Abstract
PURPOSE:
The objective is to differentiate choroidal metastases (CM) arising from various primary cancer sites based on clinical presentation and imaging.
MATERIALS AND METHODS:
A retrospective, observational study of 67 eyes (58 patients).
RESULTS:
The mean age at presentation was 60 years (range, 29–83 years). At presentation, 37 patients (64%) with CM had a known primary systemic cancer, whereas in 21 patients (36%) CM was the first manifestation of systemic cancer. Overall, the primary cancer sites were lung (n = 32, 55%), breast (n = 12, 21%), gastrointestinal tract (n = 6, 10%), genitourinary tract (n = 3, 5%), and others (n = 5, 9%). Most choroidal lesions were creamy yellow in color (84%), while 5 eyes (7%) displayed orange-colored lesions secondary to lung neuroendocrine tumors. On multimodal imaging, A-scan showed medium–high internal reflectivity in 35 eyes (69%), and medium–low reflectivity in 16 eyes (31%). Fundus fluorescein angiography (FFA) demonstrated late hypofluorescence in 17 eyes (94%), whereas indocyanine green angiography (ICG) demonstrated hypofluorescence throughout all phases in 11 eyes (69%). Optical coherence tomography (OCT) showed the presence of a lumpy-bumpy choroid with compression of the overlying choriocapillaries (n = 52, 91%), subretinal fluid (n = 40, 75%), and hyperreflective foci (HRF) (n = 25, 47%). Factors such as right eye involvement, orange tumor, the presence of HRF, increased tumor thickness, CM as the first presentation, and a shorter interval between diagnosis of primary cancer and CM were found to be strongly correlated with the origin of primary cancer from the lung compared with breast (P < 0.05).
CONCLUSION:
Ancillary imaging along with clinical presentation can provide clues to the origin of CM from various cancer sites, thereby aiding in the early diagnosis, staging, and treatment of primary cancer. CM from lung cancer is more likely to precede the diagnosis of a primary tumor than breast metastases.
Keywords: Breast cancer, choroidal metastases, eye cancer, lung cancer, multimodal imaging
Introduction
The most common site of intraocular malignancy in adults is the uveal tissue, which is often the first sign of primary tumor dissemination.[1,2] The choroid, which is a highly vascular tissue with the highest blood vasculature (80%) of the total ocular blood supply, is the most common site of involvement (88%) followed by the iris (9%) and rarely, the ciliary body (2%).[3,4]
The prevalence of uveal metastases is increasing because of recent advances in imaging and diagnostic tools as well as improved overall survival. In one-third of patients, uveal metastases are the first sign of systemic malignancy; hence, the role of an ophthalmologist in early diagnosis and prompt referral to a medical oncologist is of paramount importance.[5,6] On clinical examination, metastatic tumors to the choroid usually appear as unifocal or multifocal, flat or plateau-shaped, creamy white or pale yellow masses associated with subretinal fluid (SRF).[1,4,6,7] In a recent study by Shields et al., analysis of 1111 patients with uveal metastases revealed the primary cancer to be breast (37%), lung (27%), kidney (4%), gastrointestinal tract (4%), and others.[6] Diagnostic modalities such as ultrasonography (USG) provide information about the tumor shape, height, location, and internal reflectivity, whereas recent modalities such as OCT, fluorescein, and indocyanine green angiography help in differentiating them from other simulating choroidal lesions.
In cases where the primary tumor is unknown, the color of these lesions may help to localize the primary tumor. In a review of 520 eyes with uveal metastases by Shields et al., creamy yellow or pale white color lesions were mostly associated with breast and lung cancer (94%); orange color typically seen with renal cell carcinoma, carcinoid tumor, or thyroid cancer metastases (3%) and the brown–gray color with metastatic melanoma (3%).[4] With the ever-growing imaging modalities, it would be prudent to study the unique imaging features of choroidal metastases (CM) arising from different primary cancer sites. We aimed to study the clinical presentation and imaging features of various CMs that were presented to a tertiary care center in India to determine their correlation with the primary site.
