Paraneoplastic syndromes and the retina.

INTRODUCTION
Paraneoplastic syndromes occur in the setting of systemic malignancy as an autoimmune response to tumor antigens or to circulating tumor-derived factors [1,2]. Paraneoplastic syndromes of the retina include cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), paraneoplastic vitelliform maculopathy (PVM), and bilateral diffuse uveal melanocytic proliferation (BDUMP) [1–5].
CAR and MAR are two of the three conditions comprising autoimmune retinopathy (AIR), the other being nonparaneoplastic AIR when systemic malignancy is absent. CAR and MAR, forms of paraneoplastic AIR, are thought to occur when tumor antigens trigger an autoimmune response to retinal proteins via molecular mimicry [3,6,7]. CAR may be more common than MAR, but both are rare [8]. Multimodal imaging, electrophysiologic testing, and serologic antibody testing aids in diagnosis as clinical examination is often unremarkable [9].
PVM and BDUMP have more distinctive clinical findings with serous retinal detachments in both and multifocal, vitelliform lesions in the posterior pole in PVM and multiple pigmented or amelanotic uveal lesions in BDUMP [4,10]. PVM is thought to occur as an autoimmune response to neoplasm when immune cells cross-react with the retinal pigment epithelium (RPE) [11–13]. BDUMP is believed to occur when circulating tumor-derived factors stimulate melanocytic proliferation [10].
Diagnosis of paraneoplastic retinopathies is challenging. Prompt recognition and referral for workup and management is prudent given the systemic implications.

