Vitreous Metastasis

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Article initiated by:
Hashem Abu Serhan
All contributors:
Abdullah Ahmed, Cameron Reinisch, M.D., Savannah Hensley, Sameeha Z. Shweiki, Oase Sbei, Ayman G Elnahry, Hashem Abu Serhan
Assigned editor:
Review:
Assigned status Update Pending
.


Overview

Metastatic cancers that involve different parts of the eye are rare and most often indicate a poor prognosis for the patient, with a 5-year survival rate of 24%. [1] The choroid is the most common site for metastasis in adults due to its dense vascular supply. It is estimated that approximately 90% of intraocular metastases involve the choroid, followed by the iris (8%), ciliary body (2%), and then finally structures such as the retina and vitreous (<1-4%). [1] [2] Advanced cutaneous melanoma has been consistently documented to involve metastasis to the vitreous, which is extremely rare and more so in an isolated setting.

Disease

Vitreous metastasis is a rare occurrence (1–4% of ocular metastases), most frequently seen in patients with advanced cutaneous melanoma undergoing treatment with checkpoint inhibitors like ipilimumab, nivolumab, and pembrolizumab. The pathogenesis remains unclear. The clinical presentation can be unilateral or bilateral, with a partially asymmetric appearance that includes floaters, decreased visual acuity, and sometimes pain if neovascular glaucoma develops. [3]

Etiology/Risk Factors

Vitreous metastasis most commonly arises from advanced cutaneous melanoma or breast cancer. [4][5] Risk factors mirror those of the primary malignancy and should be evaluated by the ophthalmologist or referring physician if identified in the patient’s history.

Cutaneous Melanoma: Genetic mutations such as CDKN2A and BRAF,  family history, and prolonged history of UV exposure. [6] Patients with cutaneous melanoma often undergo treatments that involve checkpoint inhibitors. One checkpoint inhibitor, in particular, has been consistently noted in the literature to be associated with vitreous metastasis. Ipilimumab has been reported in multiple case reports in patients with cutaneous melanoma with metastasis to the vitreous cavity.[7] Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), an immune checkpoint molecule expressed on activated T cells and regulatory T cells.[8]

Breast Cancer: Mutations in BRCA1 and BRCA2, hormonal abnormalities (such as early menarche or late menopause), and lifestyle factors like obesity and alcohol use. If a patient presents with these risk factors, vitreous metastasis should be considered in the differential diagnosis for a potential masquerade syndrome or possible sequelae.[9]

General Pathology/Pathophysiology

The pathogenesis of isolated vitreous metastasis remains poorly understood, likely owing to delayed diagnosis, which often occurs only after metastasis has already developed. To date, only one documented case of cutaneous melanoma has reported isolated vitreous metastasis at a very early stage, with comprehensive longitudinal documentation of disease progression.[3]

Several theories have been proposed to explain the mechanism of vitreous metastasis. One hypothesis suggests that malignant cells migrate through the retinal vasculature into the retrohyaloid space. Another theory posits that tumor cells spread following a vitreous hemorrhage originating from retinal vessels. A third possibility is direct malignant infiltration via the optic nerve.[10][3]

In cases where malignant cells are present in both the vitreous and adjacent structures, such as the ciliary body, retina, or optic nerve, the spread is believed to originate from these surrounding tissues.[11] [12] [13] [14]

Checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1 therapies used in treating metastatic cutaneous melanoma, have been associated with an increased rate of ocular metastasis. By enhancing immune recognition of malignant cells, these agents may increase immune activity in normally immune-privileged sites like the eye.[15] Immune-related adverse events, including drug-induced ocular inflammation, have also been reported.[16] It is theorized that this immune activation creates a microenvironment and blood-retina barrier more permissive to vitreous metastasis. Additionally, the immune-privileged nature of the vitreous may allow metastatic cells to go undetected until immune activation from checkpoint inhibitors triggers inflammation, leading to symptoms and subsequent investigation unmasking underlying metastasis.[17]

Primary Prevention

Primary prevention of vitreous metastasis involves the early detection and treatment of primary cancers. Regular follow-up of metastatic disease and patient education about the signs and symptoms of visual impairment is crucial. Beyond the management of the primary malignancy, there are no specific preventive measures for vitreous metastasis.[18] [19]

Diagnosis

History

Patients typically present with a chief complaint of either unilateral or bilateral floaters or decreased vision. Patients may have a known history of underlying malignancy, most commonly cutaneous melanoma or breast carcinoma.

