Section 3 -

What's New in Vascular Tumors of Bone Andrew E. Rosenberg Massachusetts General Hospital Harvard Medical School Boston , MA USA

Introduction Vascular tumor of bone is defined as a neoplastic proliferation of endothelial cells that may be benign or malignant. Although vascular tumors of the skeleton are very common, most involve the vertebral column and the vast majority is asymptomatic. Clinically significant neoplasms are infrequent and their biology ranges from those that are relatively indolent to those that are extremely aggressive and frequently fatal. An important group of vascular tumors of bone are composed of epithelioid endothelial cells, and their unusual morphology complicates pathologic interpretation. New information regarding the realm of skeletal vascular neoplasia largely resides in the recognition and classification of epithelioid vascular tumors, which is still somewhat controversial [9] . This discussion will provide an update on these entities within the framework of vascular tumors in general Hemangioma Hemangioma is the most common vascular tumor of bone and may be found in vertebral bodies in approximately 10% of the population at the time of autopsy. Clinically detectable tumors, however, are uncommon and account for less than 1% of primary bone tumors [29] . Hemangiomas may be solitary or multifocal. Solitary lesions like some capillary hemangiomas are usually indolent tumors and are stable or slowly enlarge. Multifocal disease has been subclassified into two distinct entities: multiple primary hemangiomas and diffuse cystic angiomatosis. Multiple primary hemangiomas of bone consist of collections of lesions that individually have the radiographic findings and clinical behavior of solitary hemangiomas. Aside from their multifocality they are not clinically important. In contrast, the vascular lesions in diffuse cystic angiomatosis are large and destructive and may appear cystic on x-rays. Visceral involvement is common and can result in fatal hemorrhage. Gorham's syndrome ("disappearing bone disease") is a rare disorder characterized by an osseous hemangioma or lymphangioma that produces extensive osteolysis without forming a tumorous mass. The tumor can spread across joints from one bone to another and extend into adjacent soft tissues. Gorham's syndrome most frequently affects the bones of the skull and extremities [18] . Hemangiomas of bone most commonly arise in the vertebral column, followed by the craniofacial skeleton and the metaphyses of long bones [8, 21, 22, 25, 29] . The tumors are usually diagnosed in adulthood, with the peak incidence in the 5th decade of life. They are more common in women than men [8, 29]. Radiographically, hemangiomas including epithelioid hemangioma are radiolucent and have coarse trabeculations [28] . In the vertebral bodies they produce the characteristic "polka dot" pattern. The craniofacial tumors are usually centered within the diploë, and have a lytic appearance, often with prominent intra-lesional radiating spicules of bone which creates the so-called "sun burst" appearance [8, 29] . Elsewhere, the tumors are usually well circumscribed, may be expansile, and are lucent, with an internal web-like trabecular pattern. The tumors are usually centered in the medullary cavity and are gritty and dark red with a sponge-like appearance. They resemble conventional capillary or cavernous hemangiomas of skin and soft tissue and are composed of thin walled vascular spaces that may or may not be filled with red blood cells. The lumina are lined by a single layer of flat, uniform, cytologically bland, endothelial cells. The vessels are surrounded by loose connective tissue and typically infiltrate the pre-existing cancellous bone. Entrapped, thickened, bony trabeculae produce the radiographically detectable intralesional spicules. The endothelial cells exhibit positive immunostaining for the endothelial markers Factor VIII related antigen, ulex europeus lectin, CD34 and CD31 [19] . Smears obtained from hemangiomas are dominated by red blood cells in which are dispersed rare individual bland spindle cells and small tissue fragments composed of similar short bland spindle