Paraneoplastic retinopathy is a rare condition in which autoantibodies against an extraocular cancer cross-react with retinal or retinal pigment epithelial (RPE) antigens, resulting in retinal damage.1–10 There are two major types of paraneoplastic retinopathy: cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR).8,9 The CAR syndrome is most frequently found in patients with small cell lung carcinoma and is associated with autoantibodies against recoverin and other retinal proteins.9 The MAR syndrome occurs in the setting of metastatic cutaneous or uveal melanoma and autoantibodies against bipolar cells are found, although other antigens such as bestrophin, titan, mitofilin, and transducin-B have been described.8 In MAR, the patient manifests a normal retinal appearance or subtle RPE changes.2 Acute exudative polymorphous vitelliform maculopathy (AEPPVM) is a less common form of paraneoplastic retinopathy, most often found in patients with cutaneous or choroidal melanoma. This disorder is characterized by multifocal yellow-white pockets of shallow serous retinal detachment in the macula and peripapillary region of both eyes.11–21 We describe the clinical features and outcomes of three additional patients with AEPPVM occurring in the setting of melanoma and carcinoma.
Patients and Methods
The medical records of patients with the diagnosis of paraneoplastic retinopathy consulted at the Oncology Service, Wills Eye Institute were reviewed after approval by the Institutional Review Board and those with AEPPVM were selected for further analysis. Demographic information was collected, including patient age (years), race (white, African American, Hispanic, or Asian), and gender (male or female). The systemic findings included previous history of systemic cancer (primary tumor location, date of diagnosis, and treatment), metastases from the primary neoplasm (location, date of diagnosis, and treatment), and follow-up status.
The ocular data included presenting symptoms, best-corrected visual acuity, intraocular pressures (mm Hg), slit-lamp examination findings, funduscopic findings, fundus autofluorescence, fluorescein angiography, fundus optical coherence tomography (OCT), ultrasonography findings, electroretinography, visual field testing, and color vision. The ophthalmic findings at date last seen were documented, including months of follow-up, status of the findings (stable, improved, or worsened), and final visual acuity. Autoantibody serologic testing was documented, which was done at either the Ocular Immunology Laboratory at Casey Eye Institute, Oregon Health & Science University or at the Ocular Immunology Laboratory of the University of California, Davis.
There were five white patients (10 eyes) with AEPPVM, of whom 3 (60%) were male and 2 (40%) were female. Two cases were previously reported as case reports (cases 2 and 3).16,20
The primary neoplasm was skin melanoma with multiple organ metastases in 2 patients, choroidal melanoma with liver metastases in 1 patient, lung adenocarcinoma with bone metastases in 1 patient, and lung plus breast adenocarcinoma with liver metastases in 1 patient (Table 1). The mean age at presentation was 70 years (median: 74 years, range: 54 to 79 years). The mean interval between the diagnosis of the primary neoplasm to the presentation of ocular symptoms was 42 months (median: 60 years, range: 0 to 73 years).
Table 1: Systemic Findings of Acute Exudative Paraneoplastic Polymorphous Vitelliform Maculopathy in 5 Patients
The presenting symptom was blurred vision in 5 (100%) cases and additional photopsia and nyctalopia in one patient (20%). Initial visual acuity was 20/30 to 20/40 in 2 (20%) eyes and 20/50 to 20/100 in 8 (80%) eyes. Ophthalmoscopic findings revealed multiple yellow-white subretinal lesions that proved to be multifocal shallow areas of serous detachment of the neurosensory retina in the macula, post-equatorial retina, and peripapillary region in all 10 eyes (100%). The average number of lesions per eye was 21 (median: 14, range: 3 to 70). The average size of each lesion was 0.8 mm (median: 0.6 mm, range: 0.1 to 3.0 mm).
