Bilateral Diffuse Uveal Melanocytic Proliferation Research Articles

A Case of Bilateral Diffuse Uveal Melanocytic Proliferation Followed by Massive Unilateral Uveal Proliferation

ABSTRACT Objective To report a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) followed by massive unilateral uveal proliferation. Methods Retrospective case report. Results A 47-year-old female with history of metastatic ovarian carcinoma initially presented with bilateral vision loss and multifocal red patches on posterior poles consistent with BDUMP. Five years later, she presented with bilateral neovascular glaucoma and unilateral iris and ciliary body mass concerning for malignancy. Enucleation revealed diffuse uveal growth involving almost the entirety of the uveal tract. Conclusions BDUMP can rarely be associated with uveal proliferation. Routine examinations are recommended to monitor for any changes concerning malignancy.

Diagnostic and therapeutic considerations in patients with bilateral diffuse uveal melanocytic proliferation.

This review aims to summarize the current knowledge concerning the clinical features, diagnostic work-up, and therapeutic approach of bilateral diffuse uveal melanocytic proliferation (BDUMP). A meticulous literature search was performed in the PubMed database. A supplementary search was made in Google Scholar to complete the collected items. Our search strategy utilized the following keywords: "bilateral diffuse uveal melanocytic proliferation", "BDUMP", and "Paraneoplastic Syndrome". Articles were considered based on their relevance, with the search spanning publications up to 2023. Studies were excluded if they did not contribute pertinent information or lacked methodological rigor. A critical appraisal of included studies was conducted, assessing study design, sample size, methodology, and potential bias, ensuring a thorough and transparent review process. BDUMP is a rare and potentially sight-threatening condition characterized by the bilateral proliferation of melanocytes within the uvea. BDUMP is typically observed in middle-aged or elderly individuals and is often associated with an underlying malignancy, most commonly of gastrointestinal origin. BDUMP is frequently misdiagnosed as a benign nevus or choroidal metastasis, leading to delayed diagnosis and treatment. The ophthalmic symptoms and signs typically precede the diagnosis of a systemic malignancy, emphasizing the crucial role of ophthalmologists in the recognition of BDUMP. Several diagnostic modalities can aid in the diagnosis of BDUMP, including ophthalmic examination, imaging studies such as optical coherence tomography, fluorescein angiography, and indocyanine green angiography, and biopsy of the uveal tissue. Treatment of BDUMP is directed towards the underlying malignancy and may include chemotherapy, radiotherapy, or surgical resection. Additionally, strict monitoring with regular follow-ups may contribute to the detection of new lesions and the reduction in the size of existing ones. BDUMP can be considered a potential biomarker in the management of malignancies, especially when the primary underlying tumor has not been detected. Further research is needed to better understand the pathogenesis of BDUMP and its association with malignancy.

Successful Adjunctive Treatment of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) with High-Dose Intravenous Immunoglobulin Therapy (IVIG).

Successful Adjunctive Treatment of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) with High-Dose Intravenous Immunoglobulin Therapy (IVIG).

Multiplying Brown Spots.

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a paraneoplastic syndrome affecting the eye that is a sign of poor prognosis of underlying malignancy.This is the first documented case to show serial and sustained improvement of BDUMP following immunotherapy in the setting of primary non-small cell carcinoma of the lung. A 65-year-old man reported a gradual decrease in vision and floaters in the right eye after cataract surgery. Fundus examination demonstrated diffuse multiple brown subretinal lesions bilaterally. Next generation sequencing of melanocytic tissue of the patient described in this case revealed a specific RB1 c.411A>T (p.Glu137Asp) variant with an allele frequency of 44.8%, consistent with heterozygosity. Plasma samples from the patient and a control patient with no history of cancer and/or paraneoplastic syndrome were cultured with neonatal melanocytes, which revealed a greater than 180% increase in proliferation of normal neonatal melanocytes compared to the control. Pembrolizumab therapy was initiated which resulted in shrinkage and stabilization of the lesions documented in serial diagnostic testing. In conclusion, we report a cytologically and serologically confirmed case of BDUMP in a patient with a primary non-small cell carcinoma of the lung. Next generation sequencing of melanocytic tissue of the patient described in this case revealed a specific RB1c.411A>T (p.Glu137Asp) variant with an allele frequency of 44.8%, consistent with heterozygosity. Furthermore, we show documented serial improvement in the patient's ocular and systemic disease with treatment. This case as one of the longest surviving confirmed cases of a patient with BDUMP.

BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION MISTAKEN FOR NIVOLUMAB-INDUCED VOGT-KOYANAGI-HARADA DISEASE-LIKE SYNDROME.

To describe a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) that was mistaken for nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome. We present the case of a 58-year-old white man with metastatic renal clear cell carcinoma for which he was palliatively treated with IV nivolumab immunotherapy. The patient developed subacute onset of blurry vision and gray spots in the visual fields of both eyes, macular subretinal fluid, thickening of the retinal pigment epithelium, and swollen optic nerve heads. Differential diagnosis included nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome, and the patient was initially treated with steroids, which gave no improvement. Investigation showed the development of dark-gray patches in the peripheral retina of both eyes and cataract, which prompted reevaluation of the diagnosis, deeming BDUMP most likely. The patient was successfully treated with plasmapheresis. The initial presentation of the case was incorrectly diagnosed as nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome. On repeat studies of the patients' symptoms and imaging, we concluded we had missed signs of BDUMP. The diagnosis BDUMP was missed in the first evaluation. We present this case to discuss the similarities and differences between this disease and nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome. More importantly, we want to highlight that reevaluation of the diagnosis on worsening of a disease was key in this unusual case.

Bilateral diffuse uveal melanocytic proliferation.

Learning Point for Clinicians Bilateral diffuse uveal melanocytic proliferation (BDUMP) can occur not only in patients with cancer, but also as the first sign of subclinical malignancies. Clinicians should be aware of BDUMP when a patient presents with rapid vision loss with fundus changes.

Bilateral diffuse uveal melanocytic proliferation associated with endometrial carcinoma - multimodal imaging analysis.

Bilateral diffuse uveal melanocytic proliferation associated with endometrial carcinoma - multimodal imaging analysis.

Uveal Melanoma and Paraneoplastic Perivascular Dermal Melanocytic Proliferation in the Setting of Bilateral Diffuse Uveal Melanocytic Proliferation: The Potential Role of the Hepatocyte Growth Factor/c-Met Axis in Their Pathogenesis

Two patients, with non-small cell lung carcinoma treated with pembrolizumab, developed bilateral diffuse uveal melanocytic proliferation (BDUMP) with interesting histopathological features. The first patient developed a right ciliary body mass concurrently with BDUMP. The globe was enucleated. The ciliary body mass was a mitotically active epithelioid uveal melanoma, invading the trabecular meshwork and peripheral corneal stroma, with over 90% of the cells expressing Cyclin D1 protein. The melanoma showed no chromosome 3 or 8 changes. The background uvea showed diffuse, bland spindle cell melanocytic proliferation with much lower Cyclin D1 expression (around 10%). In the choroid, this population was punctuated by islands of pigmented epithelioid cells, some of which were necrotic. All these islands expressed a high level of Cyclin D1, and some islands expressed nuclear preferentially expressed antigen in melanoma (PRAME). The ciliary body mass, epithelioid cell islands, and the BDUMP all expressed c-Met (the receptor for hepatocyte growth factor [HGF]). The features were those of ciliary body melanoma and choroidal melanoma “tumorlets,” developing on a background of BDUMP. The second patient developed bilateral periocular skin pigmentation following a diagnosis of BDUMP, which when biopsied, showed dermal islands of paraneoplastic perivascular melanocytic cell proliferation. These cells also expressed c-Met protein. These observations implicate the HGF/c-Met axis in the pathogenesis of BDUMP, the uveal melanomas in the ciliary body and choroid in the first patient and the paraneoplastic dermal melanocytic proliferation in the second patient.

