Vascular malformations (VMs) are developmental abnormalities of the vascular system. They are as a result from abnormal -sized vascular structures or… [600775]

1.0 Introduction
Vascular malformations (VMs) are developmental abnormalities of the vascular system.
They are as a result from abnormal -sized vascular structures or an abnormal number of
vascular structures. These malformations usually manifest as coetane ous birthmarks
and have had a number of classifications, producing an array of confusing terms They
should be differentiated from vascular tumors or hemangiomas, because they have
different causes, growth patterns, treatments, and outcomes. Malformations m ay
involve any segment of the vascular tree: arteries, capillaries, veins, or lymphatic's.
High-flow arteriovenous malformations are associated with shunting of large amounts of
arterial blood into the venous system; these lesions can have alarming hemody namic
manifestations, such as venous engorgement, distal limb ischemia, and high -output
cardiac failure. Predominantly venous malformations are the most common type seen at
vascular clinics; most have a benign clinical course and require no special treatme nt. In
one series, the ratio of venous to arteriovenous malformations was 4:1.. Most VMs are
mixed, and some complex malformations such as Klippel -Trénaunay syndrome or
Parkes Weber syndrome are associated with developmental abnormalities of other
tissues, including bone and soft tissue overgrowth or digital abnormalities.

Birthmarks and congenital deformities have been described by historians and depicted
by painters for centuries. One of the first detailed medical descriptions of an
arteriovenous malform ation with pulsating varices of the head, caused by a so -called
cirsoid aneurysm, dates back to the 16th century.

Slowing of the heart rate after compression of a high -shunt congenital arteriovenous
malformation was first described by Nicoladoni in 1875. This so -called brady cardia sign
of arteriovenous fistulas was observed later by Branham in a patient with acquired
arteriovenous fistula. Excellent early descriptions of arteriovenous malformations can be
found in the works presented a detailed classifica tion of vascular malformations
(angiodysplasia).Although surgical excision may be recommended for local lesions,
selective catheterization,embolotherapy, and percutaneous sclerotherapy (usually with
absolute alcohol) have changed the management of VMs in t he last 2 decades.

Definitions
Vascular malformations are localized errors of angiogenic development, whereas
hemangiomas are vascular tumors. Mulliken and colleagues defined the endothelial
characteristics and cell biology of VMs and vascular tumors. Th e term hemangioma
should be reserved for vascular tumors alone. During the proliferative phase they
undergo growth, and then they resolve. The proliferative phase occurs during the first
year, and spontaneous involution of hemangiomas is observed in 95% of cases by age
7 years. The female -male ratio is 5:1.Thirty percent of hemangiomas are present at
birth, and the rest develop within the first 3 months of life. Endothelial hyperplasia is
evident on biopsies obtained from hemangiomas; these cells grow in ti ssue culture, and
in the proliferative phase they incorporate 3H -thymidine and have an increased mast
cell count. Most patients with hemangiomas require no treatment at all.

In contrast, VMs are developmental, congenital abnormalities. There is increasing
evidence that aberrant signaling at the molecular level results in dysfunction of normal
proliferation, differentiation, maturation, and apoptosis of the vascular cells. Localized,
superficial, mostly venous or capillary VMs —“birthmarks” of the skin and m ucosa —are
most common, but VMs also occur in the skeletal muscles, the pelvis or chest, visceral
organs such as the lungs, the gastrointestinal system, and the brain. The abnormal
vascular channels are lined by a continuous endothelium and surrounded by an
abnormal complement of mural cells. Ninety percent of them are present at birth, and
the male -female ratio is 1:1. VMs shown endothelial proliferation, and no cell growth is
observed in tissue culture; the cells do not incorporate 3H -thymidine,and no mast cells
have been observed in biopsy specimen. Clinically, no proliferation or spontaneous
involution has -been observed in VMs. The growth of the malformation is usually
commensurate with the growth of the child, although hemodynamic factors
(arteriovenous shunting, venous stasis) can accelerate growth and morbidity. Most low –
flow VMs have a benign course, although complications such as bleeding,
thrombophlebitis, skin changes, or infection may need treatment.
High-flow arteriovenous malformations usually h ave a more ominous course and a
worse prognosis. Treatment of these lesions is frequently needed.

