2014 Revised Classification of Vascular Lesions from the International Society for the Study of Vascular Anomalies: Radiologic-Pathologic Update

Abstract

Since the publication of the seminal work on the histology-based classification of vascular anomalies by Mulliken and Glowacki in 1982 and the subsequent adoption of an expanded and modified version in 1996 by the International Society for the Study of Vascular Anomalies, an increasing number of vascular lesions have been recognized as histologically distinct entities. Furthermore, there have been significant advances in detailing the behavior and underlying genetics of previously identified lesions. These developments have required restructuring and expansion of the classification scheme so that appropriate therapies may be studied and implemented in affected patients. The new classification retains the broad categories of neoplasms and malformations but now divides the tumor group into benign, locally aggressive or borderline, and malignant, with the malformation group being divided into simple, combined, those of major named vessels, and those associated with other anomalies. Additionally, a category has been created for lesions in which the histology and behavior do not yet allow clear separation into neoplasm or malformation (thus named "provisionally unclassified vascular anomalies"). The known clinical courses and imaging, histologic, and genetic findings of the most common and/or clinically relevant lesions in the newly adopted revised system are reviewed in this article. (©)RSNA, 2016.

Full text

PEDIATRIC IMAGING
1
2014 Revised Classification of Vascular
Lesions from the International Society
for the Study of Vascular Anomalies:
Radiologic-Pathologic Update1
Since the publication of the seminal work on the histology-based
classification of vascular anomalies by Mulliken and Glowacki
in 1982 and the subsequent adoption of an expanded and modi-
fied version in 1996 by the International Society for the Study of
Vascular Anomalies, an increasing number of vascular lesions have
been recognized as histologically distinct entities. Furthermore,
there have been significant advances in detailing the behavior and
underlying genetics of previously identified lesions. These develop-
ments have required restructuring and expansion of the classifi-
cation scheme so that appropriate therapies may be studied and
implemented in affected patients. The new classification retains the
broad categories of neoplasms and malformations but now divides
the tumor group into benign, locally aggressive or borderline, and
malignant, with the malformation group being divided into simple,
combined, those of major named vessels, and those associated with
other anomalies. Additionally, a category has been created for le-
sions in which the histology and behavior do not yet allow clear
separation into neoplasm or malformation (thus named “provision-
ally unclassified vascular anomalies”). The known clinical courses
and imaging, histologic, and genetic findings of the most common
and/or clinically relevant lesions in the newly adopted revised sys-
tem are reviewed in this article.
©RSNA, 2016 • radiographics.rsna.org
Arnold C. Merrow, MD
Anita Gupta, MD
Manish N. Patel, DO
Denise M. Adams, MD
Abbreviations: AVM = arteriovenous malfor-
mation; CLOVES = congenital lipomatous over-
growth with vascular malformations, epidermal
nevi, and skeletal anomalies; GLUT-1 = glu-
cose transporter 1; H-E = hematoxylin-eosin;
HHT = hereditary hemorrhagic telangiecta-
sia; PHACES = posterior fossa malformations,
hemangioma, arterial anomalies, cardiovascular
anomalies, eye anomalies, sternal clefting, and/
or supraumbilical raphe; PTEN = phosphatase
and tensin homolog protein
RadioGraphics 2016; 36:0000–0000
Published online 10.1148/rg.2016150197
Content Codes:
1From the Department of Radiology (A.C.M.,
M.N.P.) and Department of Pediatrics, Divi-
sion of Pathology and Laboratory Medicine
(A.G.), Cincinnati Children’s Hospital Medical
Center, 3333 Burnet Ave, MLC 5031, Cincin-
nati, OH 45229; and Vascular Anomalies Cen-
ter, Boston Children’s Hospital, Boston, Mass
(D.M.A.). Presented as an education exhibit
at the 2014 RSNA Annual Meeting. Received
June 22, 2015; revision requested December 9
and received January 27, 2016; accepted Febru-
ary 22. For this journal-based SA-CME activ-
ity, the author A.C.M. has provided disclosures
(see end of article); all other authors, the editor,
and the reviewers have disclosed no relevant
relationships. Address correspondence to
A.C.M. (e-mail: carl.merrow@cchmc.org).
©RSNA, 2016
After completing this journal-based SA-CME
activity, participants will be able to:
■List major categories of vascular
anomalies according to the 2014 revised
ISSVA classification.
■Identify complications of common vas-
cular anomalies.
■Recognize imaging features specific to
certain vascular anomalies.
See www.rsna.org/education/search/RG.
SA-CME
LEARNING OBJECTIVES
Introduction
In 1982, Mulliken and Glowacki (1) published the first histology-
based scheme for understanding vascular lesions, a heterogeneous
group of histologically and clinically distinct abnormalities that had
previously been grouped together by many physicians, often resulting
in misapplication of diagnosis, prognosis, and relevant therapy. De-
spite the subsequent adoption of an expanded and modified version
in 1996 by the International Society for the Study of Vascular Anoma-
lies (ISSVA) (2), misuse of nomenclature has remained widespread
through all disciplines in the medical literature, including radiology
and pathology (3). The inaccurate application of terminology for rela-
tively specific hematologic and dermatologic manifestations of certain
vascular anomalies has also led to incorrect diagnosis and inappropri-
ate treatment (3,4).
As physicians and researchers specializing in diagnosis and
treatment of these lesions have recognized an increasing number of
histologically distinct entities and advances have been made in elu-
cidating the behavior and underlying genetics of previously identi-
fied lesions, revision of the classification scheme has been required
so that appropriate therapies may be studied and implemented in
affected patients. The new classification (Table 1) includes the orig-
inal categories of neoplasms and malformations, with the tumor
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2 September-October 2016 radiographics.rsna.org
Utility of
Imaging Vascular Anomalies
Vascular anomalies most commonly present
in childhood by one of three manifestations: a
cutaneous lesion with or without a characteristic
appearance, a deeper palpable soft-tissue mass
without diagnostic cutaneous features, or a
secondar y clinical expression due to localized or
systemic influences of the primary lesion and/or a
recognized malformative association/syndrome.
Imaging is rarely necessary for diagnosis in a
single localized superficial lesion with character-
group divided into benign, locally aggressive or
borderline, and malignant subcategories (Table
2) and the malformation group divided into
simple (Tables 3–6), combined (Table 7), those
of major named vessels (Table 8), and those as-
sociated with other anomalies (Table 9) (2,5). A
distinct category has been created for lesions in
which the histology and behavior do not allow
clear separation into neoplasm or malformation
(thus named “provisionally unclassified vascu-
lar anomalies”) (Table 10). Additionally, the
number of category layers and associated lesions
has increased, and information on associated co-
agulopathies (Table 11) and established genetic
mutations (Tables 3–9) has been incorporated
into the classification.
Given the breadth of expansion, we will review
for the reader the known clinical courses and im-
aging, histologic, and genetic findings of the most
common and clinically relevant lesions in the
newly adopted revised system. (Of note, Tables
12 and 13 address all genetic and immunostain
nomenclature used in the tables and figures.)
TEACHING POINTS
■Infantile hemangioma has a characteristic life cycle where it
is not typically present at birth, appears and rapidly grows in
the first few weeks/months of life (proliferative phase), gradu-
ally involutes over years (involutional phase), and remains as a
variable amount of smaller fibrofatty tissue for the remainder
of life.
■Complications of multifocal or diffuse infantile hemangio-
mas in the liver include hypothyroidism (due to production
of type 3 iodothyronine deiodinase), heart failure (due to the
hypothyroidism), liver failure, and abdominal compartment
syndrome.
■These layering fluid-fluid levels within a lesion are highly sug-
gestive of the dependent settling of blood products within
a stagnant cavity. When multiple such levels are visible in a
soft-tissue mass in a child, a slow-flow vascular malformation
(ie, either venous or lymphatic) should be the primary consid-
eration, although such an appearance may occur infrequently
in other pediatric lesions, including hemorrhage within a ma-
lignancy, and must be considered in the context of the other
imaging features.
■When well-defined round calcifications are scattered within a
pediatric soft-tissue mass, a venous malformation is the most
likely cause. Radiographs typically provide confirmation of the
characteristic phlebolith appearance.
■Generalized lymphatic anomaly variably shows multifocal
well-circumscribed lesions of the spleen, bones, and soft tis-
sues with pleural effusions frequently present. Genetic mu-
tations have been found in CCBE1 and PIK3CA. Frank bone
destruction is not expected in generalized lymphatic anomaly
but points to Gorham-Stout disease, where progressive re-
gional osteolysis is due to an infiltrative lymphatic malforma-
tion and osteoclastic activity. In Gorham-Stout disease, viscer-
al involvement and macrocystic lymphatic malformations are
less frequent than in generalized lymphatic anomaly.
Table 1: Overview of Vascular Anomalies
Vascular tumors
Benign
Locally aggressive or borderline
Malignant
Vascular malformations
Simple
Combined
Those of major named vessels
Those associated with other anomalies
Source.—Reference 5.
Table 2: Vascular Tumors
Benign
Infantile hemangioma
Congenital hemangioma
Rapidly involuting
Noninvoluting
Partially involuting
Tufted angioma
Spindle cell hemangioma
Epithelioid hemangioma
Pyogenic granuloma
Others
Locally aggressive or borderline
Kaposiform hemangioendothelioma
Retiform hemangioendothelioma
Composite hemangioendothelioma
Papillary intralymphatic angioendothelioma
(Dabska tumor)
Kaposi sarcoma
Others
Malignant
Angiosarcoma
Epithelioid hemangioendothelioma
Others
Source.—Reference 5.

