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\begin{document}

\title{How we approach localized vascular anomalies}



\author[1]{Kristy Pahl}%
\author[1]{Waleska Pabon-Ramos}%
\author[2]{Michael Jeng}%
\affil[1]{Duke University Medical Center}%
\affil[2]{Stanford University Medical Center}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Vascular anomalies are a group of disorders divided into two distinct
subtypes: vascular tumors and vascular malformations. Vascular tumors
are proliferative in nature, while malformations are non-proliferative.
Simple, localized vascular malformations refer to a group of
malformations that are localized to a single area of involvement. These
simple malformations include capillary, lymphatic, venous, and
arteriovenous malformations. The pediatric hematologist and oncologist
is becoming increasingly involved in the diagnosis and management of
these disorders. This review presents four cases as a means to discuss
the diagnosis, clinical and imaging features, and management strategies
of simple, localized vascular malformations.%
\end{abstract}%



\sloppy


\textbf{How We Approach Simple localized vascular malformations}

\textbf{Pahl KS\textsuperscript{1}, Pabon-Ramos WM\textsuperscript{2},
Jeng MR\textsuperscript{3}}

\textbf{Department of Pediatrics, Duke University Medical Center, (2)
Department of Radiology, Duke University Medical Center, (3) Department
of Pediatrics, Stanford University School of Medicine}

\textbf{Corresponding Author:}

Kristy Pahl MD Pediatric Hematology/Oncology Duke University Medical
Center 330 Trent Drive, Room 383 Hanes House Durham NC 27710
919-684-3401 (phone) 919-681-7950 (fax) kristy.pahl@duke.edu

\textbf{No conflict of interest}

\textbf{Keywords:} vascular malformation, venous malformation, lymphatic
malformation, arteriovenous malformation, sclerotherapy

\textbf{Word Count:} Abstract- 97\textbf{,} Main text-
4149\textbf{.}Number of tables: 2\textbf{.} Number of Figures: 6

\textbf{Abbreviations:}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
VM & Venous malformation\tabularnewline
\midrule
\endhead
LM & Lymphatic malformation\tabularnewline
AVM & Arteriovenous malformation\tabularnewline
CM & Capillary malformation\tabularnewline
LIC & Localized intravascular coagulation\tabularnewline
US & Ultrasound\tabularnewline
MRI & Magnetic resonance imaging\tabularnewline
CT & Computerized tomography\tabularnewline
KMP & Kasabach-Merritt Phenomenon\tabularnewline
VIR & Vascular Interventional Radiology\tabularnewline
KTS & Klippel-Trenaunay Syndrome\tabularnewline
STS & Sodium tetradecyl sulfate\tabularnewline
mTOR & Mammalian target of rapamycin\tabularnewline
LMWH & Low molecular weight heparin\tabularnewline
\bottomrule
\end{longtable}

\textbf{I.ABSTRACT}

Vascular anomalies are a group of disorders divided into two distinct
subtypes: vascular tumors and vascular malformations. Vascular tumors
are proliferative in nature, while malformations are non-proliferative.
Simple, localized vascular malformations refer to a group of
malformations that are localized to a single area of involvement. These
simple malformations include capillary, lymphatic, venous, and
arteriovenous malformations. The pediatric hematologist and oncologist
is becoming increasingly involved in the diagnosis and management of
these disorders. This review presents four cases as a means to discuss
the diagnosis, clinical and imaging features, and management strategies
of simple, localized vascular malformations.

