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Background: Bilateral 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 Presentation: A 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., Conclusions: Identifying BDUMP warrants further investigation of a primary malignancy. Our case provided evidence for the link between gastric adenocarcinoma and BDUMP.

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.

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The mechanisms underlying cutaneous melanogenesis have been widely studied; however, very little is known about uveal melanogenesis. Melanin is normally produced by uveal melanocytes and gives the color to the iris. A derangement from this normal production may occur, for instance, by iatrogenic events, such as glaucoma therapy with prostaglandins that may enhance cutaneous and iris pigmentation. In this study, we investigated the mechanisms that regulate uveal melanogenesis in human uveal melanoma cells (92.1) and murine cutaneous melanoma cells (B16-F1). In the first part of the study, we compared the effects of known cutaneous pigmenting agents on the B16-F1 and 92.1 cells, showing an opposite response of the two cell lines. Subsequently, using argan oil, a known depigmenting agent for murine cutaneous melanoma cells, on 92.1 cells, we found that in these cells, it also functioned as an inhibitor of melanogenesis and tyrosinase expression. From a molecular perspective, treatment of the 92.1 cells with argan oil decreased melanogenesis-associated transcription factor (MITF) gene expression by inducing MITF phosphorylation at Ser73, thus leading to MITF ubiquitination and disposal. It also led to the downregulation of the extracellular signal-regulated kinase (ERK)1/2 and Akt pathways, also known to be involved in cutaneous melanogenesis, although with an opposing function. Taken together, our data indicate that: ⅰ) some differences exist in the regulation of melanogenesis between cutaneous and uveal melanoma cells; and ⅱ) argan oil exerts a depigmenting effect on 92.1 cells through its action on the ERK1/2 and Akt pathways.

Pigmented cells are derived from neural crest cells, which migrate along the peripheral nerve sheets into their specific final region. During their migration, cells progressively acquire pigment-producing capabilities, maturation, and the shape of melanocytes. These insights, along with specific clinical characteristics of melanocytic nevi, have led to new concepts of cutaneous, periocular, and iris nevogenesis. To further elucidate the specific ocular embryogenic melanoblast distribution and dissemination - that could explain the distinct distribution of uveal melanocytic neoplasms - we investigated the ocular pigmentation of dogs affected by a specific mutation called Merle, which results in either pigment- (wild type) or non-pigment- (mutated type) producing cells. Based on our observations, we propose a unifying concept of uveal pigment cell distribution and dissemination, which postulates melanoblast migration and maturation following the trigeminal V1 branch and, later, their entrance into the eye along the ciliary nerves and their finest iris branches. Our concept provides an explanation not only for the specific distribution of ocular melanocytic lesions, including uveal and iris nevi, but also for the different locations depending on the metastatic potential of the ocular melanoma. Though speculative, the higher metastatic potential of posterior uveal melanomas compared to iris melanomas may be related to a less differentiated stage in the maturation of migrating melanocytes in the posterior segment compared to the anterior segment of the eye. However, there is a need of further studies focusing on cell differentiation markers of melanocytes at different locations in the eye., (© 2016 S. Karger AG, Basel.)

Purpose: Uveal melanoma (UM) has been the subject of intense interest due to its distinctive metastatic pattern, which involves hematogenous dissemination of cancerous cells toward the liver in 50% of patients. To search for new UM prognostic markers, the Suppressive Subtractive Hybridization (SSH) technique was used to isolate genes that are differentially expressed between UM primary tumors and normal uveal melanocytes (UVM)., Methods: A subtracted cDNA library was prepared using cDNA from uncultured UM primary tumors and UVM. The expression level of selected genes was further validated by cDNA microarray, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), and immunofluorescence analyses., Results: One hundred-fifteen genes were identified using the SSH technique. Microarray analyses comparing the gene expression profiles of UM primary tumors to UVM validated a significant differential expression for 48% of these genes. The expression pattern of selected genes was then analyzed by semi-quantitative RT-PCR and was found to be consistent with the SSH and cDNA microarray findings. A down-regulation of genes associated with melanocyte differentiation was confirmed in UM primary tumors. Presence of undifferentiated cells in the UM was demonstrated by the expression of stem cell markers ATP-binding cassette sub-family G member 2 (ABCG2) and octamer-binding protein 4 (OCT4)., Conclusions: We demonstrated that the SSH technique is efficient to detect differentially expressed genes between UM and UVM. The genes identified in this study represent valuable candidates for further functional analysis in UM and should be informative in studying the biology of this tumor. In addition, deregulation of the melanocyte differentiation pathway revealed the presence of UM cells exhibiting a stem cell-like phenotype.