RG • Volume 36 Number 5 Merrow et al 3
abnormality that suggests the presence of an
intraorbital component that could ultimately im-
pair vision) or its distribution implies a signifi-
cant associated anomaly (such as a lesion overly-
ing the lumbar spine that suggests an underlying
tethering of the spinal cord). In these cases,
magnetic resonance (MR) imaging offers the
best assessment due to its contrast resolution,
various methods of interrogation, and general
lack of visualization impairment by lesion depth
or overlying bone, fat, or gas (6–8).
A slightly deeper but palpable mass that is
growing but otherwise clinically inert, particu-
larly one with absent or vague cutaneous mani-
festations, often presents a diagnostic dilemma,
as benign soft-tissue masses in children, while
more common, can be difficult to differentiate
from malignancy. In this case, ultrasonography
istic cutaneous stigmata. However, imaging may
be employed if the deep extent of the lesion is
unclear (and therefore concerning for worsen-
ing deep mass effect with an impending critical
complication, such as a periorbital cutaneous
Table 3: Simple Vascular Malformations—
Capillary
Cutaneous and/or mucosal CM (port-wine stain)
CM with bone and soft-tissue hyperplasia
CM with CNS and eye anomalies (Sturge-
Weber syndrome) (GNAQ)
CM of CM-AVM (RASA1)
Telangiectasia
Hereditary hemorrhagic telangiectasia (HHT)*
Others
Cutis marmorata telangiectatica congenita
Nevus simplex/salmon patch
Others
Source.—Reference 5.
Note.—AVM = arteriovenous malformation, CM =
capillary malformation, CNS = central nervous sys-
tem. Associated genetic mutations are in parentheses.
*ENG in HHT1, ACVRL1 in HHT2, SMAD4 in
juvenile polyposis hemorrhagic telangiectasia.
Table 4: Simple Vascular Malformations—Venous
Common VM (TIE2 somatic)
Familial VM cutaneomucosal (TIE2)
Blue rubber bleb nevus syndrome
Glomuvenous malformation (glomulin)
Cerebral cavernous malformation (CCM)*
Others
Source.—Reference 5.
Note.—VM = venous malformation. Associated
genetic mutations are in parentheses.
*KRIT1 in CCM1, malcavernin in CCM2,
PDCD10 in CCM3.
Table 5: Simple Vascular Malformations—
Lymphatic
Common (cystic) LM
Macrocystic LM
Microcystic LM
Mixed cystic LM
Generalized lymphatic anomaly
LM in Gorham-Stout disease
Channel-type LM
Primary lymphedema
Nonne-Milroy syndrome (FLT4/VEGFR3)
Primary hereditary lymphedema (VEGFC,
GJC2/connexin 47)
Lymphedema-distichiasis (FOXC2)
Hypertrichosis-lymphedema-telangiectasia
(SOX18)
Primary lymphedema with myelodysplasia
(GATA2)
Primary generalized lymphatic anomaly
(CCBE1)
Microcephaly ± chorioretinopathy, lymphedema,
or mental retardation syndrome (KIF11)
Lymphedema–choanal atresia (PTPN14)
Source.—Reference 5.
Note.—LM = lymphatic malformation. Associated
genetic mutations are in parentheses.
Table 6: Simple Vascular Malformations—
AVM or Arteriovenous Fistula
Sporadic
In HHT (ENG, ACVRL1, SMAD4)
In CM-AVM (RASA1)
Others
Source.—Reference 5.
Note.—CM = capillary malformation. Associated
genetic mutations are in parentheses.
Table 7: Combined Vascular Malformations
CM + VM (CVM)
LM + VM (LVM)
CM + LM + VM (CLVM)
CM + AVM + VM (CAVM)
CM + LM + AVM + VM (CLAVM)
Source.—Reference 5.
Note.—CM = capillary malformation, LM = lym-
phatic malformation, VM = venous malformation.

4 September-October 2016 radiographics.rsna.org
(US) serves a great purpose due to its superficial
spatial resolution, ability to allow assessment of
fluid and vascularity, lack of ionizing radiation
or need for sedation, and dynamic capabilities as
well as its ready availability, speed, and relatively
low cost (6–8). MR imaging will provide fur-
ther characterization in some specific situations
(such as the presence of intralesional fat, fluid-
fluid levels, enhancement patterns, or surround-
ing muscle edema), although biopsy may still be
required for certainty (7,8).
Finally, a secondary clinical expression (such
as a coagulopathy or overgrowth) may be the pre-
senting feature of an underlying vascular anom-
aly. MR imaging again provides the best screen-
ing and diagnostic assessment for the primary
mass or state of the regional vessels to define an
associated vascular anomaly as well as associated
malformations (particularly of the central ner-
vous system).
While a variety of lesions to be discussed can
manifest in one of these forms requiring further
investigation, the frequency of infantile heman-
gioma and its variable clinical manifestations
will provide an ideal demonstration of these
imaging concepts.
Vascular Neoplasms
True tumors (Table 2) generally arise de novo (at
varying time points) and consist of clonal cellular
proliferation with mitoses and lesional growth
that is out of proportion to the patient (6,7).
Some of the more common lesions in children
will have predictable life cycles and will not re-
quire therapy in the absence of complications.
Benign Neoplasms
Infantile Hemangioma.—By far the most com-
mon vascular anomaly encountered in children is
the infantile hemangioma, which typically mani-
fests as a single cutaneous lobular “strawberry
mark” in the first few weeks of life (9–11). These
lesions are most common in white females (3:1
female-to-male ratio). Infantile hemangioma has
a characteristic life cycle where it is not typically
present at birth, appears and rapidly grows in the
first few weeks/months of life (proliferative phase),
gradually involutes over years (involutional phase),
and remains as a variable amount of smaller
fibrofatty tissue for the remainder of life (9–11).
When a single lesion has a typical clinical history
and cutaneous appearance for an infantile heman-
gioma in a nonconcerning location, no radiologic
or histologic interrogation is necessary.
However, several specific scenarios arise in
which further workup is required. A deeper
Table 8: Anomalies of Major Named Individual
Vessels
Origin
Course
Number
Length
Diameter (aplasia, hypoplasia, ectasia, aneurysm)
Valves
Communication
Persistence (of embryonal vessels)
Source.—Reference 5.
Table 9: Vascular Malformations Associated
with Other Anomalies
Klippel-Trenaunay syndrome
Parkes Weber syndrome (RASA1)
Servelle-Martorell syndrome
Sturge-Weber syndrome (GNAQ)
Limb CM + congenital nonprogressive limb
hypertrophy
Maffucci syndrome (VM ± spindle cell heman-
gioma + enchondroma)
Macrocephaly-CM (PIK3CA)
Microcephaly-CM (STAMBP)
CLOVES (LM + VM + CM ± AVM + lipomatous
overgrowth) (PIK3CA)
Proteus syndrome (CM, VM, and/or LM + asym-
metric somatic overgrowth) (AKT1)
Bannayan-Riley-Ruvalcaba syndrome (AVM + VM
+ macrocephaly, lipomatous overgrowth) (PTEN)
Source.—Reference 5.
Note.—CLOVES = congenital lipomatous over-
growth with vascular malformations, epidermal
nevi, and skeletal anomalies; CM = capillary
malformation; LM = lymphatic malformation;
VM = venous malformation. Associated genetic
mutations are in parentheses.
Table 10: Provisionally Unclassified Vascular
Anomalies
Verrucous hemangioma
Angiokeratoma
Multifocal lymphangioendotheliomatosis with
thrombocytopenia/cutaneovisceral angiomatosis
with thrombocytopenia
Kaposiform lymphangiomatosis
PTEN hamartoma of soft tissue/“angiomatosis” of
soft tissue (PTEN)
Source.—Reference 5.
Note.—PTEN = phosphatase and tensin homo-
log protein. Associated genetic mutations are in
parentheses.

