28.02.2020
1
U N I V E R S I T Ä T S M E D I Z I N B E R L I NU N I V E R S I T Ä T S M E D I Z I N B E R L I N
Masquerades…
Uwe Pleyer
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Mimikry
Background
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Background
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Children > Adults!
Uveitis-masquerades…
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Non-malignant clinical disease Coats' disease
Juvenile Xanthogranuloma
Persistent hyperplasia
Astrocytoma
Retinal hemangioma
Retinopathy of prematurity
Norrie's disease
Incontinentia pigmenti
Retinal choroidal coloboma
Malignant clinical disease Retinoblastoma
Leukemic uveal infiltrates
Uveitis-masquerade in childhood
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Uveitis?
Masquerade syndrome?
Retinoblastoma
Leukemia
(M. Coats)
Uveitis-masquerade in childhood
Differential diagnosis
https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjF-6q5wuPTAhULIlAKHeT_COoQjRwIBw&url=https%3A%2F%2Fangeloconcuore.wordpress.com%2Ftag%2Fmimikry%2F&psig=AFQjCNEH0jbJA56OEHn9lk06XrPeGaPOdg&ust=1494437031989530https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiG--7ZwuPTAhUSI1AKHZekCGUQjRwIBw&url=http%3A%2F%2Fwww.tierchenwelt.de%2Ftierleben%2F2880-meister-der-tarnung-wie-sich-tiere-unsichtbar-machen.html%3Fstart%3D3&psig=AFQjCNEH0jbJA56OEHn9lk06XrPeGaPOdg&ust=1494437031989530https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwi7ss7gz-vaAhUFPFAKHRYHAzwQjRx6BAgBEAU&url=https%3A%2F%2Feyecancer.com%2Fpress%2Fdr-finger-spearheading-effort-create-vitreoretinal-lymphoma-registry%2F&psig=AOvVaw1YwZjzodinQZo2O8JMAqFw&ust=1525507438913811https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjF-6q5wuPTAhULIlAKHeT_COoQjRwIBw&url=https%3A%2F%2Fangeloconcuore.wordpress.com%2Ftag%2Fmimikry%2F&psig=AFQjCNEH0jbJA56OEHn9lk06XrPeGaPOdg&ust=1494437031989530https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiG--7ZwuPTAhUSI1AKHZekCGUQjRwIBw&url=http%3A%2F%2Fwww.tierchenwelt.de%2Ftierleben%2F2880-meister-der-tarnung-wie-sich-tiere-unsichtbar-machen.html%3Fstart%3D3&psig=AFQjCNEH0jbJA56OEHn9lk06XrPeGaPOdg&ust=1494437031989530
28.02.2020
2
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Child 1: f/ 6 weeks
• FH: none
• RE Leukocoria, strabism
Uveitis-masquerade in childhood
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Dx. : Bilateral Retinoblastoma
RE LE
Uveitis-masquerade in childhood
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Epidemiology
• Incidence 5,000 per year worldwide
• 45 per year in Germany
• 50% lethality worldwide
• 2% in industrialized countries
• 25% bilateral/ 75% unilateral
• 100% bilateral RB – germline mutation
• 40% germline mutation
• 100% bilateral RB - multifokal
Uveitis-masquerade in childhood
Shields et al. 2013
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Initial clinical signs of Retinoblastoma
Abramson et al, 2002
Uveitis-masquerade in childhood
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Screening program for eye disorders in general
since 2016 in Germany
Uveitis-masquerade in childhood
Any leukocoria = urgent clarification!No invasive diagnostic precedure in susp. child!
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Uveitis?
Masquerade syndrome?
