Epithelioid Hemangioendothelioma of the Orbital Bones David B. Lyon, MD, 1 Thomas T. Tang, MD, PhD,Z Thomas M. Kidder, MD3 Purpose: The authors report a case of an epithelioid hemangioendothelioma arising in the orbital bones. A review of the literature related to this rare orbital neoplasm identified eight well-documented cases, one of which occurred in a patient younger than that reported here, but none of which originated in bone. Methods: A 3V2-month-old boy had a left inferior orbital mass that had grown rapidly over a 3-day period. An emergency computed tomography scan showed a large neo­ plasm with significant bone destruction of the zygoma and maxilla. Initial examination suggested a rhabdomyosarcoma, and a transconjunctival biopsy was performed, which was complicated by significant blood loss. The final pathologic diagnosis was an epi­ thelioid hemangioendothelioma, or grade 2 hemangioendothelioma, of bone origin. No other sites of disease were found on metastatic survey. Subsequent treatment consisted of an en bloc tumor resection sparing the orbital soft tissues and globe. Results: The patient is free of disease and has normal visual fixation and ocular motility 20 months after surgery. Conclusion: Epithelioid hemangioendothelioma, a vascular malignancy of endo­ thelial cell origin, very rarely involves the orbit. This case is notable for its early devel­ opment, rapid growth, bony origin, and epithelioid histology. Ophthalmology 1992;99: 1773-1778

Acute proptosis in childhood requires prompt evaluation and a high index of suspicion for malignancy. Rhabdo­ myosarcoma leads the differential diagnosis list and, al­ though relatively rare, is the most common primary orbital malignancy in the pediatric age group. As with other sus­ pected sarcomas ofthe orbit, a diagnostic incisional biopsy is performed after a thorough history, physical exami­ nation, and appropriate radiographic studies are inter­ preted. Originally received: March 31, 1992. Revision accepted: July 2, 1992. 1

Department of Ophthalmology, University of Wisconsin, Madison.

2

Department of Pathology, Children's Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee. 3 Department of Otolaryngology and Human Communication, Medical College of Wisconsin, Milwaukee.

The authors have no proprietary interest in the development or marketing ofany drug, instrument, or piece ofequipment mentioned in this report. Reprint requests to David B. Lyon, MD, 2600 N Mayfair Rd, Suite 950, Milwaukee, WI 53226.

Application of these principles in the case presented here led to the diagnosis of an epithelioid hemangioen­ dothelioma of bone, a rare vascular malignancy of bone. 1•2 Because of its rarity, there is confusion in the literature regarding nomenclature, therapy, and prognosis. Malig­ nant vasoformative tumors in soft tissues are classified according to the proliferating cell type, termed heman­ giopericytoma if of pericytic origin and hemangioendo­ thelioma or angiosarcoma if of endothelial origin. How­ ever, several terms for endothelial-derived tumors have been used interchangeably in the literature, including hem­ angioendothelial sarcoma, angioendothelioma, malignant angioma, and malignant endothelioma. Recently, Weiss and Enzinger3 proposed the term ep­ ithelioid hemangioendothelioma for a unique soft tissue tumor of adult life characterized by an "epithelioid" or "histiocytoid" endothelial cell. Several authors have re­ ported similar epithelioid variants of hemangioendothe­ lioma of bone origin. 1•2 •4 •5 However, none of these cases has arisen from the bony orbit. Messmer and co-workers6 presented a case ofangiosarcoma of the orbital soft tissues,

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Figure 1. Initial coronal (A) and axial (B) CT shows the left inferior orbital mass with bone destruction of the maxilla and zygoma.

and their literature review uncovered seven other well­ documented orbital cases. Our purpose is to present the clinical and pathologic findings of a case of epithelioid hemangioendothelioma arising in the orbital bones. This case is notable for its location in the orbit, presentation in infancy, rapid growth, bone origin, and epithelioid histology.