Physical Examination

Slit lamp exam may exhibit diffuse or localized vitreous opacities.[18] Opacities may appear as clumps or strands, with or without pigmentation. [18] [15] Generalized vitreous haze is a common finding. Presentation with neovascular glaucoma and retinal detachment has been reported in cases of cutaneous melanoma metastasized to the vitreous.[3] [15]

Signs

Signs of vitreous metastasis include vitreous opacities, debris or haze, and decreased visual acuity. Elevated intraocular pressure in the setting of neovascular glaucoma, more commonly associated with cutaneous melanoma.[17]

Symptoms

Patients often report floaters and decreased visual acuity secondary to opacification of the vitreous. In patients with neovascular glaucoma, patients may present with pain. Presentation with retinal detachment has also been reported, and may present with flashing light, floaters, or visual field loss. [17]

Clinical Diagnosis

In the absence of a known primary malignancy, diagnosing vitreous metastasis can be challenging, particularly given its rarity. Vitreous metastasis often presents with vague symptoms such as floaters and blurred vision, along with vitreous haze or opacities on examination, findings that overlap with a range of infectious, inflammatory, and malignant conditions. A thorough history, physical examination, ophthalmic imaging, and laboratory work-up are essential.

Intraocular malignancy may be mistaken for idiopathic uveitis or vitritis, given their common exam findings. Delayed diagnosis may occur when anti-inflammatory therapy is initiated for presumed idiopathic uveitis or vitritis, as initial improvement in inflammation can mask the underlying disease.[20] Diagnostic vitrectomy may be required for definitive diagnosis.

In patients with a known underlying malignancy and systemic metastasis, vitreous opacities should raise suspicion for vitreous metastasis, particularly in cases of cutaneous melanoma and breast carcinoma. In individuals with metastatic primary cutaneous melanoma and pigmented cells in the vitreous, a presumed diagnosis of vitreous metastasis can be made. [3]

Diagnostic Procedures

B-Scan

  • May present with diffuse or focal hyperechoic vitreous opacities. Subhyaloid opacities have also been observed in metastasis of cutaneous melanoma.[21]

Optical Coherence Tomography (OCT)

  • OCT has shown utility in identifying vitreous opacities, which may appear as hyper-reflective areas within the vitreous.[21] Furthermore, it is used to assess for the presence of retinal pigment epithelial (RPE) abnormalities common in metastatic conditions.  
  • The presence of retinal metastasis may be identified by the presence of an elevated retinal mass, retinal infiltrates, or the presence of a hyperreflective lesion. [22]

Angiography

  • Fluorescein or indocyanine green angiography may be used to assess for retinal or choroidal metastasis or primary tumors.[23]  In cases of retinal involvement, fluorescein angiography typically demonstrates early hypofluorescence with mid-to-late hyperfluorescence and intrinsic vascularity.[22]

Fine-Needle Aspiration

  • Fine needle aspiration is a minimally invasive and accessible means of vitreous sampling. To reduce the risk of inadequate sampling or non-diagnostic results, it is recommended to have a cytopathologist present at the time of biopsy to ensure the sample is adequate.[24] [3]

Diagnostic Vitrectomy

  • In cases of vitreous opacities or vitritis of uncertain etiology, or where fine needle aspiration and biopsy are non-diagnostic, full diagnostic vitrectomy with core biopsy may be required to identify neoplasia.[25]

Laboratory Test

Cytology

  • In cases of vitreous metastasis, cytology typically demonstrates malignant cells with features of the primary lesion. [26] In cutaneous melanoma, this is typically a high nuclear to cytoplasm ratio and the presence of melanin granules.[27]

Immunohistochemistry

  • Cutaneous melanoma metastatic to the vitreous will often present with positive immunostaining for BRAFV600E, and has shown utility as a distinguishing feature from primary uveal melanoma. [28]
  • Cytokeratin positivity is consistent with metastatic breast carcinoma. [26]
  • Specific IHC may also be performed based on the primary tumor.

Polymerase chain reaction may be used to amplify and detect tumor-specific mRNA or DNA abnormalities with high sensitivity. It may also be utilized in cases of uveitis or vitritis of unknown etiology to rule out infectious causes.[29]