Retinoblastoma
Leukemia
(M. Coats)
Uveitis-masquerade in childhood
Differential diagnosis
28.02.2020
3
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Leukemia
Uveitis-masquerade in childhood
• Uni- or bilateral
• Granulomatous precipitates
• Pseudohypopion
• Localized or diffuse iris lesions
• Intraretinal hemorrhages
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
• Retinopathy
children < adults
• Poor prognosis
• Mainly: choroid affected
• Retinal findings
• Perivascular infiltrates
• Microinfarction
• Hemorrages
– Flame shaped
– White centered
Chen J et al., Acute promyelocytic leukemia http://webeye.ophth.uiowa.edu/eyeforum
Leukemia
Uveitis-masquerade in childhood
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
https://www.everydayhealth.com/leukemia/what-are-common-symptoms/
Uveitis-masquerade in childhood
Diagnosis: Leukemia
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Child 2: f, 2 yrs
PH: Strabism for 6 months/ Leukocoria LE
FH: none
U N I V E R S I T Ä T S M E D I Z I N B E R L I N U N I V E R S I T Ä T S M E D I Z I N B E R L I N
M. Coats Yellowish / white cholestrol crystals Viscous subretinal exudation
with sluggish flow B-Scan
Occ. subretinal gliotic nodule
Irregular dilatation
of retinal vessels
with teleangiectasia
retinal aneurysms
avascular retinal periphery
Uveitis-masquerade in childhood
• Mainly unilateral
• Young males 1/100,000
• Breakdown-blood-retinal barrier
• Slowly progressive
• Cataract, Glaucoma, Ablatio
https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjhvenow8bdAhXNyKQKHQ2hDk8QjRx6BAgBEAU&url=https%3A%2F%2Fwww.everydayhealth.com%2Fleukemia%2Fwhat-are-common-symptoms%2F&psig=AOvVaw0t7eKytKE-Yv2xuh7l1-Ch&ust=1537427961889368
28.02.2020
4
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Retinoblastoma M. Coats
BE AWARE: Exudative Retinal Detachment*
* FEVR – similar/ bilateral/ FA
Uveitis-masquerade in childhood
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Uveitis-masquerade…?
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Uveitis?
Masquerade syndrome?
Melanoma
Metastasis
Leukemia
Lymphoma
Uveitis-masquerade: Adults
Differential diagnosis
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Uveitis?
Masquerade syndrome?
Melanoma
Metastasis
Leukemia
Lymphoma
Uveitis-masquerade
Differential diagnosis
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Metastasis
Uveitis-masquerade
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Ocular history: unremarkable
General history:
Arterial hypertension, 30 Nicotine years
Ø B symptoms, Ø rheumatic disease
Visual Acuity:
OD: cc = 20/25 OS: cc = 20/20
IOP: 14 mm Hg
Anterior Segment
OD: from 6-11 o'clock Iris irregular bulging
with multiple graywhite nodular changes
Rubeosis iridis, posterior synechiae
Lens with pigmentation
Anterior chamber cells 1+
OS: unremarkable
High suspicion of iris tumor / metastasis
Uveitis-masquerade - f, 68 yrs
28.02.2020
5
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
X Ray: Distention of the Hilum formation
lymph node enlargement
chronic obstructive pulmonary disease?
=> Thorax-CT recommended
CBC: slight leukocytosis with left shift
ACE + IL 2 receptor: normal
Work-up….
Uveitis-masquerade
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Diagnostic iridectomy
Uveitis-masquerade
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
https://doi.org/10.1016/j.sjopt.2019.07.006 - (2019)
Uveitis-masquerade
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Shields CL et al. Indian J Ophthalmol. (2015)
• Search for primary tumor and
staging CT / MRI / PET scan
• Fluorescein and indocyanine
angiography
• OCT-EDI
• Biopsy (selected)
- cytological, genetic,
immunocytochemical and
immunohistochemical
Uveitis-masquerade - work-up
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Uveitis?
Masquerade syndrome?
Melanoma
Metastasis
Leukemia
Lymphoma
Uveitis-masquerade
Differential diagnosis
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Primary CNS lymphoma
Rare CNS tumor (4%) but incidence is increasing!
1973 2.5 / 10 million?
2012 30/10 million
Risk factors: HIV, EBV
Histology: mostly diffuse large B-cell lymphoma
Prognosis: worse than with other nodal lymphomas (survival time - median: 33 months)
Epidemiology
Jaehne D, Coupland SE. Primary vitreoretinal lymphoma. Ophthalmologe 115: 343-356 (2018)
28.02.2020
6
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Intraocular lymphoma will develop in 15-25% of patients with
primary CNS lymphoma
Primary intraocular lymphoma (PIOL) may present independently
BUT
90% of PIOL patients develop intracranial lymphoma
"Masquerade syndrome"!
Median age: 63 years
Men > Women
History: „interm. Uveitis"
Bilateral 60-90%
Epidemiology
Stübiger N, Kakkassery V, Gundlach E, Winterhalter S, Pleyer U. Ophthalmologe (2015) U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Clinical presentation
30% without any
ophthalmological symptoms!
