—  SPECIALTY CONFERENCE  —

Pediatric Pathology

Case 1A - Infantile Hemangioma, Late Proliferative/Early Involutive Phase

Paula E. North
Children's Hospital of Wisconsin
Milwaukee, WI





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Clinical History:
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.


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Introduction:
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 [1], 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 activity).

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 [2, 3, 4]. 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 [5]. 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 [6]. 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 [2, 3, 7]. 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 [8]. Peri-capillary masts cells increase in number [9], 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 [10]. 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 [2, 3, 4, 11, 12]. Basement membranes strongly express merosin [4]. GLUT1 immunohistochemistry has become a mainstream tool for pathologists affiliated with centers specializing in the diagnosis and treatment of vascular anomalies.

Differential Diagnosis:

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 [13, 14, 15]. KHE 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 [16]. 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 [2, 4, 11]. Some examples of KHE/TA are not associated with KMP, although many are. In contrast, IH is never a cause of KMP.

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 [17, 18, 19]. 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 [17].

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 [4, 11].

Final Diagnosis:
Infantile hemangioma, late proliferative/early involutive phase

Case Discussion:
Although all IH spontaneously involute to a variable degree, functional or significant cosmetic sequelae are not uncommon and intervention is frequently needed [20, 21]. During proliferation, potential complications include skin ulceration and scarring, bleeding, infection, airway compromise, and, rarely, congestive heart failure [22]. 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 [23]. 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 [24]. 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 [25, 26]. Topical application of the immunomodulatory agent imiquimod has been reported to be effective in causing regression of many superficial IH [27, 28]. Recent clinical studies have shown that propranolol, a non-selective beta-adrenergic blocker, can reduce growth of IH in many patients [29]. 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 [30], some of these showing linkage to chromosome 5q31-33 [31]. 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 [32] showed no significant differences in concordance between monozygotic and dizygotic pairs. This argues against a strongly predisposing inherited component.

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 [4, 33]. 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 [34]. 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 [35]; this suggests possible therapeutic targets. For further discussion regarding the pathogenesis of IH the reader is referred to recent reviews [2, 12].

Summary:
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.

References:
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  2. North PE, Waner M, Buckmiller L, James CA, Mihm MC. Vascular tumors of infancy and childhood: beyond capillary hemangioma. Cardiovasc Pathol 15:303-317, 2006.

  3. North PE. Vascular tumors and malformations of infancy and childhood. Pathology Case Review 13(6):213-235, 2008.

  4. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137:559-570.

  5. Bowers RE, Graham EA, Thominson KM. The natural history of the strawberry nevus. Arch Dermatol 1960;82:667-670.

  6. Powell TG, West CR, Pharoah PO, Cooke RW. Epidemiology of strawberry haemangioma in low birthweight infants. Brit J Dermatol 1987;116:635-641.

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  8. Razon MJ, Kraling BM, Mulliken JB, et al. Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 1998;5:189-195.

  9. Tan ST, Wallis RA, He Y, et al. Mast cells and hemangioma. Plastic Reconstr Surg 2004;113:999-1011.

  10. Li Q, Yu Y, Bischoff J, et al. Differential expression of CD146 in tissues and endothelial cells derived from infantile hemangioma and normal human skin. J Pathol 2003;201:296- 302.

  11. North PE, Waner M, Mizeracki A, et al. Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 2000;31:11-22.

  12. Ritter MR, Butschek RA, Friedlander M et al. Pathogenesis of infantile hemangioma: new molecular and cellular insights. Exp Rev Molec Med 2007;9:1-19.

  13. Sarkar M, Mulliken JB, Kozakewich HP, et al. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997;100:1377-1386.

  14. Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabach-Merritt syndrome do not have "true" hemangiomas. J Pediatr 1997;130:631-640.

  15. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol 1993;17:321-328.

  16. Lyons LL, North PE, Mac-Moune Lai F, et al. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol 2004;28(5):559-568.

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  35. Jinnin M, Medici D, Park L, Limaye N, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nature Med 2008; advance online publication:1-11.n