Benign vascular tumors and tumor-like proliferations

Seminars in Diagnostic Pathology (2008) 25, 1-16

Benign vascular tumors and tumor-like proliferations Sachiv Sheth, MD, Chi K. Lai, MD, FRCPC, Sarah Dry, MD, Scott Binder, MD, Michael C. Fishbein, MD From the Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. KEYWORDS Hemangioma; Malformation; Telangiectasia; Angiomatosis; Angioma

Appropriate nomenclature of benign vascular tumors and tumor-like conditions is problematic due to overlapping histologic features, limited understanding of the pathogenesis, and controversy regarding classification. Benign vascular anomalies are categorized into malformations, neoplasms, reactive proliferations, or ectasias based on their clinical behavior, currently accepted etiologies, and histopathology. We address controversies in the classification of some entities and also discuss recent immunohistochemical developments that have raised questions regarding the origin of certain vascular tumors. This comprehensive review focuses on the clinical presentation, behavior, associated conditions, histopathological findings, and differential diagnoses of benign vascular tumors and tumor-like conditions. © 2008 Elsevier Inc. All rights reserved.

Classification of benign vascular anomalies has been an evolving and debated subject. At times, the nomenclature has been confusing. The interdisciplinary International Society for the Study of Vascular Anomalies (ISSVA) proposed a categorical system of vascular malformations and tumors in 1996.1 In this review, we expand on the ISSVA classification system and divide benign vascular anomalies into malformations, neoplasms, reactive proliferations, and ectasias. Vascular malformations are congenital abnormalities in vasculogenesis.2 In contrast, vascular neoplasms are defined as an endothelial proliferation arising from preexisting vessels attributable to vascular growth factors (ie, secondary to postnatal defects in angiogenesis).2,3 Malformations are present at birth, grow proportionally with age, and do not involute. Neoplasms usually appear after birth, may spontaneously regress, and occasionally show a clonal expansion of endothelial cells.4-6 Reactive vascular prolifAddress reprint requests and correspondence: Michael C. Fishbein, MD, Piansky Professor of Pathology and Medicine, Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS A7-149, Los Angeles, CA 90095-1732. E-mail: [email protected].

0740-2570/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2007.10.001

erations are characterized by a rapid vascular proliferation associated with an etiologic factor such as trauma or infection. Vascular ectasias are dilatations of preexisting vessels without an increase in number, often recognized by their distinct clinical appearance. This classification scheme is attractive because it identifies etiologic distinctions among the various benign vascular lesions. However, it is important to emphasize that, in practice, precise categorization of many benign vascular anomalies is problematic because of the coexistence of entities, unclear pathogenesis, and similar histological characteristics. Furthermore, clinicians must understand that, although benign, clinical behavior varies widely within these categories, from solitary lesions that may spontaneously regress to large, diffusely infiltrative lesions with a high rate of local recurrence following excision. The (often confusing) nomenclature reflects the difficulties historically faced in precisely categorizing these various lesions. A unifying feature of benign vascular proliferations is immunohistochemical staining with antibodies to factor VIII-related antigen (von Willebrand factor, vWF), CD31, and CD34. CD34 is less specific because of staining in other

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Figure 1 Intramuscular hemangioma. (A) Blood-filled cavernous-type vessels infiltrating between skeletal muscle fibers (H&E stain; original magnification, 100⫻). (B) Mature adipose tissue frequently accompanies the vascular proliferation (H&E stain; original magnification, 100⫻).

spindle cell lesions. FVIII-r is a sensitive antibody for vascular endothelium, but CD31 is the most sensitive and specific of all antibodies for vascular endothelium.7 Typically, lymphatic vessels show moderate reactivity to CD31 and no reactivity to CD34. Recently, new immunohistochemical markers for lymphatic endothelium have emerged, including D2-40 against surface glycoprotein podoplanin, transcription factor Prox-1, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and vascular endothelial growth factor receptor-3 (VEGFR-3). D2-40 is the most promising marker for lymphatic vasculature but also recognizes mesothelial and fetal germ cells.8 Initial studies with these markers suggested that lesions such as Kaposi’s sarcoma, hobnail hemangioma, kaposiform hemangioendothelioma, and some angiosarcomas may in fact be lymphatic in nature.9

Malformations Separation of vascular malformations by flow rates is important because of differing complications and treatments. Arteriovenous malformations tend to be high-flow and are often seen on selective angiography. Low-flow malformations, such as venous, cavernous, capillary, or lymphatic malformations, are best detected on computed tomography (CT) or magnetic resonance imaging (MRI) scans.5 Two significant examples of vascular malformations include intramuscular hemangiomas (IMHs) and angiomatosis. IMHs are painful masses occurring in a single muscle, usually in the extremities. The pain is often exacerbated by exercise, warm temperatures, or stress. Although patients usually present in young adulthood, the malformation is thought to be congenital, but unrecognizable until sudden growth in adolescence causes pain and compression of other muscles and neurovascular structures. These lesions can be extensive in large muscles; for example, IMH in large muscles of the leg can exceed 10 cm.7 Histologically, the appearance varies among lesions. Typically, a mixture of various types of vessels (veins, capillaries, cavernous ves-

sels, and occasionally prominent arteriovenous components) diffusely infiltrates skeletal muscle (Figure 1A). Younger patients may have a predominantly capillary or cavernous component. The background stroma characteristically shows variable amounts of fat, smooth muscle, fibromyxoid stroma, and not infrequently, metaplastic ossification or phleboliths (Figure 1B).7,10-12 The adipocytic component can be so prominent that it overshadows the vascular elements. In fact, cases in the older literature are sometimes diagnosed as “infiltrating angiolipoma.”10 Treatment is problematic due to the diffuse nature of IMH. Incomplete excision results in local recurrence in up to half of all patients. Furthermore, local recurrence of this benign, yet infiltrative, tumor can be locally destructive. Wide local excision at presentation is recommended.7 Angiomatosis is histologically similar to IMH, but is unique in that it involves multiple planes of tissue including the subcutis, fascia, muscle, and bone. This process often extends into multiple muscle compartments within a large anatomic area of a limb or trunk. If limbs are involved, they frequently show hypertrophy.7,10-12 Involvement of the central nervous system or viscera is uncommon. Not surprisingly, treatment is difficult, and local recurrence rates are well over 50% and up to 90% in some series.11,12