Case Report A W2-month-old boy was referred by his pediatrician for eval­ uation of progressive left lower eyelid swelling that had been noted by the mother for 3 days. There was no history oftrauma, fever, irritability, or concurrent illness. The child had been de­ livered by normal vaginal delivery after an uncomplicated term pregnancy and was in excellent health. The family history in­ cluded a great uncle who had died of metastatic neuroblastoma and a second cousin with an optic nerve glioma and neurofi­ bromatosis. Ophthalmic examination showed central, steady, and main­ tained fixation for each eye. There was a firm left inferolateral orbital mass that could not be distinguished from the infraorbital rim by palpation. The left globe was displaced superiorly by 2 to 3 mm, and there was no obvious axial proptosis. Results of examination of the pupils, ocular motility, and anterior and posterior segments of both eyes were unremarkable. An orbital computed tomography (CT) scan was obtained later the same day, which confirmed a large, fairly well-demar­ cated mass in the inferolateral aspect of the left orbit with sig­ nificant bone destruction of the maxilla and zygoma (Fig I). A transconjunctival anterior orbitotomy with incisional biopsy through the inferior fornix was performed that evening. The tumor was separated from the inferior orbital fat by a thick fi­ brous capsule. Incision of the capsule to obtain biopsies resulted in brisk bleeding (80 ml blood loss), which was controlled with bipolar electrocautery and thrombin-soaked gelatin sponges. Results of frozen-section microscopic examination showed poorly differentiated tumor cells. On review of the permanent microscopic sections, a diagnosis of intermediate (grade 2) malignant hemangioendothelioma was made, which was confirmed by an outside consultant. Results of a metastatic survey, including a chest radiograph, abdominal CT, bone scan, and lumbar puncture, were negative. The ques­

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tion of the best therapy for this rare vascular neoplasm was con­ sidered at a multidisciplinary tumor board conference; gross surgical excision without exenteration and possibly followed by postoperative radiation was the consensus recommendation. The child was operated on 9 days after the original biopsy was taken. Results of clinical examination and repeat orbital CT showed significant tumor growth with greater superior dys­ topia of the left eye over this short time period (Figs 2 and 3). Through a modified Weber-Ferguson incision, the tumor was removed en bloc with margins of normal maxilla and zygoma and sparing the tooth buds. On the orbital surface, the perios­ teum, with some adherent orbital fat over the previous biopsy site, was the superior margin of resection. All margins of the specimen were free of tumor. Postoperative irradiation was de­ ferred because the tumor was completely excised and because of the significant side effects of radiation when administered in tumoricidal doses to the growing face and eye. After surgery, the child has done extremely well and has nor­ mal visual fixation and ocular motility with very minimal facial deformity after 20 months of follow-up (Fig 4). Surveillance for local and distant recurrence (orbital CT, chest radiograph, and total bone scan) has been done every 3 months and has been negative to date.

Figure 2. Clinical appearance of the infant before definitive therapy. The eyelid ecchymosis is due to the previous biopsy.

Lyon et al · Hemangioendothelioma osteoclasts, osteoblasts, and bony trabeculae. Immuno­ peroxidase assays showed that the tumor cells were pos­ itive for desmin but negative for factor VIII-related an­ tigen, vimentin, cytokeratin, and alpha-1-antichymo­ trypsin. The pathologic diagnosis was epithelioid hemangioendothelioma. Dr. K. Krishnan Unni at the Mayo Clinic reviewed this tumor and designated it as a grade 2 hemangioendothelioma.

Electron Microscopy

Figure 3. Coronal cut of the repeat orbital CT shows interval growth over 8 days with increased globe dystopia and deformation.

Pathologic Findings Gross The main specimen consisted ofa reddish soft mass, mea­ suring 30 X 26 X 22 mm with 2 fragments of bone at­ tached to each other at a right angle. Several vascular channels, 2 to 3 mm in diameter, were discernible on the mass. The superior (orbital) surface was covered by a fragment of periosteum; there was no true capsule.

Light Microscopy Sections of the mass showed numerous whorled epithe­ lioid cells around small blood sinuses. These cells had ample acidophilic cytoplasm and large single or double nuclei with prominent nucleoli (Fig 5). Atypical mitotic figures ranged 1 to 4 per 10 high-power fields (Fig 6). On silver staining, reticulin fibrils were seen surrounding groups of tumor cells. In the periphery, there were abun­ dant elongated thin spindle cells admixed with giant

The tumor consisted of fusiform cells with irregular, slightly indented, heterochromatic nuclei and cytoplasmic ribosomes, rough endoplasmic reticulum, rare mitochon­ dria and lysosomes, and abundant perinuclear interme­ diate filaments. No Weibel-Palade bodies were seen. Clusters ofpinocytotic vesicles, villous processes, and basal lamina were seen along the cellular borders.

