Localization of metastases within the orbit is of limited value and varies in reported series. Some authors suggest the lateral orbit is most frequently affected,2 whereas others found the superior and medial orbit more commonly involved,31,32 and further studies found no preference.4,33 In our series of 80 patients, the most common site was the medial orbit (23%), the lateral orbit (18%), and the superior quadrant (14%), being independent of the site of the primary lesion.5
Hematogenous spread via the pulmonary, caval, and enteric circulatory pathways seems to be the main avenue for metastases to reach the orbit. Frequently, the lung and/or the liver are also found to be involved during staging. However, these systems can be bypassed, and metastatic emboli can enter directly into the valveless paravertebral Batson plexus, reaching the dural sinuses and the orbit via changes in venous pressure.34 Melanoma and breast cancer tend to metastasize in more vascularized tissue such as the extraocular muscles and orbital fat. When affecting bone, breast cancer tends to develop an osteolytic lesion, whereas prostate cancer and melanoma can induce hyperostosis of the greater wing of the sphenoid (Fig. 21.2).1,2,5,4,9,15,33,35,36
Clinical Features and Differential Diagnosis
A detailed clinical history, including the past medical history of cancer, followed by a meticulous examination and appropriate imaging, narrows the possible list of differential diagnoses. Specific additional investigations should follow in light of a histopathologic diagnosis.
Orbital metastasis can present as a palpable mass or as a lesion inducing axial or nonaxial globe displacement (Fig. 21.3). When motility disturbance caused by involvement of one or more extraocular muscles is noticed, the differential diagnosis includes thyroid-related orbitopathy, myositis, lymphoproliferative disease, immunoglobulin G4 (IgG4)–related ophthalmic disease, arteriovenous malformation, venous–lymphatic anomalies, carotid–cavernous fistula, amyloid deposit, and parasites.17,28,37–39 Most of these conditions present a diffuse enlargement of the entire muscle, with tapering of tendons and sharply defined margins on imaging. Muscle involved by metastasis usually presents with an area of segmental widening, irregular borders against the orbital fat, with/without bone changes (Fig. 21.4).40 Pain is a key symptom that helps differentiate metastasis from benign tumors and commonly is an indication of bone destruction and perineural involvement. Osteolysis can also be encountered in other entities such as Langerhans cell histiocytosis, leukocytoclastic vasculitis, and, rarely, lymphoproliferative disease. Metastatic disease to the bony orbit may be limited to bone or may involve the soft tissue of the extraconal space (Fig. 21.5A) or the contiguous anterior or middle cranial fossa and the paranasal sinuses.40 Prostatic cancer should be differentiated from secondary hyperostosis induced by a meningioma of the greater wing of the sphenoid or frontal bone, or chronic inflammatory processes such as sarcoidosis.
Less commonly, patients may present with diffuse involvement in the intraconal space as a result of sclerosing orbital metastasis from breast, gastrointestinal, prostate, or lung cancer developing enophthalmos or a frozen globe. The possibility of early Parry Romberg syndrome should be considered, but this often also develops the characteristic linear scleroderma of facial tissues.16,17,37
Occasionally, inflammatory features can be encountered when the metastasis grows rapidly, inducing necrosis and/or bleeding. The possibility of a nonspecific orbital inflammation, orbital cellulitis, and Graves disease should be ruled out.
