Vascular tumors of bone

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Available online at www.sciencedirect.com

www.elsevier.com/locate/semdp

Vascular tumors of bone Jesse L. Hart, DOa, Mark A. Edgar, MDa, Jerad M. Gardner, MDb,n a

Department of Pathology, Emory University, Atlanta, Georgia Department of Pathology, University of Arkansas for Medical Sciences, 4301 W. Markham St, #517 Little Rock, Arkansas 72205 b

article info

abstract

Keywords:

Vascular tumors of the bone represent a variety of neoplasms, ranging from benign

Hemangioma

hemangiomas and epithelioid hemangiomas to intermediate grade hemangioendothelio-

Hemangioendothelioma

mas to frankly malignant angiosarcomas. Over the years, there has been considerable

Angiosarcoma

debate concerning the aggressivity, nomenclature, and mere existence of various nosologic

Vascular

entities, due to morphologic similarities and uncertainty regarding biologic behavior. Such

Epithelioid

debate has led to confusion among pathologists and clinicians, thus diminishing the

Endothelial

prognostic implications in the diagnosis of these lesions. Here we review the current

Bone tumor

knowledge concerning the primary vascular neoplasms of the bone and correlate clinicopathologic features with tumor behavior. & 2014 Elsevier Inc. All rights reserved.

Introduction Vascular tumors of the bone comprise of a variety of neoplasms, in which constituent cells have undergone endothelial differentiation (Table). Similar to their soft tissue counterparts, these lesions range from common (usually asymptomatic) benign lesions to uncommon high-grade sarcomas with an aggressive clinical course. Here we review the primary vascular neoplasms of the bone.

Hemangioma Primary osseous hemangioma is a fairly common neoplasm (affecting about 10% of the adult population), characterized by a well-demarcated proliferation of capillary-sized to cavernous vessels. Most cases are incidental findings, which are diagnosed on imaging alone based on their characteristic radiographic appearance, which includes coarse vertical trabecular thickening (sclerosis) within the otherwise osteopenic lesion, creating a “corduroy” pattern.1 A minority of hemangiomas of the bone are symptomatic or have radiographic n

Corresponding author. E-mail address: [email protected]. (J.M. Gardner)

0740-2570/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semdp.2014.01.003

similarity to a more significant lesion, requiring surgical intervention or tissue diagnosis. These neoplasms are benign, and local recurrence is rare. Primary osseous hemangioma may occur at any age, most frequently presenting in adults between 40 and 60 years of age, with a slight female predominance.1 Vertebral bodies (thoracic and lumbar spine) are most commonly affected, followed by craniofacial and long bones. Lesions may be unifocal or multifocal, occasionally presenting in the setting of angiomatosis, in which multiple intra-osseous hemangiomas involve a large, localized skeletal area, or widespread bony lesions are present.1 Involvement of multiple tissue planes adjacent to a vertebral hemangioma (e.g., skeletal muscle, epidural fat, skin, and even spinal cord) can suggest an aggressive tumor on imaging studies. Microscopically, tumors are composed of capillary-sized to cavernous vessels set in a loose edematous stroma (Fig. 1A and B). Vessels surround sclerotic intra-lesional trabeculae; however, the lesion itself is well-demarcated, with respect to the adjacent medullary constituents. Vascular spaces are lined by a single layer of bland, mitotically inert endothelial cells. Occasional cases contain blood-filled cavities and

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Table – Typical histologic features of vascular tumors of bone. Tumor

Aggressive growth

Solid sheets

Vascular channels

Blister cells

Atypia

Mitoses

Necrosis

Positive IHC and molecular findings

H EH ES-H

No Yes Yes

No 7 Yes

Yes Yes No

No 7 No

No Mild Mild

Rare o1/10 o1/10

No Rare o20%

EHE

7

No

No

Yes

Moda

o3/10a

Rare

AS

Yes

Yes

Yes

7

Severe

Many

Yes

CD31, CD34, and ERG CD31, CD34, ERG, and CK7 ERG, FLI1, CK (AE1/3), INI1 (retained), CD317, and CD34 negative CD31, CD34, ERG, FLI1, CK (30%), and t (1;3) CD31, CD34, ERG, FLI1, and CK (65%)