Discussion Prompt evaluation of a rapidly growing orbital mass in an infant led to the unexpected and rare diagnosis of a malignant epithelioid hemangioendothelioma of bone origin. The initial interpretation of the orbital CT was that the mass had originated in the orbital soft tissues and had caused secondary bony destruction due to advanced growth. Rhabdomyosarcoma, possibly the alveolar type because of its predilection for the inferior orbit, was be­ lieved to be the leading diagnostic possibility. The vascular nature of the neoplasm was readily apparent at the time of biopsy given the brisk bleeding upon incision of its apparent capsule, which was actually the periosteum of the orbital floor. Hemangioendothelioma and hemangiopericytoma were included in the pathologic differential diagnosis. The former was favored on the basis of the epithelioid ap­ pearance of the tumor cells, the intimal relation of the

Figure 4. Clinical (A) and coronal CT (B) appearance of the patient 20 months after surgery. Notice the depression of the left malar area and the underlying absent bone. Also notice the aeration of the normally developing maxillary sinus.

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Figure 5. Photomicrograph of the orbital mass shows epithelioid tumor cells with a large oval nucleus and a distinct nucleolus (arrows) surrounding vascular channels filled with red blood cells (R) (hematoxylin-eosin; original magnification, X 400).

tumor cells with the blood channels, and the characteristic distribution of reticulin fibrils around groups of tumor cells instead of individual ones, although it was possible that both vascular elements could coexist in the tumor. Any discussion of malignant vascular tumors of the skin, soft tissues, or bone is hampered by the lack of stan­ dardized nomenclature for these neoplasms. Enzinger and Weiss7 classify vascular tumors of soft tissue into three main categories: benign vascular tumors (hemangiomas), vascular tumors of intermediate malignancy (heman­ gioendotheliomas), and malignant vascular tumors (an­ giosarcoma, Kaposi sarcoma). The same three categories are used in the WHO classification of vascular neoplasms ofbone. 8 In this classification schema, hemangioendothe­ liomas differ from angiosarcoma not only histologically, but also by their biologic and clinical behavior. Others prefer the term hemangioendothelioma or he­ mangioendothelial sarcoma for vasoformative bone sar­ 9 11 comas of both intermediate- and high-grade histology. They divide hemangioendotheliomas into three grades, grade 3 being the most anaplastic. The size of the neo­ plastic vascular channels as well as the qualitative nature of the lining cells were helpful in assigning the histologic grade. Grade 1 tumors had abundant vascular spaces lined by cells with mild atypia. Crowding of the endothelial cells and rare mitotic figures were characteristic. Grade 3 lesions were less vasoformative with marked nuclear an­ aplasia and numerous mitotic figures. Grade 2 was as­ signed to lesions with intermediate anaplasia. Multicentric tumors were present in approximately 25% of cases. Al­ though patients were treated with a variety of modalities and comparisons are difficult, there was a definite decrease in disease-free survival with increasing grade (grade 1, 95%; grade 2, 62%; and grade 3, 20%). 9 Patients with grade 3 lesions were generally treated more aggressively. Histologic grade was the most important single criterion in predicting prognosis. Although indolent, grade 1 tumors were still

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considered malignant and distinguishable from benign hemangiomas of bone. Hemangioendotheliomas are not a homogeneous group of tumors but represent a spectrum in which each lesion may have unique or ambiguous features. Within the spectrum, however, distinct subgroups have been rec­ ognized and have been given descriptive names, such as the histiocytoid hemangiomas 12 and epithelioid heman­ gioendotheliomas. 7 Epithelioid hemangioendothelioma 3 was first described by Weiss and Enzinger in soft tissue. This vascular tumor histologically mimicked a carcinoma but had a clinical course intermediate between heman­ gioma and angiosarcoma. Comparable tumors have been recognized in the lung, liver, bone, lymph nodes, brain, and meninges. 7 The epithelioid endothelial cell is not unique to a subgroup of hemangioendotheliomas but may be seen in other vascular neoplasms such as epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) and epi­ thelioid forms ofangiosarcoma. 1The diagnostic problem is usually not in identifying the endothelial cell but in determining the relative degree of malignancy. Epithelioid hemangioendothelioma usually appears quite bland his­ tologically with little or no mitotic activity. The overall prognosis of this tumor is favorable. In approximately 25% ofcases ofepithelioid hemangioendothelioma ofsoft tissue, however, there are areas with significant atypia, mitotic activity (greater than 1 mitotic figure per 10 high­ power fields), focal spindling of cells, or necrosis which correlate with a more aggressive course (higher incidence of metastasis, shorter interval between diagnosis and me­ tastasis).1 Epithelioid forms of angiosarcoma, however, are composed of sheets of very atypical and mitotically active endothelial cells. Thus, epithelioid hemangioen­ dothelioma with atypia starts to blend with angiosarcoma. The biologic behavior of the tumor is coupled with the histologic appearance to help label borderline tumors. Epithelioid hemangioendothelioma of bone has been seen in nearly all age groups (range, 7 to 76 years) with

Figure 6. Photomicrograph of the orbital mass shows an atypical mitosis and division of a tumor cell into two epithelioid daughters (arrow) (he­ matoxylin-eosin; original magnification, X 1000).

