Heterogeneity of cultured melanocyte elongation and proliferation factor in bilateral diffuse uveal melanocytic proliferation

Highlights

• Cultured melanocyte elongation and proliferation (CMEP) factor stimulates melanocyte growth.

• CMEP, in our patient, is not concentrated in the IgG enriched fraction.

• CMEP is still present in plasma after 6 plasamapheresis treatments over 9 days.

• CMEP, in our patient, is unlikely to be an immunoglobulin, and is more likely a tumor-secreted growth factor.

Abstract

A patient with bilateral diffuse uveal melanocytic proliferation (BDUMP) associated with endometrial cancer was treated with plasmapheresis, but failed therapy with progressive serous retinal detachment. We collected plasma before and after plasmapheresis therapy. Our goal was to determine if the cultured melanocyte elongation and proliferation (CMEP) factor and hepatocyte growth factor (HGF) was present in the IgG enriched fraction and understand why our patient failed plasmapheresis therapy. Melanocytes were cultured for 3–5 days in the presence of control medium, unfractionated pre-plasmapheresis BDUMP medium, IgG enriched or IgG depleted BDUMP medium, or unfractionated post-plasmapheresis BDUMP medium. Subretinal fluid was collected from patients with BDUMP and control retinal detachments and analyzed by electropheresis with immunoblotting. Medium with unfractionated BDUMP plasma stimulated melanocyte growth 1.4–1.5 fold compared to control medium on days 3–5 (p < 0.001 for all). Both IgG enriched and IgG depleted BDUMP medium mildly increased melanocyte growth 1.3 fold (p < 0.05 for enriched, p < 0.01 for depleted) compared to control. In comparison, unfractionated BDUMP medium caused a 1.7-fold increase in melanocyte growth, which was significantly more than the enriched (p < 0.01) and depleted (p < 0.05) fractions. Pre-plasmapheresis and post-plasmapheresis unfractionated BDUMP medium equally stimulated melanocyte growth 1.7-fold (p < 0.05) compared to control. HGF was present in IgG depleted, pre-plasmapheresis, and post-plasmapheresis samples, but absent in the IgG enriched fraction. There was no enrichment of IgG in the subretinal fluid from eyes with BDUMP. In conclusion, CMEP factor is not concentrated in the IgG enriched plasma fraction in our patient who failed plasmapheresis therapy. HGF levels have no correlation with melanocyte growth. Because plasmapheresis preferentially removes immunoglobulins from the plasma, our patient responded poorly to plasmapheresis treatment with worsening retinal detachment.

Introduction

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare, paraneoplastic disease. Due to increased disease awareness and longer survival of patients with cancer, the incidence of BDUMP has increased from 1.15 cases per year from 1980 to 2000 to 4.4 cases per year during the last 5 years (Klemp et al., 2017). The cardinal features of BDUMP reported by Gass include: (1) multiple round or oval red patches in the posterior fundus at the level of the RPE, (2) early hyperfluorescence on fluorescein angiography correlating with these patches, (3) diffuse uveal tract thickening with multiple slightly elevated pigmented or non-pigmented uveal tumors, (4) serous retinal detachment (SRD), and (5) worsening cataracts (Gass et al., 1990).

Plasmapheresis has recently emerged as a potential treatment for BDUMP. Miles et al. hypothesized that an unknown circulating factor, termed cultured melanocyte elongation and proliferation factor (CMEP), stimulates melanocyte growth. This CMEP factor was also hypothesized to be either made and secreted by the cancer cells or produced by the immune system in response to the cancer (Miles et al., 2012). Miles et al. demonstrated that serum from two patients with ovarian carcinoma and BDUMP increased melanocyte growth, and that CMEP factor was present in the IgG enriched and not in the IgG depleted fraction (Miles et al., 2012). Additionally, they showed that CMEP factor did not exist in the serum from other patients with paraneoplastic syndromes, and this effect was specific to BDUMP (Miles et al., 2012). However, no further characterization of CMEP has been performed. Based upon these data, plasmapheresis has been shown to improve vision and SRF (subretinal fluid) in 5 patients with BDUMP (Jansen et al., 2015; Mets et al., 2011; Pulido et al., 2013; Schelvergem et al., 2015).

Here, we report a case of BDUMP associated with clear cell endometrial carcinoma. Unlike prior case reports, the SRD progressed despite plasmapheresis therapy. We collected plasma from the 1st and final plasmapheresis sessions to determine if the BDUMP plasma stimulated melanocyte growth, if CMEP was in the IgG enriched fraction in our patient, and if that factor was still present after the final plasmapheresis session.