Carlos Pavesio

Mandeep S Sagoo

Maria Pefkianaki

Parul Desai

Rupesh Agrawal

BMC Cancer

Springer - Publisher Connector

Pefkianaki et al. BMC Cancer  (2015) 15:23 
DOI 10.1186/s12885-015-1020-8CASE REPORT Open AccessBilateral Diffuse Uveal Melanocytic Proliferation
(BDUMP) associated with B-cell lymphoma: report
of a rare case
Maria Pefkianaki1, Rupesh Agrawal1,2,3, Parul Desai1, Carlos Pavesio1,2 and Mandeep S Sagoo1,2,4*Abstract
Background: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a paraneoplastic ocular syndrome
occurring in patients with systemic, often occult but advanced carcinoma and is the hallmark of poor prognosis.
Ocular signs precede manifestation of systemic carcinoma by 3–12 months, highlighting the need for appropriate
index of suspicion and prompt evaluation. Treatment options for BDUMP are limited. Investigations are aimed at
finding the occult primary malignancy, which can be challenging. Modalities for treatment of the ocular findings
include corticosteroids, surgery, external beam radiotherapy, and treatment of the underlying malignant neoplasm.
However, it is uncertain whether earlier intervention for the systemic malignancy will impact survival, as this
paraneoplastic phenomenon is thought to occur in advanced malignancy.
Case presentation: We report a unique rare atypical case with BDUMP causing visual loss in a 62-year-old female
as the presenting sign of central nervous system (CNS) B-cell lymphoma. Multiple grey or grey brown subretinal
lesions with pigment clumps were present in both eyes on fundoscopy and multimodal imaging demonstrated
multiple discrete lesions at the level of retinal pigment epithelium. Neuroimaging revealed presence of brainstem
and cerebellopontine lesions suggestive of CNS lymphoma, which was further confirmed on biopsy.
Conclusion: In the current atypical case, prompt diagnosis and immediate referral was key, with detailed systemic
evaluation by an internist and oncologist. The reported case is distinct for the reason that BDUMP occurred secondary
to primary CNS lymphoma, a hitherto unreported association.
Keywords: Bilateral diffuse uveal melanocytic proliferation, BDUMP, B-cell lymphomaBackground
Bilateral diffuse uveal melanocytic proliferation (BDUMP)
is a paraneoplastic ocular syndrome occurring in patients
with systemic, often occult but advanced carcinoma and is
the hallmark of poor prognosis [1,2]. There are a total of
less than 30 cases reported in world literature [3]. It is
rarely reported in non-carcinomatous conditions, such as
cervical leiomyoma [4].
The main characteristics are multiple round, red patches
at the level of the retinal pigment epithelium (RPE), a
striking pattern of multifocal areas of early hyperfluores-
cence corresponding with these patches, proliferation of* Correspondence: mandeep.sagoo@moorfields.nhs.uk
1Moorfields Eye Hospital, City Road, London EC1V 2PD, UK
2Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust
and UCL Institute of Ophthalmology, London, UK
Full list of author information is available at the end of the article
© 2015 Pefkianaki et al.; licensee BioMed Cent
Commons Attribution License (http://creativec
reproduction in any medium, provided the or
Dedication waiver (http://creativecommons.or
unless otherwise stated.choroidal nevus-like lesions as well as diffuse thickening
of the uveal tract, exudative retinal detachment, and rap-
idly developing cataract [1]. In addition glaucoma, dilated
episcleral vessels, iridocyclitis, shallow anterior chamber,
ciliary body cysts, and iridodonesis have been reported [3].
Treatment options for BDUMP are limited. Investiga-
tions are aimed at finding the occult primary malignancy,
which may be challenging. Treatment options for ocular
involvement include corticosteroids, surgery, external
beam radiotherapy, and management of the underlying
malignant neoplasm [1,5].
Herein we report a unique rare case of BDUMP causing
visual loss in an immunocompetent patient diagnosed
with central nervous system (CNS) B-cell lymphoma – a
mode of atypical presentation that, to the best of our
knowledge, has not been reported before.ral. This is an Open Access article distributed under the terms of the Creative
ommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
iginal work is properly credited. The Creative Commons Public Domain