RG • Volume 36 Number 5 Merrow et al 5
Table 11: Vascular Anomalies Associated with Thrombocytopenia/Coagulation Disorders
Vascular Anomaly Hematologic Disorder
Tufted angioma, kaposiform
hemangioendothelioma
Severe sustained thrombocytopenia, hypofibrinogenemia, consumptive coagu-
lopathy, elevated D-dimer level (Kasabach-Merritt phenomenon)
Rapidly involuting congenital
hemangioma
Transient mild to moderate thrombocytopenia ± consumptive coagulopathy
VM/LVM Chronic localized intravascular coagulopathy (may progress to DIC subse-
quent to surgery or trauma)
MLT/CAT Fluctuating moderate to severe thrombocytopenia with gastrointestinal or
pulmonary hemorrhages
Kaposiform lymphangiomatosis Mild to moderate thrombocytopenia, hypofibrinogenemia, and D-dimer elevation
Source.—Reference 5.
Note.—CAT = cutaneovisceral angiomatosis with thrombocytopenia, DIC = disseminated intravascular coagu-
lopathy, LVM = lymphatic-venous malformation, MLT = multifocal lymphangioendotheliomatosis with throm-
bocytopenia, VM = venous malformation.
Table 12: Gene Nomenclature Explanations List
Gene
Symbol Full Name
WWTR1 WW domain–containing transcription regulator protein 1
CAMTA1 Calmodulin binding transcription activator
YAP1 Yes-associated protein 1
TFE2 Transferrin receptor 2
PDCD10 Program cell death 10
CCBE1 Collagen and calcium binding EGF domains 1
PIK3CA Phosphatidylinositol-4,5-bisphosphate-3-kinase, catalytic subunit a
FLT4 Fms-related tyrosine kinase 4
VEGFR3 Vascular endothelial growth factor receptor 3
VEGFRC Vascular endothelial growth factor C
GATA2 GATA binding protein 2
ENG Endoglin
ACVRL1 Activin A receptor type II–Like 1
SMAD4 SMAD family member 4
GDF2 Growth differentiation factor 2
RASA1 RAS P21 protein activator (GTPase activating protein) 1
KRIT1 Krev interaction trapped protein 1
TIE2 Tyrosine protein kinase receptor TIE2
GNAQ Guanine nucleotide binding protein a-Q
STAMBP STAM binding protein
AKT1 V-Akt murine thymoma viral oncogene homolog 1
GJC2 Gap junction protein g 2
SOX18 Sex-determining region Y box 18
KIF11 Kinesin family member 11
PTEN Phosphatase and tensin homolog
Source.—Reference 5.
subcutaneous infantile hemangioma with mini-
mal to absent cutaneous stigmata may raise the
referring pediatrician’s concern for a rapidly
growing malignancy. As noted previously, US is
extremely useful in this scenario and will usually
show several characteristic features of infantile
hemangioma (9–11). These lesions are often
subcutaneous (rather than intramuscular) with

6 September-October 2016 radiographics.rsna.org
a lobular and ovoid or elongated configuration.
They are typically heterogeneous internally with
patchy regions of increased and decreased echo-
genicity. The masses are soft but not as com-
pressible as cystic lesions. Doppler evaluation
of the vascularity is frequently diagnostic for
infantile hemangioma. Specifically, these highly
vascular lesions will show few discrete vessels at
gray-scale imaging yet will “light up” with the
application of color Doppler US, showing five
or more vessels per square centimeter. Spectral/
pulsed Doppler interrogation will reveal abun-
dant low-resistance arterial waveforms (6,7,11)
(Fig 1). With involution, these lesions will show
increasing echogenicity with decreasing vascu-
larity and increasing vascular resistance (11).
MR imaging (or less frequently computed to-
mography [CT]) may occasionally be employed
initially, with proliferative lesions showing early
diffuse homogeneous enhancement and involut-
ing lesions showing decreasing enhancement
with increasing fatty components (such that
complete fibrofatty replacement is ultimately
noted). T2-weighted imaging may show a few
internal flow voids in a lobular, hyperintense
(but generally not “fluid bright”) proliferating
lesion (11) (Fig 2).
If five or more cutaneous lesions are present,
abdominal US is necessary to screen the liver
for infantile hemangiomas, which are typically
small to medium-sized well-circumscribed masses
(7,9,12,13) with multifocal or diffuse hepatic
involvement. Hepatic infantile hemangiomas vary
widely in echogenicity and vascularity, even during
the early proliferative stage. MR imaging will show
precontrast features similar to those described
earlier for soft-tissue hemangiomas. However, the
enhancement pattern of hepatic infantile hem-
angiomas overlaps that of other vascular hepatic
lesions, with a typical dynamic pattern of early
peripheral enhancement (often confluent rather
than discontinuous) followed by gradual central
enhancement (7,12). As expected with other vas-
cular lesions, hepatocyte-specific agents generally
show clearance from the lesions at delayed hepato-
biliary phase imaging (14).
Complications of multifocal or diffuse infantile
hemangiomas in the liver include hypothyroidism
(due to production of type 3 iodothyronine de-
iodinase), heart failure (due to the hypothyroid-
ism), liver failure, and abdominal compartment
syndrome. Patients will require echocardiography
and thyroxine (T4)/thyroid-stimulating hormone
(TSH) monitoring, by which lesional response to
therapy can be monitored (9,10,13).
Lesions surrounding the orbit may undergo MR
imaging to assess the degree of occult intraorbital
infantile hemangioma that could create vision com-
plications with rapid growth. Similarly, facial lesions
in a bearded distribution necessitate clinical airway
investigation, as obstructing infantile hemangiomas
Table 13: Immunostain Explanations List
Immunostain
Symbol Full Name
PROX-1 Prospero homeobox protein 1
CD34 Cluster of differentiation
Ki-67 Transferrin receptor 2
Source.—Reference 5.
Figure 1. Deep infantile hemangioma of the back soft tissues
in a 2-month-old girl with a soft but rapidly growing and warm
mass but no characteristic cutaneous stigmata. Transverse
color Doppler US image shows a heterogeneous subcutaneous
lesion with lobules of increased and decreased echogenicity.
There are numerous prominent vessels (more than five per
square centimeter) throughout the mass, most of which were
not visualized at gray-scale imaging alone. Many of the ves-
sels demonstrate low-resistance arterial waveforms. The patient
age, clinical history, and US findings are highly typical for an in-
fantile hemangioma and require no further imaging. However,
the child should be followed up by a clinician experienced in
pediatric vascular anomalies to correlate with relevant physical
examination findings and the expected clinical course.

RG • Volume 36 Number 5 Merrow et al 7
may be found in this setting. Lesions overlying
the lumbar spine are frequently associated with
significant spinal cord abnormalities necessitating
intervention, including tethering (10,12).
Two other segmental distributions are associated
with more widespread abnormalities that require
screening of other organ systems. The PHACES
association is found in the setting of segmental
facial lesions, while the variably named LUMBAR/
PELVIS/SACRAL association (including lower
body/truncal hemangioma, urogenital abnor-
malities, ulceration, myelopathy, bony anomalies,
anorectal malformations, and arterial and renal ab-
normalities) is found with infantile hemangiomas
extending over the spine and perineum (9–12).
At histologic analysis, proliferating infantile
hemangiomas are lobules of closely packed capil-
laries lined with plump endothelial cells that stain
positive for glucose transporter 1 (GLUT-1).
With involution, stroma increases between the
capillaries, the endothelial cells flatten, the base-
ment membrane hyalinizes, and there is gradual
fibrofatty replacement (9–12) (Fig 3).
Therapy for individual lesions may not be
necessary unless there are complications (such as
ulceration, bleeding, impingement on vital struc-
tures, or systemic complications secondary to
visceral lesions) or cosmetic issues (9,10). Since its
original description of efficacy for infantile heman-
giomas in 2008, oral propranolol (a b-blocker) has
largely replaced steroids as the drug of choice for
these lesions when therapy is warranted (9,10,15).
Steroids are still employed if an immediate re-
sponse is required or if the lesion is unresponsive
to propranolol. Topical timolol (another b-blocker)
is frequently used for isolated cutaneous lesions.
Laser therapy may be used for ulcerated lesions
(9,10). Surgery may be required in some situations.
Congenital Hemangioma.—These lesions may
occur as soft-tissue masses, visceral lesions, or
intracranial extra-axial lesions. Three distinct life
cycles have been recognized among these lesions:
rapidly involuting, noninvoluting, and partially
involuting (2,5–7,9–11). The proliferative phase
in the life cycle of these lesions has finished by
birth, although intralesional hemorrhage may
result in an episode of acute enlargement. For
rapidly involuting lesions, 90% of involution
has occurred by 3 months of life with near total
resolution by 14 months (in contrast to infan-
tile hemangiomas, in which involution does not
typically begin until 6–12 months of life and then
requires several years) (9,11). Noninvoluting le-
sions may occasionally grow commensurate with
the patient without true cellular proliferation.
Clinically, a transient and relatively mild con-
sumptive coagulopathy may be present with con-
genital hemangiomas, which has led to confusion
with the more profound and sustained consumptive
coagulopathy of the Kasabach-Merritt phenom-
enon (which is not associated with hemangiomas of
any kind but found only with kaposiform heman-
gioendothelioma and tufted angioma, discussed
later) (2,4). Cutaneous lesions may be present in
the setting of congenital hemangiomas but differ
in appearance compared with those of infantile
hemangiomas, typically being more reddish-blue
or violaceous with telangiectasias and often having
a surrounding pale halo (11). There is no female
predominance with congenital hemangiomas (16).
There are few imaging series of soft-tissue
congenital hemangiomas in the literature,
although reports indicate that they are well-cir-
cumscribed with or without surrounding edema
and are more likely than infantile hemangiomas
to show internal heterogeneity, calcification,
hemorrhage, and large vessels (11,16). There
have been numerous descriptions of the hepatic
form of congenital hemangiomas, which have
often been incorrectly termed “hemangioen-
dotheliomas.” Hepatic congenital hemangioma
represents the classic large solitary vascular
tumor of the neonatal liver that can manifest
Figure 2. Large segmental facial infantile hemangioma
in a 13-month-old infant with multiple other soft-tissue
hemangiomas. Axial contrast-enhanced fat-suppressed
T1-weighted MR image shows a lobulated diffusely en-
hancing mass (white arrow) of the orbit and periorbital
soft tissues. Multiple internal serpentine foci of low signal
intensity are due to flow voids in this high-flow prolifer-
ative-phase infantile hemangioma. The fourth ventricle
appears enlarged (black arrow) due to lack of an inferior
cerebellar vermis. This constellation of findings is consis-
tent with PHACES syndrome. (PHACES = posterior fossa
malformations, hemangioma, arterial anomalies, cardio-
vascular anomalies, eye anomalies, sternal clefting, and/
or supraumbilical raphe.)

