# Presumed Retinal Metastasis from Lung Adenocarcinoma: A Case Report and Literature Review

Authors: Gökçen Özcan; Ahmet Kaan Gündüz; Ibadulla Mirzayev; Ayhan Sağlik
Journal: Case Reports in Ophthalmological Medicine
 (2021)

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## Abstract

A 63-year-old Caucasian man with metastatic lung adenocarcinoma undergoing chemotherapy and external radiotherapy was referred for routine eye examination. Although he was asymptomatic, ocular examination revealed a relatively well-circumscribed whitish retinal lesion measuring0.5×0.5×0.5 mm located along the inferotemporal vascular arcade in the right eye. Optical coherence tomography (OCT) showed a hyperreflective dome-shaped lesion occupying the inner retinal layers with few hyperreflective dots overlying the retina in the posterior vitreous consistent with tumor cells. Fluorescein angiography revealed early hyperfluorescence and late staining without leakage at the lesion site. A diagnosis of presumed retinal metastasis from lung adenocarcinoma was made. At 2 months follow-up after completion of chemotherapy, the retinal lesion was found to have regressed completely leaving minor irregularities in the inner retinal layers on OCT. To date, there have been only 41 cases of carcinoma metastasis to the retina reported in the literature including the current case. Despite its rarity, retinal metastasis should be considered in the differential diagnosis of a white-yellow retinal mass with/without overlying vitreous cells especially in patients with a history of systemic cancer.


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## Body

## 1. Introduction

Metastatic tumors of the uveal tract are the most common intraocular malignancies, whereas retinal metastases are rare compared to uveal metastases [1]. The choroid is the most common site of uveal metastasis. The choroid receives 85% of the ocular blood flow compared to the retina which receives only 5%, thereby explaining the rarity of retinal metastasis [2]. Carcinomas metastasize to the choroid more often compared to sarcomas and melanomas. However, melanomas tend to metastasize to the retina more frequently than carcinomas [3]. Tumor cells are periodically shed to the circulation from the primary site. Expression of specific adhesion molecules on extravasated metastatic cells allows the proliferation of these cells on the metastatic host sites [4]. Several previously published papers reviewed vitreous and retinal metastasis from cutaneous melanomas [5, 6]. We hereby present a case of retinal metastasis from lung carcinoma and review the literature on carcinoma metastasis to the retina.


## 2. Case Report

A 63-year-old Caucasian man diagnosed with metastatic lung adenocarcinoma 5 months ago and receiving systemic chemotherapy and external radiotherapy to the right hip underwent routine eye examination. He had no history of known ocular disease and intervention and was asymptomatic. Best corrected visual acuities were 20/32 in the right eye and 20/20 in the left eye. Intraocular pressures were 15 mmHg and 17 mmHg in the right and left eyes, respectively. Anterior segment examination showed both eyes had moderate nuclear sclerosis. Fundus examination of the right eye revealed a relatively well-circumscribed whitish retinal lesion measuring0.5×0.5×0.5 mm located along the inferotemporal vascular arcade. There was no apparent vitreous and choroidal involvement. The left eye had normal funduscopic findings with blunted foveal reflex. Spectral domain optical coherence tomography (SD-OCT) of the right eye showed a hyperreflective dome-shaped lesion occupying the inner retinal layers with few hyperreflective dots overlying the retina consistent with tumor cells in the posterior vitreous. The outer retina was compressed by tumor and partial choroidal shadowing was observed without clinical or imaging evidence for choroidal involvement. The lesion was hypofluorescent on fundus autofluorescence (FAF) imaging. Fluorescein angiography (FA) revealed early hyperfluorescence of the lesion, late staining, and no leakage. The tumor was flat and nonmeasurable on B-mode ultrasonography. Brain magnetic resonance imaging revealed normal findings. Based on the clinical and imaging features, a diagnosis of presumed lung carcinoma metastasis to the retina was made. At a follow-up examination 2 months later after completion of systemic chemotherapy, the visual acuity in the right eye was 20/60 due to the worsening of the cataract. Fundus examination revealed that the retinal lesion in the right eye had regressed completely. There were only focal irregularities in the inner retinal layers on SD-OCT (Figure 1). The patient passed away 6 months after the diagnosis of retinal metastasis.Figure 1
(a) Whitish perivascular retinal lesion measuring approximately 0.5 x 0.5 x 0.5 mm located along the inferotemporal arcade in the right eye. (b) The lesion is hyporeflective on infrared imaging. (c) The lesion shows hypoautofluorescence on fundus autofluorescence imaging. (d) Spectral domain optical coherence tomography (SD-OCT) imaging shows the hyperreflective dome-shaped lesion replacing inner retinal structures, causing disorganization and compression of the outer retina. Multiple hyperreflective dots are observed overlying the retina consistent with tumor cells in the posterior vitreous (arrowhead). Ellipsoid zone cannot be observed clearly because of partial posterior shadowing by the tumor, but the retinal pigment epithelium is intact. (e) At 2 months follow-up examination after completion of chemotherapy, the retinal lesion regressed completely leaving only focal irregularities in the inner retinal layers on SD-OCT.
(a)(b)(c)(d)(e)


