Initially, there is a barely detectable dilatation of the thin-walled vessels of the superficial vascular plexus. Progressive ectasia occurs and there is obvious erythrocyte stasis. ⁵⁵ There is no significant increase in thickness or number of vessels with age in typical superficial lesions. In some cases there is an underlying cavernous hemangioma, which may blend with the superficial lesion. Localized exaggeration of the vascular ectasia produces the roughened surface of the older lesions.^{27. and 56.} In one case these late changes were associated with epithelial and mesenchymal hamartomatous changes. ⁵⁷ Secondary angiomatous lesions and pyogenic granulomas may occur within the main lesion.^{58. and 59.}

One study has shown that the lesions are produced by dilatations of postcapillary venules of the superficial horizontal plexus, with no evidence of new vessel formation, although most authorities now believe that there is an increase in the number of vessels. ¹⁷ The walls of the venules are thickened by basement membrane-like material and reticulin fibers. ⁶⁰ Progressive dilatation does not appear to be related to decreased fibronectin or type IV collagen in the vessel walls. ⁶¹ A decreased nerve density has been demonstrated within affected areas, and it has been proposed that abnormal neural control of blood flow may be important in the pathogenesis of this lesion. ⁶² One immunohistochemical study showed that vessels were typical of capillaries, postcapillary venules, and small veins. ⁶³ They are GLUT-1 negative.

The malformations may be found at any level of the skin, but there is a tendency for them to occur in the deep dermis and subcutis. They consist of large dilated vascular channels lined by flat endothelium (Fig. 38.2). The walls of the vessels vary in thickness, but they are generally thin and fibrous. Some vessels may have smooth muscle in their walls and resemble dilated veins. Thrombosis may complicate these lesions. Calcification of the walls and phlebolith-like calcific bodies in the lumina may be found.

Various changes, including dilated capillaries and veins in the dermis and subcutis, have been described in this condition.^{104. and 125.} A recent review of all cases of CMTC in the English-language literature found that the most common finding was dilatation of capillaries and veins in the dermis. ¹²⁶ In two cases, and in the additional case reported, there was a proliferation of vascular channels. The implications of this proliferation on the course of the disease were not clear. ¹²⁶ Focal acantholytic dyskeratosis has been reported as an incidental, but closely associated abnormality in one patient. ¹²⁷

Glomulovenous malformations have more prominent vessels and less conspicuous glomus cells than the glomus tumor proper. GVMs are poorly circumscribed and unencapsulated and consist of irregular ectatic vascular channels irregularly surrounded by small numbers of glomus cells (Fig. 38.3). Glomus cells may be so sparse that the lesions can be difficult to distinguish from conventional hemangiomas. Glomangiomatosis refers to diffuse angiomatosis with a histological excess of glomus cells. ¹⁵⁴ The exact nosological position of the glomangiomyoma is unknown. Familial generalized variants have been described. ¹⁵⁵ Their histology suggests a variant of GVM with smooth muscle cells in the wall.^{155.156. and 157.} A variant derived from glomus tumors may also exist.

The epidermis is elevated above the general level of the skin by solitary or grouped ectatic lymphatics located in the papillary dermis (Fig. 38.4). This accounts for the raised vesicles seen clinically. These channels abut closely on the overlying epidermis and are thin walled, consisting predominantly of an endothelial lining. The vessels may contain eosinophilic proteinaceous lymph or blood or thrombus, and occasionally foamy histiocytes or multinucleate giant cells. ¹⁶¹ Scattered lymphoid cells are sometimes seen in the dermis. There is atrophy of the epidermis directly over the vessels, with elongation of the rete ridges such that the vessels may appear to be intraepidermal, the picture resembling that of angiokeratoma. Deep irregular lymphatics are sometimes seen beneath the surface vessels in the dermis and subcutis, particularly in the extensive lesions. ¹⁶¹ The presence of these subcutaneous lymphatic cisterns with small amounts of smooth muscle in the wall are features that distinguish superficial lymphangioma (lymphangioma circumscriptum) from acquired lymphangiectasia, in which they are absent. Both share saccular dilatation of the superficial lymphatic channels. ¹⁸²

The channels are highlighted by the new lymphatic endothelial marker D2-40.

The histological picture of these tumors is inconstant. There are irregular dilated lymphatic channels of variable size in the dermis, subcutis, and deeper tissues. These structures vary from an endothelium-lined channel with no obvious supporting stroma to vessels with thick fibromuscular walls. The intervening dermis or subcutis may be unaltered, or there may be loose or compact fibrous stroma. ¹⁵⁹ Blood may be present in some channels. In larger lesions collections of lymphocytes are sometimes present in the stroma and cause the endothelium to bulge into the vascular lumen. Lymphatic channels can be confirmed using the D2-40 antibody.

In lymphangiomatosis involving skin, the dermis and subcutis are infiltrated by dilated lymphatic channels which dissect dermal collagen and surround pre-existing structures, a pattern seen in well-differentiated angiosarcoma. Vessels are lined by a single layer of flat endothelium which stains positively for factor VIII-related antigen, Ulex europaeus-1 antigen and, variably, with CD31 and CD34. ¹⁸⁷ Thrombomodulin is a more recent marker, which is said to be specific for lymphatic endothelium. ¹⁹⁰ Podoplanin, detected by the antibody D2-40, is now the most specific marker of lymphatic endothelium.

Fully evolved lesions consist of dermal and subcutaneous foci of small and large vessels, with overlying verrucous hyperplasia of the epidermis. There is irregular papillomatosis with acanthosis and hyperkeratosis. Angiokeratomatous areas may be present; however, unlike angiokeratomas, which are ectasias of superficial vessels (see p. 896), verrucous hemangiomas involve deeper levels.^{191. and 192.} Verrucous hemangiomas have been included in some classifications with the microcystic lymphatic malformations. ¹⁵⁸

Immunostaining shows focal GLUT-1 endothelial positivity. ¹⁹⁵ There is low-level MIB-1 reactivity. ¹⁹⁵ D2-40, a marker of lymphatic endothelium, is negative. ¹⁹⁵

Within the dermal papillae, dilated thin-walled vessels are lined by a single layer of endothelium. Ultrastructural studies have shown these to be venules. ²¹³ Abnormalities in the endothelial lining have also been reported. ²¹⁴

Thin-walled vascular channels are found in the upper dermis. They are produced by dilatation of postcapillary venules of the upper horizontal plexus (Fig. 38.5). ⁶⁰

These lesions are rarely biopsied or excised. They consist of a central ascending spiral thick-walled arteriole which ends in a thin-walled ampulla just beneath the epidermis (Fig. 38.6). From the ampulla, thin-walled branching channels radiate peripherally in the papillary dermis. Glomus cells have been described in the wall of the central arteriole. ²⁴⁴

Usually only a single large dilated vascular channel is present, in the upper dermis (Fig. 38.7). It has a very thin fibrous wall and a flat endothelial lining. A thrombus is sometimes present in the lumen or part thereof. These lesions appear to represent a dilated segment of a vein or venule. ²⁴⁷