8 September-October 2016 radiographics.rsna.org
Figure 3. Enlarging posterior auricular infantile hemangioma in a 10-month-old girl. (a) Photomicrograph shows innumerable
capillaries lined with plump endothelial cells, a typical appearance for a proliferating infantile hemangioma. (Hematoxylin-eosin [H-E]
stain; original magnification, ×200.) Inset: During involution, the lesion shows flattened endothelium, hyalinization of the basement
membrane (arrow), increased intercapillary stroma, and eventual fibrofatty replacement. (H-E stain; original magnification, ×400.)
(b) Photomicrograph shows positivity of the endothelial cells (brown stain), a characteristic feature of infantile hemangioma. (Stain
for GLUT-1; original magnification, ×200.)
as heart failure due to shunting (12,13,17,18).
These lesions are heterogeneous at US and
T2-weighted MR imaging, with intermediate to
low T2 signal intensity internally being due to a
combination of hemorrhage, fibrosis, calcifica-
tion, and/or necrosis. These lesions classically
show early peripheral enhancement, which
becomes more confluent at the lesion margin
with time. However, large central portions of
congenital hemangiomas of the liver will fail to
enhance despite delayed imaging (12,17,18).
Abundant large vessels are frequently seen in
the lesion or along the periphery, and feeding
arteries and draining veins may be markedly
enlarged, with early venous enhancement due to
shunting (12,17,18) (Fig 4).
Histologically, congenital hemangiomas
show varying sized lobules of capillaries inter-
mixed with dilated malformed vessels, foci of
endothelial eosinophilic globules, and foci of
extramedullary hematopoiesis. Unlike in infan-
tile hemangiomas, the endothelial cells within
congenital hemangiomas stain negative for
GLUT-1 (9–11,13,16,17) (Fig 5). To date, no
medical therapy has clearly shown efficacy with
congenital hemangiomas of any type (10,19).
Given their natural history, rapidly involuting
congenital hemangiomas may require no therapy
unless there is associated heart failure or mass
effect, in which case surgical resection or embo-
lization can be employed (although this is best
performed in close consultation with an experi-
enced vascular anomalies center).
Tufted Angioma.—Also called progressive capillary
hemangioma or angioblastoma of Nakagawa, these
lesions are typically cutaneous and are therefore
rarely imaged (with few imaging descriptions
found in the literature). Their importance lies in
their association with the Kasabach-Merritt phe-
nomenon, a profound and sustained coagulopa-
thy in which platelets, fibrinogen, and red blood
cells are trapped by one of two lesions (tufted an-
gioma or the more aggressive kaposiform heman-
gioendothelioma) (4,20). There is speculation
that these two lesions represent a spectrum of the
same neoplasm. At histologic analysis, the tufted
angioma contains distinct “cannonball” clusters
of packed capillaries within the dermis. Spindled
endothelial cells, extravasated red blood cells, and
hemosiderin-laden macrophages may be present.
PROX-1, a lymphatic stain, is immunoreactive
within the endothelial cells (20–22).
Pyogenic Granuloma.—Also called lobular
capillary hemangioma, this variably sized lesion
(which is typically <1 cm) is generally found as
a focal, well-defined superficial lesion in the face
or neck (including the oral or nasal mucosa)
and acral regions (Fig 6). Pyogenic granulomas
are highly vascular with a tendency to ulcerate
and bleed. They frequently occur in association

RG • Volume 36 Number 5 Merrow et al 9
Figure 6. Nasal pyogenic granuloma in a 12-year-old
girl. Axial postcontrast fat-suppressed T1-weighted MR
image shows a well-circumscribed ovoid nodule (arrow)
in the right nostril that largely enhances.
Figure 5. Rapidly involuting congenital hemangioma of the
right forearm/wrist in a 13-month-old boy. Photomicrograph
of the mass shows small dermal lobules of capillaries separated
by fibrous stroma (due to involutional change) surrounding
a dilated malformed vein. (H-E stain; original magnification,
×200.) Inset shows capillaries with moderately plump endo-
thelial cells. (H-E stain; original magnification, ×400.) The lesion
stained negative for GLUT-1.
Figure 4. Rapidly involuting congenital hemangioma in a newborn with a pre-
natally detected hepatic mass. (a) Coronal fat-suppressed T2-weighted MR image
shows a large, exophytic, heterogeneous mass (arrow) projecting inferiorly from
the liver. (b) Coronal postcontrast fat-suppressed T1-weighted MR image, approxi-
mately 20 minutes after contrast material administration during a multiphase ac-
quisition, shows confluent peripheral enhancement with a persistent large central
region of nonenhancement (arrow), typical of a liver congenital hemangioma. Pre-
ceding US showed markedly increased vascularity along the margin of the mass.
with recent trauma, inflammation, and other
vascular anomalies. At histologic analysis, these
acquired lesions show diffuse clusters of capil-
laries admixed with scattered inflammatory cells
(20–23).
Spindle Cell Hemangioma.—It remains unclear
whether this lesion represents a true neoplasm
versus a reactive process secondary to thrombus
in dilated vessels. These lesions are typically pain-
ful and slow growing and most frequently involve
the distal extremities (Fig 7). Additionally, they
may be found in association with lymphedema,
Maffucci syndrome, and Klippel-Trenaunay syn-
drome. Few imaging reports exist. At histologic
analysis, spindle cell hemangiomas contain thin-
walled cavernous vessels with occasional thrombi
that are intermixed with regions with prominent
cellularity containing bland spindled cells that
may be vacuolated (20–22) (Fig 8).
Epithelioid Hemangioma.—While these lesions
are most frequently cutaneous or subcutane-
ous, primary bone lesions may manifest with a
mixture of features inluding destruction and lysis,

10 September-October 2016 radiographics.rsna.org
Figure 8. Spindle cell hemangioma in a 21-year-old woman
with Maffucci syndrome and a chondrosarcoma. Photomi-
crograph shows bland spindled cells (arrows). These cellular
zones were intermixed with a thin-walled venous malforma-
tion with scattered organizing thrombi. (H-E stain; original
magnification, ×200.)
sclerosis, or remodeled expansion. At histologic
analysis, the lesions consist of clusters of ar-
terioles containing damaged endothelial cells
(epithelial-like) surrounded by inflammatory cells
that are predominantly eosinophils (Fig 9). These
lesions lack mitotic activity and may be reactive
rather than neoplastic (20,24,25).
Locally Aggressive
or Borderline Neoplasms
A number of neoplasms are now categorized at
this level (Table 2) with several being extremely
uncommon and beyond the scope of this article.
We will focus on a single clinically important and
infamous lesion in this category.
Kaposiform Hemangioendothelioma.—First
characterized by Zukerberg et al (26) in 1993, this
locally invasive vascular tumor manifests in infancy
in greater than 90% of cases, although cases have
rarely occurred in older adults (27). The common
presentations of this lesion include a true Kasa-
bach-Merritt phenomenon (occurring in 70% of
kaposiform hemangioendothelioma patients) with
or without a clinically apparent mass, an enlarg-
ing cutaneous/subcutaneous mass (typically in
the extremities), or musculoskeletal dysfunction/
pain (4,27). In patients presenting with Kasabach-
Merritt phenomenon, mortality has been reported
to be as high as 30%, although a more realistic
number is likely around 10% (27,28).
This lesion can manifest in virtually any region
or organ, with common locations including the
extremities and retroperitoneum. Regional nodal
spread has been described without true distant
metastases (27,28).
At imaging, kaposiform hemangioendothelioma
is frequently a poorly defined solid cutaneous, sub-
cutaneous, or intramuscular mass with infiltration
of surrounding tissues. Many kaposiform heman-
gioendotheliomas show surrounding edema that is
difficult to separate from tumor margins. The mass
frequently has lobular foci of intermediate or low
T2 signal intensity but may have high T2 signal
intensity diffusely. Diffuse early enhancement is
typical (Fig 10). Prominent vessels are frequently
seen extending up to the lesion but are rarely iden-
tified within the lesion (6–8,20). Less commonly,
the lesion may manifest as a well-circumscribed,
even exophytic mass.
Histologically, kaposiform hemangioendothe-
lioma consists of coalescing lobules of spindled
endothelial cells intermixed with extravasated
red blood cells, hemosiderin, and platelet micro-
thrombi with multiple planes of tissue involved.
Kaposiform hemangioendothelioma typically
stains positive for PROX-1 (a lymphatic marker),
smooth muscle actin (a smooth muscle marker),
CD34 (a stem cell marker), and CD31 (a vas-
cular endothelial marker) and is thus thought to
arise from multiple or polyphenotypic cells (Fig
11). These coalescing lobules are surrounded by
malformed lymphatic channels (20,26,27).
Treatment options must focus on medical
therapies for the underlying lesion, as isolated
attempts to correct the coagulopathy with
products can worsen the lesion. Platelet infusion
notoriously will cause enlargement of the mass
with pain. This is believed to be secondary to
consumption and trapping of the products but
also related to proangiogenic factors secreted by
platelet granules. Successful medical therapies
have included steroids in combination with either
Figure 7. Spindle cell
hemangioma in a teen-
age patient with soft-
tissue masses about the
foot and ankle. Coro-
nal fat-suppressed T2-
weighted MR image of
the ankle shows portions
of a lobular fluid-signal-
intensity mass contain-
ing a small central focus
of low signal intensity
(arrow), which corre-
sponded to a phlebolith
at radiography. Phlebo-
liths are found in spindle
cell hemangioma due
to abnormal venous
components.

