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Cut
aneo
us to
xici
ties
to
onco
logi
c th
erap
ies
and
Inte
rpre
tatio
n of
PD
-L1
Imm
unoh
isto
chem
istr
yM
icha
el T
. Tet
zlaf
f MD
, PhD
Asso
ciat
e Pr
ofes
sor
Depa
rtm
ents
of P
atho
logy
,Se
ctio
n of
Der
mat
opat
holo
gyan
d Tr
ansl
atio
nal a
nd M
olec
ular
Pat
holo
gyTh
e Un
iver
sity
of T
exas
MD
Ande
rson
Can
cer
Cent
er
Exec
utiv
e O
ffice
rTr
ansl
atio
nal R
esea
rch
Prog
ram
The
Allia
nce
for C
linic
al T
rials
Cut
aneo
us to
xici
ties
to
onco
logi
c th
erap
ies
Com
mon
ly e
ncou
nter
ed c
utan
eous
re
actio
ns to
targ
eted
ther
apy
and
imm
une
chec
kpoi
nt b
lock
ade
Mic
hael
T. T
etzl
aff M
D, P
hD
Asso
ciat
e Pr
ofes
sor
Depa
rtm
ents
of P
atho
logy
,Se
ctio
n of
Der
mat
opat
holo
gyan
d Tr
ansl
atio
nal a
nd M
olec
ular
Pat
holo
gyTh
e Un
iver
sity
of T
exas
MD
Ande
rson
Can
cer
Cent
er
Exec
utiv
e O
ffice
rTr
ansl
atio
nal R
esea
rch
Prog
ram
The
Allia
nce
for C
linic
al T
rials
Sign
ifica
nce
of c
utan
eous
tox
iciti
es t
o on
colo
gic
ther
apie
s
•In
dica
tor o
f res
pons
e to
ther
apy
•R
espo
nse
to E
GFR
inhi
bito
r the
rapy
co
rrel
ates
with
dev
elop
men
t and
sev
erity
of
skin
rash
•R
espo
nse
to im
mun
e ch
eckp
oint
blo
ckad
e co
rrel
ates
with
pig
men
tary
alte
ratio
n
•M
imic
ker o
f dis
ease
recu
rren
ce•
Pann
icul
itis c
an m
imic
dis
ease
recu
rren
ce
•M
ay re
quire
furt
her p
roce
dure
•SC
C in
the
cont
ext o
f RA
F in
hibi
tors
•M
ay re
quire
alte
ratio
n of
ther
apy
•B
ullo
us p
emph
igoi
d in
imm
une
chec
kpoi
nt b
lock
ade
•Sk
in o
ften
exhi
bits
toxi
city
ear
ly in
the
cour
se o
f the
rapy
and
is a
cces
sibl
e.
02
46
810
12
Toxicity Grade
Tim
e (w
eeks
)
Rash
/pru
ritis
Diar
rhea
/col
itis
Live
r tox
icity
Com
mon
spe
cific
cut
aneo
us t
oxic
ities
to
onco
logi
c th
erap
ies
•An
ti-EG
FR in
hibi
tors
•Pa
pulo
pust
ular
erup
tion
•Im
mun
e che
ckpo
int b
lock
ade (
-CTL
A4 a
nd
-PD-
1/-P
D-L1
)•
Lich
enoi
d de
rmat
itis
•B
ullo
us p
emph
igoi
d re
actio
n•
Gra
nulo
mat
ous i
nfilt
rate
s
•R
AF in
hibi
tor t
hera
py•
Squa
mou
s ne
opla
sia
•Pa
nnic
uliti
s
Cuta
neou
s to
xici
ty t
o EG
FR-in
hibi
tor
•EG
FR is
a tr
ansm
embr
ane p
rote
in th
at tr
ansm
its m
itoge
nics
igna
ls v
ia
intr
acel
lula
r tyr
osin
e kin
ase
dom
ain
•A
nti-E
GFR
inhi
bito
rs•
Mon
ocol
onal
antib
odie
s to
EGFR
: cen
tuxi
mab
,pan
itum
umab
•Sm
all m
olec
ular
inhi
bito
r: er
lotin
ib,g
efiti
nib
•D
ual k
inas
e in
hibi
tors
: lap
atin
ib, n
erat
inib
, afa
tinib
•EG
FR e
xpre
ssed
in s
kin
and
skin
adn
exal
str
uctu
res
•G
reen
MR
et a
l. Jo
urna
l of I
nves
tigat
ive
Der
mat
olog
y. 1
985.
85:
239
-245
.
•M
ost c
omm
on re
actio
ns to
EG
FR in
hibi
tors
•Pa
pulo
pust
ular
erup
tion
•Xe
rosi
s•
Chan
ges
in h
air
and
nails
•M
ucos
itis
Papu
lopu
stul
arer
uptio
n to
EG
FR-in
hibi
tor
•R
epor
ted
in u
p to
90%
of p
atie
nts
on E
GFR
i•
Mos
t dev
elop
with
in 1
-2 w
eeks
of i
nitia
ting
ther
apy
•Do
se d
epen
dent
•M
ore
seve
re w
ith m
onoc
lona
l ant
ibod
ies
than
sm
all m
olec
ular
inhi
bito
rs
•Se
verit
y of
rash
cor
rela
ted
with
res
pons
e to
th
erap
y•
Mar
ker o
f the
rape
utic
effi
cacy
•Fo
llicu
lar p
apul
es/p
ustu
les
on T
-zon
e of
face
or
seb
orrh
eic
area
s, s
calp
, and
upp
er tr
unk
Imag
e co
urte
sy o
f Dr.
Jon
Curry
MD
Papu
lopu
stul
arer
uptio
n to
EG
FR-in
hibi
tor
Papu
lopu
stul
arer
uptio
n to
EG
FR-in
hibi
tors
Papu
lopu
stul
arer
uptio
n to
EG
FR-in
hibi
tors
PPPPPPPPPPPPPPPPaaaaaaaaaaaaaaaapppppppppppppppppuuuuuuuuuuuuu
lllllllllllllllllooooooooooooooooopppppppppppppuuuuuuuuuuuuuuuuu
sssssssssssssssstttttttttttttttttuuuuuuuuuuuuuuuuuullllllllllllll
aaaaaaaaaaaaaaaaarrrrrrrrrrreeeeeeeeeeeeerrrrrrrrrrrrr
uuuuuuuuuuuuuuuuppppppppppppppptttttttttttttttiiiiiiiiiioooooooooooooooo
nnnnnnnnnnnnn tttttttttttttttooooooooooooooooo
EEEEEEEEEEEEEEEGGGGGGGGGGGGGGGG
FFFFFFFFFFFFFFFFFFRRRRRRRRRRRRRRRRRR-------iiiiiiiiiiiiiinnnnnnnnnnnnnnnnnn
hhhhhhhhhhhhhhhhhhiiiiiiiiiiiiiibbbbbbbbbbbbbiiiiiiiiiiii
ttttttttttttttttoooooooooooooorrrrrrrrrrrrrrrrsssssssssssssssss
Oth
er c
hang
es d
ue to
EG
FR-in
hibi
tor
•Pa
rony
chia
•20
% o
f tre
ated
pat
ient
s•
Invo
lvem
ent
of th
umbs
and
big
toes
, pr
edom
inan
t•
Deve
lops
afte
r 4-8
wee
ks o
f tre
atm
ent
•A
lope
cia
•Se
en in
5%
of t
reat
ed p
atie
nts
•La
te to
xici
ty, o
ccur
s m
onth
s af
ter E
GFR
ith
erap
y•
Non-
scar
ring
or s
carr
ing
alop
ecia
Bala
gula
et.a
l Int J
Der
mat
ol. 2
011,
Rob
ert e
t. al
. Lan
cet O
ncol
. 200
5
•H
and
and
foot
ski
n re
actio
n (H
FSR
)•
Com
mon
with
cla
ss II
EG
FRit
hera
py
and
with
mul
ti-ki
nase
inhi
bito
rs (
e.g.
