Orbital disease is relatively uncommon, but quite diverse in nature. Inflammatory diseases, such as infectious cellulitis, and the immunological disorders thyroid ophthalmopathy and idiopathic orbital inflammation or “pseudotumor” are encountered most often in general clinical practice. However, the soft tissues of the orbit occasionally give rise to a relatively broad spectrum of primary neoplasms, and the orbit can be involved secondarily by systemic lymphoma, metastases from distant primary cancers, or by tumors that arise in neighboring tissues such as conjunctiva, eyelid, paranasal sinuses, or even the intracranial cavity (Fig. 14-1).

The essential clinical manifestation of orbital disease is ocular proptosis or exophthalmos (Fig. 14-2A). The eye usually is pushed forward because the orbit is a semiconfined space bounded by bony walls, and most orbital diseases are space occupying. The proptotic eye may be pushed directly forward (axial proptosis) or in other directions (i.e., down and in) that are determined by and serve to indicate the location of the orbital lesion. For example, tumors of the lacrimal gland, which is located in the superotemporal orbit, typically push the eye inferomedially as well as forward, while mucoceles of the ethmoid sinus in the medial orbital wall cause lateral displacement. Retraction of the eye or enophthalmos occurs occasionally. Causes of enophthalmos include traumatic blow-out fractures of the orbital floor and sclerosing tumors such as metastatic scirrhous breast carcinoma. Other symptoms and signs of orbital disease include pain, loss of vision, and ocular motility disturbances, which may or may not be conspicuous depending on the underlying cause; some orbital tumors, that is, lymphomas, tend to be well tolerated. Others, that is, metastatic carcinoma, are more likely to be symptomatic.

Most orbital disease encountered by the ophthalmologist in general practice is inflammatory in nature. The most common inflammatory diseases of the orbit include infectious orbital cellulitides, noninfectious idiopathic orbital inflammation (inflammatory orbital pseudotumor), and Graves disease or thyroid orbitopathy.

Orbital cellulitis usually is caused by the extension of a primary sinus infection into adjacent soft tissues of the orbit (Fig. 14-3). Abscesses can form beneath the periosteum (subperiosteal abscess) or in the orbital soft tissues. Patients with orbital cellulitis have signs of acute inflammation including erythema and pain as well as proptosis. Although most orbital cellulitis is caused by bacteria, fungi such as Aspergillus or Mucor occasionally invade the orbit from primary foci in the sinuses. Haemophilus influenzae is an important cause of orbital cellulitis in children but is becoming rarer due to immunization. Rarely, a clinical picture resembling orbital cellulitis may be caused by an extensively necrotic intraocular retinoblastoma or melanoma. Orbital involvement has been reported in allergic fungal sinusitis (Fig. 14-4).

Mucormycosis is a potentially lethal opportunistic infection by saprophytic fungi that usually occurs in acidotic persons such as those with poorly controlled diabetes. The fungus is vasotropic and invades orbital vessels causing thrombosis and necrosis (Fig. 14-5). Histopathology shows both acute and chronic granulomatous inflammation and necrotic tissue. The hyphae are large and nonseptate and are easily identified in standard hematoxylin and eosin (H&E)-stained sections. Lives occasionally can be saved if an expedient diagnosis is made and antifungal therapy is instituted.

Thyroid eye disease (thyroid ophthalmopathy, Graves orbitopathy) is the most common cause of unilateral or bilateral exophthalmos (Fig. 14-2A). Affected patients have an underlying immunological disorder, which is complex and still poorly understood, that affects both the thyroid gland and orbital structures, especially the extraocular muscles. The exophthalmos is caused by enlargement of the extraocular muscles (Fig. 14-2B,C). The enlarged muscles contain foci of chronic nongranulomatous inflammation and increased quantities of glycosaminoglycans and

show endomysial fibrosis (Fig. 14-2D). The tendon of the extraocular muscle and the orbital fat characteristically are noninflamed, a feature that serves to differentiate thyroid ophthalmopathy from idiopathic orbital inflammation (pseudotumor). Visual loss due to compressive optic neuropathy occurs in some patients when the swollen muscle bellies press on the optic nerve in the crowded orbital apex. Corneal complications caused by exposure can also cause visual loss. Graves ophthalmopathy can occur in patients whose thyroid function tests are high, low, or even normal. Most cases are readily diagnosed by the demonstration of enlarged extraocular muscles on computed tomography (CT) or MRI scans. Very few cases are biopsied.