Venous malformations (venous hemangiomas) Deep seated venous malformations (VMs) are rare, generally large masses typically presenting in adulthood due to compressive effects usually within the retroperitoneum, mesentery, or extremity muscles.10,11 Cutaneous and gastrointestinal VMs tend to be smaller and multiple. They present at birth or childhood and may be associated with the Maffucci, Klippel–Trenaunay, or blue rubber bleb nevus syndromes.2 Clinically, VMs are characterized by their low flow state. Large lesions often require venography to determine extent of involvement. The low flow predisposes to the formation of phleboliths and thromboses, potentially placing the patient at risk for pulmonary emboli.12

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Figure 2 Venous malformation. (A) Thick-walled veins with focal attenuation of the smooth muscle wall (arrow; H&E stain; original magnification, 100⫻). (B) Large venous malformation with intraluminal thrombosis (asterisks; H&E stain; original magnification, 40⫻).

Grossly, VMs may be vaguely encapsulated, infiltrative, or solid-cystic. Histologically, they are characterized by large, gaping, variably sized, thick-walled veins with possible thromboses (Figure 2A and B). The irregularity and focal attenuation of the muscle wall fibers help distinguish them from varicose vessels or aneurysms.10,11 The absence of an internal elastic lamina aids in the distinction from an arteriovenous malformation.12 The presence of smooth muscle helps distinguish VMs from cavernous or capillary hemangiomas, but a spectrum of thin- and thick-walled vessels may be present. When thick-walled vessels predominate, classification as a VM is sufficient.

Cavernous malformations (cavernous hemangiomas) Cavernous malformations (CMs) mostly affect children in the head and neck, but may occur at any site. They are usually large, fairly to poorly circumscribed, and involve the skin, subcutis, or viscera. CMs can be locally destructive due to pressure effects, and often require surgical management.10 Microscopically, CMs demonstrate large, thin-walled vessels separated by narrow strands of connective tissue and smooth muscle. Thrombosis and dystrophic calcification are common, as are focal areas resembling capillary hemangioma (Figure 3A and B).10,11 Variants of CMs include synovial hemangiomas and sinusoidal hemangiomas. Synovial hemangiomas (or intraarticular cavernous hemangiomas) are lined by a reactive and papillary synovial membrane in an edematous or myxoid background with inflammatory cells and siderophages.10,12 Sinusoidal hemangiomas, unlike conventional cavernous hemangiomas, occur in the deep dermis or subcutis of the trunk and extremities of adults. Microscopically, they exhibit lobules of thin-walled, interconnecting vascular channels in a sinusoidal pattern with little intervening stroma (Figure 3C). Occasional pseudopapillary structures may be observed (Figure 3D). Unlike typical CMs, the lining cells may appear more atypical with mild nuclear hyperchromatism, raising concern for an angiosarcoma. Sinusoidal hemangiomas do not show the endothelial multi-

layering or infiltrative pattern characteristic of a well-differentiated angiosarcoma.13

Nevus flammeus Nevus flammeus is a clinically distinct congenital capillary malformation commonly involving the forehead, face, and neck of newborns. Most lesions, particularly in the glabella, disappear during infancy. However, occipital, sacral, and large facial or extremity nevus flammeus, also termed port-wine stains, may persist into adulthood as progressively thickening, dark plaques.2 Port-wine stains may be associated with numerous congenital syndromes, including the Sturge– Weber and Klippel–Trenaunay syndromes.2,10 Microscopic examination demonstrates a proliferation of ectatic, thin-walled capillaries and venules with variably sized lumina, predominantly centered in the reticular dermis.10 They presumably arise from an abnormality in the surrounding connective tissue. Marked dilation may impart a cavernous appearance to the vessels.2

Arteriovenous malformations (arteriovenous hemangiomas) Arteriovenous malformations (AVMs) are further classified as deep-seated or superficial. Deep AVMs may be located in the head and neck region, limbs, gastrointestinal tract, central nervous system, or deep soft tissues of children or young adults.11 Deep AVMs are high-flow abnormal fistulous connections between feeding arteries and draining veins that often pose a challenge to surgical correction. They are associated with a variable degree of arteriovenous shunting and can cause limb hypertrophy, heart failure, life-threatening hemorrhage, or consumptive coagulopathy (Kasabach–Merritt syndrome). The diagnosis usually requires radiological correlation.12 Superficial AVMs (cirsoid aneurysms) are cutaneous lesions usually in the extremities or the craniofacial region of middle-aged adults that are not usually symptomatic or associated with shunting.11,12,14 Both types of AVMs are microscopically composed of variable numbers of tortuous, dilated, thin- and thick-walled

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Figure 3 Cavernous malformation. (A) Intrahepatic, subcapsular lesion exhibiting gaping, thin-walled, and blood-filled vessels with an associated chronic inflammatory infiltrate in the adjacent hepatic parenchyma (H&E stain; original magnification, 20⫻). (B) The intervening stroma may show dense fibrosis and myofibroblastic proliferation (H&E stain; original magnification, 100⫻). (C) Sinusoidal variant exhibiting circumscribed, dermal proliferation of dilated, interconnecting, thin-walled vessels in a sinusoidal pattern with little intervening stroma (H&E stain; original magnification, 20⫻). (D) Pseudopapillary structure lined by prominent, hyperchromatic endothelial cells (H&E stain; original magnification, 400⫻).

vessels of varying size, usually with at least a focal presence of an internal elastic lamina (Figure 4A and B).12 Deep AVMs typically are infiltrative, whereas superficial lesions usually are well-circumscribed. Superficial AVMs may be associated with a small feeder muscular artery.14

Lymphatic malformations Lymphatic malformations (LMs) result from failure of sequestration of lymphatic tissue during embryogenesis.