Lyon et al · Hemangioendothelioma peaks in the second and third decades of life and again in later decades. 1 The majority of cases involve the axial skeleton or extremities. Multifocality is not uncommon, being present in 9 of 14 of the cases in 1 series, with a predilection for the bones of the leg. 2 Males are affected more often than females and whites are disproportionately more affected than other races. Radiographically, epithe­ lioid hemangioendothelioma of bone presents as a solitary or multifocallytic and expansile bone lesion, sometimes with sclerotic borders. Local extension beyond the peri­ osteal confines into adjacent soft tissue may occur. The light microscopic appearance of epithelioid he­ mangioendothelioma of bone includes plump polygonal to slightly elongated endothelial cells arranged in solid nests or anastomosing cords, although fascicular, diffuse, or myxoid patterns are sometimes seen. The character­ istics that allow recognition of this epithelioid cell include its rounded shape, its rounded centrally placed nucleus, and eosinophilic cytoplasm. Reticulin fibers surround the cells distinguishing them from pericytes. Moderate degrees of cellular variation and atypia and occasional mitoses, averaging 1 to 2 per 10 high-power fields, are the rule? The stromal background is myxoid and/or myxochon­ droid. Characteristically, some degree of intracytoplasmic vacuolization is seen reflecting the primitive vasoforma­ tive nature of the cells. Vascular channels at various stages of angiogenesis are seen. A mixed inflammatory infiltrate may be present. Foci of hemorrhage and necrosis may be observed. Immunohistochemical and ultrastructural findings in epithelioid hemangioendothelioma of bone mimic those of soft tissue. Stains for the endothelial markers factor VIII-related antigen and the lectin Ulex europaeus, the former of which was done and was negative in this case, are variably positive. Ultrastructurally, the cells have fea­ tures of normal endothelium such as a circumferential basal lamina, surface-oriented pinocytotic vesicles, and cytoplasmic vacuoles. Weibel-Palade bodies, specific or­ ganelles ofendothelial cells, were not seen in our case and are variably present. 1 An abundance of intermediate fil­ aments differentiates this cell from a normal endothelial cell. 3 Vascular malignancies ofendothelial cell origin are ex­ ceedingly rare in the orbit. In 1983, Messmer et al 6 de­ scribed a case of epithelioid angiosarcoma and reviewed the literature, detecting only seven other cases of orbital angiosarcoma or hemangioendothelioma with clinical and pathologic findings. Their case arose in the soft tissues of the orbital apex and histologically had epithelioid features that were likened to those reported at that time by Weiss and Enzinger. 3 In the other seven cases, the tumors were confined primarily to the orbital soft tissues, 13- 18 although one had localized osteolysis of the greater wing of the sphenoid 15 and one extended to the intracranial space through the superior orbital fissure. 18 Secondary invasion of the orbit from the maxillary sinus occurred in another case. 19 The patients ranged in age from 2 weeks to 68 years with 4 of 8 being in the pediatric age group. None of these eight orbital cases was of bony origin.

To our knowledge, only one other case of hemangioen­ dothelioma or angiosarcoma arising in the orbital bones has been reported. 20 This was the case of a 32-year-old man who had unilateral proptosis due to an angiosarcoma involving the sphenoid and orbital plate of the frontal bone. The authors reviewed the literature and found eight other cases of primary angiosarcoma of the cranium, four of which involved the frontal bone and none of which had proptosis. One other case occurred in a bone that makes up the orbit, the maxilla, but it did not encroach on the orbit. 21 Interestingly, all of the cases reviewed by Shuangshoti et al 20 affected males, most of whom were young. Three were younger than 8 years of age, and the youngest was 3 months old. In summary, we have presented the case ofa malignant vascular tumor, derived from endothelium, arising in the orbital bones of an infant. The malignant nature of this tumor was confirmed by its rapid local growth and its histologic appearance (cellular anaplasia and mitotic ac­ tivity). Complete resection has prevented recurrent local or metastatic disease to date. We have chosen to call this neoplasm an epithelioid hemangioendothelioma based on its cellular characteristics. However, it also could be des­ ignated a grade 2 hemangioendothelioma. Both of these designations reflect a slowly progressive malignant course in general, but with occasional cases showing fully malig­ nant properties such as rapid growth and metastasis to parenchymal organs. 1•9 We prefer to avoid the term an­ giosarcoma, which is primarily a neoplasm of skin and soft tissues and has a poor prognosis. 7