Idiopathic orbital inflammation or pseudotumor is relatively common (Fig. 14-6A,B). Although orbital pseudotumor undoubtedly is an immunological disorder, the details of its immunopathology and the identity of the antigens responsible for inciting the inflammation are still unclear. Idiopathic orbital inflammatory pseudotumor is a diagnosis of exclusion, from both the clinical and histopathological standpoint. The presence of fungi, bacteria, and acid-fast organisms, foreign substances, and other specific inflammatory diseases such as granulomatosis with polyangiitis (GPA; Wegener) or sarcoidosis must be excluded with special stains or appropriate tests.

Idiopathic orbital inflammation can affect both adults and children who may have either unilateral or bilateral disease. Although occasional cases are relatively asymptomatic and indolent in their course, idiopathic orbital inflammation classically presents explosively with the acute onset of pain, ocular proptosis, muscle paresis, and sometimes visual loss. The inflammation may be localized to single orbital structures such as the extraocular muscles (orbital myositis), the lacrimal gland (chronic dacryoadenitis), or the sclera or episclera (scleritis or episcleritis). A diagnostic trial of systemic corticosteroids may be administered to patients suspected of having idiopathic orbital
inflammation, because the disorder is exquisitely sensitive to steroids.

Biopsy is often performed on patients with orbital inflammatory pseudotumor. Microscopy typically discloses a polymorphous infiltrate of inflammatory cells that may contain lymphocytes, plasma cells, eosinophils, macrophages, and occasionally epithelioid histiocytes (Fig. 14-6A,B). Although vessels ringed or cuffed by chronic inflammation can be seen, this reflects diapedesis of lymphocytes, not true vasculitis. Lymphoid follicles and germinal centers occur in some cases, and fibrosis is often extensive. If the lacrimal gland is involved, its acini are destroyed by the inflammatory process and fibrosis replaces the parenchyma. The fibrosis is responsible for the typically eosinophilic appearance of specimens under low magnification light microscopy (Fig. 14-6B). This eosinophilia usually distinguishes “pseudotumor” from lymphoid tumors, which are composed of sheets of basophilic cells. Follicular lymphoid hyperplasia is considered to be an orbital lymphoid tumor by ophthalmic pathologists; it should not be called an inflammatory pseudotumor.

The sclerosing type of orbital pseudotumor may be a subset of IgG4-related disease (Fig. 14-7). It has been estimated that 40% of patients with idiopathic orbital inflammation have IgG4-related disease. The topic of IgG4-related disease is somewhat confusing, and criteria for diagnosis are not clear-cut. Classic diagnostic criteria in tissue biopsies include an intense lymphoplasmacytic infiltrate with lymphoid follicles, obliterative phlebitis, and often eosinophilia. Storiform fibrosis and obliterative phlebitis are said to be rare in orbital disease, however. There also are conflicting statements about the number of IgG4 plasma cells that are required for diagnosis. Demonstration of IgG4-positive plasma cells requires immunohistochemical stains for IgG4 and IgG (Fig. 14-7D). It is often stated that the ratio of IgG4/IgG plasma cells should be at least 40%. The actual intensity of the IgG4-positive plasma cell infiltrate is less clear. Ten or more IgG4-positive plasma cells per high-power
field is a frequently stated criterion. However, some authors require much higher counts, that is, 100/HPF for lacrimal gland involvement. The issue is complicated further by the observation that IgG4-positive plasma cells are common in orbital tissue from patients with variety of other inflammatory disorders including sarcoidosis and GPA. Patients found to have IgG4-related disease in the orbit should be investigated for involvement of other organs, because early treatment may prevent destructive changes.