IHC ¼ immunohistochemistry; H ¼ hemangioma; EH ¼ epithelioid hemangioma; ES-H ¼ epithelioid sarcoma-like hemangioendothelioma; EHE ¼ epithelioid hemangioendothelioma; AS ¼ angiosarcoma; CK ¼ cytokeratins; EMA ¼ epithelial membrane antigen; 7 ¼ variable; Mod ¼ moderate. a High-risk EHE may display marked atypia and increased mitoses.

intra-vascular thrombi, which may be associated with papillary endothelial hyperplasia. As hematopoietic elements are lost, the native adipose tissue becomes more prominent, occasionally dominating the lesion. Endothelial cells express CD31, CD34, ERG, and other vascular markers.

Epithelioid hemangioma Epithelioid hemangioma (EH) is a benign, but locally aggressive vascular neoplasm, which may demonstrate bony expansion with cortical erosion and soft tissue extension, albeit a broad, pushing border (Fig. 1C and D). EH has an

approximately 10% local recurrence risk, and rare cases reportedly may develop regional lymph node metastases3,4; widespread metastasis or death from disease has not been reported, hence its designation as a benign neoplasm. EH of the bone shows certain histologic differences from its soft tissue counterpart including a more solid growth pattern and lack of association with a damaged blood vessel. EH is an uncommon tumor, with most cases occurring in the third to sixth decades, although it may present at any age. The long tubular bones are most commonly involved, followed by the distal lower extremities, flat bones, vertebrae, and hand bones.3 Approximately 20% of cases are multifocal and rare cases present with concomitant extra-osseous EHs.3

Fig. 1 – Osseous hemangioma (A and B) does not infiltrate through the overlying cortical bone. It is composed of well-formed blood vessels lined by bland endothelial cells similar to its soft tissue counterpart. Epithelioid hemangioma of bone (C and D) encases the native bone trabeculae and often displays locally aggressive behavior including erosion through the cortical bone and invasion into adjacent soft tissue.

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Unlike conventional hemangioma, EH is generally painful. Imaging studies reveal a well-demarcated expansile lytic lesion, which may demonstrate non-destructive extension into the adjacent soft tissue. Microscopically, the tumor has a lobular architecture with encasement of native trabeculae. Lobules commonly demonstrate a hypocellular periphery, containing small arteriolesized vessels with flat endothelial cells, which gradually transition into a hypercellular center, containing wellformed compact vessels lined by plump epithelioid endothelial cells, some of which protrude into the lumen, creating a characteristic “tombstone-like” appearance (Figs. 2 and 3A).5 Large epithelioid endothelial cells contain round–oval to cleaved (often hyperlobated) nuclei with evenly dispersed chromatin; they may contain small nucleoli (Fig. 3D). The abundant eosinophilic cytoplasm occasionally contains vacuole-like intra-cytoplasmic lumina, which may contain erythrocytes. Non-vasoformative sheets of cells may predominate, but they usually make up a minor proportion of the tumor (Fig. 3C). Mitotic activity is usually low (o1 mitosis per 10 HPFs), and a loose connective tissue stroma with numerous eosinophils, lymphocytes and plasma cells is often present, similar to their cutaneous/subcutaneous counterparts (Fig. 2B–D). Cases with marked inflammation may be mistaken for osteomyelitis. Uncommon findings include focal necrosis, osteoclast-like giant cells, and deposition of woven bone. Tumors of the small tubular bones of the hands and feet often contain fascicles of bland, mitotically active spindle cells (Fig. 3B), intra-tumoral hemorrhage/hemosiderin

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deposition, and soft tissue extension3; these findings have not been associated with tumor aggressivity. Lesional cells express CD31, CD34, ERG, and other vascular markers. Similar to other epithelioid vascular neoplasms, EH commonly stains with various cytokeratin antibodies (i.e., Cam5.2 and AE1/ AE3) and EMA.6 EH is frequently misdiagnosed as a more aggressive vascular neoplasm, especially when sheets of polygonal or spindle cells are conspicuous. EH does not demonstrate a primitive corded cytoarchitecture, myxohyaline matrix, or t (1;3)(p36.3;q25) resulting in the WWTR1–CAMTA1 fusion product, findings characteristic of epithelioid hemangioendothelioma (EHE).7 The presence of multicellular endotheliumlined channels argues against the diagnosis of EHE. The lack of irregular inter-anastomosing vessels and frankly malignant cytologic atypia, as well as the low mitotic rate, allow for distinction from angiosarcoma.