Development of the Vascular System
Because the classification, clinical presentation, and prognosis of VMs depend to a
great extent on the point at which the re is an arrest or abnormality in the development of
the vascular system, it is worthwhile to review briefly the normal development of the

vascular tree of the limbs. Primitive vascular channels first appear in the third week of
gestation. During its devel opment, the vascular system undergoes differentiation
through multiple stages, first described by Woollard in 1922.
Stage 1 is the undifferentiated stage, with only a capillary network being present. Stage
2 is the retiform stage, when large plexiform str uctures can be seen. In stage 3, by the
third week of gestation, the maturation stage includes the development of large
channels, arteries, and veins.
Vascular endothelial growth factor (VEGF), secreted by keratinocytes, has been found
to be responsible fo r inducing the penetration of capillary vessels into the vascular
epidermis. This invasion and the subsequent arterial differentiation are also guided by
VEGF originating from sensory nerves.30A defective migratory response of endothelial
cells to VEGF is the consequence of abnormal signaling of VEGF receptors.
Malformations develop if the differentiation is abnormal and there is an arrest in the
development of normal vascular tissue. It is the persistence of the normal embryonic
vascular system and any add itional abnormal development that result in VMs.

Because of the complex presentation and frequently mixednature of VMs, classification
has been difficult. Malan andPuglionisi attempted to separate them based on anatomic
appearance and the presence or abse nce of arteriovenousshunting.12 The
classification of Szilagyi and olleagues was based primarily on Woollard’s stages of
embryologic development. Capillary malformations develop when there is an arrest in
stage 1 (Fig. 11 -1). Although Szilagyi named these malformations hemangiomas, they

are not tumors but capillary or cavernous VMs. Microfistulous or macrofistulous
arteriovenous malformations develop if there is an arrest in
stage 2 (see Fig. 11 -1). Persistence of large embryonic veins that develop in stage 3 is
seen in patients with persistent sciatic vein (Fig. 11 -2) or in those with large lateral veins
of the leg (Fig. 11 -3). There are many mixed VMs owing to involvement of several
segments of the vascular system(capillaries, veins, lymphatic's).
Forbes a nd associates distinguished VMs based on hemodynamic and contrast
angiographic appearance. Depending on the amount of blood supplying the
malformation, high flow and low -flow lesions are distinguished. These are called high-
shunt and low-shunt lesions; th e size of the shunt is determined by the volume of blood
that enters the feeding vessels.
High-shunt lesions correspond with macro fistulous arteriovenous malformations,
whereas micro fistulous arteriovenous.
In recent decades, much has been learned regard ing the histopathology, cause, and
treatment of vascular anomalies. As information has been gleaned, a new classification
system has emerged that divides vascular anomalies into neoplasms and alformations.
Its utility is based on accurate initial diagnosi s that correlates consistently with clinical
presentation, disease course, and treatment.

2.0 literature review
Presently, there is controversy and misconception in the diagnosis and management of
most congenital vascular malformations. The aim of thi s manuscript is to identify the
current knowledge of these poorly understood and relatively uncommon pathologies.
We will also review the updated terminology, classification, pathogenesis, clinical
presentation, diagnosis approach and management. Venous ma lformations (VMs) are
part of a spectrum of benign vascular lesions commonly found in the pediatric
population. These lesions occasionally may be difficult to distinguish solely on the basis
of their clinical appearance. In 1982, Mulliken and Glowacki classified congenital
vascular anomalies into true hemangiomas and various vascular malformations on the
basis of their histologic features.
Until recently, congenital vascular malformations (CVM) suffered from a bad reputation
among health professionals. Most doctors did not want to deal with CVM cases due to
bad experiences in the management of these pathologies, mostly due to the lack of
information and knowledge, which conditioned bad management and even worse
results.1 CVM’s misconception has drastically c hanged due to the better understanding
of pathophysiology and natural history, aspects which facilitated the creation of new
CVM classifications,2 alongside the development of new diagnosis and treatment
technology and the switch to a multidisciplinary app roach.3,4 Great results have been
accomplished with minimal morbi -mortality, few recurrences and a better acceptance of
these complex nosological entities by health professionals. The purpose of this review is

to disclose current knowledge about CVM’s etio logy, pathophysiology, genetic aspects,
diagnosis and therapeutic approach.
Terms, definitions and classifications
Vascular anomaly is a term used to describe two pathological entities; CVM and
vascular tumors represented by neonatal or infantile hemangio mas.5 However, these
two conditions are very different in their anatomy, histology, pathophysiology and
clinical presentation. CVMs are a result of a failure in angiogenesis, appear from birth
and grow accordingly to the patient’s growth. Hemangiomas are v ascular tumors
originating in the endothelium; generally appearing during the neonatal period, they
grow rapidly, but later devolve at 5 -10 years of age in the majority of cases. Angioma is
another term used indistinctly to name any vascular anomaly which causes mistakes
and improper management, thus it is preferable to avoid its use. On the other hand,
there is the denomination hemangioma, capillary or cavernous, originally described by
Virchow in 1863 to define vascular anomalies present since birth; howe ver, Virchow
only took into account its location and did not considered other important
characteristics.6 Angiodysplasia is another term coined to described CVMs, but due to
its limited practical usefulness in describing a CVM and limited help in different ial
diagnosis its use is not very recommendable.
At the beginning of the 20th century, doctors like Klippel and Trenaunay, Parkes and
Weberm, Servelle and Martorell, to name a few, reported cases of CVM, where in order
to describe them they used clinical c haracteristics which included alterations in skin, soft
tissue, bones and blood vessels and grouped them, creating syndromes which they