## 3. Discussion

Cutaneous melanoma is the most common metastatic retinal tumor. Tang et al. reviewed 42 cases of tumor metastasis to the retina published in the English literature from 1935 to 2017 and noted that the most common primary sites for metastatic tumors to the retina were cutaneous melanoma followed by lung carcinoma and gastrointestinal carcinoma [7]. Ramaesh et al. reported 39 melanoma metastases to the vitreous and retina in his literature review in 1998 [6]. Our search of the literature showed that there were at least 60 cases of melanoma metastasis to the vitreous and retina reported so far and the total number of reported carcinoma metastasis to the retina was 40. Of the 41 cases with carcinoma metastasis to the retina including our case, 15 (36.6%) cases had lung carcinoma, 13 (31.7%) cases had gastrointestinal carcinoma including 1 case of pancreatic carcinoma and 1 case of hepatocholangiocarcinoma, 6 (14.6%) had breast carcinoma, 3 (7.3%) had adenocarcinoma with unknown primary site, 2 (4.9%) had genitourinary tract carcinoma, 1 (2.4%) had uterine carcinoma, and 1 (2.4%) had nasopharyngeal carcinoma. The mean age of all reported cases was 56.1 (range 15-75, SD±11.9) years. Twenty-five out of 41 (61.0%) patients were males, and the remaining 16 (39.0%) were females.Retinal metastases are usually unilateral and solitary; however, bilateral and multifocal involvement have also been reported [8–10]. At the time of diagnosis of retinal metastasis, the majority of patients have metastasis at other sites as well (Table 1). Alternatively, ocular involvement may be the first finding of metastatic disease, and these patients must be carefully evaluated for the presence of systemic metastases at other sites.Table 1
Review of cases with metastatic retinal cancer reported in the literature.
Author/yearSexAgePrimary tumorLocationPrimary tumor known at eye diagnosisThe onset of eye findings (mo)DiagnosisOther known systemic metastasisOcular treatmentFollow-upClinical signs/pathologic findings1Arisawa, 1914 [12](cited by Kennedy et al., 1958 [20])M30Pancreatic carcinomaDiffuseYesN/AAutopsy?N/AN/AN/AVitreous seeds, optic disc involvement2Smoleroff and Agatston, 1934 [18](cited by Kennedy et al., 1958 [20])M55Esophageal adenocarcinomaInferotemporal quadrantYesN/AAutopsyLiver, lung, adrenal gland, spineN/A1 mo, deceasedWhite irregular mass arising from nerve fiber layer, retinal and subretinal but no choroidal involvement3Kennedy et al., 1958 [20]M51Rectosigmoid adenocarcinomaMaculaNo0EnucleationBrainEnucleation9 mo, deceasedGrayish white nodular lesion4Duke and Walsh, 1959 [16](cited by Tang et al., 2019 [7])F60Uterine adenocarcinomaMaculaYesN/AEnucleationBrainEnucleation6 mo, deceasedVitreous seeds, elevated white mass5Koenig et al., 1960 [10]M56Undifferentiated bronchogenic carcinomaTemporal retinaNo0EnucleationN/AEnucleation13 mo, deceasedGranulomatous uveitis, vitreous floaters, white mass with neovascularization, retinal and subretinal exudation, choroidal seeding6Flindall and Fleming, 1967 [25]M68Unknown primaryAnterior to equatorNoN/AEnucleationN/AEnucleation24 mo, aliveVitreous seeds, veil-like retinal exudates inferiorly, optic disc involvement7Levy and de Venecia, 1970 [14]M49Oat cell carcinoma of lungPosterior poleYes10AutopsyWidespreadObservation10 mo, deceasedGross ophthalmic examination was normal; histopathology revealed anaplastic cells filling the lumens of retinal vessels, nerve fiber layer, and isolated choroid involvement8Klein et al., 1977 [8]M52Squamous cell carcinoma of lungTemporal macula OD, ERD OSYesN/AAutopsyWidespreadObservation2 mo, deceasedWhite retinal infiltrate, retinal choroidal, and optic disc involvement9Young et al., 1979 [26]M63Lung adenocarcinomaMaculaYes4VAB and autopsyBrain, boneExternal radiotherapy7 