Imaging
Computed tomography (CT) and magnetic resonance imaging (MRI) are essential to evaluate the characteristics of the lesion, location within the orbit, and invasion of neighboring structures when an orbital metastasis or a secondary invasion into the orbit is suspected.5,41,42
The metastatic mass can be located in the intraconal or extraconal space. Unilateral disease is most common. Some primary malignancies such as breast cancer and melanoma can be bilateral. Extraocular muscles have a rich vascular supply and frequently manifest in cases of hematogenous spread, presenting with a mass and limited function inducing diplopia, strabismus, and blepharoptosis (Fig. 21.6). Globe indentation can be found if a lesion is in proximity to the eye. Although rare, a compressive optic neuropathy can be the first sign of metastasis in the orbital apex (Fig. 21.3) or a lesion invading from the middle cranial fossa. Cystic changes caused by central necrosis have been encountered in tumors with rapid growth. Although calcifications are rare, bone changes are common and depend on the primary tumor involved (e.g., breast and thyroid cancer have an osteolytic effect versus prostate cancer inducing hyperostosis or bone sclerosis in the greater wing of the sphenoid) (Figs. 21.2B and 21.5A).2,4,9,26,33 Less commonly, metastasis can have a diffuse pattern in the intraconal and/or extraconal space (e.g., melanoma and breast cancer), presenting with enophthalmos.2,5,9,16,26,33,41–43
CT is essential in providing bony details. Without contrast, orbital metastasis tends to appear as a well-defined mass that is relatively dense compared with the orbital fat and the optic nerve. With contrast, it is isodense with the extraocular muscles and vascular structures.2,4,9,26,33
MRI is the anatomic imaging modality of choice for soft tissue analysis, using gadolinium as a paramagnetic substance for enhancement.44 Metastatic tumors typically are isointense to extraocular muscles and hypointense to orbital fat on TI-weighted images and mildly hyperintense relative to the extraocular muscles and fat on T2-weighted images, enhanced with gadolinium.2,5,45
Imaging characteristics are not diagnostic unless there is clear active metastatic disease with multiorgan involvement. Tissue diagnosis is mandatory before any staging and treatment planning.
Combined positron emission tomography and computed tomography (PET-CT) integrates the metabolic information provided by areas with high uptake of glucose-labeled radiotracer by PET with the anatomic information provided by CT (Fig. 21.7A).46 PET-CT does not seem to provide an advantage over clinical examination and conventional imaging studies such as CT or MRI of the orbit alone. It is especially helpful for advanced metastatic orbital tumors for which the detection of distant involvement with a single comprehensive study may be preferable to performing multiple CT scans with contrast.46
Biopsy
Tissue sampling is the most useful technique to establish an accurate diagnosis of orbital metastasis, unless the malignant disease is widespread and the identification of an orbital component will not change patient management. However, in some metastases such as breast cancer, biopsy of the metastatic tissue could potentially improve the outcome by identifying what new genetic or molecular pathways are activated (e.g., the transmembrane tyrosine kinase receptor proto-oncogene ERBB2, also known as HER2, and hormone receptor testing), leading to altered and ideally more efficacious therapy.23
Fine-needle aspiration biopsy (FNAB) is a minimally invasive option that provides a cytologic sample for microscopic examination.2,19,47–50 Its supporters suggest that it is more efficient than frozen section analysis, as it allows multiple tumor sampling with less damage than traditional surgery, particularly if image guided.51 Core-needle biopsy (CNB) offers a tissue sample for histologic diagnosis rather than a cytologic smear as with FNAB. Both techniques are relatively simple, safe, and diagnostically accurate, with a low rate of complications (e.g., globe perforation, orbital hemorrhage, eye motility deficits, optic nerve damage, and tumor seeding).2,19,47–-50,52,53
Invasive diagnostic modalities are still preferred in most centers and include excisional and incisional biopsy. Their advantage is they offer larger and sufficient tissue for multiple investigations, including frozen section analysis, histopathology, immunohistochemistry, cytogenetics, molecular biology, hormonal receptor expression, and electron microscopy.2,19,47–50,53,54 However, they require surgical intervention under general anaesthesia, additional costs, and stress, which is particularly relevant for frail patients with lesions located in the posterior orbit, intraconal space, and/or orbital apex.16 Lesions involving the paranasal sinuses may be more easily biopsied through a transnasal endoscopic route.
