Spinal epithelioid hemangioendothelioma with epithelioid angiosarcomatous areas
Epithelioid hemangioendothelioma is a distinctive vascular tumor rarely involving bones. We report a case of epithelioid hemangioendothelioma in the cervical spine with angiosarcomatous areas. A 50-year-old female presented with dizziness while walking. A mixed sclerotic and osteolytic or destructive lesion was radiographically disclosed in her upper cervical vertebrae. Histologically, a laminectomy specimen exhibited areas of ordinary epithelioid hemangioendothelioma together with foci of more atypical epithelioid cell proliferation, closely resembling epithelioid angiosarcoma. This phenomenon has been exceptionally described in cases with skeletal lesions, which are typically of low-grade malignancy.
KeywordsAngiosarcoma Bone neoplasms Hemangioendothelioma Imaging Spine
Vascular tumors of bone are uncommon and rarely display an epithelioid cytologic appearance. Epithelioid hemangioendothelioma, initially identified as a peculiar lung tumor (intravascular bronchioloalveolar tumor) by Dail and Liebow in 1975 , was first coined by Weiss and Enzinger in 1982 to designate a distinctive epithelioid vascular tumor of soft tissue . After these descriptions, epithelioid hemangioendothelioma has been reported to occur in a variety of other anatomical locations, including the liver, oral cavity, stomach, brain, mediastinum, heart, lymph node, spleen, skin and bone [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]. Epithelioid hemangioendothelioma of bone is a localized or often multifocal disease characterized by a prolonged, indolent clinical course and bland epithelioid or histiocytoid cells with endothelial differentiation. Thus, the lesion has been regarded as a vascular tumor of intermediate or borderline malignancy [4, 13]. However, epithelioid hemangioendothelioma of the skin and soft tissues has recently been shown to behave more aggressively than considered before; a metastatic rate of 20–30% and mortality of 10–20%, justifying its revised classification as fully malignant [14, 15]. In addition, the tumors of soft tissues occasionally contain areas with significant cellular atypia, mitotic activity, focal spindling of the cells, or necrosis, which seem to be correlated with a more aggressive clinical course [13, 16]. In contrast to cutaneous or soft-tissue lesions, skeletal epithelioid hemangioendothelioma usually behaves as a low-grade malignant vascular neoplasm and lacks such a histologically atypical appearance .
We report a case of spinal epithelioid hemangioendothelioma with concurrent high-grade areas resembling epithelioid angiosarcoma, to further delineate such unusual tumor progression in this particular epithelioid vascular neoplasm of bone.
Intraosseous epithelioid vascular tumors are generally classified into epithelioid hemangioma, epithelioid hemangioendothelioma and epithelioid angiosarcoma . Although these tumors are similar with respect to epithelioid morphology and have some overlapping clinical features, the distinction among them is important because of the significant differences in their biological behavior and therapeutic consideration . However, their nomenclature or classification has been much confused; for instance, it is assumed that many tumors previously reported as low-grade hemangioendotheliomas or hemangioendothelial sarcomas of bone probably represented examples of epithelioid hemangiomas .
Epithelioid hemangioendothelioma of bone has a slight predilection for males and a wide age distribution ranging from the second to eighth decade of life [4, 17, 19]. The tumor often occurs multifocally (in approximately 40–50% of cases) and frequently involves long tubular bones such as the femur, tibia, fibula and humerus, followed by small bones of the hands and feet and the vertebrae [4, 17, 19]. The main clinical presentations are local pain, swelling and symptoms associated with pathologic fracture. Although the radiographic findings may be nonspecific or vary according to the location and size of the tumor, osteolytic lesions with cortical expansion and destruction are common [4, 17, 19]. In addition, the presence of multiple lesions clustered in the same region is in favor of this type of skeletal vascular tumor [20, 21]. Patients usually pursue an indolent or protracted clinical course in spite of a frequent multicentric osseous or occasional visceral involvement by the tumor and its metastatic potential. Wide resection is recommended, when feasible, and chemotherapy has been employed in a small number of patients with multiple tumors .
Histologically, the skeletal epithelioid hemangioendothelioma is comparable to that of soft tissue or at other extraskeletal sites and characterized by the presence of bland-appearing epithelioid cells and a myxohyaline matrix. The endothelial differentiation of the epithelioid cells is reinforced by frequent intracytoplasmic vacuoles containing red blood cells, which suggest an early stage of vascular lumen formation, and by immunohistochemical expressions of endothelial markers such as factor VIII-related antigen, CD34 and CD31. The clinicopathologic features of the current case mostly conform to those of epithelioid hemangioendothelioma of bone.
Salient features of our case are the coexistence of epithelioid angiosarcoma-like foci and a poor clinical outcome of the patient. Epithelioid angiosarcoma is a well-recognized, distinctive variant of angiosarcoma that usually arises in extraskeletal sites and only rarely in bones [17, 22]. The tumor cells of epithelioid angiosarcoma differ in the degree of cytologic atypia, a vasoformative histoarchitecture, and extracellular matrix from those of epithelioid hemangioendothelioma , and a relationship between these epithelioid vascular tumors has been poorly discussed. In our case, the angiosarcomatous component with limited expressions of endothelial markers and increased labeling indices of Ki-67 and p53 may represent high-grade tumor progression or dedifferentiation of a low-grade vascular neoplasm.
In about one-fourth of cases, the tumors in soft tissues contain areas with significant atypia, mitotic activity (more than 1 mitosis per 10 high power fields), focal spindling of the cells, or necrosis [13, 16]. Mentzel et al. described that four of 30 tumors in the skin and soft tissues contained small foci of solid growth composed of more pleomorphic tumor cells very similar in appearance to conventional or epithelioid angiosarcoma . In the mediastinal tumors reported by Suster et al., three of the 12 cases showed more atypical features focally characterized by greater nuclear pleomorphism, increased mitotic activity and focal areas of necrosis . Thus, a high-grade or angiosarcomatous area does not seem uncommon in the tumors at extraskeletal sites.
Such atypical histologic findings, however, have been scarcely documented in skeletal epithelioid hemangioendotheliomas. Kleer et al. described a series of 40 cases with epithelioid hemangioendothelioma of bone including those classified as grade 2 or 3 tumors based essentially on the cytologic atypia and increased mitotic activity of tumor cells . However, it is uncertain whether their intermediate- or high-grade lesions simultaneously had distinct areas of ordinary epithelioid hemangioendothelioma as seen in our case. To the best of our knowledge, only Evans et al. have recently documented a case of spinal epithelioid hemangioendothelioma with an angiosarcoma-like area similar to our case . Although the angiosarcoma-like element appeared to be confined to a limited area of the tumor, their case developed multiple bone lesions, local recurrences after surgery, and distant metastases, and the patient died of tumor at 5 years. Their case and ours suggest that the presence of an angiosarcomatous area might be related to an adverse clinical outcome of the patients. However, in the series by Kleer at al., no histologic features were identified to predict the biological behavior of their epithelioid hemangioendotheliomas of bone. Further analyses based on accumulated cases of epithelioid hemangioendothelioma of bone with high-grade morphologic features are necessary to address this point.
In conclusion, a high-grade angiosarcomatous area may rarely be present in skeletal epithelioid hemangioendothelioma, which potentially affects the patient’s prognosis.
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