so
rafe
nib)
•Sk
in fi
ssur
es•
Tric
hom
egal
y•
Xero
sis
Cuta
neou
s re
actio
n to
EG
FR-in
hibi
tor
ther
apy
A m
arke
r of
ther
apeu
tic e
ffica
cy•
Act
ivat
ing
som
atic
mut
atio
ns in
BR
AF
occu
r in
~50-
60%
of p
rimar
y cu
tane
ous
mel
anom
a•
BR
AF
activ
atio
n tr
igge
rs M
APK
sig
nalin
g vi
a ph
osph
oryl
atio
n of
dow
nstre
am ta
rget
s •
BR
AF
inhi
bito
rs (B
RA
Fi) t
arge
t act
ivat
ed B
RA
F–
Firs
t gen
erat
ion:
TKI
s (e
.g. s
oraf
enib
)–
Seco
nd g
ener
atio
n: v
emur
afen
ib, d
abra
feni
b
•M
ost c
omm
on to
xici
ty o
f BR
AFi
mon
othe
rapy
is a
cut
aneo
us e
pith
elia
l pro
lifer
atio
n•
App
roxi
mat
ely
50-7
5% o
f pat
ient
s de
velo
p.
•D
evel
op w
ithin
few
to s
ever
al m
onth
s afte
r th
erap
y•
Ran
ge: 4
-14
mon
ths
(mea
n=8.
6 m
onth
s)
Cuta
neou
s ep
ithel
ial p
rolif
erat
ions
with
BRA
Fi
Imag
e co
urte
sy o
f Dr.
Jon
Curry
MD
•K
erat
osis
pila
ris•
Sebo
rrhe
ic k
erat
osis
•Ac
tinic
ker
atos
is•
Verr
uca
vulg
aris
(ver
ruco
us k
erat
osis
)•
Ker
atoa
cant
hom
a•
Squa
mou
s ce
ll ca
rcin
oma
Cuta
neou
s ep
ithel
ial p
rolif
erat
ions
with
BRA
FiCu
tane
ous
epith
elia
l pro
lifer
atio
n in
BRA
F-in
hibi
tor
ther
apy
Verr
ucou
s Ker
atos
isK
erat
oaca
ntho
ma
Squa
mou
s ce
ll ca
rcin
oma
Mec
hani
sm o
f cut
aneo
us e
pith
elia
l pro
lifer
atio
n in
BRA
Fi
•Se
quen
ced
33 c
ance
r as
soci
ated
gen
es fr
om
237
KA
/SC
Cs
•19
BRA
Fi•
53 Im
mun
osup
pres
sed
•16
5 ‘s
pont
aneo
us’
•M
utat
ions
in 3
8/23
7 ca
ses
•B
RA
Fi-a
ssoc
iate
d tu
mor
s w
ere
enric
hed
for a
ctiv
atin
g m
utat
ions
in H
RA
S •
Para
doxi
cal a
ctiv
atio
n of
wild
type
BR
AF
by B
RA
Fith
ough
t to
‘unm
ask’
pre
-ex
istin
g R
AS-
prim
ed o
ncog
enic
ker
atin
ocyt
es
55 y
o w
oman
with
BR
AFV6
00E
mut
ant m
elan
oma
trea
ted
with
su
rger
y, r
adia
tion
and
inte
rleuk
in-2
was
enr
olle
d on
a
BR
AFi(
dabr
afen
ib) t
rial.
Afte
r 2
mon
ths
of th
erap
y, s
he
deve
lope
d m
ultip
le in
dura
ted
tend
er s
ubcu
tane
ous
nodu
les
on th
e an
terio
r thi
ghs
and
arm
s.
BRAF
i ass
ocia
ted
pann
icul
itis
•Ra
re b
ut im
port
ant c
ompl
icat
ion
of B
RAFi
•40
+ pa
tient
s re
port
ed in
the
liter
atur
e si
nce
2012
•M
edia
n ag
e: 4
3.5
year
s•
32F:
10M
•M
edia
n da
ys o
n BR
AFi=
36
(ran
ge: 3
day
s-16
mon
ths)
•In
clud
ed v
emur
afen
iban
d da
braf
enib
(+/-
tram
etin
ib)
BRAF
i ass
ocia
ted
pann
icul
itis
•Cl
inic
ally
mim
ics
recu
rren
t dis
ease
•M
ay re
quire
BRA
Fido
se a
djus
tmen
t
•Ra
re b
ut im
port
ant c
ompl
icat
ion
of B
RAFi
•Ex
trem
ities
•Ne
utro
phili
c lo
bula
r pa
nnic
uliti
s
Imm
une
chec
kpoi
nt b
lock
ade
in c
utan
eous
mal
igna
ncy
Puts
a b
rake
…on
a n
atur
al b
rake
EurJ
Sur
g O
ncol
.201
7. 4
3(3)
:604
-611
.
Imm
une
chec
kpoi
nts
are
natu
ral b
rake
s on
th
e im
mun
e sy
stem
:
•C
TLA
4 bi
nds
B7
•PD
-L1
bind
s PD
-1Da
mpe
n im
mun
e re
spon
seto
lim
it tis
sue
dam
age
Enga
gem
ent o
f PD
-L1
with
its
ligan
d PD
-1:
•In
hibi
tory
sig
nals
•R
educ
ed T
-cel
l pro
lifer
atio
n•
Red
uced
T-c
ell a
ctiv
ity
Imm
une
chec
kpoi
nt a
ntib
ody
bloc
kade
relie
ves
inhi
bito
ry s
igna
ls, a
llow
ing
cont
inue
d pr
opag
atio
n of
the
imm
une
syst
em a
gain
st tu
mor
ant
igen
s.