Materials and Methods
A retrospective chart review of patients diagnosed with CM at a tertiary eye institute was included in this study. As it was a retrospective observational study sample size estimation was not done. The study was approved by the institutional ethics committee (IRB No: LEC-BHR-P-09-23-778) and adhered to the tenets of the Declaration of Helsinki of medical research involving human subjects. All patients underwent a detailed anterior segment and fundus examination for the assessment of choroidal lesions. All patients underwent a comprehensive eye examination including unaided and best-corrected visual acuity, intraocular pressure (IOP) measurement, slit-lamp examination, and indirect ophthalmoscopy.
Patients underwent multimodal imaging such as ocular USG (Accutome Inc., Malvern, PA, USA), color fundus photography with fundus autofluorescence (FAF) imaging (Cirrus Photo 600 and Clarus 500, Carl Zeiss Meditec, Dublin, CA), fundus fluorescein angiography (FA) with indocyanine angiography (ICG-A) (Heidelberg HRA2, Heidelberg Engineering, Inc, Vista, CA), and OCT (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA).
The following baseline features were recorded in all the patients: age, sex, laterality, eye involved, presenting complaints, best-corrected visual acuity, tumor features like unifocal or multifocality of the tumor, tumor location, shape, size, extent, color and associated features such as the presence of SRF, orange pigment, and drusen. Tumor dimensions including basal diameter and height were measured using A- and B-scan USG with a 10 MHz transducer. A 5-line horizontal and vertical raster OCT scan was performed over the tumor to study its configuration, tumor shadowing, overlying Bruch’s membrane atrophy, retinal pigment epithelium thickness/atrophy, outer retinal abnormalities, presence of SRF and intraretinal fluid. Angiographic studies such as FA and ICG-A were performed after obtaining patient’s consent, particularly assessing lesion hypo/hyperfluorescence in the early, and late phases of the angiography. In patients with a known history of systemic cancer, the systemic staging was performed using whole-body positron emission tomography and computed tomography (PET CT) scan to look for relapse and distant metastases, whereas, in patients with no history of systemic cancer, serum studies for relevant cancer markers and mammography along with whole-body PET CT scan were performed. Results of tumor biopsy helped to confirm the pathological diagnosis and plan for future treatment in cases wherever it was indicated.
All qualitative variables are described in percentages, and quantitative variables are described by their mean and standard deviation. The correlation between the primary tumor site (lung and breast) and clinical and imaging features was analyzed using Fisher’s exact test for categorical variables and the Wilcoxon–Mann–Whitney test for continuous variables. A P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS (IBM, SPSS Statistics, Version 16; SPSS Inc., Chicago, IL, USA).
Results
A total of 67 eyes of 58 Asian Indian patients diagnosed with CM were included. The choroidal involvement was unilateral in 49 (84%) patients, while bilateral in 9 (16%) patients. Among the total 67 eyes involved, 41 (61%) were right eye and 26 (39%) were left eye. There were 28 (48%) male and 30 (52%) female patients. The mean age at ocular diagnosis was 60 years (median, 58 years; range, 29–83 years). The demographic profile of the patients in each group is listed in Table 1.
Table 1.