CANCER-ASSOCIATED RETINOPATHY
First described in 1967 [14], CAR arises when antiretinal antibodies (ARAs), most often antirecoverin (calcium-binding protein in photoreceptors) [15,16], damage the retina via direct cytotoxicity to photoreceptors segments and direct apoptosis of retinal cells [15,16]. Other retinal proteins targeted by ARAs include alpha-enolase, carbonic anhydrase II, heat shock cognate protein 70 (HSC70), and transducin [17–19].
CAR presents with progressive, subacute vision loss, scotomas, photopsias, and/or nyctalopia. Rods and cones are affected to differing degrees [20]. Early on, visual acuity is preserved relative to peripheral visual field restriction, and fundus appears normal. More advanced disease shows retinal vascular attenuation, diffuse retinal atrophy, RPE changes, and waxy disc pallor with intraocular inflammation less commonly present (Fig. 1a,b) [18]. Notably, the clinical presentation of late-stage CAR is similar to retinitis pigmentosa. The differential diagnosis includes inherited retinal dystrophies, vitamin A deficiency, drug toxicities, and inflammatory conditions. Hence, discussion of review of symptoms, family history, malignancy risk factors, and medication use should be done [3,8]. Small cell lung cancer is most common but other malignancies are breast, uterine, prostate, gastrointestinal, liver, and kidney cancer [8,21▪,22,23].
Diagnosing CAR is challenging since half of patients experience visual symptoms before the diagnosis of malignancy [24]. In a patient with unremarkable fundus examination but progressive vision loss, CAR should be considered. Multimodal imaging with visual field testing and electroretinogram (ERG) is helpful in diagnosis [9]. Fundus autofluorescence (FAF) often shows a hyperautofluorescent ring in the macula and less commonly shows a peripapillary hyperautofluorescent ring, speckled foveal hyperautofluorescence, patchy peripheral hyperautofluorescence, and hypo and hyper-autofluorescent perivascular lesions (Fig. 1c,d) [25,26]. Optical coherence tomography (OCT) may show macular edema, outer retinal atrophy, and ellipsoid zone loss (Fig. 1e,f); earlier on, outer nuclear layer thinning may occur in a parafoveal distribution with subfoveal preservation [8,27]. Full-field ERG is very sensitive at detecting CAR and shows rod and cone dysfunction (Fig. 2a) [3,6,8,24]. Visual fields are constricted with central or paracentral scotomas [3] (Fig. 2b,c). Fluorescein angiogram is not helpful in diagnosing CAR but is useful for ruling out other causes [24].
Once there is a high index of suspicion, a CAR antibody panel should be ordered [24]. Testing protocols for ARAs lack standardization as different testing methods exist, and laboratories must select the antibodies of interest [20]. Sensitivity can be increased by combining the Western blot analysis with confirmatory immunohistochemical testing on human retinal flatmounts to confirm localization to retinal structures [8,28]. When identified, ARAs increases suspicion for CAR, but ARAs are nonspecific, existing in normal controls and inflammatory diseases [8,29–31]. Amongst ARAs, antirecoverin antibodies have the highest specificity for CAR [3]. However, the presence of antirecoverin antibodies does not confirm the diagnosis either as these can be found in normal patients and in other ocular diseases [8,29–31].
Patients with clinical, imaging, and serologic confirmation of AIR but no known history of cancer should undergo systemic investigation for malignancy in collaboration with a primary care physician or oncologist with completion of age and sex-appropriate testing (e.g. colonoscopy, mammogram), systemic visceral organ imaging by computed tomography or magnetic resonance imaging scans, and laboratory investigations targeted at the patient's risk factors.
The underlying malignancy should be treated. However, despite treatment and even during cancer remission, CAR can still occur because the blood circulation already has the ARAs [19,24,32▪]. Given the rarity of this condition, no standardized treatment protocol exists [24]. Typically, systemic corticosteroids, oral or intravenous (i.v.), are initially used and can stabilize visual acuity and visual field loss [32▪]. Steroid sparing agents such as mycophenolate, azathioprine, and methotrexate have stabilized ERG abnormalities in some cases [3,32▪]. In a meta-analysis of AIR, rituximab, an anti-CD20 monoclonal antibody, was found to stabilize visual acuity and ERG abnormalities [32▪,33], and reports of concurrent rituximab and cyclophosphamide have shown promise [7,34]. A systematic review found that after systemic steroids, intravenous immunoglobulins (IVIGs) and plasmapheresis or plasma exchange (PLEX) therapy are the most common therapies used [35,36]. IVIG is more likely to maintain or improve visual acuity relative to untreated patients [35]. In refractory cases, plasmapheresis or plasma exchange (PLEX) therapy, which removes circulating ARAs, has been used [3,7,8,21▪] but visual improvement may be transient [3]. In one case of early initiation of PLEX therapy 3 weeks following onset of visual symptoms, the patient had good visual recovery [29]. Combination of these therapies can be effective with one case reporting improved visual acuity and retinal function on ERG after combining i.v. steroids, IVIG, and rituximab [19]. In a meta-analysis by Kapoor et al. [32▪], most patients were treated with systemic therapy; however, local treatment was done if patients could not tolerate systemic therapy. Local corticosteroid treatment can be a good option in patients who are ill, elderly, or with systemic contraindications and has been shown to improve visual acuity [24,37,38]. Huang et al. [24] reported improved visual acuity, rod function on ERG, and ellipsoid zone loss on OCT with local treatment only with intravitreal dexamethasone implant followed by 0.18-mg fluocinolone acetonide implant.
The prognosis for CAR depends on tumor origin, disease severity at presentation, timing of treatment initiation, and quantity of circulating ARA titers [21▪]. OCT and FAF can assess the extent of retinal atrophy, monitor disease, and predict long-term visual prognosis [9]. Serial ARA testing does not correlate with disease progression or treatment response [8,39]. CAR is often discovered when disease is advanced with significant photoreceptor loss so visual prognosis is often poor with high mortality rate [6]. In a natural history study of untreated patients with AIR, two-thirds experienced progressively worsened vision [35], with worse prognosis for those with antirecoverin antibodies including potentially progressing to no light perception [6].

MELANOMA-ASSOCIATED RETINOPATHY
MAR shares similarities with CAR but occurs in the setting of cutaneous melanoma. In MAR, autoantibodies to a melanoma antigen are thought to cross-react with bipolar cells in the retina. ARAs in MAR include TRPM1, S-arrestin, recoverin, enolase, aldolase A, aldolase C, HSP60, and carbonic anhydrase II with many of these also described in CAR and nonparaneoplastic AIR [40–43].
More common in men with a mean age of 60 (range 30–78) years, MAR presents on average 3.6 years after the diagnosis of cutaneous melanoma, with shorter latency periods in patients with metastatic disease. Rarely, MAR is discovered prior to diagnosis of cutaneous melanoma [40,44]. Patients present with night blindness, shimmering photopsias, and visual field constriction with relatively preserved visual acuity and color vision [45,46]. Fundus examination is usually unremarkable early on (Fig. 3). MAR can present with mild vitreous inflammation and in more advanced cases, optic disc pallor, vascular attenuation, and RPE mottling [43,46,47].
The characteristic ERG abnormality is a negative ERG, comprising a preserved A-wave and reduced B-wave with normal photopic but reduced scotopic function [40] (Fig. 4a). Limited conditions cause negative ERG including congenital stationary night blindness, juvenile X-linked retinoschisis, Goldmann-Favre, and Duchenne Muscular Dystrophy. Patients have constriction and central and paracentral scotomas on visual field testing (Fig. 4b,c) [47]. Serum testing for ARAs should be pursued to assist in diagnosis but no ARA specific to MAR has yet been identified [12].
As mentioned, most cases have a known diagnosis of cutaneous melanoma. If the primary cutaneous melanoma is not metastatic, imaging should be done to investigate for metastases [44]. If there is no cancer diagnosis, presence of cutaneous melanoma, uveal melanoma, and mucosal melanoma should be investigated [1,43,45].
Like CAR, management is a joint pursuit of tumor burden reduction, antibody elimination, and immunosuppressive therapy [45]. Evidence on treatment efficacy is limited, but therapeutic options include systemic corticosteroids, IVIG, and PLEX [45]. Subhadra et al. [48] found that IVIG improved visual fields. Systemic immunomodulator therapy can be used but efficacy is unclear as immune checkpoint inhibitors commonly used to treat metastatic cutaneous melanoma can also cause autoimmune eye disease and worsen retinopathy [49,50]. Local treatment may also be considered, as intravitreal steroid injections have improved visual symptoms, visual field, and ERG parameters [49,51] while simultaneously reducing the intraocular inflammatory effects of immune checkpoint inhibitors [52]. Hamdan et al. [53] described a case of full recovery of visual acuity and ERG following combination of rituximab, IVIG, and intravitreal corticosteroids. The prognosis of MAR depends upon early diagnosis and treatment initiation to limit irreversible damage to retinal bipolar cells [45].