In angiokeratomas there is marked dilatation of papillary dermal vessels to form large cavernous channels. There is associated irregular acanthosis of the epidermis with elongation of the rete ridges which partially or completely enclose the vascular channels (Fig. 38.8). A collarette may be formed at the margins of the lesions and there may be thrombosis of the vessels. The surface epidermis may show varying degrees of hyperkeratosis. The occurrence of a deep dermal hemangioma has been reported in association with angiokeratoma circumscriptum.^{267. and 289.} This combination may represent a verrucous hemangioma. In patients with Anderson–Fabry disease there is vacuolation of smooth muscle in arterioles and arteries and in the arrectores pilorum. Frozen sections of lesions may show PAS-positive and Sudan-black-positive granules in endothelial cells, pericytes, arrectores pilorum, and eccrine sweat glands. The vessels do not usually express CD34. ²⁸⁹

All cases have shown variable, but usually mild epidermal atrophy and capillary telangiectasia in the upper dermis. The infiltrate, which is perivascular and lymphocytic, is usually sparse, but it was a little heavier in the case overlying the hip prosthesis. ³⁰⁴

Early lesions are highly cellular and involve the dermis, but extension into the subcutis may occur. Vascular lumina are small, often slit-like and unapparent, and lined by plump endothelial cells (Fig. 38.10). Moderate numbers of normal mitotic figures are present, and mast cells and dermal dendrocytes are frequent in the intervening stroma. ⁴²² It has been suggested that the mast cells may play a role in angiogenesis and therefore in the formation of these lesions. ⁴²³ The vascular proliferation often has a marked lobular configuration; this is often more obvious in the subcutis. Here fat lobules are partly or completely replaced and the appearance may resemble that of angiolipomas. ³⁴¹ Perineural infiltration can be present. ⁴²⁴ This was in a cellular infantile variant. This finding is unusual in the light of a more recent finding that nerve bundles are absent in hemangiomas but present in vascular malformations. ⁴²⁵ Lesions with vessel proliferation, in and around sweat glands, have also been described. ⁴²⁶ As the lesions evolve, vascular lumina become larger and more obvious. A central draining lumen may become evident in each lobule. The endothelium lining the vessels becomes flatter. With regression of lesions there is disappearance of vessels, interstitial fibrosis, and fat replacement of vascular tissue in the lobules of the subcutis. ³⁴¹ Immunohistochemical studies have demonstrated endothelial (CD31⁺) and pericytic (SMA⁺) differentiation in cells. ⁴²⁷ The early involution phase is characterized by ICAM-1 (CD54) expression and a sparse infiltrate of CD8⁺ cells. ³³⁴ The endothelial cells express GLUT-1, in contrast to malformations. They also express Lewis Y antigen (LeY), merosin, and CD15.^{334. and 428.} The transcription factor encoded by the Wilms’ tumor 1 (WT1) gene is expressed in the endothelium of hemangiomas but not in vascular malformations. ⁴²⁹ It is also expressed in angiosarcomas. ⁴³⁰

A lobular architecture is characteristic of sinusoidal hemangioma (Fig. 38.11). Lobules are composed of thin-walled interconnecting vascular channels forming a sinusoidal pattern. Vessels are closely approximated, with little intervening stroma. Tangential sectioning of vessel walls produces a pseudopapillary pattern. Unlike typical ‘cavernous’ hemangiomas, lining cells may appear focally atypical with nuclear hyperchromatism. Mitotic figures are not seen. Calcification is a rare complication. ⁴³⁴

The lesions were composed of sheets of vacuolated⁴³⁶ or clear cells⁴³⁵ with intervening vessels ranging from small capillaries to large ectatic, thin-walled vessels. In the case with vacuolated cells there was some resemblance to a lipoma. ⁴³⁶ This case also showed focal necrosis and some stromal hemosiderin. The tumor cells stained for neuron-specific enolase and calponin but not for HMB-45, epithelial membrane antigen, or glial fibrillary acid protein (GFAP). Some cells were S100 positive in one case, but not the other. The vascular endothelial cells expressed CD31 and CD34.

In small early lesions, one or more dilated interconnecting thin-walled vascular channels are present in the dermal papillae. In older lesions there is loss of rete ridges and atrophy of the superficial epidermis, with formation of a polypoid lesion composed of a network of dilated communicating channels with scant intervening connective tissue (Fig. 38.12). A collarette may be present at the periphery of the lesions.

These lesions appear to be the dilated and interconnected segments of venous capillaries and postcapillary venules in the dermal papillae. The vessels of the upper horizontal plexus are not involved. The non-replicating nature of the endothelial cells comprising these lesions indicates that they are probably not true neoplasms. ⁴⁴¹ The high incidence of these lesions in old age suggests that their occurrence is an age-related degenerative phenomenon.

A case with the histological appearances of this entity, but clinical features of discrete agminated red papules coalescing into a plaque has been reported. It was called ‘acquired agminated acral angioma’. ⁴⁴²

In the characteristic glomeruloid hemangiomas described by Chan et al there are dilated (sinusoidal) dermal vascular spaces filled by grape-like aggregates of small capillary vessels, resulting in structures resembling renal glomeruli. Between these small vessels are plump cells which appear to be endothelial cells, being positive for factor VIII-related antigen. These cells and endothelial cells lining vessels contain PAS-positive eosinophilic globules, which stain for immunoglobulins at their periphery. In the cases reported without accompanying POEMS syndrome these eosinophilic globules expressed both kappa and lambda in a polytypical fashion. ⁴⁶⁰ Electron microscopy has suggested that the globules are enlarged secondary lysosomes (thanatosomes). ⁴⁶²

A recent study has shown endothelial cells with two different immunophenotypes. ⁴⁴⁴ The capillary-type endothelium had a CD31⁺/CD34⁺/UEA 1⁺/CD68⁻ phenotype, while the sinusoidal endothelium had a CD31⁺/CD34⁻/ UEA 1⁻/CD68⁺ phenotype. ⁴⁴⁴ There is increased expression of vascular endothelial growth factor (VEGF). ⁴⁶³ In cases reported recently without concurrent POEMS syndrome, the endothelial cells and plump, vacuolated cells were positive for CD31 and CD34. ⁴⁶² Isolated cells containing PAS-positive globules were positive for CD68. ⁴⁵⁹

A morphologically distinct vascular tumor has been reported in association with a solitary bone plasmacytoma. It is mentioned here because of the association of some cases of plasmacytoma with POEMS syndrome or Castleman’s disease. ⁴⁶⁴ The lesion was characterized by an extensive plaque with vascular hyperplasia and dermal mucin deposition. ⁴⁶⁴ The acronym AESOP syndrome, reflecting the component parts, has been used.