References I. Weiss SW, Ishak KG, Dail DH, eta!. Epithelioid heman­

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gioendothelioma and related lesions. Semin Diagn Pathol 1986;3:259-87. Tsuneyoshi M, Dorfman HD, Bauer TW. Epithelioid he­ mangioendothelioma of bone. A clinicopathologic, ultra­ structural, and immunohistochemical study. Am J Surg Pa­ thol 1986; 10:7 54-64. Weiss SW, Enzinger FM. Epithelioid hemangioendothe­ lioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970-81 . Tang TT, Zuege RC, Babbitt DP, eta!. Angioglomoid tumor of bone. A case report. J Bone Joint Surg [Am] 1976;58: 873-6. Goorin AM, Rosenberg AE. Case records of the Massachu­ setts General Hospital. Weekly clinicopathologic exercises. Case 10-1990. A 15-year-old girl with multiple radiolucent bony defects and multiple pulmonary nodules. N Eng! J Med 1990;322:683-90. Messmer EP, Font RL, McCrary JA III. Epithelioid angio­ sarcoma of the orbit presenting as Tolosa-Hunt syndrome. A clinicopathologic case report with review ofthe literature. Ophthalmology 1983;90: 1414-21. Enzinger FM, Weiss SW. Soft Tissue Tumors, 2nd ed. St. Louis: CV Mosby, 1988;489-580. Schajowicz F, Ackerman LV, Sissons HA. Histological Typing of Bone Tumours. Geneva: WHO, 1972;40-1 . (Int'l histological classification of tumours; no. 6).

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9. Wold LE, Unni KK, Beabout JW, eta!. Hemangioendothe­ lial sarcoma of bone. Am J Surg Pathol 1982;6:59-70. 10. Unni KK, Ivins JC, Beabout JW, Dahlin DC. Hemangioma, hemangiopericytoma, and hemangioendothelioma (angio­ sarcoma) ofbone. Cancer 1971;27:1403-14. II. Campanacci M, Boriani S, Giunti A. Hemangioendothe­ lioma ofbone: a study of29 cases. Cancer 1980;46:804-14. 12. Rosai J, Gold J, Landy R. The histiocytoid hemangiomas. A unifying concept embracing several previously described entities of skin, soft tissue, large vessels, bone, and heart. Hum Pathol 1979;10:707-30. 13. Carelli PV, Cangelosi JP. Angiosarcoma ofthe orbit. Am J Ophthalmol 1948;31 :453-6. 14. Stout AP. Hemangio-endothelioma: a tumor of blood vessels featuring vascular endothelial cells. Ann Surg 1943; 118:445­ 64. 15. Tn!heux A, Reny A, Picard JL, eta!. Tumeur rare de l'orbite chez !'enfant. J Radio! Electro! Med Nucll975;56:279-80.

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16. Nath K, Gogi R, Khan AA, Hameed S. Vascular hamartoma and vascular tumours of orbit. Indian J Ophthalmol 1977;25: 18-23. 17. Tsuda N, Takaku I. A case report of malignant vascular tumour of the orbit in a newborn infant. Folia Ophthalmol Jpn 1970;21:728. 18. Sekimoto T, Nakaseko H, Kondo K, eta!. A case of malig­ nant haemangio-endothelioma in the orbit. Folia Ophthal­ mol Jpn 1971;22:535-8. 19. Bankaci M, Myers EN, Barnes L, DuBois P. Angiosarcoma of the maxillary sinus: literature review and case report. Head Neck Surg 1979;1:274-80. 20. Shuangshoti S, Chayapum P, Suwanwela N, Suwanwela C. Unilateral proptosis as a clinical presentation in primary angiosarcoma of skull. Br J Ophthalmol 1988;72:713-9. 21. Henny FA. Angiosarcoma of the maxilla in a 3 month old infant: report of case. J Oral Surg 1949;7:250-2.

Epithelioid hemangioendothelioma of the orbital bones.

The authors report a case of an epithelioid hemangioendothelioma arising in the orbital bones. A review of the literature related to this rare orbital...
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