chromosomal translocations (eg, FUS-DDIT3 in myxoid liposarcoma) and specific oncogenic mutations (eg, KIT mutation in gastrointestinal stromal tumors); and (2) sarcomas with nonspecific genetic alterations and complex unbalanced karyotypes. Some of these genetic abnormalities, including chromosomal numerical changes, translocations, gene amplifications, and large deletions, can be apparent at the cytogenetic level (karyotyping, fluorescence in situ hybridization), while others, such as small deletions, insertions, and point mutations, require molecular genetic techniques (polymerase chain reaction and sequence analysis).

Vascular Tumors

Lymphangiomas occur in children and are characterized by fluctuation in proptosis. Lymphangiomas of the orbit are unencapsulated, diffusely infiltrating tumors that feature lymphatic vascular spaces and lymphoid aggregates in a fibrotic interstitium (Fig 14-9).

Hemangioma in the adult is encapsulated and consists of cavernous spaces (cavernous hemangioma) with variably thick, fibrosed walls (Fig 14-10). Vessels may show thrombosis and calcification. Hemangioma in the child is unencapsulated, more cellular, and composed of capillarysized vessels (capillary hemangioma).

Tumors With Fibrous Differentiation

Fibrous histiocytoma (fibroxanthoma) is one of the most common mesenchymal tumors of the orbit in adults. The median age at presentation is 43 years (with a range of 6 months to 85 years), and the upper nasal orbit is the most common site. Most fibrous histiocytomas are benign. The tumor is composed of an admixture of histiocytes and fibroblasts, some of which form a storiform (matlike or whorly) pattern (Fig 14-11). Immunohistochemistry is typically positive for CD45 and CD68. Although most are benign, intermediate and malignant varieties do exist. Malignant tumors are identified by a high rate of mitotic activity (more than 1 mitotic figure per high-power field), nuclear pleomorphism, and necrosis. Other primary tumors of fibrous connective tissue include nodular fasciitis, fibroma, and fibrosarcoma.

Hemangiopericytoma occurs mainly in adults (median age is 42 years) and manifests with proptosis, pain, diplopia, and decreased visual acuity. Histologically, a “staghorn” vascular pattern is displayed with densely packed spindle-shaped cells (Fig 14-12). The reticulin stain is useful in demonstrating tumor cells that are individually wrapped in a network of collagenous material. Hemangiopericytomas include a spectrum of benign, intermediate, and malignant lesions. Features of malignancy include an infiltrating border, anaplasia, mitotic figures, and necrosis. Immunohistochemistry is typically positive for CD34. However, these features may be absent in tumors that eventually metastasize. A solitary fibrous tumor is part of the hemangiopericytoma spectrum.

Tumors With Muscle Differentiation

Rhabdomyosarcoma

Rhabdomyosarcoma is the most common primary malignant orbital tumor of childhood (average age of onset is 7–8 years). Proptosis is often sudden and rapidly progressive; it requires emergency treatment. Reddish discoloration of the eyelids is not accompanied by local heat or systemic fever, as it is in cellulitis. Orbital rhabdomyosarcomas have a better prognosis (overall 5-year survival of about 90%) than do their extraorbital counterparts.

Rhabdomyosarcomas arise from primitive mesenchymal cells that differentiate toward skeletal muscle. Three histologic types of orbital rhabdomyosarcoma are recognized (Fig 14-13):

1.embryonal (the most common)

2.alveolar

3.pleomorphic

Embryonal rhabdomyosarcoma may develop in the conjunctiva and may present as grapelike submucosal clusters (botryoid variant). Histologically, spindle cells are arranged in a loose syncytium with occasional cells bearing cross-striations, which are found in approximately 60% of embryonal rhabdomyosarcomas. Well-differentiated rhabdomyosarcomas feature numerous cells with striking cross-striations. Immunohistochemical reactivity is typically positive for desmin, muscle-specific actin, vimentin, and, less commonly, myogenin. Electron microscopy is helpful for demonstrating the typical sarcomeric banding pattern, especially in the less-well-differentiated cases of embryonal rhabdomyosarcoma.

Leiomyomas and leiomyosarcomas

Tumors with smooth-muscle differentiation are rare. Leiomyomas are benign tumors that typically manifest with slowly progressive proptosis in patients in the fourth and fifth decades of life. Histologically, these spindle cell tumors show blunt-ended, cigar-shaped nuclei and trichromepositive filamentous cytoplasm. Immunohistochemistry displays smooth-muscle differentiation. Leiomyosarcomas are malignant lesions that typically occur in patients in their seventh decade. Histologically, more cellularity, necrosis, nuclear pleomorphism, and mitotic figures appear in leiomyosarcomas than in leiomyomas.

