Retinal Metastasis
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Disease
Retinal metastasis refers to the invasion of malignant cells into the neurosensory retina. While far less common than choroidal metastasis, its occurrence signifies advanced systemic malignancy and carries a poor overall prognosis. [1] Retinal metastases are often misdiagnosed due to their rarity and varied clinical presentations. [2] Metastatic tumors are the most common intraocular malignancy. In men, they most often come from the lung, and in women, from the breast. [3] Most intraocular metastases involve the choroid, but the vitreous, optic nerve, iris, and rarely the retina can also be affected. [1]Retinal metastases are very rare, making up less than 1% of ocular metastases. [4] This is likely because the inner and outer blood-retinal barriers prevent tumor cells from entering the retina easily. [5]The first reported case of retinal metastasis was described in 1879 by Schiess-Gemuseus and Roth in a patient with skin melanoma. [6] A review by Srivastava and Bergstrom in 2012 looked at 37 cases and found that the most common primary cancers were melanoma, lung cancer, and gastrointestinal adenocarcinomas. [7]
Etiology
Metastatic tumors reach the retina through hematogenous spread. Unlike the choroid, the retina is less frequently seeded because of the tight blood-retinal barrier[8], but certain aggressive cancers with high metastatic potential can breach these barriers. A 2012 review of 37 cases found that the most common primary source was cutaneous melanoma, followed by gastrointestinal, lung, and breast cancers. [9] Lung and breast cancers are the most common primary sources [1][4], but metastases have also been reported from gastrointestinal malignancies, renal cell carcinoma, cutaneous melanoma, and prostate cancer. [2][8]
Risk Factors
● Presence of a known systemic malignancy, particularly cutaneous melanoma, followed by gastrointestinal, lung, and breast cancers [9][10]
● Hematologic spread due to high-grade tumors[8]
● Immunosuppression (e.g., chemotherapy, organ transplantation)[11]
● Previous history of ocular involvement by other metastases (e.g., choroid) [1][4]
General Pathology
Histologically, metastatic tumor cells localize within the inner retinal layers, especially around the vascular arcades. [2] [8]Histopathology may show clusters of atypical malignant cells infiltrating the retina, sometimes associated with retinal hemorrhages, ischemia, and reactive gliosis [2][11]
Pathophysiology
To spread to distant parts of the body like the eye, cancer cells must first detach from the primary tumor, break through the basement membrane, and enter the blood or lymphatic system. [12][13][14][15]This process begins with epithelial-to-mesenchymal transition (EMT), a series of cellular changes that give tumor cells the ability to migrate. [16][17] During EMT, cancer cells alter their surface proteins, such as cadherins and integrins, and produce enzymes that break down the extracellular matrix, allowing them to move through surrounding tissues. [8][9][10][11][12][13][14][15] EMT also triggers the TGF pathway, which pushes cancer cells toward a stem cell-like state, helping them survive, replicate, and spread more easily. [18][19][20]
Since there are no lymphatic vessels inside the eye, tumor cells must travel through the bloodstream to reach ocular structures. Where metastatic cells end up within the eye depends on blood flow dynamics and specific molecular signals that support their growth. [21] [22][23]The choroid is affected more often than the retina because it has a denser vascular network. [24] [25]Tumor embolus size may also influence where the cells become lodged. [26] Once they arrive at a new site like the retina, tumor cells often undergo mesenchymal-to-epithelial transition, regaining the characteristics of the original tumor tissue. [27][28]
In contrast to the choroid, the inner and outer blood–retinal barriers are highly effective in healthy eyes, probably limiting the penetration of metastatic cells into this tissue. These barriers also explain why most of the RM are unifocal and unilateral. By contrast, choroidal metastases (although most often unifocal and unilateral) are more frequently multifocal and bilateral (15%–50% of cases) when compared with RM, as for instance in breast cancer. [29]
Primary Prevention