The lesions were primarily situated in the dermis but extension into the subcutis occurred in six cases. Discontinuous areas of papillary branching were often present. There were multiple ectatic vessels with predominantly intravascular papillary growth. The papillae had cellular cores containing pericytes and stromal cells, arranged around normal small capillaries. ⁴⁶⁵ The surfaces of the papillae were covered by focally swollen endothelial cells containing numerous hyaline globules consistent with dysfunction of the autophagocytic–lysosomal pathway. ⁴⁶⁵

There is a well-circumscribed non-encapsulated collection of large, thick-walled vessels in the upper and mid dermis (Fig. 38.13). These vessels are lined by endothelium and have a fibromuscular wall which contains elastic fibers but no definite elastic laminae. Most vessels have the characteristics of veins. ⁴⁷³ In approximately one-third of cases there are thin-walled dilated angiomatous capillaries superficial to the large tumor vessels. The stroma is often myxoid. Estrogen receptors have not been detected in the vessels. ⁴⁷²

Acquired digital arteriovenous malformations are a distinct entity thought to result from shunts between an artery and a vein in a fingertip.^{474.475. and 476.} Their extent can be determined by ultrasound imaging. ⁴⁷⁰ They are composed of thick- and thin-walled vessels, some of the former having small amounts of smooth muscle in their walls. ⁴⁷⁷ The thin-walled channels are venules. The lesions lack the tumor-like qualities of the arteriovenous hemangioma. Shunts are visible between the two classes of vessels. ⁴⁷⁴

The symplastic hemangioma is akin to other symplastic tumors which are characterized by bizarre, hyperchromatic cells, which represent a degenerative phenomenon.^{351. and 478.} It is composed of thick-walled and variably dilated vessels. The atypical cells, with markedly hyperchromatic nuclei, are located within the vascular smooth muscle wall, or in the interstitium (Fig. 38.14). They are spindle or epithelioid in shape; their nuclei may be multinucleate. ⁴⁷⁸ Perivascular hemorrhage, vascular thrombosis, and focal papillary endothelial hyperplasia are often present. Rare atypical mitoses may be present. ⁴⁷⁸ The pleomorphic cells show focal smooth muscle positivity. ⁴⁷⁸

The main characteristic of this tumor is a proliferation of thin uniform branching collapsed-looking vessels with inconspicuous lumina. The vessels involve the dermis and occasionally the superficial subcutis. The intervening stroma is collagenous, sometimes with a desmoplastic appearance. Endothelial cells are sometimes plumper than normal, but not atypical; they stain for factor VIII-related antigen, CD34, CD31, and Ulex europaeus-1 lectin. A peripheral layer of pericytes stains for smooth muscle actin.^{482. and 484.} Eosinophilic globules, commonly seen in Kaposi’s sarcoma, are not seen in this tumor.

Initially there are ectatic vascular channels lined by plump (hobnail) endothelial cells in the upper dermis. The vessels have intraluminal papillary projections. In the deep dermis and subcutis the channels dissect collagen bundles and surround sweat glands. ⁴⁹⁹ There is a variable mild inflammatory infiltrate about vessels and considerable extravasation of erythrocytes and hemosiderin (Fig. 38.15). Fibrin thrombi may be seen in the superficial vessels, a feature not present in the early lesions of Kaposi’s sarcoma. Plasma cells are also uncommon; eosinophilic globules have not been reported. Old lesions are composed of collapsed thin-walled anastomosing vascular channels with hemosiderin. Staining with D2-40, the new lymphatic endothelial marker, shows microshunts between neoplastic lymphatic channels and small blood vessels, explaining the aneurysmal microstructures and the erythrocytes and hemosiderin. ⁵⁰⁰

In one series, the tumor cells stained for CD31 in all cases tested, whereas only 3 of the 28 cases stained completely for CD34. In addition, 4 out of 8 cases stained positively for vascular endothelial growth factor receptor-3 (VEGFR-3), suggesting lymphatic differentiation. ⁴⁸⁹ This has been confirmed by the presence of lymphatic marker D2-40, and the absence of CD34 staining of endothelial cells, and the lack of actin-labeled pericytes. ⁵⁰⁰

Tumors are situated in the dermis and subcutis; rarely, they occur in the lumen of a vein. There are three main components. The first is a vascular component of thin-walled cavernous channels which may contain thrombi or phleboliths. The second is a solid area of spindle cells with slit-like vascular spaces; these areas may resemble Kaposi’s sarcoma (Fig. 38.16). The third component is plump endothelial cells, either in groups or lining vascular channels. Some of these cells have intracytoplasmic vacuoles. Fletcher et al have also noted the frequent presence of large, malformed, thick- or thin-walled vessels adjacent to the tumor, as well as bundles of smooth muscle cells near cavernous vessels or in solid areas. ⁵⁰² Nuclear atypia is minimal; mitoses are rarely seen. Lymphocytes and siderophages may be associated with the lesions, but eosinophilic globules, as seen in Kaposi’s sarcoma, have not been reported. The spindle cells in this tumor are generally more bland-looking and regular in appearance than those in Kaposi’s sarcoma. Furthermore, the spindle-cell fascicles are not as well-formed as those in Kaposi’s sarcoma. ⁵¹⁵

Immunohistochemical studies have confirmed the endothelial nature of the cells lining cavernous channels which stain for CD31, CD34, factor VIII-related antigen, and Ulex europaeus-1 lectin. Solid epithelioid and spindle-cell areas are negative for these antigens. ⁵⁰² Interleukin-8 (IL-8) is also expressed. ⁵¹⁶ Lesions do not contain HHV-8. DNA flow cytometric and immunohistochemical studies have shown that this tumor has low proliferative activity and is diploid, consistent with a reactive lesion. ⁵⁰³

There is a broad, band-like proliferation of capillary blood vessels in the superficial dermis, arranged parallel to the surface (Fig. 38.17).^{351. and 517.}

Microscopic examination shows single or grouped ectatic, congested, thin-walled capillaries in the papillary dermis. Thick-walled capillaries and downgrowth of the rete ridges between groups of vessels have also been described.^{524. and 525.} The latter lesions resemble angiokeratomas. Inflammation is not usually present. Although previously regarded as a telangiectatic process, an element of vascular proliferation appears to be present. ⁵²⁴

There are concentric arrays of oval-to-spindle cells around small endothelium-lined channels. These primitive cells arranged around the vessels tend to differentiate toward pericytes and express smooth muscle actin while the endothelial cells express CD31 and factor VIII-related antigen. Large mononuclear and multinucleate giant cells are also present. Perineural and intraneural involvement by small vessels is common. A stromal infiltrate of lymphocytes and plasma cells is another feature.

The lesion is often situated in the upper dermis. Sometimes it involves the deep dermis. It is a circumscribed, mainly solid proliferation of large polygonal epithelioid cells with eosinophilic cytoplasm, with enlarged nuclei and prominent nucleoli.^{527. and 529.} Vascular channels with epithelioid endothelium are either focal or diffuse. There are extravasated erythrocytes and hemosiderin pigment in over half. There is a scant inflammatory infiltrate, predominantly of lymphocytes. Eosinophils have been prominent in a few cases. Mild fibrosis may be present.

