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

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)'.

Heterogeneity of cultured melanocyte elongation and proliferation factor in 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.

To describe the advanced multimodal imaging findings of patients with bilateral diffuse uveal melanocytic proliferation and the changes in these findings over time. Fundus photography, fundus autofluorescence, fundus fluorescein angiography, spectral domain optical coherence tomography, B-scan ultrasonography, and ultrasound biomicroscopy images of the patients diagnosed with bilateral diffuse uveal melanocytic proliferation at a single institution between years 2006 and 2023 were evaluated. Sixteen eyes of eight patients with bilateral diffuse uveal melanocytic proliferation were included. The median age was 68 years (range: 49-77 years), and the median follow-up time was 11 months (range: 1-79 months). The most common fundus photography findings were pigmentary changes and diffuse orange pigment patches in the posterior pole. The giraffe/leopard pattern of hyperfluorescence on the posterior pole was the most prominent finding in fundus autofluorescence and fluorescein angiography. Different from previous reports, intraretinal hyperreflective foci, outer retinal tubulations, subretinal fibrosis, and bacillary layer detachment in optical coherence tomography; optic disc hyperfluorescence and peripheral vascular leakage in fluorescein angiography; 360° ciliary body thickening; and anterior rotation of the ciliary body in ultrasound biomicroscopy were detected. We presented various novel multimodal imaging features of bilateral diffuse uveal melanocytic proliferation that may warrant updating current diagnostic criteria and their changes over time. Our newly defined findings also suggest a possible inflammatory component to bilateral diffuse uveal melanocytic proliferation pathogenesis, which may have implications for treatment.

Bilateral diffuse uveal melanocytic proliferation is a poorly understood disorder characterized by the progressive proliferation of uveal melanocytes associated with a systemic nonocular malignancy. Overexpression of p53 protein plays a role in the loss of regulatory control of normal cell proliferation, and p53 is the most commonly identified oncogenic protein in human malignancies. We tested the hypothesis that the aberrant cellular activity in bilateral diffuse uveal melanocytic proliferation involves the overexpression of p53 protein. Eight eyes from four patients with bilateral diffuse uveal melanocytic proliferation were tested for p53 protein using an immunoperoxidase technique with an anti-p53 protein monoclonal antibody sensitive for normal and mutant p53 protein. The p53 protein could not be detected in any of the eight eyes. The proliferation of uveal melanocytes in bilateral diffuse uveal melanocytic proliferation does not depend on the overexpression of p53 protein. The loss of cellular regulatory control in bilateral diffuse uveal melanocytic proliferation is probably mediated through another mechanism.

Bilateral diffuse uveal melanocytic proliferation associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic syndrome

To determine if there is a factor in the serum of patients with bilateral diffuse uveal melanocytic proliferation (BDUMP) that causes melanocytic proliferation. Human melanocytes and melanoma cells were grown and exposed to serum or plasma of patients with BDUMP, other neoplastic conditions, or control media. Preliminary studies using serum were conducted in an unmasked fashion. In addition, IgG-depleted and IgG-enriched plasma was also tested in a similar fashion. Experiments using plasma were conducted triple masked. To show that the proliferation was melanocyte selective, human dermal fibroblasts, keratinocytes, and ovarian cancer cells were treated with plasma of the BDUMP cases or controls, and the effect of this exposure on their proliferation was quantified. At 72 hours, the serum of BDUMP patients caused statistically significant increased proliferation of normal human melanocytes. Further studies at 6 days demonstrated similar findings. In addition, melanocytes grown in BDUMP serum exhibited a disorganized morphology with foci of multilayered cells. Cultured melanoma cells also showed statistically significant increase in growth in serum from BDUMP patients compared with controls. Masked plasma studies further confirmed these findings and showed that the IgG fraction appeared to contain the melanocyte growth-stimulating factor. The human fibroblasts, keratinocytes, and ovarian cancer cells did not show an increase in growth with the BDUMP plasma treatment. Patients with BDUMP have a factor in the IgG fraction that selectively causes melanocyte proliferation. How it causes proliferation of human melanocytes and melanoma cells needs to be further elucidated.