Bilateral Diffuse Uveal Melanocytic Proliferation Secondary to Rectal Adenocarcinoma: A Case Report and Literature Review.

Background: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular syndrome that causes progressive visual loss in patients, and is associated with an underlying malignancy. Recently, the incidence of BDUMP has increased with the prolonged life expectancy of oncology patients.Case Presentation: We report a case of a 68-year-old man with significant visual loss in both eyes. The patient presented with a diffusely thickened choroid and ciliary body, extremely shallow anterior chamber, increased intraocular pressure, and cataract formation, accompanied by exudative retinal detachment in both eyes. He underwent a pars plana vitrectomy and choroidal biopsy, which revealed benign proliferation of melanocytes. A small amount of subretinal fluid persisted, and uveal thickness persisted in the early postoperative period. During the 1-year follow-up assessment, he underwent rectal tumor resection, and was pathologically diagnosed with rectal adenocarcinoma. Six months after the rectal tumor resection, the subretinal fluid was completely absorbed and the retina had reattached. The thickness of both the ciliary body and choroid had significantly decreased.Conclusion: This case report describes a rare paraneoplastic intraocular syndrome, BDUMP, which was associated with rectal adenocarcinoma. Treatment for the primary malignancy gradually improved the visual symptoms and signs.

BDUMP: A Rare Case of Vision Loss in a Lung Transplant Recipient

Introduction Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a potentially devastating rare paraneoplastic syndrome often associated with severe vision loss occurring in patients with underlying carcinoma. In approximately 50% of cases this may be the first sign of an underlying primary malignancy. First described in 1966 there are currently less then 100 cases described in the literature. Treatment of this condition includes treatment of the primary malignancy and plasmapheresis. We describe what we believe to be the first case reported in a lung transplant recipient. Case Report A 72 year old woman status post bilateral lung transplant for COPD was referred to ophthalmology due to increased vision loss for four months, one month prior to presentation she had undergone a left YAG capsulotomy. Maintenance immunosuppression included tacrolimus, mycophenolate mofetil, and prednisone. Fundus exam was remarkable for bilateral retinal pigment epithelium mottling and leopard spot fundus. Exam on the left showed edema. BDUMP was diagnosed, she was admitted to the hospital for plasmapheresis and an extensive evaluation for underlying malignancy. Remarkable laboratory studies showed a new acute kidney injury in the setting of chronic kidney disease with nephrotic range proteinuria. All tumor markers, ANA, ANCA, SPEP, and PLA2R were negative. CT of the head, chest, abdomen, and pelvis were unrevealing, PET scan showed a hypermetabolic breast nodule which was biopsied. The biopsy was consistent with ductal carcinoma in situ, and her mycophenolate was stopped. She completed 14 sessions of plasmapheresis and had improvement in her vision. Summary BDUMP, a rare condition which left untreated can lead to rapid vision loss, is associated with carcinomas of the cervix, uterus, ovary, lung, kidney, pancreas, breast, gastrointestinal tract, and Hodgkin lymphoma. While the exact pathogenesis for BDUMP has not yet been described it has been shown that these patients have a factor in the IgG fraction of serum that selectively causes melanocyte proliferation and thus plasmapheresis is an effective treatment. Patients that are immune suppressed are at an elevated risk for cancer, therefore it's highly important to keep up with health maintenance examinations in this population. Visual changes after transplant are also common, and a complete ophthalmologic examination should be completed with new onset of symptoms.

Extraocular Muscle Enlargement in Bilateral Diffuse Uveal Melanocytic Proliferation Associated with Hepatocellular Carcinoma

A 64-year-old man with bilateral diffuse uveal melanocytic proliferation (BDUMP) (Figs A and B) associated with hepatocellular carcinoma presented with painless ocular movement limitations. Visual acuity was count fingers and 20/100, respectively. The eyelids and orbital changes were not observed. Extraocular muscle restriction was not presented on the forced duction test in both eyes. Orbit magnetic resonance imaging demonstrated tendon sparing extraocular muscle enlargement on the rectus and oblique muscles (Fig C), and the test for thyroid function and antibodies were within normal ranges.