A 50-year-old man presented with visual disturbance at a local ophthalmology clinic. He was given a diagnosis of uveitis and treated with oral corticosteroids; however, his visual disturbance did not improve and he was admitted to our hospital. A chest CT scan showed a pulmonary nodule in the upper lobe of the right lung, and right hilar and mediastinal lymphadenopathy. Transbronchial biopsy yielded a diagnosis of squamous cell carcinoma, and an ophthalmologic examination revealed bilateral diffuse uveal melanocytic proliferation (BDUMP). BDUMP is a rare manifestation of paraneoplastic syndrome, and the characteristics of the condition have not yet been clarified in detail. BDUMP carries a very poor visual prognosis, and in the present case, the patient's visual disturbance progressed rapidly despite systemic chemotherapy and corticosteroid therapy.

Levels of eumelanin (EM) and pheomelanin (PM) of uveal melanoma cells have not been measured and compared with those of normal uveal melanocytes. EM and PM amounts in four immortal human uveal melanoma cell lines were measured by chemical degradation and microanalytical high-performance liquid chromatography and compared with those from 39 normal human uveal melanocyte cell lines reported earlier by us. Uveal melanoma cells had a very low EM/PM ratio (0.41), which was very significantly lower than that from normal melanocytes isolated both from eyes with light-colored irides (1.31) or dark-colored irides (7.32). The low EM/PM ratio was caused by a low level of EM in melanoma cells, which was only 1/8 and 1/31 of that in melanocytes from eyes with light-colored irides and dark-colored irides, respectively. The PM level in uveal melanoma cells was not statistically different from normal melanocytes from eyes with light-colored irides or dark-colored irides. The total quantity of EM and PM in uveal melanoma cells was significantly less than that in normal melanocytes. This difference was because of the low level of EM in uveal melanoma cells. The results of these studies indicate that the changes of melanin content in uveal melanoma cells mainly relate to the decrease of EM content. Low melanin and EM content may make melanoma cells more susceptible to mutagenic effects of ultraviolet radiation and oxidative stress, which may enhance the proliferation of melanoma cells and accelerate progression of melanoma.

Purpose: To report differences in the coloration of fundus lesions between Asian and Caucasian patients with bilateral diffuse uveal melanocytic proliferation (BDUMP)., Cases: This syndrome was detected in 2 Japanese patients, 69 and 73 years old, with lung cancer who visited our department complaining of visual disturbances. The coloration of the fundus lesions was investigated in these 2 patients., Results: The fundus lesions in the first patient appeared gray or grayish-brown in color at the first visit. Six months later, the fundus appeared as a mixture of white to dark-brown lesions. The fundus in the second patient exhibited a mixture of white, gray, and dark-brown lesions from the first visit., Conclusions: The fundus lesions in these BDUMP patients appeared gray or grayish-brown in color at the early stage of the disease, probably because of the abundance of melanin pigments in the uveal melanocytes. At the advanced stage, the fundus exhibited a mixture of dark-brown lesions due to melanin deposits and white, depigmented lesions caused by atrophy and/or necrosis of the melanocytes.

Diffuse uveal melanocytic proliferation is a rare paraneoplastic syndrome resulting in rapid bilateral visual loss in patients with systemic carcinoma, caused by proliferation of benign melanocytes within the choroid and the ciliary body. More often visual impairment is due to retinal detachment and cataract. The authors report two cases of presumed diffuse uveal melanocytic proliferation. The first patient was a 74-year-old man with a history of colic carcinoma and hemangioendothelioma of the liver who presented with bilateral multiple nevi of the choroid and extrascleral melanic nodule. The second patient was a 59-year-old woman who presented bilateral multiple nevi of the choroid and a history of carcinoma of the thyroid treated by thyroidectomy 2 years before. There was no evidence of systemic melanoma in either patient. Our two patients showed slow progression with no visual impairment and a longer survival than those described in the literature.

Bilateral diffuse uveal melanocytic proliferation (BDUMP) associated with systemic carcinoma is a rare paraneoplastic syndrome. It was reported to be associated with primary carcinomas of the lung, ovary, colon, gall bladder, esophagus, pancreas, uterus, and cervix. We report a case of BDUMP that occurred in a woman with cervical leiomyoma. The 79-year-old woman experienced bilateral progressive visual loss to hand motion within 2 weeks. Fundus examination showed bilateral exudative retinal detachment and multiple oval red patches. Echographic study showed diffuse thickening of the uveal tracts. Fluorescein angiography showed multiple patches of window defect without late leakage, which was correlated with the oval red patches. After screening for tumor markers and meticulous examinations, an elevated serum level of CA-125 was noted. The only neoplasm found in this patient was a cervical leiomyoma, which has never been reported to be associated with BDUMP. One month after the onset of symptoms, accidental head injury due to poor vision led to right parietal intracerebral hemorrhage and left hemiplegia. Prompt diagnosis of this paraneoplastic syndrome is important to discover the underlying malignancy in patients with no history of cancer. For those cases without malignant neoplasm, attention should be directed to the disability caused by the severe visual loss, which led to accidental head injury and intracerebral hemorrhage in this case.