RG • Volume 36 Number 5 Merrow et al 11
Figure 9. Epithelioid hemangioma in a 13-year-old boy with elbow pain and swelling after a recent fall.
(a) Sagittal fat-suppressed T2-weighted MR image of the elbow shows a heterogeneous intra-articular
mass (black arrows) splaying the joint capsule and invading the adjacent humerus (white arrow) and
radius. There is marked surrounding soft-tissue edema. (b) Photomicrograph shows abundant capillaries
lined by epithelioid endothelial cells mixed with a chronic inflammatory infiltrate composed predomi-
nantly of eosinophils. (H-E stain; original magnification, ×400.)
vincristine or sirolimus (27–29). Embolization
has been used with varying success in the setting
of prominent feeding vessels. While complete sur-
gical excision is curative, it is rarely possible due
to the frequently infiltrative nature of the lesion
into multiple compartments as well as the associ-
ated coagulopathy. Limb amputation has rarely
but successfully been used in the setting of an
isolated extremity lesion that cannot be medically
controlled in a critically ill patient (27–29).
Malignant Neoplasms
Angiosarcoma.—Only 2% of vascular tumors
are malignant, with angiosarcoma representing
0.5% of all pediatric sarcomas. Angiosarcomas
may arise in the setting of preexisting vascular
anomalies, chronic lymphedema, or toxic expo-
sures, and have been reported in many locations
throughout the body (30,31). Many hepatic cases
have been reported, with multifocal nodules
frequently found in the setting of a dominant
mass. At MR imaging, these lesions often have
hemorrhagic components with high T1 and low
T2 signal intensity plus internal fluid-fluid levels
due to layering blood products (31,32) (Fig 12).
Up to 27% of patients present with tumor rup-
ture and hemoperitoneum. Approximately 60%
have metastases at presentation. The prognosis is
dismal, with a 5-year survival of only 25%–30%
in adults who do not have metastases at presenta-
tion (30–32).
At histologic analysis, angiosarcomas con-
sist of anastomosing vascular channels lined by
atypical endothelial cells. Larger volumes of solid
areas correlate with higher lesion grades. The
Figure 10. Kaposiform heman-
gioendothelioma in a 2-week-
old boy with a purple calf mass.
(a) Transverse US image shows
a poorly defined infiltrative mass
(arrows) extending from the skin
and subcutaneous tissues into the
gastrocnemius muscle. (b) Axial
postcontrast fat-suppressed T1-
weighted MR image shows diffuse
enhancement of the mass (arrows),
which has broader superficial than
deep involvement. The degree of
gastrocnemius infiltration is better
defined on this image. Popliteal
adenopathy was noted as well.

12 September-October 2016 radiographics.rsna.org
Figure 11. Kaposiform hemangioendothelioma in a 1-week-old patient with a neck mass. (a) Photomicrograph shows coalescing
lobules of spindled endothelial cells and extravasated red blood cells. (H-E stain; original magnification, ×100.) Inset highlights the
spindled endothelial cells and extravasated red blood cells. (H-E stain; original magnification, ×400.) (b) PROX-1, a lymphatic marker,
is immunoreactive within the spindled endothelial cells. (Original magnification, ×400.)
endothelial cells are immunoreactive to CD34
and CD31 and show a high proliferative index
(Ki-67) (30–32).
Epithelioid Hemangioendothelioma.—This
uncommon vascular malignancy is frequently
hepatic in origin but may occur in a variety of
locations. Imaging descriptions include multiple
hepatic nodules with progressive peripheral to
central enhancement. Unlike other vascular tu-
mors in the liver, however, a hypoenhancing and
low T2 signal intensity rim has been reported,
creating a target or layered appearance. Addition-
ally, the lesion frequently causes capsular retrac-
tion of the liver (Fig 13). Calcifications are found
in 20% of cases (32–35).
At histologic analysis, these lesions have a
fibromyxocollagenous stroma with haphazardly
arranged atypical epithelioid tumor cells with
focal intracytoplasmic vacuoles containing red
blood cells (20). These tumor cells are posi-
tive for vascular endothelial markers including
CD34 and CD31.
This lesion has a variable clinical course and is
frequently more indolent than angiosarcoma, oc-
casionally waxing and waning spontaneously over
years. No standard chemotherapy regimen has been
adopted, although angiosarcoma regimens may be
employed. Liver transplant has occasionally been
used, even with pulmonary metastases, due to the
indolent course in some patients. Five-year sur-
vival has been reported to be up to 73%. Genetic
mutations have been described in this lesion with
WWTR1-CAMTA1 and YAP1-TFE3 translocations
found to date, potentially creating opportunities for
more targeted medicines (5,20).
Vascular Malformations
Vascular malformations are a heterogeneous
group of lesions that are typically congenital er-
rors of vessel morphogenesis. They demonstrate
cellular turnover without true proliferation, gen-
erally growing commensurate with the patient.
However, the lesions may grow rapidly at times
of hormonal stimulation, including puberty and
pregnancy, as well as when complicated by hem-
orrhage (often in the setting of minor trauma) or
infection (1,2,6,7).
Simple Malformations
Capillary Malformation (Table 3).—This lesion
represents the most common type of vascular
malformation but one of the most infrequently
imaged due to its predominant manifestation as
an isolated cutaneous patch of discoloration (6).
Examples include port-wine stain, salmon patch,
and telangiectasia. Histologic analysis reveals
haphazardly arranged capillaries within the cuta-
neous tissues (2) (Fig 14).
As an isolated lesion, imaging may be normal
or show only mild skin thickening and enhance-
ment. However, capillary malformations of
particular size or distribution have an increased

RG • Volume 36 Number 5 Merrow et al 13
Figure 13. Epithelioid hemangioendothelioma of the liver in
a 24-year-old woman. (a) Axial portal venous phase postcon-
trast fat-suppressed T1-weighted MR image shows numerous
hypointense liver lesions with mild enhancement in a layered
or target-like pattern (arrows) that did not substantially change
over time. T2-weighted images showed a hypointense rim to
the lesions and overlying liver capsule retraction. (b) Photomi-
crograph from one of the hepatic lesions shows a fibromyxo-
collagenous stroma with haphazardly arranged atypical epithe-
lioid tumor cells with focal intracytoplasmic vacuoles contain-
ing red blood cells. (H-E stain; original magnification, ×400.)
Figure 12. Angiosarcoma in a newborn with skin lesions
and sonographically detected liver masses. (a) Axial fat-
suppressed T2-weighted MR image shows numerous well-
defined lesions throughout the liver (arrows), some of which
are homogeneously hyperintense while others contain layer-
ing fluid-fluid levels (consistent with internal hemorrhage).
After contrast material administration, a few of the homo-
geneous lesions demonstrated vigorous enhancement while
most of the lesions did not. Scattered intramuscular lesions
were also noted. (b) Photomicrograph from biopsy of a skin
lesion in the same patient shows anastomosing slit-like vas-
cular channels with endothelial atypia. (H-E stain; original
magnification, ×400.)
likelihood of underlying anomalies of clinical
significance and necessitate further imaging
investigation (2,5). Capillary malformations over
the spine can implicate underlying spinal anoma-
lies including cord tethering. The classic facial
port-wine stain, particularly that in a V1 distribu-
tion, merits intracranial imaging assessment for
features of Sturge-Weber syndrome, which may
be associated with epilepsy (and has been found
to have a GNAQ mutation). MCAP is an associa-
tion of megalencephaly with capillary malforma-
tion and polymicrogyria. Hereditary hemorrhagic
telangiectasia (HHT) is another phenotype of
pulmonary and intracranial AVMs in association
with mucosal telangiectasias (and known muta-
tions of ENG, ACVRL1, SMAD4, and GDF2).
HHT may also involve the liver and bowel (2,5).
Venous Malformation (Table 4).—One of the
two most common slow- or low-flow vascular
malformations to be imaged, venous malforma-
tions may manifest clinically and radiologically