The cells express CD31, and CD34 but the latter is often focal. Smooth muscle actin labels pericytes. ⁵³⁰ In one case peripheral vessels expressed D2-40. ⁵³¹ Cells are negative for HHV-8, S100, epithelial membrane antigen (EMA), and the cytokeratin marker AE1/AE3. ⁵³⁰

The lesions consist of circumscribed collections of vessels and inflammatory cells. The vascular component comprises thick- and thin-walled vessels lined by plump endothelial cells (Fig. 38.18). These cells also occur in clumps that appear solid or sometimes contain small lumina. They are ‘epithelioid’ in appearance, with a large nucleus and abundant eosinophilic cytoplasm, and are characteristic of this condition. Prominent cytoplasmic vacuoles are seen in some cells. Normal mitotic figures are sometimes present. Intravascular proliferations of these cells may be seen in the lumina of larger vessels. ⁵³⁶ Exuberant examples may be confused with epithelioid hemangioendothelioma and epithelioid angiosarcoma. ⁵⁶³ There is one report of multinucleated cells, some of which were endothelial sprouts and others fibrohistiocytic cells. ⁵⁹⁶ Associated with the vascular and endothelial proliferations is a stromal cellular infiltrate which varies in intensity and consists of lymphocytes (sometimes with lymphoid follicle formation), eosinophils, and mast cells. The stroma may be fibrous or myxoid in character. Sometimes the fibrotic reaction is excessive. In one case it was associated with a florid granulomatous reaction with many multinucleated giant cells, often of Touton type. ⁵⁹⁷

A rare intra-arterial variant has been described. There was a prominent lymphocytic rim-like component. ⁵⁹⁸

Although these epithelioid cells share some enzymes with histiocytes⁵⁹⁹ they do not contain lysozyme; they have ultrastructural features of endothelial cells, including Weibel–Palade bodies. ⁵⁷⁴ The epithelioid cells stain for CD31, CD34, factor VIII-related antigen, and Ulex europaeus-1 lectin, but not for cytokeratins or epithelial membrane antigen.^{600. and 601.} The vacuoles in their cytoplasm possibly represent primitive vascular lumina.

Kimura’s disease is composed of reactive lymphoid follicles with a dense infiltration of eosinophils, sometimes forming eosinophilic abscesses.^{547.602.603. and 604.} An eosinophilic epithelioid granulomatous reaction with central eosinophilic abscesses has been reported. ⁶⁰⁵ Mast cells are increased.^{604. and 606.} Vessels (postcapillary venules) are increased in number, but their endothelial cells are usually flat. ⁵⁴⁷ Vascular cords are unusual. ⁵⁵⁷

‘Angiolymphoid hyperplasia with high endothelial venules’ is the term suggested for a cutaneous lesion with a characteristic admixture of lymphoid hyperplasia (without eosinophils) and a vascular proliferation previously called APACHE – acral pseudolymphomatous angiokeratoma of children (see p. 1003). ⁶⁰⁷ APACHE continues to be the designation attached to this entity. It appears to be a ‘pseudolymphoma’.^{608.609. and 610.}

Pyogenic granulomas are lobular capillary hemangiomas (Fig. 38.19). ⁶¹³ The lobular arrangement of the lesions is distinct from the pattern of capillaries in granulation tissue and, unlike granulation tissue, the capillaries do not usually involute with time. The underlying morphology is often obscured by secondary ulceration, edema, hemorrhage, and inflammatory changes. In uncomplicated lesions there is a lobulated proliferation of capillary-sized vessels. The deep lobules are compact and cellular, with small indistinct lumina. Occasional mitotic figures may be seen within the cellular lobules. The apoptotic rate is low, possibly a reflection of its rapid growth. ⁶⁷⁰ Toward the surface, the lobules are larger and less tightly packed, and have distinct capillaries with larger branching lumina. The lobules are separated by myxoid or fibrous connective tissue septa. ⁶⁷¹ The rare presence of spindle cells may mimic Kaposi’s sarcoma. ⁶⁷² A lobulated variant of Kaposi’s sarcoma mimicking pyogenic granuloma has been reported. ⁶⁷³ Extramedullary hematopoiesis has been reported in the stroma in two cases.^{674. and 675.}

The surface epithelium is attenuated, and at the margins of the lesion there is often an epidermal collarette formed by elongated rete ridges or sweat ducts. Surface ulceration and inflammation are secondary events, and sometimes lead to the formation of true granulation tissue near the surface of the lesions. Mast cells are not increased in pyogenic granuloma, unlike proliferative-phase hemangiomas.^{423. and 621.}

Lesions with the same lobular hemangiomatous pattern have also been described within veins⁶⁷⁶ and in subcutaneous tissues.^{677. and 678.} Intravenous pyogenic granuloma occurs predominantly on the neck, arms, and hands.^{676.679.680. and 681.} The lesions are composed of a lobular proliferation of capillaries set in a fibromyxoid stroma. A fibrovascular stalk usually connects the lesion to the intima of the involved vein. ⁶⁸²Subcutaneous pyogenic granuloma occurs predominantly on the upper extremities. ⁶⁷⁷

Immunohistochemistry is rarely carried out because the diagnosis can easily be made on light microscopy. It may be performed in atypical and multiple lesions. The vascular markers CD31, CD34, and factor VIII are positive. Lesions are negative for the glucose transporter GLUT-1. ⁶⁵²

There are multiple separated cellular lobules within the dermis and subcutis. Some lobules bulge the walls of dilated thin-walled vascular channels which are within the lobules or at their periphery. This sometimes gives the vessels a semilunar profile. ⁶¹¹ These larger vessels have a distinct endothelial lining.

Each lobule is composed of cells with spindle-shaped and oval nuclei (Fig. 38.20). Mitotic figures may be seen but there is no cellular atypia. Small capillary-sized vascular lumina are present in these areas. The morphology of the lobules resembles those seen in pyogenic granulomas. Hemosiderin may be present in the lesions; inflammation and edema are not usually seen. Some authors have noted proliferation of eccrine sweat glands near the vascular lobules.^{707. and 718.}

The pattern of cellular nodules with a peripheral dilated channel superficially resembles Kaposi’s sarcoma, but the lobules lack the characteristic interlacing bundles of spindle cells and slit-like vessels, and usually lack an inflammatory infiltrate with plasma cells. In endovascular papillary angioendothelioma of childhood, papillary processes lined by atypical endothelial cells protrude into vascular lumina. In Masson’s ‘vegetant intravascular hemangioendothelioma’, papular processes, composed of hyperplastic endothelium supported by fibrous stalks, are confined within vascular lumina.

