Paraneoplastic retinopathy (PR) is mediated by tumor-associated autoantibodies directed against retinal antigens. PR patients usually develop reduced visual acuity, photopsias, nyctalopia, visual field defects, and reduced a- and/or b-waves in electroretinography (ERG) [1, 2]. The two main types of PR are cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). CAR is mostly associated with small-cell lung cancer and has specific autoantibodies against photoreceptors [3, 4]. MAR typically develops in patients with metastatic cutaneous or uveal melanoma; autoantibodies against retinal bipolar cells are the hallmark of MAR [5–8]. In MAR, the fundus is unremarkable in 44% cases, although fundus changes such as focal depigmentation, optic nerve pallor, and/or retinal vascular attenuation have been reported [6, 9]. Recently, a MAR-like retinopathy phenotype, termed paraneoplastic vitelliform retinopathy, has been recognized that is also associated with cutaneous or uveal melanoma [10, 11]. Unlike the typical normal-appearing fundus in MAR, paraneoplastic vitelliform retinopathy is characterized by vitelliform retinal lesions at the level of the retinal pigment epithelium (RPE) with associated serous retinal detachment and subretinal accumulation of hyperautofluorescent material in the posterior pole [10, 12].
Similar to CAR and MAR that are immunologically heterogeneous, serum autoantibodies, such as anti-bipolar cell antigens, interphotoreceptor retinoid-binding protein (IRBP), carbonic anhydrase II (CAII), and bestrophin, are reported in patients with paraneoplastic vitelliform retinopathy [10, 13, 14]. Among them, anti-bipolar cell antibody is the most commonly identified autoantibody [15, 16]. As reduced ERG b-wave is indicative of retinal bipolar cell impairment, it is hypothesized that the autoantibodies generated by melanoma patients are directed against retinal bipolar cells in paraneoplastic vitelliform retinopathy.
Recently, a new connection between PR and bipolar cells has been made by the identification of a cation channel named transient receptor potential M1 (TRPM1, also known as melastatin 1). TRPM1 was initially identified in melanocytes and cutaneous melanoma and is a marker for metastasis and prognosis [17–19]. The loss or downregulation of TRPM1 mRNA correlates with an increased risk of metastatic melanoma [17, 18]. The patterns of TRPM1 transcript expression also help differentiate Spitz nevi from nodular melanomas, with higher ubiquitous expression in Spitz nevi and higher incidence of loss in nodular melanomas . TRPM1 is also expressed in retinal bipolar dendritic tips [20–23]. Several studies demonstrated that TRPM1 cation channel is essential for ON bipolar cell signaling [22, 24, 25]. In addition, several groups have found that human TRPM1 mutations are linked to congenital stationary night blindness [26–28]. Furthermore, it has been reported that TRPM1 is the target of autoantibodies in some PR patients [29, 30].
As a subtype of PR, the exact pathogenesis of paraneoplastic vitelliform retinopathy remains elusive. Recently, we reported the clinical manifestations and pathology of a paraneoplastic vitelliform retinopathy case with lesions in inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL) of the retina, the loci of which correspond to the clinical fundus lesions . Herein, we re-examine this case including metastatic melanoma cells in the lung with immunohistochemistry and transmission electron microscopy (TEM).