Case 1A -
Infantile Hemangioma, Late Proliferative/Early Involutive Phase
Paula E. North
Children's Hospital of Wisconsin
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An 8 month old female infant presented with a bright pink, soft, 6 x 5.5 cm plaque on her upper back.
In the center of the lesion there was an area of healing ulceration. At surgery, dissection was carried
down to the superficial fascia, and the lesion was removed intact with minimal bleeding.
This is an example of infantile hemangioma (IH), the most common tumor of
infancy. It is often inappropriately lumped under the overly-generic terms "hemangioma" or "capillary
hemangioma" with a number of other benign vascular entities that we know realize are biologically as well
as clinically dissimilar. Synonyms currently in frequent use by clinicians for this specific
clinicopathological entity include juvenile hemangioma and cellular hemangioma of infancy. The WHO has adopted the term hemangioma of infancy. Under the general, biology-based nosologic classification
scheme endorsed by the multidisciplinary International Society for the Study of Vascular Anomalies
(ISSVA) and derived in part from that proposed by Mulliken and Glowacki , IH is classified as a vascular tumor (an intrinsically proliferative lesion that arises by cellular
hyperplasia), rather than a vascular malformation (that by definition would
represent a congenital error in embryonic vascular morphogenesis with limited endothelial mitotic
Pathologic and Clinical Features:
IH is distinctive proliferation of benign capillaries with an unusual endothelial phenotype that is
shared only by capillaries of the placenta
Their typical and remarkably consistent natural
course is presentation shortly after birth, rapid proliferation in the first year of life, followed by
spontaneous involution over a period of years . Some examples are already evident at birth as
relatively inconspicuous precursor lesions, and very rare examples, usually small, abruptly "abort" and
regress shortly after appearing. Female infants are three times more likely to develop infantile
hemangiomas than males. Fair-skinned individuals are at increased risk, although all races are affected
. Approximately 60% occur on the head and neck, although they also occur on the trunk, extremities,
genitals, and in various viscera including notably the liver, the intestine, and less often the lung.
Skin and subcutis appear to be most commonly affected, even factoring in more obvious presentation,
whereas deep skeletal muscle is spared. True IH may occur in the brain, but his has been poorly
demonstrated histologically. Most present as solitary cutaneous and/or subcutaneous lesions, but a
significant percentage of patients (about 15%) have multiple skin lesions, in rare cases accompanied by
multiple visceral hemangiomas (usually hepatic).
Grossly, proliferative and early involutive IH are well-circumscribed, but unencapsulated masses with
red-to-tan cut-surfaces. Later involutive lesions are fibro-fatty in consistency and less easily
defined. The histologic features of IH change dramatically during their natural course from neonatal
presentation through rapid growth and subsequent involution, requiring the pathologist to interpret these
features within the proper clinical context
There is no sharp dividing line between
proliferation and involution, and features of involution typically co-exist with features of
proliferation during much of the process. Proliferative phase lesions are cellular masses of plump
endothelial cells and pericytes that together form capillaries with generally small rounded lumina.
Peri-capillary myeloid cells with immature dendritic features are plentiful. Basement membranes become
increasing multi-laminated over time, presumably due to repeated cycles of cell proliferation. The
proliferating capillaries are arranged in lobules, separated by delicate fibrous septi or by normal
intervening tissue. Depending upon tissue location, the capillaries intermingle with superficial
skeletal muscle fibers, peripheral nerves, salivary glands, and adipocytes. Endothelial cells and
pericytes show variably enlarged nuclei and abundant clear cytoplasm, and normally configured mitotic
figures are easily found. Immunohistochemical stains for cell proliferation markers such as Ki-67
confirm that both pericytes and endothelial cells are actively dividing. Because proliferative phase IH
are high-flow lesions, albeit without significant arteriovenous shunting, they often contain enlarged
draining veins with thickened, asymmetrical walls. Intravascular thrombosis, hemosiderin deposition, and
necrosis are rare unless extensive ulceration, or pre-surgical embolization, has occurred.
During involution, basement membranes continue to thicken and show embedded apoptotic dust .
Peri-capillary masts cells increase in number , and lesional capillaries begin to disappear. There is
no evidence of thrombosis, and inflammation is not prominent. Eventually all that remains in an
end-stage lesion is loose fibrous or fibrofatty stroma containing a few residual vessels similar to
normal capillaries or venules but with thickened basement membranes. "Ghost" vessels composed of
residual, thickened rinds of basement membrane material containing apoptotic debris and with little or no
intact cellular linings may also be seen. Epidermal atrophy and underlying fibrous scar tissue may be
present if the lesion ulcerated while in the proliferative phase. Large arteries and veins modeled
during the high-flow proliferative phase do not completely regress when the capillary bed drops out and
thus are often present in involuting IH.
The endothelial cells of IH immunoreact positively for "normal" endothelial markers of the blood
vasculature such as CD31, CD34, factor VIII-related antigen (vWf), Ulex
europaeus lectin I, Fli-1, and VE-cadherin, although negativity for CD146 has been reported .