T-ce
llAP
CTu
mor
APC
Imm
une
chec
kpoi
nt b
lock
ade
in c
utan
eous
onc
olog
y
Ipili
mum
ab
Niv
olum
ab
Pem
brol
izum
ab
Avel
umab
•Ip
ilum
ab(
-CTL
A-4)
App
rove
d by
FD
A in
201
1
•N
ivol
umab
and
Pem
brol
izum
ab (
-PD
-1)
App
rove
d by
FD
A in
201
4
•Av
elum
ab(
-PD-
L1)
Cuta
neou
s to
xici
ty t
o im
mun
e ch
eckp
oint
blo
ckad
e
•Sk
in to
xici
ty o
f any
type
and
any
gra
de•
~ 50
-70%
in
patie
nts
rece
ivin
g an
ti-C
TLA-
4•
~ 20
-30%
in
patie
nts
rece
ivin
g an
ti-PD
-1/P
D-L
1•
Spec
ific
type
s of
ski
n to
xici
ty a
re b
eing
reco
gniz
ed w
ith th
ese
antib
ody
ther
apie
s•
Infla
mm
ator
y, i
mm
unob
ullo
us, p
anni
culit
is a
nd re
gres
sing
nev
i•
Impo
rtan
t to
reco
gniz
e th
ese
occu
r as
they
can
pot
entia
llym
imic
dis
ease
recu
rren
ce o
r cau
se in
terr
uptio
n in
ther
apy
Cut
aneo
us t
oxic
ity in
imm
une
chec
kpoi
nt
bloc
kade
: ecz
ema,
lich
enoi
d, v
itilig
o
Lich
enoi
dEc
zem
aVi
tilig
o
Cuta
neou
s to
xici
ties
to P
D-1
bloc
kade
mor
e co
mm
only
bi
opsi
ed
Lich
enoi
dIm
mun
obul
lous
(bul
lous
pem
phig
oid)
Pann
icul
itis
Lich
enoi
d de
rmat
itis
with
PD-
1 bl
ocka
de
•65
-yea
r-ol
d m
an w
ith s
tage
IV B
RA
F G
466E
mel
anom
a •
Dis
cont
inue
d ip
ilim
umab
(3 m
g/kg
) af
ter 3
cyc
les
due
to th
erap
y rel
ated
ne
urop
athy
•
Beg
an p
embr
oliz
umab
(2 m
g/kg
) •
Afte
r one
wee
k, h
e de
velo
ped
eryt
hem
atou
s pa
pule
s w
hich
co
ales
ced
into
pla
ques
invo
lvin
g ha
nds a
nd le
gs a
nd ra
pidl
y pr
ogre
ssed
to th
e tr
unk
and
bila
tera
l ex
trem
ities
, with
out o
ral l
esio
ns.
Imag
e co
urte
sy o
f Sus
an C
hon,
MD.
•65
-yea
r-ol
d m
an w
ith s
tage
IV B
RA
F G
466E
mel
anom
a •
Dis
cont
inue
d ip
ilim
umab
(3 m
g/kg
) af
ter 3
cyc
les
due
to th
erap
y rel
ated
ne
urop
athy
•
Beg
an p
embr
oliz
umab
(2 m
g/kg
) •
Afte
r one
wee
k, h
e de
velo
ped
eryt
hem
atou
s pa
pule
s w
hich
co
ales
ced
into
pla
ques
invo
lvin
g ha
nds a
nd le
gs a
nd ra
pidl
y pr
ogre
ssed
to th
e tr
unk
and
bila
tera
l ex
trem
ities
, with
out o
ral l
esio
ns.
Lich
enoi
d de
rmat
itis
with
PD-
1 bl
ocka
de
Imag
e co
urte
sy o
f Sus
an C
hon,
MD.
55 y
o w
oman
with
ch
emot
hera
py r
esis
tant
ovar
ian
sero
us c
arci
nom
are
ceiv
ing
Niv
olum
ab.
Afte
r 3
cycl
es, s
he
deve
lope
d a
wid
espr
ead
eryt
hem
atou
s sc
aly
and
prur
itic
plaq
ues
on u
pper
ba
ck, c
hest
and
nec
k.
Lich
enoi
d de
rmat
itis
with
PD-
1 bl
ocka
de
Imag
e co
urte
sy o
f Aur
isH
uen
MD
, Pha
rmD
.
Lich
enoi
d de
rmat
itis
afte
r im
mun
e ch
eckp
oint
blo
ckad
e
Lich
enoi
d de
rmat
itis
with
PD-
1 bl
ocka
de
Imm
unob
ullo
usdi
seas
e w
ith P
D-1
bloc
kade
63 y
o m
an w
ith r
ecur
rent
m
etas
tatic
SC
C o
f the
tong
uere
ceiv
ing
Niv
olum
ab.
Afte
r 8
wee
ks, h
e pr
esen
ted
with
ery
them
atou
s sc
aly
plaq
ues
of th
e ne
ck a
nd c
hin
with
ove
rlyin
g te
nse
vess
icle
sra
pidl
y pr
ogre
ssin
g to
invo
lve
the
bila
tera
l for
earm
s sh
ins
and
mid
bac
k.
Imag
e co
urte
sy o
f Dr B
ella
Glit
za, M
D.
Imm
unob
ullo
usdi
seas
e w
ith P
D-1
bloc
kade
Niv
olum
ab w
as w
ithhe
ld a
nd
topi
cal s
tero
ids
wer
e ap
plie
d w
ith le
sion
al im
prov
emen
t.
Afte
r on
e m
isse
d do
se,
ther
apy
was
re-s
tart
ed.
New
cut
aneo
us b
ulla
e an
d or
al
eros
ions
dev
elop
ed fo
rcin
g ce
ssat
ion
of N
ivol
umab
and
or
al p
redn
ison
e fo
r co
mpl
ete
reso
lutio
n of
lesi
ons.
Imag
e co
urte
sy o
f Jon
Cur
ry, M
D.
Imm
unob
ullo
usdi
seas
e w
ith P
D-1
bloc
kade
Dire
ct Im
mun
oflu
ores
cenc
e (D
IF) s
tudi
esBi
opsy
from
pat
ient
’s
peri-
lesi
onal
ski
n
Add
fluor
esce
ntly
labe
lled
antib
odie
sfo
r -c
ompl
emen
t (C3
), -Ig
G,
-IgA
C3
C3
C3
C3
C3
C3
C3
Wic
k M
.Ann
als
of D
iagn
osti
c P
atho
logy
. 201
2. 1
6: 7
1-78
.
Turc
anI a
nd J
onkm
anM
F. C
ell T
issu
e R
es.
2015
. 36
0:54
5–56
9.
Biop
sy fr
om p
atie
nt’s
pe
ri-le
siona
l ski
n
Add
fluor
esce
ntly
labe
lled
antib
odie
s fo
r -c
ompl
emen
t (C3
), -Ig
G,
-IgA
DIF
biop
sy fr
om b
ullo
us le
sion -C
olIV
Imm
unob
ullo
usdi
seas
e w
ith P
D-1
bloc
kade
Imm
unob
ullo
usdi
seas
e w
ith P
D-1
bloc
kade
A to
tal o
f 13
patie
nts
desc
ribed
:•
9 M
en: 4
Wom
en•
Med
ian
age:
73
year
s (R
ange
: 42-
85y)
•M
elan
oma
(n=8
), Lu
ng A
deno
(n=2
), SC
C (n
=2),
Uro
thel
ialc
a (n
=1)
•Pe
mbr
oliz
umab
(n=6
), N
ivol
umab
(n=6
), D
irval
umab
(n=1
)•
Med
ian
time
to d
iagn
osis
: 18
wee
ks (r
ange
: 6-8
4 w
eeks
)•
Dis
cont
inua
tion
of th
erap
y: Y
ES (n
=5)
39 y
ear o
ld C
auca
sian
wom
an w
ith
hist
ory
of s
tage
III m
elan
oma
met
asta
tic to
the
right
axi
llary
ly
mph
nod
e w
ith a
BR
AFV6
00E
mut
atio
n.
Enro
lled
in a
clin
ical
tria
l to
rece
ive
ipili
mum
ab a
nd n
ivol
umab
in
the
neoa
djuv
ant s
ettin
g fo
llow
ed b
y su
rgic
al e
xcis
ion
and
sing
le a
gent
niv
olum
ab.
Imag
e co
urte
sy o
f Om
ar P
acha
, MD.
Five
mon
ths
afte
r sur
gery
whi
le o
n si
ngle
age
nt n
ivol
umab
, she
de
velo
ped
num
erou
s pa
infu
l su
bcut
aneo
us n
odul
es o
n he
r bi
late
ral l
ower
ext
rem
ities
, whi
ch
prog
ress
ivel
y en
larg
ed a
nd w
ere
mar
kedl
y 18
F-F
DG
PET
/CT
avid
.