14 September-October 2016 radiographics.rsna.org
Figure 14. Capillary malformation in a 3-month-old patient
with a port-wine stain of the cheek. Photomicrograph shows
haphazardly arranged capillaries in the papillary dermis. (H-E
stain; original magnification, ×200.)
as single or multifocal discrete lobular masses,
isolated versus extensive abnormal tubular
channels, or a combination of these appearances
(6–8). These lesions are typically soft, compress-
ible, and nonpulsatile and may be associated
with bluish skin discoloration. The Valsalva ma-
neuver will typically cause engorgement of these
masses. Thrombi or phleboliths within the lesion
may create focal nodules that are firm or hard
to palpation (36). Smaller lesions may be clini-
cally occult except for intermittent self-limited
episodes of swelling or pain due to intralesional
thrombosis, hemorrhage, or inflammation. A
sentinel episode will often lead an older child or
teenager to seek medical attention that leads to
an imaging workup. Other lesions will be more
widespread and apparent from birth or even in
the prenatal period.
Certain coagulation complications may occur
with this lesion. Intramuscular, multifocal, and dif-
fuse venous malformations are frequently associ-
ated with a localized intravascular coagulopathy
with a high D-dimer level and low (or low normal)
fibrinogen level. This can lead to disseminated in-
travascular coagulopathy if there is extensive local-
ized intravascular coagulopathy or in the setting of
some procedures without proper treatment before
and after the procedure (2,5,36). Large varices
that may occur in isolation or as part of an exten-
sive extremity malformation (often in the setting
of an abnormal deep venous system) may lead to
thromboembolism. Venous malformations about a
joint may extend into the joint capsule (correctly
termed synovial venous malformation, not synovial
hemangioma) and lead to repeated hemarthroses
with cartilage destruction and erosions mimicking
hemophilic arthropathy (36,37).
Isolated or confluent extensive venous malfor-
mations generally appear as lobulated fluid-sig-
nal-intensity masses throughout the soft tissues.
Clusters of tubular channels demonstrating
stagnant flow will appear as multiseptated fluid-
signal-intensity masses. Numerous thin septa will
be present, and fat is frequently visible along the
margins of the lesion or extending along septa.
The stagnant blood within the cavities or chan-
nels will frequently result in multiple fluid-fluid
levels within the mass, either at different heights
or occasionally as a gradient across the entire le-
sion (6–8). These layering fluid-fluid levels within
a lesion are highly suggestive of the dependent
settling of blood products within a stagnant
cavity. When multiple such levels are visible in a
soft-tissue mass in a child, a slow-flow vascular
malformation (ie, either venous or lymphatic)
should be the primary consideration, although
such an appearance may occur infrequently in
other pediatric lesions, including hemorrhage
within a malignancy, and must be considered in
the context of the other imaging features.
Thrombi will be dark on T2-weighted images
and may be bright on T1-weighted images, al-
though phleboliths will be dark with all sequences
due to calcifications (6–8). When well-defined
round calcifications are scattered within a pediat-
ric soft-tissue mass, a venous malformation is the
most likely cause. Radiographs typically provide
confirmation of the characteristic phlebolith ap-
pearance (Fig 15).
With contrast agent, the lesions may show an
early blush at four-dimensional MR angiography,
although gradual puddling of contrast material in
the lesion over time is the rule. Venous malforma-
tions generally show complete or near complete
enhancement except for regions of thrombosis or
lymphatic components.
Abnormal long tubular venous channels (and
the potentially abnormal deep venous system) may
be more easily assessed with MR imaging/venogra-
phy than US due to the complexity and number of
channels. Time-of-flight imaging will show variable
flow-related enhancement depending on the size
and rate of flow within these abnormal channels,
with most smaller channels and discrete masses
not showing bright signal with such sequences.
However, time-of-flight images are time-consum-
ing and plagued by artifact of slow flow and in-
plane signal loss mimicking occlusion/thrombosis.
Rapid imaging with postcontrast fat-suppressed
spoiled gradient-echo or Dixon sequences will
yield excellent venous visualization, particularly if
a blood pool contrast agent is used (38).

RG • Volume 36 Number 5 Merrow et al 15
Figure 15. Venous malformation in a 9-year-old girl with a compressible upper arm soft-tissue mass
since birth who presented with pain and swelling. (a) Lateral radiograph of the humerus shows numer-
ous phleboliths at the site of soft-tissue swelling, confirming a venous component to the mass (most of-
ten a venous malformation and not a hemangioma in a child). (b) Coronal fat-suppressed T2-weighted
MR image shows the multiseptated mass of predominantly increased fluid signal intensity. A round low
signal intensity focus (arrow) corresponds to one of the phleboliths. Fat was seen along the margins of
the lesion and a few septa on T1-weighted images, virtually ensuring benignity in a soft-tissue mass in
a child under 10 years of age.
Histologic analysis demonstrates large, mal-
formed, irregular venous channels with mus-
cular walls (lacking an internal elastic lamina
found in arteries) and containing internal orga-
nizing thrombi (Fig 16). Approximately 94% of
all venous malformations fall into the isolated/
sporadic/common type with approximately
50% having a TIE2 mutation (36). Typical
therapies for these lesions include compression
garments, anti-inflammatory medications, and
low-molecular-weight heparin. Sclerotherapy
and/or surgical excision are reserved for cases
of failed conservative management (36).
When multifocal venous malformations are
scattered throughout the body, blue rubber bleb
nevus syndrome should be considered. These
patients frequently have gastrointestinal bleed-
ing due to mucosal lesions of the gut (36). Lim-
ited reports have suggested a role for MR imag-
ing in detecting intestinal venous malformations
in blue rubber bleb nevus syndrome, although
capsule endoscopy is likely a more sensitive
method for screening the entire gastrointestinal
tract for very small lesions (39,40).
The glomuvenous malformation (gloman-
gioma) consists of malformed venous channels
lined by multiple layers of glomus cells (Figs 17,
18). The mass is due to a glomulin mutation on
1p21–22 and typically manifests as painful and
firm multifocal congenital skin nodules with a
“cobblestone” configuration (2,5,36,41,42).
However, up to 50% of affected patients may
show deeper subfascial involvement at imaging
(41). Phleboliths are uncommon. Time-resolved
MR angiography may show subtle foci of early
enhancement with venous shunting (42).
Other simple venous malformations include
cerebral cavernous malformation (cavernoma)
(2,5,36). Mutations may be found in KRIT1,
malcavernin, or PDCD10 with inherited syn-
dromes of CCM1, CCM2, or CCM3, respec-
tively (2,5). Cerebral cavernous malformations
frequently manifest with seizures in the setting of
minor hemorrhages, with life-threatening hemor-
rhages being less common than in AVMs.
Lymphatic Malformation (Table 5).—The
simple lymphatic malformation is a mass of
endothelial-lined channels lacking muscularized
walls that stain positive for lymphatic markers
such as PROX-1 and D2-40 (43). These lesions
range greatly in size and vary from focal well-
defined multicystic masses to infiltrative poorly
defined more solid-appearing lesions. Discrete
cysts measuring more than 1–2 cm are referred
to as macrocysts and show multiple thin-walled
rims and septa with minimal enhancement.
Many of these cysts contain fluid-fluid levels,

