improvement of vascular invasion scoring in stage i...
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Improvement of vascular invasion scoring in stage I testicular non-seminomas
to predict relapse during surveillance after orchiectomy
João Lobo
Hans Stoop, Ad Gillis, Leendert HJ Looijenga, J. Wolter Oosterhuis
No conflicts of interest8th September 2019
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Lobo et al. Hum Pathol 2018TGC
Ts:
het
ero
gen
eity
& c
ha
llen
ges
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Lobo et al. Int J Mol Sci 2019TGC
Ts:
het
ero
gen
eity
& c
ha
llen
ges “Germ cell tumors are at the crossroads between
developmental biology and cancer"
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1% male cancer
Decreasing mortality
Most curable solid neoplasms
Same cytogenetic background (i12p) and low mutational burden
Most common cancer in Caucasian men 15—44yo
Rising incidence
15-20% disseminated disease recurs (poor prognosis)
Cisplatin resistance
Iatrogeny (young patients)
Better disease biomarkers urgently neededW
hy
focu
sin
g o
n T
GC
Ts?
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1% male cancer
Decreasing mortality
Most curable solid neoplasms
Same cytogenetic background (i12p) and low mutational burden
Most common cancer in Caucasian men 15—44yo
Rising incidence
15-20% disseminated disease recurs (poor prognosis)
Cisplatin resistance
Iatrogeny (young patients)
Better disease biomarkers needed
Wh
y fo
cusi
ng
on
TG
CTs
?
Costa and Lobo et al. Epigenomics 2017
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Va
scu
lar
inva
sio
na
s a
bio
ma
rker
Prognostic marker
Metastases, recurrence
TNM (pT2, stage IA)
Patient stratification
Inter-observer agreement in reporting
Not ideal
Most common disagreement upon centralized review
Subjectivity, artifacts, criteria…
Immunohistochemistry and type of vessel
No formal recommendation (ISUP)
Lack of data
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Aim
sa
nd
Met
ho
do
log
y
1
• Inter-observer agreement in VI scoring on H&E
2
• Additional value of adding IHC for vascular markers
3
• Additional value of characterizing the type of vessel invaded
“Clean” cohort
Strict inclusion criteria
H&E + IHC panel (D2-40, CD31, FVIII)
Scoring by 3 independent
observers
✓ Consecutively diagnosed NS patients✓ Stage I✓ Only surveillance after orchiectomy
✓ 2 FFPE samples✓ >1cm2 tumor✓ Tumor-parenchyma interface
✓ Dedicated to TGCT pathology
✓ D2-40: lymph vessels✓ CD31, FVIII: blood vessels
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Co
ho
rtch
ara
cter
iza
tio
nVariables
Patient cohort
(n=52)Age [years (median, IQR)] 31 (24-35)Laterality (n, %)
Right 21/52 (40.4)Left 31/52 (59.6)
Pre-operative serum tumor markers
(n, %)Within normal range 20/52 (38.5)Elevated 32/52 (61.5)
Histologic subtypes (n, %)Pure embryonal carcinoma 5/52 (9.6)Pure postpubertal-type teratoma 2/52 (3.8)Mixed tumor, without seminoma 21/52 (40.4)Mixed tumor, with seminoma 24/52 (46.2)
Multifocality (n, %)Absent 50/52 (96.2)Present 2/52 (3.8)
Largest tumor size [cm (median, IQR)] 3.5 (2.5-5.4)Rete testis invasion (n, %)
Absent 30/42 (71.4)Present, stromal 9/42 (21.4)Only pagetoid spread of GCNIS 3/42 (7.1)
Vascular invasion (n, %)Absent 25/50 (50.0)Present 25/50 (50.0)
VariablesPatient cohort
(n=52)Relapse (n, %)
No 21/52 (40.4)Yes 31/52 (59.6)
Type of relapse (n, %)Early 28/31 (90.3)Late 3/31 (9.7)
Site of relapse (n, %)Only serum markers 6/31 (19.4)Serum markers + PAoLN 14/31 (45.2)Only PAoLN 4/31 (12.9)Only Lung 2/31 (6.5)Serum markers + Lung + PAoLN 4/31 (12.9)Serum markers + Liver + Lung + PAoLN 1/31 (3.2)