A case report of ultrasonographic findings in bilateral diffuse Uveal melanocytic proliferation

BackgroundTo report undescribed characteristics of patients with bilateral diffuse uveal melanocytic proliferation (BDUMP) on ultrasound biomicroscopy (UBM) and high-frequency B-scan ultrasonography.Case presentationTwo of four participants presented with worsening bilateral vision after previously diagnosed primary pulmonary or ovarian carcinoma. The other two patients were diagnosed with lung carcinoma after presentation with BDUMP. All patients had ciliary body nevi-like lesion in combination with iris or ciliary body cysts, and uveal thickening on UBM. Focally elevated choroidal nevi-like lesion and exudative retinal detachment with choroidal thickening were detected with B-scan ultrasonography.ConclusionsOur case series demonstrates the uveal characteristics of patients with BDUMP based on high-frequency B-scan ultrasonography and UBM. Ultrasonographic findings are crucial in the diagnosis of BDUMP because it is occult in nature.

Ocular Paraneoplastic Syndromes.

Ocular-involving paraneoplastic syndromes present a wide variety of clinical symptoms. Understanding the background pathophysiological and immunopathological factors can help make a more refined differential diagnosis consistent with the signs and symptoms presented by patients. There are two main pathophysiology arms: (1) autoimmune pathomechanism, which is presented with cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), cancer-associated cone dysfunction (CACD), paraneoplastic vitelliform maculopathy (PVM), and paraneoplastic optic neuritis (PON), and (2) ectopic peptides, which is often caused by tumor-expressed growth factors (T-exGF) and presented with bilateral diffuse uveal melanocytic proliferation (BDUMP). Meticulous systematic analysis of patient symptoms is a critical diagnostic step, complemented by multimodal imaging, which includes fundus photography, optical coherent tomography, fundus autofluorescence, fundus fluorescein angiography, electrophysiological examination, and sometimes fundus indocyjanin green angiography if prescribed by the clinician. Assessment of the presence of circulating antibodies is required for diagnosis. Antiretinal autoantibodies are highly associated with visual paraneoplastic syndromes and may guide diagnosis by classifying clinical manifestations in addition to monitoring treatment.

Pigment-induced glaucoma secondary to bilateral diffuse uveal melanocytic proliferation.

We report the first case of pigment-induced glaucoma in a patient presenting with bilateral diffuse uveal melanocytic proliferation (BDUMP) syndrome. Despite treatment with plasma exchange, the patient developed progression of her lesions and bilateral glaucoma. Surgical treatment with Ahmed valve implant was performed to control her increased intra-ocular pressure. This case demonstrates that BDUMP can be a cause of a refractory pigment-induced glaucoma.

Melanocytic Lesions in Buccal Mucosa in BDUMP

A 64-year-old woman with metastatic uterine carcinosarcoma presented with bilateral diffuse uveal melanocytic proliferation (BDUMP). Visual acuity was 20/400 and hand motions, respectively. Examination showed multiple subretinal oval grey patches with an inferior exudative retinal detachment (ERD) (Fig A) in the right eye, and a nearly complete ERD in the left. On fluorescein angiogram, multifocal areas of early hyperfluorescence were present (Fig B). OCT revealed hyperreflective areas (white arrow) in outer retina interspersed with regions of subretinal fluid (Fig C, green arrow). Numerous melanocytic lesions in buccal mucosa (Fig D), rarely seen in BDUMP, were observed. A careful review of the literature failed to reveal a previous report of these lesions in association with BDUMP in uterine carcinosarcoma. (Magnified version of Fig A-D is available online at www.aaojournal.org).