Demographic profile of patients with choroidal metastases
| Demographic profile | Breast (n=14 eyes, 12 patients), n (%) | Lung (n=36 eyes, 32 patients), n (%) | GI tract (n=6 eyes, 6 patients), n (%) | GUT (n=4 eyes, 3 patients), n (%) | Others (n=7 eyes, 5 patients), n (%) | Total (n=67 eyes, 58 patients), n (%) |
|---|---|---|---|---|---|---|
| Age (years), mean | 51.42 | 59.13 | 68.16 | 71.75 | 51.57 | 60.4 |
| Gender | ||||||
| Male | 0 | 18 (56) | 5 (83) | 2 (67) | 3 (60) | 28 (48) |
| Female | 12 (100) | 14 (44) | 1 (17) | 1 (33) | 2 (40) | 30 (52) |
| Eye | ||||||
| Right | 6 (43) | 27 (75) | 4 (67) | 1 (25) | 3 (43) | 41 (61) |
| Left | 8 (33) | 9 (25) | 2 (33) | 3 (75) | 4 (57) | 26 (39) |
| Known history of systemic cancer | ||||||
| Yes | 10 (83) | 17 (53) | 2 (33) | 3 (100) | 5 (100) | 37 (64) |
| No | 2 (17) | 15 (47) | 4 (67) | 0 | 0 | 21 (36) |
| Biopsy proven cancer | ||||||
| Yes | 9 (75) | 7 (22) | 2 (33) | 0 | 0 | 18 (31) |
| No | 3 (25) | 25 (78) | 4 (67) | 3 (100) | 5 (100) | 40 (69) |
GI=Gastrointestinal, GUT=Genitourinary tract
Primary cancer
The most common primary cancer sites were lung (n = 32, 55%), breast (n = 12, 21%), gastrointestinal (GI) tract (n = 6, 10%), genitourinary (GUT) tract (n = 3, 5%), and others (n = 5, 9%) [Figure 1]. Others included metastasis from leiomyosarcoma, supraglottic squamous cell carcinoma, acute myeloid leukemia, and thyroid carcinoma. The most common quadrant involved was the temporal quadrant (49%), especially in the superotemporal quadrant (24%) [Figure 2]. Of the 67 eyes, optic nerve and macula involvement were seen in 19 (28%) and 27 eyes (40%), respectively. At the time of diagnosis of CM, 37 patients (64%) reported having a known history of systemic cancer, while 21 patients (36%) were diagnosed with primary cancer after the ocular diagnosis.
Figure 1.
A 40-year-old female presented with decreased vision in the right eye for 2 weeks. She had a history of right-side mastectomy 2 years ago and is currently undergoing hormonal treatment. Fundus examination of the right eye showed a yellowish-colored choroidal lesion in the superior quadrant measuring 12.5 mm × 12 mm × 4.8 mm, 0 mm from the optic disc, and 2 mm from the fovea with surrounding subretinal fluid (SRF) (a). Ultrasonography revealed an elevated smooth acoustically dense choroidal lesion with a high surface and medium– high internal reflectivity (b). Optical coherence tomography line scan showed a lumpy– bumpy choroidal lesion with compression of the overlying choriocapillaris and the presence of SRF (c). Blue autofluorescence (AF) image showed an area of central hypoAF corresponding to the lesion and an area of peripheral hyperAF corresponding to SRF (d). Fundus fluorescein angiography in the early phase revealed hypofluorescence with an area of pinpoint hyperfluorescence in the late phase (e and f). Indocyanine green angiography demonstrated hypofluorescence in both the early and late phases of the angiogram (g and h). Multimodal imaging and a recent whole-body positron emission tomography and computed tomography scan confirmed the diagnosis of choroidal metastases from primary breast cancer
Figure 2.
A 33-year-old female presented with pain and diminution of vision in the right eye for 1 month. Fundus examination of the right eye showed a yellowish-colored choroidal lesion in the superonasal quadrant involving the optic disc with surrounding subretinal fluid (SRF) and inferior exudative retinal detachment (a). Ultrasonography revealed an elevated smooth acoustically dense choroidal lesion with a high surface and medium–high internal reflectivity (b). Optical coherence tomography line scan showed a lumpy–bumpy choroidal lesion with compression of the overlying choriocapillaris and the presence of SRF with hyperreflective foci, (c). Blue autofluorescence (AF) image showed an area of hypoAF corresponding to the lesion and an area of hyper AF corresponding to inferior exudative retinal detachment (d). Fundus fluorescein angiography in the early phase revealed hypofluorescence with perilesional hyperfluorescence in the late phase (e and f). Indocyanine green angiography demonstrated hypofluorescence corresponding to the area of the lesion in both the early and late phases (g and h). Multimodal imaging raised the suspicion of choroidal metastasis, and the patient was advised to undergo whole-body positron emission tomography and computed tomography, which revealed the presence of metabolically active lesions in the right lower lobe of the lung with subcarinal and subhilar node positivity. The patient was referred to an oncologist for systemic treatment
The most common presenting symptom was blurring of vision (93%), followed by associated pain (18%) and few were asymptomatic (3%). The mean IOP was 17 mm Hg and 15 mm Hg in breast and lung carcinoma groups, respectively. Elevated IOP secondary to neovascular closed angles was seen in 14% of eyes, especially in the lung carcinoma group. Based on the clinical appearance, most of the patients from the lung cancer group (84%) were creamy yellow in color, while about 14% were orange in color. The varied clinical presentation based on the site of primary cancer is shown in Table 2.