OCT documented numerous areas of dome-shaped serous detachment of the neurosensory retina in all 10 (100%) eyes, with additional cystoid macular edema in 2 (20%) eyes and later development of multiple RPE detachments in 2 (20%) eyes. The choroid, when visualized, appeared normal in each case. The average central macular thickness in the 10 eyes was 398 micrometers (median: 334 micrometers, range: 235 to 644 micrometers). Ultrasonography confirmed subretinal fluid in only 4 (40%) eyes. Autofluorescence demonstrated hyperautofluorescence corresponding to the areas of neurosensory retinal detachment in all 8 (80%) eyes where it was done. Fluorescein angiography depicted the regions of subretinal fluid with localized persistent hypofluorescence in 6 (60%) eyes and slight hyperfluorescence in 4 (40%) eyes.
Full-field electroretinogram analyzing cone and rod function separately was performed in 6 eyes; it revealed diminished rod and cone responses in 2 (20%) eyes and normal response in 4 (40%) eyes. Autoantibody testing was performed in 3 cases and demonstrated antiretinal antibodies in each case. In 2 cases, anti-retinal antibodies against a 29-kDa protein (carbonic anhydrase 2) and a 68-kDa protein were found. The remaining patient had antiretinal antibodies against a 145-kDa protein compatible with interphotoreceptor retinoid binding protein. After mean follow-up of 5 months (median: 5 months, range: 2 to 10 months), 3 (60%) patients had died of metastases. The two survivors showed visual acuity improvement and complete resolution of vitelliform lesions in one case (after 2 months) and no change in the other case (after 10 months).
Each case is summarized in Tables 1 and 2.
Table 2: Ocular Findings of Acute Exudative Paraneoplastic Polymorphous Vitelliform Maculopathy in 5 Patients
A 79-year-old white man with known metastatic cutaneous melanoma of the neck 5 years earlier developed gradual painless loss of visual acuity to 20/50 in the right eye and 20/30 in the left eye. Funduscopy revealed multifocal shallow yellow-white pockets of subretinal fluid in the post-equatorial region of each eye. Testing is listed in Table 2. A diagnosis of AEPPVM was rendered. The patient died of multiple systemic melanoma metastases 7 months later (Fig. 1).
Figure 1. (Case 1) A 79-year-old man with vitelliform lesions (A and B) demonstrating hyperautofluorescence (C and D), slight hyperfluorescence on fluorescein angiography (E and F), and small regions of shallow subretinal fluid and cystoid macular edema on optical coherence tomography (G and H).
A 74-year-old white man with known metastatic cutaneous melanoma of the neck 14 months earlier developed gradual painless loss of visual acuity to 20/70 in the right eye and 20/60 in the left eye. Funduscopy revealed multifocal shallow yellow-white pockets of subretinal fluid in the post-equatorial region of each eye. Testing is listed in Table 2. A diagnosis of AEPPVM was made. The patient died of multiple systemic melanoma metastases 3 months later.
A 69-year-old white woman with known metastatic breast and lung adenocarcinoma 5 and 2 years earlier, respectively, developed nyctalopia, photopsia, and gradual painless loss of visual acuity to 20/80 in the right eye and 20/70 in the left eye. Funduscopy revealed multifocal shallow yellow-white pockets of subretinal fluid in the post-equatorial region of each eye. Testing is listed in Table 2. A diagnosis of AEPPVM was rendered. After 10 months of follow-up, the patient is alive with stable vision in both eyes (Fig. 2).
Figure 2. (Case 3) A 69-year-old woman with symptomatic vitelliform lesions (A and B), demonstrating hyperautofluorescence (C and D) and hypofluorescence (E and F) on angiography and shallow subretinal fluid on optical coherence tomography (G and H).
A 60-year-old white woman with known metastatic choroidal melanoma in the left eye treated with plaque radiotherapy 6 years earlier developed gradual painless loss of visual acuity to 20/30 in the right eye and 20/100 in the left eye. Funduscopy revealed multifocal shallow yellow-white pockets of subretinal fluid in the post-equatorial region in the right eye more than in the left eye with regressed choroidal melanoma in the left eye. Testing is listed in Table 2. A diagnosis of AEPPVM was rendered. The patient died of liver metastasis 2 months later (Fig. 3).
Figure 3. (Case 4) A 54-year-old woman with treated choroidal melanoma in the left eye showed symptomatic vitelliform lesions in the right eye (A and B), corresponding hyperautofluorescence in the right eye more than the left eye (C and D), hypofluorescence on angiography (E and F), and subretinal fluid on optical coherence tomography (G and H).