mo, deceasedPerivascular white infiltrates around optic disc, white macular mass10Piro et al., 1982 [17]F56Breast carcinomaVitreous opacities OUNo0PPV and autopsy OD, autopsy OSNoObservation12 mo, deceasedUveitis, vitreous seeds, no retinal infiltration; histopathology showed solitary tumor cells in retina11Eagle, 1988 [27](cited by Srivastava and Bergstrom, 2013 [28])F53Unknown primaryMaculaNo0VAB, retinal and choroidal biopsyBrain, lungN/A5 mo, deceasedVitreous balls, white macular lesions with satellites, and vascular sheathing12Takagi et al., 1989 [19]M45Adenocarcinoma of lungInferotemporal quadrantYes24EnucleationAdrenal gland, rectumEnucleation3 mo, deceasedVitreous seeds, white exudates along the retinal veins, optic disc involvement, tumor cell emboli in central retinal vein13Leys et al., 1990 [29]M49Oat cell carcinoma of lungTemporal maculaYes0AutopsyBrain, kidney, liverObservation1 mo, deceasedVitreous seeds, ERD, partially obscured retinal arteriole14Striebel-Gerecke et al., 1992 [24](cited by Srivastava and Bergstrom, 2013 [28])F47Oat cell carcinoma of lungInferonasal quadrantYesN/AVAB, autopsyBrain, liver, adrenal glandN/A2.5 mo, deceasedWhite cone shape mass in vitreous, plaque like retinal infiltration15Tachinami et al., 1992 [30](cited by Srivastava and Bergstrom, 2013 [28])M61Rectal adenocarcinomaSuperior maculaYesN/AAutopsyBrain, lymph nodesN/A5 mo, deceasedWhite retinal mass, ERD16Spraul et al., 1995 [31]F74Muir-Torre syndrome/adenocarcinoma of lung or breastSuperotemporal quadrantYesN/AEnucleationLungEnucleation10 mo, aliveYellow-white tumor, shallow ERD, adenocarcinoma cells involving the retina17Cangiarella et al., 1996 [32]F51Esophageal adenocarcinomaUnknownNo0VABLymph nodesN/A4 mo, aliveVitreous seeds, white retinal infiltrate, ERD18Hutchison et al., 2001 [33](cited by Srivastava and Bergstrom, 2013 [28])F63Colon adenocarcinomaSuperotemporal maculaYesN/AN/ALungN/A3 mo, alivePale elevated vascular lesion superotemporal to macula, ERD19Gupta et al., 2002 [13]M46Oat cell carcinoma of lungJuxtapapillaryNo0ClinicalSkin, lymph nodesChemotherapy only1 mo, deceasedPale elevated juxtapapillary lesion, necrosis, optic disc, retinal and choroidal involvement20Truong et al., 2002 [34]F59Breast carcinomaTemporal to foveaYes36ClinicalBrain, lung, liverExternal radiotherapyN/AWhite retinal and subretinal mass, ERD21Saornil et al., 2004 [35]M70Gastric adenocarcinomaJuxtapapillaryYes192EnucleationMediastinal lymph nodeEnucleation23 mo, deceasedWhite retinal tumor, iris neovascularization (neovascular glaucoma), ERD22Apte et al., 2005 [23]M39Cecal adenocarcinomaInferior maculaYes3PPV, excisional biopsyLiver, lungExternal radiotherapy3 mo, aliveVitreous seeds, ERD23Rossi et al., 2005 [36]M41Non-small-cell lung carcinomaSuperotemporal macula OUYes6ClinicalBone, brainChemotherapy only3 mo, deceasedWhite elevated retinal mass, ERD24Rundle and Rennie, 2006 [22]F55Breast carcinomaTemporal to foveaYes108ClinicalLungPhotodynamic therapy2 mo, aliveWhite retinal mass, SRF25Sirimaharaj et al., 2006 [37]F60Breast carcinomaNasal midperipheral retinaYes36PPVSpine, lung, brainExternal radiotherapy8 mo, deceasedVitreous cell clumps, white precipitates vascular sheathing26Alegret et al., 2009 [21]M15Nasopharyngeal carcinomaInferotemporal arcadeYes12ClinicalLungChemotherapy onlyN/AWhite nodular lesion27Kim et al., 2010 [38]F64Gastric adenocarcinomaMacula OU, vitreous ODYes24PPVLung, liver, peritonealExternal radiotherapy1 mo, aliveVitreous seeds, white nodular lesion28Coassin et al., 2011 [39]F54Small cell lung carcinomaTemporal maculaN/aN/APPV, retinal biopsyBrainN/A7 mo, aliveVitreous seeds, white retinal infiltrates29Payne et al., 2012 [40]M62Small cell lung carcinomaTemporal maculaN/aN/AVAB, retinal biopsy, PPVN/AExternal radiotherapy10 mo, aliveVitreous