cells with plump ovoid cells along the edge of the tissue fragments [16] . Curettage is usually the mode of therapy for symptomatic lesions and is associated with a low rate of local recurrence. The differential diagnosis of conventional skeletal hemangioma is limited. The vascular spaces may be difficult to appreciate and, as a result, one may fail to recognize the lesion. A hemangioma should always be considered when confronting a bone biopsy that appears to be normal, as the vessels can be subtle and on biopsy may consist of a few fragments of thin walled structures. Epithelioid hemangioma is most commonly encountered in the skin and subcutis. The skeleton, however, is probably the second most common location for this type of neoplasm where it is multifocal in less than 50% of cases. The tumors range in size from 2.5-15 cms (mean 5 cm), and are usually are not very destructive in that they uncommonly expand the bone or extend into the soft tissues. They frequently pose diagnostic difficulty because of the plump "histiocyte-like" or epithelioid appearance of the neoplastic endothelial cells [2, 5, 15, 17, 19, 20] . The hallmark of epithelioid endothelial cells is their polyhedral shape and their abundant densely eosinophilic cytoplasm that frequently contains one or more large vacuoles. The vacuoles represent the earliest stage of vessel lumen formation and may be empty or contain intact or fragmented red blood cells. As vacuoles from neighboring cells fuse they create vascular spaces of varying degrees of differentiation. Well-formed vessels are numerous in epithelioid hemangioma, and the epithelioid endothelial cells bulge into their lumens in a "tombstone " or "hobnailed-like" fashion. In some cases, the cells are arranged in solid cords and even sheets, which can cause confusion with more aggressive lesions. Numerous inflammatory cells, including plasma cells and eosinophils present in the stroma of occasional cases can mimic osteomyelitis. In a minority tumors there is abundant intralesional hemorrhage admixed with cytologically bland spindle cells, and little or no accompanying inflammation [12] . Immunohistochemically, the epithelioid endothelial cells express the usual markers of endothelial cells (CD31, CD34, factor VIII related antigen), however, approximately 50% also stain for keratin and epithelial membrane antigen and the staining can be extensive and strong [19] . Treatment generally consists of intralesional curettage or local resection. Local recurrences are uncommon [8, 19, 29] . In patients with multiple lesions in which only the largest tumors are ablated, the untreated tumors usually remain stable. No definite metastases have been reported, however, tumors involving bone and other distant sites and types of tissue have rarely been described [10, 23] . The differential diagnosis of epithelioid hemangioma includes epithelioid hemangioendothelioma and epithelioid angiosarcoma, which are both discussed in detail below. Epithelioid Hemangioendothelioma Epithelioid hemangioendothelioma (EHE) is an uncommon endothelial tumor that most frequently arises in the soft tissues, liver, lung, and skeleton [14, 26] . It usually behaves as a low-grade sarcoma, however, a minority are aggressive and life threatening. Similar to other skeletal vascular tumors, epithelioid hemangioendothelioma demonstrates multifocal osseous involvement in approximately one-third to one-half of cases [26] . Unfortunately, some of the literature analyzing skeletal epithelioid hemangioendothelioma is confusing, because, in our opinion, many of the reported cases represent epithelioid hemangioma or other types of vascular neoplasms [1, 3, 8, 24] . Epithelioid hemangioendothelioma can be seen in most age groups and has its peak frequency in the 2nd decade [14] . The tumor affects males and females equally and develops in whites disproportionately more often than members of other races. Like other vascular tumors of bone, epithelioid hemangioendothelioma frequently involves multiple sites in a single bone or multiple bones simultaneously. The tumor tends to arise in the extremities, pelvis and spine. In the extremities, the long bones, as well as