A 74-year-old white man with newly diagnosed metastatic adenocarcinoma of the lung developed painless loss of visual acuity to 20/60 in both eyes. Funduscopy revealed multifocal shallow pockets of subretinal fluid in the macula in both eyes. Two weeks later, multifocal RPE detachments were noted. A diagnosis of AEPPVM was rendered and chemotherapy was initiated. After 2 months, visual acuity improved to 20/30 in the right eye and 20/20 in the left eye and complete resolution of the vitelliform lesions was noted in each eye (Fig. 4).
Figure 4. (Case 5) A 74-year-old man with glaucoma developed reduced vision without visible vitelliform lesions (A and B), confirmed as subretinal fluid on optical coherence tomography (OCT) (C and D). Later, vitelliform lesions were noted (E and F) and OCT showed retinal pigment epithelial detachments (G and H) and slight hyperfluorescence on angiography (I and J). Two months later, resolution of symptoms, vitelliform lesions (K and L), and normal OCT (M and N) were documented.
Paraneoplastic syndromes represent a remote immunologic effect of cancer.1 There are several paraneoplastic syndromes that manifest in the ocular region, including CAR, MAR, bilateral diffuse uveal melanocytic proliferation, optic neuropathy, motility disorders, and others. CAR syndrome is a paraneoplastic retinal disorder that was described first by Sawyer et al. in 1976.22 It most often is associated with small cell carcinoma of the lung, although it has also been described in patients with breast cancer, invasive thymoma, uterine cervical cancer, endometrial cancer, lymphoma, and other malignancies.23–27 CAR syndrome involves antibodies against retinal elements and causes both rod and cone dysfunction. Although the 23-kd photoreceptor protein recoverin was the first and the most common retinal antigen linked to CAR syndrome, more than 15 other proteins expressed by rods, cones, and ganglion cells of the retina are now thought to act as potential autoantigens.23
MAR syndrome occurs in the setting of metastatic cutaneous or uveal melanoma and autoantibodies against bipolar cells are usually found, although other antigens such as bestrophin, titan, mitofilin, and transducin-B have been described.4,5,8 Typical symptoms include nyctalopia, photopsia, and varying visual loss. Classically, the fundus appears normal with occasional subtle RPE mottling or vascular attenuation. The electroretinogram shows attenuation in the b-wave and normal a-wave.7,8
Idiopathic AEPVM is a rare multifocal exudative fundus disorder first described by Gass in two patients in 1988 and later in a third patient in 1997.28,29 All three patients had acute onset of vision loss associated with multiple oval yellow-white lesions presumably at the level of RPE surrounding the disk and in the macular region in both eyes, as well as bilateral serous macular detachments.28,29 There was no OCT at that time to confirm the findings.
There have been few subsequent reports of the paraneoplastic form of AEPPVM.6,12–19,21 Early reports attributed the fundus lesions to RPE detachments.12,14 More recent reports clarified the yellow-white fundus findings to shallow neurosensory retinal detachment rather than RPE detachment.11,13,15–20 Similarly, in our series of 5 cases, the yellow-white fundus findings appeared clinically to represent localized RPE detachments but careful scrutiny of high-resolution OCT disclosed features more consistent with subretinal rather than sub-RPE fluid. In one case (case 5), the patient manifested multifocal regions of subretinal fluid initially and multifocal RPE detachments later, both confirmed on OCT.
In the literature, AEPPVM has been associated with cutaneous melanoma (n = 5 cases),6,11,12,16,17 choroidal melanoma (n = 5 cases),13,14,15,17,18 visceral melanoma (n = 1 case),26 and metastatic melanoma from an unknown primary site (n = 2).13,19 Grunwald et al. recently reported the first case of AEPPVM with carcinoma, not melanoma.20 In our series, the primary malignancy was cutaneous melanoma (2 cases), choroidal melanoma (1 case), and carcinoma (2 cases).
