Table 3. Clinical and histological features distinguishing EH, EHE, and EAS.

EH: epithelioid hemangioma; EHE: epithelioid hemangioendothelioma; EAS: epithelioid angiosarcoma

Histomorphological features	EH		EHE	Pseudomyogenic hemangioendothelioma	EAS
Neoplastic nature	Benign with metastasizing potential [46].		Intermediate [46].	Intermediate [47].	High-grade [4].
Association with artery	Intimately associated with and symmetrically distributed with a small muscular artery.		Lacks intimate association with a muscular artery [4].Typically affects the veins rather than arteries [4].	Lacks intimate association with a muscular artery [4].	Lacks intimate association with a muscular artery [4].
	Presence of mature vessel foci with open lumen formation [25].		Mature vessels absent [4].	Mature vessels absent [4].	Mature vessels absent [4].
Molecular pathology	FOS gene rearrangement in nearly 1/3 of EH cases in various locations [32].Recurrent ZFP36–FOSB fusion in a subset of EH cases with atypical morphological features that do not suggest FOS gene rearrangement [48]. Recurrent ZFP36–FOSB fusion in a subset of EH cases with atypical histological features. Confirmed FOSB-positive by immunohistochemistry [48]. Negative for WWTR1–CAMTA1 fusion [48].		Recurrent t(1;3)(p36;q25) chromosomal translocation, resulting in WWTR1–CAMTA1 fusion [37].	SERPINE1-FOSB fusion [47].	Complex cytogenetic aberrations. No WWTR1–CAMTA1 fusion or FOS gene rearrangement [37].
Sites	Femur, phalanges, tibia, fibula, metatarsals, scapula, humerus, ilium, vertebrae, sacrum, ribs, and sternum [5].		May involve any bone and has been detected in the femur, tibia, fibula, humerus, radius, ulna, ribs, vertebral bodies, pelvis, scapula, and small bones of the hands and feet [49].	Superficial or deep soft tissue of extremities [47].	Predilection for the femur. Other affected bones include the tibia, calcaneus, humerus, radius, and small bones of the hand, rib, and pelvis [50]
Multifocality	Unicentric to multicentric [4].		Unicentric to multicentric [49].	Multicentric [47].	Unicentric to multicentric [50].
Age	Second to eighth decades of life (mean age of 34 years) [20].		Slight male predominance and a wide age distribution extending from the second to eighth decades of life [49].	Males. Young adults. [47]	Striking male predominance with a mean age of 57 years [50].
Gross	Ranges from 2 to 15 cm in the biggest dimension, well-circumscribed, and dark red in color. Mostly confined to the affected bone where they infiltrate the marrow space, surround the bony trabeculae, and abut or erode the cortex. Occasionally, large tumors transgress the cortex and form soft-tissue masses [51].		Ranges from 2 cm to >10 cm. Frequently tan in color and solid in structure. Usually centered in the medullary cavity and grow in an infiltrative and destructive fashion [49].	Ranges from 1 to 2.5cm only with approximately 10% of tumors being >3cm [47]. Grossly, the tumor is ill-defined, usually multifocal, with a white-to-brown cut surface [47].	Usually >5 cm and soft, red, and hemorrhagic. Usually originates in the medullary cavity and invades the cortex and neighboring soft tissues [50].
Radiology	Usually lucent with well-defined expansile margins [20]. In some cases, they show a mixed lytic and sclerotic appearance with septations, partial cortical destruction, and thick periosteal reactive bone formation [6].		Usually lytic or mixed lytic and blastic with well- or poorly defined margins. Can expand the bone contour and elicit a periosteal reaction, especially if a soft-tissue component is present [49].	Usually lytic, lobulated, and well-circumscribed on CT and radiography. On MRI, the lesions are hypointense on T1-weighted images and hyperintense on T2-weighted and stir-weighted images [47].	Predominantly destructive or exclusively lytic, frequently extending into soft tissues.
		Microscopy
Growth pattern	Lobular growth pattern showing symmetric association with the vessel wall. Infiltrative and destructive but non-metastasizing [10,20].		The lobular growth pattern characterizing EH is absent. No involvement of medium-sized or larger vessels. Infiltrative, destructive, and metastasizing. Higher rates of multifocality and distant spread [4,9-10].
Tumor architecture	The central areas of the lobules contain epithelioid endothelial cells in solid sheets but without a coherent structure. The periphery shows well-formed vessels [9-10,20].		Primitive epithelioid endothelial cells present singly in cords, clusters, and/or sheet-like arrangements. If spindled, they tend to be oriented in fascicles. Well-formed vascular channels are relatively scant or absent. [4].	Ill-defined nodules and fascicles. Desmoplastic stroma [47].	Irregular vascular spaces, sometimes with a papillary pattern, sheets, and areas of solid growth. May protrude into lumens of well-developed vascular spaces in the form of solid tufts or nodules.