All stages of IH can be distinguished from other benign vascular anomalies and reactive proliferations by
their strong endothelial positivity for a distinct set of antigens, including GLUT1, Lewis Y antigen,
FcγRII, CD15, and IGF2
Basement membranes strongly express merosin . GLUT1
immunohistochemistry has become a mainstream tool for pathologists affiliated with centers specializing
in the diagnosis and treatment of vascular anomalies.
Proliferative phase IH.
Proliferative phase IH must be distinguished from other cellular vascular proliferations including
pyogenic granuloma, intramuscular "hemangioma" (which many consider a vascular malformation rather than a
vascular tumor), kaposiform hemangioendothelioma/tufted angioma, and congenital non-progressive
hemangiomas (so-called R.I.C.H. and N.I.C.H.). Immunohistochemistry for GLUT1, which will strongly mark
the endothelial cells of IH, is helpful and can be performed using routinely fixed specimens and
commercially available antibodies.
"Pyogenic granulomas" are reactive capillary proliferations that can occur in all age groups, but
when seen in young infants may be confused with IH. They typically show distinct separation of capillary
lobules by thick bands of fibrous tissue, explaining the term often preferred by pathologists, "lobular
capillary hemangioma". These commonly exophytic lesions grow rapidly and tend to ulcerate, often taking
on the appearance of inflamed granulation tissue.
Cellular, small vessel-type intramuscular "hemangiomas" may focally resemble infantile hemangioma, but
on close inspection lack the architecture of IH, are GLUT1-neagitive, and have a prominent large vessel
and arteriolar component. These present as relatively well-defined "masses" by MRI and typically show
angiographic and/or clinical features of AV-shunting. They are clinically more consistent with vascular
malformations and do not regress. It is of interest that true IH do not occur in deep skeletal muscle
(e.g., the large muscles of the extremities or the muscles of mastication),
although they may non-destructively insinuate between loosely arranged superficial skeletal muscle fibers
such as those of facial expression and the chest wall.
Rare vascular tumors, almost exclusively kaposiform hemangioendothelioma (KHE) or the closely related
entity tufted angioma (TA), are associated with the life-threatening bleeding diathesis known as
Kasabach-Merritt Phenomenon (KMP) that is caused by intra-tumoral platelet trapping
consist of capillary-like proliferations punctuated by fascicles of moderately plump, spindled
endothelial cells that form slit-like lumina containing erythrocytes, reminiscent of Kaposi's sarcoma.
The spindled cells often sweep around more epithelioid cellular nests rich in pericytes surrounding
platelet-rich microthrombi that can be highlighted by CD61 or CD31 immunostaining . TA is a
superficial lesion that shares many of the histological and immuophenotypic features of KHE, albeit with
a less pronounced spindle cell component, and is likely part of the KHE biological spectrum. Unlike the
endothelial cells of IH, the spindled endothelial cells of KHE and TA are positive for the lymphothelial
marker podoplanin and are negative for GLUT1 and other placental vessel-associated markers
Some examples of KHE/TA are not associated with KMP, although many are. In contrast, IH is never a cause
Congenital nonprogressive hemangiomas differ from the classical IH in that they present fully formed
at birth, then follow a static or rapidly involuting course, the latter much more rapid than that
characteristic of IH
The capillary lobules of congenital nonprogressive hemangiomas are
separated by abnormally dense fibrous tissue, with skin atrophy and loss of dermal adnexal appendages in
the overlying skin. This is unlike IH, in which the tumor lobules are separated by normal-appearing
tissue elements. Foci of hemosiderin deposition and extramedullary hematopoiesis are common, and
sclerosis often extends into the lobules either peripherally or globally. Capillary lobules often have
central stellate draining vessels. Endothelial cells are negative for GLUT1 .
Involutive phase IH.
Involutive phase IH may be confused with vascular malformations due to a combination of loss of
mitotic activity and persistence of large arteries and veins modeled during the high-flow proliferative
phase. Consideration of clinical history and overall histological appearance of the lesion is usually
adequate to make the correct diagnosis. If needed, any uncertainty can be resolved by GLUT1
immunoreaction, since involuting and even end-stage IH, but not malformations, will show endothelial
GLUT1 immunopositivity in residual lesional vessels
Infantile hemangioma, late proliferative/early involutive phase
Although all IH spontaneously involute to a variable degree, functional or significant cosmetic
sequelae are not uncommon and intervention is frequently needed
During proliferation, potential
complications include skin ulceration and scarring, bleeding, infection, airway compromise, and, rarely,
congestive heart failure . Occlusion of the developing visual axis by periorbital IH causes
amblyopia, and large lesions of the face may result in jaw mal-alignment. Psychological sequelae of
deforming facial lesions during early social interactions in pre-school and kindergarten can be very
significant. Although most IH of skin and subcutis show a focal, tumor-like pattern of growth, others
show a more plaque-like pattern with a distinctly segmental distribution . Segmental IH of the face
are sometimes seen in association with one or more of the following abnormalities: posterior fossa brain
malformations, arterial cerebro-vascular anomalies, cardiovascular anomalies, and eye anomalies,
described by the acronym PHACE syndrome, or PHACES syndrome when accompanied by sternal defects and/or
supraumbilical raphe . The etiology of this association is not understood.
