Management of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP)-A Case Report.

Background and Objectives: This study reports a case of a 62-year-old patient experiencing a significant decline in vision over the past three months. The initial best-corrected visual acuity (BCVA) of 20/20 in both eyes diminished to 20/200 in the right eye (RE) and counting fingers (CF) in the left eye (LE) within this timeframe. The patient was diagnosed with stage 4 ovarian cancer just one month before the significant vision deterioration. Materials and Methods: A thorough ophthalmologic examination revealed a notable progression of cataracts and the presence of subretinal fluid on the posterior pole, accompanied by choroidal thickening. The right eye exhibited multifocal, orange-pigmented, and elevated choroidal lesions, while the left eye's fundus examination was impeded by dense cataracts. Optical coherence tomography (OCT) revealed bilateral choroidal thickening with overlying folds and subretinal fluid, and ultrasound imaging of the choroidal lesions indicated moderate homogenous internal reflectivity. Results: The patient received a diagnosis of BDUMP (bilateral diffuse uveal melanocytic proliferation), a paraneoplastic syndrome marked by simultaneous, bilateral, painless vision loss and the rapid onset of bilateral cataracts with serous retinal detachments. Despite cataract extraction, the expected visual recovery was not achieved (RE: CF; LE: 2/200, respectively). Plasmapheresis showed some success in stabilizing vision loss attributed to serous retinal detachments. Conclusions: BDUMP necessitates addressing the underlying malignancy for effective treatment. Left untreated, it can lead to near blindness within a year. The prognosis remains grim, with an average survival time ranging from 12 to 15.7 months from the time of diagnosis. Considering this case report, it is crucial to establish effective management plans and further investigate potential treatment methods and predictive markers centered around BDUMP. Collaboration between healthcare professionals and researchers is crucial in addressing the complexities of BDUMP, as the timely diagnosis and treatment of the disease remains a top priority.

Paraneoplastic ocular syndrome: a pandora's box of underlying malignancies.

Paraneoplastic syndromes affecting the visual system are a group of conditions that arise in the systemic malignancy framework. In this review, we have provided a detailed and comprehensive overview of the published literature on the various ophthalmic paraneoplastic manifestations. A systematic review of many databases has been performed to identify ample literature on the paraneoplastic syndromes related to ophthalmology. We have discussed here the clinical features, pathogenesis, and treatment strategies of various ophthalmic paraneoplastic syndromes. It can be challenging to distinguish these disorders from their non-paraneoplastic counterparts and to determine the appropriate systemic assessment for the tumour responsible, to have a proper approach towards the management of the syndrome. METHOD: We searched PubMed, Science Direct and Journal of Ophthalmology for studies published in English between 1995 and April 2020, incorporating the general search term "paraneoplastic ocular syndrome" with connecting terms relevant to subheadings-e.g. Key search terms were cancer-associated retinopathy, (CAR), melanoma-associated retinopathy, (MAR), paraneoplastic retinopathy, autoimmune retinopathy, autoimmune-related retinopathy, and optic neuropathy, (ARRON), acute zonal occult outer retinopathy, (AZOOR), paraneoplastic vitelliform maculopathy, paraneoplastic vitelliform retinopathy, bilateral diffuse uveal melanocytic proliferation, (BDUMP), paraneoplastic optic neuropathy, (PON), polyneuropathy, organomegaly, endocrinopathy, monoclona gammopathy, and skin changes syndrome (POEMS) and various other terms. References from identified studies have been reviewed and included if deemed appropriate, valid, and scientifically important. If referenced in a selected English paper, we contemplated papers in other languages too. We preferentially selected papers that have been published in the last 10 years, but we have included relevant older references.

Broad locations of antigenic regions for anti-TRPM1 autoantibodies in paraneoplastic retinopathy with retinal ON bipolar cell dysfunction.