Table 2.
Clinical features of choroidal metastasis
| Imaging features | Breast (n=14), n (%) | Lung (n=36), n (%) | GI tract (n=6), n (%) | GUT (n=4), n (%) | Others (n=7), n (%) | Total (n=67 eyes, 58 patients), n (%) |
|---|---|---|---|---|---|---|
| Laterality | ||||||
| Unilateral | 10 (83) | 28 (88) | 6 (100) | 2 (67) | 3 (60) | 49 (85) |
| Bilateral | 2 (17) | 4 (13) | 0 | 1 (33) | 2 (40) | 9 (15) |
| Tumor focality | ||||||
| Unifocal | 11 (79) | 24 (67) | 6 (100) | 4 (100) | 3 (43) | 48 (72) |
| Multifocal | 3 (21) | 12 (33) | 0 | 0 | 4 (57) | 19 (28) |
| Colour | ||||||
| Yellow | 11 (79) | 30 (83) | 6 (100) | 4 (100) | 5 (71) | 56 (84) |
| Orange | 0 | 5 (14) | 0 | 0 | 0 | 5 (7) |
| Other | 3 (21) | 1 (3) | 0 | 0 | 2 (29) | 6 (9) |
| Optic nerve involvement | ||||||
| Yes | 4 (29) | 11 (31) | 1 (17) | 2 (50) | 1 (14) | 19 (28) |
| No | 10 (71) | 25 (69) | 5 (83) | 2 (50) | 6 (86) | 48 (72) |
| Symptoms | ||||||
| Blurred vision | 13 (93) | 34 (94) | 6 (100) | 4 (100) | 5 (71) | 62 (93) |
| Pain | 4 (29) | 6 (17) | 1 (17) | 1 (25) | 0 | 12 (18) |
| Watering | 2 (14) | 6 (17) | 0 | 0 | 1 (14) | 9 (13) |
| Redness | 2 (14) | 2 (6) | 0 | 0 | 0 | 4 (6) |
| Associated RD | ||||||
| Yes | 7 (50) | 16 (44) | 4 (67) | 2 (50) | 2 (29) | 31 (46) |
| No | 7 (50) | 20 (56) | 2 (33) | 2 (50) | 5 (71) | 36 (54) |
| IOP (mmHg), mean | 17 | 15 | 13 | 13 | 14 | 14 |
| Secondary glaucoma | ||||||
| Yes | 1 (7) | 5 (14) | 0 | 0 | 0 | 6 (9) |
| No | 13 (93) | 31 (86) | 6 (100) | 4 (100) | 7 (100) | 61 (91) |
GI=Gastrointestinal, GUT=Genitourinary tract, RD=Retinal detachment, IOP=Intraocular pressure
Ocular USG was performed in 54 eyes. All the lesions were acoustically dense (100%) with corresponding A-scan demonstrating medium-to-high internal reflectivity in 35 (69%) eyes and medium-to-low internal reflectivity in 16 (31%) eyes. The mean basal diameter and tumor thickness were 9.9 mm (median, 10 mm; range, 3.6–17.2 mm) and 3.9 mm (median, 3.5 mm; range, 1.5–7.2 mm), respectively. The average tumor thickness to basal diameter ratio was extremely low (0.4) highlighting a diffuse flat growth with minimal thickness.
Autofluorescence was performed in 32 eyes, demonstrating hypofluorescent lesions in 25 (78%) eyes and hyperfluorescent lesions in 7 (22%) eyes. OCT was performed in 53 eyes, demonstrating a lumpy-bumpy appearance of the choroid in 52 (98%) eyes, compression of overlying choriocapillaris in 48 (91%) eyes, and the presence of SRF and/or neurosensory detachment in 40 (75%) eyes. Invasive imaging such as FA and ICG were performed in 18 and 16 eyes, respectively. Most of the lesions remained hypofluorescent in the early and late phases (80%). The imaging findings are enumerated in Table 3.
