Volume 5, Chapter 34. Metastatic Cancer to the Eye and Adnexa

Chapter 34
Metastatic Cancer to the Eye and Adnexa
ERIC P. SHAKIN and JERRY A. SHIELDS
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INCIDENCE
LOCATION OF METASTASIS
PRIMARY MALIGNANCY
METASTATIC TUMORS TO THE INTRAOCULAR STRUCTURES
CANCER METASTATIC TO THE CONJUNCTIVA AND SCLERA
CANCER METASTATIC TO THE EYELID
CANCER METASTATIC TO THE ORBIT
PARANEOPLASTIC SYNDROMES
EVALUATION
MANAGEMENT
PROGNOSIS
SUMMARY
REFERENCES

Cancer remains the second leading cause of death among adults in the United States. The annual incidence of cancer is 1.2 million cases/year, and the death rate is about 0.5 million cases/year.¹ The most commonly encountered malignancies include gastrointestinal cancer, breast cancer, and lung cancer. The eye and adnexa may be involved by either metastasis (dissemination of a distant primary malignancy) or a secondary malignancy that has invaded the eye and adnexa from the surrounding structures. Ocular metastases are usually spread to the eye and orbit by hematogenous dissemination.² The eye and adnexa may also be involved indirectly by effects from paraneoplastic syndromes or toxicity from chemotherapy.

INCIDENCE

The prevalence of metastasis to the ocular region (in patients with known cancer) ranges from as little as 0.07% to as high as 27%^3–10 in a series of patients with breast cancer. There was a 4%⁷ rate of cancer metastatic to the eye in an autopsy series of patients who died with systemic carcinoma. This suggests that there are more than 20,000 new cases of metastatic cancer to the eye each year. Therefore, metastatic cancer to the eye is the most common intraocular malignancy in comparison to other primary intraocular malignancies.⁸ Furthermore, prior studies have demonstrated that there is no prior history of cancer in about 1/3 of patients who presented with an intraocular metastatic tumor¹¹ or in about ¼ of patients with orbital metastatic tumor.⁹^,¹²

LOCATION OF METASTASIS

Cancer metastatic to the ocular region most commonly involves the uveal tract. The isolated metastasis to the eye/orbit ratio ranges from 6:1 to 9:1 in adults.⁹^,¹⁰^,¹² Simultaneous metastasis to the orbit and uvea occurs in up to 2% to 9% of patients.¹⁰^,¹¹ Metastatic cancer to the eyelid is rare. Concomitant metastasis to the central nervous system is reported in 7%¹¹ to 45%⁶ of patients with metastatic breast cancer to the ocular region.

PRIMARY MALIGNANCY

Most metastases to the eye are carcinoma, although sarcoma, lymphoproliferative malignancies, and melanoma have been reported to metastasize to the eye. The lymphoproliferative disorders are discussed in another section. The most common primary malignancies reported in most series include breast, lung, gastrointestinal, renal, skin,¹¹^,¹³ and prostate cancer^3–12 (Table 1). The site of the gastrointestinal primary includes esophagus,¹¹ stomach,¹¹ colon,¹¹ bile duct,¹¹ liver,¹⁴ and pancreas.¹¹ Other less common primary sites include carcinoid tumors,¹⁵ uveal melanoma,¹⁶ testicular cancer,¹⁷ uterine cancer, cervical cancer,¹⁸ ovarian cancer, choriocarcinoma, bladder cancer, adrenal gland cancer, osteogenic sarcoma, Ewing's sarcoma,¹⁹ fibrosarcoma, neuroblastoma,²⁰ Wilms tumor, parotid gland adenocarcinoma,²¹ laryngeal cancer, Merkel cell carcinoma,²² and nasopharyngeal cancer.²³ In various series, the site of the primary malignancy is unknown in 9% to 17% of cases. It should be emphasized that nearly 34% of patients with intraocular metastasis have no known history of cancer at the time of ocular diagnosis.¹¹

TABLE 1. Location of Primary Malignancy for Intraocular and Orbital Tumors

Primary Site	Number Men	Number Women	Total (%)	Number Orbital Tumors (%)
Breast	2	194	196 (47)	18 (51)
Lung	55	35	90 (22)	2 (6)
Gastrointestinal	13	5	18 (4)	2 (6)
Kidney	8	1	9 (2)	1 (3)
Skin	5	4	9 (2)	1 (3)
Prostate	9	0	9 (2)	6 (17)
Others	5	11	16 (4)
Unknown	40	33	73 (17)	6 (17)
Total	137	283	420	36

Data for intraocular tumors from Shields CL, Shields JA, Gross NE et al: Survey of 520 eyes with uveal metastases. Ophthalmology 1997;104:1265. Data from orbital tumors from Shields CL, Shields JA, Peggs M: Metastatic tumors to the orbit. Ophthalmic Plast Reconstr Surg 1988;4:73.