PURPOSE: Cancer-associated retinal ON bipolar cell dysfunction (CARBD), which includes melanoma-associated retinopathy (MAR), has been reported to be caused by autoantibodies against the molecules expressed in ON bipolar cells, including TRPM1. The purpose of this study was to determine the antigenic regions of the autoantibodies against TRPM1 in the sera of CARBD patients, in whom we previously detected anti-TRPM1 autoantibodies. METHODS: The antigenic regions against TRPM1 in the sera of eight CARBD patients were examined by Western blots using HEK293T cells transfected with the plasmids expressing FLAG-tagged TRPM1 fragments. The clinical course of these patients was also documented. RESULTS: The clinical course differed among the patients. The electroretinograms (ERGs) and symptoms were improved in three patients, deteriorated in one patient, remained unchanged for a long time in one patient, and were not followable in three patients. Seven of the eight sera possessed multiple antigenic regions: two sera contained at least four antigen recognition regions, and three sera had at least three regions. The antigen regions were spread over the entire TRPM1 protein: five sera in the N-terminal intracellular domain, six sera in the transmembrane-containing region, and six sera in the C-terminal intracellular domain. No significant relationship was observed between the location of the antigen epitope and the patients' clinical course. CONCLUSIONS: The antigenic regions of anti-TRPM1 autoantibodies in CARBD patients were present not only in the N-terminal intracellular domain, which was reported in an earlier report, but also in the transmembrane-containing region and in the C-terminal intracellular domain. In addition, the antigenic regions for TRPM1 were found to vary among the CARBD patients examined, and most of the sera had multiple antigenic regions.

Bilateral diffuse uveal melanocytic proliferation with multifocal diffuse integumentary melanocytic proliferation paraneoplastic syndrome: A case report.

Bilateral diffuse uveal melanocytic proliferation (B-DUMP) is a rare paraneoplastic syndrome typically presenting with bilateral visual loss. B-DUMP is associated with extraocular systemic malignancies with the most common being lung cancer in males and uro-gynaecological cancer in females (mainly ovarian cancer). Cutaneous and/or mucosal involvement in patients with B-DUMP has been reported but it is not well characterised. Herein, we present a female in her 70s with diagnosis of stage IV vaginal clear-cell carcinoma and metastatic melanoma of unknown primary that developed progressive bilateral loss of visual acuity compatible with 'B-DUMP'. Simultaneously, she developed multifocal bilateral bluish-greyish patches on the skin that were shown to have a proliferation of dermal melanocytes. We propose that the clinical and histopathologic cutaneous findings seen in patients with B-DUMP be termed 'diffuse integumentary melanocytic proliferation (DIMP)'.

Recurrent monocular exudative retinal detachment as the first manifestation of squamous cell lung cancer: A case report.

RATIONALE: In this report, we present an extremely rare case of recurrent monocular exudative retinal detachment without concomitant ocular metastases. This turned out to be the first symptom of squamous cell lung cancer. PATIENT CONCERNS: A 63-year-old woman was referred to our ophthalmology clinic by her primary care physician with a complaint of deteriorating vision in her right eye that had started four months prior, without concomitant pain. DIAGNOSES: We observed a detachment in the lower part of the retina during her ophthalmoscopy. We did not find any tears, holes, or degenerative changes in the periphery of the retina of the right eye during the surgery. In addition, plaques, tumor masses, and metastases were absent. Therefore, we diagnosed her with unilateral paraneoplastic exudative retinal detachment. Imaging tests performed before surgery revealed perihilar density with a visible air bronchogram in the middle field of the left lung. This turned out to be squamous cell carcinoma. INTERVENTIONS: Patient underwent pars plana vitrectomy and routine laboratory and imaging tests before the procedure that utilized 20-gauge instrumentation. The subretinal fluid and was drained and a tamponade using Densiron (Fluoron Co, Neu-Ulm, Germany) was applied. After ophthalmic treatment, patient underwent complex oncological treatment based on chemotherapy and radiotherapy. OUTCOMES: Despite the application of heavy silicone oil (Densiron) into the vitreous chamber, we observed a recurrence of retinal detachment in the right eye during the follow-up visit, 13 months after the first ophthalmic surgery. Following subsequent pars plana vitrectomy, the Densiron and subretinal membranes were removed. Despite oncological treatment, the patient died, twenty months after the appearance of the first ocular symptoms. LESSONS: Exudative retinal detachment without tumor metastasis to the eyeball can be one of the first signs of lung cancer in rare cases. Multidisciplinary care and imaging methods with greater accuracy will provide comprehensive care to the patients. It will not only facilitate timely detection and treatment of lung tumors but also for a plethora of oncological diseases.

Novel LRRFIP2-RAF1 fusion identified in an acral melanoma: A review of the literature on melanocytic proliferations with RAF1 fusions and the potential therapeutic implications.