Tumor cells are positive for CD31 and CD34, but stain only weakly or not at all for factor VIII-related antigen. ⁷¹⁹ They are negative for GLUT-1. ⁷²⁰ The dilated vessels partly stain with D2-40, but the proliferative capillaries are negative. ⁷²⁰

The glomus tumor proper is a well-circumscribed or encapsulated dermal tumor which may extend into the subcutis. It is composed of solid aggregates of glomus cells surrounding inconspicuous vessels. Glomus cells are rounded, regular cells with eosinophilic cytoplasm and darkly staining round to oval nuclei (Fig. 38.21). Tumor cells and vessels are embedded in a fibrous stroma. Some tumors contain large amounts of myxoid stroma (Fig. 38.22). ⁷⁴¹ The tumor matrix contains small unmyelinated nerve fibers and mast cells. The uniformity of the cells and their lack of pleomorphism are features of these tumors. Oncocytic and epithelioid variants have been described.^{742. and 743.} The latter are composed of large polygonal to spindle-shaped cells with abundant eosinophilic cytoplasm and large irregular nuclei. The cytological atypia is thought to represent cellular senescence. ⁷⁴³ The term ‘symplastic glomus tumor’ has been used for these lesions, which have a high nuclear grade in the absence of any other malignant features. ¹⁵⁴ Another variant is the infiltrative glomus tumor, characterized by an infiltrative growth pattern at the periphery of the lesion. ⁷⁴⁴ Some of these lesions have been regarded in the past as malignant glomus tumors. This category of infiltrative glomus tumor is not included in the recent classification proposed by Folpe et al. ¹⁵⁴ Extensive glomus cell hyperplasia has been reported in the vicinity of a cluster of multiple glomus tumors. ⁷²²

Immunohistochemical techniques have demonstrated vimentin, muscle-specific actin and α-smooth muscle actin in the cytoplasm; laminin and type IV collagen are present in the basal lamina-like material.^{130.745. and 746.} The cells lack the cell markers of endothelial cells (CD31, CD34). The absence of desmin from the tumor cells is a feature shared with some cells of vascular smooth muscle.^{130. and 746.}

Multiple nerve fibers containing substance P have been identified within solitary glomus tumors. ⁷⁴⁷ Substance P is known to be a sensory afferent neurotransmitter for mediating painful stimuli.

It is composed of clusters and nests of small to medium-sized epithelioid cells intimately associated with small vascular channels. There is a superficial resemblance to a glomus tumor or paraganglioma. ⁷⁵⁰ Small nerve bundles are present in the stroma. A complex hamartoma composed of elements resembling a neurovascular hamartoma, a lipomatous hamartoma, and glomus bodies has been reported in the intergluteal region. ⁷⁵¹

The cells express muscle-specific actin, vimentin, and neuron-specific enolase. The small nerves are highlighted by an S100 preparation. The epithelioid cells are weakly positive for smooth muscle actin, and negative for desmin, synaptophysin, and chromogranin. The endothelial cells of the vessels stain for CD31. ⁷⁴⁸

The lesions are composed of dilated blood vessels in the upper dermis, lined by plump ‘hobnail’ endothelial cells. ⁷⁵² The endothelial cells have not always been enlarged. ⁷⁵⁶ A mild perivascular infiltrate of lymphocytes has been present in most cases.^{755. and 761.}

The lesions associated with graft-versus-host disease are angiomatous in nature with large, dilated vascular spaces. They bear no resemblance to this entity.^{758. and 759.} In contradistinction, they have been called eruptive angiomatosis.

It is not clear whether multinucleate cell angiohistiocytoma is primarily a vascular or stromal cell tumor. The two main components are increased numbers of ectatic or narrow vessels in the upper and mid dermis, and large angulated multinucleate cells (Fig. 38.23). In addition, there is a less conspicuous component of ‘fibrohistiocytic’ (dendritic) cells scattered between the collagen bundles in a horizontal pattern. ⁷⁶⁸ These cells express factor XIIIa. ⁷⁷³ The vessels are small venules and capillaries, lined by endothelial cells with prominent nuclei. Angulated multinucleate cells have 3–10 nuclei arranged in a ring or clumped together; they are basophilic. These large cells stain with vimentin but not with macrophage markers (Mac387, CD68, lysozyme), CD31, CD34, S100, or factor XIIIa. ⁷⁷² A recent paper did show staining of these multinucleate cells with factor XIIIa. ⁷⁶⁹ Other interstitial cells appear to be indeterminate or Langerhans cells (CD1a positive) or macrophages (lysozyme, CD68, and Mac387 positive).^{764. and 770.} Discrete foci of inflammatory cells are also present. The ultrastructural features have also been described. ⁷⁶⁵

Reactive angioendotheliomatosis is characterized by a benign intraluminal proliferation of endothelial cells which may occlude the vascular lumina. The vessels are dilated. A proliferation of vessels also occurs which may have a diffuse, lobular, or mixed pattern. ⁷⁸¹ Sometimes the proliferated endothelial cells produce a glomeruloid appearance. The cells may be large and mildly atypical but they are not malignant. Thrombi and protein deposits are sometimes found. The dermis may show reactive (fasciitis-like) alterations. ⁷⁸¹ There is usually only minimal inflammation, if any. The cells express CD31, CD34, and factor VIII-related antigen. In one case, the intraluminal cells stained with CD68, a feature seen in intravascular histiocytosis. ⁷⁸⁸

Granular deposits of IgA, IgM, and complement were found around the vessels and at the dermal–epidermal junction in two cases. ⁷⁹⁰

In diffuse dermal angiomatosis the hyperplastic endothelial cells diffusely infiltrate the papillary and reticular dermis, sometimes forming small vascular lumina.^{791. and 792.} The cells stain with CD31 and CD34. ⁷⁹⁹ This contrasts with the intravascular proliferation seen in reactive angioendotheliomatosis.

The papules and nodules consist of a proliferation of small dilated vessels in an edematous dermis (Fig. 38.24). The vessels have fairly regular profiles and lack the jagged outline and ‘promontory’ sign seen in early lesions of Kaposi’s sarcoma. ⁸²¹ Plump endothelial cells, without atypia, line the vessels. The cells are positive for CD31 and CD34, ⁸²³ but negative for HHV-8, and D2-40. ⁸²⁴ The perivascular cells do not stain for CD34. ⁸¹¹ A slight perivascular fibroblastic proliferation is also seen but is not marked. Some lesions show nodular collections of vessels with narrow lumina. ⁸²² Extravasated red blood cells, hemosiderin, and a variable round-cell infiltrate are seen around the vascular proliferation. Plasma cells are usually not present. Mast cells may be numerous. ⁸¹¹ The overlying epidermis may show hyperkeratosis.

There is a multinodular and plexiform intravascular proliferation of spindle-shaped myofibroblasts with elongate cells set in a fibromyxoid stroma. A meshwork of elastic fibers surrounds the individual tumor nodules. ⁸²⁶ It has some similarities to intravascular fasciitis. ⁸²⁷

The spindle cells are reactive for smooth muscle actin, muscle-specific actin, and calponin. There may be a collarette of desmin positivity at the periphery of the lesion. ⁸²⁷ The endothelial cells express CD31 and CD34. ⁸²⁵

In most examples the proliferation is limited to the lumen of an identifiable vein or vessel in a vascular abnormality (Fig. 38.26). Occasionally there is only a fibrous capsule lacking definite features of a vessel wall. Rarely, the proliferation extends outside the lumen, possibly due to rupture of the wall of the vessel. Masses of papillary processes are present within the lumen and they are almost always associated with some thrombus. Each papillary frond is covered by a single layer of plump endothelial cells. Mitotic figures may be present but they are never frequent. There is no multilayering of the cells, and solid cellular areas, cellular tufts, atypia, and necrosis are not usually evident; however, Renshaw and Rosai have described severe cytological atypia in lesions from the lip. ⁸⁴¹ The core of the papillae consists of fibrin or collagenous connective tissue, depending on the stage of organization.

