Hemangioma Versus Vascular Malformation
Presence of Nerve Bundle Is a Diagnostic Clue for Vascular Malformation
Patrick A. Adegboyega, MD; Suimin Qiu, MD, PhD
Context.Arteriovenous vascular malformations and
hemangiomas are benign vascular lesions that are difficult
to distinguish from one another clinically. Also, they may
be confused with each other at histopathology. Therefore,
histochemical stains for the presence of an artery are fre-
quently used to distinguish between the two.
Objective.Because it is clinically relevant to differen-
tiate between arteriovenous vascular malformations and
hemangiomas, this study was carried out to explore addi-
tional diagnostic clues that may help in the diagnosis and
differentiation of these lesions.
Design.A total of 167 cases of benign extracranial vas-
cular lesions were retrieved from the anatomic pathology
file of our institution. These comprised 66 cases diagnosed
as arteriovenous vascular malformations and 101 cases
previously diagnosed as hemangiomas. The hematoxylin-
eosinstained glass slides were reviewed, Movat penti-
chrome histochemical stain was used to identify elastic
vessels (arteries/arterioles), and S100 immunostain was
used to identify nerves within these vascular lesions. For
immunohistochemistry, the avidin-biotin detection method
was used.
Results.With Movat stain, the presence of thick-walled
V ascular lesions are very common, with vascular tu-
mors constituting the most common tumors in child-
hood.1 The diagnosis and treatment of these lesions in-
volve several medical subspecialties, including surgeons,
radiologists, internists, and histopathologists. The diag-
nosis and management of vascular lesions continue to pre-
sent diagnostic and therapeutic challenges to all. This is
in part because of lack of agreement regarding the nosol-
ogy and classifications of the lesionsboth for diagnostic
and therapeutic purposes.2 Many authors use the term
hemangioma to describe or qualify vascular malformations
and a potpourri of vascular anomalies, whereas others
continue to use the term cavernous hemangioma for venous
malformation and port-wine stain for capillary malforma-
tion,3 venous malformation, and arteriovenous malforma-
tions (AVMs),4 thus perpetuating the nosologic confusion
Accepted for publication January 17, 2005.
From the Department of Pathology, University of Texas Medical
Branch, Galveston.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Patrick A. Adegboyega, MD, Department of Pathology, Uni-
versity of Texas Medical Branch, 2.190 John Sealy Annex, 301 Uni-
versity Blvd, Galveston, TX 77555-0588 (e-mail: paadegbo@utmb.edu).
772 Arch Pathol Lab MedVol 129, June 2005
elastic arteries was detected in 12 of the 101 cases previ-
ously diagnosed as hemangiomas, and these cases were
therefore reclassified as vascular malformations. Using the
same criterion, 2 of the 66 cases originally diagnosed as
arteriovenous vascular malformations were reclassified as
hemangiomas because they lacked arterial structures. Thus,
with this strict criterion, we ended up with 91 cases of
hemangiomas and 76 cases of arteriovenous vascular mal-
formations. Intralesional nerves were identified in 91%
(69/76) of cases of arteriovenous vascular malformations,
including all the 12 arteriovenous vascular malformations
previously diagnosed as hemangiomas. In contrast, no in-
tralesional nerve was detected in any of the 91 hemangi-
omas.
Conclusions.These results show that nerve bundles are
consistently present in vascular malformations and absent
in hemangiomas and so can be used as a diagnostic clue
to differentiate between these lesions. Also, in addition to
describing a previously unreported component of vascular
malformations, these data further confirm the hamartoma-
tous nature of these lesions.
(Arch Pathol Lab Med. 2005;129:772775)
and the attendant problems. A simple 2-tier classification
system proposed by Mulliken and Glowacki5 in 1982,
which was later modified and adopted by the Internation-
al Society for the Study of Vascular Anomalies,6 has
helped simplify the clinical classification and management
of the lesions. However, the diagnosis and pathogenesis of
these lesions continue to challenge histopathologists, who
are often called on to help with the definitive diagnosis
and classification of these lesions. The presence of arteries,
arterioles, or both as an integral part of the lesions (as
shown by elastic tissue stains) is often used as a diagnostic
criterion for differentiating AVMs from hemangiomas.7 To
further characterize the histomorphologic differences be-
tween hemangioma and AVM, we used histochemical
elastic stains (Movat pentichrome stain) and S100 (an im-
munohistochemical stain for nerve and nerve fibers) to
study the various tissue components present in these le-
sions.