In the published literature, autoantibodies in AEPPVM have included a 120-kDa photoreceptor protein, bestrophin-1, a 145-kDa interphotoreceptor retinoid-binding protein, a 26-kDa protein (peroxiredoxin 3), and recoverin 23 kDa.16–19,21 In our series, autoantibodies disclosed a different protein in each case, perhaps reflecting the specificity of the autoantibody for the individual malignancy. Despite the dissimilar autoantibodies, the ocular manifestations were remarkably parallel. The affected eyes were symmetric in terms of number, size, and distribution of vitelliform lesions. For example, the patient with a 29-kDa protein (case 1) showed 10 lesions in each eye of approximately 0.5 mm diameter, whereas the patient with a 145-kDa protein (case 2) showed 3 to 6 lesions in each eye of approximately 1 to 3 mm diameter.
There is little information regarding therapy or outcome of this disorder because most patients die of their underlying malignancy within months. In our series, 3 of 5 patients were dead within 4 months and another patient only had 2 months of follow-up. Koreen et al. provided follow-up in 1 case in which complete resolution of subretinal fluid and visual recovery was documented after 1 year.19 One patient in our series (case 5) showed similar resolution of subretinal fluid and visual recovery after 2 months of observation.
AEPPVM is a unique paraneoplastic retinopathy with numerous yellow-white (vitelliform) macular and perimacular lesions representing shallow pockets of serous retinal detachment. Vision loss results from subfoveal detachment or cystoid macular edema. Various anti-retinal and anti-RPE antibodies have been documented. This condition portends an ominous prognosis.
- Solomon SD, Smith JH, O’Brien J. Ocular manifestations of systemic malignancies. Curr Opin Ophthalmol. 1999;10:447–451. doi:10.1097/00055735-199912000-00013 [CrossRef]
- Berson EL, Lessell S. Paraneoplastic night blindness with malignant melanoma. Am J Ophthalmol. 1998;106:307–311. doi:10.1016/0002-9394(88)90366-2 [CrossRef]
- Milam AH, Saari JC, Jacobson SG, Lubinski WP, Feun LG, Alexander KR. Autoantibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Invest Ophthalmol Vis Sci. 1993;34:91–100.
- Weinstein JM, Kelman SE, Bresnick GH, Kornguth SE. Paraneoplastic retinopathy associated with antiretinal bipolar cell antibodies in cutaneous malignant melanoma. Ophthalmology. 1994;101:1236–1243.
- Potter MJ, Thirkill CE, Dam OM, Lee SA, Milam AH. Clinical and immunocytochemical findings in a case of melanoma-associated retinopathy. Ophthalmology. 1999;106:2121–2125. doi:10.1016/S0161-6420(99)90493-1 [CrossRef]
- Borkowski LM, Grover S, Fishman GA, Jampol LM. Retinal findings in melanoma associated retinopathy. Am J Ophthalmol. 2001;132:273–275. doi:10.1016/S0002-9394(01)00915-1 [CrossRef]
- Lei B, Bush RA, Milam AH, Sieving PA. Human melanoma-associated retinopathy antibodies alter the retinal ON-response of the monkey ERG in vivo. Invest Ophthalmol Vis Sci. 2000;41:262–266.
- Thirkill CE. Cancer-induced, immune-mediated ocular degenerations. Ocul Immunol Inflamm. 2005;13:119–131. doi:10.1080/09273940590928733 [CrossRef]
- Thirkill CE, Fitzgerald P, Sergott RC, Roth AM, Tyler NK, Keltner JL. Cancer-associated retinopathy (CAR syndrome) with antibodies reacting with retinal, optic nerve, and cancer cells. N Engl J Med. 1989;321:1589–1594. doi:10.1056/NEJM198912073212307 [CrossRef]
- Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol. 2001;21:173–187. doi:10.1097/00041327-200109000-00004 [CrossRef]
- Gass JDM. Acute Vogt-Koyanagi-Harada-like syndrome occurring in a patient with metastatic cutaneous melanoma. In: Matti Saari K. Uveitis Update: Proceedings of the International Symposium on Uveitis, Hansaari. Espoo, Finland. Amsterdam: Elsevier Science Publishers; 1984:407–408.