Epithelioid sarcoma-like hemangioendothelioma (pseudomyogenic hemangioendothelioma) Epithelioid sarcoma-like hemangioendothelioma (a.k.a. pseudomyogenic hemangioendothelioma) (ES-H) is a rare, locally aggressive malignancy with endothelial differentiation, usually presenting as multiple soft tissue lesions in the lower extremity, although upper extremity, trunk, or head and neck may also be involved. There is a marked male predominance (82%).8 ES-H most commonly arises in the skin and soft

Fig. 2 – Epithelioid hemangioma. (A) The central aspect of the tumor lobules may be hypercellular (left), but the periphery is hypocellular and composed of well-formed arteriole-sized vessels (right). (B–D) The small blood vessels are lined by epithelioid endothelial cells, which protrude into the lumen in a “tombstone-like” manner. Stromal eosinophils may be abundant.

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Fig. 3 – Epithelioid hemangioma. (A) A closer look at the transition between hypocellular peripheral areas (left) and hypercellular central areas (right). Well-formed vessels are clearly seen. (B) Focal areas may show a predominance of spindled endothelial cells. Scattered osteoclasts may also be present. (C) The hypercellular areas sometimes appear sheet-like, a finding which may lead to confusion with angiosarcoma. (D) The endothelial cells are large and epithelioid but, unlike angiosarcoma, display minimal cytologic atypia and relatively few mitoses.

tissue, but a subset of cases demonstrate bony involvement, as well (14%).8 Primary osseous lesions (without concomitant soft tissue involvement) are rare, but have been reported.8–10 As such, radiographic analysis of the affected limb, with special attention to the superficial and deep soft tissue planes, is warranted before diagnosing primary ES-H of the bone. Early recurrence/development of additional regional soft tissue tumor nodules is common (approximately 60%)8,11; however, widespread metastasis and death from disease are very rare.8 Primary bone lesions may be aggressive, with cortical destruction and soft tissue invasion (Figs. 4A and 5A and B).9 Both unifocal and multifocal primary bone lesions have been reported, the latter of which has involved distal tibia and fibula of the affected extremity.9,10 The lesions are often painful.8 Microscopically, epithelioid sarcoma-like hemangioendothelioma is composed of infiltrative sheets and fascicles of mildly atypical plump spindled to epithelioid cells, with dense, eosinophilic cytoplasm and vesicular nuclei with readily identifiable nucleoli; a minority of cases demonstrate marked cytologic atypia (Figs. 4 and 5C and D).8 Mitotic figures are generally sparse (1 per 10 HPF), but occasional cases have increased proliferative activity. Prominent stromal neutrophils are a diagnostic clue, present in nearly 50% of cases (Fig. 5C).8,9 Despite immunophenotypic evidence of endothelial differentiation, histologically identifiable vessel formation does not occur. The paucity of vascular channel or

lumen formation may result in misdiagnosis as a benign fibrous histiocytoma, rhabdomyosarcoma, or epithelioid sarcoma. ES-H demonstrates strong, diffuse immunoreactivity with AE1/AE3, Fli1, and ERG. About 50% of tumors express CD31, and occasional cases are smooth muscle actin (SMA) positive. S100 protein, desmin, cytokeratin MNF116, EMA, and CD34 are negative whereas INI1 (hSNF5/SMARCB1) is retained, allowing for differentiation from other diagnostic considerations, most notably epithelioid sarcoma.2,8,11

Epithelioid hemangioendothelioma Epithelioid hemangioendothelioma (EHE) is a rare low- to intermediate-grade mesenchymal neoplasm, characterized by short cords and nests of epithelioid tumor cells with endothelial differentiation set in a myxohyaline matrix. Primary sites include skin, superficial and deep soft tissues, numerous visceral organs (lung, liver, pleura, and lymph nodes.), and bone. Long and short tubular bones of the extremities are the most common sites of skeletal disease, but pelvic, rib, and vertebral lesions are not uncommon.12,13 EHE may present at any age, but the majority are seen in adolescents and adults between 10 and 50 years of age.12 Localized pain and swelling are common. Imaging reveals lytic lesions, which may be either well defined or poorly circumscribed; cortical erosion and soft tissue invasion may also be seen.