Superficial lesions are characterized by small round blood vessels in an edematous stroma. Deeper lesions are more cellular and compact. In both forms blood vessels are lined by plump, epithelioid endothelial cells. A background inflammatory cell infiltrate of lymphocytes, histiocytes, and neutrophils is also present. Neutrophils are plentiful in deeper lesions. A peripheral collarette and ulceration are seen in superficial lesions (Fig. 38.27). Pseudoepitheliomatous hyperplasia is a rare event. ⁸⁶⁶ Organisms are seen as clumps of amphophilic granular material, particularly near neutrophils; they are readily demonstrated by a Giemsa, Warthin–Starry, or Grocott–methenamine silver stain.^{850. and 867.} Immunohistochemical techniques and PCR-based methods have also been used to identify organisms.^{848. and 868.} Ultrastructurally, organisms are seen in the interstitium of lesions and are pleomorphic structures with a trilaminar wall and coarsely granular cytoplasm. ⁸⁶⁹

Superficial lesions consist of a proliferation of capillary-like vessels in the papillary dermis, with the formation of a collarette. There is an associated inflammatory infiltrate composed of lymphocytes and plasma cells. In nodular lesions there is a multilobular proliferation or more solid aggregation of cells in the dermis, and sometimes also in the subcutis. Vascular lumina are fewer and smaller. The ‘tumor cells’ are large and epithelioid; groups of them are surrounded by a reticulin network. Mitotic figures are frequent. A spindle-cell element is occasionally seen and may make distinction from Kaposi’s sarcoma extremely difficult. Immunohistochemical studies have identified these cells as endothelial in nature, as they are positive for both factor VIII-associated antigen and Ulex europaeus-1 lectin. ⁸⁷¹ In regressing lesions there is involution and necrosis of the vascular elements, associated with a heavy infiltrate of lymphocytes, histiocytes, and neutrophils. There is subsequent fibrosis.

The causative organism is not seen by light microscopy but may be found on ultrastructural examination, predominantly in an extracellular location but occasionally in phagosomes. ⁸⁷¹ Rocha Lima inclusions, consisting of conglomerates of apparently intracellular cytoplasmic granules that are colored red by Romanowsky–Giemsa stains, may be seen within the endothelial cells. Ultrastructurally these appear to consist of phagosomes containing organisms and interstitial matrix-like material as well as a labyrinth of cisternal channels with similar contents. ⁸⁷¹

The main feature is the presence of thin-walled interconnecting vascular channels at various levels of the dermis or subcutis. These vessels tend to be arranged horizontally, particularly in the upper dermis. Vessels are smaller, more irregular, angular and cleft-like at deeper levels, and ‘dissect’ the dermal collagen bundles. The vessels are lined by flat to plump endothelial cells with some focal nuclear hyperchromasia and crowding. No frank atypia or mitotic figures have been reported. No intraluminal cell clumps are seen. Vessels contain proteinaceous material, a few red blood cells, or are empty. The vessels are usually surrounded by chronic inflammatory cells, often including a few plasma cells. ⁸⁹⁵

Immunohistochemical studies are conflicting: endothelial cells have been reported as staining positively or negatively for factor VIII-related antigen and Ulex europaeus-1 lectin, and positively for CD34 and CD31.^{884. and 896.} The cells stain strongly with the lymphatic endothelial marker D2-40, but further cases should be studied before accepting that positivity with this marker is applicable to other cases. ⁸⁹⁷ They are negative for HHV-8. ⁸⁹⁸ Basement membrane has been shown to be present by positive staining for type IV collagen and laminin. It has been absent by electron microscopy. A smooth muscle component has also been demonstrated focally, around the vascular spaces.^{841.876.880.882.883. and 886.}

Histologically, this lesion may mimic angiosarcoma and patch-stage Kaposi’s sarcoma. The distinction from well-differentiated angiosarcoma, particularly from the D2-40 positive cases can be very difficult; usually there is more cellular atypia or cellular tufts in angiosarcoma. The long clinical history and the site of the lesion may be helpful. The face and scalp are the usual sites for cutaneous angiosarcoma. Early Kaposi’s sarcoma may be impossible to distinguish from lymphangioendothelioma, but in the former there may be red blood cells, hemosiderin, and an inflammatory cell infiltrate which includes plasma cells. Inflammation is minimal in lymphangioendothelioma. ⁸⁴¹ The patch stage of Kaposi’s sarcoma is usually seen in AIDS-related cases, and lesions are often multiple. Although it is also D2-40 positive, Kaposi’s sarcoma stains for HHV-8, which does not occur in lymphangioendothelioma.

Benign lymphangiomatous papules of the skin (BLAP) consist of markedly dilated vascular spaces in the upper dermis exhibiting atypical features which include endothelial cells with plump or flattened nuclei, and numerous small papillary projections. As the lesions descend into the deeper dermis, the spaces become smaller and their lumina irregular, focally dissecting the collagen. ⁸⁸⁷ Some of the postradiation cases reported as angiosarcomas in the past may be this benign entity, ⁸⁸⁹ but as Sharon Weiss and colleagues have demonstrated recently, these atypical vascular lesions (as they prefer to call them) may be a precursor, rather than a risk factor for the development of angiosarcoma. ⁸⁹¹ The endothelial cells are positive for Ulex europaeus-1 lectin and weakly positive for CD31, CD34, and factor VIII-related antigen. They stain with the lymphatic endothelial marker D2-40. ⁸⁹⁹

The microscopic appearance of the lesions is identical in the different types of KS.^{1080. and 1081.} They evolve through patch, plaque, and nodular stages. ¹⁰⁸² The earliest lesions, corresponding to the flat macule or patch stage, are predominantly vascular in nature. Within the dermis there is a proliferation of irregular, often jagged, vascular channels which partly surround pre-existing blood vessels in some areas. This characteristic appearance has been termed the ‘promontory sign’ (Fig. 38.28). ⁸²¹ The vascular proliferation is also present about appendages and between collagen bundles. The vessels are thin walled and lined by plump or inconspicuous endothelial cells. Scattered groups of perivascular lymphocytes and plasma cells may also be present (Fig. 38.29). Extravasated erythrocytes and deposits of hemosiderin are also found in the dermis.

The papules, nodules, and plaques consist of a dermal proliferation of interlacing bundles of spindle cells and intimately related, poorly defined slit-like vessels (Fig. 38.30). The proportion of vessels and spindle cells varies. There is an associated inflammatory cell infiltrate consisting predominantly of lymphocytes and plasma cells. Dilated thin-walled vessels are found at the periphery of the tumor. The spindle-cell component shows variable nuclear pleomorphism. Mitotic figures are present, but not usually frequent. Erythrocytes can be seen within vascular lumina and extravasated in and around the lesion.