- Palmowski AM, Haus AH, Pföhler C, et al. Bilateral multifocal chorioretinopathy in a woman with cutaneous malignant melanoma. Arch Ophthalmol. 2002;120:1756–1761.
- Jampol LM, Kim HH, Bryar PJ, Shankle JB, Lee RT, Johnston RL. Multiple serous retinal detachments and subretinal deposits as the presenting signs of metastatic melanoma. Retina. 2004;24:320–322. doi:10.1097/00006982-200404000-00028 [CrossRef]
- Nieuwendijk TJ, Hooymans JM. Paraneoplastic vitelliform retinopathy associated with metastatic choroidal melanoma. Eye (Lond). 2007;21:1436–1437. doi:10.1038/sj.eye.6702949 [CrossRef]
- Zacks DN, Pinnolis MK, Berson EL, Gragoudas ES. Melanoma-associated retinopathy and recurrent exudative retinal detachments in a patient with choroidal melanoma. Am J Ophthalmol. 2001;132:578–581. doi:10.1016/S0002-9394(01)01086-8 [CrossRef]
- Bianciotto C, Shields CL, Thirkill CE, Materin MA, Shields JA. Paraneoplastic retinopathy with multiple detachments of the neurosensory retina and autoantibodies against interphotoreceptor retinoid binding protein (IRBP) in cutaneous melanoma. Br J Ophthalmol. 2010;94:1684–1685. doi:10.1136/bjo.2008.151480 [CrossRef]
- Sotodeh M, Paridaens D, Keunen J, Van Schooneveld M, Adamus G, Baarsma S. Paraneoplastic vitelliform retinopathy associated with cutaneous or uveal melanoma and metastases. Klin Monbl Augenheilkd. 2005;222:910–914. doi:10.1055/s-2005-858840 [CrossRef]
- Eksandh L, Adamus G, Mosgrove L, Andreasson S. Autoantibodies against bestrophin in a patient with vitelliform paraneoplastic retinopathy and a metastatic choroidal malignant melanoma. Arch Ophthalmol. 2008;126:432–435. doi:10.1001/archopht.126.3.432 [CrossRef]
- Koreen L, He SX, Johnson MW, Hackel RE, Khan NW, Heckenlively JR. Anti-retinal pigment epithelium antibodies in acute exudative polymorphous vitelliform maculopathy: a new hypothesis about disease pathogenesis. Arch Ophthalmol. 2011;129:23–29. doi:10.1001/archophthalmol.2010.316 [CrossRef]
- Grunwald L, Kligman B, Shields CL. Acute exudative polymorphous paraneoplastic vitelliform maculopathy in a patient with carcinoma, not melanoma. Arch Ophthalmol. 2011;129:1104–1106. doi:10.1001/archophthalmol.2011.215 [CrossRef]
- Javaheri M, Khurana RN, Bhatti RA, Lim JI. Optical coherence tomography findings in paraneoplastic pseudovitelliform lesions in melanoma-associated retinopathy. Clin Ophthalmol. 2008;2:461–463.
- Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol. 1976;81:606–613.
- Keltner JL, Thirkill CE. Cancer-associated retinopathy vs recoverin-associated retinopathy. Am J Ophthalmol. 1998;126:296–302.
- Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol. 2001;21:173–187. doi:10.1097/00041327-200109000-00004 [CrossRef]
- Misiuk-Hojlo M, Jurowska-Liput J, Gorczyca W. Cancer associated retinopathy. Nowotwory J Oncol. 2004;54:584–586.
- Suhler EB, Chan CC, Caruso RC, et al. Presumed teratoma-associated paraneoplastic retinopathy. Arch Ophthalmol. 2003;121:133–137. doi:10.1001/archopht.121.1.133 [CrossRef]
- To KW, Thirkill CE, Jakobiec FA, Lessell S, Berson EL. Lymphoma-associated retinopathy. Ophthalmology. 2002;109:2149–2153. doi:10.1016/S0161-6420(02)01261-7 [CrossRef]
- Gass JDM, Chuang EL, Granek H. Acute exudative polymorphous vitelliform maculopathy. Trans Am Ophthalmol Soc. 1988;86:354–366.
