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Neuroendocrine Lung Tumors – Myers
Jeffrey L. Myers, M.D.
A. James French Professor Director, Anatomic Pathology & MLabs University of Michigan, Ann Arbor, MI
myerjeff@umich.edu
Diagnosis and Classification of Neuroendocrine Lung Tumors
Lost In Processing
As a result of this presentation, attendees who were fully engaged will be able to,
• apply criteria for separating low grade from high grade neuroendocrine tumors, and
• articulate the clinical, biological, histologic, immunohistochemical, and molecular overlap between them.
Neuroendocrine Lung Neoplasms
Neuroendocrine Lung Neoplasms
Classification
WHO* Other
Typical carcinoid Well differentiated/
low grade
Ne
uro
en
do
crin
e
ca
rcin
om
a
Atypical carcinoid Moderately differentiated/
intermediate grade
Small cell carcinoma
Poorly differentiated/
high grade Large cell
neuroendocrine
carcinoma
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
Neuroendocrine Lung Tumors – Myers
Neuroendocrine Lung Neoplasms
Classification
WHO* Other
Typical carcinoid Well differentiated/
low grade
Ne
uro
en
do
crin
e
ca
rcin
om
a
Atypical carcinoid Moderately differentiated/
intermediate grade
Small cell carcinoma
Poorly differentiated/
high grade Large cell
neuroendocrine
carcinoma
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
TYPICAL CARCINOID TUMOR
~ 75% central ~ 25% peripheral
TYPICAL CARCINOID TUMOR Definition*
• “neuroendocrine” growth pattern
“organoid, trabecular, insular, palisading, ribbon, rosette-like”
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
Neuroendocrine Lung Tumors – Myers
“organoid, trabecular, insular, palisading, ribbon, rosette-like”
“organoid, trabecular, insular, palisading, ribbon, rosette-like”
“organoid, trabecular, insular, palisading, ribbon, rosette-like”
Neuroendocrine Lung Tumors – Myers
uniform cytology ± “atypia”
TYPICAL CARCINOID TUMOR Definition*
• “neuroendocrine” growth pattern
• uniform cytology ± “atypia”
• < 2 mits/2 mm2
• no necrosis
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
Neuroendocrine Lung Neoplasms
Classification
WHO* Other
Typical carcinoid Well differentiated/
low grade
Ne
uro
en
do
crin
e
ca
rcin
om
a
Atypical carcinoid Moderately differentiated/
intermediate grade
Small cell carcinoma
Poorly differentiated/
high grade Large cell
neuroendocrine
carcinoma
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
Neuroendocrine Lung Tumors – Myers
ATYPICAL CARCINOID TUMOR Definition*
• “neuroendocrine” growth pattern
• uniform cytology ± “atypia”
• 2-10 mits/2 mm2, and/or
• necrosis
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
TYPICAL VS. ATYPICAL CARCINOID TUMOR Ha et al. Lung Cancer 2013; 80: 146
Histology
Typical
(40)
Atypical
(23) p value
rosettes 0 6 (26%) .001
parenchymal invasion* 5 (13%) 9 (39%) .01
vascular invasion 0 3 (13%) .04
lymphatic invasion 2 (5%) 6 (26%) .04
abundant basophilic
cytoplasm 10 (25%) 0 .01
*“invasion to the adjacent lung parenchyma with an infiltrative border”
Neuroendocrine Lung Tumors – Myers
TYPICAL VS. ATYPICAL CARCINOID TUMOR Ha et al. Lung Cancer 2013; 80: 146
“moderate” “marked”
“invasion to the adjacent lung parenchyma with an
infiltrative border”
*
ATYPICAL CARCINOID TUMOR Comparison with Typical Carcinoid
typical carcinoid
atypical carcinoid
Survival 5 years 10 years
89-99% 82-93%
61-78% 35-67%
from Garcia-Yuste et al. Eur J CV Surg 2007 (n = 661 surgical patients)
• “neuroendocrine” growth pattern
• uniform cytology ± “atypia”
• 2-10 mits/2 mm2
ATYPICAL CARCINOID TUMOR Definition*
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
97 (91.5%) of 106 cases had ≥ 2 mits/2 mm2
Beasley et al Hum Pathol 2000; 31: 1255
Neuroendocrine Lung Tumors – Myers
TYPICAL VS. ATYPICAL CARCINOID TUMOR Ha et al. Lung Cancer 2013; 80: 146
Mitoses
• “neuroendocrine” growth pattern
• uniform cytology ± “atypia”
• 2-10 mits/2 mm2