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Symptoms Total (%)
Ataxia 10 (4,6)
"Dizziness" 4 (1,8)
Headache 4 (1,8)
Disorientation 3 (1,4)
Others 6 (2,8)
Subjective ocular
complaints
Subjective extraocular
complaints
Initial complaints (n=217)
The Japanese Intraocular Lymphoma Study Group, Jpn J Ophthalmol. 56:383-9; 2012
Primary intraocular lymphoma
Symptoms Total (%)
Visual loss 157 (72,4)
"Floater" 48 (22,1)
"Visual Field..." 5 (2,3)
Incidental finding 3 (1,4)
Others 4 (1,8)
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Initial eye findings n=217 (%)
Vitreous opacity 197 (90.8)
Subretinal infiltration 124 (57.1)
Iritis 68 (31.3)
Corneal precipitates 54 (24.9)
Retinal vasculitis 21 (9.7)
Secondary glaucoma 9 (4.1)
Retinal bleeding 5 (2.3)
Papilledema 4 (1.8)
Vitreous hemorrhage 3 (1.4)
Retinal exudates 3 (1.4)
Retinal detachment 2 (0.9)
Subconjunctival tumor 1 (0.5)
Scleritis 1 (0.5)
Hypopyon 1 (0.5)
The Japanese Intraocular Lymphoma Study Group, Jpn J Ophthalmol. 56:383-9; 2012
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
• Fluffy sub-retinal and
sub-RPE infiltrates
• "Vasculitis"
• "Retinitis"
• Uveal "tumor" (rare)
Findings
Stübiger N, Kakkassery V, Gundlach E, Winterhalter S, Pleyer U. Ophthalmologe (2015)
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
PIOL - Presentation
Imaging
Primary intraocular lymphoma
https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwi7ss7gz-vaAhUFPFAKHRYHAzwQjRx6BAgBEAU&url=https%3A%2F%2Feyecancer.com%2Fpress%2Fdr-finger-spearheading-effort-create-vitreoretinal-lymphoma-registry%2F&psig=AOvVaw1YwZjzodinQZo2O8JMAqFw&ust=1525507438913811
28.02.2020
7
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Primary school teacher
for weeks “visual field changes”
LE: "Micropsia"
"Had a lot of stress" ....
Visual acuity: 0.6
(external) DX: RCS, Drusen
"Chorioretinitis work-up"
"all OK"
Holger Hermsdorf – m, 52 yrs
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Follow-up
- Edema decreased under acetazolamide
- Visual acuity increased to 20/20
- 2 months later edema regression, no complaints
- New: "Cotton-wool“- like spot LE (ischemic?)
- Cardiovascular consultation, incl. Carotid duplex
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Follow-up
6 months later
subj. "Deterioration"
Visual acuity both eyes cc. 20/20
worse contrast vision
multiple diffuse whitish-yellow, partly confluent?
bilateral: subretinal infiltrates!
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Diagnostic work-up
Invasive diagnostics
Aqueous humor: IL-10 >>> IL-6 (> 500pg / ml)
PPV + Retinal biopsy?
"B-cell dominant lymphocytic infiltrate"
Neurological work-up
cMRT: Intrabulbar lesion
No intracerebral involvement
Lumbar and BM puncture: unremarkable
Diagnosis: „Primary“ intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N Williams BK, et al. Graefes Arch Clin Exp Ophthalmol. 248:1837-42, 2010
Primary intraocular lymphoma
https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiw4u28zOvaAhVHK1AKHXmMDgIQjRx6BAgBEAU&url=https%3A%2F%2Fwww.researchgate.net%2Ffigure%2FAutofluorescence-and-optical-coherence-tomography-OCT-imaging-in-the-left-eye-of-the_fig2_318789923&psig=AOvVaw1YwZjzodinQZo2O8JMAqFw&ust=1525507438913811https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiX7IvNzOvaAhVIEVAKHTX1DrYQjRx6BAgBEAU&url=https%3A%2F%2Fwww.researchgate.net%2Ffigure%2FOptical-coherent-tomography-OCT-of-the-patient-in-Figure-1-A-Cross-sectional-images_fig2_51763468&psig=AOvVaw1YwZjzodinQZo2O8JMAqFw&ust=1525507438913811http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click on image to zoom&p=PMC3&id=2974205_417_2010_1427_Fig1_HTML.jpg
28.02.2020
8
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Diagnosis
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Cytology
Immunocytology
Molecular pathology
Biopsy
Aqueous humor
analysis
Diagnostics
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Biopsy
Aqueous humor
analysis
Significance of aqueous
humor analysis
Interleukin-10 as an
"index" cytokine
vs. interleukin-6
(inflammation)
