Bilateral Diffuse Uveal Melanocytic Proliferation as a Precursor to Multiple Systemic Malignancies

Abstract

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare, intraocular paraneoplastic syndrome characterized by multiple, elevated, pigmented uveal lesions, diffuse thickening of the uveal tract, and rapidly progressive cataracts. We report a 70-year-old Caucasian male with an inferotemporal conjunctival-scleral pigmented lesion of the right eye. Funduscopy and ultrasonography revealed multiple elevated pigmented choroidal lesions in both eyes. Genome-wide single nucleotide polymorphism (SNP) analysis of intraoperative transscleral fine-needle aspiration biopsies from both eyes revealed a whole gain on chromosome 5. BDUMP was diagnosed, and the patient underwent a thorough systemic investigation, which was negative for an underlying malignancy; however, by maintaining a high index of suspicion, multiple malignancies were uncovered and appropriately treated over the ensuing years. This report presents the clinical, cytologic, and cytogenetic features of BDUMP, and is the first to demonstrate a novel finding of a whole gain in chromosome 5 by SNP analysis of the choroidal lesions. Additionally, this is the first case to potentially associate BDUMP and both transitional cell carcinoma of the bladder as well as renal clear cell carcinoma.

Bilateral Diffuse Uveal Melanocytic Proliferation: Molecular Genetic Analysis of a Case and Review of the Literature

“…They also looked for mutations in GNAQ, GNA11 and BRAF V600E in the BDUMP melanocytes, but did not demonstrate these. Rahimy et al [10] showed chromosome 5 gain in their case, and interestingly also described focal cytological atypia within the cells. The lack of GNAQ/GNA11 mutations in these 2 cases and in ours would suggest that if BDUMP represents a neoplastic process, it is one that possibly follows a different oncogenic pathway to uveal naevi and the majority of uveal melanomas [12].…”

“…Although there are over 50 cases of BDUMP reported in literature, only 3 of these have been evaluated for genetic alterations, with 2 of the 3 cases showing genetic abnormalities [8,10]. Mudhar et al [8] described gains in chromosome 6 and X, and deletions in chromosome 19 in the BDUMP case they analysed.…”

“…The median survival of most BDUMP patients is 15.6 months [4]; however, there are reports of BDUMP patients surviving as long as 4 years and about 8.6 years, without and with enucleation [5,7]. These patients may even have multiple systemic malignancies and may present after several months to years with the systemic malignancy, so that prolonged systemic surveillance is mandatory [10]. Twenty-five percent of the BDUMP cases may have associated oral/mucosal and/or cutaneous involvement [9], so that extensive systemic and dermatological examination is mandatory in all cases with BDUMP.…”

“…It is characterized microscopically by an extensive proliferation of benign-appearing melanocytes, which have a very low proliferation index and which diffusely replace the uveal tract, causing overlying retinal and retinal pigment epithelial changes. There are few reports on genetic alterations in proliferating melanocytes of BDUMP [8,9,10]. We present a case of BDUMP, which we analyzed for chromosomal alterations using multiplex ligation-dependent probe amplification (MLPA), and for GNAQ and GNA 11 mutational status.…”

“…Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare and well-recognized ocular paraneoplastic syndrome with an enigmatic pathogenesis [1,2,3,4,5,6,7,8,9,10]. It is most commonly associated with carcinomas of the ovary and lungs, followed in frequency by the gastrointestinal and genitourinary malignancies.…”