Infantile hemangiomas (IH) are present in about 4% of newborns.³ They are an extremely common type of vascular tumor that have a distinctive natural history.

Risk factors for the development of IH are well characterized and include female gender, low birth weight, and Caucasian skin type. The etiology of IH remains incompletely understood; however, experts believe that a somatic mutation may be responsible.

IH are typically not present at birth. Rather, they may exist initially as a premonitory mark/precursor lesion, such as an
area of pallor or telangiectasia; initially, they may resemble a bruise. Hemangiomas may occur anywhere on the body but may have a predilection for the head and neck. Hemangiomas grow rapidly over the first 5 to 7 weeks of life, ultimately growth stabilizes, and IH involute or regress slowly over the course of years.⁴ There are several clinical subtypes, including superficial, deep, mixed, and IH with minimal or arrested growth. All have a typical clinical appearance in the skin. Superficial IH are well-demarcated bright red vascular plaques. Deep IH are bluish-hued subcutaneous nodules. Mixed IH demonstrate both a red superficial component and a deeper underlying bluish tumor. IH with minimal or arrested growth tend to favor the lower body and are often flat or telangiectatic in their appearance, with proliferation occurring only in <20% of the lesion, most often at the periphery (Figure 25-1A-D clinical subtypes). IH may be solitary or multifocal in their presentation. When they appear to occupy a region or territory of the body, for example large facial hemangiomas on the frontotemporal area, they may be associated with underlying structural anomalies as seen in Posterior fossa anomalies, large facial Hemangioma, Arterial anomalies, Cardiac anomalies, Eye anomalies (PHACE).⁵

In its proliferative phase, IH exhibits lobules and sheets of capillaries lined by plump endothelial cells arranged in “back-to-back” fashion, with little intervening stroma (Figure 25-2A and B). IH may be centered superficially, deep or both. Occasional mitoses and scattered mast cells may be observed.⁶,⁷ In the involutional phase, stromal fibrosis is increased between the vascular lobules. Endothelial cells are typically more flattened, basement membranes thicken, and mitotic activity is diminished. Biopsy of fully involuted IH demonstrates a “fibrofatty” residuum, with thinned epidermis, scar tissue (including loss of cutaneous appendages), and diminished dermal elastic fibers. The sparse remaining vessels appear small and “ghosted” with thickened basement membranes and often occluded lumens.⁶

The histopathologic differential diagnosis for IH includes congenital hemangiomas (see following paragraphs) and pyogenic granuloma; glucose transporter protein isoform 1 (GLUT1) immunostain readily distinguishes IH from other vascular anomalies, the majority of which exhibit negative staining. GLUT1 facilitates glucose transport across the cell membranes of erythrocytes and is widely expressed in fetal tissue.⁸ GLUT1 immunostain labels IH endothelial cells in all phases of its evolution.

Congenital hemangiomas (CH) are an uncommon but benign type of vascular tumor that present fully formed at birth. They are distinct from IH in many ways, including their natural history and histopathologic features. CH occur much less frequently than IH in only 0.3% of newborns, according to one prospective study.³

CH may occur anywhere on the body and have no clear gender predilection. They are typically solitary, although multifocal variants have been reported. Clinical variants of CH include rapidly involuting congenital hemangioma (RICH), noninvoluting congenital hemangioma (NICH), and partially involuting congenital hemangioma (PICH).⁹ These three subtypes share significant clinical and histopathologic overlap and also genetic etiology. Mutations in GNAQ and GNA11 have been reported in both RICH and NICH.¹⁰ Thus, many authors believe that these uncommon vascular tumors exist on a spectrum.

RICH is likely the most common variant. These tumors present right at birth as solitary, large, violaceous vascular tumors. They may be exophytic and often have a surrounding halo of vasoconstriction (Figure 25-3A). They are high-flow vascular tumors and demonstrate high flow on Doppler evaluation. Usually, they are asymptomatic, although rarely, ulceration, bleeding (much more high flow than an IH), or transient thrombocytopenia may occur. They involute rapidly over the first few months of life, leaving behind atrophic, anetodermalike plaques with prominent veins (Figure 25-3B).

NICH are less common. They typically present as round or oval plaques or nodules with a bluish hue and overlying venules and telangiectasias (Figure 25-4). They also demonstrate a surrounding halo of pallor/vasoconstriction and high blood flow on Doppler evaluation. NICH are generally asymptomatic, although because they persist over time, they may become more symptomatic or bothersome. Pain is sometimes reported, and lesions may expand or worsen during times of hormonal excess such as puberty or pregnancy.¹¹

RICH is comprised of small, mostly similar-sized dermal lobules of capillaries. Endothelial cells are plump and surrounded by layers of pericytes. Prominent fibrous tissue is typically present, surrounding individual capillary lobules. Centrally, RICH often has near-absence of these lobules but instead shows dense fibrosis and large, thickened draining veins with irregular muscular walls. Aneurysmally dilated vessels, interstitial hemosiderin, and calcification are also commonly present. Extramedullary hematopoiesis may also be seen⁶,¹² (Figure 25-5A and B).