There are currently no targeted measures to prevent retinal metastasis specifically. [30] Control of the primary malignancy through early diagnosis, systemic chemotherapy, radiation therapy, and close oncologic follow-up remains critical.[6] Maintaining effective systemic cancer surveillance may reduce the likelihood of ocular metastasis. [8]
Diagnosis
History
Key aspects of history include:
● Onset and progression of visual complaints (gradual vs. sudden)
● History of systemic cancer diagnosis, type, stage, and current treatment status[8]
● Symptoms of systemic disease progression (weight loss, fatigue, organ dysfunction)[1]
● Recent infections or inflammatory episodes (to differentiate from infectious retinitis)
Patients with retinal metastasis often have a prior cancer diagnosis, but in rare cases, ocular findings may precede systemic recognition of the primary tumor. [11]
Physical Examination
A thorough examination involves:
● Best-corrected visual acuity testing
● Pupillary responses (looking for relative afferent pupillary defect)
● Slit-lamp biomicroscopy of the anterior segment and vitreous
● Dilated fundus examination to assess the posterior pole and periphery [4]
Signs
● Solitary or multiple creamy-white/yellowish retinal masses [1]
● Retinal thickening or edema near lesions
● Overlying or adjacent intraretinal hemorrhages [2]
● Vitreous cells or haze
● Exudative retinal detachment in severe cases
Lesions are often located near the vascular arcades but can appear anywhere in the retina. [8]
Symptoms
● Progressive decrease in visual acuity (ranging from 20/20 to light perception)
● Floaters due to vitreous cells or hemorrhage [8]
● Photopsias (flashing lights)
● Metamorphopsia (visual distortion)
● Occasionally, no visual symptoms, especially if lesions are peripheral
The degree of symptoms often correlates with lesion location and size. [8][12]
Clinical Diagnosis
Clinical suspicion is heightened when a retinal mass is identified in a patient with a known systemic malignancy.[5] The diagnosis integrates fundoscopic findings with imaging modalities (OCT, FA, B-scan ultrasonography) and systemic evaluation [4][8]
Diagnostic Procedures
Clinical evaluation and imaging techniques have improved the ability to detect and localize retinal metastases. [31]
Key imaging findings include:
● Infrared imaging: Speckled hyporeflectivity
● Fundus autofluorescence (FAF): Marked hypoautofluorescence in tumor areas
● Fluorescein angiography (FA):
○ Early-phase: Intratumoral vascularization
○ Late-phase: Progressive leakage
● Indocyanine green angiography (ICGA):
○ Early-phase: Hypofluorescence
○ Late-phase: Gradual filling of abnormal, dilated vessels [30]
Optical Coherence Tomography (OCT) is widely used to evaluate intraocular tumors, though its diagnostic role in retinal metastasis continues to evolve. [31] Characteristic OCT findings include:
● Hyperreflective intraretinal masses
● Subretinal fluid or exudation
● Localized infiltration of the inner retina [30]
● Example: Hyperreflective dots in a lung cancer metastasis case [31]
When to Consider Biopsy
Although imaging and a history of systemic cancer often suggest the diagnosis, a tissue biopsy may still be necessary to:
- Confirm metastasis and rule out mimicking inflammatory conditions
- Identify tumor cell type via cytology and immunohistochemistry
- Provide molecular information to guide systemic treatment
Evolution of Biopsy Techniques
● Pre-1979: Most cases diagnosed postmortem or after enucleation [5]
● 1988: First reported diagnosis via vitreous aspiration and trans-scleral biopsy [32]
● 1995–2000s: Development of:
○ Local tumor resection [33]
○ Trans-scleral chorioretinal biopsy [34]
● Recent: Advanced endoresection technique using pars plana vitrectomy (PPV) with:
○ Subretinal fluid injection
○ Diathermy
○ Bimanual retinectomy
○ Air-fluid exchange
○ Laser photocoagulation
○ Gas tamponade [24]
Preferred Biopsy Approach
Today, PPV is the standard method for obtaining intraocular samples:
● Requires an experienced cytopathologist for interpretation
● Immunohistochemistry helps confirm tumor type [35][36]
Note:
○ A negative biopsy doesn’t rule out metastasis, especially if confined to the retina [29]
○ If suspicion remains high, retinal or retinal-choroidal biopsy is considered [24][37]
○ RPE or choroid sampling is usually not needed
○ Fine-needle aspiration is discouraged if no visible mass is present due to low diagnostic yield
Systemic Evaluation
All patients with suspected retinal metastasis should undergo a full systemic workup, in collaboration with oncology:
● Search for a primary tumor or restage a known cancer
● Recommended investigations:
● Brain MRI
● Lumbar puncture (if CNS involvement is suspected)
● Whole-body imaging to assess metastatic spread
Laboratory Test
Laboratory tests are not diagnostic of retinal metastasis but support systemic evaluation. A complete blood count (CBC) can help detect anemia or thrombocytopenia, and a comprehensive metabolic panel (CMP) can reveal organ dysfunction. Tumor markers such as carcinoembryonic antigen (CEA) for colon cancer, CA 15-3 for breast cancer, and prostate-specific antigen (PSA) for prostate cancer may be useful depending on the suspected primary tumor. [8][10]PET-CT or full-body imaging is typically performed to assess metastatic spread. [8] In selected cases, ocular fluid cytology from anterior chamber taps or vitreous sampling can assist in confirming the diagnosis. [9]
Differential Diagnosis
● Choroidal metastasis: Deeper location; usually appears as a dome-shaped subretinal mass; OCT helps differentiate.[4]
● Primary intraocular lymphoma (PIOL): Can mimic retinal metastasis with vitreous cells; requires cytologic confirmation. [11][12]
● Infectious retinitis: CMV, toxoplasmosis, or fungal infections can mimic retinal infiltrates. Clinical context and lab tests aid differentiation. [13]
● Retinal vascular occlusion: Retinal hemorrhages and whitening may resemble metastasis; FA distinguishes ischemia from tumor. [8]
● Primary retinal tumors: Rare in adults, but retinal astrocytomas or retinoblastomas (in children) should be considered. [10]
Management
Management of retinal metastasis requires a multidisciplinary approach aimed to restore visual acuity and therefore improve the patients' quality of life for their remaining life span. There is a wide range of management options for intraocular metastases. The choice of treatment depends on several factors, including the extent, location, and origin of the metastasis, and the patient's general well-being and life prognosis.
General Treatment
● Systemic chemotherapy remains the mainstay of treatment for widespread disease. It is typically used to control systemic malignancy and may also result in regression of ocular metastasis. [38]
● Radiotherapy is one of the most frequently employed treatments, especially for lung and breast primary malignancy and their metastasis, as both are radiosensitive. [39]
Medical Therapy
Local management is generally considered with good systemic status and reasonable life expectancy. It is usually avoided in cases of poor general condition or limited life expectancy due to the invasiveness of procedures and associated risks; it is usually not used in poor systemic conditions and short life expectancy.
● External Beam Radiotherapy ( EBRT): delivered using x-rays, often with or without lens sparing techniques.
○ Effective in cases where retinal pigment epithelium (RPE) function remains intact, as it allows resolution of subretinal fluid and restoration of visual acuity.
○ External radiotherapy is time-consuming as most treatments are fractionated 15–20 times over 3 to 4 weeks [40]
● Proton beam radiotherapy: it has a high cost and comparable results to EBRT, delivered via linear accelerator [41]
○ The major advantage of EBRT is that it is widely available; hence, these treatments do not need to be performed in an Ocular Oncology center. Also, successful vision restoration has been reported in 86% of patients treated with this type of management. [42]
● Intravitreal chemotherapy:
○ Agents: intravitreal Melphalan injection (20-30 μg) and[43] Topotecan (20 μg)[44]
○ Technique: administered via the trans pars plana route with triple freeze-thaw cryotherapy at the injection site during needle withdrawal for prevention of extraocular seeding.
○ Treatment plan: administered in six cycles.
○ Lower doses were associated with a higher recurrence rate. However, retinal toxicity and complications were reported more in higher doses.
● Intravitreal anti-VEGF therapy: best suited for small, circumscribed metastases, and it is suitable in cases with exudative retinal detachment [45]
○ Agents: Bevacizumab (effective range dose 1.25-4 mg)[46]
○ Frequency: injections can be repeated every 4–6 weeks, depending on response.
● Photodynamic therapy has recently proved to be effective for shallow, well-circumscribed solitary retinal metastases and metastasis refractory to chemotherapy and radiotherapy. [46][47]
○ Protocols: using standard TAP [48] (treatment of age-related macular degeneration) protocol using 600 mW/cm2 delivered over 83 seconds, following intravenous verteporfin infusion.