Although any site except the eye and brain may be involved, LMs are mostly seen in the head and neck region or axilla of children and adolescents as cutaneous proliferations or as deep seated large masses up to 30 cm.15 Cutaneous lymphatic malformations are classified as lymphangioma circumscriptum or benign lymphangioendothelioma (acquired progressive lymphangioma). Lymphangioma circumscriptum consists of a circumscribed proliferation of dilated lymphatics in the superficial dermis, often present in association with deep seated lymphatic malformations (Figure

Figure 4 Arteriovenous malformation in patient with Osler–Weber–Rendu syndrome and recurrent lower gastrointestinal bleeding. (A) Ulcerated (asterisk) colonic mucosa with a submucosal vascular lesion (H&E stain; original magnification, 20⫻). (B) This lesion consists of an admixture of thin- (white arrow) and thick-walled (black arrow) vessels (H&E stain; original magnification, 100⫻).

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Figure 5 Lymphatic malformations. (A) Lymphangioma circumscriptum exhibiting a superficial, circumscribed, subepithelial proliferation of small, thin-walled lymphatic vessels with associated collarette of acanthotic squamous epithelium (H&E stain; original magnification, 100⫻). (B) Lymphangioma showing a microcystic proliferation of thin-walled lymphatic vessels (H&E stain; original magnification, 40⫻). (C) Cystic hygroma demonstrating macrocystic, dilated, thin-walled lymphatic vessels, intraluminal proteinaceous fluid, and intervening fibrous stroma with scattered lymphoid aggregates (H&E stain; original magnification, 40⫻). (D) Lymphangiomatosis involving liver with extensive and diffuse infiltration of hepatic parenchyma (H&E stain; original magnification, 40⫻). (E) Primary intestinal lymphangiectasis exhibiting dilated lymphatic channels within lamina propria (HPS stain; original magnification, 100⫻).

5A).2,11 Benign lymphangioendothelioma, also known as acquired progressive lymphangioma (APL) is a solitary, benign, slow-growing dermal lesion typically in children or adults following surgery, irradiation, or minor injury.10 APL is composed of anastomosing lymphatic vessels dissecting between dermal collagen, creating a pseudoangiosarcomatous pattern. Although challenging at times, the distinction of APL from well-differentiated angiosarcoma is facilitated by the lack of atypia and mitoses. Distinction from patch stage Kaposi’s sarcoma is facilitated by staining with human herpes virus 8 (HHV-8).16 Deep seated lymphatic malformations include lymphangioma/cystic hygroma and lymphangiomatosis. Lymphangiomas are circumscribed, multiloculated, microcystic, and/or macrocystic lesions with variably sized lymphatic spaces. The cystic spaces are lined by flat endothelium and the adjacent stroma contains lymphoid aggregates, granulation tissue, foam cells, myofibroblastic proliferation, and collagen bundles.12,17 Lymphangiomas are referred to as cystic hygromas when the lymphatic channel dilation is macroscopically visible (Figure 5B and C).11 Lymphangiomatosis denotes a diffuse and infiltrative form of lymphangioma dissecting through collagen and multiple planes of tissue resulting in serious morbidity and may cause death, especially when visceral organs are involved (Figure 5D).10,11,16,18

The differential diagnosis of lymphangiomas includes lymphangiectasis, a pathologic dilation of preexisting lymphatics. Primary lymphangiectasis presents in visceral organs of neonates and is usually fatal at birth (Figure 5E). Secondary lymphangiectasis results from impaired lymph drainage and demonstrates multifocal dilatations along lymphatic routes, rather than a localized proliferation of lymphatic channels, as in a lymphangioma.19 Lymphangiomyoma and lymphangiomyomatosis may also be considered in the differential diagnosis of lymphangiomas, but these lesions usually show a diffuse HMB-45-positive smooth muscle proliferation within lymphatic channels and occur in reproductive-aged females.18 Differentiation from other vascular malformations, especially cavernous hemangiomas, may be very difficult but is facilitated by the presence of lymphoid aggregates and D2-40 immunoreactivity.

Hemangiomas Infantile hemangioma (juvenile capillary hemangioma) Infantile hemangiomas (IHs) are common benign neoplasms, especially in infants where the incidence is esti-

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Figure 6 Infantile hemangioma. (A) Lobular proliferation of capillaries involving the dermis and subcutis (H&E stain; original magnification, 40⫻). (B) Variably sized capillaries typically wrap around adnexal structures (H&E stain; original magnification, 100⫻). (C) The presence of perineural invasion (asterisk) does not signify malignancy (H&E stain; original magnification, 200⫻).