Table 3.
Multimodal imaging features of various choroidal metastases
| Clinical profile | Breast (n=14 eyes, 12 patients) | Lung (n=36 eyes, 32 patients) | GI tract (n=6 eyes, 6 patients) | GUT (n=4 eyes, 3 patients) | Others (n=7 eyes, 5 patients) | Total (n=67 eyes, 58 patients) |
|---|---|---|---|---|---|---|
| Ultrasound (n=51) acoustic | ||||||
| Hollow | 2 | 2 | 0 | 0 | 0 | 4 |
| Dense | 8 | 27 | 6 | 4 | 2 | 47 |
| Internal reflectivity | ||||||
| Medium-high | 6 | 19 | 4 | 4 | 2 | 35 |
| Medium-low | 4 | 10 | 2 | 0 | 0 | 16 |
| Dimensions | ||||||
| Basal diameter | 9.4 | 9.26 | 12.5 | 11.89 | 6.63 | 9.9 |
| Thickness | 3.16 | 3.85 | 4.65 | 4.07 | 3.98 | 3.9 |
| Thickness/diameter ratio | 0.3 | 0.4 | 0.3 | 0.3 | 0.6 | 0.38 |
| FFA (n=18) | ||||||
| Early phase | ||||||
| Hypofluorescent | 1 | 9 | 1 | 0 | 0 | 11 |
| Hyperfluorescent | 1 | 4 | 1 | 1 | 0 | 7 |
| Late phase | ||||||
| Hypo fluorescent | 2 | 12 | 2 | 1 | 0 | 17 |
| Hyperfluorescent | 0 | 1 | 0 | 0 | 0 | 1 |
| ICGA (n=16) Late phase | ||||||
| Hypofluorescent | 5 | 6 | 0 | 0 | 0 | 11 |
| Patchy filling | 1 | 3 | 1 | 0 | 0 | 5 |
| Auto fluorescence (n=32) | ||||||
| Hypo | 4 | 19 | 0 | 1 | 1 | 25 |
| Hyper | 2 | 3 | 1 | 1 | 0 | 7 |
| OCT (n=53) | ||||||
| Lumpy bumpy appearance | 11 | 29 | 6 | 2 | 4 | 52 |
| SRF/NSD | 9 | 22 | 6 | 2 | 1 | 40 |
| Compression of choriocapillaries | 9 | 26 | 6 | 2 | 5 | 48 |
| HRF | 2 | 15 | 5 | 2 | 1 | 25 |
| RPE undulation | 7 | 14 | 4 | 0 | 1 | 26 |
GI=Gastrointestinal, GUT=Genitourinary tract, FFA=Fundus fluorescein angiography, ICGA=Indocyanine green angiography, OCT=Optical coherence tomography, SRF=Subretinal fluid, NSD=Neurosensory detachment, HRF=Hyperreflective foci, RPE=Retinal pigment epithelium
Various clinical and imaging features were significantly correlating with primary cancer origin, particularly in patients with lung and breast cancers [Tables 4 and 5]. Factors found to be strongly correlating with the origin of primary cancer from the lungs were right eye involvement, orange tumor, hyperreflective foci on OCT, greater tumor thickness on B-scan, CM as the presenting feature of primary cancer, and a shorter interval between diagnosis of primary cancer and CM compared with breast cancer (P < 0.05).
Table 4.
