diagnosis helps genetic counseling and
guide further imaging for eventual undetected mal-
formations. Patients with AVM with associated mac-
rocephaly should be screened for PTEN mutations.
Identification of a germline mutation would enable
precise counseling and inclusion in cancer surveillance
programs.
DIFFERENTIAL DIAGNOSIS
See Table 147-8.
During childhood, AVM is often mistaken for a CM
or hemangioma because of its presentation as a faint,
ill-defined, macular red stain. However, dispropor-
tionate warmth on palpation is a clue to its fast-flow
component. A pulse, thrill, and bruit are other signs
supporting AVM. Doppler ultrasonography can help
differentiate a slow-flow CM from a fast-flow AVM or
hemangioma. Hemangiomas have equatorial feeding
arteries, peripheral veins, variable echogenicity, and
fast flow but no true arteriovenous shunting.
Other dermatologic lesions can mimic AVM.
Epithelioid hemangioendothelioma occurs in the
extremity as a purple and locally aggressive lesion.
Tumid lupus erythematosus, sarcoidosis of the face,
and Melkersson-Rosenthal syndrome of the lip can
mimic AVM. Dabska tumor can simulate an AVM on a
child when it is located in the ear.
CLINICAL COURSE
AND PROGNOSIS
AVMs tend to worsen with time, causing local destruc-
tion or life-threatening bleeding. Puberty and trauma
trigger growth of the lesion. Improper management,
often because of misdiagnosis, such as ligation of feed-
ing arteries, or partial resection of the nidus, can have
TABLE 147-8
Differential Diagnosis of Arteriovenous
Malformation
Most Likely
At birth
■ Congenital hemangioma
■ Infantile fibrosarcoma
■ Other sarcoma
Rapid growth after birth
■ Infantile hemangioma
Rule Out
Ear, nose
■ Lupus erythematosus tumidus
■ Sarcoidosis
■ Dabska tumor
Lip
■ Melkersson-Rosenthal syndrome
08/12/18 3:09 pm
 dramatic consequences and expansion of the AVM (see
Fig. 147-23). The CMs in CM-AVM are harmless and
usually of only cosmetic importance, although flow
characteristics are commonly abnormal.
MANAGEMENT
This fast-flow VM is the most complex and difficult
vascular anomaly to treat. Its management is multi-
disciplinary. AVMs should be followed by periodic
evaluation. The goal of cure of an AVM is based on
obliteration (by embolization) and complete removal
of the nidus. Partial resection and proximal ligation
of the feeding arteries lead to severe complications,
recurrence, and reexpansion over time. Furthermore,
ligature of the proximal arteries prevents access to the
nidus for embolization, stimulates recruitment of new
feeding arteries, and therefore expands the malforma-
tion. Mismanagement of AVM can lead to amputation.19
INTERVENTIONS
Medications: In a limb AVM or multiple AVFs,
elastic stockings can stabilize the lesion and protect the
skin, especially in the early stage. Because AVM is dif-
ficult to eradicate, the focus of management is often to
control the evolution of the malformation rather than
to cure the patient.40,45 A pharmacologic approach with
Marimastat, a synthetic matrix metalloproteinase inhib-
itor, has been used to treat extensive AVMs with good
results. It reduced extension of the malformation and
decreased pain and bruit.46 Unfortunately, the drug is
no longer available. Thalidomide was successfully used
to reduce the frequency and duration of nosebleeds in
patients with HHT.165 It has also been used in unresect-
able stage 3 AVMs for which standard treatment had not
been successful. For some patients, it was used in com-
bination with embolization to improve efficacy.
Procedures: Superselective embolization: In contrast
to AVF, superselective arterial embolization alone is
only palliative and is done only in unresectable, com-
plicated AVM. The embolized particles need to reach
the epicenter of the lesion to avoid refilling of the nidus
through new collaterals.166 Direct puncture of the nidus
is another possibility in patients with previous arterial
ligation or embolization.167 The most common materi-
als are liquids (ethanol, isobutylcyanoacrylate), par-
ticles (Ivalon), foam, and implantable devices (coils,
microspheres). Embolization is rarely curative unless
performed for an arteriovenous fistula. Embolization
can be used alone (palliative approach) or followed
by complete surgical excision (curative approach).
The site of injection must be as close as possible to the
nidus to permit a superselective approach. Proximal
occlusion is responsible of secondary refilling of the
nidus through collateral arteries.24
Radical excision: Surgical resection is usually done
only after embolization to minimize perioperative
Kang_CH147_p2636-2668.indd 2663
bleeding.168 Excision should be complete and radical
with carcinologic margins when possible. It is pre-
22
ceded with superselective embolization to occlude
the nidus and reduce intraoperative bleeding.19,26 The
overlying skin can be saved if normal; otherwise, it is
widely excised. Coverage options include tissue expan-
sion or a local or free flap.29 Cutaneous expansion can
be done before embolization or surgery but may act
as a trigger to stimulate growth of the malformation.
Early intervention for “quiescent AVM” (Schobinger
stage I) is debatable and should be considered only if
complete resection is possible.169 Follow-up for at least
5 years with annual Doppler ultrasonography or MRI
(or both) is mandatory after any treatment.
Chapter 147 :: Vascular Malformations
For patients with Parkes Weber syndrome, treatment
should be as conservative as possible. Epiphysiodesis
may be necessary to control leg-length discrepancy.
This procedure can sometimes aggravate the AVM.146
For patients with HHT, multiple treatments have been
tried to reduce bleeding, including topical application
of antiinflammatory drugs, laser, or surgery. Because
of the extensiveness of the lesions, they all give limited
symptom-free intervals.
Counseling: Genetic counseling is mandatory in
CM-AVM, HHT, and PHTS.
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