\textbf{II. INTRODUCTION}

The International Society for the Study of Vascular Anomalies (ISSVA)
initially proposed, and continues to update, a widely held
classification system for approaching vascular anomalies. There are two
broad general groups: 1) tumors (which are proliferative in nature) and
2) malformations (which are non-proliferative in nature). Simple
malformations refer to capillary (CM), lymphatic (LM), venous (VM), or
arteriovenous malformations (AVM) (1). Malformations can be localized to
a specific body area, or more extensive in nature. Vascular
malformations are thought to arise from somatic mutations acquired
during fetal development (2). Most will present at birth or in early
childhood (3). They exhibit a wide variability of clinical impact
ranging from asymptomatic lesions, to cosmetic concerns, and even
life-threatening symptoms due to close proximity to vital structures
such as the airway or lungs (4,5). In general, clinical evaluation and
imaging is usually diagnostic, but occasionally biopsy is needed if
atypical features are present. Biopsy is not without risk, as lesions
are prone to bleed. Immuno-histochemical markers and examination of
vascular architecture can clarify diagnosis. CD34 confirms endothelial
origin (6), while D2-40 (podoplanin) and LYVE-1 are associated with
lymphatic vessels. CD31 and SMA stain positive in VMs (7). Genetic
analysis of tissue will become more important as options for targeted
therapy become increasingly available. In this review, we describe four
cases and examine the clinical features, diagnostic options, and
management strategies of simple, localized malformations. As a
multi-disciplinary team is often needed to manage these complex
patients, we will examine the role of multiple disciplines, including
the pediatric hematologist and oncologist, in the care of patients with
vascular malformations.

\textbf{III. CASES}

\textbf{Case 1: Localized venous malformation of the lower extremity}

\textbf{A 13-year-old male presented with new onset swelling of the
right lower extremity near his ankle (Figure 1). A mass was noted months
earlier, but at time of presentation the lesion had increased in size
causing daily pain, limiting use of the extremity. No other skin lesions
were noted and the child was otherwise healthy. On physical exam, a 6 cm
x 6 cm soft, tender, palpable mass was present within the subcutaneous
tissue of the ankle near the lateral malleolus. The overlying tissue
demonstrated a slight bluish hue. No hardened nodules were palpated.
Differential diagnosis included fatty tumors such lipoblastoma,
inflammatory process (abscess, subcutaneous granuloma annulare),
sarcoma, or vascular anomaly.}

\textbf{An ultrasound with Doppler demonstrated a compressible,
heterogeneous lesion with low flow. Laboratory workup was significant
for a platelet count of 175,000 (normal
150,000-450,000x10\textsuperscript{9}/L), d-dimer of 455 ng/ml (normal
\textless{}500 ng/ml), and fibrinogen of 250 mg/ml (normal 213-435
mg/ml). The patient was diagnosed with a pure venous malformation, and
referred to vascular interventional radiology (VIR) for management.}

\emph{Approachx\textbackslash{}}

\emph{Background}

VM are the most common type of vascular malformation, with an incidence
of 1-2 per 10,000 births (2). VMs are typically located in the skin or
mucosa, but can involve subcutaneous tissue, muscles, joints, nerves,
and internal organs (4,5,8). Most commonly, VMs present as soft
subcutaneous masses with bluish colored overlying skin. They can enlarge
with Valsalva maneuvers or on dependent positions (9). While VMs most
commonly appear in childhood, delayed presentation in adolescence or
adulthood can occur (3). Trauma, infection, hemorrhage, or hormonal
changes during puberty or pregnancy can lead to growth (4,10,11).
Spontaneous regression does not occur (4). VMs can be focal or diffuse
and may be associated with other malformation types in characterized
syndromes, such as Klippel-Trenaunay Syndrome (KTS) (3). The majority of
VMs are caused by gain-of-function mutations in the TIE-2 receptor
(12,13,14), which is integral to regulation of vascular proliferation,
migration and adhesion (14,15).

\emph{Diagnosis}

The pediatric hematologist and oncologist is often called upon to
distinguish between malignant versus benign masses, and vascular
anomalies should be on the differential of a new onset mass. Clinical
examination combined with imaging can generally lead to a diagnosis and
rule out malignancy. Experienced clinicians and radiologists familiar
with these entities are optimal. If unusual features are present on
physical exam or imaging, or if concerning clinical history is present,
biopsy must be considered. Caution must be taken with biopsy of vascular
lesions given their propensity to bleed.