16 September-October 2016 radiographics.rsna.org
Figure 17. Glomuvenous malformation in a teenage
patient with firm painful skin nodules. Coronal postcon-
trast fat-suppressed T1-weighted MR image shows su-
perficial nodular clusters of enhancing abnormal vascu-
lar channels in the medial left lower extremity. No high
flow was seen in the lesions at flow-sensitive imaging.
Figure 16. Venous malformation in a 3-year-old boy with a
scrotal lesion. Photomicrograph shows large malformed vessels
with muscularized walls lined by flat endothelial cells that lack
atypia. PROX-1 immunostain (a lymphatic marker) was nega-
tive. (H-E stain; original magnification, ×40.)
particularly after rapid growth due to hemor-
rhage (6–8,43). Internal components may be
T1 bright, particularly with fat suppression,
although fat signal intensity may occasionally
occur within the lesional fluid. Microcystic
lesions appear more solid at imaging and may
show diffuse enhancement.
These subtypes often coexist and frequently
extend through multiple soft-tissue compartments
(6–8). While they may occur anywhere, the ante-
rior neck is a classic location, with superficial and
deep involvement frequently extending from the
scalp to the airway and mediastinum (Figs 19, 20).
Bilateral face/neck involvement is typical and can
help distinguish these congenital masses from cer-
vical teratomas. The airway is frequently affected
by these lesions, including tracheal compression
and tongue infiltration (43). Similar to venous
malformations, smaller or more internal lymphatic
malformations may be occult until complexity oc-
curs later in life.
Depending on the specifics of the lesion, surgi-
cal therapy may be employed in treating lym-
phatic malformations; however, as with several
other vascular lesions, complete surgical excision
is often not possible due to the extensive and
infiltrative nature of many lymphatic malforma-
tions. Sclerotherapy can be used successfully with
macrocystic components, employing a variety
of sclerosing agents (43). Medical therapy with
sirolimus has shown promise in microcystic lym-
phatic malformations, demonstrating radiologic
and clinical improvement in treated patients (44).
Generalized lymphatic anomaly variably shows
multifocal well-circumscribed lesions of the spleen,
bones, and soft tissues with pleural effusions fre-
quently present (Fig 21). Genetic mutations have
been found in CCBE1 and PIK3CA (2,5). Frank
bone destruction is not expected in generalized
lymphatic anomaly but points to Gorham-Stout
disease, where progressive regional osteolysis is
due to an infiltrative lymphatic malformation and
osteoclastic activity (Fig 22). In Gorham-Stout
disease, visceral involvement and macrocystic
lymphatic malformations are less frequent than in
generalized lymphatic anomaly (45,46).
Central conducting lymphatic anomalies, or
channel-type disorders, result in failed clearance
of lymph due to obstruction or dysmotility of
channels. The first clinical and imaging find-
ings to be appreciated are typically secondary
manifestations surrounding sites of failed lymph
transport. These include chylous accumulations
(eg, pleural effusions, ascites), pulmonary lym-
phangiectasia, or body wall or extremity edema.
Bowel wall edema and protein-losing enteropa-
thy with diarrhea may also occur (46). Injection
of lymph nodes proximal to the channel abnor-
mality will show (at fluoroscopy, nuclear medi-
cine, or MR lymphangiography) lack of normal
central drainage with obstruction and collaterals
or potentially a leak (47).
Primary lymphedema is a poorly understood
abnormality that cannot clearly be traced back
to a central channel-type disorder. Genetic
mutations have been associated with specific
phenotypes including Nonne-Milroy syndrome
(FLT4/VEGFR3), primary hereditary lymph-
edema (VEGFC), and lymphedema with myelo-

RG • Volume 36 Number 5 Merrow et al 17
Figure 19. Predominantly macrocystic lymphatic
malformation in a newborn. Axial fat-suppressed T2-
weighted MR image shows a large superficial multi-
cystic mass arising from the anterior neck. Many of the
compartments contain fluid-fluid levels (arrows) due to
layering blood products. Some cysts show greater inter-
nal heterogeneity due to retracted clot. Images through
other levels showed deeper infiltration of the lesion
across tissue planes of the neck.
Figure 18. Glomuvenous malformation in a 17-year-old
boy with lesions of the right thigh, right knee, and abdomen.
Photomicrograph shows malformed venous channels lined by
a proliferation of glomus cells (arrows). The glomus cells are
immunoreactive to smooth muscle actin. (H-E stain; original
magnification, ×20.)
dysplasia (GATA2) (2,5,46,48). The primary im-
aging manifestation of lymphedema is extensive
reticular foci of increased fluid signal intensity
throughout the subcutaneous fat (48). In severe
cases, poorly defined fluid accumulations may
develop in dependent areas. No well-defined
fluid collections, cysts, or masses should be
seen. Additionally, the underlying veins should
be normal. However, it remains to be seen
whether localized or central lymphatic anoma-
lies have a role in this phenotype.
Arteriovenous Malformation (Table 6).—This
lesion is one of the few true high-flow or fast-
flow vascular malformations and may occur
sporadically or in association with syndromic
forms including HHT (with pulmonary and brain
AVMs) or in association with capillary malforma-
tions (2,5,49). Causative mutations have been
established in the genes for HHT1 (ENG), HHT2
(ACVRL1), HHT5 (SMAD4), HHT with juvenile
polyposis (GDF2), and HHT with capillary mal-
formation (RASA1). Complex communications
of primitive arteries and veins result in shunting
of oxygenated blood away from intended tissues.
Symptoms may include ulceration, pain, ischemia,
bleeding, and heart failure. Clinically, these lesions
are warm with a bruit or thrill (49).
At imaging, these lesions classically consist
of tangles of enlarged arteries and veins. One
or more enlarged feeding arteries and one or
more enlarged draining veins are typically as-
sociated with a cluster of malformed high-flow
vessels (Figs 23, 24). Doppler US shows low-
resistance arterial waveforms with arterialized
venous waveforms. CT angiography can show
detailed arterial and venous anatomy for inter-
vention planning. MR imaging classically shows
numerous flow voids on spin-echo images and
flow-related enhancement on gradient-echo and
time-of-flight images. Due to shunting, associ-
ated draining veins show early enhancement
relative to adjacent uninvolved veins and are
best elucidated with four-dimensional time-
resolved MR angiography (6–8).
Classic teaching is that no significant sur-
rounding soft-tissue mass should be seen. How-
ever, recent work confirms that soft-tissue AVMs
of the extremities may be associated with sur-
rounding edema, enhancement, and fibrofatty
change without meeting requirements for other
lesions such as tumor or hamartoma (49,50). In
the brain, AVMs show parenchymal loss without
mass effect (in the absence of a hemorrhage) and
may be associated with an aneurysm (most com-
monly of a feeding artery but rarely of a draining
vein). Of note, the pulmonary AVMs found in
HHT appear more like arteriovenous fistulas,
with directly connecting pulmonary arteries and
veins but no intervening capillary bed (51).
Arteriovenous Fistula.—Fistulas are direct com-
munications that most commonly occur secondary
to trauma, particularly iatrogenic such as biopsy or

18 September-October 2016 radiographics.rsna.org
Figure 20. Lymphatic malformation in a 2-year-old boy with a neck mass. (a) Photomicrograph shows malformed microcysts lined
by round endothelial cells. (H-E stain; original magnification, ×200.) (b) PROX-1, a lymphatic marker, highlights the endothelium in
a macrocyst. (Original magnification, ×200.)
vascular cannulation. They may rarely be congeni-
tal, with two typical such lesions being the vein of
Galen malformation and a hepatic arterioportal
fistula. Dural arteriovenous fistulas tend to be
acquired and have been shown to be related to ce-
rebral venous thrombosis (52). The classic imaging
manifestations include enlargement of a feeding
artery/arteries and associated draining veins with-
out an intervening nidus. The classic US findings
of a fistula include perilesional tissue vibration,
aliasing, and venous arterialization (6–8). It is
helpful to decrease the Doppler sensitivity of the
interrogated organ to bring out the abnormal high
flow of an arteriovenous fistula.
Combined Malformations
Combinations of all types of vascular malforma-
tion occur (Table 7) with intermixed features
of the simple malformations described earlier.
Combined lesions are frequently extensive
throughout a limb and portions of the trunk and/
or head/neck. Combined malformations contain-
ing venous components may have abnormalities
of underlying deep veins throughout a limb, with
resulting large abnormal deep and superficial
venous channels (53,54). These patients have nu-
merous long-term pain and functional issues with
quality-of-life improvements noted on sirolimus
therapy beyond the imaging response.
Anomalies of Major Named Vessels
A variety of abnormalities can affect major
named vessels (Table 8), including alternate
origin, course, number, length, diameter (such as
Figure 21. Generalized lymphatic anomaly in
a 5-year-old boy who presented with shortness
of breath and had radiographic abnormalities of
pleural effusions and lucent bone lesions. Coro-
nal short t inversion-recovery (STIR) MR image
shows numerous well-circumscribed lobular
fluid-signal-intensity lesions of the bones (solid
arrows) without cortical destruction. Large pleu-
ral effusions and numerous splenic lesions (dot-
ted arrow) are also identified.

RG • Volume 36 Number 5 Merrow et al 19
Figure 23. AVM of the thumb in a 22-year-old patient with increasing pain. (a) Pulsed Doppler US image through the soft tissues
of the thumb shows a tangle of high-flow vessels with low-resistance arterial waveforms. (b) Arteriogram shows opacification of the
nidus (white arrow). Due to shunting, there is early washout of the radial artery and early opacification of the radial vein (solid black
arrow) while the ulnar artery remains partially opacified (dotted arrow).
aplasia, hypoplasia, focal stenosis, ectasia, or an-
eurysm), valves, communication, and persistent
embryonic veins (2,5). Examples include the Ab-
ernethy malformation (with partial or complete
congenital absence of the portal vein), carotid
artery anomalies associated with PHACES syn-
drome, sciatic vein persistence, and vein of Galen
malformation. It is critical to look for nearby
upstream/downstream causes of such vascular
anomalies (such as nearby venous occlusion caus-
ing collaterals or an arteriovenous fistula causing
dilated vessels) rather than assuming that they are
isolated congenital malformations.
Malformations
Associated with Other Anomalies
An evolving list of syndromic malformations has
been incorporated into the classification scheme
(Table 9) (2,5). Representative forms include the
following syndromes: Klippel-Trenaunay (over-
growth associated with extensive capillary-venous-
lymphatic anomaly), Parkes Weber (overgrowth
Figure 22. Gorham-Stout disease (van-
ishing bone disease) in a preadolescent
boy with hand pain. Posteroanterior radio-
graph shows extensive bone involvement
with remodeling of the second, fourth,
and fifth metacarpals and near-complete
osteolysis of the third metacarpal, result-
ing in a shortened third digit. Erosive-type
changes are also seen in the distal carpal
bones. Follow-up radiographs demon-
strated progressive bone destruction.