If true vasculitis, granulomatous inflammation, and focal necrosis are observed, the patient may have GPA, formerly called Wegener granulomatosis (Fig. 14-6D). About one third of patients with GPA have ophthalmic manifestations during the course of their disease, and they may present with ocular findings such as orbital infiltration or peripheral corneal ulceration. Clinical suspicion is important because the classic histopathologic features of GPA are found in few orbital biopsies. Most patients have concurrent sinus disease. The cytoplasmic antineutrophilic cytoplasmic antibody (c-ANCA) test is a helpful diagnostic adjunct but may be negative in the early stages of the disease.

Lacrimal gland biopsy typically discloses discrete noncaseating granulomas composed of epithelioid histiocytes and giant cells in sarcoidosis, which is another diagnosis of exclusion (Fig. 3-10A). Lacrimal gland biopsy occasionally is performed to confirm the diagnosis of sarcoidosis histopathologically.

Unusual inflammatory reactions related to the iatrogenic use or instillation of various materials occasionally are encountered in the eyelids, conjunctiva, or orbit. These substances include proprietary formulations of collagen or hyaluronic acid used as dermal fillers in cosmetic surgery and silicone oil used to tamponade the retina during vitreoretinal surgery. Leaking silicone oil stimulates lipogranulomatous inflammation that contains large vacuoles of oil and vacuolated histiocytes (Fig. 14-8).

A wide variety of benign and malignant primary neoplasms are spawned by the tissues of the orbit. Most of these tumors are relatively rare. Secondary involvement of the orbit by blood-borne metastases, systemic lymphoproliferative disorders, or direct invasion from contiguous structures also occurs. Children and adults are affected by different spectra of orbital tumors.

Orbital lymphoid tumors constitute a spectrum that includes polyclonal reactive lymphoid hyperplasias and malignant lymphomas composed of clonal proliferations of lymphoid cells (Figs. 14-9 and 14-10). Immunophenotypic analysis has shown that most lesions previously classified light microscopically as atypical lymphoid hyperplasias are low-grade lymphomas. Lymphoma is also discussed in Chapter 5.

Orbital lymphoma usually is a disorder of older patients that is diagnosed on average at age 60 years. The onset of orbital lymphoma is usually insidious. Orbital lymphoid tumors typically present with painless, well-tolerated proptosis, because the tumor has no fibrous stroma, is soft and pliable, and molds to the globe and other orbital structures. Some patients may present with a conjunctival mass or patch of salmon-colored tissue on the epibulbar surface or fornix (Figs. 5-32A,B and 14-9A). The tumor’s characteristic
salmon hue reflects the presence of many fine capillaries. The lymphoid infiltrate is often delimited sharply by tissue planes. The latter are evident on imaging studies as linear margins. Lymphomas diffusely infiltrate and thicken the lacrimal gland, which drapes around the globe assuming an appearance that Jakobiec has facetiously termed a “pregnant pancake.” The latter contrasts with epithelial neoplasms of the lacrimal gland, which typically are rounded. Ninety percent of orbital lymphomas involve the superior part of the orbit behind the orbital septum. More than 40% involve the lacrimal gland and often affect its palpebral lobe. Bone destruction is very rare except in multiple myeloma. When extraocular muscles are involved, usually a single muscle is affected. Motility remains normal because the lymphoma does not stimulate fibrosis.

Ocular lymphomas are extranodal by definition because the orbit lacks lymphatics and lymph nodes, and most are diffuse, as well. About two thirds of ocular adnexal lymphoid tumors are malignant non-Hodgkin lymphomas (NHL) composed of a monoclonal proliferation of B lymphocytes, and most of these are low-grade lesions composed of well-differentiated lymphocytes. In recent years, pathologists have used the WHO classification to classify lymphomas. Types of NHL in the WHO classification that typically affect the ocular adnexa include extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (often called MALT lymphoma), follicular lymphoma, mantle cell lymphoma, diffuse large cell lymphoma, and small lymphocytic lymphoma (SLL) (Fig. 14-9C,D).