Under ultrasound examination, VMs appear as heterogeneous lesions
typically containing anechoic vascular channels. The lesions are
compressible if near the skin surface. VMs demonstrate slow flow, and
Doppler analysis typically shows minimal to no color flow that can be
augmented upon releasing compression or with Valsalva maneuvers.
Spectral analysis reveals no waveforms or a monophasic venous waveform
(16,17). If Doppler does not demonstrate color flow and/or spectral
waveforms, flow within the malformation may be too slow for sonographic
detection, or vessels may have thrombosed (18). Slow blood flow
contributes to the development of phleboliths, which are painful
thrombosis and a common occurrence of VMs. On exam, they are palpated as
hardened nodules (19). On US, they appear as a hyperechoic foci with
posterior shadowing and are considered pathognomonic for VM (20).

As in this patient, on magnetic resonance imaging (MRI), VMs appear
hyperintense on T2 weighted images (Fig 2). On T1 weighted images, they
appear iso- or hypointense but may contain hyperintense areas
representing blood products, fat, or calcifications. VMs enhance on T1
weighted images obtained after intravenous contrast administration. MRI
not only aids in the classification of vascular malformations, but it
also can determine lesion extent and relationship to surrounding
structures (21,22).

\emph{Management}

The decision to treat a VM is dependent on location of the lesion,
extension into adjacent tissue, presence of pain, functional impairment,
or aesthetic appearance. Small, focal VMs which are not causing pain or
functional impairment are often treated conservatively with observation
alone. Compression garments improve vascular flow and reduce stasis, and
help with pain. Custom compression garments are recommended to ensure
proper fit and comfort, with typical pressures of 20-40 mmHg (23,24).
Compression should always be encouraged in VMs, as it can help prevent
or slow the development of venous ectasia. Analgesics may be used for
mild to moderate pain.

This patient had a small, focal, symptomatic VM which is amenable to
sclerotherapy. Multiple rounds of sclerotherapy may be needed depending
on lesion size and clinical symptoms. In this procedure, sclerosing
agents are percutaneously injected into the VM. Sclerotherapy can be
used alone for symptomatic relief, or in a staged approach in which
pre-operative sclerotherapy is performed to improve success of
subsequent excisional or debulking surgeries (25). The efficacy of
sclerotherapy is generally related to the sclerosing agent and dwell
time within the VM. Choice of sclerosing agent is dependent on a number
of different factors, including VM location (depth, and proximity to
adjacent structures), as well as ability to control venous drainage
(26,27). If robust venous drainage is present, occlusion of outflow
veins is needed prior to injection of the sclerosing agent to prevent it
from flowing out of the VM without proper endothelial contact time.
Occlusion of venous drainage can be accomplished by use of a tourniquet,
or by embolizing the outflow vein(s) with liquid embolic agents, coils
or plugs (28). Table 1 lists a selection of commonly used sclerosing
agents, their mechanism of action, and potential side effects. Given the
superficial nature of the lesion described above, bleomycin or sodium
tetradecyl sulfate (STS) would be acceptable choices. Alcohol should be
avoided for lesions near nerves, superficial lesions, or VMs involving
the mucosa given risk for inflammation, edema and necrosis which may
affect nearby structures and damage surrounding tissues (29,30). This
patient had a positive response to sclerotherapy, with decreased
swelling and minimal pain six months after treatment (Fig 3).

Surgical intervention can be considered in patients with symptomatic VMs
if excision with appropriate margins does not injure vital structures.
This approach may be appropriate for lesions which are not amenable to
sclerotherapy. Depending on the extent of the lesion, surgery may or may
not be curative, as VMs are prone to regrow if vascular tissue remains
after surgery (35,36). A surgical approach should focus on a defined
anatomical area, preservation of critical neurovascular structures, and
minimizing blood loss by staged approaches if needed (37).

