Lymphangiectases are characterized by the presence of dilated lymphatic vessels within superficial and mid dermis (Fig. 14.1). The overlying epidermis may exhibit hyperkeratosis and acanthosis. There may be red blood cells and lymphocytes within these lymphatic channels. Stromal edema is a histologic feature that is consistently seen in all examined patients with localized massive lymphedema [15]. In addition, multinucleated giant cells, lymphangiectasia, dermal chronic inflammation, and fibrosis are seen in subset of cases [15].

By immunohistochemistry, the lymphatic endothelial cells are positive for D2-40, Prox-1, and CD31, yet they are negative for CD34 [3] (Table 14.2). D2-40 or podoplanin is a relatively specific immunostain for lymphatic endothelium [16]. Prox-1 is a homeobox-containing nuclear transcription factor that has recently been shown to exhibit better specificity for lymphatic endothelium than D2-40 [17].

Acquired lymphangiectasis has similar clinical and histologic features to lymphangioma circumscriptum, a developmental defect of the deep dermal and subcutaneous lymphatics. Clinical history is essential to differentiate the two since lymphangiomas are present since birth or early childhood, while acquired lymphangiectasis is associated with a number of causes [4, 8]. (See Vignette 3 at the end of this chapter.) While acquired lymphangiectasis affects the superficial and mid lymphatics, lymphangioma circumscriptum affects those within the deep dermis and subcutaneous tissue. The lack of CD34 expression is helpful in distinguishing acquired lymphangiectasia from other vulvar vascular lesions. Angiokeratomas are small and not associated with damage to lymphatic drainage [18]. In addition, angiokeratomas do not recur and do not typically require additional treatment. Vulvar varices, also known as venous lake, would have erythrocytes within a dilated lumen. (See Vignette 1 at the end of this chapter.)

All variants of angiokeratomas share similar histologic features including the presence of dilated thin-walled blood vessels, lined by a layer of endothelial cells, in the papillary dermis and a variable degree of hyperkeratosis (Fig. 14.2a). The overlying epidermis often exhibits irregular acanthosis with elongated rete ridges partially surrounding the vascular channels (Fig. 14.2b). There is minimal dermal inflammation. Vacuolation of smooth muscle of arterioles and arteries and pilar muscles is seen in lesions associated with Fabry’s disease. Electron-dense lipid bodies can be demonstrated ultrastructurally in the cytoplasm of endothelial cells, pericytes, smooth muscle cells, and fibroblasts [26].

Clinically, angiokeratomas of the vulva may resemble benign as well as malignant melanocytic lesions, seborrheic keratosis, condyloma acuminatum, vulvar intraepithelial neoplasia, pyogenic granuloma, and lymphangioma [18, 19]. The main histologic differential diagnosis would be a hemangioma, which would not have associated epidermal acanthosis that is seen in angiokeratoma. Although a verrucous angioma would have marked epidermal hyperplasia, it has a deep vascular component that is not typically present in angiokeratoma.

Pyogenic granuloma, at least in its initial phase, is an exuberant proliferation of vessels of different sizes and shapes, lined by prominent endothelium embedded in an edematous stroma (Fig. 14.3a, b). The overlying epidermis is often ulcerated; thus, the lesion has associated acute as well as chronic inflammatory infiltrate, similar to granulation tissue.

The clinical differential diagnosis of pyogenic granuloma would include other polypoid lesions including condylomas, angiomas, and verrucous carcinoma. The main histologic differential diagnosis would be granulation tissue and a hemangioma. Some do consider pyogenic granuloma is a subtype of hemangioma. Clinical history is needed to distinguish pyogenic granuloma from granulation tissue.

The proliferation of endothelial cells is present within one or more vascular lumina that have been occluded by a thrombus (Fig. 14.1a). In fully developed lesions, numerous papillary fronds lined by a single layer of plump endothelial cells extend from the wall of the vessel into the lumina. The histologic features of intravascular papillary endothelial hyperplasia are not specific, but can be found in multiple vascular proliferations (Fig. 14.4b).