mated at 1% to 10% of live births.4 Recent work suggests that these arise from an uncontrolled clonal expansion of an endothelial cell of placental origin.6 They are red, ⬍5 cm macules or plaques usually occurring in the head and neck regions of infants. Involvement of visceral organs may rarely be seen. Certain sites and patterns, such as lumbosacral, ophthalmic, or facial lesions in a beard-like distribution, may be associated with more serious internal anomalies. IHs usually enlarge rapidly during infancy and subsequently involute in childhood.14,20 Histologically, IHs are multilobular tumors of varying cellularity occurring in the dermis and subcutis with frequent involvement of skin adnexal structures (Figure 6A and B).4 Very immature lesions are often densely cellular, which may obscure the characteristic lobular pattern and vascular spaces. With maturation, the vessels dilate and become replaced by increasing amounts of fibrofatty tissue that may completely obliterate the remaining vascular lumina in the oldest lesions.11,14 Most IHs consist of multiple lobules of capillaries and varying degrees of solid endothelial cell proliferations admixed with surrounding pericytes, fibroblasts, and mast cells in the dermis or subcutis. A feeding arteriole may be seen at the deep margin.10,11 Perineural invasion and brisk mitotic activity may be identified, but their presence does not signify malignancy (Figure 6C).4,11 A reticulin stain may help highlight capillary lumina in early, cellular lesions.11 IH in all stages of its evolution stains with GLUT-1 (erythrocyte-type glucose transporter protein), which is a marker of placental fetal vessels and is not present in other vascular tumors of childhood. GLUT-1 positivity differentiates IH from other similar appearing vascular lesions, such as tufted angioma, kaposiform hemangioendothelioma, or pyogenic granuloma.1 IHs must be distinguished from the so-called congenital hemangiomas, which have similar demographic characteristics and histologic appearances as IHs, but exhibit different clinical behaviors. Congenital hemangiomas are classified as rapidly involuting congenital hemangioma (RICH) or noninvoluting congenital hemangioma (NICH). Unlike IHs, they are typically negative for GLUT-1.1 Microscopically, the tumor lobules are not separated by normal appearing tissue elements, but rather by bands of dense fibrosis

with prominent thin-walled draining channels and arteriolobular fistulas.21

Lobular capillary hemangioma (pyogenic granuloma) Lobular capillary hemangiomas (LCHs) are exophytic, solitary, red, friable, usually ⬍2.5 cm, rapidly growing polypoid masses occurring on the skin and oral mucosa of children or young adults. These tumors were initially thought to be reactive due to their often pronounced inflammatory changes, resemblance to granulation tissue, and frequent association with irritation, medications (e.g., cyclosporine), trauma, or hormonal factors.22 However, the ISSVA reclassified pyogenic granulomas as LCH, primarily based on their growth pattern and lobulated appearance.1 Microscopically, the overlying epithelium may be ulcerated or atrophic with underlying mixed inflammation. The key feature is the circumscribed, lobulated capillary proliferation within an edematous or fibromyxoid stroma (Figure 7A and B).10,12 The capillaries within the lobules are variably sized and composed of bland-appearing, plump endothelial cells with brisk mitotic activity.10,12,22 Recent studies have suggested separating these lesions into LCH and nonLCH types, which may address the confusion in categorizing them as hemangiomas or reactive proliferations. The LCH type is more frequently sessile with deeper lobules. The lobular aggregates exhibit sparse inflammation in the nonulcerated areas. The non-LCH type is typically pedunculated and resembles granulation tissue within the center away from the ulcerated area. It is more frequently associated with etiological factors.22,23 Variants of PGs include granuloma gravidarum, a subcutaneous variant, and an intravenous type. Granuloma gravidarum typically occurs abruptly on the gingival surface during the first trimester of pregnancy and regresses after parturition.10 Intravenous PG mostly arises within a large vein in the neck and upper extremities and is often mistaken for an organizing thrombus. Subcutaneous PG has a predilection for the upper limb, usually does not become ulcer-

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Figure 7 Pyogenic granuloma. (A) Polypoid cutaneous lesion exhibiting a circumscribed, lobulated vascular proliferation with an overlying atrophic epidermis (H&E stain; original magnification, 20⫻). (B) The lobules consist of capillaries set within a fibromyxoid stroma containing scattered inflammatory cells (H&E stain; original magnification, 200⫻).

ated, and is not associated with secondary inflammatory changes.4,10,11

Acquired tufted angioma Acquired tufted angiomas are slow-growing, distinctly tender, indurated, dusky papules or plaques measuring up to 10 cm. They typically arise on the neck and upper trunk of children and young adults. Clinically, patients may exhibit hypertrichosis overlying the lesion and rarely the Kasabach–Merritt phenomenon.24 At low power, there are variably sized, irregular, tightly packed, and cellular lobules in a characteristic “cannonball” pattern within the reticular dermis and subcutis (Figure 8A).10,11 An associated eccrine glandular proliferation may be present.25 The vascular tufts consist of near solid aggregates of endothelial cells with admixed pericytes. Elongated, narrowed, and dilated vascular spaces are seen at the periphery of lobules, where they have a semilunar appearance (Figure 8B).10,11 Endothelial cells may contain intracytoplasmic crystalline inclusions

and exhibit occasional mitoses.11,26 The histologic differential diagnosis includes infantile hemangioma and lobular capillary hemangioma. The former can be distinguished by its different clinical appearance, more regular-appearing lobules histologically, and GLUT-1 immunoreactivity. The latter has more edematous stroma, greater proportion of dilated capillaries, and frequent association with thickwalled feeding vessels.10

Spindle cell hemangioma The categorization of spindle cell hemangioma as a malformation, benign neoplasm, or reactive proliferation has been problematic. It was originally described in 1986 as “spindle cell hemangioendothelioma” and thought to have low-grade malignant potential. However, subsequent work has led to its reclassification as a benign lesion.10 Spindle cell hemangiomas have characteristics of a benign neoplasm with their growth pattern and elements of a malformation due to frequently surrounding abnormal vasculature with

Figure 8 Acquired tufted angioma. (A) Variably sized, compact, and cellular lobules of capillaries in a characteristic “cannonball” pattern in the superficial and deep dermis (H&E stain; original magnification, 100⫻). (B) Vascular tufts consist of near solid aggregates of endothelial cells with admixed pericytes. An elongated and compressed vascular space with a semilunar appearance is seen at the periphery of a lobule (arrowheads; H&E stain; original magnification, 200⫻).

