REVIEW

CURRENT
OPINION Management of lymphatic malformations
in children
Naina Bagrodia , Ann M. Defnet , and Jessica J. Kandel

Purpose of review
To review the literature on lymphatic malformations and to provide current opinion about the management
of these lesions.
Recent findings
Current treatment options include nonoperative management, surgery, sclerotherapy, radiofrequency
ablation, and laser therapy. New therapies are emerging, including sildenafil, propranolol, sirolimus, and
vascularized lymph node transfer. The primary focus of management centers on the patient’s quality of life.
Summary
Multimodal treatment of lymphatic malformations continues to expand as new information about the
biology and genetics of these lesions is discovered, in addition to knowledge gained from clinical practice.
A patient-centered approach should guide timing and modality of treatment. Continued study of lymphatic
malformations will increase and solidify a treatment algorithm for these complicated lesions.
Keywords
lymphatic malformation, new therapies, sclerotherapy, surgery, treatment

INTRODUCTION causing enlargement of the subcutaneous tissue in

Lymphatic malformations are low-flow vascular
anomalies of the lymphatic system, occurring in
one out of 2000–4000 live births [1]. They can be
characterized into macrocystic (diameter >1 cm),
microcystic (diameter <1 cm), or mixed. The Inter-
national Society for the Study of Vascular
Anomalies has further classified lymphatic malfor-
mations, as shown in Table 1. Lymphatic malfor-
mations commonly appear as ballotable masses.
The overlying skin may be uninvolved, may be
marked by lymphatic papules, or may manifest
cutaneous vascular marks (such as capillary malfor-
mations). The skin may have a blue hue if the cysts
of the lymphatic malformation are large, or can
appear as dark-red domes if intralesional bleeding
occurs [2]. When examined histologically, lym-
phatic malformations are composed of thin-walled
irregular vascular spaces of varying size lined with
lymphatic endothelial cells [3]. Lymphatic malfor-
mation cysts may be empty, or can be filled with
protein-rich fluid containing lymphocytes and
macrophages [4].
Congenital lymphedema is thought to possibly
represent a subtype of lymphatic malformations,
and is defined as a localized accumulation of
protein-rich fluid in superficial interstitial space
a limb. Over time, areas with lymphedema undergo
adipose and fibrous tissue deposition that further
increases limb volume. Unlike other forms of lym-
phatic malformations, lymphedema can be primary
(idiopathic or congenital) or secondary (acquired)
[5]. Primary lymphedema has been associated with
other lymphatic malformations, including intesti-
nal and pulmonary lymphangiectasia [6].
Cystic hygroma is the term historically used
for cervical macrocystic lymphatic malformations.
These lesions may be diagnosed prenatally by
increased nuchal translucency via ultrasound in
the first trimester, a finding that can also be
Department of Surgery, Section of Pediatric Surgery, University of
Chicago Medicine & Biological Sciences, Chicago, Illinois, USA
Correspondence to Jessica J. Kandel, MD, Mary Campau Ryerson
Professor of Surgery and Chief, Section of Pediatric Surgery, Sur-
geon-in-Chief, Comer Children’s Hospital, University of Chicago Medi-
cine & Biological Sciences, 5839 S. Maryland Suite A-426, MC 4062
Chicago, IL 60637, USA. Tel: +1 773 702 6175; fax: +1 773 304 2510;
e-mail: jkandel@surgery.bsd.uchicago.edu

Naina Bagrodia and Ann M. Defnet contributed equally to the writing of
this article.
Curr Opin Pediatr 2015, 27:356–363
DOI:10.1097/MOP.0000000000000209

www.co-pediatrics.com Volume 27  Number 3  June 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