METASTATIC TUMORS TO THE INTRAOCULAR STRUCTURES

A retrospective study reviewed 570 patients with metastatic cancer to the eye referred to the oncology service at Wills Eye Hospital over a 20-year period.¹¹ In this study, 90% were white and 67% were female. The average age at the time of diagnosis was 58 years. The right eye was involved in 48%, the left eye was involved 52%, and there was bilateral involvement in 24% of patients.

ANTERIOR UVEA

Cancer to the iris and ciliary body accounts for 4% to 11%¹⁰^,¹¹^,^24–26 of intraocular metastasis. Patients with cancer metastatic to the ciliary body and angle structures usually have associated injected epibulbar vessels and anterior uveitis. An iris metastasis is typically a yellow, gelatinous mass located within the iris stroma. Rarely, the iris tumor may be friable and may seed into the aqueous, producing a pseudohypopyon composed of tumor cells⁸ (Fig. 1). Other associated finding in those eyes with metastases to the anterior uvea include ocular hypertension, hyphema, uveitis, rubeosis, cataract, and infiltration into the surrounding structures.⁸^,^24–26 The differential diagnosis of cancer metastatic to the iris includes amelanotic melanoma, granulomatous uveitis, iris cysts, retained foreign body, and retinoblastoma in children.⁸^,²⁶

Fig. 1. Slit-lamp photograph of a patient with colon cancer metastatic to the iris. Note the pseudohypopyon composed of tumor cells seeding from the iris tumor.

CHOROID

The choroid is the most common site of carcinoma metastatic to the eye (88% of eyes).⁶^,⁷^,¹⁰^,¹¹ Patients with choroidal metastasis usually complain of painless vision or visual field loss. About 47% of the choroidal lesions were temporal to the disc.¹¹ Metastatic cancer to the eye was multifocal in the choroid in 28% of the eyes.¹¹ Breast cancer was more commonly bilateral (33%) and multifocal (32%) compared with other primary neoplasms.¹¹ There is an associated nonrhegmatogenous retinal detachment in 73% of the eyes.¹¹ Carcinoma metastatic to the choroid is typically a placoid or dome-shaped yellow tumor of varying diameter and thickness. Multiple lesions are not infrequent (Fig. 2). The mean thickness in our series was 3 mm. Rarely a rip to the retinal pigment epithelium can develop.²⁷ Regressed lesions are relatively flat with overlying pigment and lack of associated subretinal fluid. The differential diagnosis of choroidal metastases include amelanotic malignant melanoma, amelanotic nevus, choroidal hemangioma, choroidal osteoma, posterior scleritis, uveal effusion syndrome, Harada's disease, and central serous choroidopathy.²⁸

Fig. 2. Fundus photograph (A) of the left eye of a patient with breast cancer metastatic to the choroid. Several tumor nodules can be appreciated. Fluorescein angiography (B) reveals staining of the tumors in the full venous phase.

OPTIC DISC

Metastatic cancer to the optic disc is rare (4.5% intraocular metastases).²⁹ The optic disc is usually affected by direct extension of an adjacent choroidal metastatic tumor that infiltrates the optic disc (Fig. 3). Occasionally, tumor emboli enter the optic disc by hematogenous or intrathecal invasion (meningeal carcinomatosis). There is an adjacent juxtapapillary choroidal lesion in 74% of eyes.²⁹ The associated findings include optic disc edema, venous stasis, an afferent pupillary defect, and less commonly hemorrhage or obstruction of a retinal artery or vein.⁸^,²⁹ The optic disc appears to be edematous, hyperemic, or atrophic in patients with meningeal carcinomatosis involving the optic nerve sheath.²^,¹⁰^,²⁹ Most cases are from breast, lung, or an unknown primary malignancy. The differential diagnosis includes papilledema, optic neuritis, granuloma, optic disc drusen, and capillary hemangioma.⁸

Fig. 3. Fundus photograph of the right eye of a patient with breast cancer metastatic to the optic disc.

RETINA

Metastatic cancer to the retina, which has rarely been reported,⁸^,¹³ reaches the retina by either direct invasion from the adjacent choroid or by tumor emboli through the central retinal artery. The retinal tumors may appear as patchy yellow lesions associated with hemorrhage or exudate.

Sometimes there are overlying clumps of tumor cells in the vitreous such as in cases of cutaneous melanoma metastatic to the retina. The differential diagnosis includes cotton-wool spots, vascular obstructions, and retinitis.