NICH exhibits larger, varying sized lobules of capillaries that may coalesce into larger masses (Figure 25-5C). These capillaries are lined by plump endothelial cells with little cytoplasm; some lobules may contain more dilated capillaries lined by hyperchromatic small nuclei that often hobnail into the vascular lumen. Cytoplasmic eosinophilic globules are occasionally present. The main differential diagnosis for RICH and NICH includes IH and pyogenic granuloma. GLUT1 immunostain is highly effective in distinguishing between IH and congenital hemangioma, because the latter is consistently negative.

Pyogenic granuloma (PG) is one of the most commonly acquired vascular tumors in children. It is a benign tumor with a male predilection that can occur at any site on the body at any age, although the vast majority occur in children.

Recently, the majority of PGs have been shown to arise secondary to mutations in BRAF, and in a smaller subset, to mutations in RAS.¹³,¹⁴ In the case of the BRAF mutation, this is the same “hotspot” that is present in many human cancers, including melanoma, leading to a constitutive activation of RAS-MAPK signaling in mutated cells. Interestingly, PGs are also known to arise in the setting of treatment with BRAF inhibitors, which may represent a paradoxical activation of MAPK signaling in this setting.¹⁵,¹⁶

Clinically, PG present as bright red, pedunculated papules varying in size from a few millimeters up to several centimeters, often with a surrounding collarette of scale (Figure 25-6). The overlying epidermis is often eroded or ulcerated. Thus, common complications include bleeding and infection. PGs may occur sporadically or arise secondarily. For example, there may be a history of antecedent trauma, such as an insect bite or scratch, hormonal or other factors involved. In addition, PGs are known to occur secondarily within several different types of vascular anomalies, including capillary malformations and arteriovenous malformations (AVMs), which may be directly related to their genetic etiology.¹⁷

PG exhibits an exophytic, polypoid tumor predominantly within the upper dermis, often with central shallow ulceration and an adjacent epidermal collarette (Figure 25-7A). Clusters of capillaries and venules are lined by plump endothelial cells and are typically organized into discrete lobules by interlacing strands of fibrotic stroma. Dermal edema and lymphocytes are commonly present, as are neutrophils in cases of ulceration. A larger feeding arterial vessel may be present at the base of the tumor. PG with partial regression
demonstrates increased fibrosis and diminished vascular lobules. Deep dermal or subcutaneous presentations of PG are not uncommon and may be intravascular. Intravascular PG presents within the lumen of a vein or artery. Intravenous PG was originally described by Cooper et al. in 1979,¹⁸ as an intraluminal polyp comprised by lobules of capillaries lined by flattened or rounded endothelial cells (Figure 25-7B). A surrounding fibrous stroma is also usually observed.¹⁹,²⁰

The primary differential diagnosis for PG in a neonate or infant is a superficially sampled IH. Negative GLUT1 immunostaining will confirm the diagnosis in this situation. Deep PG may resemble other benign vascular tumors such as tufted angioma; the characteristic lymphatic structures in tufted angioma aid in differentiation.

Spindle cell hemangioma (SCH) was originally described as a hemangioendothelioma, implying low-grade malignant potential.²¹ As it is now understood to have benign biologic behavior, it is classified as a hemangioma.²² SCH is one of the characteristic findings in Mafucci syndrome.

The majority of SCH are known to arise because of mutations in IDH1 or IDH2.²³ This mutation is common both to sporadic SCH and those found in Maffucci syndrome. IDH mutations appear to be specific to this vascular tumor and have not been observed in other vascular anomalies.²³

SCH presents as red-brown to blue nodules in the dermis or subcutaneous tissue. SCH is often multifocal and occurs most frequently on the distal extremities.²⁴ Lesions are often tender to palpation.

SCH is a tumor seen in both the dermis and the subcutis, which exhibits an admixture of thin-walled dilated venous channels, and nodules of spindled cells with extravasated erythrocytes, which resemble nodular Kaposi’s sarcoma (KS)²¹,²² (Figure 25-8). Microthrombi with organization may be seen within venous channels. A subpopulation of ovoid cells with readily visible cytoplasmic vacuoles may also be seen. This latter cell population and the presence of venous channels permit distinction from KS, as does negative HHV8 staining. Focal positivity with lymphatic immunostains including D2-40, Prox1, and Wilms tumor-1 (WT-1) in both the vascular structures and spindle cell population suggests a lymphatic origin.²⁵

Epithelioid hemangioma (EH) is a rare vascular tumor with highly variable histomorphology. Nonetheless, it is a distinctive vascular neoplasm displaying well-formed vascular channels lined by prominent epithelioid endothelial cells.²⁶

EH has previously been described under numerous designations, including angiolymphoid hyperplasia with eosinophilia (ALHE), intravenous atypical vascular tumor, inflammatory angiomatous nodule, and histiocytoid hemangioma.²⁷ In the past, this tumor was believed to arise primarily in the skin of the head and neck. However, it is now recognized that EH may occur anywhere on the body in any tissue or organ, particularly in the bone.²⁸ Bony EH may lead to significant destruction, and thus, it is important to distinguish it from malignant vascular tumors or other neoplasms.