Diffuse bilateral uveal melanocyte proliferation is a rare paraneoplastic syndrome causing severe visual impairment. We report the case of a 58 year old man with progressive visual loss due to multiple retinal pigment epithelial lesions with a serous detachment of the posterior pole in both eyes. Visual acuity improved with systemic corticoids. Two years later, he again experienced visual loss. Meanwhile this patient had undergone a resection of a large cell anaplastic lung carcinoma. The fundus appeared unchanged except for the appearance of multiple naevoid lesions. The choroid was diffusely thickened. Visual acuity improved again with systemic corticoids. This case is quite exceptional as the visual acuity was well preserved during a follow up of more than two years. The case is compared with those published previously and the differential diagnosis is discussed.

A 52-year-old woman noted loss of vision in August 1984. Clinical examination disclosed iris cysts and ciliary body cysts, macular edema, and uveal nevi. Cataract extraction and pressure-lowering operations were required in both eyes because of a tumor-induced angle-closure glaucoma. Vision, however, progressively decreased to light perception in each eye. Both eyes were finally enucleated because a malignant melanoma could not be ruled out, though iris tissue obtained in 1985 suggested a nevuslike process. Histologic study indicated a bilateral uveal hyperplasia. Results of light and electron microscopy, immunologic studies, and suspension cell culture suggested that the uveal hyperplasia was more likely a melanoma of low malignancy than a nevuslike process. We could not detect an extraocular primary tumor and assumed that this condition constituted an oncogenic syndrome.

In a substrain of Sinclair miniature black swine, bred for increasing incidence of cutaneous malignant melanomas, tumor regression occurs spontaneously and is accompanied by depigmentation of the skin, hair, and eyes. We conducted a 12-month longitudinal study of the ocular phenomena in 30 swine beginning at 3 weeks of age. The clinically observed sequence of depigmentation of the fundus and iris was correlated with histopathologic changes in selected enucleated eyes. Normal melanocytes of the uveal tract are destroyed between the 4th and 16th week of life. Melanocyte destruction is preceded by an invasion of the uveal tract by mononuclear cells having the ultrastructural features of lymphocytes and monocytes. Melanin and other cellular debris of ruptured melanocytes are ingested by macrophages which then migrate to the walls of blood vessels. Cataracts and band keratopathy develop secondary to the uveitis in some animals. Pilot electroretinograms show diminished electrical activity in photoreceptors of totally depigmented eyes possibly indicating ischemic or toxic damage to the retina. The retinal pigment epithelium remains essentially normal during the acute stages of uveal inflammation; later some damage and reparative hyperplasia may occur. The death of normal uveal melanocytes that occurs during the systemic attack on the cutaneous malignant melanomas appears to be an "innocent bystander" error in the immune recognition mechanism. The antigenic basis of this immunologic cross reaction is under investigation.

Melanocytomas are pigmented tumors of the uvea and optic nerve head composed of plump polyhedral melanocytes which have been regarded as nevus cells. There are few reports of malignant change in these usually benign lesions. This study documents 16 cases of malignant melanoma of the uvea, eight of which were characterized by the presence of plump polyhedral melanocytes in and around the tumor. The melanocytoma cells were aggregated throughout the tumors and/or at the margins of the lesions; these cells did not appear between the melanoma and the sclera, as has been reported with spindle-type nevus cells. Electron micrographs of these plump melanocytes had the characteristics of common uveal melanocytes, while the tumor cells had features of malignant melanoma cells. The clinician should recognize the potential of melanocytomas for undergoing malignant change and should follow patients who have this lesion with this in mind. Article is followed by comments of Dr. L. E. Zimmerman.

The ultrastructure of the ocular pigment abnormality of human Chédiak-Higashi syndrome is described. The presence of giant abnormal melanosomes, probably the end result of the fusion of smaller abnormal organelles, was the most striking pathologic finding. This defect involved both optic cup and neural crest-derived melanocytes; the former were affected more severely. Giant lysosome-like organelles were also observed.

Sinclair strain miniature swine spontaneously develop and regress malignant melanoma lesions, with uveitis and vitiligo occurring subsequent to tumor regression. Peripheral blood lymphocytes (PBL) of Sinclair swine undergoing tumor regression and melanocyte destruction demonstrated significant lytic activity against K562, porcine semiallogeneic uveal melanocytes, and melanoma cells in 4-h chromium release assays. The ability of porcine PBL to lyse these target cells appears to be an age-associated immune response, as evidenced by the relative inability of PBL of pigs less than 4 weeks old to lyse target cells. In young adult pigs, however, PBL cytotoxic activity significantly increases; piglets 6 weeks old and older demonstrate efficient killing of all three targets. Conjugate formation assays demonstrate that a lymphoid effector cell possessing large granular lymphocyte (LGL) morphology may be involved in melanocyte destruction. These findings suggest that a LGL subpopulation may participate in melanoma and melanocyte destruction which can induce a uveitic syndrome in Sinclair swine with melanoma.