Categorical variables comparison between lung and breast tumors
| Variables | Study groups | Fisher’s exact test (P) | |
|---|---|---|---|
| Breast (n=10), n (%) | Lungs (n=29), n (%) | ||
| Gender | |||
| Male | 0 | 15 (100) | 0.006 |
| Female | 10 (42) | 14 (58) | |
| Laterality | |||
| Unilateral | 8 (25) | 24 (75) | 1.000 |
| Bilateral | 2 (29) | 5 (71) | |
| Eye | |||
| Right | 3 (13) | 21 (87) | 0.027 |
| Left | 7 (47) | 8 (53) | |
| Focality | |||
| Unifocal | 9 (28) | 23 (72) | 0.653 |
| Multifocal | 1 (14) | 6 (86) | |
| Macula | |||
| Yes | 9 (35) | 17 (65) | 0.120 |
| No | 1 (8) | 12 (92) | |
| Optic nerve | |||
| Yes | 3 (23) | 10 (77) | 0.455 |
| No | 7 (27) | 19 (73) | |
| Tumor color | |||
| Yellow | 10 (30) | 23 (70) | 0.02 |
| Others | 0 | 6 (100) | |
| FFA (early) | |||
| Hyper | 1 (14) | 6 (86) | 1.00 |
| Hypo | 1 (20) | 4 (80) | |
| FFA (late) | |||
| Hyper | 1 (11) | 8 (89) | 0.455 |
| Hypo | 1 (33) | 2 (67) | |
| ICGA (late) | |||
| Hyper | 1 (50) | 1 (50) | 1.00 |
| Hypo | 5 (50) | 5 (50) | |
| OCT | |||
| SRF/NSD (yes) | 6 (27) | 16 (73) | 1.00 |
| SRF/NSD (no) | 2 (29) | 5 (71) | |
| HRF (yes) | 1 (9) | 10 (91) | 0.003 |
| HRF (no) | 7 (39) | 11 (61) | |
| RPE undulations (yes) | 4 (29) | 10 (71) | 1.00 |
| RPE undulations (no) | 4 (27) | 11 (73) | |
| AF | |||
| Hyper | 4 (24) | 13 (76) | 0.585 |
| Hypo | 2 (40) | 3 (60) | |
| What was diagnosed first? | |||
| Primary cancer | 7 (50) | 7 (50) | 0.019 |
| CM | 3 (12) | 22 (88) | |
FFA=Fundus fluorescein angiography, ICGA=Indocyanine green angiography, OCT=Optical coherence tomography, AF=Autofluorescence, SRF=Subretinal fluid, NSD=Neurosensory detachment, HRF=Hyperreflective foci, RPE=Retinal pigment epithelium, CM=Choroidal metastases
Table 5.
Continuous variables comparison between lung and breast tumors
| Variables | Study groups, mean±SD | P | |
|---|---|---|---|
|
| |||
| Breast (n=10) | Lung (n=29) | ||
| Age (years)# | 50.06±15.25 | 56.52±10.61 | 0.184 |
| Tumor basal diameter (mm)# | 9.58±4.13 | 9.71±3.38 | 0.923 |
| Tumor thickness (mm)# | 3.13±1.75 | 4.10±2.2 | 0.03 |
| Ratio (thickness: Diameter)# | 0.34±0.17 | 0.41±0.15 | 0.248 |
| IOP (mmHG)*, median (Q3–Q1) | 15 (18.5–11.5) | 15 (17.5–12) | 0.862 |
| Interval between diagnosis of primary cancer and CM (months)*, median (Q3–Q1) | 24 (48–1) | 1 (2–1) | 0.008 |
*Mann–Whitney U-test, #t-test. SD=Standard deviation, IOP=Intraocular pressure, CM=Choroidal metastases
Discussion
The choroid is a highly vascular tissue and is the predominant site of metastases from primary tumors. CM is the most common intraocular malignancy seen in adults, followed by choroidal melanoma.[1,4] In the majority of patients (70%), a prior history of systemic cancer confirms the diagnosis; however, in 8%–30% of cases, CM would be the first manifestation of undiagnosed systemic cancer.[5,6] The clinical differentiation of CM based on the tumor color such as creamy-white or pale-yellow CM from breast or lung tumors, orange color from neuroendocrine, renal, and thyroid tumors, and brown-black color from cutaneous melanoma could provide a diagnostic clue to the underlying primary cancer site.[4] A recent study by Blasi et al. studied the ultrasonographic characteristics of CM from lung cancer, and showed that CM from lung cancer displays dome-shaped configuration with medium–low reflectivity compared to those arising from breast cancer which displays plateau-shaped configuration with medium–high reflectivity (P = 0.02).[8] With the recent advances in multimodal imaging, we aimed to explore the specific characteristics of CM using various diagnostic procedures, such as color fundus photography with fundus autofluorescence, ocular USG, OCT, FA, and ICG-A, to determine their correlation with the primary cancer site.