A small subset of cutaneous melanomas harbor oncogenic gene fusions, which could potentially serve as therapeutic targets for patients with advanced disease as novel therapies are developed. Fusions involving RAF1 are exceedingly rare in melanocytic neoplasms, occurring in less than 1% of melanomas, and usually arise in tumors that are wild type for BRAF, NRAS, and NF1. We describe herein a case of acral melanoma with two satellite metastases and sentinel lymph node involvement. The melanoma had a concomitant KIT variant and LRRFIP2-RAF1 fusion. This constellation of molecular findings has not been reported previously in melanoma. We review the existing literature on melanocytic neoplasms with RAF1 fusions and discuss the potential clinical implications of this genetic event.

A case of melanoma-associated retinopathy with autoantibodies against TRPM1.

PURPOSE: To report a case of melanoma-associated retinopathy (MAR) with autoantibodies against the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) with asymmetric severe vision loss. METHODS: We evaluated a patient with heel skin melanoma showing progressive vision loss in both eyes confirmed with a baseline ophthalmic examination, fluorescein angiography, spectral domain optical coherence tomography (OCT), visual field test, and full-field electroretinogram (ERG). Immunofluorescence assays and western blot analysis revealed autoantibodies in the patient's serum. RESULTS: The patient's best-corrected visual acuities were 20/50 in the right eye and hand motion in the left eye. Visual field test showed severely depressed visual fields especially in the left eye. Fluorescein angiography and OCT revealed extrafoveal choroidal neovascularization in the left eye. The patient had an electronegative ERG, suggesting MAR, and autoantibodies against TRPM1 and aldolase C were detected in the patient's blood sample. CONCLUSIONS: The clinical features of MAR patients with positive anti-TRPM1 autoantibodies can be manifested as severe vision loss, and the identification of autoantibodies can be helpful for confirming the diagnosis.

Small cell carcinoma presenting as ocular paraneoplastic syndrome due to CRMP-5.

We report the case of a lady who presented with 3 weeks of visual floaters and optic disc swelling. Subsequent investigations revealed deep white matter changes on brain imaging, and enlarged mediastinal nodes. The presence of anti-CRMP-5 antibodies finally led to the diagnosis of a paraneoplastic syndrome, and mediastinal lymph node biopsy confirmed the diagnosis of small-cell lung cancer. The learning points from this case include that optic neuritis can be the only presenting feature of a paraneoplastic neurological syndrome, and the usefulness of anti-neuronal antibody measurement as a diagnostic marker of an underlying paraneoplastic disease process. The great challenge is to recognise these tumour-associated autoimmune system presentations early, as they often appear long before the primary cancer is evident. Prompt treatment leads to an earlier reduction in circulating auto-antibody possibly due to reduction in tumour size, and thus less likelihood of permanent neuronal damage.

Bilateral Diffuse Uveal Melanocytic Proliferation Associated With Bladder Cancer: A Novel Imaging Finding.

The authors report a case of bilateral diffuse uveal melanocytic proliferation associated with transitional cell carcinoma of the bladder. A novel imaging finding on indocyanine green angiography of a "string of sausages" pattern in the large choroidal vessels is described. This occurs in areas of alternating retinal pigment epithelial hypertrophy and destruction, which is likely to be its cause. To the authors' knowledge, it has not been previously described. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:525-528.].

Cancer-associated Retinopathy with Neuroendocrine Combined Large-cell Lung Carcinoma and Adenocarcinoma.

We herein report the case of a 74-year-old woman with a lung tumor. She presented with complaints of blurred and rapid, progressively impaired vision. A visual field examination revealed bilateral concentric contraction of the visual field and a ring scotoma in the right eye. She was diagnosed with cancer-associated retinopathy (CAR) combined with large-cell neuroendocrine carcinoma (LCNEC) of the lung via a visual field examination and underwent thoracoscopic surgery. CAR has been mostly associated with small-cell lung cancer (SCLC). Combined LCNEC is relatively rare and accounts for 10.6% of all LCNECs. This is the first case report of CAR-combined LCNEC.

Diffuse Uveal Melanocytic Proliferation With Primary Vitreoretinal Lymphoma.

Importance: Bilateral diffuse uveal melanocytic proliferation is a rare sign of several systemic malignant neoplasms. Observations: A patient presenting with uveal melanocytic proliferation underwent a detailed physical examination and extensive imaging. No systemic malignant neoplasm was found. Chorioretinal biopsy was performed, and its immunohistochemical results revealed the presence of primary vitreoretinal lymphoma. Conclusions and Relevance: This patient's results suggest that diffuse uveal melanocytic proliferation may be associated not just with systemic malignant disease, but also with primary intraocular tumors, in this case a primary vitreoretinal lymphoma.