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Fig. 4 – Epithelioid sarcoma-like hemangioendothelioma. (A–D) The tumor is composed of infiltrative sheets and fascicles of plump spindled to epithelioid cells with dense, eosinophilic cytoplasm.

Fig. 5 – Epithelioid sarcoma-like hemangioendothelioma. (A and B) Aggressive growth with cortical destruction and soft tissue invasion may be seen. (C and D) The tumor cells are spindled to epithelioid with dense, eosinophilic cytoplasm, mildly atypical vesicular nuclei, and readily identifiable nucleoli. Marked atypia may be seen occasionally. The presence of stromal neutrophils (C) is a useful diagnostic clue.

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Most cases behave in an indolent fashion, but similar to their soft tissue counterparts, EHE of the bone has an 20% risk of widespread metastasis and death from disease.12 Both skeletal and extra-skeletal EHE often present with multifocal lesions14; specifically, over 50% of osseous tumors involve one bone or separate bones within a localized anatomical region.12 EHE of the bone and extra-skeletal sites contains a highly characteristic recurrent genetic abnormality, namely t(1;3) (p36.3;q23-25), resulting in the WWTR1–CAMTA1 fusion product. Separate tumors in “multifocal” EHE have been shown to contain identical breakpoints, suggesting multifocality actually represents regional metastatic spread, as opposed to multifocal synchronous primary tumor development.7,15 Although many vascular tumors of the bone are characterized by a hemorrhagic and spongy gross appearance, EHE is typically more solid with a gray to tan color and rubbery consistency. Microscopically, EHE is an infiltrative lesion, composed of cords, nests, and single cells set in a myxohyaline matrix (Figs. 6 and 7A). Especially in osseous EHE, this matrix has a tendency to mineralize, a feature that may raise concern for a bone-forming neoplasm (Fig. 7B). Well-formed vascular structures are seldom present, helping to differentiate these lesions from epithelioid hemangioma (EH) and epithelioid angiosarcoma, which display vascular channel formation. Lesional cells range from large, epithelioid to spindled cells, and have vesicular nuclei with nucleoli. Nuclear atypia is generally moderate and scattered folded to “dumbbell-shaped” nuclei are frequently observed. Epithelioid cells contain abundant eosinophilic, frequently

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vacuolated cytoplasm, and the presence of cells with round intra-cytoplasmic primitive lumina containing erythrocytes or red cell fragments (“blister cells”) is a histologic hallmark of EHE (Fig. 7C and D). The combination of myxoid background with cords of epithelioid, vacuolated cells can mimic chordoma. Occasional cases demonstrate marked nuclear atypia, increased mitotic rate, extensive cell spindling and necrosis, features that correspond to an increased risk of metastasis; EHE with these features has been previously termed “malignant epithelioid hemangioendothelioma” in the previous edition of the WHO blue book.16 A risk stratification model for EHE of soft tissue has subsequently been developed that dichotomizes lesions into high-risk (tumors 43 cm in greatest dimension or 43 mitoses per 50 HPFs) and low-risk (tumors o3 cm and o3 mitoses per 10 HPFs) groups.17 Similar to most epithelioid vascular neoplasms, EHE stains with vascular markers (CD34, CD31, Fli1, and ERG) with some cases also expressing cytokeratin (30–35%).12,18 The diagnosis of EHE may be a challenge, especially on limited biopsy material, as tumors can mimic metastatic carcinoma and myoepithelial and chondroid neoplasms. An appropriate immunohistochemical panel to include vascular markers helps to avoid misdiagnosis.

Angiosarcoma Primary angiosarcoma of the bone is a rare, aggressive, highgrade malignant neoplasm with endothelial differentiation

Fig. 6 – Epithelioid hemangioendothelioma. (A and B) Although both of these cases are contained by the cortex, cortical destruction and soft tissue invasion may sometimes be seen. Even from low magnification, the dense myxohyaline background can be appreciated. (C and D) The tumor is composed of epithelioid endothelial cells arranged in cords and nests that course through the dense myxohyaline background. The tumor cells do not form well-defined vascular channels.