haze, retinal whitening30Shields et al., 2014 [3]F75Breast carcinomaInferotemporal quadrantYes103N/AN/AObservationN/AYellow retinal mass, irregular contour, intrinsic hemorrhage, SRF31Shields et al., 2014 [3]M56Esophageal adenocarcinomaN/AYes26N/AN/AObservation1 mo, deceasedRetinal whitening, SRF32Shields et al., 2014 [3]F58Breast carcinomaN/AYes214N/AN/AObservation1 mo, deceasedRetinal whitening, SRF33Shields et al., 2014 [3]F64Lung carcinomaTemporal maculaYes20Fine needle biopsyN/APlaque radiotherapy4 mo, deceasedWhite retinal mass, vitreous seeds, intrinsic vascularity, vitreous hemorrhage34Taubenslag et al., 2015 [20]M75Non-small-cell lung carcinomaSuperotemporal quadrantNo0PPV, retinal biopsyNoExternal radiotherapy18 mo, aliveBranch retinal vein occlusion, SRF, vitreous cells, presumed optic disc involvement35Praidou et al., 2017 [41]M70Hepatocholangio carcinomaInferotemporal arcadeYes11PPV, retinal biopsyLiverResection and chemotherapy12 mo, aliveVitreous seeds, white retinal lesion, SRF36Essadi et al., 2017 [42]M62Clear cell renal carcinomaN/AYes28ClinicalLungChemotherapy only4 mo, aliveLarge retinal mass, retinal hemorrhage37Whalen et al., 2018 [9]M55Bladder cancerInferonasal quadrantYes48PPVNoExternal radiotherapy, enucleation23 mo, aliveUveitis, pseudohypopyon, SRF, and satellite lesions38Mano et al., 2018 [43]M69Esophageal adenocarcinomaMacula and peripheral retinaYesN/APPVWidespreadAntiviral treatment3 mo, deceasedVitreous seeds, white infiltrates simulating acute retinal necrosis39Ramtohul et al., 2019 [44]M51Colon adenocarcinomaSuperior maculaYesN/AN/AN/AN/A6 mo N/ALarge vascularized retinal mass, retinal hemorrhage (initially), choroidal involvement (at 6 mo follow-up)40Jorge et al., 2020 [15]F63Lung carcinomaJuxtapapillaryNo0ClinicalLiverChemotherapy only8 mo aliveYellow retinal lesionM: male; F: female; N/A: not available; SRF: subretinal fluid; ERD: exudative retinal detachment; VAB: vitreous aspiration biopsy; PPV: pars plana vitrectomy; OD: right eye; OS: left eye; OU: both eyes; mo: month.Decreased vision, floaters, and ocular pain are the common presenting features in carcinoma metastasis to the retina. However, retinal metastasis can be asymptomatic as in our case. This underlines the necessity for patients with metastatic systemic cancer to have periodic eye examinations. Carcinoma metastasis to the retina most commonly presents as a focal, yellow-white, intraretinal mass with ill-defined borders. However, the tumor borders can sometimes be relatively well-circumscribed, as in our case. Overlying vitreous cells can be observed mimicking uveitis. Vitreous involvement may be seen as white-yellow cellular clumps or strands, sometimes hindering the view of the retina. Sometimes anterior chamber cells and a pseudohypopyon formed by tumor cells can also be observed [9, 10]. Glaucoma secondary to the obstruction of aqueous outflow by tumor cells in the trabecular meshwork may be observed.Metastatic retinal melanoma usually presents with a brown lesion with ill-defined borders, but amelanotic melanoma metastasis with yellow color has also been described. Vitreous metastasis from cutaneous melanoma is characterized by pigmented cellular clumps. On the other hand, retinal carcinoma metastasis is characterized by ill-defined whitish retinal infiltration with overlying nonpigmented cellular aggregates [11].In our literature review of metastatic retinal cancer (Table1), vitreous involvement in addition to retinal metastasis was found in 17 (41.5%) cases. Optic disc and choroidal involvement together with retinal metastasis were reported in 5 (12.2%) cases [8, 10, 12–15]. Retinal involvement usually starts from the retinal nerve fiber and ganglion cell layers. The superficial vascular plexus located in the ganglion cell layer and supplied