Cytomegalovirus retinitis is the most frequent ocular opportunistic infection among patients with acquired immunodeficiency syndrome and is relatively common in other immunocompromised hosts.1,2 In contrast to choroidal metastasis, the most common intraocular malignancy in adults, metastatic disease of the retina is exceedingly rare.3,4 Patients often present with white or yellow-white retinal patches, intraretinal hemorrhages, and perivascular infiltrates.3 Although these entities can be distinguished by their histopathologic characteristics, obtaining adequate tissue for diagnostic purposes prior to enucleation can be challenging. In this report, we describe the surgical technique of pars plana vitrectomy and excisional biopsy in a patient with intraretinal metastatic adenocarcinoma that simulated cytomegalovirus retinitis.
A 62-year-old man with a history of small-cell lung cancer presented with a 2-week history of acute, painless vision loss in the left eye. Nine months prior to symptom onset, he was diagnosed as having a high-grade, small-cell lung carcinoma that had metastatic spread to bone and supraclavicular lymph nodes. He subsequently completed chemotherapy with carboplatin and etoposide and prophylactic brain radiotherapy (30 Gy), which included the posterior one-third of the globes, approximately 2 months prior to symptom onset. Visual acuity at presentation was 20/20 in the right eye and 20/400 in the left eye. There was no relative afferent papillary defect, but a large nasal visual field defect. Examination of the left eye showed no anterior chamber cell, 1+ vitreous haze, and a large area of retinal whitening in the temporal macula and mid-periphery with associated preretinal hemorrhage (Figures 1A–1B). Optical coherence tomography revealed thickening and hyperreflectance of the inner retina, and ultrasound showed a 2.4-mm thick lesion with medium internal reflectivity (Figures 1C–1D). Based on suspicion for viral retinitis, he underwent a vitreous paracentesis and intravitreal injection of foscarnet 2.4 mg, and started oral valacyclovir 900 mg twice a day. Polymerase chain reaction testing of the vitreous fluid was negative for cytomegalovirus, varicella zoster virus, herpes simplex virus, and Toxoplasmosis gondii. Cytologic examination of the vitreous fluid showed proteinaceous material, but no neoplastic cells.
Figure 1. Clinical features at presentation. (A) Color fundus photograph shows mild to moderate vitreous haze and an area of retinal whitening with intraretinal hemorrhage temporal to the fovea. (B) Montage photograph shows the extent of retinal whitening and layering of blood and cellular aggregate on the posterior hyaloid inferiorly. (C) Spectral-domain optical coherence tomography image demonstrates thickening and hyperreflectance of the inner retina temporal to the fovea. (D) B-scan ultrasonography shows a 2.4 mm thick retinal lesion temporal to the macula.
With no clinical improvement for 2 weeks, the patient underwent pars plana vitrectomy, retinal biopsy, endolaser, and C3F8 gas tamponade. Histopathologic examination revealed sheets of tumor cells with pleomorphic nuclei and positive immunohistochemical staining for AE1/3, consistent with metastatic adenocarcinoma (Figures 2A–2B). Examination by transmission electronmicroscopy showed sheets of cells with pleomorphic nuclei, prominent nucleoli, and chromatin margination (Figure 2C).
Figure 2. Pathologic examination. (A) Low power magnification shows sheets of tumor cells (arrowheads) with pleomorphic nuclei overlying the retina (arrows) (hematoxylin-eosin, original magnification ×100). (B) Immunohistochemical staining for cytokeratins AE 1/3 is positive in the tumor cells (arrows) on the inner retina (original magnification ×100). (C) Transmission electronmicrograph shows tumor cells with prominent nucleoli and chromatin margination overlying the internal limiting membrane (*) (original magnification ×1,900).
Repeat magnetic resonance imaging shortly after surgery failed to show brain metastasis. The patient subsequently underwent palliative external beam radiation (45 Gy over 25 fractions) to the left eye and orbit. Ten months after presentation the patient was alive. At final follow-up, the patient’s vision was counting fingers at 2 feet, and although the retina was fully attached, the vasculature was sclerotic and the metastatic retinal lesion appeared atrophic (Figure 3).
Figure 3. Postoperative appearance. Color fundus montage of the left eye three months after surgery reveals a flat chorioretinal scar at the retinal biopsy site, as well as patches of retinal pigment epithelial atrophy. The retinal vessels near the macula appear particularly sclerotic.
Metastastic disease of the retina, which was first described in 1934,5 is rare and can be difficult to diagnose.3 In 2006, Pelzek and Schachat reviewed the 28 reported cases of retinal metastasis and found that patients often have known primary tumors at diagnosis, most commonly pulmonary or gastrointestinal adenocarcinomas or cutaneous melanomas.3 Conditions most likely to simulate retinal metastases include infectious retinitis and vaso-occulsive disorders.3,6–8 Patients with cytomegalovirus retinitis characteristically exhibit patches of yellow to white retinal necrosis and edema often with associated hemorrhage.9 The distribution of retinitis is often in a vascular pattern and when involving the macula can wrap circumferentially around the fovea.10 Furthermore, patients with cytomegalovirus retinitis typically present with symptoms of blurred central vision and loss of peripheral visual field. Our patient exhibited all of these clinical features and could be considered immunocompromised because of his recent chemotherapy and brain radiation. However, the amount of retinal thickening and medium internal reflectivity on ultrasonography was atypical for cytomegalovirus retinitis. Our patient also exhibited a layering of large white blood cells along the posterior hyaloid in a pseudohypopyon pattern (Figure 1B), which is uncharacteristic of cytomegalovirus retinitis.