named in accordance with the doctors who first described them.7 These names, based
in eponyms, have been used for decade s and even nowadays are still in use, but do not
provide information about the etiology, pathophysiology and anatomy of these complex
CVMs. Nevertheless, each syndrome has a historical significance and although the
Hamburg classification is the one that is currently used, these classifications are still
useful to some extent to describe certain mixed forms of CVMs.
A significant step towards clearing the confusion on the subject of CVMs was the
publication by Mulliken et al8 in 1982, where a differentiation between CVMs and
hemangiomas was definitely made. Moreover, they created a classification based on
the characteristics of the predominant endothelium, the hemodynamic state of the
vascular malformation (high flow: AV, AVM or low flow: CM, VM, or LM), find ings during
physical examination and natural evolution (table 1). Subsequently, this classification
was redefined by Mulliken et al5 in 1988.
Vascular malformations are true congenital lesions, which by definition are always
present at birth, although they are not always detected. They are classified according to
the main channel type present: capillary, lymphatic, arterial, venous, or mixed. These
lesions do not occur in one sex more than the other. They often grow in proportion to
the child and can displa y periods of active growth. Vascular lesions have been
categorized further into low – and high -flow types ( 3) on the basis of the hemodynamic
characteristics of the lesions, a distinction that is important in the ch oice of management
strategies. By definition, vascular malformations do not regress spontaneously.

Another major development in the classification of the enigma that CVMs represent,
was the creation of the Hamburg Classification (HC). The Hamburg classific ation is the
result of a consensus reached by experts on the subject who gathered at the 7th
International Workshop on Vascular Malformations held in Hamburg, Germany in 1988.9
VMs often can be diagnosed on the basis of clinical characteristics: They are b luish,
easily compressible, cold, and increase in size with maneuvers aimed at increasing
venous pressure ( 2). However, malformations occasionally may manifest atypical
features, and ancillary studies are needed to confirm the diagnosis. A precise diagnosis
will lead to the most appropriate treatment; the standard for the diagnosis of VM is
venography or biopsy. To our knowledge, the role of Doppler ultrasonography (US) has
not been reported. The aim of this study, therefore, is to emphasize the value of Doppler
US in the diagnosis of soft -tissue VMs in pediatric and young adult patients.
This classification forbids the term angioma, and properly classifies CVMs according to
the type of predominantly affected vessel or its combinations, and to the embryological
state where the malformation occurs using anatomic, histologic, and physiopathology
criteria as well as a hemodynamic state to define them. It has been accepted by most of
the medical community because of its p roven superiority in the application during
clinical practice to perform a clinical -anatomical diagnosis, defining treatment and
facilitating communication between different specialists.10
Within HC CVMs are divided into five classes, depending on the pred ominant vascular
component: arterial malformation (AM), venous malformation (VM), lymphatic
malformation (LM), arterio -venous malformations (AVM) and mixed or combined

vascular malformations (MVM). At first, capillary malformations were not included in thi s
classification because they were believed to have no clinical significance and to be
equivalent to other CVMs, but in the 1992 HC revision in Denver11 they were included
and later confirmed in 2002 in Seoul.12
Each CVM is divided into two types, accordin g to the embryological stage in which it
was developed (its clinical presentation, natural evolution, and the results of the
treatment depend on this): troncular and extra -troncular (table 2B).
The extra -troncular type develops in a very early stage in emb ryological development, in
which the vascular system is in reticular phase. This type of lesion is composed of
remnants of embryonic mesenchymal tissue that preserve angioblast characteristics.
These cells retain the potential of growing and proliferating with internal stimuli
(menarche, pregnancy, etc.) or external stimuli (trauma and surgery) and present a high
recurrence incidence. Extra -troncular lesions can be presented as infiltrative and diffuse
lesions or localized lesions which cause mechanical com pression in nearby tissues and
organs.
Troncular lesions are formed in the late embryonic stage where vascular trunks are
being formed,13 and at the same time are subdivided into obstructive and/or dilated
lesions (figure 1). Cells forming this type of les ion have lost the ability to proliferate and
are presented as a remnant of fetal vasculature, being displayed as aplastic,
hypoplastic, or hyperplastic vessels (aneurysms, vascular networks, etc.). Due to the
type of these cellular lesions, risk of recurre nce is low, but the associated hemodynamic
consequences can be severe.