Nerve Sheath Tumors

Neurofibromas are the most common nerve sheath tumor. This slow-growing tumor includes an admixture of endoneural fibroblasts, Schwann cells, and axons. Neurofibromas may be circumscribed but are not encapsulated. The consistency is firm and rubbery. Microscopically, the spindle-shaped cells are arranged in ribbons and cords in a matrix of myxoid tissue and collagen that contains axons. Cytogenetic studies indicate that the most frequent structural rearrangements involve chromosome arm 9p.

Isolated neurofibromas do not necessarily indicate systemic involvement, but the plexiform type of neurofibroma is associated with neurofibromatosis type 1 (NF1) (Fig 14-14). Studies indicate that a limited number of pathways are potentially involved in tumorigenesis of the plexiform neurofibroma. The CCN1 gene may be a useful diagnostic or prognostic marker and form the basis for novel therapeutic strategies. The CCNs (cysteine-rich proteins) have been shown to have key roles as matricellular proteins, serving as adaptor molecules that connect the cell surface and the extracellular matrix (ECM).

The neurilemoma (also called schwannoma) arises from Schwann cells. Slow growing and encapsulated, this yellowish tumor may show cysts and areas of hemorrhagic necrosis. It may be solitary or associated with neurofibromatosis. Two histologic patterns appear microscopically: Antoni A spindle cells are arranged in interlacing cords, whorls, or palisades that may form Verocay bodies (collections of fibrils resembling sensory corpuscles). The Antoni B pattern is made up of stellate cells with a mucoid stroma. Vessels are usually prominent and thick-walled, and no axons are present (Fig 14-15). Immunohistochemistry is typically positive for S-100, vimentin, and CD68.

Liu K, DeAngelo P, Mahmet K, Phytides P, Osborne L, Pletcher BA. Cytogenetics of neurofibromas: two case reports and literature review. Cancer Genet Cytogenet. 2010;196(1):93–95.

Pasmant E, Ortonne N, Rittié L, et al. Differential expression of CCN1/CYR61, CCN3/NOV, CCN4/WISP1, and CCN5/WISP2 in neurofibromatosis type 1 tumorigenesis. J Neuropathol Exp Neurol. 2010;69(1):60–69.

Adipose Tumors

Lipomas are rare in the orbit. Pathologic characteristics include encapsulation and a distinctive lobular appearance. Because lipomas are histologically difficult to distinguish from normal or prolapsed fat, their incidence might have been previously overestimated.

Liposarcomas are malignant tumors that are extremely rare in the orbit. Histologic criteria depend on the type of liposarcoma, but the unifying diagnostic feature is the presence of lipoblasts. These tumors tend to recur before they metastasize.

Bony Lesions of the Orbit

Fibrous dysplasia of bone may be monostotic or polyostotic. When the orbit is affected, the condition is usually monostotic, and the patient often presents during the first 3 decades of life. The tumor may cross suture lines to involve multiple orbital bones. Narrowing of the optic canal and lacrimal drainage system can occur. Plain radiographic studies show a ground-glass appearance with lytic foci. Cysts containing fluid also appear. As a result of arrest in the maturation of bone, trabeculae are composed of woven bone with a fibrous stroma that is highly vascularized rather than lamellar bone. The bony trabeculae often have a C-shaped appearance (Fig 14-16).

Fibro-osseus dysplasia (juvenile ossifying fibroma), a variant of fibrous dysplasia, is characterized histologically by spicules of bone rimmed by osteoblasts (Fig 14-17). At low magnification, ossifying fibroma may be confused with a psammomatous meningioma.

Osseous and cartilaginous tumors are rare; of these, osteoma is the most common. It is slow growing, well circumscribed, and composed of mature bone. Most commonly, an osteoma arises from the frontal sinus. Other primary tumors in this group include

osteoblastoma giant cell tumor chondroma Ewing sarcoma

osteogenic sarcoma chondrosarcoma

See the appendix for AJCC definitions and staging of orbital sarcomas.

Metastatic Tumors

Secondary orbital tumors are those that invade the orbit by direct extension from adjacent structures, such as sinus, bone, or eye. Metastatic tumors are those that spread from a primary site. The most common primary tumor sites with orbital metastasis are the breast in women and the prostate in men. In children, neuroblastoma is the most common primary tumor metastatic to the orbit.