• ± necrosis
ATYPICAL CARCINOID TUMOR Definition*
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
71 (67%) of 106 cases had necrosis
Beasley et al Hum Pathol 2000; 31: 1255
Neuroendocrine Lung Neoplasms
Classification
WHO* Other
Typical carcinoid Well differentiated/
low grade
Ne
uro
en
do
crin
e
ca
rcin
om
a
Atypical carcinoid Moderately differentiated/
intermediate grade
Small cell carcinoma
Poorly differentiated/
high grade Large cell
neuroendocrine
carcinoma
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
Neuroendocrine Lung Tumors – Myers
SMALL CELL CARCINOMA General
• cigarette smoking
• ~ 15% of incident cases
• men ≥ women (~1-2:1)
• central >> peripheral
SMALL CELL CARCINOMA General
clinical stage (n=7,960†)
I 7%
II 4%
III 32%
IV 57%
limited 45%
extensive 55%
clinical stage (n=4,532†)
†from Shepherd et al. J Thorac Oncol 2007
†from Shepherd et al. J Thorac Oncol 2007
Survival (n = 7,960†)
cStage % of pts 1 year 5 years
I 7% 41% 28%
II 4% 73% 21%
III 32% 54% 11%
IV 57% 22% 1%
clinical stage (n=4,532†)
limited 45%
extensive 55%
SMALL CELL CARCINOMA General
Neuroendocrine Lung Tumors – Myers
SMALL CELL CARCINOMA WHO Definition
malignant epithelial tumor consisting of,
• small cells with scant cytoplasm, ill-defined cell borders
“usually less than the size of three small resting lymphocytes”
WHO “size rule” ≤ 3 x lymphocyte diameter
• small cells with scant cytoplasm, ill-defined cell borders
SMALL CELL CARCINOMA WHO Definition
Neuroendocrine Lung Tumors – Myers
• small cells with scant cytoplasm, ill-defined cell borders
• finely granular nuclear chromatin, and absent or inconspicuous nucleoli
SMALL CELL CARCINOMA WHO Definition
• finely granular chromatin • absent/inconspicuous nucleoli
“In 29 cases, a varying percentage of cells demonstrated nucleoli that were conspicuous but small.” Nicholson et al. AJSP 2002
Neuroendocrine Lung Tumors – Myers
• small cells with scant cytoplasm, ill-defined cell borders
• finely granular nuclear chromatin, and absent or inconspicuous nucleoli
• cells are round, oval and spindle-shaped; nuclear molding is prominent
SMALL CELL CARCINOMA WHO Definition
round, oval and spindle-shaped
nuclear molding is prominent
Neuroendocrine Lung Tumors – Myers
nuclear spooning is prominent
“spooning”
high mitotic count (>10/2 mm2)
Neuroendocrine Lung Tumors – Myers
• small cells with scant cytoplasm, ill-defined cell borders
• finely granular nuclear chromatin, and absent or inconspicuous nucleoli
• cells are round, oval and spindle-shaped; nuclear molding is prominent
• mitotic count is high (>10/2 mm2)
SMALL CELL CARCINOMA WHO Definition
CLASSIFICATION OF LUNG TUMORS Rates of Diagnostic Agreement†
0% 25% 50% 75% 100%
SCLC
LCC
Adca
SqCC
Reg
ion
al P
ath
olo
gis
ts
Central Pathologist
SCLC
SqCC
Adca
LCC
Mixed
Other
N = 668 (tissue ± cytology specimens) SCLC highest rates of agreement (92%, Κ = 0.82)
†Stang et al. Lung Cancer 2006; 52: 29-36
WHO IASLC WHO (1981) (1988) (1999-2004)
oat cell small cell small cell
intermediate cell
mixed small/large cell
combined combined combined
small cell small cell small cell
SMALL CELL CARCINOMA Histologic Variants
Neuroendocrine Lung Tumors – Myers
& adenocarcinoma small cell
Neuroendocrine Lung Neoplasms
Classification
WHO* Other
Typical carcinoid Well differentiated/
low grade
Ne
uro
en
do
crin
e
ca
rcin
om
a
Atypical carcinoid Moderately differentiated/
intermediate grade
Small cell carcinoma
Poorly differentiated/
high grade Large cell
neuroendocrine
carcinoma
*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
LARGE CELL CARCINOMA WHO 2004
• poorly differentiated NSCLC that lacks cytologic and architectural features of SCLC and glandular or squamous differentiation
Neuroendocrine Lung Tumors – Myers
• poorly differentiated NSCLC that lacks cytologic and architectural features of SCLC and glandular or squamous differentiation