While not applicable to this case as the patient had a localized VM
amenable to sclerotherapy, patients with larger VMs not responsive to
sclerotherapy or non-surgical candidates can consider the use of
sirolimus. Sirolimus is an oral mammalian target of rapamycin (mTOR)
inhibitor, which has been shown to be highly effective in patients with
a wide variety of vascular anomalies. In patients with VM, multiple
studies have described a benefit in reduction of lesion size and pain
symptoms with the use of sirolimus (38). Sirolimus is generally dosed at
0.8 mg/m2 per dose every 12 hours, with monitoring of trough levels for
dose adjustment. Target trough levels depend on lesion type, and the
balance between treatment benefit and the potential for side effects.
Potential side effects of sirolimus therapy include mucositis, count
suppression, hypercholesterolemia, and increased liver enzymes. These
side effects are reversible with either dose reduction or cessation of
therapy (39). Patients receiving sirolimus are advised to seek medical
attention with fevers and are prescribed prophylaxis against
pneumocystis jiroveci pneumonia (PJP).

\textbf{Case 2: Localized venous malformation with Phleboliths}

\textbf{A 5-year old female presents with left hand pain. At birth, she
had a bluish hue to the fingernail of her left thumb along with a
compressible, blue colored mass (Fig 4). At 18 months of age she
underwent an MRI which was consistent with a VM. After her diagnosis of
VM, she was started on 3 mg/kg daily of aspirin given parenteral
concerns of tenderness with palpation of the lesion. She is compliant
with wearing a custom compression garment, but lately developed pain
from her malformation despite aspirin therapy. Parents can occasionally
palpate hardened nodules within the malformation, and also note a slight
increase in the size of the VM. She has occasional short nosebleeds with
dry weather, but no other bleeding symptoms. There is no significant
family history of thrombosis or bleeding complications. She was
initially examined by VIR, but referred to pediatric hematology given
elevated d-dimer. Her most recent laboratory analysis revealed a
platelet count of 275,000 (normal
150,000-450,000x10\textsuperscript{9}/L), d-dimer of 1200 ng/ml (normal
\textless{}500 ng/ml), fibrinogen of 272 mg/ml (normal 213-435 mg/mL),
partial prothrombin time of 28 seconds (normal 24 seconds - 32 seconds),
and prothrombin time of 12 seconds (normal 11.5 seconds to 13.1
seconds).}

\emph{Approach:}

\emph{Background}

Localized intravascular coagulation (LIC) is common in patients with
VMs. Large malformation size, involvement of deep structures, diffuse
nature, and presence of palpable phleboliths are associated with the
presence of LIC (40,41). LIC is a consumptive coagulopathy,
characterized by elevated d-dimer, and in more severe cases, low
fibrinogen and thrombocytopenia. The exact mechanism driving LIC is
unknown, but slow blood flow within malformed venous channels is thought
to lead to activation of the coagulation system and consumption of
clotting factors (42). Progression to overt DIC can occur in the setting
of stressors such as infection (43), sclerotherapy (44), or surgery
(45). It is important to distinguish LIC from the Kasabach-Merritt
phenomenon (KMP), which occurs in vascular tumors such as kaposiform
hemangioendothelioma and tufted angioma. LIC is characterized
predominantly by clotting factor consumption, while KMP is characterized
by platelet consumption and profound thrombocytopenia. This distinction
is important, as the management of these two conditions is different
(46). While thought to be rare, case reports of thromboembolic
complications from VMs have been reported (47,48,49). Increasing age,
larger extent of malformation, and palpable phleboliths have been shown
to be risk factors for thromboembolic complications (49,50). As with the
patient above, phleboliths can be present in VMs, and are palpated on
physical exam as hardened nodules. They occur because of intravascular
thrombi which calcify over time, and can be exquisitely painful (19).

\emph{Management}

In this patient, symptomatic LIC was initially treated with aspirin.
Aspirin may be helpful in selected patients, although no prospective
studies have analyzed safety and efficacy. A retrospective survey of
patients with VMs on aspirin reported 45\% of participants obtaining a
positive response, manifested as either less aching pain, less shooting
pain, decreased fullness/swelling, and shrinkage of VM. Bleeding and
bruising were reported complications (51). If aspirin does not improve
symptoms, anti-coagulation can be considered. A thorough personal and
family history of bleeding should be completed prior to initiation of
anti-coagulation. Prior studies have documented a lack of response to
vitamin K antagonists (46), and generally low molecular weight heparin
(LMWH) is the agent of first choice. Patients are typically started on
prophylactic dosing (0.5 mg/kg twice a day) of LMWH, with appropriate
monitoring of complete blood count, renal function, and LMWH levels.
Treatment dosing of LMWH (1.0 mg/kg twice a day) may be needed depending
on patient response. Duration of treatment is variable, with patients
requiring either episodic or continuous dosing (52). As the direct oral
anti-coagulants become approved for use in children, these agents may
play a more significant role in anti-coagulation for VM associated LIC.
Case reports of their use in adult patients with VMs have shown
improvement in LIC symptoms (53,54).