Primary intraocular lymphoma
Dunn JP. Retina. 38:647-649 (2018)
U N I V E R S I T Ä T S M E D I Z I N B E R L I N Fisson S, et al., PLoS One; 2013
Cytokine Pattern (n=49)
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Cytokine Pattern: Therapy Course
Fisson S, et al., PLoS One; 2013
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N Dunn JP. Retina. 38:647-649 (2018)
Primary intraocular lymphoma
IL-10/IL-6 ratio > 1 Vitreous Sensitivity= 93% Specificity= 100%Cut off 65/30pg ml Aqueous humor Sensitivity= 78% Specificity= 97%
http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=3566156_pone.0052385.g004.jpg
28.02.2020
9
U N I V E R S I T Ä T S M E D I Z I N B E R L I N Gonzales J et al., Br J Ophthalmol.; 102: 6–8. (2018)
Primary intraocular lymphoma
Metagenomic
deep sequencing
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
PPV/Biopsy
Anterior chamber
paracentesis
Indication: Aqueous humor analysis/ppV/Biopsy
Chronic "therapy-resistant"
uveitis
Suspicious sub-retinal /
sub-RPE lesions
Clinical suspicion
of lymphoma
Elderly patients with initial Dx of
intermediate "uveitis"
Immunocompromised
individuals
Chemotherapy
Stübiger N, Kakkassery V, Gundlach E, Winterhalter S, Pleyer U. Ophthalmologe (2015)
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Treatment options
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
IntravitrealChemotherapy
Radiotherapy(Eyes)
SystemicChemotherapy
Radiotherapy(CNS)
Intraocular relapseor after CNS
Radiation
Only intraocular(untreated)
Intraocular andCNS lymphoma
(untreated)
one eye both eyes both eyesboth eyes one eye one eye
Primary intraocular lymphoma
Treatment options
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
• The therapy recommendations
of the International Primary
Central Nervous System
Lymphoma Collaborative
Group from 2011
• Unilateral PIOL: local
intravitreal therapy
• Bilateral PIOLs: systemic
chemotherapy in combination
with intravitreal therapyChan CC et al. Primary vitreoretinal lymphoma. Oncologist 16:1589-99 (2011)P. Fox et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B‐cell lymphoma.Br J Hematology, 2018
Treatment recommendation
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
P. Fox et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B‐cell lymphoma. Br J Hematology, 2018
Primary intraocular lymphoma
https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5754869_bjophthalmol-2017-311151f01.jpg
28.02.2020
10
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
• 8/2008 – 8/2017
• 11 centers (Berlin, Bonn, Düsseldorf, Würzburg, Münster, Heidelberg, Lübeck)
• 43 Patients
• Age: median 75 years [41-90]
PIOL in newly diagnosed lymphoma:
32/43 (74%)
PIOL in case of relapse: 11/43 (26%)
PIOL isolated : 5
PIOL + CNS involvement 6
PIOL: German registry study
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Results: therapy (n=43)
Systemic only 13
HD-MTX/Ifosfamide+Rituximab 21
CHOP 3
Others 4
Local + systemic 18
Radiation 2
Intraocular therapy 24Rituximab 13
Rituximab + Methotrexate 2
Methotrexate 1
other / unknown 8
PIOL: German registry study
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Progression-free survival (n=35)
Relapse (n=19 Patienten)
-Only CNS 8
-Only Eye 6
-CNS+Eye 1
-Others (jaw) 1
-Unknown 3
Median 26 months
PIOL: German registry study
U N I V E R S I T Ä T S M E D I Z I N B E R L I N Akiyama H et al., Japanese PIOL Study Group Cancer Sci. 107:1458-1464 (2016)
Weekly intravitreal MTX
+
5 Cycles systemic
High-Dosis MTX (3.5 g/m2 )
biweekly
5 - Annual survival rate
61 % (n=195)
Prognosis – Follow-up (n=195)
Primary intraocular lymphoma
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Important, vital differential
diagnosis in “intraocular
inflammation“
Initial diagnosis: still late…!
Invasive diagnostics!
Clear trend from purely local
therapy to systemic therapy
Further data with longer follow-
ups is necessary
Summary
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Augenwerkstatt
28.02.2020
11
U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Mange
for din opmærksomhed!