 Management of lymphatic malformations in children Bagrodia et al.
KEY POINTS
 Further understanding of the genetics of lymphatic
malformations, specifically defects in the PI3K/AKT/
mTOR pathway, may allow for new treatment options
in the future.
 There is a multidisciplinary approach to the treatment of
lymphatic malformations with the priority being the
patient’s quality of life.
 Surgery may be important for patients with life-
threatening problems, after failed sclerotherapy, and
those who have microcystic disease.
 Sclerotherapy is recommended for macrocystic lesions
whereas radiofrequency ablation (RFA) can be used for
buccal lymphatic malformation lesions and lasers for
cutaneous lymphatic malformation lesions.
 New therapies including sildenafil, propranolol,
sirolimus, and vascularized lymph node transfer are
emerging as new information about the biology, and
genetics of these malformations is discovered.
associated with aneuploidy, other chromosomal
abnormalities, cardiac malformations, and perinatal
death [7]. Most prenatally diagnosed cervicofacial
lymphatic malformations are not associated with
these abnormalities, so this distinction becomes
important, especially when counseling parents.
GENETICS
Little is known about the genetics of lymphatic
malformations [8], with most appearing in
patients who do not manifest known syndromes.
In a minority of patients, lymphatic malformations
can be associated with syndromic disorders,
including Turner syndrome, Proteus syndrome,
Table 1. The International Society of the Study of Vascular
Anomalies classification of lymphatic malformations.
Adapted from issva.org/classification
Lymphatic malformations
Common (cystic) LM
Macrocystic LM
Microcystic LM
Mixed cystic LM
Generalized lymphatic anomaly
LM in Gorham–Stout disease
Channel type LM
Primary lymphedema
Others
LM, lymphatic malformation.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Klippel–Trenaunay–Weber syndrome, and congen-
ital, lipomatous, overgrowth, vascular malfor-
mations, epidermal nevi and spinal/skeletal
anomalies and/or scoliosis (CLOVES) syndrome
&&
[9 ]. Patients with Proteus syndrome have a somatic
mutation in AKT1, the RAC-alpha serine-threonine
protein kinase, which is thought to play a role in
&&
lymphangiogenesis [9 ,10,11]. Somatic mutations
activating phosphatidylinositol 4,5-bisphosphate
3-kinase catalytic subunit alpha (PIK3CA) were ident-
ified in patients with CLOVES syndrome and in
some patients with Klippel–Trenaunay–Weber syn-
&&
drome [9 ,12]. These genes are key elements in the
phosphoinositide 3-kinase/serine-threonine protein
kinase/mammalian target of rapamycin (PI3K/AKT/
&&
mTOR) pathway [9 ], and discovering further defects
may inform future opportunities for treatment.
Nonne–Milroy disease is a dominantly inher-
ited primary congenital lymphedema. In some fam-
ilial cases, heterozygous mutations in vascular
endothelial growth factor receptor 3, VEGFR3, have
been identified [8]. FLT4, which encodes VEGFR-3,
has been shown to have mutations in the tyrosine-
&&
kinase domain of the receptor [9 ]. These mutations
inhibit phosphorylation and downstream signaling
[13]. Published data show that recessive mutations
of VEGFR3 cause hypoplasia or aplasia of the lym-
&&
phatic system [6,9 ].
Thus far, mutations in RASA1 have been associ-
ated with capillary and arteriovenous malformations
[14]. However, some patients with mutations in the
RAS signaling pathway develop lymphedema, chylo-
&&
thorax, or chylous ascites [9 ] suggesting the RAS
pathway may additionally play a role in maintenance
of the lymphatic system. The RASA1 gene encodes the
p120 Ras GTPase-activating protein, and when RASA1
function is lost, Ras activity is deregulated [14,15].
Burrows et al. [14] induced RASA1 loss in adult mice,
and using near-infrared fluorescence lymphatic imag-
ing showed hyperplasia of the initial lymphatics,
chylothorax, and in some cases chylous ascites. These
findings suggest that inactivation of this gene can
&&
result in lymphatic system abnormalities [9 ,14,16].
DIAGNOSIS
Diagnosis of many lymphatic malformations is
made prenatally via ultrasound performed in the
late second to third trimesters. Many recent case
reports have demonstrated the accuracy of prenatal
ultrasound in diagnosing lymphatic malformations,
and in determining proximity to and extension into
surrounding structures. This information can guide
delivery and perinatal care [17–19].
Fetal MRI may also provide important anatomic
information about lymphatic malformations in
www.co-pediatrics.com 357
Surgery
&
utero. Koelblinger et al. [20 ] describe the use of fetal
MRI to provide exact delineation of the extent of the
lymphatic malformation, a more succinct differential
diagnosis, and further characterization of other
associated anomalies. They also describe making
clinical decisions based on fetal MRI imaging, includ-
ing termination of pregnancy and need for extra-
&
utero intrapartum treatment, among others [20 ].
Lymphatic malformations that are not diagnosed
prenatally are typically diagnosed at birth or in early