Given the location on the hand, medical management was chosen. Surgical
resection would be difficult and could lead to nerve or muscle damage,
and similar concerns were present in regards to the potential
complications of sclerotherapy. This patient was started on prophylactic
dosing of lovenox with improvement in pain. If this patient had
undergone sclerotherapy or surgical resection, discussion regarding the
peri-procedural management of her LIC would be warranted. Unfortunately,
there is a lack of evidence-based data to guide approach. The d-dimer
threshold which places patients at risk for procedural complications,
including both bleeding and thrombosis, is not known. Prior published
guidelines from the Vascular Anomalies Special Interest Group of the
American Society of Pediatric Hematology and Oncology recommended that
patients with d-dimer greater than five times the upper limit of normal
be administered LMWH for two weeks pre- and post-procedure (55).

\textbf{Case 3: Localized Lymphatic Malformation}

\textbf{An 8-year-old male presented to his pediatrician for new onset
right neck mass. He recently had a viral upper respiratory infection,
and during this illness the mass became apparent. He was referred to
pediatric hematology and oncology out of concern for malignancy. On
further history, he denies fever, unintentional weight loss, or night
sweats. His exam is notable for a mobile, tender, soft tissue mass
measuring 2x3cm on the lower left neck. Range of motion was not
inhibited. Overlying skin has a normal appearance. Ultrasound revealed a
3.0 x 1.1 x 2.6 cm complex subcutaneous lesion concerning for a vascular
malformation. Complete blood count was unremarkable, LDH and uric acid
were normal, d-dimer was 256 mg/ml (normal \textless{}500 mg/ml),
fibrinogen 262 (normal \textgreater{}150 mg/dL), PTT 30 seconds (normal
24 seconds-32 seconds), and PT 14.5 seconds (normal).}

\emph{Approach:}

\emph{Background:}

Prior to any imaging, when there is a question of type of malformation,
screening labs are often obtained to help guide the clinician. In this
case, a CBC, coagulation testing, d-dimer, and fibrinogen are our
institution's standard screen. This cohort of tests helps rule out a
vascular tumor which can be associated with KMP. Additionally, d-dimer
can be used to help distinguish between malformation types, with LMs
typically having normal d-dimer levels while VMs often have varying
degrees of elevation (42).

LMs can present at birth, early childhood, or adolescence, and are most
commonly located in the head and neck area. On exam, they are soft
masses with often normal overlying skin, but can exhibit a bluish hue,
or have associated lymphatic vesicles or blebs (11). LMs can be
associated with other syndromes such as KTS or congenital lipomatosis
overgrowth, vascular malformations, epidermal nevi and
scoliosis/skeletal/spinal anomalies (CLOVES) (56). The majority of LMs
are due to somatic mutations in the
phosphatidylinositol-4,5-biphosphonate 3-kinase catalytic subunit alpha
(PIK3CA) gene (57). This gain of function mutation leads to a
constitutively active PI3K/AKT/mTOR pathway, resulting in increased cell
proliferation, survival and angiogenesis (56).There is a wide spectrum
of clinical symptoms secondary to LMs, ranging from asymptomatic lesions
to those that cause significant complications. Given their propensity
for involvement of the head and neck area, functional impairment of the
airway, feeding, or speech issues may arise in addition to cosmetic
concerns (58). Increased pain and swelling can be associated with
bacterial or viral infection, inflammation, trauma, or intra-lesional
bleeding (59).