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Figure 9 Spindle cell hemangioma. (A) Mixture of dilated and collapsed cavernous vessels alternating with fascicles of myofibroblastic spindle cells (H&E stain; original magnification, 100⫻). (B) Characteristic epithelioid endothelial cells with intracytoplasmic lumina (arrows) are admixed with spindle cells (H&E stain; original magnification, 200⫻). (C) Some of these epithelioid endothelial cells appear to line vascular spaces (circled area; H&E stain; original magnification, 400⫻).

irregularly attenuated walls, herniations, and intraluminal webs. Additionally, the suggestion of the development of spindle cell hemangiomas due to adjacent disruptions in local blood flow intimates a reactive process.27 Spindle cell hemangiomas occur in the dermis or subcutis of the distal extremities in young adults and measure ⬍2 cm. They have also been reported in viscera such as the spleen and pancreas.28 Microscopically, they are poorly circumscribed and composed of a mixture of dilated and collapsed cavernous vessels and solid areas (Figure 9A). The latter contains bland spindle cells appearing myofibroblastic in nature. Admixed within solid areas are epithelioid endothelial cells, varying numbers of which contain an intracytoplasmic vacuole (Figure 9B and C). The periphery may show thick-walled muscular vessels. Many of these

lesions are intravascular. Mitotic activity is very low, but recurrence is common, usually from inadequate resection.10,27 The spindle cells are characteristically negative for CD34, HHV-8, and other vascular markers and positive for smooth muscle actin. In contrast, the spindle cells of its main differential diagnostic consideration, Kaposi’s sarcoma, are positive for vascular markers and negative for smooth muscle actin.12,29

Hobnail hemangioma (targetoid hemosiderotic hemangioma) Hobnail hemangiomas have a distinct clinical appearance characterized by a central violaceous papule surrounded by a pale area and an outermost ecchymotic ring

Figure 10 Hobnail hemangioma. (A) Wedge-shaped proliferation of ectatic vessels predominantly in the sclerotic papillary dermis. These become smaller and more slit-like as they ramify into the deeper dermis (H&E stain; original magnification, 40⫻). (B) Vascular space demonstrating intraluminal papillary tufts lined by protruding, plump endothelial cells (H&E stain; original magnification, 400⫻). (C) The stroma contains extravasated erythrocytes and hemosiderin pigment (arrows; H&E stain; original magnification, 400⫻).

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Figure 11 Microvenular hemangioma. (A) Poorly circumscribed proliferation of relatively uniform, branching, and angulated thin-walled vessels involving the entire depth of the sclerotic reticular dermis (H&E stain; original magnification, 100⫻). (B) These collapsed vessels are lined by flat endothelial cells and accompanied by a rim of pericytes (H&E stain; original magnification, 200⫻).

resembling a target.4 Microscopically, there is a wedgeshaped proliferation of ectatic vessels within the papillary dermis (Figure 10A).14 These vascular spaces often demonstrate intraluminal papillary projections lined by protruding, plump endothelial cells in a tombstone pattern (Figure 10B).10 The peripheral halo and deeper areas show more irregular, angulated, slit-like vascular channels with flatter endothelial cells dissecting between collagen bundles.4,10,11 The endothelial lining of the vascular channels recently has been reported to react with D2-40 immunohistochemical stain, which suggests lymphatic differentiation. The presence of blood within the spaces could be due to microshunts between lymphatic channels and small vessels.30 The dermis shows hemosiderin deposits, mild chronic inflammation, and dermal sclerosis, suggesting that hobnail hemangiomas may arise from a traumatized hemangioma (Figure 10C).4,14 The primary differential diagnostic consideration is patch stage Kaposi’s sarcoma. The latter can be differentiated from hobnail hemangiomas by presence of vascular channels dissecting around adnexal structures

(the so-called “promontory sign”), diffuse rather than wedge-shaped vascular proliferation, conspicuous presence of spindle and plasma cells, and immunoreactivity for HHV-8.

Microvenular hemangioma Microvenular hemangiomas are slow-growing, ⬍2-cm lesions occurring on the forearms and lower extremities of young adults.4,14 Histologically, there is a poorly circumscribed proliferation of uniform, branched, angular, collapsed, and thin-walled vessels involving the entire depth of a sclerotic reticular dermis (Figure 11A).14 The collapsed vessels are lined by flat endothelial cells accompanied by a rim of pericytes (Figure 11B).4,11 The differential diagnosis includes patch stage Kaposi’s sarcoma, which can be distinguished from microvenular hemangioma by the aforementioned histologic features (see Hobnail hemangioma).

Figure 12 Papillary endothelial hyperplasia. (A) Organizing thrombus exhibiting patchy collagenous areas with hyalinized papillary structures, some of which have fused to give an anastomosing vascular pattern (H&E stain; original magnification, 40⫻). (B) The hyalinized papillae contain sclerotic cores and are lined by plump endothelial cells (H&E stain; original magnification, 200⫻). (C) Fusion of papillae result in an anastomosing vascular pattern mimicking angiosarcoma (H&E stain; original magnification, 200⫻).

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Figure 13 Bacillary angiomatosis. (A) Prominent lobular capillary proliferation with admixed inflammation in the dermis (H&E stain; original magnification, 100⫻). (B) Plump endothelial cells with cytoplasmic clearing are present within a background of mixed inflammation comprised of neutrophils, histiocytes, and lymphocytes. The most characteristic findings are aggregates of granular, pink–purple material (circled area) that are positive for Warthin–Starry stain (not shown) and represent bacillary organisms of Bartonella spp. (H&E stain; original magnification, 400⫻).

