From the Department of Ophthalmology, University of California, San Francisco, California.
Supported by That Man May See, Inc., Research to Prevent Blindness, and the UCSF Hearst Fellowship.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Jay M. Stewart, MD, UCSF Department of Ophthalmology,10 Koret Way, K301, San Francisco, CA 94143-0730. E-mail: email@example.com
Fewer than 40 cases of intraretinal metastasis without choroidal involvement have been described in the literature, and these data furnish a scarce source of indications for the management of such metastasis.1–3 The most common primary tumor is cutaneous melanoma, followed by lung carcinoma, gastrointestinal adenocarcinoma, and breast carcinoma.1,4 Only two cases where the primary malignancy remained unknown were published. The average survival time was calculated as 10.5 months (range: 2 weeks to 5 years).4 The improved survival rates for patients with carcinoma and the increased awareness of the medical community will likely increase the number of retinal metastasis cases seen in retinal practices.
Metastatic neoplasm may present with vitreous cells or opacities and yellow-white retinal patches with or without white perivascular infiltrates, pigment, hemorrhages, and exudates, depending on the type of primary malignant tumor.4,5 The differential diagnosis includes, but is not limited to, infectious retinitis, granulomatous uveitis, collagenopathies, amyloidosis, intraocular lymphoma, retinal vaso-occlusive disorders, primary choroidal melanoma with retinal invasion, and choroidal metastases. Optical coherence tomography (OCT) is a relatively new tool to study retinal lesions, and no OCT images are available in the literature.
The diagnosis and management of retinal metastasis represent a difficult clinical challenge. We describe a case of metastatic cancer to the retina with special emphasis on the diagnostic dilemma and management options.
A 54-year-old woman with a strong smoking history was evaluated for progressive dizziness, gait changes, headache, and bilateral arm numbness. Magnetic resonance imaging revealed a 38-mm mass in the right cerebellum, and she underwent craniotomy and resection of the tumor. Light microscopy examination disclosed small round neoplastic cells growing in a nested architecture with scant cytoplasm, nuclear pleomorphism, and abundant mitoses. Immunohistochemical evaluation of these cells was positive for thyroid transcription factor-1, pan-cytokeratin, and synaptophysin and negative for CD3, CD20, and CD30. These features were interpreted as being most consistent with a small cell undifferentiated carcinoma metastatic to brain from lung. Imaging was unremarkable except for computed tomography of the chest, which showed solely right hilar adenopathy. It was assumed that the primary tumor was a small cell carcinoma of the lung and the patient received adjuvant radiation therapy to the brain and chest.
Two years later, she was referred to us because of blurred vision and floaters in the right eye. The visual acuity was 20/40 and 2+ vitreous cells were present; a whitish retinal infiltrate with irregular margins, intraretinal hemorrhages, telangiectatic blood vessels, and hard exudates was seen in the right macula temporally, sparing the fovea (Fig. 1A). Fluorescein angiography demonstrated blocked fluorescence in the area of the lesion and marked perivascular leakage and late staining. The diagnosis of retinal metastasis was made clinically and a total radiation dose of 4,000 cGy was delivered in 20 treatments.
Figure 1. (A) Fundus photograph at presentation, showing a white retinal infiltrate, vascular changes, and exudates in the right eye. (B) Six weeks following radiation therapy, the extent of retinal infiltration was increased.
Six weeks after radiation, the patient returned to our clinic complaining of further decrease in vision; visual acuity was 20/200. The macular infiltrate was more extensive, involving the entire macula beyond the temporal arcades and including the peripapillary area, with significant subretinal fluid, diffuse retinal thinning, intraretinal hemorrhages, hard exudates, perivascular sheathing, and some fibrosis (Fig. 1B). Fluorescein angiography was remarkable for diffuse retinal non-perfusion at the posterior pole. High-definition spectral-domain OCT demonstrated large pockets of subretinal fluid with loss of normal retinal architecture: areas of retinal disorganization, thinning with atrophy of both the inner and outer layers, retinal splitting with multiple cord-like hyperreflective structures, thickening with intraretinal nests, and large sub-internal limiting membrane deposits of an amorphous hyperreflective infiltrate (Figs. 2A to 2C). Small drusen-like deposits were present at the level of the retinal pigment epithelium. No discontinuities were seen at the retinal pigment epithelium level and the inner choroid was apparently unremarkable, suggesting that the disease was limited to the neurosensory retina. Ocular echography also showed no choroidal involvement.
Figure 2. High-definition spectral-domain optical coherence tomography imaging of the right macula. (A) Horizontal scan passing throughout the foveola showing vitreous debris, large pockets of subretinal fluid, and areas of retinal thinning and disorganization with a hyperreflective infiltrate. Drusen-like deposits were present at the retinal pigment epithelium level. Significantly, the nasal aspect of the fovea was spared. Visual acuity was 20/200. (B) Vertical scan passing 200 microns from the foveola demonstrating severe alteration of the normal retinal architecture. Subretinal fluid and cystoid intraretinal edema were present. The neoplastic infiltrate was organized in round nests and larger sub-internal limiting membrane amorphous deposits with tiny hyperreflective spots. (C) Horizontal scan passing one disc diameter inferotemporal to the fovea, showing multiple cord-like hyperreflective structures in the inner aspect of the retina. The choroid was apparently unremarkable.