• 5 variants: – large cell neuroendocrine – basaloid carcinoma – lymphoepithelioma-like carcinoma – clear cell carcinoma – large cell ca with rhabdoid phenotype
LARGE CELL CARCINOMA WHO 2004
LARGE CELL NEUROENDOCRINE CARCINOMA
Definition
• neuroendocrine morphology
Neuroendocrine Lung Tumors – Myers
• neuroendocrine morphology
• necrosis (extensive)
• >10 mitosis/2 mm2 (10 hpf)
• cytologic features of NSCLC: – large size, low N:C, nucleoli, coarse
chromatin
LARGE CELL NEUROENDOCRINE CARCINOMA
Definition
Neuroendocrine Lung Tumors – Myers
• neuroendocrine morphology
• necrosis (extensive)
• >10 mitosis/2 mm2 (10 hpf)
• cytologic features of NSCLC: – large size, low N:C, nucleoli, coarse
chromatin
• immunohistochemical confirmation
LARGE CELL NEUROENDOCRINE CARCINOMA
Definition
chromogranin
LARGE CELL NEUROENDOCRINE CARCINOMA
Comparison with Atypical Carcinoid
atypical carcinoid LCNEC
NE morphology
necrosis ±
atypia mitotic rate 2-10/2 mm2 >10/2 mm2
Asamura et al. J Clin Oncol 2006; 24: 70-6
Neuroendocrine Lung Tumors – Myers
LCNEC atypical carcinoid
10 mits/2 mm2
LARGE CELL NEUROENDOCRINE CARCINOMA
Comparison with Atypical Carcinoid
LCNEC small cell ca
≤ 3 x lymphocytes, nucleoli, cytoplasm
LARGE CELL NEUROENDOCRINE CARCINOMA
Comparison with Small Cell Carcinoma
Hypothesis: LCNEC & SCLC are different
They look (and stain) differently.
They behave differently.
They are genetically distinct.
Neuroendocrine Lung Tumors – Myers
Large Cell Neuroendocrine Carcinoma Definition
• neuroendocrine morphology
• necrosis (extensive)
• >10 mitosis/2 mm2 (10 hpf)
• cytologic features of NSCLC: – large size, low N:C, nucleoli, coarse
chromatin
• immunohistochemical confirmation LCNEC vs
SCLC
Is cell size a reliable criterion for separating large cell
neuroendocrine carcinoma from
small cell carcinoma?
Large Cell Neuroendocrine Carcinoma Definition
† Marchevsky et al. Am J Clin
Pathol 2001; 116: 466.
0
50
100
1 2 3 4 5 6 7
e.g. type A (peak TC/L = 2)
• n = 12 LCNEC and 16 SCLC
• measured tumor cell (TC) and lymphocyte (L) nuclear areas
• histograms for each peak TC/L: A = 2 B = 3 C = 4 D = 5 E = 6 F no peak
SCLC vs LCNEC Nuclear Size Overlap†
Neuroendocrine Lung Tumors – Myers
†Marchevsky et al. Am J Clin Pathol 2001; 116: 466.
0
1
2
3
4
5
6
7
8
TC/L = 2
(Type A)
TC/L = 3
(Type B)
TC/L = 4
(Type C)
TC/L = 5
(Type D)
TC/L = 6
(Type E)
no peak
(Type F)
SCLC
LCNEC
5 (31%) of 16 “SCLC” had predominant population of cells 4-6 times larger than
lymphocytes
* * *
“small”
“large”
SCLC vs LCNEC Nuclear Size Overlap†
0%
50%
100%
typical
carcinoid (16)
atypical
carcinoid (6)
small cell ca
(7)
LCNEC (14)
c-kit pos
bcl-2 pos
c-kit/bcl-2 pos
†LaPoint et al. Appl IHC Mol Morphol 2007; 15: 401-6
c-kit/bcl-2 expression in
SCLC & LCNEC
SCLC vs LCNEC Role of Immunohistochemistry†
0%
30%
60%
90%
typical carcinoid
(44)
atypical
carcinoid (7)
small cell ca
(26)
LCNEC (3)
Diffuse (> 10%)
2-3+ intensity
PAX-5 expression in
SCLC & LCNEC
†Sica et al. Am J Clin Pathol 2008; 129: 556-62
SCLC vs LCNEC Role of Immunohistochemistry†
Neuroendocrine Lung Tumors – Myers
CRMP5 expression in
SCLC & LCNEC
†Meyronet et al. Am J Surg Pathol 2008; 32: 1699-708
0%
20%
40%
60%
80%
100%
typicalcarcinoid
(31)
atypicalcarcinoid
(15)
small cell ca(54)
LCNEC (4)
POSITIVE EQUIVOCAL
NEGATIVE
SCLC vs LCNEC Role of Immunohistochemistry†
†Hiroshima et al. Mod Pathol 2006; 19: 1358
0%
20%
40%
60%
80%
100%
CRG SYN CD56 mASH1 NeuroD TTF p63 p16 PTEN
SCLC
LCNEC
p .0018
p .0422
p .0022 p .0369
p .0150
SCLC vs LCNEC Role of Immunohistochemistry†
†Ha et al. Histopathology 2012; 60: 731-9
0%
20%
40%
60%
80%
100%
TC (19) AC (6) LCNEC (17) SCLC (18)
FoxM1
p27kip1(high)
p21waft1/cip1(+)
SCLC vs LCNEC Role of Immunohistochemistry†
Neuroendocrine Lung Tumors – Myers
Large Cell Neuroendocrine Carcinoma Conclusion
Neither cell size nor immunohistochemistry reliably
separate large cell neuroendocrine carcinoma
from small cell carcinoma.
