Comprehensive Melanoma‐Related Gene Analysis of Bilateral Diffuse Uveal Melanocytic Proliferation: A Case Report

A man in his early 70s with a history of bilateral vision loss of unknown etiology presented with black nodules on both eyes (Figure 1A). Ophthalmologic examination revealed multiple variably sized black nodules on both sclerae, and bilateral enucleation was performed due to strong clinical suspicion of uveal melanoma (Figure 1B,C). Histopathological examination showed diffusely thickened uveal tissue with scattered small nodules composed of proliferating spindle-shaped melanocytes with slight cytologic atypia and scant melanin pigmentation (Figure 1D–F). Focal scleral infiltration was observed, suggesting melanoma-like behavior; however, mitotic figures were rare and no necrosis was identified. Retinal detachment was present in some areas. Immunohistochemically, the melanocytes were positive for MART-1, HMB-45, S-100, and SOX10, negative for PRAME, and showed a low Ki-67 labeling index (0%–1%) (Figure 1G–K). Targeted next-generation sequencing of melanoma-related genes (AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, RET, TERT, and TP53) was performed using the Archer VARIANTPlex Solid Tumor Focus v2 panel. Only two TP53 variants—p.T377P (variant allele frequency, 5.9%) and p.S378P (variant allele frequency, 3.1%)—were identified, both of which were classified as variants of uncertain clinical significance. Their low variant allele frequencies relative to the estimated melanocyte content suggest that these alterations represent minor subclonal events with limited clinical relevance. Notably, no mutations were detected in GNAQ or GNA11, including hotspot codons Q209 and R183, which are recurrent driver mutations in approximately 80%–90% of uveal melanomas and lead to constitutive activation of the MAPK and YAP signaling pathways [1]. Nuclear expression of BAP1 was preserved (data not shown). Comprehensive systemic evaluation revealed no evidence of melanoma or other malignancies at that time. Collectively, a diagnosis of bilateral diffuse uveal melanocytic proliferation (BDUMP) was established. Concomitantly, multiple small, uniform gray-to-black macules were observed on the oral mucosa (Figure 2A,B), penis (Figure 2C–E), and palms and soles (Figure 2F). Seven months after the diagnosis of BDUMP, a gradually enlarging nodule was detected in the right lung on computed tomography, raising strong suspicion of lung cancer. However, the patient declined both biopsy and follow-up evaluation, and unfortunately, a definitive diagnosis could not be established. BDUMP is a rare syndrome characterized by diffuse, benign-appearing melanocytic proliferation within the uveal tract, typically affecting both eyes and causing rapid visual impairment due to exudative retinal detachment or cataract formation [2]. Although its etiology remains unclear, BDUMP is considered a paraneoplastic syndrome, as most cases are associated with extraocular malignancies, including gynecologic cancers in women and lung cancers in men [2]. A serum factor within the IgG fraction, termed cultured melanocyte elongation and proliferation factor, has been implicated, supported by clinical improvement after treatment of the primary tumor, plasmapheresis, plasma exchange, and corticosteroid therapy [2, 3]. Conversely, genetic or chromosomal abnormalities in uveal melanocytes, such as RB1 heterozygosity and aberrations involving chromosomes 3, 5, 6, 8, and X, have also been reported [2-4], and atypical melanoma-like and benign melanocytes may coexist within the same uveal tissue [2]. These findings suggest that neoplastic melanocytic proliferation may occur in a subset of BDUMP cases. Mucocutaneous pigmentation occurs in approximately 15% of patients, most commonly involving the mucosa, skin, and conjunctiva [3, 5]. Histopathologically, these lesions show basal hyperpigmentation, irregular rete ridge elongation, and scattered melanocytes and melanophages and may improve following plasmapheresis [3, 5]. In summary, this is the first BDUMP case to include comprehensive mutation analysis of melanoma-associated oncogenes in uveal melanocytes. The detection of only nonsignificant TP53 mutations supports a predominantly paraneoplastic mechanism, although further genetic and molecular studies are needed to clarify BDUMP pathogenesis. The authors have nothing to report. Written informed consent for publication of the case details was obtained from the patient, and the consent form was signed by the corresponding author on his behalf. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.