MATERIALS AND METHODS
The study materials were retrieved from the anatomic pathol-
ogy file of our institution and consisted of 167 consecutive cases
of benign vascular lesions that were diagnosed during a period
of 8 years (19952002) in our division of surgical pathology. The
material consisted of 101 cases originally diagnosed as heman-
Hemangioma Versus Vascular MalformationAdegboyega & Qiu
Figure 1. Hematoxylin-eosinstained (A, B, C) and Movat pentichrome stained (D) sections showing the presence of intralesional nerves in
arteriovenous malformations. The nerves range from small twigs (A, D) to medium-sized and large nerve bundles (B and C, respectively). Movat
stain also shows the presence of thick-walled arterial vessels with elastic lamina (D) (original magnification 3100).
giomas (with exclusion of pyogenic granulomas) and 66 cases
originally diagnosed as AVMs. To be included in the study, a
lesion must have been extracranial and must have had available
hematoxylin-eosin (H&E) glass slides for review and formalin-
fixed, paraffin-embedded tissue blocks for further histochemical
and immunohistochemical studies. Cases in which the available
tissue blocks did not contain adequate lesion for both histochem-
ical stain and immunohistochemistry were excluded. The glass
slides were reviewed to confirm the diagnosis and also to look
for the presence of intralesional nerves in these lesions. For de-
finitive characterization and subcategorization of the lesions as
hemangiomas or AVMs, Movat pentichrome histochemical stain
was used to identify elastic lamina in the walls of the blood ves-
sels (arteries/arterioles). All cases that were previously diag-
nosed as hemangiomas but contained arteries, arterioles, or both
(based on findings with Movat stain) were reclassified as AVMs.
In addition, cases that were previously diagnosed as AVMs but
were shown by Movat stain to lack blood vessels with elastic
lamina in their walls were reclassified as hemangiomas. In a pre-
liminary study,8 intralesional nerves were reported to be present
in vascular malformations and absent in hemangiomas. There-
fore, all confirmed cases of AVMs in which intralesional nerve
was not observed in H&E-stained tissue sections were subjected
to immunohistochemical staining with S100 antibody to evaluate
the presence of nerves within those lesions. Also, all hemangio-
mas that were equivocal for the presence of nerves in the H&E-
Arch Pathol Lab MedVol 129, June 2005
stained tissue sections were stained with S100. For that purpose,
we used a polyclonal S100 antibody that is known to react
strongly with human S100A and S100B (Dako Corporation, Car-
pinteria, Calif; working dilution 1:6000). Immunohistochemistry
was done on representative 4-mm-thick sections of the paraffin-
embedded tissue blocks using citrate buffer antigen retrieval and
established avidin-biotin detection method (Vector, Burlingame,
Calif), as previously described.9 The immunostained sections
were evaluated with light microscopy for the presence or absence
of nerves within the vascular lesions.
RESULTS
Twelve of the 101 cases originally diagnosed as hem-
angiomas were reclassified as AVMs based on the pres-
ence of thick-walled elastic arteries or arterioles as part of
the lesion as demonstrated by Movat stain (Figure 1, B
through D). With the same stain, 2 of the 66 cases previ-
ously diagnosed as AVMs were reclassified as hemangio-
mas. Following this reclassification, therefore, we had 91
confirmed cases of hemangioma and 76 confirmed cases
of AVM.
Of the 91 confirmed cases of hemangioma, 79 were from
skin and subcutaneous tissues, 5 from oral mucosa, 1 from
maxillary sinus, 1 from vocal cord, 1 from vulva, 1 from
Hemangioma Versus Vascular MalformationAdegboyega & Qiu 773

Figure 2. S100 highlighting the presence of a small nerve bundle in
an arteriovenous vascular malformation (original magnification 3400).
Note the presence of nerve fibers in the upper right quadrant of this
micrograph.
liver, and 3 from bone. Fifty-three of the 76 cases of con-
firmed AVM were from the skin and subcutaneous tissues,
5 from oral mucosa, 7 from gastrointestinal mucosa, 3
from the urinary bladder, 7 from the endomyometrium
and uterine adnexae, and 1 from the lung. All the lesions
studied were excisional resection specimens except the 1
from the lung, which was a needle biopsy specimen.
