Bilateral diffuse uveal melanocytic proliferation (BDUMP)

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Disease

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular syndrome that results in severe vision loss. Gass et al.[1]1 described the syndrome with the following cardinal ocular signs (1) multiple round or oval red patches in the fundus, (2) multifocal, early hyperfluorescence correlating with fundus lesions on fluorescein angiography (FA), (3) scattered pigmented and nonpigmented uveal melanocytic tumors with diffuse choroidal thickening, (4) exudative retinal detachment, and (5) rapidly progressing cataracts.

Pathogenesis

BDUMP is characterized by an extensive infiltration of predominantly benign uveal melanocytes that is unrelated to a primary visceral tumor. Histopathology shows proliferation of spindle-shaped melanocytic cells without mitosis or atypia.[2] There are a few reported cases which presented with a co-existing malignant melanoma.[2] From a molecular standpoint, BDUMP does not share the same hallmarks of uveal nevi or uveal melanoma.

The exact pathogenesis is unclear at this time due to the rarity of the disease. The three main postulations for the pathogenesis include: (1) synchronous growth of the uveal melanocytes and visceral carcinoma due to a shared unknown oncogenic stimulus, (2) uveal melanocytic proliferation due to an unknown stimulus released by the primary extraocular tumor, and (3) coincidental development of BDUMP and visceral carcinoma due to an unknown genetic predilection.[1][3] In vitro studies investigated serum samples from patients with BDUMP and found that the IgG-enriched portion stimulated melanocyte to multiply; however, it was unclear how or why this occurred.[4]

The infiltration of the uveal melanocytes leads to the destruction of the overlying retinal pigment epithelium (RPE) and outer retinal layers while the choriocapillaris is typically spared. The striking correspondence of the early hyperfluorescence with the subretinal lesions suggests that the focal destruction causes fenestrations in the RPE. As the areas of damage enlarge, a reticular pattern of the remaining orange-pigmented epithelium forms.[1]

The mechanism of retinal detachment formation is thought to be due to impaired RPE function and/or the breakdown of the blood-retinal-barrier by an unknown byproduct.[5][6]

It is hypothesized that iris and ciliary body involvement may contribute to the rapid progression of cataracts and increased risk for angle-closure glaucoma.[7]

Associations/Epidemiology

The most commonly associated systemic carcinomas include ovarian carcinoma in women and lung carcinoma in men. A literature review of patients with BDUMP found 25 of 36 women had urogenital cancer and 12 of 23 men cases had lung carcinoma.[2] Other associated malignant neoplasms include cervical, uterine, gall bladder, pancreatic, urinary bladder, breast, primary ocular lymphoma, CNS lymphoma, liver, renal, Bartholin gland, esophageal and colorectal cancers.[2][4][8][9]

Median age of presentation has been reported at both 58 and 65 years old with a range of 34 to 89 years old with equal distribution of sex.[2][6] The incidence is unknown given the limited number of known cases.

History

Patients typically present with simultaneous, bilateral, painless vision loss without a clear etiology. Shortly after initial presentation, they rapidly acquire bilateral cataracts and serous retinal detachments. Cataracts can form as early as 3 months. Visual deterioration typically precedes the diagnosis of a visceral carcinoma which can make diagnosing BDUMP difficult. In one literature review, 31 of 57 cases (54%) had no previous visceral carcinoma diagnosis at presentation, and in 5 of those cases, a primary tumor could not be identified.[2]

Physical examination

Fundoscopic findings include numerous round or oval red spots, choroidal thickening that spares the choriocapillaris, serous retinal detachment and rapid cataract formation.[1] The red-orange sub-retinal patches are the first to appear and remain present as the other signs develop.[1] These lesions hyperfluoresce on fluorescein angiography which is characteristic of the syndrome. With time, the residual RPE will coalesce into a Y-shaped pattern.

Other ocular findings may include glaucoma, ciliary body enlargement, ciliary body cysts, dilated episcleral vessels, iridocyclitis, iris body cysts, shallow anterior chamber and iridodonesis.[1][7][9] Extrabulbar hyperpigmentation of mainly skin or mucous membranes was reported in 26% of 28 cases reviewed.[6]

Diagnostic procedures

  • Fluorescein angiography (FA)
    • FA shows a reticular pattern of hypofluorescence surrounded by a background of choroidal hyperfluorescence during the early arteriovenous phase. The hyperfluorescence correlates with the red subretinal lesions seen on fundoscopy, while the hypofluorescent areas represent the residual confluent RPE.
  • OCT
    • Optical coherence tomography shows RPE atrophy, loss of photoreceptors and subretinal fluid.[2]
  • UBM/AS-OCT
    • Ultrasound biomicroscopy and anterior segment OCT may identify iris and ciliary body cysts. Secondary angle closure may be observed due to posterior iris cysts and ciliary body thickening.[7][10]

Clinical Diagnosis

Given that ocular signs precede the diagnosis of a systemic carcinoma, it is important to have a high index of suspicion for a primary malignancy. If the clinical exam is suggestive of BDUMP, patients should be referred to internal medicine and oncology for evaluation and treatment of the primary tumor.