The management of bilateral diffuse uveal melanocytic proliferation is controversial, with most earlier reports advocating for plasmapheresis. Here, we report a case of bilateral diffuse uveal melanocytic proliferation secondary to gastric adenocarcinoma that was successfully treated with adjunctive intravenous immunoglobulin, using a loading dose followed by a treat-and-extend strategy. Clinical case report with 3 years of follow-up including serial ophthalmologic examinations. Functional assessments included visual acuity and subjective visual complaints. Periodic anatomic assessments were performed including serial optical coherence tomography, ultra-widefield fundus imaging, multimodal angiography, and ophthalmic ultrasound. A 75-year-old man presented with a 6-month history of blurry vision and difficulty with dark and light adaptation in both eyes. A diagnosis of bilateral diffuse uveal melanocytic proliferation was established based on clinical findings and subsequent discovery of an underlying gastric malignancy; the diagnosis of a paraneoplastic syndrome was further substantiated by documentation of cancer-associated antiretinal antibodies and serum reactivity against human retina by immunohistochemistry. Treatment with high-dose (2 g/kg) intravenous immunoglobulin was initiated with biweekly, followed by monthly, then q2-3 monthly dosing intervals. Meanwhile, the patient received surgical resection and systemic chemotherapy resulting in complete radiographic remission of the primary cancer. Over the course of 3 years, the patient has demonstrated clinically significant improvements in visual acuity and subjective visual function. Rapid and sustained anatomic improvements were observed in serous retinopathy and choroidal thickness. Intravenous immunoglobulin may be a viable adjunctive treatment option for some patients with bilateral diffuse uveal melanocytic proliferation.

Bilateral diffuse uveal melanocytic proliferation is a rare paraneoplastic syndrome that presents with bilateral progressive loss of vision. A 70-year-old woman presented with a 3-month history of progressive, bilateral vision loss. The patient had bilateral, diffuse, shallow, subretinal fluid with patchy, reddish-brown lesions at the level of the retinal pigment epithelium (RPE) that showed significant early hyperfluorescence on fluorescein angiography and a corresponding loss of autofluorescence. Optical coherence tomography of both eyes revealed complete RPE and inner segment/outer segment junction loss with adjacent areas of thickening at the level of the RPE. Bilateral diffuse uveal melanocytic proliferation was diagnosed based on these clinical findings, and a systemic evaluation for malignancy revealed metastatic endometrial adenocarcinoma. Both autofluorescence and optical coherence tomography demonstrated unique imaging characteristics that correlated with the reported histopathology of bilateral diffuse uveal melanocytic proliferation. These imaging modalities can contribute to the rapid and accurate diagnosis of bilateral diffuse uveal melanocytic proliferation.

To report a case of bilateral diffuse uveal melanocytic proliferation over 30 months follow-up. Multimodal imaging including ultra-wide-field color fundus photography, blue light fundus autofluorescence, swept-source optical coherence tomography, fluorescein angiography, and indocyanine green angiography. A 49-year-old woman presented with decreased vision 2 months after bladder cancer surgery. Exudative retinal detachment and leopard spot pattern chorioretinopathy were observed in the right eye. Chemotherapy and cystectomy were initiated. Progressive bilateral vision loss occurred with melanocytic proliferation, choroidal thickening, subretinal fibrosis, fluid extravasation, rapid development of mature cataract, multiple iris cysts, and rubeosis, despite plasmapheresis and IV immunoglobulins. After cataract surgery, massive fibrin reaction resulted in a ciliolenticular block. One year later, positron emission tomography-computed tomography revealed absence of metastases. At Month 23, choroidal thickness increased in line with tumor progression. Palliative systemic therapy was initiated. Secondary macular neovascularization was treated with intravitreal antivascular endothelial growth factor injections. Visual acuity was light perception in the right eye and 20/200 in the left eye at last follow-up. Bilateral diffuse uveal melanocytic proliferation results in progressive melanocyte proliferation and exudation, leading to severe visual loss. In our case, visual acuity was preserved at a low level in one eye under continuous systemic treatment. Systemic corticosteroids are recommended for cataract surgery in the setting of bilateral diffuse uveal melanocytic proliferation to prevent massive fibrin reaction. Intravitreal antivascular endothelial growth factor injections may be indicated if secondary macular neovascularization develops.

Bilateral diffuse uveal melanocytic proliferation 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 bilateral diffuse uveal melanocytic proliferation after immunotherapy in the setting of primary non-small-cell carcinoma of the lung. Single-center, case report. 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 >180% increase in proliferation of normal neonatal melanocytes compared with 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 bilateral diffuse uveal melanocytic proliferation 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 RB1 c.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 bilateral diffuse uveal melanocytic proliferation.

SUMMARY Bilateral diffuse uveal melanocytic proliferation is a rare paraneoplastic disorder where bilateral blindness is caused by uveal thickening, serousretinal detachment, and rapid cataract formation.Several different malignancies have been associated with bilateral diffuse uveal melanocytic proliferation, but ovarian carcinoma in women and lungand pancreatic carcinoma in men are the most common.The underlying mechanism is thought to be related to a an endogenous factor wich regulates the proliferation of uveal melanocytes.We present the case of a 75-year-old man with bilateral diffuse uveal melanocytic proliferation secondary to pulmonary adenocarcinoma.