VITREOUS

Metastatic cancer to the vitreous can be associated with metastasis to the retina or ciliary body.⁸^,³⁰ Clumps of tumor cells are visible in the vitreous. Cutaneous malignant melanoma and lymphoproliferative disorders such as large cell lymphoma are known to disseminate to the vitreous, although breast cancer and lung cancer have been associated with metastatic cells in the vitreous cavity. The differential diagnosis includes primary ocular lymphoma, vitritis, and other vitreous opacities.

CANCER METASTATIC TO THE CONJUNCTIVA AND SCLERA

Cancer metastatic to the conjunctiva is associated with intraocular metastasis in 1% of the eyes in our study.¹¹ Cancers metastatic to the conjunctiva are fleshy vascular tumors⁸^,³¹ (Fig. 4). Leukemia and lymphoma can also occur in the conjunctiva. The sclera was involved by direct extension of a choroidal metastasis in 11% of patients in one series.⁵

Fig. 4. Slit-lamp photograph of metastatic cancer to the conjunctiva. Note that this fleshy vascular tumor extends anterior to the limbus.

CANCER METASTATIC TO THE EYELID

Malignant tumors including the lymphoproliferative disorders metastatic to the eyelid account for 0.3% to 1.1% of eyelid neoplasms.³² Metastatic cancer to the eyelid can appear as a solitary nodule, as diffuse induration of the eyelids with infiltration of the local lymphatic drainage, or as an ulcerative lesion (Fig. 5). The tumor cells usually infiltrate the dermis or less commonly the conjunctival surface of the eyelid. Breast cancer, lung cancer, and cutaneous malignant melanoma are the most common primary malignancies to metastasize to the eyelid.³²

Fig. 5. Photograph of a patient with breast carcinoma metastatic to the left upper eyelid.

CANCER METASTATIC TO THE ORBIT

The incidence of cancer metastatic to the orbit ranges from 2% to 9% of orbital neoplasms.⁹^,¹⁰^,¹²^,³³ Orbital metastases usually occur more commonly in women between the ages of 40 to 60 years. The presenting signs in patients with metastatic cancer to the orbit include proptosis or rarely enophthalmos; a painful, palpable mass; and ophthalmoplegia. Less common signs include vision loss, choroidal folds, or an afferent pupillary defect¹⁴ (Fig. 6). The reported primary malignancies includes breast cancer, lung cancer, gastrointestinal cancer, genitourinary tract cancers, thyroid cancer, adrenal cell cancer, and cutaneous malignant melanoma.⁹^,¹⁰^,¹²^,³³ We have reported a case of uveal malignant melanoma metastatic to the contralateral eye and orbit.¹⁶ Neuroblastoma,¹²^,³³ Ewing's sarcoma,¹⁹ and Wilms tumor¹²^,³³ have been known to metastasize to the orbit in children.

Fig. 6. Computerized axial tomography scan of head, axial section, in a patient with metastatic breast cancer to the right orbit.

PARANEOPLASTIC SYNDROMES

Cancer associated retinopathy (CAR syndrome, paraneoplastic retinopathy, visual paraneoplastic syndrome) was first described by Sawyer and coworkers.³⁴ The syndrome is characterized by progressive photoreceptor degeneration with subsequent insidious vision loss over several months. The photoreceptor degeneration is a remote effect of the primary malignancy caused by a retinal toxic tumor cell product or more likely by an autoimmune response to a tumor antigen that cross-reacts with various cells in the retina such as retinal ganglion cells and photoreceptors.^35–37 There are a variety of serum antibodies to retinal antigens detected in these patients. The protean symptoms include diminished visual acuity, visual obscurations, photopsia, nyctalopia, and scotoma. The associated visual field defects include ring scotoma, central scotoma, and generalized constriction of the isopters. The optic disc is usually normal. The retinal arterioles are attenuated or sheathed. Intravenous fluorescein angiography is characterized by a delay in the transit time and transmission window defects corresponding to areas of atrophy of the retinal pigment epithelium especially in a perivascular pattern. Sometimes there is associated vascular leakage. The electroretinogram and electro-oculogram are subnormal. This paraneoplastic syndrome is associated with small cell carcinoma of the lung, breast cancer, cutaneous malignant melanoma, and cervical cancer. The ocular condition may be accompanied by other neurologic, myopathic, or endocrinologic disorders. Melanoma-associated retinopathy³⁸ is thought to be a distinct entity because of the rapid onset of nyctalopia and antibodies to retinal bipolar cells. Some cases have been associated with circumcised areas of retinal pigment epithelial (RPE) atrophy. Treatment with systemic steroids or intravenous immunoglobulins has been limited and disappointing.³⁷^,³⁹

Bilateral diffuse uveal melanocytic proliferation (BDUMP), another paraneoplastic syndrome, is a proliferation of uveal melanocytes in response to a systemic malignancy such as ovarian, uterine, and lung cancer.^40–42 Clinically, the tumors extend over large areas with a thickness of 3 to 5 mm, associated with an overlying retinal detachment. The lesions lack a p53 protein that is commonly associated with uveal malignant melanoma.⁴¹ This lends support to the theory that the lesions in BDUMP are not malignant.