childhood [2]. Lymphatic malformations often mani-
fest a waxing and waning course with changes in size
associated with viral or bacterial infections, intrale-
sional hemorrhage, inflammation, and trauma [21],
which can often be elicited on a thorough history
and physical exam. Both ultrasound and MRI are
important in further work up of lymphatic malfor-
mations in the neonate or young child. Lymphoscin-
tigraphy can also be used in infants and small
children safely. Traditional contrast lymphangio-
gram has been abandoned as an imaging modality
in most infants and small children given the difficulty
in performing the study, with MR lymphangiography
reported to be useful in the classification of primary
lymphedema in one recent study [22].
INDICATIONS FOR TREATMENT
The clinical presentation of lymphatic malfor-
mations can be quite variable, ranging from a focal
area with minimal swelling to large areas of diffusely
infiltrating aberrant lymphatic channels with com-
promise of adjacent structures [23]. The goal of lym-
phatic malformation management and treatment is
to maintain functionality, control associated symp-
toms, and preserve aesthetic integrity [21,24].
Depending on their location and extent of the
lesion, lymphatic malformations can compromise
vital functions. Up to 75% of lymphatic malfor-
mations are found in the cervicofacial region [25],
and their presence in the aerodigestive tract can lead
to life-threatening airway obstruction, impaired oral
feeding, as well as speech and communication dif-
ficulties [13,26–28]. Orbital lymphatic malfor-
mations can result in vision loss, decreased
extraocular motility, ptosis, proptosis, and globe
dystopia [29]. Other symptoms include macroglos-
sia and overgrowth of the mandible [21]. Lymphatic
malformations are also found in the chest/axilla,
mediastinum, retroperitoneum, buttocks, and ano-
genital region [30]. Extremity lymphatic malfor-
mations can be associated with overgrowth of
both soft tissue and skeletal tissue in the affected
limb [2]. Severe life-threatening functional impair-
ment mandates early intervention [21].
Associated symptoms include pain, bleeding,
skeletal, and cosmetic changes [21,28]. Lymphatic
358 www.co-pediatrics.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
malformations have been associated with lympho-
penia, which has resulted in increased infection risk
[28,31]. Infection or intracystic hemorrhage can
lead to lesional expansion necessitating treatment
[27].
A final component in the treatment of lym-
phatic malformations is consideration of the
patient’s quality of life and support for managing
the associated social stigma [28,32]. In order to best
address this, a multidisciplinary team is needed that
includes surgeons, pediatricians, speech pathol-
ogists, nutritionists, and psychologists [28].
CONSERVATIVE MANAGEMENT
Traditionally, treatment of lymphatic malfor-
mations has often relied on surgery alone. Although
this modality is still widely used today, a conserva-
tive approach has been more recently described for
the treatment of lymphatic malformations. Gilony
et al. [33] retrospectively reviewed all patients with
lymphatic malformations that underwent treat-
ment and placed them into three separate treatment
arms including surgery, sclerotherapy, and obser-
vation. Patients in the observation arm had lym-
phatic malformations that did not require urgent
intervention and were only mildly disfiguring,
whereas the surgery arm was reserved for airway-
threatening lesions, need for a histological diagno-
sis, microcystic lesions, or those lesions resistant to
sclerotherapy. Their results showed that 45% of
those lymphatic malformations deemed observable
regressed spontaneously. Only one patient in the
sclerotherapy arm required surgery after failure of
treatment, whereas 95% of patients had an excellent
to fair response with sclerotherapy alone. In the
surgery group, 67% of patients had complete resol-
ution after surgery, 20% had incomplete removal
with fair cosmetic result, and 13% had a poor cos-
metic result. The authors indicate that there is a role
for all treatment modalities in the management of
lymphatic malformations, and that most patients
can be observed for a period before requiring either
sclerotherapy or surgery [33].
A recent study comparing primary surgery to
primary sclerotherapy in the treatment of less com-
plex head and neck lymphatic malformations
showed no difference in effectiveness after the first
&&
intervention or at one year [34 ]. This suggests a
conservative approach to management is feasible for
most lesions. For complex disease, this study recom-
mends management at a center experienced in the
&&
treatment of lymphatic malformations [34 ].
Treatment of symptoms also constitutes a part
of conservative therapy. Some patients receive
tonsillectomy, tongue reduction, and even early
Volume 27  Number 3  June 2015
 Management of lymphatic malformations in children Bagrodia et al.
tracheostomy to alleviate impending airway
obstruction without full surgical resection [35].