Imag
e co
urte
sy o
f Om
ar P
acha
, MD.
Five
mon
ths
afte
r sur
gery
whi
le o
n si
ngle
age
nt n
ivol
umab
, she
de
velo
ped
num
erou
s pa
infu
l su
bcut
aneo
us n
odul
es o
n he
r bi
late
ral l
ower
ext
rem
ities
.Th
ese
wer
e 18
F-F
DG
PET
/CT
avid
.
•Sp
ecia
l sta
ins (
Gra
m/F
ITE/
GM
S) n
egat
ive
for b
acte
rial (
incl
udin
g ac
id-f
ast)
and
fu
ngal
org
anis
ms;
cul
ture
s als
o ne
gativ
e.
•
Imm
unoh
isto
chem
ical
stu
dies
with
an
anti-
mel
anoc
ytic
coc
ktai
l (H
MB4
5, a
nti-
MAR
T1 a
nd a
nti-t
yros
inas
e) a
nd a
ntib
odie
s fo
r S10
0 an
d So
x-10
neg
ativ
e fo
r m
etas
tatic
mel
anom
a •
No
imm
unoh
isto
chem
ical
evi
denc
e to
supp
ort
a su
bcut
aneo
us T
-cel
l or N
K ce
ll ly
mph
oma.
•Fu
rthe
r rev
iew
of h
er ch
art:
•
No
rece
nt h
isto
ry o
f or c
linic
al e
vide
nce
to s
ugge
st re
cent
/ong
oing
infe
ctio
n.
•N
o hi
stor
y of
(add
ition
al)
rece
nt ch
ange
s in
med
icat
ion.
•
No
evid
ence
of p
ulm
onar
y sy
mpt
oms
or h
ilar
lym
phad
enop
athy
. •
ACE
leve
ls w
ithin
nor
mal
lim
its.
Furt
her w
ork-
up…
…
Gra
nulo
mat
ous
infla
mm
ator
y in
filtr
ate
in
skin
/sub
cutis
durin
g im
mun
e ch
eckp
oint
blo
ckad
e:
A ra
re b
ut im
port
ant m
imic
ker
of d
isea
se re
curr
ence
•Va
rious
mor
phol
ogic
typ
es o
f ski
n to
xici
ty
may
occ
ur to
imm
une
chec
kpoi
nt t
hera
py
•Ea
rly re
cogn
ition
ski
n to
xici
ty w
ill b
e cr
itica
l fo
r app
ropr
iate
pat
ient
man
agem
ent
•M
imic
kers
of d
isea
se re
curr
ence
•In
dica
tors
of t
hera
peut
ic re
spon
se•
Poss
ible
furt
her i
nter
vent
ion
or a
ltera
tion
of
regi
men
PD-L
1 in
Der
mat
opat
holo
gyIm
mun
e ch
eckp
oint
blo
ckad
e in
de
rmat
opat
holo
gy a
nd th
e re
leva
nce
of P
D-L
1 im
mun
ohis
toch
emic
al
stud
ies
in d
aily
pra
ctic
e
Mic
hael
T. T
etzl
aff M
D, P
hD
Asso
ciat
e Pr
ofes
sor
Depa
rtm
ents
of P
atho
logy
,Se
ctio
n of
Der
mat
opat
holo
gyan
d Tr
ansl
atio
nal a
nd M
olec
ular
Pat
holo
gyTh
e Un
iver
sity
of T
exas
MD
Ande
rson
Can
cer
Cent
er
Exec
utiv
e O
ffice
rTr
ansl
atio
nal R
esea
rch
Prog
ram
The
Allia
nce
for C
linic
al T
rials
PD-L
1 Im
mun
ohis
toch
emic
al s
tudi
es in
der
mat
opat
holo
gy•
Imm
une
chec
kpoi
nt b
lock
ade
in c
utan
eous
mal
igna
ncy
•Ip
ilum
umab
(CTL
A-4
blo
ckad
e) in
mel
anom
a•
Niv
olum
ab a
nd P
embr
oliz
umab
(PD
-1 b
lock
ade)
in m
elan
oma
•Pe
mbr
oliz
umab
(PD
-1 b
lock
ade)
and
Ave
lum
ab(P
D-L
1 bl
ocka
de) i
n M
erke
l cel
l car
cino
ma
•C
orre
latin
g PD
-L1
expr
essi
on w
ith c
linic
al re
spon
se: W
HAT
TO
REP
OR
T?•
In m
elan
oma,
it d
epen
ds o
n th
e re
gim
en to
be
used
•In
gen
eral
, PD
-L1
posi
tivity
cor
rela
tes
with
resp
onse
to s
ingl
e ag
ent N
ivol
umab
or
Pem
brol
uzim
ab, B
UT
LESS
IMPO
RTA
NT
FOR
PD
-1 M
ON
THER
APY.
•La
ck o
f PD
-L1
expr
essi
on m
ay in
dica
te n
eed
for c
ombi
natio
n th
erap
ies
•H
ow d
o w
e de
tect
PD
-L1
in p
ract
ice?
Wha
t are
the
chal
leng
es?
•D
iffer
ent F
DA
-app
rove
d co
mpa
nion
ant
ibod
ies d
epen
ding
on
the
drug
.•
Are
they
com
para
ble?
Doe
s it
mat
ter?
•M
echa
nism
s of
PD
-L1
expr
essi
on in
mel
anom
a—un
ders
tand
ing
the
patte
rns
•In
duce
d ve
rsus
intr
insi
c
PD-L
1 Im
mun
ohis
toch
emic
al s
tudi
es: C
ase
exam
ple
•Th
ings
to c
onsi
der:
•Ho
w d
oes
PD-L
1 st
ain
in m
elan
oma?
•
Is it
mem
bran
ous?
Cyt
opla
smic
? Ar
e ot
her c
ells
pos
itive
?•
Whi
ch P
D-L1
ant
ibod
y cl
one
(22C
3 vs
28-
8) s
houl
d yo
u us
e?
•Do
es it
mat
ter?
Do
the
diffe
rent
clo
nes
stai
n tu
mor
s si
mila
rly?
•W
hat d
eter
min
es “
PD-L
1 po
sitiv
ity”?
Are
ther
e cu
t-offs
? •
Wha
t are
the
pitfa
lls o
f int
erpr
etat
ion?
•D
r. Pi
gmen
t, lo
cal m
edic
al o
ncol
ogis
t, ph
ones
you
in th
e of
fice.
•“Y
ou s
igne
d ou
t pat
ient
Joh
n Sm
ith’s
nee
dle
core
bio
psy
spec
imen
as
mel
anom
a to
a ly
mph
nod
e.
•I w
ant t
o st
art h
im o
n im
mun
e ch
eckp
oint
blo
ckad
e th
erap
y.
•Ca
n yo
u ru
n PD
-L1
imm
unoh
isto
chem
istr
y?”