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

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.

Giraffe or leopard spot chorioretinopathy as an outstanding finding: case report and literature review.

PURPOSE: Presentation of two typical cases with characteristic leopard retinopathy secondary to bilateral diffuse uveal melanocytic proliferation (BDUMP) and idiopathic uveal effusion syndrome (IUES) and brief review of the literature about leopard spot retinopathy. CASE REPORT: A 43-year-old women, who was a known case of ovarian carcinoma, referred with gradual bilateral visual loss. In ophthalmic examination, subretinal fluid, multiple patchy subretinal hyperpigmented lesions and leopard spot chorioretinopathy were evident in her both eyes. Fluorescein angiography showed multiple nummular hyperfluorescent lesions surrounded by zones of hypofluorescence. Spectral domain optical coherence tomography revealed increased retinal thickness, subretinal fluid and RPE irregularities in both eyes. Enhanced depth imaging OCT (EDI-OCT) showed bilateral subfoveal choroidal thickening. During next 2-year follow-up, she underwent cataract surgery and later on developed neovascular glaucoma in her both eyes. The second case was a 45-year-old man who had developed decreased visual acuity in his left eye for 3 years. Anterior segment examination was unremarkable, and both eyes had normal intraocular pressure. No vitreous inflammation was observed. Fundoscopy revealed diffuse exudative retinal detachment in his left eye. Fluorescein angiography showed leopard spot retinopathy of posterior pole, and EDI-OCT disclosed subfoveal choroidal thickening. After exclusion of other causes of exudative retinal detachment and with diagnosis of IUES, he underwent intravitreal triamcinolone injection (2 mg) which improved his final vision to 20/40. CONCLUSION: Leopard spot retinopathy is an uncommon but clinically distinct manifestation of various disorders. BDUMP may present with leopard spot retinopathy, anterior uveal tract involvement and neovascular glaucoma. As EDI-OCT showed involvement and increased thickening of choroid in both cases of BDUMP and IUES, it may be better to consider such cases as leopard chorioretinopathy and categorize these entities as a member of pachychoroid pigment retinopathy disorders.

Immunopathogenesis of ophthalmological paraneoplastic syndromes: Recent findings.

The aim of this study was to summarize the current knowledge of paraneoplastic syndromes involving eyes. The main interest was the immunopathogenesis of the abovementioned entities. A web search was conducted using Medline, Web of Science and Scopus engines. Key words concerning ocular paraneoplastic syndromes (OPS) such as: "ocular paraneoplastic syndrome", "cancer-associated retinopathy", "cancer-associated cone dysfunction", "melanoma-associated retinopathy", "bilateral diffuse uveal melanocytic proliferation", and "paraneoplastic optic neuritis" were combined with "immunology", "immune response", "antibodies", or "autoantibodies". Numerous papers were found as a result of "ocular paraneoplastic syndrome" search and many of them matched the chosen criteria. We focused on the most recent papers - published in the last 5 years - and eventually, 92 items were found. Only several papers from each detailed category fulfilled both OPS and immunologic criteria. Site-specific paraneoplastic syndromes still remain a difficult clinical challenge. The immunopathogenesis of some of them seems to be more complex than previously thought.

In Vivo Adaptive Optics Ophthalmoscopy Correlated with Histopathologic Results in Cancer-Associated Retinopathy.

PURPOSE: To demonstrate the validity of adaptive optics scanning laser ophthalmoscopy (AOSLO) imaging of the retina in human disease based on clinicopathologic correlation in a patient with cancer-associated retinopathy (CAR). DESIGN: Case report. PARTICIPANT: Sixty-four-year-old man with CAR. METHODS: Fundus photography, electroretinography, visual field testing, fundus autofluorescent imaging, spectral-domain OCT scans, AOSLO, and histopathologic analysis were performed. MAIN OUTCOME MEASURE: Comparison of AOSLO with histopathologic results. RESULTS: Changes in photoreceptor morphologic features were correlated highly between AOSLO and histopathologic results. CONCLUSIONS: We present a unique case where a patient with a rare and fatal disease, CAR, underwent AOSLO imaging during the course of the disease, and then shortly thereafter, postmortem histopathologic analysis of the eyes was carried out. This is the first report of use of AOSLO to elucidate further the retinal changes that occur in CAR and the first study to demonstrate correlation of AOSLO with histopathologic results in any human disease.