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Fig. 7 – Epithelioid hemangioendothelioma. (A) The tumor is composed of epithelioid endothelial cells arranged in cords and nests that course through a myxohyaline background. (B) The background may be densely sclerotic and display mineralization resembling osteoid (left), a finding that could lead to confusion with bone-forming neoplasms. (C and D) The large epithelioid tumor cells typically have vesicular nuclei with nucleoli and mild to moderate nuclear atypia. The presence of cells with round intra-cytoplasmic vacuoles containing erythrocytes or red cell fragments (“blister cells”) (arrows) is a characteristic finding.

and a very high mortality; 1- and 5-year survival rates are approximately 55% and 33%, respectively.19,20 Most tumors arise in the long and short tubular bones of the extremities, followed by the pelvis and axial skeleton. Approximately 70% of lesions are unifocal, with the remainder being multifocal at presentation, usually involving contiguous skeletal sites, although widespread disease may be present.19 Most cases present in adults older than 30 years, but very rare childhood examples do occur.19 The majority of primary osseous angiosarcomas are sporadic, but occasional cases have been reported subsequent to radiation therapy.21 Lesions are usually painful and radiographic studies reveal an aggressive-appearing lytic mass, often with destructive cortical permeation and invasion of the adjacent tissue. Microscopically, primary angiosarcoma of the bone is characterized by solid sheets of markedly atypical epithelioid (or less commonly spindled) cells with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli (Figs. 8A and 9A). Vasoformative areas, in which well-formed anastomosing vascular spaces are lined by malignant endothelial cells, are present in over half of the cases (Figs. 8B and 9B and C).19,20 Intra-cytoplasmic lumina (“blister cells”), as seen in EHE, may also be seen (Fig. 9D). Mitotic figures (including morphologically abnormal forms), tumor necrosis, and large areas of hemorrhage are common. Additionally, angiosarcoma of the bone often contains an inflammatory infiltrate, which may be rich in neutrophils, providing a diagnostic clue

to its endothelial nature.20 As emphasized above, the marked cytologic atypia and high mitotic rate usually present in angiosarcoma is not typical of EH or EHE. Angiosarcoma of the bone usually demonstrates CD31, CD34, FLi1, and ERG immunoreactivity. Over 65% of cases express cytokeratin, particularly in the epithelioid cells. Scattered cells may express smooth muscle actin.19,20 Angiosarcoma of bone, particularly the epithelioid subtype, can easily be mistaken for metastatic carcinoma on a small biopsy that shows only atypical cytokeratin-positive epithelioid cells or poorly formed vascular spaces that may simulate glands (Fig. 8C and D). A high index of suspicion for angiosarcoma, coupled with an immunohistochemical panel that includes endothelial markers, may help avoid misdiagnosis.

Conclusion Vascular tumors of the bone include a spectrum of lesions ranging from benign hemangiomas to malignant angiosarcomas, with subcategories of hemangioendothelioma representing tumors of intermediate biologic behavior. Several critical diagnostic pitfalls exist in this area of bone pathology. Epithelioid hemangioma can be mistaken for epithelioid angiosarcoma. Epithelioid hemangioendothelioma may be confused with angiosarcoma or vice versa, and both of these tumors may be misdiagnosed as non-endothelial neoplasms

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Fig. 8 – Angiosarcoma. (A) Hemorrhage and necrosis are commonly seen (right). (B) The tumor cells are arranged into solid sheets (left) and infiltrative anastomosing vascular channels (right). (C and D) Epithelioid tumor cells may be arranged into compact nests, and formation of vascular lumina within nests can mimic glandular differentiation. These features, coupled with the common expression of cytokeratin in angiosarcoma, can lead to confusion with metastatic carcinoma.

Fig. 9 – Angiosarcoma. (A) The tumor is composed of markedly atypical epithelioid cells with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. (B and C) Formation of infiltrative anastomosing vascular channels lined by markedly atypical endothelial cells is the hallmark of angiosarcoma. (D) Nuclear atypia is striking in most cases. Vacuolated “blister cells” containing erythrocytes or red cell fragments, similar to those seen in epithelioid hemangioendothelioma, may be present.