Pathology
In patients with a history of cancer, obtaining an orbital biopsy will allow comparison of tissue with the primary tumor, which will often be adenocarcinoma.5,15–18 Breast cancer, followed by prostate and lung tumors, is the most frequent metastatic orbital epithelial malignancy.4,5,16,26 Less frequently, skin melanomas, carcinoid tumors, and sarcomas can reach the orbit, and between 4.8% and 35% are of unknown origin and tend to be poorly differentiated lesions.3–5,24,55,56
Immunohistochemistry is fundamental for diagnosis. Staining for cytokeratin (CK7, CK20) and polyclonal or monoclonal carcinoembryonic antigen (CEA) can be positive in tumors of epithelial origin.57–59 BRST1 and BRST2 positivity suggests breast cancer, whereas prostate-specific antigen (PSA) positivity implies a prostate origin (Fig. 21.5C).59 Tumors of neuroendocrine nature, such as carcinoid, often are positive for the avidin–biotin complex with primary antibodies to CAM5.2, neuron-specific enolase, synaptophysin, chromogranin A, and protein gene product 9.5 (PGP 9.5).60 Metastatic melanoma can show positive staining for S100, HMB45, vimentin, CAM5.2, p53 and Bcl2, and endothelial tumors show positivity for CD34 and CD31.61 Many additional special markers can be used to identify the primary tumor.
Management
Orbital metastasis often represents an end-stage disease, and it is important to consider the effect of any treatment on the patient’s multiorgan involvement, quality of life, change in survival, and life expectancy.5,16
A multidisciplinary team, including a medical oncologist and a radiation specialist, is crucial to establish the appropriate therapy in individual cases. Additional psychological expertise and emotional support plays an important role in patient compliance and better quality of life.
Treatment modalities include radiotherapy, chemotherapy, hormone therapy, surgery, and immunotherapy, depending on the histologic type, the anatomic extension, and whether the goal is to cure or provide palliation.2,4,5,10,16,18
Radiotherapy
Radiotherapy for orbital metastasis should balance tumor responsiveness with toxicity to vital structures. Depending on the type of primary tumor, orbital radiation is usually delivered between 18 to 40 grays (Gy) in 10 to 15 fractions, combining anterior and lateral fields over a 2- to 5-week period.16,18 Reduction in mass effect, decrease in pain, and improvement in vision have been reported.2,5,62–64 The possible development of radiation retinopathy, neovascular glaucoma, optic neuropathy, and corneal scarring should be considered in those patients with longer survival expectancy, particularly if the eye cannot be shielded.2,65
Chemotherapy
Chemotherapy is still the main line of treatment for many metastatic cancers, particularly when there is systemic involvement. Protocols will differ depending on the type of primary tumor involved, the biologic behavior of the metastasis, the extent of the disease, and the host immune competency. Occasionally, chemotherapy can provide prolonged remission, but usually its effects are palliative. Frequently it is used in combination with immunotherapy and/or radiation.5
Hormonal Therapy
Hormonal deprivation is a more selective option that may provide temporary remission in patients with metastatic breast and prostate cancers, particularly if the lesions are well differentiated.3 Newer agents decrease the survival of hormone-sensitive cancer cells with adaptation to a low-hormonal environment, prolonging the patient’s survival.
Immunotherapy
Newer anticancer agents have been introduced into clinical practice and have shown promising response rates in patients with metastatic disease. They have demonstrated favorable results as monotherapy and synergistically with other agents by reducing the development of tumor resistance. Systemic immune-related adverse events include life-threatening infections and secondary blood-related malignancies.
Surgery
Surgery in metastatic orbital disease provides tissue to confirm the diagnosis in questionable cases and to guide treatment. Exceptionally, it may have a curative role decreasing the symptoms and improving survival by reducing the tumor mass in isolated renal cell tumors.36,78 In local recurrent lesions with significant detriment in the quality of life, surgery may provide a palliative role, despite poor survival.