Recently, FOS gene rearrangements have been observed in nearly one-third of EH in a variety of anatomic locations and histologic variants. Of note, bony EHs tended to harbor this rearrangement most frequently, whereas very few of the cutaneous ALHE-type EHs (ie, the head and neck-predominant variant) demonstrated this change.²⁷

Cutaneous variants of EH present as red-to-blue firm, round nodules or clustered papules that tend to itch; patients may also report a pulsatile sensation. As noted previously, the head and neck regions are the most common cutaneous locations, but EH may present at any anatomic site, including the penis.²⁷

Cutaneous EH is typically centered within the dermis, with circumscribed borders and an often lobulated growth pattern. EH is composed of capillaries lined by epithelioid endothelial cells that are occasionally vacuolated (Figure 25-9A and B). These capillaries have patent lumens. The surrounding stroma contains a variably dense inflammatory infiltrate of eosinophils, lymphocytes, and occasionally plasma cells.

The differential diagnosis varies on the basis of EH presentation. ALHE-type lesions may be confused with Kimura disease; the latter tends to exhibit deeper tissue involvement and a predominantly inflammatory pattern (commonly with
lymphoid follicles) and a lesser vascular element. More cellular EH types may mimic malignant tumors such as epithelioid hemangioendothelioma (EHE) or even epithelioid angiosarcoma (AS) (Figure 25-9C). Immunohistochemistry and molecular studies such as fluorescent in situ hybridization (FISH) can be helpful in ruling in these malignant tumors, because 90% of EHE demonstrate a characteristic WWTR1-CAMTA1 fusion, which results from a t(1;3)(p36;q25) translocation,²⁹ and many ASs demonstrate MYC amplification on FISH and/or MYC-positivity on immunohistochemistry.³⁰

Microvenular hemangioma is an uncommon, acquired benign vascular tumor; less than 100 cases have been reported in the medical literature. It typically presents as a solitary lesion in adulthood, with a slight female predominance and an average age of onset of 32, but occasionally may be seen in children.³¹,³² A patient as young as 16 months of age has been reported.³¹

As a sporadic, typically solitary tumor of adult onset, the pathogenesis of microvenular hemangioma is not well understood. A single patient with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) presenting with multiple microvenular hemangiomas has been reported³³; all other reported patients with multiple lesions have had no identifiable comorbidities.³⁴

Microvenular hemangioma presents in most cases as a solitary lesion, most commonly on the trunk or upper extremities, with a reddish brown papule or plaque less than 2 cm in diameter.³¹ Most are asymptomatic.

The characteristic microscopic finding is of many small, thinwalled vessels interstitially arrayed, dissecting between collagen fibers in the mid-dermis (Figure 25-10A and B). Adnexocentricity may present. Endothelial cells are bland in appearance, with a visible surrounding pericyte layer. Surrounding stromal collagen may be mildly sclerotic, and mild lymphoplasmacytic inflammation is often present. Lesional cells uniformly stain with CD31, CD34, and ERG, and are negative on D2-40.³¹ GLUT1 immunostaining is consistently negative.³⁵

TAs are rare vascular tumors that are usually limited to the skin and subcutis and may occur anywhere on the body. TA tends to grow slowly and is unlikely to be infiltrative. It is usually solitary, and may appear clinically as an indurated, violaceous plaque with overlying hypertrichosis or hyperhidrosis (Figure 25-11). In the case of very extensive lesions, TA may also be associated with KMP; however, this is less common in the setting of TA than in that of KHE. The clinical course for TA is variable; some lesions may regress spontaneously, whereas others persist.

TA exhibits well-defined lobules of closely apposed capillaries within the dermis and upper subcutis. Given their notably round, blue appearance at scanning magnification, these lobules are colloquially referred to as “cannonballs” (Figure 25-12A and B). Endothelial cells are often subtly spindled.³⁷ Individual lobules exhibit a surrounding thin, crescentic lymphatic channel, which labels positively with lymphatic marker immunostains such as D2-40 and PROX-1. Spindled endothelial cells may demonstrate similar positivity, although most of the central portions of lobules are D2-40 negative.³⁸

The primary differential diagnosis is KHE. KHE and TA exhibit many overlapping features; in addition to the abovementioned findings, both may also exhibit microthrombi, hemosiderin-laden endothelial cells, extravasated red blood cells, and a lymphatic immunoprofile. These overlapping features underscore the difficulty in conclusively differentiating TA and KHE on biopsy. Correlation with clinical and imaging features (deeper, multiplane involvement is more typical of KHE) is often required for definitive diagnosis between these two entities.