  • In cases of cutaneous melanoma, BRAF mutations may be detected via PCR; however, immunohistochemical methods of determining BRAF status are considered non-superior to PCR and more cost-effective.[30]
  • Uveal melanoma is associated with GNAQ and GNA11 mutations; recent studies have also detected  PLCB4, CYSLTR2, BAP1, SF3B1, and EIF1AX mutations.[31]
  • The use of reverse-transcriptase PCR (RT-PCR) has been used to detect cytokeratin-19 (CK19) has been used to detect circulating tumor cells as a prognostic marker in patients with metastatic breast cancer.[32] There is no current evidence demonstrating its use in the analysis of vitreous biopsy.
  • The presence of the MYD88 mutation is consistent with primary vitreoretinal lymphoma.[33] PCR quantification of interleukin-10 and interleukin-6 with an IL-10:IL-6 > 1 is indicative of VRL.[34]
  • In cases of uveitis or vitritis of unknown etiology, PCR can be used to rule out infectious agents, including CMV, VZV, HSV, EBV, HTLV-1, and Toxoplasmosis, and may demonstrate increased sensitivity over serologic studies.[29][35]

Additional Testing

  • Additional analysis of vitreous sampling may include tumor-specific Next-Gen sequencing. [36]
  • Serologic studies may be required to assess for the presence of underlying autoimmune,  inflammatory, or infectious conditions leading to the patient’s presentation.

Differential Diagnosis

The differential diagnosis for vitreous metastasis includes conditions that commonly present with intraocular inflammation, vitreous opacities, or vitreous haze. In individuals with underlying risk factors, suspicion should be raised for metastasis.[37] [38]


Malignant

  • Primary vitreoretinal lymphoma

Infectious

  • Tuberculosis
  • Syphilis
  • Cytomegalovirus
  • Herpes Simplex Virus
  • Varicella Zoster Virus
  • Epstein-Barr Virus
  • Toxoplasmosis

Autoimmune

  • Idiopathic
  • Behcets
  • Sarcoidosis
  • Other systemic autoimmune diseases

Other

  • Tobacco dust (Shafer’s sign)
  • Vitreous hemorrhage
  • Endophthalmitis

Management

General Treatment

The management of vitreous metastasis requires a multidisciplinary approach involving ocular oncologists, medical oncologists, and radiation oncologists.[39] Given that vitreous metastasis typically occurs in the setting of advanced systemic cancer, treatment goals are often palliative.[1] The primary focus is on:

1.    Confirming the diagnosis through appropriate investigations, including diagnostic vitrectomy when necessary

2.    Preserving functional vision and controlling ocular symptoms

3.    Coordinating with systemic therapy for the underlying malignancy

4.    Improving the patient’s quality of life [39] [21]

Local treatment specifically targeting the eye is typically indicated when the ocular disease threatens vision or when systemic therapy alone is insufficient to control the metastasis.[39] Treatment strategies must be carefully tailored to the individual’s overall prognosis, performance status, and quality of life considerations. Vitreous metastases comprise less than 1-4% of all ocular metastases and represent a unique therapeutic challenge due to their location within an immune-privileged site.[1] [40]

Medical Therapy

Systemic Therapy

Systemic therapy remains foundational in treating vitreous metastasis as part of metastatic disease management:

·  Systemic chemotherapy achieves tumor regression in approximately 68% of ocular metastasis cases.[39] Regimens are tailored to the primary tumor type (e.g., docetaxel or paclitaxel for breast cancer).

·  Hormonal therapy may be beneficial in hormone-sensitive cancers, particularly breast cancer.[41]

·  Immunotherapy, especially checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4), has shown promising results for metastatic melanoma and lung cancer with vitreous involvement.[21] [17] Response rates approach 50% for immunogenic tumors but are lower (≤15%) for “cold” tumors. [39]

·  Targeted therapies for specific molecular alterations (e.g., trastuzumab and pertuzumab for HER2-positive breast cancer, BRAF/MEK inhibitors for BRAF-mutated melanoma) can achieve response rates up to 70%, with 92% of patients maintaining stable or improved vision.[39]

A unique relationship exists between checkpoint inhibitor therapy and vitreous metastasis, particularly in cutaneous melanoma. Most patients (8/11) with vitreous metastasis from cutaneous melanoma had received checkpoint inhibitors during their treatment course.[21] Two mechanisms may explain this relationship: (1) checkpoint inhibitors may “unmask” previously subclinical disease through immune activation that modifies the blood-retinal barrier, or (2) prolonged survival from effective immunotherapy may allow more time for metastasis to unusual sites like the vitreous.[17] [42]

The blood-retinal barrier may limit the effectiveness of some systemic agents in reaching and controlling metastases within the vitreous, necessitating consideration of local therapy.[21] [42]

Local Therapy

Intravitreal Chemotherapy

Intravitreal chemotherapy has emerged as an important local treatment modality, particularly for cases originating from melanoma and lymphoma.[21] This approach delivers high local drug concentrations while minimizing systemic exposure. Commonly used agents include:

·  Melphalan: An alkylating agent frequently employed for vitreous metastasis from melanoma, with dosages ranging from 20-30 μg in 0.05-0.075 mL.[17] [42] [43] In melanoma vitreous metastases treated with intravitreal melphalan, complete response occurred in 3/5 cases with monthly injections.[42] Localized retinal pigmentary changes at the injection site are seen in about two-thirds of treated eyes.[43]

·  Methotrexate: A dihydrofolate reductase inhibitor effective against lymphoma and sometimes used for other vitreous metastases, typically dosed at 400-500 μg in 0.10 mL.[21] [42] Intravitreal methotrexate for cutaneous melanoma vitreal metastasis, when melphalan was unavailable, achieved stabilization but not complete resolution of disease.[42]

1-2 weekly injections are often recommended initially, with the frequency adjusted based on treatment response.[42] The technique for intravitreal injection in metastatic disease should include careful selection of a tumor-free injection site and measures to prevent extraocular tumor spread, such as triple freeze-thaw cryotherapy at the injection site.[42]

·  Bevacizumab: An anti-VEGF agent that may reduce subretinal fluid and potentially control tumor growth by inhibiting angiogenesis, administered at 1.25 mg in 0.05 mL.[44] A case of hepatocholangiocarcinoma with retinal and vitreous metastasis treated with intravitreal bevacizumab showed improved vision from 6/24 to 6/7.5 at two months post-procedure.[45]

Radiation Therapy

Radiation therapy is another established local treatment option:

·  External beam radiation therapy (EBRT) typically delivers 30-40 Gray (Gy) in 10-20 fractions over several weeks.[17] EBRT (30-40 Gy) was used in 6 of 14 eyes with vitreous metastasis from cutaneous melanoma, with good tumor control.[17] EBRT achieves tumor control in approximately 90-94% of ocular metastasis cases.[15] [39]

·  Plaque radiotherapy involves placing a radioactive plaque on the surface of the eye near the tumor. While effective for localized choroidal metastases, its applicability to diffuse vitreous metastasis may be limited.[41] Brachytherapy has been used in some cases of focal intraocular metastasis with good local control.[15]

Radiation therapy can improve vision in some patients but carries risks of complications, including radiation retinopathy, papillopathy, cataract formation, and neovascular glaucoma.[18]

Medical Follow-up

Regular follow-up examinations are essential for patients with vitreous metastasis to assess treatment response and monitor for disease progression or recurrence.[41] Follow-up protocols typically include:

·  Frequency: Initial follow-up at 1 day and 1 week post-treatment, then monthly for the first 3-6 months.[39] More frequent visits may be necessary for symptomatic or progressive disease.

·  Ophthalmic assessment: Each visit should include visual acuity testing, intraocular pressure measurement, slit-lamp examination, and dilated fundus examination.[39]

·  Imaging studies: Optical coherence tomography (OCT), B-scan ultrasonography, and wide-field photography should be performed periodically to monitor structural changes and track disease status.[39] [46]

·  Coordination with oncology: Given the systemic nature of the disease, coordination with oncology services for monitoring the primary cancer and other metastatic sites is crucial.[39]

For patients undergoing intravitreal chemotherapy, ongoing monitoring is necessary to assess treatment response, detect recurrence, and identify potential ocular side effects.[21] The specific frequency and type of monitoring should be individualized based on the patient’s treatment regimen and disease status.[39]

Surgery

Diagnostic and Therapeutic Vitrectomy

Pars plana vitrectomy (PPV) serves both diagnostic and therapeutic purposes in vitreous metastasis management:

·  Diagnostic vitrectomy is often crucial for confirming the diagnosis through vitreous biopsy and cytological analysis.[22] [46] Wang et al. reported that pathological diagnosis was obtained in 70.5% of eyes with retinal/vitreous metastasis, with PPV with vitreous/retinal biopsy being the most common method (53.5%).[22]

·  Therapeutic vitrectomy removes vitreous opacities caused by metastatic cells, potentially improving visual acuity.[46] Ashkenazy et al. recommend PPV for both diagnosis and debulking of tumor cells as the first step in management, followed by periodic intravitreal chemotherapy.[42]

·  Surgical technique: Gündüz and Mirzayev describe using standard 23- or 25-gauge pars plana vitrectomy. They recommend treatment of sclerotomies with double or triple freeze-thaw cryotherapy to prevent extraocular extension.[42] [47] For cases with suspected retinal involvement, the same authors note that advanced techniques may be necessary, including chandelier illumination for bimanual manipulation, focal retinal detachment creation with a 41-gauge subretinal cannula, and diathermy demarcation of the biopsy site.[47]

·  Biopsy techniques: Gündüz and Mirzayev describe several approaches to obtain diagnostic material, including FNAB (transvitreal or transscleral), transretinal biopsy via PPV, and partial lamellar sclerouvectomy.[47] The choice of technique depends on tumor location, size, and associated findings.

