Rhinocerebral or rhino-orbitocerebral zygomycosis (mucormycosis) usually occurs in patients with poorly controlled diabetes mellitus (especially those with ketoacidosis), solid malignancies, or extensive burns; in patients undergoing treatment with corticosteroid agents; or in patients with neutropenia related to hematologic malignancies. Fungal infection of the orbit is caused by adjacent sinus infection. Histologically, inflammation (acute and chronic) is present in a background of necrosis and is often granulomatous. Histiocytes are common. Broad, nonseptated hyphae may be identified with H&E, periodic acid–Schiff (PAS), and Gomori methenamine silver (GMS) stains. Diagnosis is achieved by biopsy of necrotic-appearing tissues in the nasopharynx. These fungi can invade blood vessel walls and produce a thrombosing vasculitis.

Sino-orbital aspergillosis is caused by Aspergillus infection of the orbit from the adjacent sinuses and may occur in immunocompromised or otherwise healthy individuals. With slowly progressive and insidious symptoms, sino-orbital aspergillosis is often unrecognized, producing a sclerosing granulomatous disease. Aspergillus has often been difficult to culture but may be observed in tissue as septated hyphae with 45° angle branching (Fig 14-5). Despite aggressive surgical therapy and adjunctive therapy with antifungal agents, orbital infections with Aspergillus may be fatal if extension into the brain occurs.

Allergic fungal sinusitis is a form of noninvasive fungal disease resulting from an IgE-mediated hypersensitivity reaction in atopic individuals and is caused by several species of fungi. The disease may extend into the orbit and intracranially in some instances.

Parasitic infections of the orbit are rare and may be produced by Echinococcus (orbital hydatid cyst), Taenia solium (cysticercosis), and Loa loa ocular filariasis (loiasis). These infections are mostly seen in patients who come from, or have traveled to, areas where the infections are endemic. Enzyme-linked immunosorbent assay for serum antibodies may be helpful in the diagnosis. See BCSC Section 7, Orbit, Eyelids, and Lacrimal System.

Degenerations

Amyloid

Amyloid deposition in the orbit occurs in primary systemic amyloidosis. When it involves the extraocular muscles and nerves, it can produce ophthalmoplegia and ptosis.

See Chapters 5, 6, 10, and 13 in this volume and BCSC Section 8, External Disease and Cornea.

Neoplasia

Neoplasms of the orbit may be primary, they may be extensions of locally invasive tumors from adjacent structures, or they may represent metastatic disease. Approximately 60% are benign and 40% malignant, with malignant lesions being more common in adults. The incidence of primary neoplasms is low, with lymphoma being the most common (10%) and hemangioma the next most common (5%). Secondary tumors, either metastatic or extending from adjacent structures, are slightly more common than primary tumors.

In children, approximately 90% of orbital tumors are benign. Benign cystic lesions (epidermoid or simple epithelial cysts) are the most common cystic lesions and represent 50% of orbital lesions in childhood. Rhabdomyosarcoma is the most common orbital malignancy in childhood and represents

adenoma or de novo in the lacrimal gland. The tumor is slightly more common in women than in men, and the median age of presentation is about 40. Unlike pleomorphic adenoma, adenoid cystic carcinoma is not encapsulated; it tends to erode the adjacent bone and invade orbital nerves, accounting for the pain that is a frequent presenting complaint. Grossly, the appearance is grayish white, firm, and nodular. Histologically, a variety of patterns may appear, including the cribriform (Swiss cheese) pattern, which is the most common (Fig 14-7). Other histologic patterns include basaloid (solid), comedo, sclerosing, and tubular. Presence of a basaloid pattern has been associated with a worse prognosis (5-year survival of 20%) compared to tumors without a basaloid component (5-year survival of 70%). Immunohistochemistry is typically positive for S-100, keratin, and actin with areas of epithelial and myoepithelial differentiation. There is a positive correlation between prognosis and protein expression of bcl-2 and bax. Expression of p53 is associated with a poor prognosis. Genetic microarray analysis has demonstrated loss of 1p36 as an initial event in the pathogenesis of adenoid cystic carcinoma.

Because of the diffuse infiltration of this tumor, exenteration may be recommended, often with removal of adjacent bone. Despite aggressive surgical intervention, the long-term prognosis is poor.

Ahmad SM, Esmaeli B, Williams M, et al. American Joint Committee on Cancer classification predicts outcome of patients with lacrimal gland adenoid cystic carcinoma. Ophthalmology. 2009;116(6):1210–1215.

Font RL, Smith SL, Bryan RG. Malignant epithelial tumors of the lacrimal gland: a clinicopathologic study of 21 cases. Arch Ophthalmol. 1998;116(5):613–616.