Treatment performed for relapses (n, %)Only chemotherapy 26/31 (83.9)Chemotherapy + RPLND 5/31 (16.1)
Vital status at last follow-up (n, %)A-NED 50/52 (96.2)D-NED 1/52 (1.9)DFD 1/52 (1.9)
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Pro
gn
ost
icva
lue
On multivariable analysis (age, tumor size, serum tumor markers, rete testis invasion)
VI showed an independent impact in predicting disease relapse
(HR 3.163, 95% CI 1.31-7.63)
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Inte
r-o
bse
rver
ag
reem
ent
Testicular germ cell tumor-dedicated pathologists’ assessment of vascular invasion
Agreement
Cohen’s Kappa = 0.54 (p<0.001)
Pathologist 3
Absent Present
Pathologist 1
Absent 23 4
Present 8 17
Agreement
Cohen’s Kappa = 0.50 (p<0.001)
Pathologist 2
Absent Present
Pathologist 1
Absent 22 5
Present 8 17
Agreement
Cohen’s Kappa = 0.49 (p<0.001)
Pathologist 2
Absent Present
Pathologist 3
Absent 24 7
Present 6 15
Agreement among TGCT-dedicated pathologists was moderate, as
reported(κ 0.49-0.54)
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Per
form
an
ce in
pre
dic
tin
gre
lap
se
Vascular invasion
scoring
Sensitivity
(%)
Specificity
(%)
PPV
(%)
NPV
(%)
Accuracy
(%)
H&E (consensus) 61.3 85.7 86.4 60.0 71.2
Immunohistochemistry
(D2-40 + FVIII +
CD31)
71.0 71.4 78.6 62.5 71.2
IHC resulted in increase in sensitivity and decrease in
specificity
IHC upgraded 8 cases of “absent VI on H&E” → 3 of them developed
relapseIHC downgraded 2 cases of
“present VI on H&E” → both did not develop relapse
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Va
scu
lar
inva
sio
n:
cha
llen
ges
Mis
sed
ca
ses
on
H&
E a
sses
smen
t
Va
scu
lar
inva
sio
n m
imic
kers
H&E
D2-40
CD31
FVIII
H&E
D2-40
CD31
FVIII
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Typ
eo
fve
ssel
Vascular invasion scoring No relapse (n) Relapse (n)
IHC showing LVI only 3 12
IHC showing BVI only 3 2
IHC showing LVI + BVI 0 8
“Double vascular invasion patients”: 100% accuracy in predicting disease
relapse
Active selection for adjuvant treatment instead of surveillance?
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Co
ncl
usi
on
s
1
• Inter-observer agreement in VI scoring on H&E
2
• Additional value of adding IHC for vascular markers
3
• Additional value of characterizing the type of vessel invaded
Moderate among TGCT-dedicatedpathologists, but can be improved
Increase in sensitivity for predictingdisease relapse
Identification of high-risk patients
(both LVI and BVI)
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Co
ncl
usi
on
s
Indication for routine IHC use?
Endpoint: relapse-free survival
Large, prospective studies, with IHC
FUTURE
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Supervising team:Rui Henrique
Carmen JerónimoLeendert Looijenga
Department of PathologyÂngelo Rodrigues
Paula LopesMariana Cantante
Rita Guimarães
Cancer Biology & Epigenetics GroupVera Gonçalves
Daniela Barros SilvaSandra Nunes
Ethics approval: CES IPO 1/2018
IPO Porto
The Netherlands
Project Funding: POCI-01-0145-FEDER-29043Doctoral Grant: SFRH/BD/132751/2017
Urology ClinicJorge Oliveira
Joaquina MaurícioIsaac Braga
Department of EpidemiologyLuís Antunes
PMC Utrecht (Group Looijenga)Ad Gillis
Annette van den BergRachita Lahri
Dennis Timmerman
Erasmus MC Rotterdam & LEPO
Wolter OosterhuisLambert Dorssers
Hans StoopWillem Boellaard
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Thank you for your attention!