Also, antibiotics and steroids may be used when
lymphatic malformations become infected to man-
age patients through the acute phase response [35].
SCLEROTHERAPY
Published reports suggest that sclerotherapy is effec-
tive in treating and resolving macrocystic lymphatic
malformations, with much less efficacy in micro-
cystic lymphatic malformations [2,13,23]. Sclero-
sants include picibanil (OK-432), doxycycline,
bleomycin, ethanol, sodium tetradecyl sulfate, ace-
tic acid, and hypertonic saline [21,24,36]. These
agents are discussed in Table 2. Despite the plethora
of sclerosing agents, there is not yet a consensus on
which agent is clearly optimal [21,36].
Sclerotherapy is performed by entering the
cystic cavity by a direct puncture, aspirating the
cystic fluid, and finally injecting the sclerosant
[2]. The aspirated fluid helps to confirm the diag-
nosis, creates space for increased volume of the
sclerosant, and increases the surface area between
the sclerosant and the cyst wall [36]. Adverse reac-
tions after sclerotherapy include soft tissue edema
resulting in airway obstruction, skin necrosis, and
neuropathy [23,35]
SURGERY
Few recent advances have been made in the surgical
management of lymphatic malformations. Endo-
scopic techniques have been described to fully elu-
cidate the size of macrocystic lesions before
undergoing surgical resection [52]. Laparoscopic
techniques have been used to resect abdominal
lymphatic malformations [53]. As described above,
surgery is used in conjunction with or after sclero-
therapy. Surgery is often no longer a primary treat-
ment, unless the airway is compromised [23,33].
Surgical treatment appears to be less morbid and
more effective when performed at tertiary centers
with experienced lymphatic malformation surgeons
[26]. Complications can include cranial nerve injury
in cervicofacial lymphatic malformations, and
recurrence in any area if resection is incomplete [54].
ABLATION AND LASERS
Microcystic lymphatic malformations are notoriously
difficult to treat and are typically managed conserva-
tively [36]. Radiofrequency ablation (RFA), also
known as coblation, has been described as a method
for reducing mucosal lymphangiomatous lesions,
especially microcystic lymphatic malformations
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[23,55–60]. There are two methods for the delivery
of RFA. The first is the high-frequency mode, which
allows for destruction of deep tissue without affecting
adjoining structures or mucosa. Lesional size is dimin-
ished because of subsequent fibrosis. In low-frequency
mode, RFA allows energy to be transmitted through a
conductive medium (such as isotonic saline) for
removal of a thin superficial layer with minimal injury
to nearby tissue [27,60]. With little collateral damage
to adjacent structures, it may be an attractive option
for lymphatic malformation removal in the airway
[59,61].
Published data suggest that RFA is effective in
reducing the size of oral cavity lymphatic malfor-
mations [55–57,62] and improving symptoms
including pain, bleeding, and infection [56,60]. A
recent case report discussed hemostasis and precision
in the removal of large lymphatic malformations
while sparing surrounding vital structures [59].
Successful use of carbon dioxide lasers, continu-
ous wave neodymium:yttrium–aluminum–garnet
lasers, and pulsed dye lasers have been reported
[63–65]. Carbon dioxide lasers vaporize the tissues
nonselectively and seal lymphatic channels [63].
They can be used to remove mucosal microvesicles
[23,66], which is rarely curative but may improve
symptoms [67]. The disadvantages of this method
include the need for local or general anesthesia and
subsequent scarring [63,68–72]. The neodymiu-
m:yttrium–aluminum–garnet laser can be used to
debulk lymphatic malformations in the oral cavity
[63,70,71]. The pulsed dye laser can be used to treat
cutaneous lesions [63,72].
NEW THERAPIES
New therapies continue to emerge for the treatment
of lymphatic malformations, given the frequent
morbidity of these lesions and the lack of thera-
peutic options for complicated or recurrent lym-
phatic malformations. Sildenafil, propranolol, and
sirolimus are three oral medications that have been
reported to be effective in the recent literature. Case
reports show that sildenafil can decrease lymphatic
malformation size and alleviate associated symp-
toms [73,74]. In a small, open-label study, sildenafil
was shown to have a therapeutic response in six out
of seven patients without significant side-effects
&&
[75 ]. Propranolol is routinely used for infantile
hemangiomas, and recent studies have shown its
efficacy in the treatment of some lymphatic malfor-
mations, although not all patients respond to treat-
&&
ment [76 ,77]. It has been hypothesized that those
malformations which responded were thought to be
mixed vascular malformations, with propranolol
&&
affecting only hemangiomatous portions [76 ].
www.co-pediatrics.com 359
 360
Table 2. Sclerosants used in the treatment of lymphatic malformations
Surgery