by the central retinal artery is the major source of metastatic tumors to the retina. As retinal metastasis grows, it replaces deeper retinal tissue. After full-thickness retinal involvement occurs, tumor cells may break through the retina pigment epithelium/Bruchs membrane and invade the choroid [10, 16]. Tumor cells may also penetrate the inner limiting membrane and spread into the vitreous cavity. Isolated carcinoma metastases to the vitreous have also been reported; however, histopathologic findings of enucleated eyes with isolated carcinoma metastases to the vitreous showed microscopic retinal involvement [5, 17].Retinal metastases tend to be angiocentric and grow around the vessels as they are bloodborne [14, 18]. Histopathologic examination shows tumor emboli in the lumens of retinal vessels in the ganglion cell layer around retinal infiltrations [5, 14, 17, 19]. Retinal vascular occlusion has been reported leading to retinal nonperfusion and neovascularization [10, 20]. Complete disappearance of retinal metastatic lesion after chemotherapy as in our case is rare and has been reported only once before in a 15-year-old boy with nasopharyngeal carcinoma [21].Diagnostic methods used in retinal metastatic tumors include OCT, OCT angiography, ultrasonography, FAF, FA, fine needle aspiration biopsy, pars plana vitrectomy, and chorioretinal biopsy. The differential diagnosis of carcinoma metastasis to the retina includes cotton wool spots, retinal astrocytic hamartoma, inflammatory retinitis, and primary vitreoretinal lymphoma. The former 2 lesions originate from the retinal nerve fiber layer, whereas carcinoma metastasis to the retina demonstrates multilayer involvement of the retina. Nonpigmented vitreous cells also pose a diagnostic challenge as they can resemble vitreoretinal lymphoma, amyloidosis, candida endophthalmitis, or intermediate uveitis. Cellular aggregates in the vitreous appearing as spherules or strands should always alert the clinicians to the possibility of metastatic cells.Treatment options for carcinoma metastasis to the retina include observation, systemic chemotherapy, intravitreal chemotherapy, plaque radiotherapy, external radiotherapy, photodynamic therapy, surgical excision, and enucleation for a blind, painful eye [22–24]. The survival rate for patients with carcinoma metastasis to the retina is poor, and the mean survival for all reported cases with retinal metastasis was only 5.7 (range 1-23, SD±5.2) months (Table 1).In summary, carcinoma metastasis to the retina is rare with only 41 cases being reported so far including the current case. The lung is the most common primary site for carcinoma metastasis to the retina followed by the gastrointestinal system. Retinal metastases are angiocentric, originate from the superficial vascular plexus, and are usually initially located in the inner retina. Vitreous involvement may also be seen. Patients generally have widespread metastasis at the time of diagnosis, and the life expectancy is poor. Treatment options are varied and should be tailored to the patients’ needs.


## 4. Method of Literature Search

The literature search consisted of a systematic review of the literature using PubMed database till January 2021 using the following key words: “retinal metastasis” or “carcinoma metastasis to the retina” or “metastatic carcinoma to the retina”. The reference lists of the index publications identified through PubMed were also evaluated and relevant papers were retrieved. Chapters on metastatic tumors to the retina in major ophthalmology textbooks were reviewed. Articles written in non-English languages were also included. A total of 40 cases with carcinoma metastasis to the retina were found and reviewed for this study.



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