Other paraneoplastic syndromes such as in the opsoclonus-myoclonus syndrome, brain stem encephalitis, or Lambert-Eaton syndrome can affect oculomotor function. Alterations of the pupil, uveitis, and optic neuritis have also been described.

EVALUATION

The evaluation of patients with suspected metastatic cancer to the eye or ocular adnexa should include a comprehensive systemic survey for metastatic disease, as well as a complete ocular evaluation. Other useful tests may include intravenous fluorescein angiography, ultrasonography, fine needle aspiration biopsy, and wedge biopsy. The fluorescein angiogram is useful in distinguishing neoplasms that are hyperfluorescent in contrast to metastatic lesions that are hypofluorescent in the arterial phase of the angiogram⁸ (Fig. 7). The ultrasound may reveal a lesion of medium reflectivity without choroidal excavation.⁸

Fig. 7. Fundus photograph of the right eye (A) of a patient with breast cancer metastatic to the choroid temporal to the macula and associated with overlying fluid. The actual tumor is better appreciated in the full venous phase of the fluorescein angiogram (B).

Biopsies are useful in combination with special immunohistochemical stains to help localize the primary malignancy.⁴³Although magnetic resonance imaging (MRI), computed tomography (CT) scans, and positron emission tomography are not characteristic for these lesions, these imaging studies may reveal the extent of the tumors or other associated intracranial metastases.⁸^,³³

MANAGEMENT

Therapy for metastatic cancer to the eye and the adnexa is palliative. The indications for treatment include loss of vision by involvement or impending involvement of the fovea by the tumor or subretinal fluid; anterior chamber invasion; and orbital involvement associated with diplopia, pain, or optic neuropathy. If the metastatic tumor appears to be undergoing regression with chemotherapy (Fig. 8), then no other specific treatment is necessary. External beam radiotherapy is delivered to the entire posterior segment of the globe in a dose of 3000 to 4000 cGy over a 4- to 6-week period; regression occurs in 80% to 100% of patients.⁸^,⁴⁴

Fig. 8. Fundus photograph of the right eye of a patient with metastatic lung cancer to the choroid treated with radiotherapy. Note the characteristic pigment clumping (“leopard skin”) pattern.

Some solitary lesions have been treated with brachytherapy⁴⁵ by a one-time application of an episcleral plaque. Transpupillary thermotherapy has also been described.⁴⁶ Rarely localized resection for diagnostic purposes is performed. Rarely enucleation is necessary for intractable pain. Some authors have advocated the use of chemotherapy alone for the palliation of breast cancer metastatic to the eye.⁴⁷ The adverse effects of treatment include radiation dermatitis, conjunctivitis, keratopathy, cataracts, retinopathy, uveitis, and tumor necrosis with hemorrhage. Ptosis and ophthalmoplegia occur in patients treated with vincristine. Cataracts are described in association with allopurinol, busulfan, 5-fluorouracil, methotrexate, and mitotane. Mitotane and tamoxifen are associated with retinopathy. Carmustine, tamoxifen, and vincristine may result in optic neuropathy. Interferon is associated with retinal and choroidal ischemia.⁴⁸

PROGNOSIS

The prognosis for patients with metastatic cancer to the eye and orbit depends on the primary malignancy and the extent of metastatic disease in each patient. Generally the prognosis in patients with metastatic cancer to the eye or orbit is similar to a patient with any stage IV malignancy. Overall, the median survival from the time of ocular diagnosis to the time of death ranges from 7.4 to 10.5 months⁸^,¹⁰^,⁴⁹ and 13 to 15.6 months⁹^,³³^,⁴⁹ in patients with metastasis to the eye and orbit, respectively. In one series, the 1-year survival rate was 57% for patients with breast cancer and 20% for patients with lung cancer metastatic to the eye.⁸

SUMMARY

Several cancers are known to metastasize to the eye and adjacent structures. Cancer metastatic to the uvea is the most common intraocular malignancy. About one third of patients with cancer metastatic to the uvea or orbit had no known prior history of malignancy. The tumors that most commonly disseminate to the uvea and orbit include breast cancer in women and lung cancer in men. The primary malignancy was not discovered in about 17% of patients with uveal metastasis.

The evaluation of patients should include a comprehensive systemic survey for the primary malignancy and metastatic disease and a complete ocular examination. Therapy for metastatic cancer to the eye and orbit is palliative. Many such tumors are controlled with chemotherapy alone, but others that are threatening vision may require radiotherapy. The long-term prognosis for survival is poor in many patients with cancer metastatic to the ocular region.

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