g/publicdomain/zero/1.0/) applies to the data made available in this article,
Pefkianaki et al. BMC Cancer  (2015) 15:23 Page 2 of 6Case presentation
A 62-year-old female presented with a one-year history
of visual disturbances and six-month history of reduc-
tion of vision in the left eye. Best corrected visual acu-
ities were 6/6 in the right eye and 6/18 in the left eye
with no signs of active or old inflammation in the anter-
ior and posterior segments of both eyes. Mild posterior
subcapsular cataract was noted in the left eye. Intraocu-
lar pressure was within normal limits.
Gray or gray-brown lesions were noted at the level of
the RPE with diffuse distribution in the fundus of both
eyes (Figure 1). In addition, non-specific pigment clumps
were present in the posterior pole of the left eye. Fluor-
escein angiography (FA) of both eyes showed the presence
of multiple discrete and partially confluent hyperfluores-
cent lesions due to window defects (Figure 2). In the right
eye these lesions were multiple hyperfluorescent areas
involving the macula in both early (2A) and late (2B)
arteriovenous phase. However, the lesions became more
discrete and also reduced in number in late phase. A
similar pattern was observed in the left eye (Figure 2C and
2D) but the number of lesions remained the same in the
late phase. Indocyanine green angiography (ICG) demon-
strated hypofluorescent spots from early to late phase,
corresponding with multiple choroidal nevus-like lesions
(Figure 3). There were fewer lesions in the right eye as
compare to the left eye. Ultrasound B-scan did not show
any elevated lesions.
Optical coherence tomography (OCT) demonstrated
significant subfoveal fluid in the left eye as well as
disruptions of the RPE in both eyes, corresponding to
the plaque like areas on the fundus photographs and the
areas of window defects on FA (Figure 4). Increased
choroidal thickness (458 μm) was noted on OCT. Fun-
dus autofluorescence showed complete absence of sig-
nals in these multiple nummular areas and also showed
many more lesions as compare to angiographic images
(Figure 5A and 5B). No electrodiagnostic studies were
done, and also no serologic tests for paraneoplastic auto-
antibodies. HIV serology was negative.Figure 1 Color fundus photograph showing presence of multiple roun
left (B) eye.The differential diagnosis included metastasis from
occult primary or one of the forms of a white dot
syndrome. The widespread lesions in both eyes were not
typical of any of the inflammatory choriocapillaritis or
stromal choroiditis disorders. Birdshot retinochoroido-
pathy was the closest of the inflammatory conditions but
there was no retinal involvement to justify this entity
and serum HLA29 was negative. Lesions were large for
multiple evanescent white dot syndrome and too small
for acute placoid multifocal pigment epitheliopathy.
The differential diagnosis of bilateral primary intraocu-
lar lymphoma was also considered, though the character-
istic subretinal and subretinal pigment epithelial deposits
were absent.
Systemic evaluation revealed the presence of cerebellar
symptoms. Neuroimaging showed brainstem and right
cerebellopontine lesions suggestive of CNS lymphoma,
which prompted MRI guided posterior fossa biopsy from
the cerebellar peduncle. The biopsy showed large B cells
that were CD20 positive, CD3 negative, CD79a positive,
CD10 negative, bcl-6 positive, MUM1 positive, bcl-2
positive and EBER negative. Ki67 expression, which is an
index of proliferation, showed 60% proliferation fraction
in this area of biopsy. The histopathological findings
confirmed diffuse large B-cell lymphoma of the brain with
non-germinal centre subtype. The patient responded to a
methotrexate-based systemic chemotherapy regimen, under
the care of the oncologists. At 6 months, her ophthalmic
condition remained stable on topical non-steroidal anti-
inflammatory drops. Though the ocular lesion remains un-
resolved, the left macular oedema improved to give a final
visual acuity of 6/12.
Discussion
This unique case illustrates that BDUMP should be con-
sidered in the differential diagnosis of patients with atyp-
ical diffuse pigmented fundus lesions. The five cardinal
signs of BDUMP described by Gass et al. [1] are: (1)
multifocal, faintly visible, round or oval, red, subretinal