\emph{Diagnosis}

As described in the vignette, on ultrasound exam, LMs present as
multi-loculated cystic masses. Fluid levels may be present if the cystic
spaces contain blood, pus or chyle (60,61). LMs can be classified as
either microcystic (less than 1 cm in size), macrocystic (greater than 1
cm in size) or mixed (62). The US image for this patient is seen in Fig
5A and 5B, and was consistent with a macrocystic LM. Similar to
ultrasound, on MRI, LMs present as cystic masses. No solid enhancing
component should be seen, unless a LM is microcystic in which case it
can appear as a solid mass (61). Table 2 summarizes key imaging features
of both LM and VM by imaging modality including US, CT and MRI.

\emph{Treatment}

In asymptomatic patients without functional impairment or significant
cosmetic concerns, careful observation is warranted. If treatment is
indicated, options include surgery, sclerotherapy, or medical treatment
with sirolimus; either alone or in combination. Surgical treatment for
LM is most successful in patients with localized malformations that do
not invade important adjacent structures (37), but debulking procedures
for large, complex malformations may be indicated. Surgery could be
offered to the patient above, but sclerotherapy is the most reasonable
approach given high success rates with treatment of macrocytic lesions.
Sclerotherapy is the first line treatment for macrocystic or mixed
micro/macrocystic lesions (64), but is less efficacious for microcystic
LMs (65). In microcystic lesions medical therapy with sirolimus has been
shown to be beneficial in softening the lesions and also decreasing the
size in general, leading to an improved quality of life (66).

Unless symptomatic, sclerotherapy is often not performed until the
patient is at least 6 months of age. Given the location and symptomatic
nature of the patient above, sclerotherapy would be the preferred
treatment course for this patient. For treatment of LMs, a needle is
inserted into the cystic space, lymphatic fluid is drained, and
sclerosing agent is injected. Large cysts may require multiple
injections over 24 to 48 hours, so a pigtail catheter is inserted to
facilitate repeated injections (37,64). Similar to VMs, success of
sclerotherapy is dependent on the sclerosing agent used, dwell time, and
type of LM. Higher rates of cure are seen in macrocystic LMs, as the
entire endothelium can be treated. Doxycycline has the highest success
rates for LM, with a meta-analysis of treated head and neck LM
demonstrating an 80\% efficacy rate (34). For lesions in the head and
neck area, which involve the airway, orbit or are close to nerves,
bleomycin, which causes minimal swelling, is the agent of choice (65).
Dose dependent pulmonary toxicity is a potential complication of
bleomycin therapy. Bleomycin doses in sclerotherapy are typically much
smaller than the cumulative dose of 400 mg or greater that is associated
with toxicity (68). Macrocystic LMs respond well to treatment with
OK-432, but microcystic or mixed lesions have a less favorable response
(37). LMs can re-expand over time and require repeated procedures.

\textbf{CASE 4: Arteriovenous malformation}

\textbf{An 9-year old previously healthy female presented for her
regular annual well visit to her pediatrician, who noted a round, raised
pulsating area over her right clavicular region (Fig 6). ~Her parents
report that they noticed this about 3-4 months ago, and she denied pain,
bleeding, or trauma to the area. ~She does endorse intermittent
headaches of varying severity, occurring every 2 weeks, and not
associated with visual changes. Acetaminophen and rest provide relief
for the more severe headaches. Of note, there is no other medical
history or family history of vascular issues or epistaxis.}

\emph{approach:}

\emph{Background}

AVMs may present at any age and are the least common vascular
malformation diagnosed in children (69). An AVM is a high flow lesion
and occurs when an artery directly connects to the venous system and
bypasses the capillary beds. The natural history of these abnormal
vascular connections is progressively ectatic veins due to the high
velocity blood flow, with eventual rupture. Rupture is the most feared
complication for any AVM and therefore intervention is almost always
warranted. The rate of rupture is higher in children when compared to
adults, making timely intervention of higher consideration (70). High
flow through AVMs can lead to hypoperfusion, hypoxic ischemia, and pain,
in a phenomenon known as steal syndrome (71).