More than half of ocular adnexal lymphomas are MALT lymphomas. About 23% are follicular lymphomas, 5% mantle cell, and 4% small lymphocytic lymphoma (SLL/CLL). These four entities are very difficult to differentiate using routine light microscopy alone, but distinguishing them is important clinically because they differ greatly in prognosis and the proper choice of therapy requires accurate classification. The cells of extranodal marginal zone or MALT lymphoma are CD20 positive but are negative for
CD3, CD5, and CD10 (Fig. 14-10A). Mantle cell lymphoma is usually widely disseminated on presentation and has a poor prognosis. Its CD20-positive B cells coexpress T-cell marker CD5 and BCL-1 (also called cyclin D1) (Fig. 14-10B). The cells constituting the neoplastic follicles of follicular lymphoma stain with CD20, CD10, and BCL-2 (Fig. 5-34). About one third of patients who have orbital lymphomas have a past history of, or will develop, systemic lymphoma. All patients with ocular adnexal lymphoid tumors need to be evaluated by a hematologist-oncologist. Some patients with polyclonal lymphoid proliferations are a risk for systemic lymphoma.

Lymphoid tumors of the orbit and ocular adnexa are treated with external beam radiotherapy, chemotherapy, and immunotherapy with agents such as rituximab, a monoclonal antibody directed against B lymphocytes. External beam radiotherapy with appropriate eye shielding can be used if there is no evidence of systemic disease. Chemotherapy or immunotherapy should be used if extraocular systemic lymphoma is present. This may be supplemented with adjuvant radiotherapy if ocular regression is subtotal.

Cavernous hemangioma or malformation is probably the most common primary orbital tumor (Fig. 14-11). These lesions recently have been categorized as nondistensible venous malformations. Cavernous hemangiomas typically occur in middle-aged women. They cause low-grade proptosis and usually are well tolerated, sparing vision and ocular motility. Some cases are discovered incidentally when imaging is performed for headache or other indications. These benign vascular tumors are well-circumscribed, encapsulated lesions with a pebbly surface that appear dusky red or purplish-blue grossly (Fig. 14-11B). They are composed of large round or oval vascular spaces lined by endothelium, which are separated by thick
septa of fibrous tissue that may contain smooth muscle (Fig. 14-11C,D). Cavernous hemangiomas show little contrast enhancement on imaging studies because their circulation is relatively stagnant. Other vascular lesions that affect the orbit include varices and arteriovenous malformations. Patients with orbital varices often show variable proptosis that depends on head position and is increased by a Valsalva maneuver. Histopathology shows a markedly dilated vein that may contain a thrombus (Fig. 14-12D). Intravascular papillary endothelial hyperplasia may develop in the thrombosed varix. Tumors previously diagnosed as hemangiopericytomas are now considered to be SFTs. Lymphangioma and capillary hemangioma are discussed in the “Pediatric Orbital Tumors” section below (Fig. 14-12).

The lacrimal gland is a minor salivary gland that is located in a bony fossa behind the superotemporal orbital rim (Fig. 14-16). Lacrimal gland tumors constitute only 10% to 15% of orbital lesions. Most lacrimal gland lesions encountered in nonreferral clinical practice are inflammatory or lymphoid tumors, which are at least five times more prevalent than primary epithelial tumors. Epithelial neoplasms of the lacrimal gland are quite rare, but they are important because about half are highly malignant tumors that are potentially lethal.

Granulomatous dacryoadenitis can cause bilateral lacrimal gland enlargement and a characteristic “s”-shaped lid fissure in patients with sarcoidosis (Fig. 14-6C). Keratoconjunctivitis sicca develops in patients with Sjögren syndrome when intense lymphocytic infiltration replaces
the parenchyma of the lacrimal gland. Damaged ducts and epimyoepithelial islands persist in the resultant benign lymphoepithelial lesion, and patients are at risk for lymphoma. Cystic dilation of lacrimal gland ducts (dacryops) may simulate a primary lacrimal gland tumor. Concretions or stones (dacryolithiasis) occasionally form in the ducts of the lacrimal gland.