patches, with (2) associated striking pattern of associatedd oval diffuse subretinal faint grey brown lesions in right (A) and
Figure 2 Fundus fluorescein angiogram showing presence of hyperfluorescent lesions in right (A and B) and left (C and D) eye in early
and late arteriovenous phase.
Pefkianaki et al. BMC Cancer  (2015) 15:23 Page 3 of 6hyperfluorescence during the early phases of angiography;
(3) development of multiple, slightly elevated, pigmented
and non-pigmented uveal melanocytic tumors, as evidence
of diffuse thickening of uveal tract; (4) exudative retinal
detachment; and (5) rapid progression of cataract [1].Figure 3 Indocyanine green angiogram showing presence of numerou
The lesions remained hypofluorescent in very late frames as well (B and DOur case demonstrated some of these features, indicat-
ing an earlier stage of BDUMP, before the onset of ex-
udative retinal detachment and progression of cataract.
However, multifocal, faintly visible, roundish oval subret-
inal lesions, which were hyperfluorescent on FA suggesteds hypofluorescent lesions in right (A and B) and left (C and D) eyes.
).
Figure 4 Spectral domain OCT (Heidelberg) scans of right (A) and left (B) eyes showing presence of retinal pigment epithelial
disturbances with excrescences at level of retinal pigment epithelium and presence of subretinal fluid in the left eye.
Pefkianaki et al. BMC Cancer  (2015) 15:23 Page 4 of 6the diagnosis of BDUMP. The precise correspondence of
the focal areas of early hyperfluorescence and the subret-
inal patches suggest that they are fenestrations of the
pigment epithelium caused by its depigmentation and
focal destruction in the absence of RPE and excrescences
in inner segment-outer segment (IS-OS) junction demon-
strated the level of lesions in the RPE. The same was also
demonstrated in our case on spectral-domain OCT scan.
To our knowledge, this case is distinct in the literature inFigure 5 Fundus autofluorescence of the right (A) and left (B) eye sho
to the angiogram.demonstrating those changes in RPE on real time non-
invasive scans. The other possible differential diagnoses of
choriocapillaritis or stromal choroiditis were less likely as
there were no classical clinical signs of any of those en-
tities. Birdshot retinochoroidopathy was the closest differ-
ential diagnosis but due to lack of classical clinical and
angiographic signs, the diagnosis of masquerade syndrome
was kept and hence the patient was investigated for possible
systemic association. Lymphoma-associated retinopathy aswing a greater number of hypofluorescent lesions as compared
Pefkianaki et al. BMC Cancer  (2015) 15:23 Page 5 of 6described by To et al. [6], was a pigmentary retinopathy oc-
curring on the onset of chemotherapy for Hodgkin lymph-
oma. Our case had pale gray brown nummular lesions,
rather than retinitis pigmentosa-like pigmentary migration
of lymphoma-associated retinopathy. Our case fits in with
BDUMP features as described by Gass: multifocal, faintly
visible, round or oval, red, subretinal patches, with associ-
ated striking pattern of associated hyperfluorescence during
the early phases of angiography [1].
Two types of melanocytes are found in the normal
uveal tract: the normal melanocytes and, in many pa-
tients, nevus cells. Normal melanocytes are nonreactive
cells that rarely, if ever, proliferate. Nevus cells that are
present, either focally or diffusely (melanocytosis), do
have the capability of proliferation that, in part, is
subject to hormonal control and that normally is limited
to the prepubertal and early adult years [7].
Suggestions for the pathogenesis of BDUMP have been
postulated as either the de novo development of uveal
melanocytic proliferation and the systemic carcinoma in
response to a common oncogenic stimulus, [8] or the de
novo development of uveal melanocytic proliferation in
response to a hormone-secreting visceral carcinoma, or
possibly coincidental development of bilateral low-grade
diffuse uveal melanomas and a systemic carcinoma in pa-
tients genetically predisposed to neoplasia [1]. In addition,
Miles et al. have recently shown that there is cultured
melanocytic elongation and proliferation factor (CMEP)
factor, in the serum that causes uveal melanocytes to
proliferate [7].
Systemic carcinomas reported with BDUMP are ovarian,
