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Neuroendocrine neoplasms of the lung
M Papotti, L Righi, &
M Volante
University of Turin at
San Luigi Hospital
TORINO
NETs OF THE LUNG
Menu
- Spectrum of NE lung tumors
- CARCINOID TUMORS
- SCLC /LCNEC
- Combined NE and non-NE carcinomas
- Mechanisms driving NE differentiation
- Predictive markers of response to therapy
SPECTRUM OF LUNG NETs
typical
carcinoid
atypical
carcinoid
Small or Large
cell NE carcinoma
very rare
common rare
rare
Most benign
2004
Malignant
SCLC
TC
AC
-Different
-Different
-Different
-Different
& separate subtypes in the WHO
epidemiology and pathology
therapy & clinical behavior
Authors…..
LB WOOLNER
TC
AC
LCNEC
WD TRAVIS
LCNEC
J AZZOPARDI
SCLC
among
others
SPECTRUM OF PULMONARY NETs
typical
carcinoid
atypical
carcinoid
rare
Most benign
(low grade)
very rare
Small or Large
cell NE
carcinoma
common rare
Malignant
DIAGNOSIS of CARCINOIDS
No major diagnostic problems for the
typical “typical carcinoid” (surgical specimen)
TC
DIAGNOSIS of CARCINOIDS
TC
AC
1972
at
Mayo
SCLC
Difficulties in identifying
the intermediate entities
-Hypercellularity &
disorganised structure
-Nuclear pleomorphism
-Mitotic count>5-10/10HPF
-Necrosis
Arrigoni,
Woolner et
al 1972
SPECTRUM OF LUNG NE TUMORS
AC
TC
SCLC
Different survival
2-9 mitoses
or necrosis
Ki67
20 years
later…..
TC
SPECTRUM OF LUNG
NE TUMORS
AC
LCNEC
SCLC
<2 mitoses 2-9 mitoses >10 mitoses small cells
no necrosis or necrosis (necrosis)
(necrosis)
Significantly
MITOSES
different survival
p<0.0001
Significantly
different survival
p<0.0001
NO significantly
Travis et al 1991 & 1998 different survival
SPECTRUM OF PULMONARY NETs
Poorly
differentiated
Well
differentiated
typical
carcinoid
atypical
carcinoid
rare
very rare
Most benign
Small or Large
cell NE
carcinoma
common
rare
Malignant
LCNEC:
HISTORY
Travis WD, et al. Neuroendocrine
tumors of the lung with
proposed criteria for large-cell
NE carcinoma.
AJSP 1991;15:529-53
Travis WD, et al. Survival
analysis of 200 pulmonary NE
tumors with clarification of
criteria for atypical carcinoid
and its separation from typical
carcinoid.
NE differentiated
AJSP 1998;22:934-44
LCNEC morphology
-
Organoid growth
Large cells
Extensive necrosis
Atypias & nucleoli
High mitotic index
CgA
Ki67
LCNEC: diagnostic
challange. Mitotic
count & necrosis as
crucial criteria
Where
was
LCNEC
“born”
from?
See blue
circle
N
Anaplastic
LCC
NE differentiated
cell
Atypical >10
carcinoid mitoses
intermediate
cell type
SCLC
oat cell
HISTORY OF SCLC
No major diagnostic problems for the
classical oat cell type
-solid growth of small cells
-3 lymphocytes in size
-finely granular chromatin
dark nucleus
SCLC
SYN
CGA
-DNA crush
artifacts:
(Azzopardi’s phenomenon)
-extensive necrosis
-high mitotic count
TTF1
DISTINGUISHING SCLC FROM LCNEC:
does it matter?
Significant indicators
for differential dx:
organoid growth,
tumor cell size,
N/C ratio,
nuclear molding,
rosette formation,
prominent nucleoli
Sun, Pathol Int 2009
However, large degree of overlap exists:
eg: cell size
chromatin texture
Hiroshima,
Modern Pathol 2006
immunoprofile
In addition:
- Similar
behavior &
survival.
- Similar
therapy of
LCNEC
and SCLC
Asamura et al JCO 24, 70-76, 2006
DISTINGUISHING SCLC FROM LCNEC:
does it matter?
NO !!!!!!!!!!!!
MIXED SMALL AND LARGE CELL CAs:
does it matter?
Same case, but = cell size
xS
M
S
XL
L
SPECTRUM OF LUNG NE TUMORS
TC
AC
TC
AC
LCNEC
SCLC
LCNEC
SCLC
NO significantly
different survival
NET DIAGNOSIS
No major diagnostic problems for the two entities
at the extremes of the spectrum at least in
histological material
TC
SCLC
?
Peripheral, size 11 mm
necrosis
Mitoses
3 mit
2 mit
4 mit
5 mit
WHERE DOES THIS TUMOR
STAND IN THE SPECTRUM?
TC
AC
LCNEC
SCLC
Diagnostic work up:
Structure: organoid + diffuse
Cytology: small cell type (mostly) + spindle
Diagnostic criteria: high grade (by mitoses)
Tentative diagnosis:
High grade NE carcinoma
WHAT ELSE ?????
SPECTRUM OF PULMONARY NETs
typical
carcinoid
atypical
carcinoid
rare
Most benign
very rare
Small or Large
cell NE
carcinoma
common rare
Malignant
+ Combined small/large cell NE and
adeno- or squamous carcinoma
+ Conventional adenocarcinoma with NE differentiation
pure
NE tum.