As per the reported literature, the most common primary cancer site of CM is the breast (40% to 53%) followed by the lung (20% to 29%), gastrointestinal tract (4%), prostate (2%), kidney (2%), and skin (2%).[1,2,3,4,5,6,7,9,10] In our series, lung carcinoma (55%) was the most common primary cancer followed by the breast (21%) and gastrointestinal tract (10%). The rising incidence of lung carcinoma among both genders can be attributed to cigarette smoking, tobacco consumption, and environmental factors.[11] Of 30 female patients, 12 were diagnosed with breast carcinoma, highlighting the increasing trend, especially among urban Indian women, which currently accounts for every one in 22 women who are at risk of developing breast carcinoma during their lifetime.[12,13] The most common presenting complaint was blurring of vision followed by ocular pain (18%). This is an important presenting feature to differentiate CM from primary choroidal tumors where ocular pain as a presenting feature is seen in < 1% of cases compared with 14% seen in CM.[4,14,15] The cause of ocular pain is thought to be secondary to tumor necrosis, microscopic scleral invasion producing a scleritis-like picture, or perineural invasion around the posterior ciliary nerves.[15]
As per previously published literature, unilateral unifocal tumors are mostly associated with lung cancer, while bilateral, multifocal tumors are the most common secondary to breast cancer.[4,8,9] In our series, majority of tumors had a unilateral (84%) presentation with no significant difference between lung and breast cancer. However, unifocal tumors (72%) were relatively more common in patients with breast cancer compared to lung cancer (79% vs 67%). This can be explained by the fact that the epidemiology, lifestyle, built, genetic makeup, reproductive and breastfeeding patterns, and molecular subtypic characteristics of Indian females are quite different from those of Western females.[16] On clinical examination, most tumors appeared creamy-yellow or pale-white (84%). Furthermore, all eyes (n = 10) with CM from GIT and GUT presented as pale-white lesions with majority (80%) presenting as unilateral, unifocal tumors with associated total exudative retinal detachment. Subretinal hemorrhage associated with exudative retinal detachment (four eyes) is an important clinical feature of GIT tumors, as described in a few case reports.[17,18] There were five eyes (14%) with orange-colored CM, and all originated from bronchial carcinoid tumors (P = 0.02). This is an important differentiating feature for identifying primary cancer sites based on CM color. In a study of nine patients diagnosed with a distinctive orange-colored CM, it was noted that all arose from a carcinoid tumor.[19]
Ultrasonography is one of the most important noninvasive imaging modalities for the diagnosis of CM. Ultrasonographic B-scan, which measures the tumor dimensions as well as tumor echogenicity, have been useful in distinguishing CM (nonhomogeneous lesions) from choroidal melanoma (homogeneous lesion with acoustic hollowness). In our series, 92% of eyes showed heterogeneous dense lesions with a mean basal diameter of 9.9 mm and tumor thickness of 3.9 mm. This is comparable to a previous study showing nonhomogeneous lesions in 82% of eyes with a mean tumor thickness of 4.3 mm.[8] The tumor configuration of CM appears to be a flat lesion diffusely infiltrating the choroid, resulting in an irregular shape on USG.[20] The mean tumor thickness for CM was 3.9 mm, giving it a much lower thickness-to-base diameter ratio (0.38) than that reported for choroidal melanoma (0.6).[21] Similarly, the A-scan, which measures the surface and internal reflectivity, showed medium–high internal reflectivity in 69% of eyes, which was similar to the previous studies.[8,22] This is attributed to the internal characteristics of CM, which contains solid epithelial nests or glandular structures along with intrinsic vascularization-producing acoustic interfaces, resulting in high reflectivity and an irregular internal structure.[23,24]