lung, gall bladder, cervical, uterine, kidney, pancreatic,
breast, esophageal, and colorectal cancers. They may also be
associated with melanocytic proliferation in other tissues
[8,9]. Although rare, BDUMP has consistently resulted in
devastating visual consequences. Usually during the year
preceding death, patients with this paraneoplastic syndrome
have severe bilateral vision loss. Vision decline has been
attributed to destruction of photoreceptors and underlying
RPE, serous retinal detachments, and, later, cataracts [1].
In the current case, the prompt diagnosis and immedi-
ate referral was key, with detailed systemic evaluation by
internists and oncologists. As per the original descrip-
tion by Gass et al. [1] ocular signs precede manifestation
of systemic carcinoma by 3–12 months, highlighting the
need for the appropriate index of suspicion and prompt
evaluation [10]. It is uncertain whether earlier interven-
tion for the systemic malignancy will impact survival, as
this paraneoplastic phenomenon is thought to occur in
advanced malignancy.
Treatment of BDUMP is usually directed towards the
primary cancer. Although transient visual improvement
has been reported in patients with BDUMP in response
to systemic corticosteroids and chemotherapy, [9] mostcases have shown no effect of corticosteroid therapy
alone [3] and no significant effect of radiotherapy [1].
Our case responded to systemic chemotherapy along
with topical non-steroidal anti-inflammatory drops.Conclusions
This atypical case of BDUMP is unique for several rea-
sons. Although it had the presence of subretinal lesions,
which were hyperfluorescent on FA, exudative retinal
detachment or cataract were absent, indicating perhaps
an earlier stage in the evolution of this condition. Fur-
thermore, we documented OCT changes similar to re-
ported histopathological changes in BDUMP [10]. Finally,
this case is distinct for the reason that BDUMP occurred
secondary to primary CNS lymphoma, a hitherto unre-
ported association.Consent
Written informed consent was obtained from the patient
for publication of this Case report and any accompany-
ing images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal. This report
adhered to the tenets of the Declaration of Helsinki.
Abbreviations
BDUMP: Bilateral diffuse uveal melanocytic proliferation; CNS: Central nervous
system; RPE: Retinal pigment epithelium; FA: Fluorescein angiography;
OCT: Optical coherence tomography; MRI: Magnetic resonance imaging;
IS-OS: Inner segment-o uter segment; ICG: Indocyanine green angiography;
CMEP: Cultured melanocytic elongation and proliferation factor.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MP had written the first draft of the manuscript and was involved in patient
care. RA has edited the draft, did literature review and was involved in
patient care and intellectual input. PD was involved in patient care and
reviewing the draft. CP was directly involved in patient care and edited the
draft and intellectual inputs. MSS was involved in patient care and edited the
draft significantly alongwith intellectual input. All authors read and approved
the final manuscript.
Acknowledgements
“This work was supported by the National Institute for Health Research
(NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS
Foundation Trust and UCL Institute of Ophthalmology. The views expressed
are those of the author(s) and not necessarily those of the NHS, the NIHR or
the Department of Health. RA was on overseas research training fellowship
from Singapore sponsored by National Medical Research Council, Singapore”.
Author details
1Moorfields Eye Hospital, City Road, London EC1V 2PD, UK. 2Biomedical
Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL
Institute of Ophthalmology, London, UK. 3National Healthcare Group Eye
Institute, Tan Tock Seng Hospital, Singapore, Singapore. 4St. Bartholomew’s
Hospital, London, UK.
Received: 30 June 2014 Accepted: 13 January 2015
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Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) associated with B-cell lymphoma: report of a rare case

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Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) associated with B-cell lymphoma: report of a rare case

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