Considering the progression of the disease and in an effort to make a definitive diagnosis, an extensive work-up was conducted, but computed tomography scans of the abdomen, pelvis, chest, and brain, magnetic resonance imaging of the thyroid, spine, and brain, whole body positron emission tomography–computed tomography scan, bone scan, and mammogram and lumbar puncture were negative. Because the site of the primary tumor was not proven at this point and given the concern of the similarity of the clinical picture with other retinal conditions such as infectious retinitis and intraocular lymphoma, it was decided to perform a diagnostic vitrectomy and retinal biopsy in the right eye.
The procedure was performed with a 20-gauge vitrectomy system and an approximately 1 × 1 mm sample of retinal tissue was removed with micro-forceps from the area of tumor just above the optic nerve head outside the arcades. A complete air–fluid exchange was performed at the end of the surgery.
The specimen consistent with undiluted, fresh retina was submitted for pathology examination, but serial sections of all paraffin block failed to show tissue useful for diagnosis. The undiluted vitreous fluid was analyzed for leukocyte (CD45) and B-cell surface markers (CD19 and immunoglobulin light chain kappa and lambda) with flow cytometry and the pathologists excluded a lymphoproliferative disorder. Cultures from the vitreous aspirate were negative.
Cytospin of the vitrectomy cassette fluid (routinely stained with May Grünwald-Giemsa) showed several fragments of tumor cells characterized by scant cytoplasm and enlarged, molded, hyperchromatic nuclei with indistinct nucleoli; there was a background of smaller cells and lymphocytes (Fig. 3A). These features were thought to be consistent with small cell carcinoma and to be similar in appearance to the previous cerebellar biopsy (Fig. 3B).
Figure 3. (A) Cytospin of fluid from the vitrectomy cassette demonstrating tumor cells characterized by scant cytoplasm and enlarged, molded, hyperchromatic nuclei with indistinct nucleoli. (B) These features were similar to the cerebellar tumor that was biopsied 2 years before, showing small neoplastic cells with abundant mitoses.
Postoperatively, the visual acuity was 20/200 and the intraocular pressure was 14 mm Hg. Having already received a full radiation treatment to the right eye, the patient was not a candidate for further radiation therapy of the orbital region. The oncology team recommended temozolomide for a metastatic epithelial malignancy of unknown primary origin, but the patient refused to start chemotherapy.
She returned 5 months later with no light perception in the eye and evidence of neovascular glaucoma and growth of the retinal metastasis. She refused ocular or systemic treatment, electing to receive only palliative care.
All patients with tumors who complain of blurred vision or floaters need an extensive ophthalmic evaluation. Retinal metastasis presenting as whitish patches and vitreous opacities may be misdiagnosed as an inflammatory disease, infection, or intraocular lymphoma. The source is usually skin melanoma or lung and gastrointestinal carcinoma, and should be searched for appropriately with physical examination and modern imaging techniques (eg, x-rays, computed tomography, magnetic resonance imaging, and positron emission tomography). The primary tumor sometimes remains undiagnosed even after a complete work-up.4 Ocular ultrasonography does not usually help with these thin lesions, which also do not present with pathognomonic patterns on fluorescein and indocyanine green angiography. Consequently, further evaluation of the suspicious lesions may require invasive ocular procedures to determine the necessary therapeutic intervention.
Aspirates of the aqueous and vitreous humor for cytological and microbiological examination have been useful in the diagnosis of retinal metastasis.4 In our case, a vitrectomy was performed to furnish a larger volume sample, and cytospin was key in demonstrating the presence of tumor cells. Flow cytometry evaluation to exclude lymphoproliferative disorders may be limited by sample volume, and arrangements with the immunocytology team before the surgical procedure are recommended.
We collected a tiny biopsy of retinal tissue during the surgery that was lost during the processing for pathology evaluation. We recommend staining of the retinal tissue with toluidine blue at the time of surgery to help pathologists in identifying the specimen.
Choroidal, retinal, and vitreous biopsies have been reported as a useful tool in the diagnosis of intraocular tumors.4 Fine-needle aspiration biopsy of intraocular lesions can also be useful in the diagnostic dilemma. The efficacy and safety of fine-needle aspiration biopsies and vitrectomy have been demonstrated with no increase in mortality rates.5
In this case, OCT was helpful in the diagnostic process, disclosing a new aspect of retinal malignancies and partially making up for the lack of evidence from the retinal biopsy. Our detailed OCT images, supported by the histological findings, may represent a unique reference for future clinicians dealing with suspicious retinal lesions and no evidence of primary tumor.
- 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;245:733–740. doi:10.1007/s00417-006-0469-1 [CrossRef]
- Sirimaharaj M, Hunyor AP, Chan WC, Arnold J. Unusual ocular metastasis from breast cancer. Clin Experiment Ophthalmol. 2006;34:74–76. doi:10.1111/j.1442-9071.2006.01148.x [CrossRef]
- Apte RS, Dibernardo C, Pearlman JR, et al. Retinal metastasis presenting as a retinal hemorrhage in a patient with adenocarcinoma of the cecum. Arch Ophthalmol. 2005;123:850–853. doi:10.1001/archopht.123.6.850 [CrossRef]
- Ryan SJ. Retina, 4th ed. Philadelphia: Elsevier Mosby; 2006.
- Char DH, Kemlitz AE, Miller T. Intraocular biopsy. Ophthalmol Clin North Am. 2005;18:177–185. doi:10.1016/j.ohc.2004.08.007 [CrossRef]