In severe cases with painful blind eyes or extensive disease with complications such as neovascular glaucoma, enucleation (surgical removal of the eye) may be considered as a palliative measure.[42]

Surgical Follow-up

Following vitrectomy for vitreous metastasis, appropriate post-operative care is critical:

·  Medication: Patients typically receive eye drops, including antibiotics to prevent infection, steroids to reduce inflammation, and cycloplegics to dilate the pupil and prevent adhesions.[43]

·  Initial follow-up: First post-operative visit typically occurs within 24-48 hours, with subsequent visits at 1 week and then monthly for 3-6 months.[39]

·  Assessment parameters: Each follow-up visit should include visual acuity testing, intraocular pressure measurement, and a thorough slit-lamp and fundus examination to evaluate the vitreous and retina for signs of recurrence or complications.[39] [47]

·  Imaging: OCT, B-scan ultrasonography, and wide-field photography can document the post-operative status and track any changes. [46]

For patients who undergo plaque brachytherapy, tumor response is typically evaluated at 3 months, assessing for flattening and resorption of exudative signs via imaging studies such as ultrasonography and OCT.[39]

Complications

Vitreous metastasis and its treatments can lead to various complications:

Disease-Related Complications

Vitreous metastasis can cause a spectrum of visual impairments ranging from mild blurriness to profound vision loss, depending on the extent and location of metastatic involvement.[39] Wang et al. reported final best-corrected visual acuity of ≤20/200 in 66.7% of eyes with retinal/vitreous metastasis.[22] Secondary glaucoma is particularly common, with Ashkenazy et al. reporting elevated intraocular pressure in 4 of 5 cases (80%) of vitreous metastasis from cutaneous melanoma.[42] Wang et al. found that retinal detachment can occur in 11.1-28.6% of cases.[42] [22]

Treatment-Related Complications

·  Radiation-related complications: Radiation therapy, while effective, can lead to several ocular complications, including radiation retinopathy and papillopathy, cataract formation, dry eye syndrome, and neovascular glaucoma, according to Shields et al.[1] Thariat et al. reported these complications in approximately 8% of cases treated with external beam radiation therapy.[39]

·  Intravitreal chemotherapy complications: Local delivery of chemotherapeutic agents can result in several ocular side effects. Yousef et al. reported that retinal toxicity is the most common side effect of intravitreal melphalan, seen in 62-67% of cases, typically manifesting as localized retinal pigmentary changes confined to the injection site.[43] The same study noted cataract formation in 12% of cases following intravitreal melphalan.

·  Surgery-related complications: Vitrectomy procedures carry their risks. Wang et al. reported vitreous hemorrhage in 42.7% of cases undergoing diagnostic vitrectomy for retinal/vitreous metastasis.[22] Other potential complications include endophthalmitis, retinal detachment, cataract progression, and post-vitrectomy macular edema.[47]

Prognosis

The prognosis for patients with vitreous metastasis is generally guarded, as it often signifies advanced systemic cancer.[40] A median survival of 11 months after diagnosis of retinal/vitreous metastasis was found in a systematic review.[22] Several factors influence outcomes:

Visual Prognosis

With appropriate local treatment, short-term visual improvement can be achieved in some cases of retinal/vitreous metastasis, though the visual prognosis remains poor overall. In a study conducted by Wang et al., among participants who received local treatment for retinal/vitreous metastasis, the final visual acuity turned out to be ≤20/200 in 66.7% of eyes.[22] The response to both systemic and local treatments plays a vital role in preserving functional vision.[48]

Systemic Prognosis

The systemic prognosis for vitreous metastasis is also limited, with a median overall survival of approximately 11 months after diagnosis.[22] Mortality rates are high, with one study reporting mortality in 56.8% of patients during follow-up.[22] The primary source of the cancer significantly impacts the outcome; for instance, vitreous metastasis originating from lung and gastrointestinal cancers typically has a more challenging trajectory compared to those from breast cancer.[22] Furthermore, there appears to be an association between vitreous metastasis and central nervous system (CNS) metastasis, as observed in a series where 6 out of 11 patients (55%) with vitreous metastasis from cutaneous melanoma also had CNS involvement.[41]