Most Common Types of Orbital Metastases
Carcinomas are, by far, the most frequent histologic type in adults.5,15,17,18 Combined large and small studies report breast, lung, skin melanoma, prostate gland, and carcinoid tumors as the most prevalent orbital metastases (see Table 21.1 and Figs. 21.1, 21.2, 21.4–21.11),5,13,14,32,66–80 followed by the kidney and the gastrointestinal tract.2,5,15 Other less common primary sites include the thyroid gland, liver, pancreas, and salivary gland, and choroidal melanoma is also included.2,4,5,15 Children are rarely affected and commonly have unilateral involvement, with neuroblastoma (which may be bilateral) as the most frequent, followed by Wilms tumor and Ewing sarcoma.2,4,5,7
Breast Cancer
Breast cancer is the most common cause of cancer-related death in women in Western countries, with a lifetime risk of 12.3%; it was shown to account for 29% to 53% of the orbital metastases in large-series studies.4,5,10,17,23,55 Less than 1% affects men. The biologic properties and clinical features appear to be similar in both genders.81,82
In the majority of cases, orbital metastasis emerges years or even decades after a successful initial treatment, or the patient presents with an orbital mass in the context of an active multisystemic malignancy under treatment. The orbit is rarely the first presentation.17,18
Diplopia and impaired ocular motility are commonly encountered because of its preference for localizing within the orbital fat and/or extraocular muscle (Figs. 21.1 and 21.6). In the sclerosing form, it can induce enophthalmos and even gaze-evoked amaurosis.83,84 Breast cancer can have bilateral involvement in up to 15% of cases (Fig. 21.1).2
Histology usually shows a formed single-file linear cord or poorly cohesive tumor cells that are diffusely scattered or loosely packed while infiltrating periocular soft tissue. Morphologic comparison with the matched primary tumor commonly shows the metachronous metastatic specimens acquire a higher histologic grade exhibiting marked nuclear atypia, a tendency toward solid growth in loosely packed sheets of cells, and a higher mitotic activity.3,17,18,85 The infiltrating lobular subtype has the highest prevalence in the orbit as a result of inactivation of the tumor suppressor gene E-cadherin and is almost always estrogen receptor (ER) positive.85,86
Targeted treatments against the transmembrane tyrosine kinase receptor proto-oncogene ERBB2 (also called HER2, NEU), such as the humanized monoclonal antibody trastuzumab, have significantly improved survival in patients with metastatic HER2-positive breast cancer,87 in combination with chemotherapy (epirubicin/cyclophosphamide and taxane, doxorubicin/cyclophosphamide, docetaxel/capecitabine, vinorelbine alone, etc.) and hormone therapy with ER antagonists (tamoxifen, fulvestrant, aromatase inhibitors, etc.).88–92 Lapatinib, a small-molecule inhibitor of HER2 and EGFR, has shown efficacy in metastasis after relapse on trastuzumab-based therapy.93 However, there is extensive heterogeneity between primary breast carcinomas and their metastases, as well as among multiple metastatic breast carcinomas in the same patient.94
The most common modality of radiotherapy is external beam radiation, with stereotactic techniques preferred, where possible. Total doses range from 32 to 50 Gy, depending on the tumor location relative to the anterior eye, and are delivered with conventional fractionation. Technical advances in image guidance and radiation delivery with stereotactic radiosurgery (cyberknife), have offered better targeting of ablative radiation doses to orbital metastasis with less side effects.95 Despite the progress in these therapies, metastatic disease is frequent in patients with breast cancer and remains the leading cause of death among them. For those with established metastases and orbital involvement, therapy is palliative in most cases, with few breaks and with mounting adverse effects.3,17 Prevention with regular mammography, routinely starting at age 40 years, or 35 years when there is family history, allows for early detection of any suspicious lesions and possible prevention of further spread. Genetic screening for known breast cancer genes is increasingly being used in families with a strong family history, allowing for prophylactic mastectomy in some cases.
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