The differential diagnosis includes pyogenic granuloma, Kaposi’s sarcoma, and angiosarcoma. Pyogenic granuloma is a proliferation of blood vessels of variable sizes and shapes. An infiltrative architecture as well as cytologic atypia would be seen in Kaposi’s sarcoma and angiosarcoma, whereas Masson’s tumor is a circumscribed lesion with a central thrombotic zone.

These lesions are comprised of large, dilated, blood-filled vessels lined by flattened endothelium. These vessels can be either in a lobular arrangement or a haphazard fashion. Arteriovenous hemangioma consists of a well-circumscribed proliferation of thick-walled muscle-containing blood vessels, lined by a single layer of endothelial cells involving the upper and mid-reticular dermis (Fig. 14.5a, b).

Cavernous hemangioma can be mistaken clinically as vulvar varices (see Vignette 1 at the end of this chapter) as reported in a case of vulvar hemangioma [40]. Lymphangioma would not have blood-filled vessels, and these endothelial cells would be positive for lymphatic markers such as D2-40 and Prox-1.

The histopathologic composition of infantile hemangiomas varies with the age of the lesion. Early hemangiomas are highly cellular and are characterized by plump endothelial cells aligned to vascular spaces with small inconspicuous lumina (Figs. 14.6 and 14.7). As the lesions mature, blood flow increases, endothelium flattens, and the lumina of the vessels enlarge and become more obvious. During this interval the vessels convey a “cavernous” appearance that can be misinterpreted as a venous malformation. Regression is portrayed as progressive interstitial fibrosis and adipose metaplasia, a process without known stimulus.

Immunohistochemical studies have shown a complex expression profile including markers for endothelial cells (CD31 positive), pericytes (SMA positive), dendritic cells (factor XIIIa positive), and mast cells [42]. Of particular clinical importance, IH express high levels of erythrocyte-type glucose transporter protein, isotope 1 (GLUT-1), which is not expressed in the vasculature of normal skin nor in other tumors or vascular malformations, making it a highly selective and diagnostically useful marker (Fig. 14.8) [45]. GLUT-1 is also expressed in normal endothelium at sites of blood-tissue barriers, including the brain, eye, nerve, and placenta. North et al. [46] showed that of these tissues, IH’s expression profile is closest to that of fetal placental microvasculature, suggesting a possible origin of these tumors.

The differential diagnosis of IH includes vascular malformations and congenital hemangiomas. Fortunately, vascular malformations and congenital hemangiomas that affect the infant population usually do not stain for GLUT-1 (Table 14.3). Congenital hemangiomas differ from IH in that they are fully formed in utero. They can be detected by ultrasound as early as 12 weeks’ gestation [47]. Two types have been recognized based on their natural history: rapidly involuting congenital hemangioma (RICH) and non-involuting congenital hemangioma (NICH) [48, 49].

RICHs are fully developed at birth, may be large and exophytic, and, as their name implies, involute rapidly during the first month of life. RICHs also rarely require treatment, although they may elicit clinical concern due to associated transient abnormalities (thrombocytopenia, low fibrinogen, and elevated fibrin degradation products). Histopathologically, RICHs are highly cellular with multiple well-defined lobules of proliferating capillaries that anastomose with each other to form ribbons within the dermis or subcutaneous tissue.

NICH grow proportionately with the child. Their vessel walls are often thicker than in IH, and their endothelium may be hobnail in appearance [50]. NICH do not regress as do the other infantile hemangiomas, while RICHs involute in a short period of time. NICH are characterized histopathologically by lobular collections of small, thin-walled vessels with large, often stellate, central lumina, separated by variable amounts of fibrous tissue richly supplied with normal and abnormal veins and arteries.

Dilated lymphatic channels are seen at the junction of papillary and reticular dermis in the superficial form or lymphangioma circumscriptum (Figs. 14.9a, b). Both the superficial and deep lymphatic channels are involved in the deep type.

The clinical differential diagnosis of lymphangioma circumscriptum of the vulva includes molluscum contagiosum and genital warts [56]. The histologic differential diagnosis includes acquired lymphangiectasis, vulvar varices (venous lake), and angiokeratoma. Clinical history is essential to distinguish primary from acquired lymphangiomas, since lymphangiomas are present since birth or early childhood, while acquired lymphangiectasis is a secondary change associated with a number of causes.