Sclerosant Description Proposed mechanism of action Use Complications References

Picibanil (OK-432) Lyophilized mixture
Group A Streptococcus
pyogenes
Benzylpenicillin
Doxycycline Tetracycline antibiotic
Inflammatory response resulting in Macrocystic LMs Anaphylaxis [21,24,35,37]
cytokine production by leukocytes
Inhibits matrix metalloproteinases and Macrocystic LMs Tooth discoloration [14,21,24,35,36,38–44]
cell proliferation
Suppresses VEGF-induced Electrolyte abnormalities

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angiogenesis and
lymphangiogenesis
Deposition of collagen and fibrin with
involution of cyst
Bleomycin Chemotherapeutic agent Inhibits DNA synthesis Macrocystic LMs Interstitial pneumonia [21,45–47]
Causes inflammatory reaction on Pulmonary fibrosis (with IV administration
endothelial cells of cumulative doses greater than
400 mg)
Pingyangmycin Chemotherapeutic agent Selective destruction of lymphatic Macrocystic LMs Hair loss [45,48–50]
endothelial cells lining cyst
Increased collagen deposition in cyst Microcystic LMs Gastrointestinal reaction
cavity
Skin pigmentation change
Pulmonary fibrosis
Ethanol Desiccant Rapid cellular dehydration of Macrocystic LMs Respiratory depression [21,24,40,44,51]
lymphatic endothelial cells (infrequently)
Cardiac arrhythmias
Rhabdomyolysis
Hypoglycemia
Seizures
Sodium tetradecyl Detergent Emulsify cell membrane lipoproteins Macrocystic LMs Increased risk of infection [24,39,51]
sulfate
Increase membrane permeability Orbital LMs
Enhance cell death and fibrosis when

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used in combination with
doxycycline or ethanol

IV, Intravenous; LM, lymphatic malformation; VEGF, vascular endothelial growth factor.

Volume 27  Number 3  June 2015

 Management of lymphatic malformations in children Bagrodia et al.
Sirolimus, an mTOR inhibitor, was found to be
effective in the treatment of a tongue lesion that
did not respond to surgery or propranolol [78].
Randomized controlled trials of these treatment
strategies are lacking, which would be needed to
fully assess their therapeutic efficacy.
New surgical techniques have also been utilized
in the treatment of lymphatic malformations. Ultra-
sound-guided liposuction was shown to be effective
in reducing limb size in eight patients with large
extremity microcystic lymphatic malformations
[79]. Liposuction has also been used in conjunction
with sclerotherapy to better treat multicystic lym-
phatic malformations of the neck by rupturing cyst
walls with good effect and no complications [80].
A surgical technique currently used for the treat-
ment of secondary lymphedema is vascularized
lymph node transfer. During this procedure healthy,
vascularized tissue, and lymph nodes are transferred
to an area of lymphedema [81]. There are two
theories proposed to explain the efficacy of this
procedure. The first is that the healthy lymph nodes
secrete growth factors that induce lymphangiogen-
esis [82]. Alternatively, lymph nodes themselves
may function as a lymphatic pump [83]. Limb size
reduction for this procedure has been reported.
However, comparative studies are difficult as many
methodological differences exist between centers
and patient selection is not uniform [81]. Better
understanding of the mechanisms underlying
the success of this technique in selected patients,
currently those with secondary lymphedema, might
allow an understanding of its potential use in
primary lymphedema.
CONCLUSION
The management and treatment of lymphatic mal-
formations necessitate a multifocal and multidisci-
plinary approach, with the patient’s quality of life
being the priority. Based upon the current trends,
observation is a reasonable first option, especially if
there is no functional deficit, associated symptoms,
or aesthetic compromise. Sclerotherapy is recom-
mended for macrocystic lesions. Surgery may be
important for patients with a life-threatening prob-
lem such as airway obstruction, after failed sclero-
therapy, and those who have microcystic disease.
Preliminary published data show promising results
when using RFA for buccal lymphatic malformation
lesions and lasers for cutaneous lymphatic malfor-
mation lesions. The current lack of understanding of
the biology and genetics of lymphatic malfor-
mations should prompt further basic investigation,
with the goal of developing more effective treat-
ments for these patients.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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 Management of lymphatic malformations in children Bagrodia et al.

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