Reactive vascular proliferations Papillary endothelial hyperplasia (Masson’s tumor) Papillary endothelial hyperplasia (PEH) is an unusual variant of an organized thrombus. It is considered to be a reactive process due to its growth pattern, relationship to trauma, and ultrastructural resemblance to granulation tissue. PEHs are typically ⬍2 cm and occur predominantly in an isolated, dilated vessel located within the subcutis of the head and neck region, trunk, and digits in individuals of all ages. PEH may be associated with other vascular tumors or hematomas.10,31 Microscopically, PEH is circumscribed with small, peripheral, hyalinized papillae lined by a single layer of plump

endothelial cells (Figure 12A and B). The center of the lesion demonstrates organized collagenous areas with fused papillae imparting an anastomotic vascular appearance often mimicking angiosarcoma (Figure 12C).4,10 The background characteristically shows hemosiderin, organizing thrombi, and surrounding chronic inflammation.31 Differentiation from angiosarcoma may be difficult, particularly if the involved vessel ruptures, creating a pseudoinfiltrative pattern. Unlike angiosarcoma, however, PEH lacks cytologic atypia, mitotic activity, and solid areas of growth.4,11,31

Bacillary angiomatosis Bacillary angiomatosis (BA) is a reactive vascular proliferation caused by fastidious, Gram-negative rods of Bar-

Figure 14 Epithelioid hemangioma. (A) Vascular proliferation with prominent mixed inflammatory infiltrate in the dermis (H&E stain; original magnification, 40⫻). (B) Plump, epithelioid endothelial cells line well-formed, small-caliber blood vessels. The inflammatory infiltrate consists of eosinophils, mast cells, and lymphocytes (H&E stain; original magnification, 200⫻).

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Figure 15 Kimura’s disease in Asian male with peripheral eosinophilia. (A) Areas of vascular proliferation with mixed inflammatory infiltrate (asterisks). The background contains multiple lymphoid follicles and bands of dense stromal fibrosis (H&E stain; original magnification, 40⫻). (B) The inflammatory infiltrate consists of eosinophils, mast cells, lymphocytes, and increased numbers of vessels with plump endothelial cells having eosinophilic cytoplasm, open chromatin, and prominent nucleoli (original magnification 400⫻; H&E stain).

tonella spp. Although immunocompromised patients are predominantly affected, certain South American species that cause life-threatening Oraya fever may affect immunocompetent hosts.4 Bartonella organisms target endothelial cells and cause pro-inflammatory activation and subsequent vasoproliferative growth.32 BA typically presents as multiple, pink, elevated, pinpoint lesions in the skin, soft tissue, and viscera that transform into larger nodules, often accompanied by systemic symptoms.4 Histologically, there is a compact lobular pattern with prominent capillary proliferation (Figure 13A).4 The endothelial cells are plump without significant atypia and demonstrate clear cytoplasm with vesicular nuclear chromatin. However, the most characteristic findings are the background neutrophils, leukocytoclastic debris, and variably sized aggregates of granular, purple material highlighted by the Warthin–Starry stain (Figure 13B).4,10,32 The primary differential diagnostic consideration is lobular capillary hemangioma (LCH). In contrast to LCH, the connective tissue septa of bacillary angiomatosis intersecting the lesion are less conspicuous. However, distinction between these entities may be nearly impossible in the absence of Warthin–Starry-positive debris.4 Polymerase chain reaction (PCR) detection of Bartonella spp. may be helpful.

Table 1

Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) Epithelioid hemangioma (EH) is a reactive lesion in young adults often associated with a damaged vessel from trauma or certain hormonal states like pregnancy.10 It is an unencapsulated but fairly defined lesion measuring ⬍3 cm and typically occurs in the skin and subcutis of the digits and head and neck region, particularly the temporal area. Localization to extracutaneous sites, such as the deep muscles, bone, and salivary glands, has been reported.33 Microscopically, EH is characterized by well-formed, small-caliber vessels lined by plump endothelial cells admixed with a prominent inflammatory infiltrate comprised of eosinophils, mast cells, and lymphocytes (Figure 14A and B).14 The periphery shows irregular, thick-walled, larger vessels as well as rare infiltrative foci. The center may have solid nests of epithelioid endothelial cells which have abundant eosinophilic cytoplasm and nuclei with open chromatin and prominent nucleoli. Occasionally, vacuolated cytoplasm representing primitive vascular lumina may be seen. Mitotic activity is low, and recurrence occurs with incomplete excision.11 Immunohistochemically, CD31 and CD34 may

Clinical and histologic differences between epithelioid hemangioma and Kimura’s disease34,35

Clinical features Sex Race Lymphadenopathy Peripheral eosinophilia IgE levels Histologic features Depth Shape Vessels Lymphoid follicles Stromal fibrosis

Epithelioid hemangioma

Kimura’s disease

Slight female predominance No racial predilection Uncommon ⬃20% of cases Normal

Male predominance Asians Common Invariably present Increased

Superficial Circumscribed Prominent Occasional Not prominent

Deep seated Noncircumscribed Not prominent Abundant Prominent

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Figure 16 Glomeruloid hemangioma. (A) Multiple dilated vascular spaces and aggregates of capillary loops in the dermis (H&E stain; original magnification, 20⫻). (B) These aggregates project into the dilated blood vessels resembling glomeruli. Note the presence of interstitial cells containing eosinophilic, PAS-positive globules likely representing immunoglobulin (arrows; H&E stain; original magnification, 400⫻). Courtesy of Dr. Brian Rubin (Cleveland Clinic).