the small bones of the hands and feet are commonly involved and typically cause localized pain that may be associated with swelling. Some patients also have disease in the soft tissues, liver or lung at the time of diagnosis of the skeletal disease. The radiographic features of epithelioid hemangioendothelioma are variable. Most lesions range in size from 1-3cm and are round or elongate and predominately lytic. The margins may be well delineated or poorly defined, and the adjacent bone is usually sclerotic [14, 26, 30] . Epithelioid hemangioendothelioma is pale tan in color, and lacks the red, hemorrhagic appearance of conventional hemangiomas. Microscopically, it is composed of large epithelioid and spindle endothelial cells with round or elongate nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. Intracytoplasmic lumens appear as vacuoles that may contain intact or fragmented red blood cells. The vacuoles may coalesce to form primitive vascular channels, recapitulating embryonic angiogenesis, however well-formed blood vessels are not prominent in most cases. Instead, the tumor cells are arranged in cords and nests which are embedded within a myxoid to hyalinized ground substance that may resemble cartilaginous matrix [14, 26, 30]. Only in a minority of cases is a prominent inflammatory infiltrate present. The neoplastic cells generally show limited cytologic atypia and mitotic activity, but in some cases, nuclear hyperchromasia and pleomorphism are significant and mitoses numerous, making it difficult to distinguish the neoplasm from high-grade angiosarcoma. Scattered single, polygonal or even plasmacytoid appearing cells admixed within a background rich in red blood cells, typifies the smears from epithelioid hemangioendotheliomas. The tumor cells have eccentric nuclei and abundant cytoplasm. The cytoplasm frequently contains one or two vacuoles, representing an early stage in lumen formation. Cytologic atypia is usually minimal. The tumor cells express the full spectrum of immunohistochemical endothelial markers including Factor VIII, CD34, and CD31 and, like epithelioid endothelial cells in general, may also exhibit intense and extensive positive staining for keratin and epithelial membrane antigen. The tumor cells usually do not stain with antibodies to S-100 protein, and desmin. Ultrastructurally, the neoplastic cells contain abundant intermediate filaments, pinocytotic vesicles, intracytoplasmic lumens and basal lamina material. Epithelioid hemangioendothelioma is treated by complete surgical excision if feasible. However, multifocal lesions may be difficult to excise and may require radiation or thermal ablation. Predicting the outcome for patients with osseous epithelioid hemangioendothelioma is problematic as the clinical behavior is not always predicted by the morphologic features of the tumor. In one large series, 20% of patients succumbed to disease; of those who died most had concurrent visceral tumors [14] . In the absence of parenchymal organ involvement, epithelioid hemangioendothelioma of bone usually behaves in an indolent fashion and infrequently metastasize. They may locally recur following curettage or slowly enlarge if left untreated. The differential diagnosis of epithelioid hemangioendothelioma includes other epithelioid vascular neoplasms particularly epithelioid hemangioma and angiosarcoma. Epithelioid hemangioendothelioma is distinguished from epithelioid hemangioma by its characteristic hyalinized stroma and the paucity of well-formed vessels. Angiosarcoma also lacks the hyalinized stroma and usually shows a greater degree of cytologic atypia and mitotic activity. The epithelioid features of the tumor cells, their cohesive nature, and intracytoplasmic vacuoles can also mimic metastatic adenocarcinoma. The staining of tumor cells of epithelioid hemangioendothelioma for epithelial markers can further complicate this distinction. Fortunately, metastatic carcinomas do not stain for endothelial markers, and the myxoid or hyalinized stroma is distinct from the desmoplastic seen in metastatic carcinoma. The cells in cartilaginous tumors do not form cohesive nests, stain immunohistochemically for S-100 