Prognostic Factors

Several factors influence the prognosis of vitreous metastasis, including the type and histology of the primary cancer, the extent of systemic disease, the patient’s response to systemic therapy, their overall performance status, and the time interval between the diagnosis of the primary cancer and the development of metastasis.[21] Furthermore, there is a notable association between vitreous metastasis and central nervous system (CNS) metastasis, particularly in cases originating from cutaneous melanoma, where CNS metastasis occurred in 6 of 11 patients (55%) in one study.[15] This association highlights the critical need for neuroimaging as part of the diagnostic evaluation for patients presenting with vitreous metastasis.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Shields CL, Kalafatis NE, Gad M, et al. Metastatic tumours to the eye. Review of metastasis to the iris, ciliary body, choroid, retina, optic disc, vitreous, and/or lens capsule. Eye (Lond). 2023;37(5):809-814. doi:10.1038/s41433-022-02015-4
  2. ↑ 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)30148-1
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Jaissle, Gesine B., et al. A Case of Cutaneous Melanoma Metastatic to the Vitreous Cavity: Possible Pathomechanism and Review of the Literature. Nov. 2006, https://doi.org/10.1007/s00417-006-0469-1
  4. ↑ Jaissle GB, Szurman P, Rohrbach JM, Gelisken F, Bartz-Schmidt KU. A case of cutaneous melanoma metastatic to the vitreous cavity: possible pathomechanism and review of the literature. Graefes Arch Clin Exp Ophthalmol. 2007;245(5):733-740. doi:10.1007/s00417-006-0469-1
  5. ↑ Zaldivar RA, Michels M, Grant KF, Clark WL, Grossniklaus HE. Metastatic breast carcinoma to the vitreous. Retina. 2004;24(2):226-230. doi:10.1097/00006982-200404000-00006
  6. ↑ Goggins W, Gao W, Tsao H. Association between female breast cancer and cutaneous melanoma. Int J Cancer. 2004;111(5):792-794. doi:10.1002/ijc.20322
  7. ↑ Kellermann N, Maier M, Feucht N. Glaskörpermetastase eines malignen Melanoms der Haut unter Ipilimumab [Vitreous metastasis of malignant cutaneous melanoma during treatment with ipilimumab]. Ophthalmologe. 2017;114(2):163-166. doi:10.1007/s00347-016-0271-3
  8. ↑ Graziani G, Tentori L, Navarra P. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res. 2012;65(1):9-22. doi:10.1016/j.phrs.2011.09.002
  9. ↑ Nelson HD, Zakher B, Cantor A, et al. Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med. 2012;156(9):635-648. doi:10.7326/0003-4819-156-9-201205010-00006
  10. ↑ Manusow JS, Khoja L, Pesin N, Joshua AM, Mandelcorn ED. Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma. J Immunother Cancer. 2014 Dec 16;2(1):41. doi: 10.1186/s40425-014-0041-1
  11. ↑ Bowman CB, Guber D, Brown III CH, Curtin VT (1994) Cutaneous malignant melanoma with diffuse intraocular metastases. Arch Ophthalmol 112:1213–1216
  12. ↑ Pollock SC, Awh CC, Dutton JJ (1991) Cutaneous melanoma metastatic to the optic disc and vitreous. Arch Ophthalmol 109:1352–1354
  13. ↑ Robertson DM, Wilkinson CP, Murray JL, Gordy DD. (1981) Metastatic tumor to the retina and the vitreous cavity from primary melanoma of the skin. Treatment with systemic and subconjunctival chemotherapy. Ophthalmology. 88:1296–1301
  14. ↑ Soheilian M, Mirbabai F, Shahsavari M, Parvin M, Manieei F (2002). Metastatic cutaneous melanoma to the vitreous cavity masquerading as intermediate uveitis. Eur J Ophthalmol 12:324–327.
  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 Francis JH, Berry D, Abramson DH, et al. Intravitreous Cutaneous Metastatic Melanoma in the Era of Checkpoint Inhibition: Unmasking and Masquerading. Ophthalmology. 2020;127(2):240-248. doi:10.1016/j.ophtha.2019.09.018