Lymphoproliferative Lesions

Most classifications of lymphoid lesions have been based on lymph node architecture, and such nodal classifications have been difficult to apply to so-called extranodal lymphoid lesions. Because there are no lymph nodes in the orbit, it is problematic to classify these lesions according to the criteria used for lymph nodes. The development of classification schemes for lymphomas is, thus, an ongoing and controversial process. In general, lymphoproliferative lesions are divided into reactive lymphoid hyperplasia (RLH), atypical lymphoid hyperplasia (ALH), and ocular adnexal lymphoma (OAL). OAL is then subtyped according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. The more recent American Joint Committee on Cancer–International Union Against Cancer TNM-based staging system for OAL defines disease extent and identifies clinical and histomorphologic features of prognostic significance. Data revealing OAL patients’ prognosis using these classifications are beginning to emerge. Many lymphoid masses in the orbit that were previously classified as reactive or atypical hyperplasia would now be considered neoplastic under the TNM-based staging system.

Unlike patients with nonspecific orbital inflammation, those with orbital lymphoproliferative lesions present with a gradual, painless progression of proptosis. Every patient with an orbital lymphoproliferative lesion must be investigated for evidence of systemic lymphoma, including examination for lymphadenopathy, a complete blood count (CBC) and differential, and imaging of the thoracic and abdominal viscera. In general, biopsy of an accessible lymph node is preferred over an orbital biopsy because nodal architecture is helpful in diagnosis and the procedure may be safer. A bone marrow biopsy is preferred to an aspirate because it includes bone spicules; the presence of a paratrabecular lymphoid infiltrate may indicate systemic lymphoma. In contrast to most cases of nonspecific orbital inflammation, which are treated with corticosteroids, lymphoproliferative lesions confined to the orbit are treated with radiation.

The ophthalmologist taking a biopsy of an orbital or conjunctival lymphoproliferative lesion should consult with the pathologist to determine the optimal method for handling the tissue. Fresh

(unfixed) tissue is preferred for touch preparations, immunohistochemistry, flow cytometry, and gene rearrangement studies. The type of fixative used for permanent sections varies from one laboratory to another. For biopsy of suspected lymphoma, the surgeon should alert the pathologist in advance and may need to perform the procedure near a pathology laboratory. Exposure of the biopsy specimen to air for long periods should be avoided. Tissue samples may be wrapped in salinemoistened gauze and transported on ice. It is very important that the tissue be handled gently; crush artifact can prevent the pathologist from rendering a diagnosis. See also Chapter 4, Table 4-1.

Demirci H, Shields CL, Karatza EC, Shields JA. Orbital lymphoproliferative tumors: analysis of clinical features and systemic involvement in 160 cases. Ophthalmology. 2008;115(9):1626–1631, 1631.e1–3.

Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008.

Reactive lymphoid hyperplasia

Reactive lymphoid hyperplasia is composed of well-differentiated, somewhat pleomorphic lymphocytes, with occasional plasma cells, macrophages, eosinophils, and follicles with germinal centers. Usually, the follicles contain tingible body macrophages (containing apoptotic debris), and there is mitotic activity; they also often have vessels with endothelial hyperplasia.

Atypical lymphoid hyperplasia

Atypical lymphoid hyperplasia is diffuse lymphoid proliferation, generally without reactive germinal centers. It is composed of an admixture of small, mature-appearing lymphocytes and larger lymphoid cells of questionable maturity.

Lymphoma

Lymphomas of the orbit may be a presenting manifestation of systemic lymphomas, or they may arise primarily from the orbit. The incidence of orbital involvement in systemic lymphomas is approximately 1%–2%. Hodgkin disease is exceedingly rare in the orbit, and the majority of primary malignant orbital lymphomas are non-Hodgkin lymphomas. Multinucleated Reed-Sternberg cells are the characteristic histologic finding in Hodgkin disease. Immunohistochemistry is typically positive for CD45, CD15, and CD30. Non-Hodgkin lymphomas constitute one-half of malignancies arising in the orbit and the ocular adnexa (Fig 14-8). They have diffuse architecture and mark immunophenotypically as B cells with immunopositivity for CD19 and CD20. In rare instances, T-cell lymphomas of the orbit are found and demonstrate immunopositivity for CD3, CD4, and CD8. See Chapter 5.

Soft-Tissue Tumors

Soft-tissue tumors make up a small subset of human benign and malignant tumors, but they can be life threatening and may pose significant diagnostic and therapeutic challenges. Recognizing the main histologic patterns of soft-tissue tumors, which include round cell, spindle cell, myxoid, epithelioid, pericytomatous, and pleomorphic, is the most important aspect in the diagnosis of these tumors. Immunohistochemistry is also helpful; the characteristic pathologic features and immunohistochemistry staining patterns of soft-tissue tumors can be found on websites such as Pathol ogyOutlines.com (http://www.pathologyoutlines.com/eye.html). Typically, a panel including S-100, CD99, CD34, vimentin, actin, desmin, and CD68 is used for initial differentiation, and the results direct further studies.

Malignant soft-tissue tumors, or sarcomas, can be divided into 2 major genetic groups: (1) sarcomas with specific genetic alterations and usually simple karyotypes, such as reciprocal