20 September-October 2016 radiographics.rsna.org
Figure 24. AVM of the cheek in a 6-year-old patient after embolization. (a) Photomicrograph shows skeletal muscle fibers inter-
mixed with malformed arteries containing onyx material as well as a malformed vein and a brisk capillary angioproliferative compo-
nent. (H-E stain; original magnification, ×20.) (b) Photomicrograph with elastic stain highlights the disruption of the elastic lamina
characteristic of arteries. (Verhoeff–van Gieson stain; original magnification, ×400.)
with capillary-arterial-venous anomaly), Sturge-
Weber (facial capillary stain with seizures due to
intracranial manifestations of abnormal cerebral
venous drainage), Maffucci (enchondromatosis
with soft-tissue venous malformations and spindle
cell hemangiomas), and CLOVES (congenital
lipomatous overgrowth with vascular malforma-
tions, epidermal nevi, and skeletal anomalies) (Fig
25) (2,5,53,54). The major importance of this list
lies in pursuing further patient workup for other
syndromic features once a typical manifestation
is recognized so that appropriate counseling and
intervention may take place in a timely fashion.
Provisionally
Unclassified Vascular Anomalies
Lesions in this category include poorly under-
stood focal or multifocal masses with or without
other tissue/organ anomalies (Table 10). These
lesions generally have overlapping features of
both neoplasm and congenital malformation.
Select lesions include the following:
Kaposiform Lymphangiomatosis.—This un-
common but distinct lymphatic anomaly almost
always affects the thorax, with mediastinal, lung,
and pleural involvement seen most commonly
(46,55,56). Pleural and/or pericardial effusions
are frequently present. The spleen and bones are
also involved in approximately 50% of cases each,
Figure 25. CLOVES syndrome in an in-
fant. Coronal short t inversion-recovery
(STIR) whole-body MR image shows
numerous foci of lymphatic anomaly
(solid arrows) intermixed with regions
of overgrowth and discrete fatty masses
(dotted arrow).

RG • Volume 36 Number 5 Merrow et al 21
Figure 27. Kaposiform lymphangiomatosis in a 24-year-
old man with pericardial and pleural effusions. Photomicro-
graph of the specimen from a lung wedge biopsy shows
dilated malformed lymphatic channels within the pulmo-
nary septa with clustered foci of intra- and perilymphatic
short spindled cells (arrow) intermixed with extravasated
red blood cells and foci of hemosiderin. This spindled area
was immunoreactive for the lymphatic marker PROX-1. (H-E
stain; original magnification, ×40.)
Figure 26. Kaposiform lymphangiomatosis in a teenage girl
with shortness of breath and coagulopathy. Coronal contrast-
enhanced chest CT image shows poorly defined, hazy fluid
attenuation expanding the mediastinal and hilar soft tissues
(arrows) due to abnormal lymphatics. Other images demon-
strated bilateral pleural disease plus peribronchial and inter-
lobular septal thickening.
with less frequent involvement of the subcu-
taneous tissues and retroperitoneum. Patients
frequently present with gradual onset of respira-
tory problems, hemorrhage (due to an associated
coagulopathy), or a mass, with a median age at
presentation of 6.5 years (46,55,56).
At imaging, kaposiform lymphangiomatosis
shows infiltrative, poorly defined lesions of fluid
attenuation/signal intensity that cause soft-tissue
expansion and adjacent fluid accumulation.
Peribronchial and interlobular septal thickening
of the lung parenchyma is usually present (Fig
26). The abnormal soft tissue is bright on T2-
weighted MR images, with variable enhancement
after contrast agent administration. However,
discrete macroscopic cysts are rarely identified
(unlike in generalized lymphatic anomaly, where
typical macrocystic lymphatic malformations are
frequently present) (55,56). Splenic involvement
ranges from minimal (with a few small cysts in a
normal-sized spleen) to severe (with cystic lesions
filling an enlarged spleen). Bone lesions most
commonly affect vertebral bodies, with typical
lesions being described as lucent without frank
cortical destruction (46,55,56).
At histologic analysis, kaposiform lymphangi-
omatosis shows malformed lymphatic channels
with intra- and perilymphatic spindle cells that
stain positive for PROX-1 and D2-40 (lymphatic
markers). Foci of intermixed hemosiderin-laden
macrophages and extravasated red blood cells are
typical (Fig 27).
To date, the prognosis has been poor, with a
5-year survival of approximately 50%. Improved
outcomes have been reported with vincristine
and sirolimus (55,56).
PTEN Hamartoma of Soft Tissue.—The phos-
phatase and tensin homolog protein (PTEN) is
a tumor suppressor gene product encoded from
chromosome 10q23.3. Patients with mutations
in the PTEN gene have a variety of phenotypic
manifestations, including Cowden and Bannayan-
Riley-Ruvalcaba syndromes. Clinical charac-
teristics include macrocephaly, penile freckling,
developmental delay, and benign and malignant
tumor predisposition. A variety of vascular and
fatty hamartomatous lesions, including high- and
low-flow masses, are now grouped as PTEN ham-
artomas of soft tissue (53,57,58) (Figs 28, 29).
Verrucous Hemangioma.—This uncommon
superficial vascular lesion, which occurs most
frequently in the extremities of young children,
is prone to bleeding and infection due to its
warty growth. Unlike angiokeratoma, this lesion
extends into the subcutaneous fat (21). Imaging
reports are sparse.
Multifocal Lymphangioendotheliomatosis with
Thrombocytopenia/Cutaneovisceral Angioma-
tosis with Thrombocytopenia.—A small number
of infants with benign cutaneous and gastrointes-
tinal proliferative vascular lesions associated with
thrombocytopenia have been described as having
both multifocal lymphangioendotheliomatosis

22 September-October 2016 radiographics.rsna.org
Figure 29. PTEN hamartoma in a 12-year-old girl with a soft-
tissue lesion of the right knee. Photomicrograph of the lesion
shows excessive fibroadipose tissue with clusters of concentri-
cally thick-walled arteries, pulmonary alveolar–like clusters of
lymphatic channels (arrows), and foci of myxoid degeneration.
(H-E stain; original magnification, 340.)
Figure 28. PTEN hamartoma in a 12-year-old boy with pe-
nile freckling, macrocephaly, and a shoulder mass. Subtracted
postcontrast four-dimensional MR angiogram shows large mal-
formed arteries and veins at the level of the mass. Fat-sensitive,
fluid-sensitive, and postcontrast soft-tissue sequences revealed
lipomatous and enhancing soft-tissue components to the mass.
with thrombocytopenia (MLT) and cutaneovis-
ceral angiomatosis with thrombocytopenia (CAT).
These conditions typically manifest as numerous
congenital plaques, macules, and papules with
onset of gastrointestinal hemorrhage in infancy.
Radiologic testing has not played a significant role
in diagnosis of these patients to date, although
complications (including multiple reports of
intracranial hemorrhage) have warranted imaging
and could raise the possibility of this diagnosis in
the correct clinical setting (59–61). Imaging may
prove useful in screening for lesions in other loca-
tions (such as the lungs).
Conclusion
Vascular anomalies cover a wide spectrum of
lesions predominantly affecting children but,
in many cases, creating lifelong sequelae with
varying severities. This group of lesions ranges
from benign to malignant, simple to complex,
isolated to syndromic, and unifocal to multifo-
cal to diffuse. The 2014 revised classification
of the International Society for the Study of
Vascular Anomalies serves as an evolving frame-
work for understanding lesion phenotype and
genotype in order to provide accurate diagnosis,
risk stratification, and intervention as well as
study potential therapies. Radiologist familiarity
with this evolving classification, particularly in a
multidisciplinary partnership with clinicians and
pathologists experienced with these lesions, will
facilitate appropriate diagnostic and therapeutic
recommendations for affected patients.
Acknowledgment.—We would like to thank Chris Woods, Di-
vision of Pathology and Laboratory Medicine, Cincinnati Chil-
dren’s Hospital Medical Center, Cincinnati, Ohio, for techni-
cal support with the histologic images.
Disclosures of Conflicts of Interest.—A.C.M. Activities related
to the present article: disclosed no relevant relationships. Activi-
ties not related to the present article: personal fees from Amirsys/
Elsevier. Other activities: disclosed no relevant relationships.
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