Clusters of eosinophilic hyaline globules, varying in size from just visible with the light microscope to larger than an erythrocyte, may be seen within spindle cells and macrophages or in an extracellular location. These were first described in African cases, but are also seen in classic KS and in the epidemic form.^{1035. and 1083.} They resemble Russell bodies and are PAS positive, stain bright red with Mallory’s trichrome stain (Fig. 38.31) and are autofluorescent. ¹⁰⁸⁴ They are seen in early patch lesions in some cases. ¹⁰³⁵ They appear to represent effete red blood cell fragments that have been phagocytosed. ¹⁰⁸⁵ Erythrophagocytosis by tumor cells has been described in all stages of Kaposi’s sarcoma. ¹⁰⁸⁶ Apoptosis of endothelial cells is seen quite often in plaques and nodules; it is seen less often in patch-stage lesions. ¹⁰⁸⁷ Lesions regressing as a consequence of HAART become surrounded by a dense fibrous stroma which eventually obliterates the lesion.^{1070. and 1088.} Pharmacologically induced regression is characterized by a complete loss or decrease in spindle cells, increased lymphocytes, and dermal siderophage deposition. ¹⁰⁸⁹

Lymphangioma-like KS is an uncommon variant accounting for less than 5% of all cases.^{1090.1091. and 1092.} It consists of grossly dilated channels lined by flattened endothelial cells with a bland appearance (Fig. 38.32). ¹⁰⁹³ There are irregular, anastomosing channels, closely applied to the dermal collagen, with slender papillary projections into the lumen. Most of the spaces are devoid of erythrocytes, further enhancing the lymphangioma-like features. Clinically, the lesions may have a bulla-like appearance. ¹⁰⁹⁴ There is usually an admixture of more typical lesions. There is strong reactivity of the tumor cells with anti-HHV-8 latent nuclear antigen-1. ¹⁰⁹⁵

Pyogenic granuloma-like KS is a recently described variant of KS which closely simulates pyogenic granuloma. ⁶⁷³ No distinguishing histological features are present. Only the presence of HHV-8 latent nuclear antigen-1 (LNA-1) allows a distinction to be made. ⁶⁷³

Intravascular KS is another histological variant. ¹⁰⁹⁶ It does not seem to be associated with a more aggressive behavior. The vascular channels have the morphological features of veins. There is an intravascular growth of interlacing fascicles of spindle cells with formation of cleft-like spaces, hyaline globules, and a lymphoplasmacytic infiltrate. The cells stain for HHV-8, CD31, and CD34. ¹⁰⁹⁶ The D2-40 marker was not used.

An anaplastic form has been reported in African and sporadic cases.^{943.1097. and 1098.} The anaplastic lesions exhibit greater cellularity, nuclear pleomorphism, and more frequent mitotic figures, and may have areas resembling angiosarcoma or fibrosarcoma.^{930. and 1097.} In several cases, anaplastic KS developed in a lymphedematous (postmastectomy) arm, thus mimicking Stewart–Treves syndrome.^{1073. and 1099.} Epidermal changes vary with the lesion and include atrophy and ulceration over raised lesions. A peripheral epidermal collarette is sometimes present about papules and nodules. Lesions with prominent hyperkeratosis sometimes occur. ¹¹⁰⁰

Immunohistochemical studies have demonstrated the presence of CD31 and D2-40, the new marker for lymphatic endothelium in nearly every case tested.^{8.1062.1063. and 1101.} CD34 and factor VIII-related antigen were noted in some of the earlier studies.1101. ^{and 1102.} HHV-8 can be detected by PCR in paraffin-embedded tissue, although the viral load appears to be low.^{1103. and 1104.} It is much easier to perform immunohistochemistry using the commercially available antibody against HHV-8, latent nuclear antigen-1 (LNA-1). It detects HHV-8 in the majority of cases. ¹¹⁰⁵ It is largely confined to the spindle cells in the nodular phase, but it is found in the endothelial cells of the slit-like vessels in the early patch stage (Fig. 38.33). ⁹¹⁷ Calcitonin receptor-like receptor, which plays an important role in angiogenesis, is strongly expressed in KS and other vascular tumors. ¹¹⁰⁶

The immunohistochemical demonstration of HHV-8 DNA may be a useful adjunct in the diagnosis of KS by fine needle aspiration, ¹¹⁰⁷ and when difficult lesions are encountered. ¹¹⁰⁸

The adult type exhibits the characteristic pattern of tightly packed cellular areas surrounding endothelium-lined ramifying vessels. The cell boundaries are poorly defined; the nuclei are round or oval. Tumor cells are separated from the endothelial cells by a basement membrane and are themselves surrounded by a meshwork of reticulin fibers. Histological variations include myxoid areas, fibrotic areas, and, rarely, osseous and cartilaginous metaplasia. ¹¹¹² The deep variant with mature fat reported as a lipomatous hemangiopericytoma¹¹³⁰ has been regarded by others as a fat-containing variant of solitary fibrous tumor. ¹¹³¹ Epithelioid histiocytomas may exhibit hemangiopericytoma-like areas.^{1132. and 1133.} Tumor cells express vimentin only; they are negative for α-smooth muscle actin and α-sarcomeric actin. ⁷⁴⁶ Normal vascular pericytes are uniformly reactive for vimentin and α-isoforms of actin, and sometimes stain for desmin and HLA-DR. Tumor cells also stain for factor XIIIa, CD34, CD57, and HLA-DR¹¹³⁴ but these are not specific markers. Pericytes express 3G5 ganglioside. ¹¹³⁵ Further studies are needed to see if this marker leads to the retention of hemangiopericytoma as a diagnostic entity. Several studies have stressed the difficulty in predicting the behavior of these tumors from their histological appearance, but frequent mitotic figures, necrosis, hemorrhage, and increased cellularity are features that indicate a poor prognosis. ¹¹¹³ DNA flow cytometry and immunohistochemical stains for PCNA are not helpful in predicting outcome in these tumors. ¹¹³⁶

Congenital and infantile hemangiopericytomas have the typical pattern of cells and vessels as described above, but they are multilobulate, with perivascular and intravascular tumor outside the main tumor mass.^{1112. and 1120.} Endothelial proliferation within vascular lumina has been described. ¹¹¹² Mitotic figures and necrosis may be seen but do not indicate a bad prognosis as these tumors have a benign course. ¹¹¹⁶ Hemangiopericytoma-like areas are sometimes seen in infantile myofibromatosis (see p. 821), which affects infants and children and may involve skin and subcutis. ¹¹³⁷ Conversely, foci of cells having a spindled, myoid appearance typical of myofibroblasts can be seen in typical cases of infantile hemangiopericytoma. These cases show focal staining for actin. In another case smooth muscle actin stained numerous cells around the vascular spaces, and some endothelial cells. ¹¹²⁹ This is similar to infantile myofibromatosis. ¹¹²⁹

As with Kaposi’s sarcoma, there are interconnecting sheets or nodules of spindled endothelial cells lining slit-like or crescent-shaped vessels. The spindle-cell fascicles are generally shorter and narrower than those found in Kaposi’s sarcoma. ⁵¹⁵ Small rounded vessels may also be seen. Unlike Kaposi’s sarcoma, there may be nests of epithelioid-like endothelial cells with eosinophilic cytoplasm containing hemosiderin and cytoplasmic vacuoles. Cellular atypia is minimal and mitoses infrequent. Hemosiderin may also be present in the spindle cells. Hyaline eosinophilic globules similar to those in Kaposi’s sarcoma are also seen. An occasional finding is microthrombi in vessel lumina. In the skin and subcutis there is surrounding dense hyaline fibrosis. Spindle cells stain for CD34 and focally for CD31.^{1145. and 1150.} In the series of 33 cases reported by Sharon Weiss and colleagues, the endothelial cells in the nodules expressed CD31, CD34, and FLI1, but not GLUT-1, LeY, or HHV-8. ¹¹⁴⁴ In a series from Japan, all four cases expressed D2-40. ⁷²⁰ In three cases the response was markedly reactive, and in the fourth it was reactive in the peripheral area of KS-like proliferative capillaries and negative in the surrounding dilated vessels. ⁷²⁰ In contrast, the staining was reversed in tufted angioma with partial positivity in the dilated vessels but no staining in the cannonball-like proliferative capillaries. ⁷²⁰ The tumor has some similarities to spindle-cell hemangioendothelioma, but the latter occurs predominantly in adults, is superficial, and may have cavernous vessels and phleboliths. Kaposi’s sarcoma is usually multifocal; it is very rare in children, except as the endemic form.