○ The resolution of subretinal fluid and restoration of visual acuity is a rapid process that occurs over the next 6–8 weeks. However, the long-term benefit of this treatment remains unpublished.
○ Both anti-VEGF and PDT are suitable treatments for patients who are unable to withstand multiple daily visits to the hospital. Those can be done in a clinic. They showed their effectiveness in the decrease of exudative complications
● Internal plaque brachytherapy: suitable for small solitary lesions. [49]
○ Radioisotopes: iodine or ruthenium.
○ It can be completed in only a few days, which is helpful for patients with a limited life expectancy.
Medical Follow-up
Close follow-up is essential in patients with retinal metastasis to monitor both ocular treatment response and systemic disease progression. The frequency of follow-up depends on treatment modality and the ocular status of the patient. Assessment at each visit should include best corrected visual acuity (BCVA), intraocular pressure, fundus examination, and OCT to monitor tumor regression, subretinal fluid resolution, retinal or optic nerve toxicity.
Fundus photography and B-scan are needed for documentation.
Surgery
Surgical treatment may be considered in selected cases for palliative or vision-saving purposes, vitrectomy performed in limited cases such as:
● Non clearing vitreous hemorrhage secondary to tumor associated neovascularization.
● Tractional retinal detachment threatening macula
● Endolaser photocoagulation and cryotherapy should be done at sclerotomy sites to minimize tumor seeding risk.
● Enucleation: is reserved for patients with intractable pain due to neovascular glaucoma.
Surgical Follow-up
Close follow-up during the first month post-operative to monitor complications like retinal detachment, inflammation, or any new vitreous hemorrhage
Complications
Medical management is well tolerated, but it isn’t without complications.
● Intravitreal chemotherapy complications include:
○ Retinal toxicity, especially in high doses of Melphalan or Topotecan; manifested as retinal thinning , pigmentary changes, or macular atrophy
○ Cataract formation
○ Extraocular extension through the injection site.[43]
● Intravitreal anti-VEGF therapy:
○ Transient elevation of IOP
○ Inflammation or endophthalmitis
○ Minimal systemic absorption , though caution is advised in patients with cardiovascular risks.[45]
● Photodynamic therapy ( PDT):
○ RPE and choroidal ischemia.
○ Transient vision drop due to fluid shift or damage to the overlying retina
○ Photosensitive reaction[47][48]
● Radiotherapy:
○ Radiation retinopathy and optic neuropathy occur months post-treatment
○ Cataract formation, especially with lens-sparing protocols
○ Dry eyes
○ Scleral necrosis or thinning : rare
Prognosis
The improvement in visual acuity after treatment ranges from 20/20 to no light perception. Systemic prognosis is guarded with an average survival of 10 months (range 2 weeks to 5 years) following diagnosis of retinal metastasis [10], the repertoire of treatment options for metastatic disease to the eye is increasing which helped patients with metastatic disease to live longer, owing to improvements in systemic treatments, such as immune modulatory drugs and targeted chemotherapy of cancer.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Shields CL, Shields JA, Gross NE, Schwartz GP, Lally SE. Survey of 520 Eyes with Uveal Metastases. Ophthalmology. 1997;104(8):1265-1276. doi:10.1016/S0161-6420(97)30155-6
- ↑ 2.0 2.1 2.2 2.3 2.4 Odashiro AN, Maloney SC, Fernandes BF, et al. Retinal Metastasis from Lung Cancer: A Clinicopathological Report. Retina. 2006;26(9):1105-1108. doi:10.1097/01.iae.0000247152.73497.3d
- ↑ Redmond KJ, Wharam-Jr MD, Schachat AP. Choroidal metastases. In: Retina, vol. 3. 5th ed. St. Louis: Mosby; 2012. p. 2324–9.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Shields CL, McMahon JF, Atalay HT, Hasanreisoglu M, Shields JA. Retinal metastasis from systemic cancer in 8 cases. JAMA Ophthalmol. 2014;132(11):1303–8.
- ↑ 5.0 5.1 5.2 Mathis T, Jardel P, Loria O, et al. New concepts in the diagnosis and management of choroidal metastases. Prog Retin Eye Res. 2019;68:144–76.
- ↑ 6.0 6.1 Uhler EM. Metastatic malignant melanoma of the retina. Am J Ophthalmol. 1940;23:158–62.