  16. ↑ Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint Inhibitor Immune Therapy: Systemic Indications and Ophthalmic Side Effects. Retina. 2018;38(6):1063-1078. doi:10.1097/IAE.0000000000002181
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Francis JH, Berry D, Abramson DH, et al. Intravitreous Cutaneous Metastatic Melanoma in the Era of Checkpoint Inhibition: Unmasking and Masquerading. Ophthalmology. 2020;127(2):240-248. doi:10.1016/j.ophtha.2019.09.018
  18. ↑ 18.0 18.1 18.2 18.3 Shields CL, Kalafatis NE, Gad M, et al. Metastatic tumours to the eye. Review of metastasis to the iris, ciliary body, choroid, retina, optic disc, vitreous, and/or lens capsule. Eye (Lond). 2023;37(5):809-814. doi:10.1038/s41433-022-02015-4
  19. ↑ 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)30148-1
  20. ↑ Rothova A, Ooijman F, Kerkhoff F, Van Der Lelij A, Lokhorst HM. Uveitis masquerade syndromes. Ophthalmology. 2001;108(2):386-399. doi:10.1016/s0161-6420(00)00499-1
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 21.9 Ashkenazy N, Harbour JW, Dubovy SR, et al. Vitreous metastasis from cutaneous melanoma: diagnosis and management. Arq Bras Oftalmol. 2023;87(5):e20220215. Published 2023 Apr 17. doi:10.5935/0004-2749.2022-0215
  22. ↑ 22.00 22.01 22.02 22.03 22.04 22.05 22.06 22.07 22.08 22.09 22.10 22.11 Wang LU, Hsieh TH, Chen FT, Chen YJ, Wang JK, Hsu YR. Insights into Retinal Metastasis from Systemic Carcinoma: A Systematic Review of Clinical and Multimodal Imaging Characteristics. Journal of Clinical Medicine. 2024;13(20):6037. doi:10.3390/jcm13206037
  23. ↑ Mathis T, Jardel P, Loria O, et al. New concepts in the diagnosis and management of choroidal metastases. Prog Retin Eye Res. 2019;68:144-176. doi:10.1016/j.preteyeres.2018.09.003
  24. ↑ Eide N, Walaas L. Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review. Acta Ophthalmol. 2009;87(6):588-601. doi:10.1111/j.1755-3768.2009.01637.x
  25. ↑ Patel DS, Khan IJ, Zayed MG, et al. Full Diagnostic Vitrectomy With Posterior Vitreous Detachment Induction for the Diagnosis of Vitritis due to Uncertain Etiology. Retina. 2019;39(10):1872-1879. doi:10.1097/IAE.0000000000002243
  26. ↑ 26.0 26.1 Zaldivar RA, Michels M, Grant KF, Clark WL, Grossniklaus HE. Metastatic breast carcinoma to the vitreous. Retina. 2004;24(2):226-230. doi:10.1097/00006982-200404000-00006
  27. ↑ Spraul CW, Martin DF, Hagler WS, Grossniklaus HE. Cytology of metastatic cutaneous melanoma to the vitreous and retina. Retina. 1996;16(4):328-332. doi:10.1097/00006982-199616040-00009
  28. ↑ Neerukonda VK, Kim IK, Stagner AM. Primary vitreoretinal involvement and immunopositivity for BRAFV600E help distinguish metastatic from primary intraocular melanoma: a detailed histopathologic study of metastatic cutaneous melanoma to the eye. Histopathology. 2022;80(7):1061-1070. doi:10.1111/his.14640
  29. ↑ 29.0 29.1 Fekri S, Barzanouni E, Samiee S, Soheilian M. Polymerase chain reaction test for diagnosis of infectious uveitis. Int J Retina Vitreous. 2023;9(1):26. Published 2023 Apr 12. doi:10.1186/s40942-023-00465-w
  30. ↑ O'Brien O, Lyons T, Murphy S, Feeley L, Power D, Heffron CCBB. BRAF V600 mutation detection in melanoma: a comparison of two laboratory testing methods. J Clin Pathol. 2017;70(11):935-940. doi:10.1136/jclinpath-2017-204367
  31. ↑ Nell RJ, Versluis M, Menger NV, et al. Digital PCR-based genetic profiling from vitreous fluid as liquid biopsy for primary uveal melanoma: a proof-of-concept study. J Exp Clin Cancer Res. 2025;44(1):124. Published 2025 Apr 17. doi:10.1186/s13046-025-03374-y
  32. ↑ Park HS, Han HJ, Lee S, et al. Detection of Circulating Tumor Cells in Breast Cancer Patients Using Cytokeratin-19 Real-Time RT-PCR [published correction appears in Yonsei Med J. 2017 Mar;58(2):473. doi: 10.3349/ymj.2017.58.2.473.]. Yonsei Med J. 2017;58(1):19-26. doi:10.3349/ymj.2017.58.1.19