There is some variability.^{1151. and 1159.} Irregular vascular channels are present in the dermis and subcutis. They are lined by endothelial cells ranging from flattened to columnar in shape. Some cells have a ‘hobnail’ appearance. Within the lumina of these vessels are papillary structures covered by similar cells. The cores of the papillae are avascular and consist of fibrous tissue or peculiar eosinophilic hyaline globules, some with central clearing. These features are not seen in retiform hemangioendothelioma.

Some of these vascular structures have a glomeruloid appearance. Lymphocytes are seen both within the lumina of the vascular channels, in intimate association with the endothelial cells, and also in the extravascular stroma. There is nuclear hyperchromatism and mitotic figures are present. ¹¹⁵¹

Immunohistochemical and ultrastructural studies have confirmed the endothelial nature of the tumor cells and identified the hyaline globules as basal lamina-like material.^{1152. and 1153.} Tumor cells are positive for vimentin, factor VIII-related antigen, CD31, and focally for CD34. They are negative for keratins, EMA, S100 protein, and desmin. ⁹ Vascular endothelial growth factor receptor type 3 (VEGFR3), a marker for lymphatic endothelia, was positive in all cases studied. The lymphatic endothelial marker D2-40 was positive in all three cases of Dabska tumor studied in one report, ¹⁰⁶³ confirming the lymphatic nature of this tumor.

The appearances are similar in the three groups.^{1162.1163.1164. and 1182.} The lesions are poorly circumscribed dermal tumors which infiltrate subcutaneous fat and other tissues and often have a multifocal distribution. Angiomatous and solid patterns may be seen (Fig. 38.34). In the angiomatous areas a meshwork of anastomosing dilated vessels extends between pre-existing dermal collagen bundles and around skin appendages. The vessels are irregular and lined by crowded endothelial cells, which range in appearance from virtually normal-looking to plump atypical protuberant cells with enlarged hyperchromatic nuclei (Fig. 38.35). Papillary processes may extend into the lumen of the vessel. In the solid areas of the poorly differentiated tumors the cells vary from spindle-shaped to polygonal. A spindle-cell pattern may predominate. ¹²³⁹ Some areas may resemble Kaposi’s sarcoma. ¹²⁴² Cytoplasmic vacuoles resembling primitive vascular lumina may be seen in some cells. Reticulin stains show that the cellular proliferation is on the luminal side of the reticulin fibers in the angiomatous areas. Generally, as architectural differentiation decreases, cytological atypia and cell size tend to increase. ¹¹⁶³ Lymphocytic infiltrates are commonly seen and may obscure the underlying lesion, particularly in well-differentiated tumors with minimal cellular atypia. ¹¹⁶³ Mast cells appear to be increased.^{1219. and 1243.} Distinguishing the well-differentiated angiomatous areas from benign vascular proliferations depends on the recognition of cellular atypia, the presence of crowding of lining cells and of solid papillary clusters of cells, and an irregular interconnecting pattern of vessels. The use of antibodies specific for signal transduction pathways is a feasible method for distinguishing benign from malignant endothelial processes in paraffin-embedded tissue. There is strong expression of mitogen-activated protein kinase (MAPK) in benign endothelial tumors and a greatly decreased expression in angiosarcoma. ¹²⁴⁴ Infectious endothelial lesions (Kaposi’s sarcoma and verruga peruana) stain strongly. ¹²⁴⁴ Caveolin, a scaffolding cell membrane protein, has a higher level of expression in benign vascular tumor than in angiosarcomas, including the well-differentiated variants. ¹²⁴⁵ It has been suggested that caveolin expression might be useful in separating benign and malignant vascular tumors. ¹²⁴⁵ The differentiation of early lesions from early lesions of Kaposi’s sarcoma may be dependent on clinicopathological correlation.

Poorly differentiated tumors with polygonal and epithelioid cells can resemble carcinomas and even amelanotic melanoma. ¹²⁴⁶ Immunohistochemical markers for keratins and S100 protein will help to distinguish between these tumors, although S100-positive angiosarcomas have been reported.^{1246. and 1247.} Epithelioid, spindle and granular cell variants of angiosarcoma have also been described. ⁵¹⁵ The epithelioid variant sometimes expresses keratin (see below).^{1183.1248.1249. and 1250.} When it occurs on the breast, the epithelioid angiosarcoma may be mistaken for mammary carcinoma, although the latter tumor does not express CD34 and CD31. In epithelioid angiosarcoma up to a third of the neoplastic cells can express MIB-1. ¹²⁵¹ Another histological variant is the verrucous angiosarcoma, in which there are striking verrucous changes in the overlying epidermis. ¹²⁵² Another variant, which may be mistaken for cutaneous lymphoma, is the pseudolymphomatous variant. ¹²⁵³ It consists of irregular anastomosing vascular channels with pleomorphic endothelial cells which express CD31, CD34, and D2-40. There is a dense lymphocytic infiltrate between the vessels obliterating and destroying some of the channels. Germinal centers may also be present. ¹²⁵³

Many immunohistochemical markers for endothelial cell differentiation have been used, including factor VIII-related antigen, Ulex europaeus-1 lectin,^{601. and 1254.} PAL-E, ¹²⁵⁵ CD34, ¹¹⁶² and CD31. ¹¹⁰² Epithelioid angiosarcomas often express CK8 and CK18 (approximately 50%), whereas the non-epithelioid types express CK7, CK8, and CK18 in about 20% of cases. One case of CD30⁺-epithelioid angiosarcoma has been reported. ¹²⁵⁶ Epithelial membrane antigen (EMA) is expressed in about a third of non-epithelioid angiosarcomas, ¹²⁵⁰ although the figure was lower than this in a recent study. ¹²⁵⁷ Thus caution is needed in interpreting EMA positivity as evidence for an epithelial tumor. The monoclonal antibody AE1, which does not react with cytokeratins 7, 8, and 18, is advantageous in the differential diagnosis of angiosarcoma and carcinoma.^{1250. and 1258.} Angiosarcomas also express WT1. ⁴³⁰ A variety of vascular tumors, including angiosarcoma express annexin II, also known as p36. ¹²⁵⁹