Diagnosis of bilateral diffuse uveal melanocytic proliferation unveils primary gastric adenocarcinoma: a case report

BackgroundBilateral diffuse uveal melanocytic proliferation (BDUMP) is an extremely rare paraneoplastic syndrome, with most cases reported as secondary to female urogenital and male lung malignancies. We reported this case of BDUMP patient whose primary malignancy was gastric adenocarcinoma verified with gastroscopy and subsequent pathological test.Case presentationA patient complaining blurred vision was suspected of bilateral diffuse uveal melanocytic proliferation (BDUMP), due to bilateral round oval patches at the posterior pole and cardinal signs in retinal angiography. Malignancy screening was suggested, and pathological report from gastroscopy confirmed the primary lesion as gastric adenocarcinoma. The patient chose palliative care due to late stage and unresectable nature of the malignancy.ConclusionsIdentifying BDUMP warrants further investigation of a primary malignancy. Our case provided evidence for the link between gastric adenocarcinoma and BDUMP.

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.

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.

Prevalence of Hepatocyte Growth Factor and Autoantibodies to α-HGF as a New Etiology for Bilateral Diffuse Uveal Melanocytic Proliferation Masquerading as Neovascular Age-Related Macular Degeneration.

Objective:The goal was to test the hypothesis that high serum hepatocyte growth factor (HGF) and retinal autoantibodies against α-HGF contribute to the pathology of bilateral diffuse melanocytic proliferation (BDUMP).Methods:Case report of an elderly diagnosed with neovascular age-related macular degeneration (n-AMD) treated with bilateral Bevacizumab injections. Examination included comprehensive ophthalmic examination and images obtained by fundus photography, fundus autofluorescence, fluorescein angiography, spectral-domain optical coherence tomography (OCT), and B-scan ultrasonography. The levels of HGF and circulating HGF receptor (c-MET) were measured in the serum by ELISA and anti-retinal autoantibodies by western blotting.Results:Patient received Bevacizumab injections for presumed n-AMD and had a history of papillary renal cell carcinoma stage 4 with a tumor containing gene mutation Y1230C in the mesenchymal-epithelial transition factor (MET). Visual acuity was 20/200 OD and CF OS. Multimodal imaging was consistent with BDUMP. Plasma exchange therapy was recommended but could not be started until 10 months later due to deterioration in his medical condition. Pre- and post-plasma exchange sera demonstrated anti-retinal autoantibodies against 69-kDa protein of the same molecular weight as the α-HGF. Serum autoantibodies reacted with purified recombinant α-HGF on the blot.Conclusions:BDUMP can mimic n-AMD, which can delay treatment. Plasma exchange resulted in resolved inflammation, resolution of exudative detachments and improved vision after cataract surgery. Consideration of the tumor genetics led to the recognition of elevated HGF levels and autoantibodies to α-HGF (anti-69-kDa), which suggested a new pathogenic mechanism of BDUMP. We believe that therapy with tyrosine kinase inhibitors and a checkpoint inhibitor may contribute to the high HGF levels and subsequent immune response.

Seeing is believing: A review of apheresis therapy in the treatment of ophthalmologic disease.

Apheresis procedures have a role in treatment of disparate diseases involving many different organ systems. Often the disease processes where apheresis plays a role in treatment are considered "orphan diseases"-relatively rare disease processes that lack specific pharmaceutical agents or established treatment protocols. Many of these disease processes can affect the eye with devastating results for the eyesight of these patients. The unique ability of apheresis to affect disease by modifying blood plasma and modulating disease-causing agents therein renders apheresis procedures valuable tools in the treatment of certain ophthalmologic diseases. This review comprehensively evaluates the role of apheresis in the treatment of ophthalmologic diseases of the eye and surrounding orbit including age-related macular degeneration, bilateral diffuse uveal melanocytic proliferation, paraneoplastic retinopathy, atopic keratoconjunctivitis, sympathetic ophthalmia, and endocrine-associated ophthalmopathy. Apheresis procedure parameters are provided for the apheresis practitioner based on review of the relevant literature.