  33. ↑ Hiemcke-Jiwa LS, Ten Dam-van Loon NH, Leguit RJ, et al. Potential Diagnosis of Vitreoretinal Lymphoma by Detection of MYD88 Mutation in Aqueous Humor With Ultrasensitive Droplet Digital Polymerase Chain Reaction. JAMA Ophthalmol. 2018;136(10):1098-1104. doi:10.1001/jamaophthalmol.2018.2887
  34. ↑ Frenkel S, Pe'er J, Kaufman R, Maly B, Habot-Wilner Z. The importance of cytokines analysis in the diagnosis of vitreoretinal lymphoma. Acta Ophthalmol. 2020;98(6):e668-e673. doi:10.1111/aos.14347
  35. ↑ Choi W, Kang HG, Choi EY, et al. Clinical utility of aqueous humor polymerase chain reaction and serologic testing for suspected infectious uveitis: a single-center retrospective study in South Korea. BMC Ophthalmol. 2020;20:242. doi:10.1186/s12886-020-01471-w
  36. ↑ Neerukonda VK, Kim IK, Stagner AM. Primary vitreoretinal involvement and immunopositivity for BRAFV600E help distinguish metastatic from primary intraocular melanoma: a detailed histopathologic study of metastatic cutaneous melanoma to the eye. Histopathology. 2022;80(7):1061-1070. doi:10.1111/his.14640
  37. ↑ Asencio-Duran M, Vallejo-Garcia JL, Pastora-Salvador N, Fonseca-Sandomingo A, Romano MR. Vitreous diagnosis in neoplastic diseases. Mediators Inflamm. 2012;2012:930704.
  38. ↑ Fukunaga H, Kaburaki T, Shirahama S, et al. Analysis of inflammatory mediators in the vitreous humor of eyes with pan-uveitis according to aetiological classification. Sci Rep. 2020;10(1):2783. Published 2020 Feb 17. doi:10.1038/s41598-020-59666-0
  39. ↑ 39.00 39.01 39.02 39.03 39.04 39.05 39.06 39.07 39.08 39.09 39.10 39.11 39.12 39.13 39.14 39.15 39.16 Thariat J, Boudin L, Loria O, Nguyen AM, Kodjikian L, Mathis T. How to Manage a Patient with Ocular Metastases? Biomedicines. 2022;10(12):3044. doi:10.3390/biomedicines10123044
  40. ↑ 40.0 40.1 Shields JA, Shields CL. Intraocular Tumors: An Atlas and Textbook. Lippincott Williams & Wilkins; 2008.
  41. ↑ 41.0 41.1 41.2 41.3 Smith AG, A.Skvortsova N, Phelps P, Miller AM, Wells J. Choroidal Metastases - EyeWiki. April 2023. Accessed April 26, 2025. https://eyewiki.org/Choroidal_Metastases
  42. ↑ 42.00 42.01 42.02 42.03 42.04 42.05 42.06 42.07 42.08 42.09 42.10 42.11 42.12 Ashkenazy N, Dubovy S, Albini TA, et al. Diagnosis, treatment, and outcomes in patients with vitreous metastasis from cutaneous melanoma. Published online 2020. https://www.retinasociety.org/content/meetingarchive/2020/ashkenazy-noy-diagnosis-treatment.pdf
  43. ↑ 43.0 43.1 43.2 43.3 Yousef YA, Noureldin AM, Sultan I, et al. Intravitreal Melphalan Chemotherapy for Vitreous Seeds in Retinoblastoma. J Ophthalmol. 2020;2020:8628525. doi:10.1155/2020/8628525
  44. ↑ An Update on Intravitreal Chemotherapy. Retinal Physician. July 2019. Accessed April 26, 2025. https://retinalphysician.com/issues/2019/julyaugust/an-update-on-intravitreal-chemotherapy/
  45. ↑ Praidou A, Jacob S, Irion L, et al. Retinal and vitreous metastases from hepatocholangiocarcinoma. BMC Cancer. 2017;17:430. doi:10.1186/s12885-017-3429-8
  46. ↑ 46.0 46.1 46.2 46.3 Gelman R, Lee SE, Rocha N, Kayserman LG, Vallar RV, Marr BP. Vitreous Metastasis in a Case of Metastatic Breast Cancer. Ocul Oncol Pathol. 2020;6(5):323-327. doi:10.1159/000506949
  47. ↑ 47.0 47.1 47.2 47.3 47.4 Ahmet Kaan Gündüz IM. Surgical Approach in Intraocular Tumors. doi:10.4274/tjo.galenos.2021.24376
  48. ↑ Matsumoto K, Kase S, Namba K, Iwata D, Matsuno Y, Ishida S. A Case of Intraocular Metastasis of Lung Cancer Diagnosed Using Cell Block Preparation of the Vitreous Humor. CDP. 2022;3(1):130-134. doi:10.21873/cdp.10190
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