In the H&E-stained tissue sections, intralesional nerve
bundles were detected in none of the cases of hemangio-
ma. In contrast, intralesional nerve bundles were detected
in 85% (65/76) of the correctly categorized cases of AVM.
Of the 12 AVMs previously diagnosed as hemangiomas,
10 had intralesional nerves in H&E sections (Figure 1, A
through C), and S100 showed intralesional nerves in the
remaining 2 cases. The nerves ranged from small twigs
(Figure 1, A and D) to large nerve bundles (Figure 1, B
and C). In the 11 cases of AVM in which nerve bundles
were not observed in the H&E- and Movat pentichrome
stained sections, S100 immunostain revealed intralesional
nerve bundles in 4 (Figure 2). Therefore, in all, intrale-
sional nerves were seen in 91% (69/76) of cases of AVM.
Cases of AVM in which nerve bundles were not detected
in any of the sections examined included 1 case from the
stomach, 2 myometrial, 1 paratubal, and 3 subcutaneous
lesions (1 from the forearm and 2 from the leg). In the
hemangioma group, there was also a good correlation be-
tween the results of Movat stain and S100 immunostain;
nerve bundles were not detected (with S100 immunostain)
in any of the cases classified to be hemangioma using
Movat stain.
Three of the vascular lesions we studied were intra-
muscular in location (1 in the tongue, 1 in the upper chest
wall, and 1 in the thigh). Two of the lesions were classified
as AVMs based on the presence of intralesional arteries/
arterioles as highlighted by Movat stain, and they both
contained intralesional nerves. The third intramuscular
lesion (located in the pectoral muscle) was classified a
hemangioma because, as confirmed with Movat stain, it
contained no arterial vessel, and no intralesional nerve
bundles were detected with S100 immunostaining of that
lesion.
774 Arch Pathol Lab MedVol 129, June 2005
COMMENT
Vascular lesions are very common and have been de-
scribed as the oldest tumor because of the discovery of
intraosseous hemangiomas in dinosaur vertebrae.1 But to
this day, they continue to pose diagnostic and therapeutic
challenges to clinicians and histopathologists alike, with
consequent and often protracted distress for the patients,
who sometimes shuffle from physician to physician seek-
ing help.10 In this study, we show the presence of intrale-
sional nerve to be a helpful discriminator that can be of
diagnostic utility for histomorphologists for the correct
classification and diagnosis of hemangiomas and AVMs.
Arteriovenous malformations are the result of errors in
morphogenesis and are divided into subtypes based on
the constituent vessels: capillary, venous, arterial, lym-
phatic, and combined forms. Hemangiomas, on the other
hand, result from a derangement in angiogenesis with ex-
uberant proliferation of vascular elements due to imbal-
ance between angiogenic and angiostatic forces.3,11,12
Therefore, arteries and arterioles are not part of the lesion.
Arteriovenous malformations are a complex network of
intercommunicating arterial and venous structures.13
Hence, pathologists rely on elastic stains as ancillary tools
for making a definitive diagnosis of AVMs, because arter-
ies and arterioles (with elastic lamina in their walls) are
an integral part of AVMs.7 The presence of intralesional
nerve in AVM, as reported in this study, provides an ad-
ditional diagnostic criterion that is simple and reliable and
can be readily used to differentiate AVMs from heman-
giomas, even in H&E-stained tissue sections. Also, the
presence of nerve in AVMs supports the theory that AVMs
are hamartomas, which by definition are mass lesions
composed of an abnormal architectural organization of
tissues that are normally present at a particular site or
organ.7
Only a handful of previous studies have focused on the
presence or distribution of nerves in benign vascular le-
sions. Rydh et al4 reported absence of nerve bundles and
paucity of nerve fibers around the dilated vessels in 9 cas-
es of port-wine stains (which they called venous malfor-
mations) and concluded that loss of vascular tone due to
absence of adequate nerve supply may be responsible for
the vascular ectasia that characterizes those lesions. Con-
sidering the absence of nerve bundles in those lesions, we
suggest they are better classified as venous hemangiomas.
Robinson et al14 studied the innervation of 6 intramuscular
hemangiomas using S100 immunohistochemical stain.