Vasoformative tendency	Vasoformative tendency and vessel maturation increase from the center to the periphery. [9,10,20].		Frequent intracytoplasmic lumens.	Not present [47].	Vascular channels. Intracytoplasmic lumens [52]
Tumor cell morphology	The cytoplasm is abundant, eosinophilic, and frequently contains one or more large clear vacuoles (Figure 3).		Populations of elongated and spindle-shaped cells. Elongated cells have prominent intracytoplasmic vacuoles, whereas vacuoles are rare in spindle cells.	Plump spindle or epithelioid cells, with abundant brightly eosinophilic cytoplasm, sometimes mimicking rhabdomyoblasts [47].	Numerous intracytoplasmic vacuoles [52].
Nuclear morphology	Consistent absence of anaplasia, cytologic atypia, and necrosis. Minimal necrotic activity.		The tumor cells contain vesicular nuclei, often with small nucleoli. Greater variability in size and degree of nuclear atypia than with EH. Differentiation from EAS may be difficult if atypia is severe.	The tumor cells contain vesicular nuclei, often with small nucleoli. The degree of nuclear atypia is usually mild, and mitotic activity is scarce [47].	Marked nuclear atypia and pleomorphism.
	Usually <5 mitoses per 10 hpf. Mitotic figures are structurally normal [1].		Greater atypia than EH;>5 mitoses per 10 hpf [1].	Greater atypia than EH;>5 mitoses per 10 hpf [47].	Abundant atypical mitotic figures (>20 per hpf) [1].
Tumor-associated inflammation and stroma	The stroma contains loose, fibrous connective tissue that often contains lymphocytes, varying numbers of eosinophils (Fig 4), and sometimes numerous extravasated red blood cells.		Little inflammatory infiltrate or peritumoral reactive change, unlike EH.	Approximately 50% of cases contain prominent stromal neutrophils, unlike epithelioid hemangioendothelioma (EHE) and angiosarcoma.	Neutrophilia and diffuse interstitial hemorrhage are common and necrosis may be extensive. Little lymphoplasmacytic infiltrate or eosinophilic infiltrate, unlike EH.
	No stromal hyalinization or a basophilic ground substance resembling the cartilage (a feature characteristic of EHE). Reactive woven bone is commonplace and when abundant can mimic a bone-forming neoplasm.		Characteristically, stroma has a hyalinized or basophilic appearance and lacks inflammatory cells. [44,53-54]. This finding is associated with the epithelioid appearance of tumor cells frequently resulting in EHE being mistaken as metastatic carcinoma or a primary cartilage neoplasm.	Occasionally contain focally myxoid stroma [47].	Hyalinized or basophilic stroma is absent. Myxohyaline stroma can be a focal feature. Post-radiation specimens may show prominent fibrosis and hyalinization.
IHC for muscle-specific actin	Zonation pattern [33].		No zonation pattern.	No zonation pattern.	No zonation pattern.
Other IHC markers and their predictive values.	CD34+, CD31+, Fli-1+, ERG+, FOSB +, CKs+, CAMTA1-, INI-1 retained. (100% CAMTA1, TFE3 negative 21% FOSB-positive) [47].		CD34+, CD31+, Fli-1+, ERG+, FOSB -, CKs+, CAMTA1+, INI-1 retained. (100% FOSB-negative, 62% CAMTA1-positive-TFE3 negative, 38% CAMTA1-negative, TFE3-positive) [47].	CD34-, CD31+, Fli-1+, ERG+, FOSB+, CKs+, CAMTA1 -, INI-1 retained. (100% CAMTA1, TFE3 negative, 100% FOSB-positive) [47].	CD34+ (50%), CD31+, Fli1+, ERG+, FOSB -, CKs+, CAMTA1 -, INI-1 retained. (100% -CAMTA1,TFE3-negative, FOSB-negative) [47].
Treatment	Depending on the size and location of the lesion(s), curettage, conservative en block excision, or wide resection is recommended.		The number, size, location, and stage of the tumor determine the treatment type. Wide resection is recommended when feasible. Chemotherapy has been suggested for widespread multisystemic involvement.	The treatment of choice has been surgery (wide resection), with certain cases receiving radiotherapy or chemotherapy. Recently, high expression of mTOR has been demonstrated by immunohistochemistry, and two cases treated with mTOR inhibitors showed clinical improvement [7, 36].	Wide surgical resection with or without adjuvant radiation and chemotherapy. These tumors have an extremely high rate of metastasis and virtually all patients die within 1–2 years of diagnosis.