Nivo
lum
ab im
prov
es s
urvi
val i
n pa
tient
s w
ith
met
asta
tic m
elan
oma
n=41
8 pa
tient
s with
met
asta
tic m
elan
oma
•Pr
evio
usly
unt
reat
ed•
No B
RAF
mut
atio
n
Nivo
lum
ab3
mg/
kg/2
wee
ksDa
carb
azin
e3
wee
ks
Pem
brol
izum
ab im
prov
es s
urvi
val i
n pa
tient
s w
ith
met
asta
tic m
elan
oma
n=54
0 pa
tient
s w
ith ip
ilum
abm
etas
tatic
mel
anom
aIf
BR
AFV
600E
mut
atio
n, a
lso
BRAF
/MEK
i ref
ract
ory
Pem
brol
izum
ab2
mg/
kg/2
wee
ksIn
vest
igat
or c
hoic
ech
emot
hera
pyPe
mbr
oliz
umab
10 m
g/kg
/2 w
eeks
Dete
rmin
ants
of r
espo
nse
to P
D-L1
blo
ckad
ePD
-L1
expr
essi
on b
y tu
mor
cel
ls a
nd d
ensi
ty o
f tum
or a
ssoc
iate
d T-
cell
infla
mm
ator
y in
filtr
ate
•Pr
edic
tors
of r
espo
nse
to P
D-1
mon
othe
rapy
bloc
kade
(Pem
bro)
:•
High
er tu
mor
ass
ocia
ted
CD8+
T-c
ell i
nfilt
rate
bef
ore
and
durin
g th
erap
y•
High
er P
D-L1
exp
ress
ion
by tu
mor
cel
ls, a
lthou
gh lo
w P
D-L
1 do
es n
ot e
xclu
de
How
is P
D-L1
exp
ress
ed in
mel
anom
a?
Tum
or a
ssoc
iate
d in
flam
mat
ory
cells
driv
e ex
pres
sion
SciT
rans
lMed
. 201
2 M
ar 2
8;4(
127)
:127
ra37
.
Tum
ors
with
mor
e in
flam
mat
ion
expr
ess
high
er le
vels
of P
D-L
1
How
doe
s th
e as
soci
ated
imm
une
infil
trate
driv
e PD
-L1
expr
essi
on in
mel
anom
a
CD
8PD
-L1
CD
8PD
-L1
Tum
ors
expr
essi
ng h
ighe
r lev
els
of P
D-L
1 al
so e
xpre
ssed
mor
e IF
N
Tum
ors
with
mor
e in
flam
mat
ion
ex
pres
s hi
gher
leve
ls o
f PD-
L1
IFN
Patte
rns
of P
D-L1
exp
ress
ion
in m
elan
oma
Four
pat
tern
s of
PD
-L1
expr
essi
on
in m
elan
oma
refle
ct d
istin
ct
mec
hani
sms
of e
xpre
ssio
n
PD-L
1
IFN
T-ce
llT-
cell
PD1
Mel
anom
a ce
ll
Mac
roph
age
PD-L
1
Reg
iona
l exp
ress
ion
+ TI
LSPD
-L1
PDPDPDPDPDPPDPDPDPDPDPPD-----L
1L1L1L1L1L1L1L1L1LLLL1L1L CD8
“Ind
ucib
le” e
xpre
ssio
n
SciT
rans
lMed
. 201
2 M
ar 2
8;4(
127)
:127
ra37
.
Driv
ers
of P
D-L1
exp
ress
ion
in m
elan
oma
PD-L
1
IFN
T-ce
llT-
cell
PD1
Mel
anom
a ce
ll
Mac
roph
age
PD-L
1
Reg
iona
l exp
ress
ion
+ TI
LSPD
-L1
“Ind
ucib
le” e
xpre
ssio
n
Four
pat
tern
s of
PD
-L1
expr
essi
on
in m
elan
oma
refle
ct d
istin
ct
mec
hani
sms
of e
xpre
ssio
nSc
iTra
nslM
ed. 2
012
Mar
28;
4(12
7):1
27ra
37.
Driv
ers
of P
D-L1
exp
ress
ion
in m
elan
oma
PD-L
1
IFN
T-ce
llT-
cell
PD1
Mel
anom
a ce
ll
Mac
roph
age
PD-L
1PD
-L1
“Ind
ucib
le” e
xpre
ssio
n
Four
pat
tern
s of
PD
-L1
expr
essi
on
in m
elan
oma
refle
ct d
istin
ct
mec
hani
sms
of e
xpre
ssio
nSc
iTra
nslM
ed. 2
012
Mar
28;
4(12
7):1
27ra
37.
No
expr
essi
on +
TIL
S “i
mm
une
tole
ranc
e”
Driv
ers
of P
D-L1
exp
ress
ion
in m
elan
oma
PD-L
1
IFN
T-ce
llT-
cell
PD1
Mel
anom
a ce
ll
Mac
roph
age
PD-L
1
No
expr
essi
on –
TILS
“i
mm
une
igno
ranc
e”
PD-L
1
“Ind
ucib
le” e
xpre
ssio
n
Four
pat
tern
s of
PD
-L1
expr
essi
on
in m
elan
oma
refle
ct d
istin
ct
mec
hani
sms
of e
xpre
ssio
nSc
iTra
nslM
ed. 2
012
Mar
28;
4(12
7):1
27ra
37.
Driv
ers
of P
D-L1
exp
ress
ion
in m
elan
oma
PD-L
1
IFN
T-ce
llT-
cell
PD1
PD-L
1On
coge
nic d
river
m
utat
iuon
s
Mel
anom
a ce
ll
Mac
roph
age
PD-L
1
Diff
use e
xpre
ssio
n-TI
LS in
depe
nden
tPD
-L1
“End
ogen
ous”
exp
ress
ion
Four
pat
tern
s of
PD
-L1
expr
essi
on
in m
elan
oma
refle
ct d
istin
ct
mec
hani
sms
of e
xpre
ssio
nSc
iTra
nslM
ed. 2
012
Mar
28;
4(12
7):1
27ra
37.
Driv
ers
of P
D-L1
exp
ress
ion
in m
elan
oma
Sum
mar
y of
pat
tern
s of
PD-
L1 e
xpre
ssio
nIn
duci
ble
or e
ndog
enou
s ex
pres
sion
on
the
mem
bran
e of
tum
or c
ells
Reg
iona
l exp
ress
ion
Abs
ent e
xpre
ssio
nD
iffus
e exp
ress
ion
Wha
t are
the
pitfa
lls o
f PD
-L1
IHC
inte
rpre
tatio
n in
mel
anom
a?
PD-L
1PD
-L1
PD-L
1
Pitfa
lls o
f PD-
L1 im
mun
ohis
toch
emic
al s
tudi
es in
mel
anom
a
Asso
ciat
ed
stro
mal
/ in
flam
mat
ory
cells
als
o ex
pres
s PD
-L1,
pa
rtic
ular
ly
HIS
TIO
CYT
ES
PD-L
1
Mel
anin
pig
men
t ca
n ob
scur
e or
m
imic
PD
-L1
posi
tivity
. Gie
msa
co
unte
rsta
in h
elps
to
dis
tingu
ish
mel
anin
from
DAB
.
Pitfa
lls o
f PD-
L1 im
mun
ohis
toch
emic
al s
tudi
es in
mel
anom
a
Mel
anin
pig
men
t ca
n ob
scur
e or
m
imic
PD
-L1
posi
tivity
. Gie
msa
co
unte
rsta
in h
elps
to
dis
tingu
ish
mel
anin
from
DAB
.
Pitfa
lls o
f PD-
L1 im
mun
ohis
toch
emic
al s
tudi
es in
mel
anom
a
PD-L
1G
iem
sa
Anti-
PD-L
1 oc
casi
onal
ly
high
light
s tu
mor
nu
clei
. Unc
lear
et
iolo
gy.
NO
T PO
SITI
VE.