\emph{Diagnosis}

AVMs can be found incidentally, or present with a wide variety of
symptoms depending on location and size. On physical examination,
auscultation typically demonstrates a bruit, which is due to abnormally
high blood flow. Pulsation is a feature of AVMs as well (72). In this
patient, an ultrasound revealed a vascular malformation in the
musculature of the right neck/shoulder, with a clear communication with
the right common carotid artery. The malformation exhibited venous flow,
while the vascular connection demonstrated arterial waveforms. MRI with
and without contrast showed an abnormal hypervascular lesion at the C2
level in the retropharyngeal space, extending inferiorly posterior to
the carotid space. The arterial supply appeared to arise from the right
subclavian artery and a small branch from the external carotid artery.
She had no evidence of intra-cranial AVMs or steal syndrome.

When an AVM is diagnosed in a child, a complete family history and
physical examination is warranted to assess the possibility for a
systemic genetic syndrome such as hereditary hemorrhagic telangiectasia
(HHT). HHT is inherited in an autosomal dominant fashion with variable
penetrance. AVMs can occur in the brain, lungs, or liver in addition to
mucosal telangiectasia. Early diagnosis is crucial so appropriate
screening can be completed to avoid complications (73). In patients with
AVMs, routine monitoring for high output heart failure is necessary
depending on the degree of shunting across the AVM (74).

\emph{Management}

The approach to management of AVMs is dependent on location, and they
are classified as either intracranial or extracranial. A cranial lesion
leads to the inclusion of neurosurgery to guide care. Otherwise, a
multidisciplinary approach to clinical decisions will help to promote
optimal outcomes through consideration of the risks and benefits of the
treatment options for both types of AVMs. Traditionally procedures such
as surgical endovascular resection, embolization using a chemical for
glue, coil placement, and radiation therapy are considered the primary
interventions for AVM management (75). Recently, several investigators
have reported an association with somatic KRAS mutations and AVMs (76).
These mutations lead to aberrant activation of the MAPK signaling
pathway. Several case reports describe radiologic response to inhibition
of this path with biologic agents, such as AKT inhibitors (76,77).
Therefore, medical therapies for AVMs may be new modalities for
treatment in the future and several studies are underway (78).

Following her initial visit, the patients headaches resolved. Therefore,
a non-urgent elective embolism with interventional radiology was
recommended in the next year. The parents were asked to monitor for
increased size or new symptoms. Approximately six months later, the
patient re-presented with cramping pain in the right supraclavicular
area and there was an increase in size of the AVM. A selective
embolization utilizing n-butyl cyanoacrylate (Onyx) was performed (79).
In addition, peri-procedural sirolimus was used in order to decrease
post-embolism collateralization (80,81). A cerebral angiogram was
performed to allow better visualization of the anatomic vasculature, and
revealed a malformation within the right upper thoracic and cervical
regions, with significant blood supply from the thyrocervical trunk and
common origin, ascending cervical, deep cervical and right occipital
arteries. She underwent 3 embolization procedures, every 2 weeks, and
had a good response. Her lesion became smaller both on clinical exam and
by MRI imaging. She was asymptomatic and followed every 6 months for a
year and then annually with both exam and MRI. She has been followed
post procedure for 5 years without recurrence or increase in AVM. Of
note, no genetic testing was performed due to lack of biopsy tissue
sampling.

\textbf{IV. Summary}

Simple, localized vascular malformations are composed of a heterogeneous
population of lesions which include capillary, lymphatic, venous or
arteriovenous malformations. Clinical symptoms vary widely, with many
children having asymptomatic lesions which require expectant
observation. Other children develop lesions which cause significant
pain, functional, or cosmetic impairment and require a
multi-disciplinary approach to their care. Diagnosis of simple vascular
malformations is often accomplished through clinical exam and imaging,
but biopsy is indicated if atypical features are present. Management of
vascular malformations is dependent on type of malformation and lesion
location, but can involve medical management, surgical resection, or
sclerotherapy. The pediatric hematologist and oncologist is playing an
ever-increasing role in the care of patients with vascular
malformations. As our understanding of the genetic basis for vascular
malformations grows, targeted therapy originally developed for oncologic
indications, such as KRAS inhibitors, will play a more substantial role
in the treatment of vascular malformations.

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