only partially stain the epithelioid endothelial cells, and keratin stains may be focally positive.33 The differential diagnosis includes epithelioid angiosarcoma and epithelioid hemangioendothelioma. Angiosarcoma is more infiltrative, with more atypia and mitoses. Epithelioid hemangioendothelioma usually does not have welldefined vascular channels. Neither of these lesions normally demonstrates prominent lymphoid hyperplasia as in EH.33 Previously, Kimura’s disease (Figure 15A and B) was considered to be on the same spectrum as EH due to similarity in location, presence of vascular proliferation, and eosinophilic inflammation.34,35 However, reports now suggest they are different entities based on both clinical and pathologic findings. The clinical and pathologic differences are summarized in Table 1. Epithelioid angiomatoid nodule (EAN) is a circumscribed, ⬍1.5-cm, cutaneous lesion that may also enter the differential diagnosis of EH. Unlike EH, however, EAN is confined to the dermis of the trunk and extremities and histologically demonstrates a unilobular, sheet-like proliferation of large polygonal epithelioid, vacuolated endothelial cells. In contrast to EH, well-formed vascular channels are only focal, and the inflammatory infiltrate is peripheral rather than admixed.36

typic immunoglobulin, are present (Figure 16B).4,10,11,14 The capillary and outer sinusoidal endothelium demonstrate distinct immunophenotypes, with the capillary endothelium having a CD31⫹/CD34⫹/vWF⫹/CD68⫺ phenotype and the outer sinusoidal endothelium expressing a CD31⫹/CD34⫺/ vWF⫺/CD68⫹ phenotype.14,37 The microscopic differential diagnosis includes intravascular LCH, which shows more lobulation and a fibromyxoid stroma. Acquired tufted angioma shows solid areas typically absent in GH and also lacks the characteristic PASpositive cells of GH.4

Cherry angiomas (senile angiomas) Cherry angiomas are common acquired, incompressible, red papules measuring a few millimeters on the trunk and extremities.4 With age, they increase in number and size and have been associated with POEMS syndrome, hormonal

Glomeruloid hemangioma Glomeruloid hemangiomas are reactive, ⬍1-cm, domeshaped papules on the trunk and proximal extremities erupting specifically in patients with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes (POEMS) syndrome and multicentric Castleman’s disease.4,14 Microscopically, these hemangiomas exhibit multiple dilated vascular spaces in the upper dermis containing aggregates of capillary loops resembling renal glomeruli (Figure 16A and B). The capillaries are lined by flat to plump, vacuolated endothelial cells surrounded by pericytes. Large, intermingling, eosinophilic interstitial cells containing PAS-positive globules, likely representing poly-

Figure 17 Cherry angioma. Polypoid proliferation of variably thickened, dilated, and congested capillaries in the papillary dermis with little intervening stroma (H&E stain; original magnification, 100⫻).

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13 of parallel-oriented, thin-walled vessels in the papillary dermis in a background of solar elastosis.39

Vascular ectasias Angiokeratoma

Figure 18 Angiokeratoma. Superficially dilated and congested capillaries and venules with overlying papillomatous epidermis exhibiting irregular acanthosis and hyperkeratosis (H&E stain; original magnification, 100⫻).

factors, and chemotherapy.4,14 Histological examination demonstrates a polypoid proliferation of variably thickened, dilated, and congested capillaries in the papillary dermis with little intervening stroma (Figure 17).4,14 Some reports have suggested that, due to frequent involvement by intravascular B-cell lymphoma (IVL), biopsies of cherry angiomas may be helpful. IVL is a rare subtype of extranodal, diffuse large B-cell lymphoma that is often difficult to diagnose due to a lack of specific laboratory, imaging, or clinical findings.38

Acquired elastotic hemangioma Acquired elastotic hemangiomas are rare, 2- to 5-cm plaques mostly affecting sun-exposed skin of elderly females. Microscopically, they show a band-like proliferation

Angiokeratomas are benign papules that may cluster or coalesce into verrucoid nodules or plaques over the lower trunk, genitalia, or extremities of children and young adults.4,14 They may arise from radiotherapy or with enzymatic disorders such as Fabry’s disease.14 Clinically, they are classified into several types based on presentation and location, but all have a similar histological appearance. Microscopically, angiokeratomas are composed of superficially dilated and congested capillaries and venules with an overlying epidermis that exhibits hyperkeratosis, parakeratosis, papillomatosis, and irregular acanthosis (Figure 18).40 In Fabry’s disease, intracytoplasmic lipid vacuoles may be seen within the endothelial cells.2,11 The differential diagnosis of angiokeratomas includes verrucous hemangioma and lymphangioma circumscriptum. The former is classified as a malformation and occurs in the lower extremities of children. It may measure up to several centimeters and exhibits similar epidermal changes as angiokeratomas (Figure 19A).14 However, unlike angiokeratomas, there are increased numbers of ectatic capillaries and larger cavernous spaces which extend much deeper into the dermis and subcutis (Figure 19B).40,41 Lymphangioma circumscriptum has a similar verrucoid epidermis and superficially dilated vessels as angiokeratomas, but the former is clinically and histologically distinguished by small vesicles and proteinaceous contents within the vascular spaces.

Figure 19 Verrucous hemangioma. (A) Papillomatous, hyperkeratotic epidermis with underlying ectatic capillaries and larger cavernous spaces (H&E stain; original magnification, 20⫻). (B) Unlike angiokeratomas, the vascular proliferation extends much deeper into the dermis and subcutis (H&E stain; original magnification, 100⫻).