PARANEOPLASTIC VITELLIFORM MACULOPATHY
PVM, occurring in the context of malignancy, is a form of acute exudative polymorphous vitelliform maculopathy (AEPVM) which can also be secondary to other causes [54]. PVM is hypothesized to occur when immune cells triggered by malignancy cross-react with the RPE, impairing RPE phagocytosis, resulting in lipofuscin accumulation, photoreceptor outer segment shedding, and serous retinal detachments [54,55]. Auto-antibodies have been identified against peroxiredoxin 3 (PRDX3), bestrophin 1, and other RPE components [11,12,56]. PVM is usually associated with cutaneous melanoma and secondarily choroidal melanoma but other malignancies like breast carcinoma, lung adenocarcinoma, and clear cell sarcoma have been reported [54,57]. Typically occurring after cancer diagnosis, one review described PVM developing 2–23 years following enucleation for choroidal melanoma [57]. In many cases, PVM indicates metastatic disease [58,59].
Patients often experience acute bilateral blurry vision and headaches [55,60]. Classically, examination shows serous retinal detachments and multiple yellow-white subretinal lesions of variable morphology in the posterior pole. However, if caught early, only serous retinal detachments may be present as subretinal lesions may require at least 1 month of follow-up before being observable [61]. As subretinal fluid (SRF) resorbs, polymorphous yellow vitelliform deposits accumulate and start in a honeycomb pattern along the arcades before coalescing and forming a larger, curvilinear pseudo-hypopyon which are hyperautofluorescent on FAF [13,56,60,62]. OCT demonstrates serous retinal detachments and may show intraretinal cysts in the inner and outer nuclear layers or intraretinal hyperreflective deposits [56,60]. Fluorescein angiogram may show mildly hyperfluorescent areas corresponding to the vitelliform lesions and serous retinal detachments or blocked fluorescence from large accumulations of subretinal material [13,60]. EOG is abnormal [11,62]. ERG may be normal or show rod or cone dysfunction [29,54,61,63].
In a patient with AEPVM, a comprehensive work-up is usually performed to rule out other infectious and autoimmune causes. Assuming work up is negative, age- and gender-appropriate screening for malignancy should be considered, including thoracoabdominal imaging and dermatologic screening [29].
Visual prognosis is favorable as ocular disease often improves spontaneously [63]. Even if ERG still shows persistent abnormalities, visual acuity usually improves as SRF resolves [64]. Evidence is insufficient to identify the efficacy of early systemic or intraocular immunosuppression [62,65–67]. Recovery does not seem to be significantly impacted by intravitreal corticosteroids tried for intraretinal edema [65]. With secondary choroidal neovascularization, antivascular endothelial growth factor (anti-VEGF) is used to decrease vascular leakage and control disease progression [62,68]. Gao et al. [66] reported a case of visual acuity improvement and resolution of SRF following adjuvant intravitreal methotrexate along with systemic treatment of the underlying malignancy; the eye treated with intravitreal methotrexate showed greater improvement in visual acuity and edema on OCT compared to the untreated eye [66].

BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION
First reported by Machemer in 1966 [61], BDUMP is currently hypothesized to occur via cultured melanocyte elongation and proliferation (CMEP), a tumor-secreted factor which stimulates diffuse melanocytic proliferation within the choroid, ciliary body, and iris causing damage to the RPE and outer retina [69,70▪].
Patients present with progressive bilateral blurry vision. Historically, the five cardinal signs of BDUMP were multifocal, round/oval, red-orange, subretinal patches, corresponding to hyperfluorescent pattern on FA, multiple, elevated uveal melanocytic tumors and diffuse thickening of the uveal tract (Fig. 5 a,b), exudative retinal detachment, and rapid cataract progression [71]. Other findings include shallow anterior chamber, glaucoma from anterior rotation of the ciliary body, dilated episcleral vessels, iridocyclitis, iris and ciliary body cysts, and iridodonesis [72,73].
More recently, Sarigul Sezenoz et al. [74▪▪] described novel multimodal imaging findings in BDUMP. Ultra-wide fundus photography showed diffuse reticular orange pigment patches and speckled pigmentary changes in the posterior pole with pigmentary changes progressing to the mid-periphery and periphery later in the disease. Vessel attenuation was also seen late in disease [74▪▪]. The most prominent finding on fluorescein angiogram and FAF is the classic “giraffe-like” pattern with patchy alternating hypo and hyper-fluorescence and autofluorescence, respectively (Fig. 5c--e) [70▪,75]. OCT most commonly shows SRF and subretinal hyperreflective material (Fig. 6a--c); other findings include elongated photoreceptor outer segments, ellipsoid zone and RPE loss with adjacent thickened zones, and diffuse intraretinal hyperreflective foci in all inner and outer retinal layers [74▪▪,75,76]. B scan ultrasonography shows low reflective choroidal thickening and multifocal, exudative retinal detachments (Fig. 7a,b) [74▪▪]. Ultrasound biomicroscopy is also required as may demonstrate ciliary body thickening or detachments, iridociliary cysts, and angle closure (Fig. 7c--f) [74▪▪].
Urgent oncology referral for malignancy work-up is warranted, as half of patients with BDUMP present prior to diagnosis of systemic malignancy [76]. The most common cancers are ovarian and uterine in women and lung in men [77]. Again, treatment of the malignancy is required but no standardized treatment for ocular disease exists. Some case reports describe PLEX as having the greatest efficacy in preventing disease progression by removing serum immunoglobulin G which stimulates melanocytes, although vision improvement may be temporary [70▪,76]. One case of high-dose IVIG did restore vision and maintained sustained improvement [78]. Most case reports of BDUMP still have poor visual prognosis, though IVIG and PLEX is thought to stabilize disease [73]. Other treatments have been done to treat SRF, including intravitreal anti-VEGF, local and systemic steroids, intravitreal methotrexate, oral acetazolamide, and orbital radiotherapy [79–81]. Cataract surgery can be considered, although peri-operative systemic, intravitreal, and topical steroids should be considered to mitigate a significant fibrin reaction postoperatively [73]. Despite treatment of the malignancy, overall prognosis is poor with mean survival rate of 12–15.7 months after presentation [76].

CONCLUSION
Early recognition of paraneoplastic retinopathies allows prompt management of systemic malignancy and ocular disease. High degree of clinical suspicion should be maintained in the cancer patient with unexplained vision loss or degree of vision loss that does not align with overall clinical findings. Multimodal imaging is helpful in diagnosis. CAR and MAR present with progressive visual symptoms that may be out of proportion to fundus findings. OCT, visual field, ERG, and serum ARA testing are useful in diagnosing CAR and MAR. PVM presents with vitelliform lesions and serous retinal detachments with relatively good visual prognosis. BDUMP typically presents with serous retinal detachments, rapidly progressive cataracts, diffuse uveal thickening, and a distinctive patchy giraffe pattern of hyper and hypo-autofluorescence on FAF. Overall, evidence on treatment efficacy is limited by the rarity of these conditions, but generally, in addition to treatment of the malignancy, systemic immunosuppression with adjuvant local ocular therapy is used. Further studies are needed to develop a standardized treatment protocol for paraneoplastic disorders of the retina.

Acknowledgements

The authors would like to thank Dr Amir Akhavanrezayat, Dr Quan Dong Nguyen, and the Stanford uveitis team for their assistance in caring for many of these patients.

Financial support and sponsorship

This work was supported by the P30 Vision Research Core Grant, National Eye Institute (NEI) P30-EY026877, and Research to Prevent Blindness, New York and the Alan and Irene Adler Initiative in Ocular Cancer.

Conflicts of interest

There are no conflicts of interest.