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such as metastatic carcinoma. Epithelioid sarcoma-like hemangioendothelioma may also be confused with nonendothelial malignancy such as epithelioid sarcoma. Clear knowledge of diagnostic criteria, careful attention to histologic detail, correlation with clinical features, and appropriate utilization of immunohistochemistry in select cases can all assist the general pathologist in correct classification of vascular tumors of the bone.

r e f e r e n c e s

1. Wenger DE, Wold LE. Benign vascular lesions of bone: radiographic and pathologic features. Skeletal Radiol. 2000;29(2):63–74. 2. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumors of Soft Tissue and Bone, 4th ed Lyon: IARC Press; 2013. 3. Nielsen GP, Srivastava A, Kattapuram S, et al. Epithelioid hemangioma of bone revisited: a study of 50 cases. Am J Surg Pathol. 2009;33(2):270–277. 4. Floris G, Deraedt K, Samson I, Brys P, Sciot R, et al. Epithelioid hemangioma of bone: a potentially metastasizing tumor? Int J Surg Pathol. 2006;14(1):9–15. 5. Lewis VO, Montag AG, Simon MA. Epithelioid hemangioma of bone: spontaneous clinical and radiographic remission. Clin Orthop Relat Res. 2003;407(1):167–172. 6. O’Connell JX, Kattapuram SV, Mankin HJ, Bhan AK, Rosenberg AE, et al. Epithelioid hemangioma of bone. A tumor often mistaken for low-grade angiosarcoma or malignant hemangioendothelioma. Am J Surg Pathol. 1993;17(6):610–617. 7. Errani C, Zhang L, Sung YS, et al. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer. 2011;50(8):644–653. 8. Hornick JL, Fletcher CDM. Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol. 2011;35(2):190–201. 9. Sheng WQ, Wang J. Primary pseudomyogenic hemangioendothelioma of bone. Histopathology. 2012;61(6):1219–1224.

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10. McGinity M, Bartanusz V, Dengler B, Birnbaum L, Henry J, et al. Pseudomyogenic hemangioendothelioma (epithelioid sarcoma-like hemangioendothelioma, fibroma-like variant of epithelioid sarcoma) of the thoracic spine. Eur Spine J. 2013;22(suppl 3):S506–S511. 11. Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol. 2003;27(1):48–57. 12. Kleer CG, Unni KK, McLeoud RA. Epithelioid hemangioendothelioma of bone. Am J Surg Pathol. 1996;20(11):1301–1311. 13. O0 Connell JX, Nielsen GP, Rosenberg AE. Epithelioid vascular tumors of bone: a review and proposal of a classification scheme. Adv Anat Pathol. 2001;8(2):74–82. 14. Lau K, Massad M, Pollak C, et al. Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: insights from an Internet registry in the study of a rare cancer. Chest. 2011;140(5): 1312–1318. 15. Errani C, Sung YS, Zhang L, Healey JH, Antonescu CR, et al. Monoclonality of multifocal epithelioid hemangioendothelioma of the liver by analysis of WWTR1–CAMTA1 breakpoints. Cancer Genet. 2012;205(1-2):12–17. 16. Fletcher CDM, Unni KK, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone, 3rd ed. Lyon: IARC Press; 2002. 17. Deyrup AT, Tighiouart M, Montag AG, Weiss SW, et al. Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases. Am J Surg Pathol. 2008;32(6):924–927. 18. Gill R, O0 Donnell RJ, Horvai A. Utility of immunohistochemistry for endothelial markers in distinguishing epithelioid hemangioendothelioma from carcinoma metastatic to bone. Arch Pathol Lab Med. 2009;133(6):967–973. 19. Verbeke SL, Bertoni F, Bacchini P, et al. Distinct histological features characterize primary angiosarcoma of bone. Histopathology. 2011;58(2):254–264. 20. Deshpande V, Rosenberg AE, O’Connell JX, Nielsen GP, et al. Epithelioid angiosarcoma of the bone: a series of 10 cases. Am J Surg Pathol. 2003;27(6):709–716. 21. Mittal S, Goswami C, Kanoria N, Bhattacharya A, et al. Postirradiation angiosarcoma of bone. J Cancer Res Ther. 2007;3 (2):96–99.