0%
NE tum.
focal
non-NE
combined combined
(intermingled)
(collision)
pure
non-NE
ca.
non-NE
ca. focal
NE
100%
30%
non-NE
NE
100%
30%
0%
Combined LCNEC & squamous ca
CgA
HMW CK
Q3: What do mixed tumors look like?
SEPARATE
FRUITS
SINGLE
FRUITS
NEARBY
FRUIT
SALAD
SEPARATE COLLISION COMBINED
(COMPOSITE)
TUMORS TUMORS
What about
this
condition?
(ie cherries + very
few strawberries)
courtesy dr Volante
FRUIT
SALAD
MIXED
TUMOR
Conventional
ADC with
focal NE
differentiation
Unfortunately,
the identification of
a NE component is largely depending
on the selected method & marker
12.5% + by CgA IHC
37.5% + by CgA RTPCR
HMW cytokeratins: useful non-NE marker
Combined SCLC
& squamous ca
mixed
(collision)
CgA
HMW CK
COMBINED
LUNG
CARCINOMAS
CgA
SCLC +
Squamous ca
7 cases studied
Am J Clin Pathol 131, 376,
2009
HMW CK
Q3: What do
mixed tumors
look like?
pure
NE tum.
0%
100%
NE tum.
focal
non-NE
mixed
mixed
(intermingled)
(collision)
NE
30%
NE
non-NE
ca. focal
pure
non-NE
ca.
non-NE
50%
Combined SCLC/LCNEC
GEP MANEC
30%
100%
0%
Conventional NSCLC with focal
NE differentiation
pure
NE tum.
0%
NE tum.
focal
non-NE
combined combined
(intermingled)
(collision)
non-NE
ca. focal
NE
30%
100%
nonNE
NE
100%
pure
non-NE
ca.
30%
0%
NE DIFFERENTIATION in NSCLC
PATHOLOGIST:
“Present in up to
25% of NSCLC,
depending on the
method used to
assess NE
phenotype”
ONCOLOGIST:
“Define the clinical
significance,
if any !!”
NO
BREAST and
COLORECTAL
CANCERS
Y/N ?
YES
NSCLC
STOMACH &
PROSTATE
CANCERS
YES
Prognostic significance
NO
>5% NE
cells
Ionescu, Gown. NSCLC with NE
differentiation-an entity of no
clinical or prognostic
significance. AJSP 2007;31:26
yrs
OS
Segawa et al. IHC detection of
NE differentiation in non-smallcell lung cancer and its clinical
implications. J Cancer Res Clin
Oncol. 2009 Jan 17
NETs OF THE LUNG
Menu
- Spectrum of NE lung tumors
- CARCINOID TUMORS
- SCLC /LCNEC
- Combined NE and non-NE carcinomas
- Mechanisms driving NE
differentiation
- Predictive markers of response to
therapy
WHO DRIVES NE DIFFERENTIATION?
Role of hASH-1 ?
Family of basic helixloop-helix (bHLH)
transcription factors
(Johnson et al., Nature 1990)
Critical role in
normal development
of peripheral nerves
(Lo & Anberson, Neuron 1995)
and endodermal
endocrine cells
(Guillemot et al. Cell.1993)
Human homologue-1 of
achaete-scute gene
from Drosophila
hASH-1 in human NE tumors:




Medullary thyroid carcinoma (Ball, PNAS 1993)
Neuroblastoma (Rostomlily, Cancer Res 1997)
Gastrointestinal NE ca (Takashi, Cancer Res 2005)
Small Cell Carcinoma of the lung
(Hirotaka, Cancer Res 2005;
Borges, Nature 1997)
SCLC
NSCLC
In SCLC, ASCL1 gene modulates tumor-initiating
capacity by directly regulating stem cell marker
genes (CD133 and ALDH1A1).
Jiang et al. Cancer Res. 2009;69:845
By in situ
hybridisation
By immunohistochemistry
hASH-1
CgA
TC
SCLC
LCNEC
hASH-1 in NE differ prostate & lung ca
In combined lung
cancers, hASH1 is mostly
expressed in the NE
component, both in
chromogranin positive
and negative cells
CgA
Mod Pathol 2008
hASH1 transfected NSCLC cell
lines express hASH1 de novo
and NE markers in parallel.
H522
cells
hASH-1
hASH1
CgA
Rapa et al manuscript in preparation
SUMMARY
TC
AC
LCNEC
SCLC
Menu
- Spectrum of NE lung tumors
- CARCINOID TUMORS
- SCLC /LCNEC
- Combined NE and non-NE carcinomas
- Mechanisms driving NE differentiation
Thank you!!
Susanna Cappia
Marco Volante
Luisella Righi
Ida Rapa
Valentina Monica
Eleonora Duregon
Arianna Votta
Jessica Giorcelli
Gaia Gatti
University of Turin at San Luigi Hospital
HISTOLOGICAL TYPES
WHO 1981: A- oat cell, Bintermediate cells (round
or spindled) C- combined
with a NSCLC histotype
IASLC 1988 : A- oat cell,
B- mixed small & large
cell, C- combined small &
non-small cell lung
carcinoma