Ocular, Orbital, and Optic Nerve Tumors

Periocular Skin Cancers

Basal cell cancers make up 90% of eyelid skin cancers; the other 10% is composed of squamous cell carcinomas. Skin cancers of the periorbital skin (including the nasal bridge, medial canthus, and eyelid) most frequently occur on the lower eyelid and medial canthus. Immunosuppressed patients and sun-exposed patients have an increased incidence of these cancers.

Uveal Melanoma

Approximately 95% of uveal melanoma arises from melanocytes of the uveal tract (iris, ciliary body, and choroid), with 95% of uveal melanoma arising from the ciliary body and/or choroid and 5% arising in the iris. The incidence of uveal melanoma in the United States has remained relatively unchanged and is estimated to be 5.2 per million patients per year. There continues to be a statistically significant gender-based difference in incidence (males: 6.0, 95% CI, 5.7–6.3; females: 4.5, 95% CI 4.3–4.7). Uveal melanoma is more common in lightly pigmented persons and is infrequent in nonwhite races. Other risk factors associated with uveal melanoma include cutaneous nevi, cutaneous freckles, iris nevi, and ocular/oculodermal melanocytosis. The role of ultraviolet exposure is less clear for the development of uveal melanoma than for cutaneous melanoma.

Conjunctival melanoma is rare (5% of uveal melanoma), with lesions arising from melanocytes in the basal layer of the conjunctival epithelium. They most commonly arise from primary acquired melanosis or conjunctival nevus ( eFig. 36.1 ). In contrast to uveal melanoma, the incidence of conjunctival melanoma is increasing, suggesting a possible association with ultraviolet light exposure.

Choroidal Metastases

Choroidal metastases are the most common intraocular malignancy in adults. The primary cancers most commonly associated with choroidal metastases are breast cancer, followed by lung cancer in females, and lung cancer, followed by gastrointestinal cancers in males.

Primary Intraocular Lymphoma

Primary intraocular lymphoma is a distinct clinical and biologic disease entity relative to the primary adnexal lymphoma. Primary intraocular lymphoma may present with malignant lymphoid cells involving the retina or vitreous, with or without concurrent central nervous system (CNS) involvement. Primary intraocular lymphoma usually occurs in the fifth and sixth decades of life and may be associated with an immunosuppressed state.

Retinoblastoma

Retinoblastoma is discussed in Chapter 82 .

Orbital Tumors

Rhabdomyosarcoma is the most common malignant orbital tumor in children, representing 3% of all orbital masses; lymphoma is the most common malignant tumor in older patients, representing 10% of orbital masses.

Rhabdomyosarcoma

Rhabdomyosarcoma is discussed in Chapter 79 .

Primary Adnexal Lymphoma

Primary adnexal lymphoma is rare, accounting for less than 1% of all lymphomas. It occurs in the adnexal structures (conjunctiva, lacrimal gland, orbit, and eyelids). The low-grade subtype of non-Hodgkin's lymphoma, known as mucosa-associated lymphoid tissue (MALT)-type lymphoma, is the most common type of adnexal lymphoma. Primary adnexal lymphoma is not associated with human immunodeficiency virus infection. Some studies have indicated etiologic association with Chlamydia psittaci infection, similar to the association of Helicobacter pylori with primary gastric MALT lymphoma.

Lacrimal Gland Tumors

Primary lacrimal gland tumors are rare. Benign pleomorphic adenomas represent the majority of benign lacrimal masses. Adenoid cystic carcinoma is the most common lacrimal gland epithelial malignancy.

Optic Nerve Sheath Meningioma

Optic nerve sheath meningiomas arise from the meningothelial cap cells of arachnoid villi. They can develop anywhere along the optic nerve, from the globe to the prechiasmal intracisternal optic nerve, and may be unilateral, bilateral, or multifocal. Patients with neurofibromatosis type 2 are predisposed to bilateral or multifocal lesions and are diagnosed at an earlier age. Meningiomas from other locations can also extend to involve the optic nerve.

Orbital Pseudotumor

Orbital pseudotumor is an idiopathic, nonspecific inflammation of the orbital structures including orbital fat, extraocular muscles, and lacrimal glands. The diagnosis of pseudotumor remains one of exclusion. Autoimmune disease, endocrinopathies, granulomatous processes, and local infection with secondary involvement of the orbit, such as sinusitis and subperiosteal abscess, must be ruled out.

Graves Ophthalmopathy

The pathogenesis of Graves ophthalmopathy is thought to be autoimmune, triggered by an autoantigen, which then triggers T lymphocytes. These T cells invade the orbit and interact with orbital fibroblasts to propagate multiple intracellular signaling cascades resulting in glycosaminoglycan synthesis, adipogenesis, and orbital inflammation. Tissue edema and marked enlargement of the extraocular muscles subsequently develop, displacing the eyeball forward and resulting in proptosis and extraocular muscle dysfunction. Typically, the ophthalmopathy goes through three phases: progression, stabilization, and perhaps some improvement. Residual signs of ophthalmopathy after the disease has reached a plateau are thought likely to be the result of fibrosis and other tissue changes rather than persistent inflammation.