KHE is a rare, locally aggressive vascular tumor. In one study, the prevalence of KHE in New England was estimated at 0.91 cases per 100 000 children.³⁹ In the same study, authors estimated that KMP is present in up to 71% of children or infants presenting with KHE.

KHE has a predilection for occurrence on the extremities, but may also occur in the retroperitoneum, head and neck, trunk or groin.⁴⁰ They present most commonly as a violaceous, indurated plaque or nodule in early infancy. Similar to TA, hypertrichosis or hyperhidrosis may be observed. As discussed earlier, KHE can develop into a KMP more commonly than in tufted hemangiomas. Rapid expansion, bruising, or purpura may be associated with lesions undergoing KMP (Figure 25-13). KHE are often deep and infiltrative; thus, if deep tissues such as muscle or fascia are involved, it may lead to fibrosis and chronic pain later in the course.

KHE demonstrates coalescent lobules of mostly poorly canalized vessels with rounded or spindled endothelial cells (Figure 25-14). Sheets and fascicles of spindled cells which form slit-like vessels resemble those seen in nodular KS. Clusters of cells with a glomeruloid appearance may be seen, similar to those in TA, although these tend to be larger and less circumscribed in KHE. Extension into the subcutis and deeper tissue planes is more common than in TA, and KHE tends to have a more infiltrating architectural pattern. Cytologic atypia is minimal, and mitotic figures are uncommon. Microthrombi are commonly present in capillaries, and hemosiderin may be seen within individual endothelial cells. The interlobular stroma of KHE commonly demonstrates fibrosis, edema, or mucin deposition.⁴¹ Lesional cells stain positively for lymphatic markers including D2-40/podoplanin, PROX-1, and other vascular markers such as CD31.⁴¹,⁴² As noted earlier, the differential diagnosis includes nodular KS, although HHV8 staining in KHE is consistently negative.⁴³

Papillary intralymphatic angioendothelioma (PILA or Dabska tumor) was first described in 1969 by Maria Dabska. This borderline malignant vascular tumor occurs almost exclusively in children and young adults.⁴⁴ PILA tumors are quite rare, and usually involve only the skin and subcutis, although deeper infiltrative PILA tumors have also been described.⁴⁴ Because of their rarity, their long-term behavior and overall prognoses are not understood. However, it should be noted that in some cases, regional lymph node involvement and at least one case of disseminated metastatic disease resulting in death have been reported.⁴⁵

Lesions present as ill-defined, erythematous to violaceous vascular plaques or nodules. There are several reports of PILA/Dabska tumors arising in the setting of an underlying lymphatic malformation (LM) or other vascular anomalies.

PILA demonstrates both slit-like and widely dilated vascular channels lined by hyperchromatic endothelial cells with prominent hobnailing (Figure 25-15). The characteristic finding is of intravascular papillary clusters (“tufts”) of endothelial cells surrounding a central hyaline core. These tufts may resemble glomeruli and can fill and occlude vascular channels. Dense lymphocytic inflammation may also be present adjacent to vascular structures.²² The differential diagnosis includes papillary endothelial hyperplasia (Masson’s phenomenon), retiform hemangioendothelioma, and the glomeruloid hemangioma associated with POEMS syndrome. The characteristic appearance of tufts in PILA, with eosinophilic cores and surrounding roundish endothelial cells, typically permits distinction.

Composite hemangioendothelioma, so named because it exhibits multiple histologically distinct components (originally described as demonstrating overlapping features of benign, low-grade, and malignant-appearing vascular tumors⁴⁶), is considered to be a low-grade malignancy with frequent local recurrence and a low risk of lymph node or distant metastasis.⁴⁷ The majority of cases present in adulthood, although childhood (and rarely congenital⁴⁸) presentations are described. The overall incidence is unknown, but it is believed to be quite rare; fewer than 40 cases have been reported.⁴⁹

A molecular basis for this rare tumor has not been established. Most are reported to arise sporadically, without underlying comorbidities, although rare associations with vascular malformations, Mafucci syndrome, lymphedema, or prior irradiation have been described. An aggressive variant of composite hemangioendothelioma that expresses neuroendocrine markers has recently been reported.⁴⁹

Tumors present as slow-growing, nodular masses or zones of ill-defined soft tissue swelling, most commonly on the lower extremities, up to 6 cm in diameter.⁴⁶ Patients may report pain. Surface skin changes may include purpura, a violaceous hue, or alopecia.⁵⁰