Common treatment modalities include surgical excision, corticosteroids (topical, intralesional, and
systemic), pulsed dye laser, and, most recently, propranolol. Clinically innocuous lesions are often
best left alone to regress spontaneously. Recombinant interferon-alfa, a known inhibitor of
angiogenesis, has been helpful in controlling the infantile hemangioma growth, but its use is restricted
to life-threatening hemangiomas due to significant risk of irreversible spastic diplegia
Topical application of the immunomodulatory agent imiquimod has been reported to be effective in causing
regression of many superficial IH
Recent clinical studies have shown that propranolol, a
non-selective beta-adrenergic blocker, can reduce growth of IH in many patients . As a result,
relatively widespread off-label use of propranolol for treatment of IH patients has ensued, although
treatment must be maintained for several months to prevent rebound.
The vast majority of IH are sporadic, although rare families expressing 'hemangiomas and/or vascular
malformations' as an autosomal dominant trait with high penetrance have been reported , some of these
showing linkage to chromosome 5q31-33 . This suggests that mutation in a gene within this region
might predispose family members to IH development. IH are more common in low birth weight infants and
twins, although a study of 118 twin pairs with IH  showed no significant differences in concordance
between monozygotic and dizygotic pairs. This argues against a strongly predisposing inherited
Although the most commonly used marker in surgical pathology practice for the diagnosis of IH, GLUT1
is only one of many markers of IH that distinguish it from other vascular lesions, together constituting
a unique molecular phenotype that is shared only by the fetal capillaries of placental chorionic villi
The etiological significance of this unexpected expression pattern remains controversial;
current evidence favors origin from multipotent vascular precursor cells quite possibly arising in the
placenta . A very recent study reported low VEGFR1 expression in cultured endothelial cells from IH,
compared to various controls, with resultant activation of VEGRF2 and its downstream targets ; this
suggests possible therapeutic targets. For further discussion regarding the pathogenesis of IH the
reader is referred to recent reviews
IH is a very common, but clinically, histologically, and biologically unique capillary proliferation
of infancy that is fundamentally related at the molecular level to the capillaries of human placenta.
Within the broader nosologic spectrum of Vascular Anomalies that includes both Vascular Tumors and
Vascular Malformations, it is categorized as a benign vascular tumor. Clinically, it is distinguished by
perinatal presentation, proliferation during the first year or so of life, and slow spontaneous
involution. Time course of proliferation and involution is remarkably predictable, with rare outliers;
presentation outside of infancy does not occur. Histological features vary according to stage of
proliferation and involution and are sometimes confused with those of other histologically overlapping,
but biologically unrelated vascular anomalies, including congenital nonprogressive hemangioma, pyogenic
granuloma, intramuscular "hemangioma", and kaposiform hemangioendothelioma (which may focally resemble
proliferative phase IH) and vascular malformations (which may resemble involutive phase IH). Features in
the proliferative phase include: plump endothelial cells and pericytes, both demonstrating occasional
mitotic figures, forming rounded capillaries with increasingly redundant basement membranes, abundant
peri-capillary myeloid cells with immature monocytic/dendritic features, delicately defined capillary
lobules separated by thin fibrous septi or normal intervening tissue, free and non-destructive
intermingling of lesional capillaries with peripheral nerves, adipocytes, superficial skeletal muscle
fibers, and salivary glands, prominence of supportive arteries and veins, and absence of thrombosis and
necrosis unless associated with nearby ulceration. Histological features of involuting lesions include
flattening of endothelial cells and pericytes, luminal enlargement, reduced mitotic activity, scattered
apoptotic debri within thickened, focally hyalinized capillary basement membranes, abundant perivascular
mast cells, progressive capillary drop-out and replacement by loose connective tissue, and eye-catching
persistence of large servicing vessels that may mimic vascular malformation. End-stage lesions consist
largely of loose fibrous or fibrofatty tissue containing sparse residual thickened "rinds" of basement
membrane material with little intact endothelial lining. Pathogenesis is unclear, but evidence does not
support a strongly predisposing inherited component. The fundamental and unique similarity of the
endothelial phenotype of IH and placental capillary endothelial cells, exemplified by strong positivity
for GLUT1, suggests shared regulatory mechanisms, at a minimum, and possibly a shared precursor cell
originating in the placenta that would explain the universally perinatal presentation of this common
tumor. Regardless of etiological speculation, endothelial GLUT1 immunoreactivity has become the
international gold standard for confirmation of the histological diagnosis of IH.
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