They reported the nerve content of hemangiomas to be
the same as that in normal tissue and that in surrounding
margins of the lesions. They also observed increased pres-
ence of nerves in the immediate (13 mm) vicinity of the
intramuscular hemangiomas. Increased neuropeptides
(substance P and calcitonin generelated products) were
found within the lesions, and the authors surmised that
these neuropeptides were responsible not only for creating
the symptom of pain but also for inducing growth of the
lesions by stimulating proliferation of fibroblasts and en-
dothelial cells. The nerve bundles observed in that study
and also previously reported in other benign intramus-
cular vascular lesions15,16 were likely to be nerve bundles
that are normally present within the richly innervated
skeletal muscles in which those hemangiomas are located.
Jang et al17 studied 15 hemangiomas (6 proliferating and
9 involuting) and 7 vascular malformations of unspecified
Hemangioma Versus Vascular MalformationAdegboyega & Qiu
types and looked at nerve fiber (not nerve) contents of
these lesions. They reported an increased number of nerve
fibers in proliferative hemangiomas compared with their
involuting counterparts and AVMs, and based on that,
they hypothesized that neuropeptides released by nerve
fibers in proliferating hemangiomas may play some an-
giogenic role in promoting the growth of hemangiomas.
In our study, we found nerve bundles to be present only
in AVMs and not in hemangiomas, but small nerve fibers
(highlighted by S100 immunostain) were observed in both
lesions. In agreement with the finding reported by Jang et
al,17 we noticed comparable presence of nerve fibers in the
hemangiomas and AVMs we studied, which may be be-
cause all the hemangiomas we studied were past the pro-
liferative phase (which usually occurs in infancy).
Additional fundamental differences between hemangi-
omas and AVMs include (1) the timing of their clinical
appearance, (2) their growth patterns, (3) the biologic be-
havior or growth characteristics of their endothelial lining
in cell culture, (4) the stromal cellular and extracellular
matrix compositions, and (5) the response of the lesions
to pharmacotherapeutic agents.
Hemangiomas appear very early in life, either at birth
or within the first 2 weeks of life.2,3,5 Arteriovenous mal-
formations by definition are technically present at birth
but may not become noticeable until much later in life,
with some coming to sight as late as during puberty or
even during the postpubertal period. The timing of the
clinical appearance of vascular malformation depends on
the type of vessels involved.18 Capillary and lymphatic
malformations are usually evident at birth or within the
first year of life, venous malformations any time between
birth and early adulthood, and arterial malformations and
AVMs often at puberty or during pregnancy because of
the associated hormonal changes.18,19 Hemangiomas grow
with a rapid growth phase during the first year of life and
usually involute within the first decade of life.5,19 In con-
trast, AVMs grow proportionately with the patient; do not
involute; and may sometimes increase in size because of
vascular ectasia induced by conditions such as sepsis,
trauma, puberty, and pregnancy.18 The endothelial lining
of hemangiomas (particularly in the proliferative phase)
is plump, and when cultured, they proliferate and form
tubular structures reminiscent of vascular channels. The
endothelial cells that line AVMs are quiescent flat cells that
neither proliferate nor differentiate into vascular struc-
tures in vitro.19 Immunohistochemical studies have shown
that, unlike the extracellular matrix of vascular malfor-
mations or normal tissues, the extracellular matrix of hem-
angiomas contains increased fibronectin, perlecan, and
laminin3,20,21; increased growth factors (basic fibroblast
growth factor, insulin-like growth factor, and vascular en-
dothelial growth factor)20,2224; proteases (type IV collage-
nase and urokinase); and adhesion molecule E selectin.25
Also in line with their divergent growth characteristics,
hemangiomas (especially in the proliferative phase) re-
spond to corticosteroids, interferon 2a, ionizing radiation,
and laser photocoagulation,18,26,27 all of which have no
growth-inhibiting effects on AVMs.
Considering the differences in the pathobiology and
natural history of these lesions, as well as the therapeutic
and prognostic implications of accurately distinguishing
between hemangiomas and AVMs, it is important that
these lesions be correctly diagnosed. Not only will AVMs
Arch Pathol Lab MedVol 129, June 2005
that are misdiagnosed as hemangiomas and treated as
such fail to respond to medical treatment with pharma-
cologic agents, error in surgical management of such le-
sions may also result in treatment failure and loss of an-
gio-access for proper management of the lesion in the fu-
ture.28 We here show the presence of intralesional nerve to
be a simple, reliable, and cost-neutral diagnostic criterion
for correctly distinguishing between hemangiomas and
AVMs.
Thanks to Mr Thomas Bednarek for his assistance with pho-
tography.
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