Pterygium

A pterygium is a benign growth of fibrovascular tissue on the cornea. These lesions may become red and inflamed and encroach upon the visual axis. Most pterygia are located medially on the nasal conjunctiva. Pterygia is associated with chronic sun and ultraviolet light exposure; it is more common among Caucasians.

Uveal Melanoma

Uveal melanoma is a biologically distinct malignancy relative to its cutaneous counterpart with data suggesting that specific chromosomal aberrations within the tumor may be associated with clinical outcomes. A cytogenetic analysis of 74 primary uveal melanomas led to the identification of common cytogenetic chromosomal losses, including 1p (24%), 3p (41%), 3q (42%), and 6q (28%). Common chromosomal gains include 6p (18%) and 8q (53%). Although the degree to which each chromosomal aberration impacted disease-free survival varied, monosomy of chromosome 3 appeared to have the largest impact when adjusting for other confounding factors as it is detected in more than 70% of metastasizing and 20% of nonmetastasizing uveal melanoma; by contrast, the loss of 1p occurred only in the metastasized uveal melanoma. Concomitant loss of 1p and monosomy of chromosome 3 were strongly predictive of decreased survival. A combination of monosomy 3 and gains in chromosome 8q have also been shown to be associated with a high risk of systemic metastasis.

Recent efforts to classify uveal melanoma with biomarker-based assays to predict distant disease-free survival have focused on gene expression profiling and have resulted in the classification of tumors into two classes: class 1 or low-grade tumors, which have a reduced propensity for distant spread, and class 2 or high-grade tumors, which have a higher level of aneuploidy, proliferation rate, and much reduced survival relative to class 1 tumors (95% in class 1 vs. 31% in class 2 at 7 years). This classification has been prospectively validated as a better prognostic marker than monosomy 3 and the TNM staging system. Circulating tumor cells or circulating tumor DNA may also help identify patients at risk for metastasis.

The most common genetic mutations in uveal melanoma are uncommon in cutaneous melanoma ( eTable 36.1 ). For instance, BRAF , which is among the more common mutations in cutaneous melanoma, occurs at a low frequency in uveal melanoma; however, its incidence in iris (~50%) and conjunctival melanoma (22.7%) is much higher. Those mutations more common in the posterior uvea are distinct from iris and conjunctival melanoma, and include GNAQ , GNA11 , and BAP1 ( BRCA1 -associated protein-1). Of all uveal melanoma, 80% harbor mutations in either GNAQ (~50%) or GNA11 (~30%). These are heterotrimeric guanosine triphosphate-binding protein alpha-subunits that couple G-protein signaling to MAPK activation. The high incidence of these mutations in nearly all uveal lesions and some blue nevi suggests that these mutations may be early oncogenic events in the development of melanoma, and have led to studies exploring mitogen-activated protein kinase kinase inhibitors for uveal melanoma. The sequential mutation of BAP1 in uveal melanoma is thought to be a late oncogenic event relative to other insults such as GNAQ mutations. Somatic mutations in BAP1 are common among class 2 uveal melanoma (84%), but not class 1 melanoma. This protein facilitates the transformation to a class 2 melanoma by unknown means and results in a highly metastatic phenotype. PTEN loss, similar to BAP1 mutations, occurs in a high proportion of class 2 uveal melanoma and results in unfettered PI3K-Akt signaling, leading to resistance to apoptosis, increased growth potential, and reduced disease-free survival. Conversely, EIF1AX or SF3B1 mutations, which are mutually exclusive with those in BAP1 , predict low risk or delayed risk for metastasis, respectively.

Primary Intraocular Lymphoma

Primary intraocular lymphoma is believed to be a subset of primary CNS lymphoma with roughly 90% of cases being a diffuse, large B-cell lymphoma (DLBCL) subtype and roughly 10% being either Burkitt's or T-cell lymphoma. Given the difficulty with pathologic diagnosis, flow cytometry is often done to document the presence of monoclonal populations of B lymphocytes derived from immunoblasts or centroblasts, which probably arise from a late germinal center or postgerminal center lymphoid cells. These cells have a predilection for clustering around cerebral blood vessels secondary to an incompletely understood neurotropism. Expression profiling has resulted in the description of two different DLBCL subtypes: germinal center B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL. ABC DLBCL has a poorer survival and responds less effectively to chemotherapy. MYC alterations have also been found in DLBCL to be prognostic, and are often associated with BCL2 and/or BCL6 translocation in “double-hit” or “triple-hit” lymphoma. MYC protein expression is associated with protein expression of BCL2 in “double-expresser lymphoma,” and is also associated with worse outcomes.