protein, and are negative for endothelial markers. Angiosarcoma Skeletal angiosarcoma, also known as hemangioendothelial sarcoma, is a very uncommon tumor and accounts for little more than 1% of primary bone sarcomas [7] . It is a neoplasm of adulthood and usually arises in the appendicular skeleton [4, 8, 11, 27, 29, 30] . Most angiosarcomas are solitary, however as many as one-third present with involvement of multiple bones [30] . Angiosarcoma of bone is usually a high-grade, poorly differentiated neoplasm and we feel thatmany tumors that were previously classified as low-grade hemangioendothelial sarcoma, likely represent examples of epithelioid hemangioma [19] . Angiosarcoma of bone usually presents as a painful enlarging mass that may cause pathologic fracture. It rarely arises in association with previous radiation, Paget's disease, bone infarction, and skeletal hemangiomatosis. The tumor manifests on x-ray as an ill-defined, lytic mass with prominent destruction of the underlying bone. The tumor may erode the cortex, elicit a periosteal reaction, and extend into the soft tissues [4, 8, 11, 27, 29, 30] . Skeletal angiosarcoma is usually 5-10 cm in size, appears dark red and hemorrhagic, has poorly defined, irregular borders and may infiltrate the neighboring soft tissues. Frequently, the underlying bone appears ravaged, and tumor necrosis may be prominent. Angiosarcoma is composed of cytologically malignant spindle and epithelioid endothelial cells that have the capacity to form rudimentary blood vessels. In the epithelioid variant, the tumor is composed almost entirely of epithelioid cells, and, as with the other epithelioid vascular tumors, some of the cells contain intracytoplasmic vacuoles [6] . Mitoses are numerous, and atypical mitotic figures are frequently present. The stroma is inconspicuous and consists of small amounts of fibrous tissue. Smears from angiosarcomas are characterized by abundant background blood and contain a population of anaplastic spindle or ovoid cells [13] . The malignant endothelial cells may form three-dimensional clusters of tightly packed cuboidal or polygonal cells forming slit-like structures [13] . The nuclear atypia is usually obvious and severe. Immunohistochemistry shows that the neoplastic cells express one or more of the endothelial markers including Factor VIII, CD31, and CD34. The neoplastic cells in epithelioid angiosarcoma may also stain prominently with antibodies to keratin and epithelial membrane antigen. Ultrastructurally, the neoplastic cells have the features of primitive endothelial cells. Angiosarcoma of bone is best treated with complete en bloc excision. Adjuvant radiation and chemotherapy have little proven effect. The prognosis is poor, as most of the tumors are high-grade, and usually metastasize. The differential diagnosis of osseous angiosarcoma includes vascular tumors such as epithelioid hemangioma and epithelioid hemangioendothelioma, as well as metastatic carcinoma, malignant melanoma, and other high-grade sarcomas. Epithelioid angiosarcoma differs from epithelioid hemangioma because it demonstrates significantly more cytologic atypia and a paucity of well-formed blood vessels. It is distinguished from epithelioid hemangioendothelioma mainly by the lack of hyalinized or chondroid stroma. Immunohistochemistry and electron microscopy are very useful in excluding metastatic carcinoma and melanoma. In this differential diagnosis, it is important to note that most carcinomas and melanomas are negative for Factor VIII related antigen, CD31 and CD34 and angiosarcoma does not express S-100 protein. Accordingly, immunohistochemistry employing antibodies directed against endothelial markers should be performed on unusual epithelioid tumors of bone. References Abrahams, T. G., Bula, W. and Jones, M. Epithelioid hemangioendothelioma of bone. A report of two cases and review of the literature. Skeletal Radiol 21, 509-13, (1992). Ben Romdhane, K., Khattech, R. and Ben Othman, M. Epithelioid hemangioma of bone [letter; comment]. Am J Surg Pathol 18, 1270-1, (1994). Boutin, R. D., Spaeth, H. J., Mangalik, A. and Sell, J. J. Epithelioid hemangioendothelioma of bone. Skeletal Radiol 