Differential diagnosis

o Metastatic Melanoma

o Choroidal melanoma

o Diffuse choroidal melanoma

o Multifocal subretinal hematomas

o Multiple choroidal nevi

o Congenital hypertrophy of the retinal pigment epithelium

Management

The focus of treating BDUMP is aimed at addressing the underlying malignancy. Miles et al. reported that plasmapheresis and plasma exchange demonstrated some success with stabilizing or improving vision loss due to serous retinal detachments.[4] This may be due to clearing the serum IgG factor that was found to selectively stimulate melanocytes.[4] Many patients undergo cataract extraction without obtaining the expected visual recovery.[6] Variable results have been seen with local and systemic corticosteroids.[2][7] Local treatment of uveal lesions is largely ineffective. Prior cases indicated ocular radiation, brachytherapy and proton beam radiation to be unsuccessful.[2]

Prognosis

Vision typically deteriorates to near blindness within a year from presentation. Overall prognosis is generally poor as patients succumb to their primary malignancy. Mean survival is reported at 12-15.7 months from the time of ocular diagnosis.[2][10] Although there are case reports of survival up to 4-10 years, it is unclear how earlier intervention for systemic carcinoma affects survival.[10][11][12]


References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 Gass JD, Gieser RG, Wilkinson CP, Beahm DE, Pautler SE. Bilateral diffuse uveal melanocytic proliferation in patients with occult carcinoma. 1990. Retina (Philadelphia, Pa). 2003;23(6 Suppl):527-33.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Klemp K, Kiilgaard JF, Heegaard S, Nørgaard T, Andersen MK, Prause JU. Bilateral diffuse uveal melanocytic proliferation: Case report and literature review. Acta Ophthalmol. 2017;95(5):439-445.
  3. Margo CE, Pavan PR, Gendelman D, Gragoudas E. Bilateral melanocytic uveal tumors associated with systemic non-ocular malignancy. Malignant melanomas or benign paraneoplastic syndrome?. Retina (Philadelphia, Pa). 1987;7(3):137-41.
  4. 4.0 4.1 4.2 4.3 Miles SL, Niles RM, Pittock S, et al. A factor found in the IgG fraction of serum of patients with paraneoplastic bilateral diffuse uveal melanocytic proliferation causes proliferation of cultured human melanocytes. Retina (Philadelphia, Pa). 2012;32(9):1959-66.
  5. Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) Website: https://webeye.ophth.uiowa.edu/eyeforum/cases/197-BDUMP.htm Updated December 7, 2014. Accessed April 6, 2020.
  6. 6.0 6.1 6.2 6.3 O'neal KD, Butnor KJ, Perkinson KR, Proia AD. Bilateral diffuse uveal melanocytic proliferation associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic syndrome. Surv Ophthalmol. 2003;48(6):613-25. 
  7. 7.0 7.1 7.2 7.3 Joseph A, Rahimy E, Sarraf D. Bilateral diffuse uveal melanocytic proliferation with multiple iris cysts. JAMA Ophthalmol. 2014;132(6):756-60.
  8. Jampol LM, Leskov I, Lyon AT. Diffuse Uveal Melanocytic Proliferation With Primary Vitreoretinal Lymphoma-Reply. JAMA Ophthalmol. 2019
  9. 9.0 9.1 Pefkianaki M, Agrawal R, Desai P, Pavesio C, Sagoo MS. Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) associated with B-cell lymphoma: report of a rare case. BMC Cancer. 2015;15:23.
  10. 10.0 10.1 10.2 Duong HV, Mclean IW, Beahm DE. Bilateral diffuse melanocytic proliferation associated with ovarian carcinoma and metastatic malignant amelanotic melanoma. Am J Ophthalmol. 2006;142(4):693-5.
  11. De salvo G, Prakash P, Rennie CA, Lotery AJ. Long-term survival in a case of bilateral diffuse uveal melanocytic proliferation. Eye (Lond). 2011;25(10):1385-6.
  12. Alrashidi S, Aziz AA, Krema H. Bilateral diffuse uveal melanocytic proliferation: a management dilemma. BMJ Case Rep. 2014;2014