Prior to 1979, most cases of retinal metastasis were diagnosed at the time of autopsy or enucleation.3 Since then, the clinical diagnosis has been verified in some cases by intraocular fluid cytology and in a few cases by chorioretinal biopsy.3 In 1988, Eagle reported a case of carcinomatous retinitis which had been diagnosed by vitreous aspirate and eye wall biopsy.6 In 1995, Balestrazzi et al. described local resection of a retinal metastatic lesion by a cutaneous melanoma,11 and later Spadea et al. described the technique for a chorioretinal biopsy using a transscleral approach.12 The surgical technique described in this report is advantageous because it yields an adequate sample for histopathologic examination and causes relatively little injury to the eye.
At the time of presentation, it was thought that his metastatic lung adenocarcinoma had been adequately treated with systemic chemotherapy and prophylactic brain radiotherapy, which included radiation to the posterior one-third of the globes. Because there were no other new metastatic brain foci at the time of presentation and because he had recently undergone eye/brain radiotherapy, there was a need to confirm the diagnosis with histopathologic examination. The implications of having recurrent metastatic disease of the central nervous system following chemotherapy and brain radiation were important factors in our recommendations for pars plana vitrectomy and retinal biopsy.
The biopsy site for this procedure was chosen at the edge of normal and abnormal retina to provide a “clean” margin for pathologic examination. Additionally, a peripheral location was chosen to minimize visual sequelae. By creating a localized retinal detachment with a subretinal cannula, the retina was able to be excised fairly easily without damaging the underlying choroid. The 2 × 2 mm sample obtained in this case was adequate for diagnosis and demonstrated sheets of tumor cells with pleomorphic nuclei in the inner retina.
Over the past 25 years, patients with retinal metastasis have most often been treated with palliative external beam radiation, as in this case, with enucleation being reserved for those with intractable pain.3 Systemic prognosis is guarded with an average survival of 10.5 months following diagnosis.3 Duration of survival reflects the aggressiveness of the primary cancer and the extent of metastasis.3 Our patient has tolerated his palliative external beam radiotherapy well and has shown regression of the intraocular metastatic disease at final follow-up.
We report the clinical features of a patient with intraretinal metastasis of a small-cell adenocarcinoma of the lung, which shared many similarities to cytomegalovirus retinitis. Additionally, we describe the surgical technique for performing a retinal biopsy using pars plana vitrectomy, subretinal fluid injection, endoresection, air–fluid exchange, laser and long-acting gas tamponade. This surgical procedure may potentially be beneficial for select patients with retinal metastatic disease for diagnostic and therapeutic purposes.
- Jabs DA, Ahuja A, Van Natta M, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: five-year outcomes. Ophthalmology. 2010;117:2152–2161. doi:10.1016/j.ophtha.2010.03.031 [CrossRef]
- Chung H, Kim KH, Kim JG, Lee SY, Yoon YH. Retinal complications in patients with solid organ or bone marrow transplantations. Transplantation. 2007;83:694–699. doi:10.1097/01.tp.0000259386.59375.8a [CrossRef]
- Pelzek CD, Schachat AP. Retinal metastasis. In: Ryan SJ, ed. Retina. St. Louis: Elsevier; 2006:641–650.
- 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]
- Smoleroff JW, Agatston SA. Metastatic carcinoma of the retina: report of a case, with pathologic observations. Arch Ophthalmol. 1934;12:359–365. doi:10.1001/archopht.1934.00830160063007 [CrossRef]
- Eagle RC Jr, . Carcinomatous retinitis. Presented at Eastern Ophthalmic Pathology Society annual meeting. ; October 25–28, 1998. ; Sanibel-Captiva Island, FL. .
- Young Se, Cruciger M, Lekeman J. Metastatic carcinoma to the retina: case report. Ophthalmology. 1979;86:1350–1354.
- Leys AM, Van Eyck LM, Nuttin BJ, Pauwels PA, Delabie JM, Libert JA. Metastatic carcinoma to the retina: clinicopathologic findings in two cases. Arch Ophthalmol. 1990;108:1448–1452. doi:10.1001/archopht.1990.01070120096036 [CrossRef]
- Whitley RJ, Jacobson MA, Friedberg DN, et al. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. Arch Intern Med. 1998;158:957–969. doi:10.1001/archinte.158.9.957 [CrossRef]
- Luckie AP, Ai E. A foveal-sparing pattern of cytomegalovirus retinitis in the acquired immunodeficiency syndrome. Aust N Z J Ophthalmol. 1996;24:53–59. doi:10.1111/j.1442-9071.1996.tb01552.x [CrossRef]
- Balestrazzi E, Blasi MA, Marullo M, Greco IM, Spadea L. Local excision of retinal metastasis from cutaneous melanoma. Eur J Ophthalmol. 1995;5:149–154.
- Spadea L, Bisti S, Colucci S, Balestrazzi E. Normal EOG values in intraretinal metastasis from cutaneous melanoma: a case report. Doc Ophthalmol. 1999;96:305–309. doi:10.1023/A:1001843702335 [CrossRef]