- ↑ Srivastava SK, Bergstrom C. Retinal metastases. In: Retina, vol. 3. 5th ed. St. Louis: Mosby; 2012. p. 2185–95.
- ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 Gündüz K, Shields CL, Shields JA. Retinal Metastasis from Systemic Cancer. Int Ophthalmol Clin. 2007;47(3):69-78. doi:10.1097/IIO.0b013e3180591ed6
- ↑ 9.0 9.1 9.2 9.3 Srivastava SK, Bergstrom C. Retinal metastases. In: Retina, vol. 3.5th ed. St. Louis: Mosby; 2012. p. 2185–95.
- ↑ 10.0 10.1 10.2 10.3 10.4 A.D. Singh, B. Damato (eds.), Clinical Ophthalmic Oncology, 91 DOI 10.1007/978-3-642-39489-8_8, © Springer-Verlag Berlin Heidelberg 2014
- ↑ 11.0 11.1 11.2 11.3 11.4 Arepalli S, Kaliki S, Shields CL. Choroidal Metastases: Origin, Features, and Therapy. Indian J Ophthalmol.2015;63(2):122-127. doi:10.4103/0301-4738.156918
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- ↑ Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18(2):128–34
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- ↑ Scheel C, Eaton EN, Li SH, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011;145(6):926–40.
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- ↑ 24.0 24.1 24.2 Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases. Arch Ophthalmol. 1974;92(4):276–86.
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- ↑ Ferry AP. Metastatic carcinoma of the eye and ocular adnexa. Int Ophthalmol Clin. 1967;7(3):615–58.
- ↑ Chao YL, Shepard CR, Wells A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer. 2010;9:179.
- ↑ Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED. Mesenchymal-to-epithelial transition facilitates blad-der cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 2006;66(23):11271–8.
- ↑ 29.0 29.1 Thariat J, Boudin L, Loria O, Nguyen AM, Kodjikian L, Mathis T. How to Manage a Patient with Ocular Metastases? Biomedicines. 2022 Nov 25;10(12):3044. doi: 10.3390/biomedicines10123044. PMID: 36551800; PMCID: PMC9775125.
- ↑ 30.0 30.1 30.2 Gascon P, Matet A, Gualino D, Nguyen AM, Papegaey M, Levy N, Arnould T, Kodjikian L, Mathis T. Clinical features of retinal metastases: new cases integrated in a systematic review of the lit-erature. Retina. 2022;42(7):1370–83.
- ↑ 31.0 31.1 31.2 Yalcinbayir O, Gelisken O, Sen F, Yasar S, Alizadegan F. Retinal metastasis from the squamous cell carcinoma of the lung: a case presentation. Retin Cases Brief Rep. 2019;13(2):141–4.
- ↑ Eagle-Jr RC. Carcinomatous retinitis. Hilton Head, SC: Eastern Ophthalmic Pathology Society; 1988.
- ↑ Balestrazzi E, Blasi MA, Marullo M, Greco IM, Spadea L. Local excision of retinal metastasis from cutaneous melanoma. Eur J Ophthalmol. 1995;5(3):149–54.
- ↑ Spadea L, Bisti S, Colucci S, Balestrazzi E. Normal EOG values in intraretinal metastasis from cutaneous melanoma: a case report. Doc Ophthalmol. 1998;96(4):305–9.
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- ↑ Mruthyunjaya P, Jumper JM, McCallum R, Patel DJ, Cox TA, Jaffe GJ. Diagnostic yield of vitrectomy in eyes with suspected posterior segment infection or malignancy. Ophthalmology. 2002;109(6):1123–9.
- ↑ Coassin M, Ebrahimi KB, O’Brien JM, Stewart JM. Optical coher-ence tomography for retinal metastasis with unknown primary tumor. Ophthalmic Surg Lasers Imaging. 201
- ↑ Shah S.U., Mashayekhi A., Shields C.L., Walia H.S., Hubbard G.B., Zhang J., Shields J.A. Uveal Metastasis from Lung Cancer: Clinical Features, Treatment, and Outcome in 194 Patients. Ophthalmology. 2014
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- ↑ Rundle P, Rennie I. Photodynamic therapy for solitary retinal metastasis from breast carcinoma. Eye (Lond) 2006
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