Pitfa
lls o
f PD-
L1 im
mun
ohis
toch
emic
al s
tudi
es in
mel
anom
a
PD-L
1
Anot
her
chal
leng
e: D
iffer
ent P
D-L1
ant
ibod
y cl
ones
va
lidat
ed in
diff
eren
t tria
ls w
ith d
iffer
ent
-PD-
1 dr
ugs
Ant
ibod
y cl
one
Targ
et
Dom
ain
Dev
elop
erC
ut-o
ffD
rug
rela
ted
Ref
eren
ce
5H11
Extra
cellu
larLi
eping
Che
n’s
lab%
mem
bran
ous
staini
ng o
f tum
or
cells
ND
(1,2)
E1L3
NIn
trace
llular
Cell
Sign
aling
Te
chno
logy
% m
embr
anou
s sta
ining
of t
umor
ce
lls H-s
core
ND
(50)
E1J2
JEx
trace
llular
Cell
Sign
aling
Te
chno
logy
ND
ND
--
22C3
Extra
cellu
larD
ako
(*)
mem
bran
ous
staini
ng o
f tum
or
cells
or i
mm
une
cells
that
are
int
erca
lating
or a
t the
tum
or in
terfa
ce
Pem
broli
zum
ab(3
9)
Mer
ck
SP14
2In
trace
llular
Ven
tana
Each
spec
imen
ass
igned
a sc
ore b
ased
on
bot
h tu
mor
and
imm
une
cell
PD-L
1:A
tezo
lizum
ab(M
PDL3
280A
)(4
5)
Gene
ntec
h/Ro
che
TC3/
IC3
PD-
%
TC2/
IC2
PD-L
1 5-
49%
TC1/
IC1
PD-L
1 1-
4%
TC0/
IC0
PD-
%
28-8
Extra
cellu
larD
ako
% m
embr
anou
s sta
ining
of t
umor
ce
lls (m
inim
um 1
00 c
ells
evalu
ated
)N
ivolum
ab(1
)
Brist
ol-M
eyer
s Sq
uibb
SP26
3Ex
trace
llular
Ven
tana
% m
embr
anou
s sta
ining
of t
umor
ce
lls
H-s
core
Dur
valum
ab
(MED
I473
6)(4
3,39)
Med
Imm
une/
Astr
aZen
eca
Niv
olum
ab
Pem
brol
izum
ab
Avel
umab
Tabl
e co
urte
sy o
f Dr.
Jai
me
Rodr
igue
z
NIV
O: 2
8-8
>5%
tum
or c
ell c
ut-o
ff***
Pem
bro:
22C
3>1
% tu
mor
cel
l cut
-off
Diffe
rent
PD-
L1 c
lone
s va
lidat
ed in
diff
eren
t tria
ls w
ith
diffe
rent
-P
D-1
drug
s w
ith d
iffer
ent c
ut-o
ffs fo
r ‘p
ositi
vity
’
Do
the
diffe
rent
PD
-L1
clon
es h
ave
diffe
rent
op
erat
ing
char
acte
ristic
s?
Diffe
rent
PD-
L1 c
lone
s: D
o th
ey m
ake
a di
ffere
nce?
> 1%
> 5%
90 c
ases
of N
SCLC
with
IHC
per
form
ed fo
r PD
-L1
usin
g fo
ur c
lone
s: 2
2C3,
28-
8, S
P142
, and
E1L
3N
scor
ed b
y 13
pat
holo
gist
s to
inte
rrog
ate
conc
orda
nce
amon
g (1
) ass
ays
and
(2) p
atho
logi
sts
Goo
d as
say
conc
orda
nce,
but
som
e im
porta
nt
diffe
renc
es e
xist
—pa
rtic
ular
ly fo
r SP1
42 c
lone
Hig
h in
ter-
path
olog
ist c
onco
rdan
ce fo
r tu
mor
cel
l PD
-L1,
not
str
omal
cel
l
Diffe
rent
PD-
L1 c
lone
s:
Do th
ey m
ake
a di
ffere
nce
in m
elan
oma?
N=3
4 m
elan
omas
ass
esse
d by
IH
C fo
r PD
-L1
usin
g 5
diffe
rent
an
tibod
ies.
•D
iffer
ence
s in
rela
tive
%
PD
-L1+
tum
or c
ells
due
to:
•H
eter
ogen
eous
PD
-L1
disp
lay i
n•
Geo
grap
hica
lly d
istin
ct
regi
ons o
f the
tum
or th
at
varie
d ev
en b
etw
een
near
by s
ectio
ns•
Not
due
to d
iffer
ence
s am
ong
the
antib
odie
s in
m
elan
oma
sam
ples
.
Diffe
rent
PD-
L1 c
lone
s:
Do th
ey m
ake
a di
ffere
nce
in m
elan
oma?
Ove
rall
high
con
cord
ance
am
ong
the
diffe
rent
clo
nes
(R2 =
0.81
2-0.
961)
.
Diffe
rent
PD-
L1 c
lone
s:
Inte
nsity
or p
erce
ntag
e of
tum
or c
ells
pos
itive
?
•M
ost s
tudi
es a
sses
s“%
PD-
L1 p
ositi
ve
tum
or c
ells
”, b
ut d
o no
t inc
lude
a
mea
sure
men
t of
tum
or c
ell i
nten
sity
.
•Us
ing
an H
-sco
re (s
tain
ing
inte
nsity
) de
mon
stra
te a
str
ong
asso
ciat
ion
betw
een
H-sc
ore
and
% P
D-L1
pos
itive
tum
or c
ells
.
•Th
eref
ore,
to th
e ex
tent
that
H-s
core
and
%
are
not i
ndep
ende
nt v
aria
bles
, the
re is
not
a
stro
ng ra
tiona
le to
mea
sure
bot
h.
Does
the
sour
ce o
f the
tiss
ue m
ake
a di
ffere
nce?
Prim
ary
vers
us m
etas
tasi
s an
d ag
e of
the
spec
imen
…
68 p
re-tr
eatm
ent s
peci
men
s fr
om 4
1 pa
tient
s w
ith m
elan
oma,
NSC
LC, R
CC
, CR
C w
ith IH
C
perf
orm
ed fo
r PD
-L1
•PD
-L1
expr
essi
on b
y tu
mor
cel
ls c
orre
late
d w
ith c
linic
al re
spon
se•
PD-L
1 ex
pres
sion
by
TILS
did
NO
T co
rrel
ate
with
res
pons
e•
Det
ectio
n of
PD
-L1
in tu
mor
cel
ls d
id n
ot v
ary
with
spe
cim
en a
ge o
r sp
ecim
en s
ize
(nee
dle
core
ver
sus
exci
sion
al b
iops
y•
Cor
rela
tion
betw
een
PD-L
1 ex
pres
sion
and
clin
ical
out
com
e no
t re
late
d to
tim
ing
of th
e tis
sue
acqu
isiti
on.
•Fo
r pat
ient
s w
ith m
ultip
le s
ampl
es, ‘
PD-L
1 po
sitiv
ity’ i
n “a
ny
spec
imen
” de
term
ined
cor
rela
tion
with
out
com
e.•
Ther
e w
as s
igni
fican
t int
er-a
nd in
tra-
tum
oral
hete
roge
neity
.