- Gass JDM. Acute idiopathic exudative polymorphous vitelliform maculopathy. In: Gass JDM, ed. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 4th ed. St. Louis: CV Mosby; 1997:168–169.
Systemic Findings of Acute Exudative Paraneoplastic Polymorphous Vitelliform Maculopathy in 5 Patients
|Patient||Age (Years)/Race/Sex||Primary Neoplasm||Systemic Metastases||Treatment of Primary and Systemic Cancer||Interval (Months)a||Systemic Status (Months of Follow-up)|
|1||79/W/M||Cutaneous melanoma of neck||Multiple organs||Chemotherapy, EBRT, surgical excision||62||Dead from metastases (7)|
|2||74/W/M||Cutaneous melanoma of face||Multiple organs||Chemotherapy, EBRT, surgical excision||14||Dead from metastases (3)|
|3||69/W/F||Lung and breast adenocarcinoma||Liver||Chemotherapy, EBRT, surgical excision||60||Alive with metastases (10)|
|4||54/W/F||Choroid melanoma||Liver||Plaque (I125) chemotherapy||73||Dead from metastases (2)|
|5||74/W/M||Lung adenocarcinoma||Bones||Chemotherapy||0||Alive with metastases (2)|
Ocular Findings of Acute Exudative Paraneoplastic Polymorphous Vitelliform Maculopathy in 5 Patients
|Patient||Ocular Symptoms||VA||Funduscopic Features||OCT CFT Findings (μm)||US Findings||Autofluorescence||IVFA||ERG||Autoantibodies|
|Findings||No.a||Diameter (mm)b||Quadrants Affected||Findings||Choroid Thickness (mm)|
|1 OD||Blurred vision||20/50||Multifocal serous RD with yellow-white SRF||10||0.5||4 quadrants posteriorly||644 SRF + CME||SRF||1.7||Hyper-autofluorescent||Hyperfluorescence all phases||Subnormal rod & cone responses||AB (29-kDa & carbonic anhydrase 2 proteins)|
|1 OS||Blurred vision||20/30||Multifocal serous RD with yellow-white SRF||13||0.5||4 quadrants posteriorly||548 SRF + CME||SRF||1.7|
|2 OD||Blurred vision||20/70||Multifocal serous RD with yellow-white SRF||3||2.0–3.0||4 quadrants posteriorly||490 SRF||Normal||1.2||Hyper-autofluorescent||Hypofluorescence all phases||Normal||AB (145-kDa protein)|
|2 OS||Blurred vision||20/60||Multifocal serous RD with yellow-white SRF||6||1.0–2.0||4 quadrants posteriorly||287 SRF||Normal||1.2|
|3 OD||Blurred vision, photopsia, nyctalopia||20/80||Multifocal serous RD with yellow-white SRF||14||0.5–1.0||4 quadrants posteriorly||377 SRF||CT||1.6||Hyper-autofluorescent||Hypofluorescence all phases||Not performed||Not performed|
|3 OS||Blurred vision, photopsia, nyctalopia||20/70||Multifocal serous RD with yellow-white SRF||17||0.5–1.0||4 quadrants posteriorly||362 SRF||CT||1.6|
|4 OD||Blurred vision||20/30||Multifocal serous RD with yellow-white SRF||70||0.5–1.0||2 superior quadrants posteriorly||336 SRF||SRF||1.6||Hyper-autofluorescent||Hypofluorescence all phases||Normal||AB (68-kDa protein)|
|4 OS||Blurred vision||20/100||Multifocal serous RD with yellow-white SRF||4||0.5||None||332 SRF||SRFc||1.7c|
|5 OD||Blurred vision||20/60||Multifocal serous RD with yellow-white SRF||30||0.1–0.2||Macula||235 SRF||Not performed||Not performed||Not performed||Hyperfluorescence all phases||Not performed||Not performed|
|5 OS||Blurred vision||20/60||Multifocal serous RD with yellow-white SRF||40||0.1–0.2||Macula||329 SRF|