To report an unusual case of delayed-onset bilateral diffuse uveal melanocytic proliferation in a patient with a remote history of gastric adenocarcinoma 17 years earlier. Case report of a patient with bilateral diffuse uveal melanocytic proliferation including comprehensive systemic and ocular examinations. A 78-year-old man presented with a history of progressive bilateral vision loss during the 4 previous years associated with fever of unknown origin. He underwent total gastrectomy 17 years earlier as a treatment for gastric adenocarcinoma. Funduscopic examination revealed multiple subretinal pigmented and nonpigmented lesions involving the posterior pole of both eyes. These lesions showed early hyperfluorescence on fluorescein angiography, producing a giraffe pattern. Spectral-domain optical coherence tomography showed intraretinal and subretinal fluid with multiple hyperreflective mounds involving the retinal pigment epithelium. Treatment with the intravitreal anti-vascular endothelial growth factor agent, ranibizumab, produced anatomical improvement in both eyes but visual improvement in just the right eye. Although delayed-onset bilateral diffuse uveal melanocytic proliferation may occur, it is important to rule out a second malignancy. To the knowledge of the authors, this is the first report of delayed-onset bilateral diffuse uveal melanocytic proliferation associated with gastric adenocarcinoma. Treatment with intravitreal anti-vascular endothelial growth factor therapy warrants further evaluation.

Purpose: To describe a case of bilateral diffuse uveal melanocytic proliferation in the setting of metastatic ovarian cancer. Methods: A single case was analyzed and a literature review of treatment efficacy performed. Results: A 64-year-old woman presented to ophthalmology in July 2022 for evaluation of blurred vision in the setting of ovarian cancer and a possible reaction to chemotherapy. A comprehensive workup led to the diagnosis of bilateral diffuse uveal melanocytic proliferation. Treatment to potentially preserve the patient's vision comprised a sub-Tenon triamcinolone injection and plasmapheresis. Conclusions: Plasmapheresis did not improve the visual acuity (VA) in the patient's right eye; however, 6 months after the last treatment, the VA in the left eye improved from 20/50 to 20/30, corresponding to a decrease in macular edema. Given the rarity of bilateral diffuse uveal melanocytic proliferation, its uncertain pathogenesis, and its varied responses to treatment, it is imperative to establish a diagnostic management and treatment algorithm to improve visual outcomes.

We describe a case of a 65-year old patient presenting with unusual mucocutaneous melanocytic proliferations of a Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) imitating a multifocal melanoma in situ, which improved dramatically after plasmapheresis. The patient first presented at the dermatology department due to rapidly evolving brown and black macules on the glans penis. Further skin involvement of the perineal and perianal region, mamillae and oral mucosa was stated. Histology from a penile biopsy was compatible with a melanoma in situ. Due to the distribution pattern and elevated serum tumor marker S100B, metastatic melanoma was considered. Staging examinations using PET-CT scan however, revealed a lung tumor, later confirmed as a Non-small-cell lung cancer (NSCLC). Primary radio chemotherapy was initiated to treat NSCLC. Shortly after initiation of radio chemotherapy the patient developed massive vision impairment and a NSCLC-associated BDUMP was diagnosed which led to the correct classification of melanocytic skin lesions as mucocutaneous BDUMP manifestation. Plasmapheresis was started resulting in a rapid improvement of vision starting ten days after the first plasmapheresis. In contrast skin manifestations started to disappear with a marked delay 4 months after the last plasmapheresis cycle. This case highlights the importance of memorizing multiple rapidly progressing melanocytic skin and/or mucous membrane spots together with visual impairment as a possible paraneoplastic BDUMP that needs a fundamentally different therapeutic approach compared to multifocal melanoma in situ.What is already known about this topic? Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) is a paraneoplastic syndrome with melanocytic uveal proliferation leading to vision impairment. Extraocular manifestation is rare, mainly affect the subepidermal compartment and is hard to treat. Plasmapheresis has been shown to be an effective treatment mainly for vision improvement in some but not all cases.What does this study add? Our BDUMP case with widespread skin and mucosal involvement initially mimicked a multifocal melanoma in situ and showed an excellent treatment response to plasmapheresis. Improvement of mucocutaneous lesions has not been documented well in the literature so far. We show a more than one year lasting follow up still underlining the beneficial effect of plasmapheresis in this case. In-vitro data supports the hypothesis that plasma exchange eliminates a “Cultured melanocyte elongation and proliferation (CMEP)” factor out of patient blood leading to decreased melanocyte proliferation shown numerically in-vitro and clinically in-vivo. Our case clearly indicates that before establishing a definite diagnosis and therapy in patients with rapidly evolving melanocytic skin and/or mucosal lesions BDUMP mimicking multifocal melanoma in situ should be considered making a thorough diagnostic workup mandatory.