Whe
n PD
-L1
expr
essi
on le
vels
rea
lly c
ount
IPI-N
IVO
ther
apy
has
high
toxi
city
….
but P
D-L
1 ne
gativ
e pa
tient
s be
nefit
mos
t
n=95
4 pa
tient
s pr
evio
usly
unt
reat
ed p
atie
nts
with
un
rese
ctab
lest
age
III o
r IV
met
asta
tic m
elan
oma
Nivo
lum
abIp
ilim
umab
Com
bina
tion
Ipilu
mab
and
Nivo
lum
ab
Whe
n PD
-L1
expr
essi
on le
vels
rea
lly c
ount
Com
bina
tion
ther
apy
has
high
toxi
city
, so
know
ing
PD-L
1 m
atte
rs
n=95
4 pa
tient
s pr
evio
usly
unt
reat
ed p
atie
nts
with
un
rese
ctab
lest
age
III o
r IV
met
asta
tic m
elan
oma
Nivo
lum
abIp
ilim
umab
Com
bina
tion
Ipilu
mab
and
Nivo
lum
ab
PD-L
1 po
sitiv
e M
M f
are
the
sam
e w
ith si
ngle
age
nt N
ivo
or
com
biIp
i/Niv
o
PD-L
1 ne
gativ
e M
M re
spon
d be
tter t
o co
mbi
Ipi/N
ivo
vers
us
sing
le a
gent
Niv
o
•G
rade
3 a
nd 4
toxi
citie
s oc
curr
ed: 4
4% N
ivo,
56%
Ipi,
but i
n 69
% C
ombi
natio
n Ip
i/Niv
o•
Inte
rpre
tatio
n of
PD-
L1 IH
C ha
s im
port
ant i
mpl
icat
ions
for
com
bina
tion
Ipi/N
ivo
•Pa
tient
s w
ith “
PD-L
1 po
sitiv
e” m
elan
omas
res
pond
sim
ilarly
to
Nivo
as
to Ip
i/Niv
o
Whe
n is
PD
-L1
‘neg
ativ
e’?
We
stru
ggle
the
mos
t with
de
sign
atio
n of
gr
eate
r tha
n or
le
ss th
an 1
%.
Pitfa
lls o
f PD-
L1 im
mun
ohis
toch
emis
try in
mel
anom
aW
hat i
s 1%
?PD
-L1
Imm
unoh
isto
chem
ical
stu
dies
: Cas
e ex
ampl
e
•D
r. Pi
gmen
t, lo
cal m
edic
al o
ncol
ogis
t, ph
ones
you
in th
e of
fice.
•“Y
ou s
igne
d ou
t pat
ient
Joh
n Sm
ith’s
nee
dle c
ore
biop
sy s
peci
men
as
mel
anom
a to
a ly
mph
nod
e.
•I w
ant t
o st
art h
im o
n im
mun
e ch
eckp
oint
blo
ckad
e th
erap
y.
•C
an yo
u ru
n PD
-L1
imm
unoh
isto
chem
istr
y to
dete
rmin
e if
he q
ualif
ies?
”
PD-L
1 Im
mun
ohis
toch
emic
al s
tudi
es: C
ase
exam
ple
An
imm
unoh
isto
chem
ical
stu
dy p
erfo
rmed
at t
he re
ques
t of t
he tr
eatin
g cl
inic
ian
with
ant
ibod
ies
for P
D-L
1 (2
8-8
clon
e) h
ighl
ight
s 15
% o
f the
tu
mor
cel
ls w
ith m
embr
anou
s pa
ttern
.
PD-L
1
Thin
gs to
avo
id:
1.Th
e tu
mor
is ‘p
ositi
ve’ o
r the
tum
or is
‘neg
ativ
e’—
GIV
E %
TU
MO
R C
ELLS
2.N
ot n
eces
sary
to c
omm
ent o
n %
Str
omal
/Infla
mm
ator
y cel
ls p
ositi
ve.
PD-L
1 Im
mun
ohis
toch
emic
al s
tudi
es: C
ase
exam
ple
72 y
o m
an w
ith a
his
tory
of
inva
sive
mel
anom
a of
th
e le
ft sc
alp
pres
ents
w
ith a
n ex
pand
ing
left
neck
mas
s. N
eedl
e co
re
biop
sy s
how
n.
Requ
estin
g “P
D-L1
im
mun
ohis
toch
emis
try.
PD-L
1
An
imm
unoh
isto
chem
ical
stu
dy p
erfo
rmed
at t
he re
ques
t of t
he tr
eatin
g cl
inic
ian
with
ant
ibod
ies
for P
D-L
1 (2
8-8
clon
e) h
ighl
ight
s >9
0% o
f the
tu
mor
cel
ls w
ith m
embr
anou
s pa
ttern
.
PD-L
1PD
-L1
Imm
unoh
isto
chem
ical
stu
dies
: Cas
e ex
ampl
e
55 y
o m
an w
ith a
his
tory
of
inva
sive
mel
anom
a of
th
e rig
ht c
alf p
rese
nts
with
an
expa
ndin
g rig
ht
ingu
inal
lym
ph n
ode
mas
s. N
eedl
e co
re
biop
sy s
how
n.
Requ
estin
g “P
D-L1
im
mun
ohis
toch
emis
try”
.
PD-L
1
An
imm
unoh
isto
chem
ical
stu
dy p
erfo
rmed
at t
he re
ques
t of t
he
trea
ting
clin
icia
n w
ith a
ntib
odie
s fo
r PD
-L1
(28-
8 cl
one)
. A
ntib
odie
s for
PD
-L1
do n
ot h
ighl
ight
the
tum
or c
ells
(<1%
).
PD-L
1
83 y
o w
oman
with
m
elan
oma
of u
nkno
wn
prim
ary
with
met
asta
sis
to th
e lu
ng.
Exci
sion
al
biop
sy s
how
n.
Requ
estin
g “P
D-L1
im
mun
ohis
toch
emis
try”
.
PD-L
1 Im
mun
ohis
toch
emic
al s
tudi
es: C
ase
exam
ple
Cas
e co
urte
sy o
f Dr.
Car
los
A To
rres
-Cab
ala
PD-L
1 Im
mun
ohis
toch
emic
al s
tudi
es: C
ase
exam
ple
PD-L
1 Im
mmuuuuunnnnnnnnnnnnnnnn
oooooooooohhiiss
ttoooocccccccccchhhhhhhhhhhh
eeeeeeeeeeeeemmmmmmmmmmmmmmiiiiiiiiiiiiiccccccccccccccc
aaaaaaaaaaaaaaaaallllllllllllll ssssssssss
ttttttuuuuuuuuuuuuudddddddddddddddddiiiiiiiiiiiii
eeeeeeeeeeeeesssssssssssss:::::::::::::::::::: CCCCCCCCCCCCCCC
aaaaaaaaaaaaaaaaassssssssssssssssseeeeeeeeeeeeeee
eeeeeeeeeeeeeexxxxxxxxxxxxxxxaaaaaaaaaaaaaaaammmmmmmmmmmmmmm
pppppppppppppppplllllllllllllleeeeeeeeeeeeeeeePD
-L1
Cas
e co
urte
sy o
f Dr.
Car
los
A To
rres
-Cab
ala
PD-L
1
Cas
e co
urte
sy o
f Dr.
Car
los
A To
rres
-Cab
ala
Sox-
10/P
D-L1
Cas
e co
urte
sy o
f Dr.
Car
los
A To
rres
-Cab
ala
Sox-
10/P
D-L1
An
imm
unoh
isto
chem
ical
stu
dy p
erfo
rmed
at t
he re
ques
t of t
he
trea
ting
clin
icia
n w
ith a
ntib
odie
s fo
r PD
-L1
(28-
8 cl
one)
. A
ntib
odie
s for
PD
-L1
do n
ot h
ighl
ight
the
tum
or c
ells
(<1%
).