After the creation of the Hamburg and Mulliken -Glowacky classifications, both with
advantages and disadvantages in its use, the International Society for the Study of
Vascular Anomalies (ISSVA) simplified CVMs classifications in 1996, furthermore,
adding a vascular tumors section. This classification is revised every 2 years (table
3).14,15
In the new classification, the components of the Klippel -Trenaunay syndromes are
defined as CVM co nstituted by CM, VM, and LM, however, in conjunction they are
referred to as hemolymphatic malformation (figure 1), those from Maffucci syndrome
like VM, LM and enchondromas (figure 2) and Parkes -Weber syndrome like MVM
constituted by CM, VM, LM, and VAM.

Figure 3 Early -onset primary lymphedema of the right lower extremity in a 10 -year-old
female patient.
On the other hand, Puig et al16 classified venous vascula r malformations in function of
their anatomic location, where they drain and their hemodynamic characteristics, a
result that is especially useful to assess the efficacy of sclerosis therapy. In order to
define the lesion’s hemodynamic characteristics, a p hlebography must be performed,

and with the results from this procedure venous malformations are divided into four
types: I. isolated malformations without peripheral drainage; II. malformation that drains
into normal veins; III. malformations that drain i nto dysplastic veins, and IV.
malformations that drain into dilated veins.
Types I and II are the easiest to treat and have a better response to sclerotherapy.
Epidemiology
CVM incidence is 0.3 -1.5%; it is high compared to congenital heart diseases (0.88% ) or
spina bifida (0.2%), but lower than hemangiomas, which have an incidence of 2 -3% in
newborns and increases to 10% at the end of the first year of life.5,17,18
Distributions between the different CVMs are as follows: venous malformations (VM)
48.5%, ar terial malformations (AM) and arterio -venous malformations (AVM) 35.8%,
lymphatic malformations (LM) 10%, and mixed combined malformations (MCM) 5.7%.
Regarding CVM subtypes, the most frequent are extra -troncular, corresponding to 57%.
In the distribution by gender, male -female ratio for VM is 1:1.2, VAM is 1:4 and LM is
1:1.
Capillary malformations (CM) appear from birth, MVs are present from birth, but
become visible and symptomatic during childhood or later, MLs can manifest from birth
up to adulthood (f igure 4) and VAMs appear fundamentally in childhood and
adolescence (figure 5).

CONCLUSIONS
The correct treatment for pediatric AVMs needs to be tailored for each patient. The
characteristics of the AVM and
the local expertise and experience with endovascular and micro vascular surgery will
determine the appropriate treatment paradigm for a patient. In general, microsurgery
should be performed whenever reasonab ly possible because it provides immediate
extirpation of the nidus. Radio surgical patients treated with smaller nidus volumes, no
prior remobilization, and higher prescription doses are likely to achieve obliteration with
a low likelihood of complication. The risk of hemorrhage during the latency period
persists, and patients must be followed up with serial imaging to detect late
complications.

References

1.Szilagyi DE, Smith RF, Elliott JP, Hageman JH. Congenital arteriovenous anomalies
of the limbs. Arc h Surg. 1976;111:423 -29.
2.Belov St. Classification of congenital vascular defects. Int Angiol. 1990;9:141 -6.
3.Lee BB, Bergan JJ. Advanced management of congenital vascular malformations: a
multidisciplinary approach. Cardiovasc Surg. 2002;10:523 -33.
4.Lee BB. Statues of new approaches to the treatment of congenital vascular
malformations (CVMs) — single centre experiences. Eur J Vas Endovasc Surg.
2005;30:184 -97.
5.Mulliken JB, Young AE, editors. Vascular birthmarks: hemangiomas and
malformations. Phi ladelphia: WB Saunders;1988. p. 30 -9.
6.Mulliken JB. Cutaneous vascular anomalies. Semin Vasc Surg. 1993;6:204 -18.
7.Klippel M, Trenaunay J. Du noevus variqueux et osteohypertrophique. Arch Gen Med.
1900;3:641 -72.
8.Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and
children: a classification based on endothelial characteristics. Plast Reconstr Surg.
1982;69:412.
9.Belov St. Classification of congenital vascular defects. Int Angiol. 1990;9:141 -6.
10.Lee BB. Critical issues o n the management of congenital vascular malformation. Ann
Vasc Surg. 2004;18:380 -92.
11.Rutherford RB. Editorial introduction. Sem Vasc Surg. 1993;6:197 -8.