Unilateral dermatomal distribution; may affect oral mucosa

Progressively ascending dilated capillaries in upper dermis

Autosomal dominant; skin, particularly palms and soles, oral and nasal mucosa, and internal organs; associated with other vascular malformations

Autosomal dominant; solely cutaneous and widespread

Autosomal recessive; face, neck, limbs, conjunctiva; progressive cerebellar ataxia and immune dysfunction

F⬎M

F ⬎ M; middle age

M ⫽ F; young to middle age

M⫽F

M ⫽ F; children

Unilateral nevoid telangiectasia

Generalized essential telangiectasia

Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease)

Hereditary benign telangiectasia

Ataxia telangiectasia

Nevus araneus (spider angioma) Nevus araneus is a common lesion affecting 10% to 15% of normal adults and children. It is often seen in pregnancy, thyrotoxicosis, and liver disease. Clinically, there is a central, slightly elevated, red punctum with radiating vessels.2 Histologically, there is a central arteriole ending in a thinwalled ampulla beneath the epidermis with radiating delicate arterial branches in the papillary dermis.10

Venous lake Venous lakes are soft, dark blue papules occurring on sun-exposed skin or the oral mucosa of elderly patients. Microscopic sections show a markedly dilated venule immediately beneath the epidermis with a thin, irregular layer of smooth muscle (Figure 20).11 It is often thrombosed and may show papillary endothelial hyperplasia.

Telangiectasias Telangiectasias are visible, permanent dilatations of preexisting venules, capillaries, or arterioles in the papillary dermis. Primary telangiectasias are seen in unilateral nevoid telangiectasia, hereditary benign telangiectasia, generalized essential telangiectasia, hereditary hemorrhagic telangiecta-

Table 2

Angioma serpiginosum is a persistent, slowly progressive lesion typically occurring in the lower extremities of young females. It is characterized by multiple, red–purple, purpuric-like macules extending over months in serpiginous patterns.11 Microscopically, the dermal papillae contain clusters of dilated capillaries with thickened, collagenous walls. Inflammation is usually absent.42

Clinical and histologic features of primary telangiectasias2

Angioma serpiginosum

Dilated capillaries in upper dermis; increased estrogen and progesterone receptors Dilated capillaries in upper dermis; absent estrogen and progesterone receptors Dilated venules near overlying epithelium; thickwalled vessels around base often with dense lymphocytic infiltrate around vessels; frequently hemorrhagic Dilated arterioles and/or venules in upper dermis; not associated with bleeding diathesis Dilated capillaries in upper dermis

Clinical features

Figure 20 Venous lake. Markedly dilated, blood-filled venule with a thin, irregular smooth muscle wall immediately beneath the epidermis (H&E stain; original magnification, 20⫻).

Age/sex

Histologic features

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Type

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sia (Osler–Rendu–Weber disease), or ataxia–telangiectasia (Table 2).2 Secondary telangiectasias occur in a variety of conditions, including collagen vascular diseases, cutaneous mastocytosis, graft-versus-host disease, trauma, radiation, steroid use, or sun damage, and often show coexisting epidermal or dermal changes, such as atrophy or depigmentation.43

Conclusion Appropriate nomenclature for benign vascular proliferations remains problematic because of overlapping histology and a limited understanding of the pathogenesis. Though benign, these lesions show diverse clinical presentations and behavior, from involuting solitary lesions to slowly progressive, clinically asymptomatic lesions to large, diffuse, symptomatic lesions recurring locally following excision. An interdisciplinary approach combining radiographic, pathologic, and clinical features is important for proper diagnosis and to guide management. In the future, improved understanding of the molecular mechanisms governing vasculogenesis and angiogenesis may direct new therapies and offer improved insights into the etiology and pathogenesis of these lesions.

Acknowledgments We would like to thank Dr. Steven Billings (Cleveland Clinic) for providing the photomicrographs of glomeruloid hemangioma.

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16 34. Seregard S: Angiolymphoid hyperplasia with eosinophilia should not be confused with Kimura’s disease. Acta Ophthalmol Scand 79:91-93, 2001 35. Chen H, Thompson LD, Aguilera N, et al: Kimura disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 28:505-513, 2004 36. Brenn T, Fletcher CD: Cutaneous epithelioid angiomatous nodule: a distinct lesion in the morphologic spectrum of epithelioid vascular tumors. Am J Dermatopathol 26:14-21, 2004 37. Kishimoto S, Takenaka H, Shibagaki R, et al: Glomeruloid hemangioma in POEMS syndrome shows two different immunophenotypic endothelial cells. J Cutan Pathol 27:87-92, 2000 38. Satoh S, Yamazaki M, Yahikozawa H, et al: Intravascular large B cell lymphoma diagnosed by senile angioma biopsy. Intern Med 42:117120, 2003

Seminars in Diagnostic Pathology, Vol 25, No 1, February 2008 39. Requena L, Kutzner H, Mentzel T: Acquired elastotic hemangioma: a clinicopathologic variant of hemangioma. J Am Acad Dermatol 47: 371-376, 2002 40. Mittal R, Aggarwal A, Srivastava G: Angiokeratoma circumscriptum: a case report and review of the literature. Int J Dermatol 44:1031-1034, 2005 41. Tennant LB, Mulliken JB, Perez-Atayde A, et al: Verrucous hemangioma revisited. Pediatr Dermatol 23:208-215, 2006 42. Ohnishi T, Nagayama T, Morita T, et al: Angioma serpiginosum: a report of 2 cases identified using epiluminescence microscopy. Arch Dermatol 135:1366-1368, 1999 43. Salama S, Rosenthal D: Cutaneous collagenous vasculopathy with generalized telangiectasia: an immunohistochemical and ultrastructural study. J Cutan Pathol 27:40-48, 2000