Than
k yo
u!D
epar
tmen
t of P
atho
logy
, Sec
tion
of
Der
mat
opat
holo
gy, M
DA
CC
•Vi
ctor
G. P
rieto
MD
, PhD
•Jo
nath
an L
Cur
ry M
D•
Car
los A
. Tor
res-
Cab
ala
MD
•D
oina
Ivan
MD
•Pr
iyad
hars
ini N
agar
ajan
MD
, PhD
•Ph
yu A
ung
MD
, PhD
Depa
rtmen
t of M
elan
oma
Med
ical
Onc
olog
y•
Mic
hael
A D
avie
s M
D, P
hD•
Rod
a Am
aria
MD
•Hu
ssei
n Ta
wbi
MD
Depa
rtmen
t of S
urgi
cal O
ncol
ogy
•Je
nnife
r A. W
argo
MD
Mos
t com
mon
cut
aneo
us t
oxic
ities
to
onco
logi
c th
erap
ies
Diff
eren
tial d
iagn
osis
: Sub
-epi
derm
al b
ullo
us
dise
ase
•Po
rphy
ria C
utan
eaTa
rda
•A
cute
gra
ft ve
rsus
hos
t dis
ease
•B
urn
rela
ted
bulla
•Su
ctio
n bl
iste
r•
Eryt
hem
a m
ultif
orm
e•
Lich
en s
cler
osus
•B
ullo
us d
rug
erup
tion
•B
ullo
us in
sect
bite
eru
ptio
n
•B
ullo
us P
emph
igoi
d (B
P)•
Cic
atric
ialP
emph
igoi
d•
Epid
erm
olys
isB
ullo
saA
cqui
sita
(EB
A)
•B
ullo
us L
upus
Ery
them
atos
us•
Ant
i p20
0 pe
mph
igoi
d•
Der
mat
itis
Her
petif
orm
is (D
H)
•Li
near
IgA
dise
ase
•B
ullo
us P
emph
igoi
d (B
P)•
Cic
atric
ialP
emph
igoi
d•
Epid
erm
olys
isB
ullo
saAc
quis
ita(E
BA)
•B
ullo
us L
upus
Ery
them
atos
us•
Anti
p200
pem
phig
oid
•D
erm
atiti
s H
erpe
tifor
mis
(DH
)•
Line
ar Ig
A di
seas
e
Turc
anI a
nd J
onkm
anM
F. C
ell
Tiss
ue R
es (
2015
) 36
0:54
5–56
9.
Diff
eren
tial d
iagn
osis
: Sub
-epi
derm
al b
ullo
us
dise
ase
•B
ullo
us P
emph
igoi
d (B
P)•
Cic
atric
ialP
emph
igoi
d•
Epid
erm
olys
isB
ullo
saAc
quis
ita(E
BA)
•B
ullo
us L
upus
Ery
them
atos
us•
Anti
p200
pem
phig
oid
•D
erm
atiti
s H
erpe
tifor
mis
(DH
)•
Line
ar Ig
A di
seas
e
Turc
anI a
nd J
onkm
anM
F. C
ell
Tiss
ue R
es (
2015
) 36
0:54
5–56
9.
Diff
eren
tial d
iagn
osis
: Sub
-epi
derm
al b
ullo
us
dise
ase
•B
ullo
us P
emph
igoi
d (B
P)•
Cic
atric
ialP
emph
igoi
d•
Epid
erm
olys
isB
ullo
saAc
quis
ita(E
BA)
•B
ullo
us L
upus
Ery
them
atos
us•
Anti
p200
pem
phig
oid
•D
erm
atiti
s H
erpe
tifor
mis
(DH
)•
Line
ar Ig
A di
seas
e
Turc
anI a
nd J
onkm
anM
F. C
ell
Tiss
ue R
es (
2015
) 36
0:54
5–56
9.
Diff
eren
tial d
iagn
osis
: Sub
-epi
derm
al b
ullo
us
dise
ase
Indi
rect
Imm
unof
luor
esce
nce
stud
ies:
“SAL
T SP
LIT”
ski
n1.
0 M
NaC
lA
dd p
atie
nt s
erum
Add
fluo
resc
ent
-IgG Sa
lt sp
lit im
age
cour
tesy
of D
r. Ry
an H
ick,
MD,
Pro
path
Labs
.
Indi
rect
Imm
unof
luor
esce
nce
stud
ies:
“SAL
T SP
LIT”
ski
n1.
0 M
NaC
lA
dd p
atie
nt s
erum
Add
fluo
resc
ent
-IgG Sa
lt sp
lit im
age
cour
tesy
of D
r. Ry
an H
ick,
MD,
Pro
path
Labs
.
Imm
une
chec
kpoi
nt b
lock
ade
in M
erke
l cel
l car
cino
ma
56%
obj
ectiv
e res
pons
e ra
te to
PD
-1 in
hibi
tor a
mon
g st
age
IIIb
or IV
MC
C p
atie
nts w
ho h
ad n
ot re
ceiv
ed
prio
r sys
tem
ic th
erap
y—in
depe
nden
t of M
CPy
Vst
atus
or r
elat
ive
expr
essi
on o
f PD
-L1
(Clo
ne 2
2C3)
.
32%
(28/
88) p
atie
nts
with
sta
ge IV
MC
C w
ho fa
iled
at le
ast o
ne p
rior s
yste
mic
ther
apy
achi
eved
ra
pid
and
sust
aine
d re
spon
se to
PD
-L1
inhi
bito
r—in
depe
nden
t of M
CPy
Vst
atus
or r
elat
ive
expr
essi
on o
f PD
-L1
(Clo
ne 7
3-10
).
PD-L
1
An
imm
unoh
isto
chem
ical
stu
dy p
erfo
rmed
at t
he re
ques
t of t
he tr
eatin
g cl
inic
ian
with
ant
ibod
ies
for P
D-L
1 (2
2C3
clon
e) h
ighl
ight
s 15%
of t
he
tum
or c
ells
with
mem
bran
ous
patte
rn.
Derm
atol
ogic
To
xici
ty
No.
Ca
ses
M:F
A
ge
(rang
e)
Imm
une
Chec
kpoi
nt
Antib
ody
Prim
ary
Dise
ase
Ons
et o
f DT
in
Mon
ths
(rang
e)
Trea
tmen
t
Lich
enoi
d de
rmat
itis
34
9:8
67 (1
8-83
) N
ivo=
8 Pe
mbr
o= 7
an
ti-PD
-1 =
16
anti-
PD-L
1=3
Mel
anom
a=24
N
SCLC
=4
Uro
thel
ial C
A=3
Oth
er=3
3 (<
1 to
9)
Topi
cal
ster
oids
±s
yste
mic
Bullo
us
pem
phig
oid
12
7:3
73
(63:
85)
Niv
o=6
Pem
bro=
3 an
ti-PD
-L1=
1 N
S=2
Mel
anom
a=5
NSC
LC=2
U
roth
elia
l CA=
2 O
ther
=3
6
(<1
to 2
1)
Syst
emic
st
eroi
ds
± to
pica
l
Regr
esse
d ne
vi
3 3:
0 70
(5
0-82
) Pe
mbr
o=2
Ipi=
1 M
elan
oma=
3 7
(4-1
2)
Biop
sy o
r ex
cisio
n