Various studies have used OCT to demonstrate the unique characteristics of CM, such as the irregular contour of the anterior surface of the tumor (lumpy bumpy), the presence of SRF overlying as well as adjacent to tumor boundary, compression of the overlying choriocapillaris, and photoreceptor damage.[25,26,27,28] In our series, 98% of eyes showed a lumpy-bumpy appearance of the anterior surface of tumor, 91% of eyes showed compression of the overlying choriocapillaris, and 75% of eyes had SRF. SRF has been studied for its fluid composition and optical density, which can serve as a biomarker for differentiating different choroidal lesions.[29,30] Compared with choroidal melanoma, the SRF quantity and protein content within the CM are significantly lower than those of choroidal melanoma.[30] Among the various OCT features, the presence of hyperreflective foci (HRF) significantly correlated with underlying primary lung cancer (P = 0.003). This can be attributed to the dome-shaped configuration of lung tumors compared with plateau-shaped breast tumors, leading to compression of the overlying choriocapillaris, thereby shedding the outer photoreceptor segment in the subretinal spaces, which is described as HRF or speckles.[28,31]
The role of invasive diagnostic imaging such as FA and ICG-A is very limited due to variable intrinsic tumor architecture and blood supply. On FA most of the lesions remain hypofluorescent in early phases with late hyperfluorscence or leakage in few cases. On the contrary, CM remains hypofluorescent throughout all the phases of ICG-A.[32] This may be due rapid growth of metastases leading to the obscuration of large choroidal vessels and hence the lesion remains hypofluorescent on ICG-A.[33] In our series, 11 of 16 eyes showed hypofluorescence throughout all phases of ICG-A, while five eyes showed patchy filling of tumor vessels in the late phase.
The CM factors that were found to be strongly correlating with primary lung cancers included right eye involvement, orange tumor, hyperreflective foci on OCT, greater tumor thickness, CM as the presenting feature, and a shorter interval between diagnosis of primary cancer and CM (P < 0.05). This finding of a shorter interval between primary cancer and CM from lung cancer compared to CM from breast cancer has been previously reported.[9,15] Regarding laterality, some authors have shown left eye predilection due to a direct path to the eye from the left common carotid originating from the aorta, whereas others have reported right eye involvement.[34,35] However, previous larger series have observed no particular difference in laterality.[4,5] Although there was no statistically significant difference among any of the imaging features such as FA, AF, and ICG between the CM from lung and breast cancers, we observed that CM from lung cancer had larger tumor thickness compared to CM arising from breast cancer (P = 0.03). This is comparable to previous reports in which CM from breast cancer have a plateau-shaped configuration, whereas those from lung cancer are dome shaped.[4,8]
Limitations
Our study has a few limitations that need to be addressed. First, because this was a retrospective study, there is a potential bias due to multiple surgeons and optometrists performing ultrasound imaging and inaccuracies in the uniform imaging of cases with different machines at different time points. Second, in few patients due to poor media clarity or general health conditions, invasive imaging such as FA and ICG were not available for all patients. Third, because of the smaller sample size, the statistical power to differentiate lung and breast tumors based on the primary cancer sites was undermined. Further tumor size is related to their growth time which was overlooked in the study due to its retrospective nature. Nevertheless, our study highlights the unique clinical and imaging features of various CM in an Asian Indian population, which could help develop guidelines for uniform data documentation and prompt early referral to an ocular oncologist. In the future, multicenter studies with larger sample sizes are needed to complement our results and integrate various conglomerations of findings to elucidate the significant correlation between primary cancer sites and CM.
Conclusion
Ancillary imaging along with clinical features provided greater insights into the structural and vascular features of CM to distinguish them from other choroidal lesions. Along with clinical presentation, it can provide clues to the origin of choroidal metastasis from various cancer sites, thereby aiding in the early diagnosis, staging, and treatment of primary cancer. Choroidal metastases from lung cancer are more likely to precede the diagnosis of a primary tumor than breast metastases.
Ethical statement
This study was approved by the Institutional Review Board at L V Prasad Eye Institute.
Data availability statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of interest
The authors declare that there are no conflicts of interests of this article.
Funding Statement
This work was supported by an unrestricted departmental grant from Hyderabad Eye Research Foundation, Hyderabad, India.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.