25, 391-5, (1996). Campanacci, M., Boriani, S. and Giunti, A. Hemangioendothelioma of bone: a study of 29 cases. Cancer 46, 804-14, (1980). Cone, R. O., Hudkins, P., Nguyen, V. and Merriwether, W. A. Histiocytoid hemangioma of bone: a benign lesion which may mimic angiosarcoma. Report of a case and review of literature. Skeletal Radiol 10, 165-9, (1983). Deshpande, V., Rosenberg, A. E., O'Connell, J. X. and Nielsen, G. P. Epithelioid angiosarcoma of the bone: a series of 10 cases. Am J Surg Pathol 27, 709-16, (2003). Dorfman, H. D. and Czerniak, B. Bone cancers. Cancer 75, 203-10, (1995). Dorfman, H. D., Steiner, G. C. and Jaffe, H. L. Vascular tumors of bone. Hum Pathol 2, 349-76, (1971). Evans, H. L., Raymond, A. K. and Ayala, A. G. Vascular tumors of bone: A study of 17 cases other than ordinary hemangioma, with an evaluation of the relationship of hemangioendothelioma of bone to epithelioid hemangioma, epithelioid hemangioendothelioma, and high-grade angiosarcoma. Hum Pathol 34, 680-9, (2003). Floris, G., Deraedt, K., Samson, I., Brys, P. and Sciot, R. Epithelioid hemangioma of bone: a potentially metastasizing tumor? Int J Surg Pathol 14, 9-15; discussion 16-20, (2006). Hartmann, W. H. and Stewart, F. W. Hemangioendothelioma of bone: Unusual tumor characterized by indolent course. Cancer 15, 846-854, (1962). Keel, S. B. and Rosenberg, A. E. Hemorrhagic epithelioid and spindle cell hemangioma: a newly recognized, unique vascular tumor of bone. Cancer 85, 1966-72, (1999). Khiyami, A., Green, L. K., Gyorkey, F. and Landon, G. Primary angiosarcoma of the cuboidal bone: a case report. Diagn Cytopathol 7, 520-3, (1991). Kleer, C. G., Unni, K. K. and McLeod, R. A. Epithelioid hemangioendothelioma of bone. Am J Surg Pathol 20, 1301-11, (1996). Lamovec, J. and Bracko, M. Epithelioid hemangioma of small tubular bones: a report of three cases, two of them associated with pregnancy. Mod Pathol 9, 821-7, (1996). Layfield, L. J. (2002). Cytopathology of Bone and Soft Tissue Tumors. Oxford: Oxford University Press. Ling, S., Rafii, M. and Klein, M. Epithelioid hemangioma of bone. Skeletal Radiol 30, 226-9, (2001). Moller, G., Priemel, M., Amling, M., Werner, M., Kuhlmey, A. S. and Delling, G. The Gorham-Stout syndrome (Goram's massive osteolysis). A report of six cases with histopathological findings. J Bone J Surg 91B, 501-506, (1999). O'Connell, J. X., Kattapuram, S. V., Mankin, H. J., Bhan, A. K. and Rosenberg, A. E. Epithelioid hemangioma of bone. A tumor often mistaken for low-grade angiosarcoma or malignant hemangioendothelioma [see comments]. Am J Surg Pathol 17, 610-7, (1993). O'Connell, J. X., Nielsen, G. P. and Rosenberg, A. E. Epithelioid vascular tumors of bone: a review and proposal of a classification scheme. Adv Anat Pathol 8, 74-82, (2001). Palacios, E. and Valvassori, G. Temporal bone hemangioma as a cause of facial paralysis. Ear Nose Throat J 78, 84, (1999). Pinna, V., Clauser, L., Marchi, M. and Castellan, L. Haemangioma of the zygoma: case report. Neuroradiology 39, 216-8, (1997). Rosenberg, A. E. Expert Commentary. Int J Surg Pathol 14, 17-20, (2006). Shin, M. S., Carpenter, J. T., Jr. and Ho, K. J. Epithelioid hemangioendothelioma: CT manifestations and possible linkage to vinyl chloride exposure. J Comput Assist Tomogr 15, 505-7, (1991). Sweet, C., Silbergleit, R. and Mehta, B. Primary intraosseous hemangioma of the orbit: CT and MR appearance. AJNR Am J Neuroradiol 18, 379-81, (1997). Tsuneyoshi, M., Dorfman, H. D. and Bauer, T. W. Epithelioid hemangioendothelioma of bone. A clinicopathologic, ultrastructural, and immunohistochemical study. Am J Surg Pathol 10, 754-64, (1986). Volpe, R. and Mazabraud, A. Hemangioendothelioma (angiosarcoma) of bone: a distinct pathologic entity with an unpredictable course? Cancer 49, 727-36, (1982). Wenger, D. E. and Wold, L. E. Benign vascular lesions of bone: radiologic and pathologic features. Skeletal Radiol 29, 63-74, (2000). Wold, L. E., Swee, R. G. and Sim, F. H. Vascular lesions of bone. Pathol Annu 20, 101-37, (1985). Wold, L. E., Unni, K. K., Beabout, J. W., Ivins, J. C., Bruckman, J. E. and Dahlin, D. C. Hemangioendothelial sarcoma of bone. Am J Surg Pathol 6, 59-70, (1982).