Large Cell Neuroendocrine Carcinoma Definition
• neuroendocrine morphology
• necrosis (extensive)
• >10 mitosis/2 mm2 (10 hpf)
• cytologic features of NSCLC: – large size, low N:C, nucleoli, coarse
chromatin
• immunohistochemical confirmation
LCNEC vs other NSCLC
organoid?
squamous cell carcinoma
Neuroendocrine Lung Tumors – Myers
trabecular?
CK5/6 POS
p63 POS
TTF1 NEG
squamous cell carcinoma, basaloid variant
ribbons?
Neuroendocrine Lung Tumors – Myers
small cell?
CD56
SYN
LCNEC?
†den Bakker et al. Histopathol 2010; 56: 356
0
40
80
120
SCLC LCNEC Comb Carcinoid OtherNSCLC
Unsuitable
n = 170 large bxs, resections, mets 9 assessors (“special interest in lung cancer”)
20 (12%) = unanimous 117 (69%) = consensus (≥ 5)
Neuroendocrine Lung Tumors Diagnostic Reproducibility†
Neuroendocrine Lung Tumors – Myers
SCLC & LCNEC accounted for the largest number of outliers compared to the
consensus diagnosis
†den Bakker et al. Histopathol 2010; 56: 356
Neuroendocrine Lung Tumors Diagnostic Reproducibility†
They look (and stain) differently.
They behave differently.
Hypothesis: LCNEC & SCLC are different
LCNEC versus SCLC? Survival
J Clin Oncol 2006; 24: 70-6
Asamura, 2006
P = .9147
Neuroendocrine Lung Tumors – Myers
LCNEC versus SCLC?
Survival in Stage I Disease
Takei 2002
P =.1851
Asamura 2006
†Varlotto et al. J Thorac Oncol 2012; 6: 1050
“multivariate Cox analysis
demonstrated no significant differences between SCLC and
LCNELC . . . or between OLC
and LCNELC.”
LCNEC versus SCLC?
Survival in Stage I Disease†
Lung cancer-specific survival by histology for patients undergoing lobectomy or bilobectomy without
radiation for pT1N0 tumors
SEER database 2000 – 2007
†Rossi, G. et al. J Clin Oncol 2005; 23: 8774-8785
†Fig 5. Kaplan-Meier curves for overall survival stratified according to chemotherapeutic
protocols in the adjuvant setting and tumor stage
LCNEC is more likely to respond to chemotherapeutic strategies targeting
SCLC
“SCLC-based” = platinum-etoposide
Neuroendocrine Lung Tumors – Myers
They look (and stain) differently.
They behave differently.
They are genetically distinct.
Hypothesis: LCNEC & SCLC are different
neuroendocrine
tumors (38)
typical (12) & atypical (1)
carcinoids
“pure” small cell ca (15)
small cell & adca (2)
“pure” LCNEC (6)
LCNEC & adca (2)
large cell carcinoma (13)
well differentiated adenocarcinoma (12)
normal (30)
2,803 differentially expressed genes
unsupervised hierarchical clustering
Lancet 2004; 363 (9411): 775
Most SCLC & LCNEC were co-
mingled in 2 related but
distinct groups
HGNT1 4 “pure” SCLC
1 SCLC & adca
1 “pure” LCNEC
HGNT2 8 “pure” SCLC
4 “pure” LCNEC
HGNT3
2 “pure” SCLC
1 “pure” LCNEC
1 LCC
Lancet 2004; 363 (9411): 775
Neuroendocrine Lung Tumors – Myers
Lancet 2004; 363 (9411): 775
genetic profiles, but not histologic classification, separated patients with high grade NE tumors
into prognostically distinct groups
They look (and stain) differently.
They behave differently.
They are genetically distinct.
Hypothesis: LCNEC & SCLC are different
Large Cell Neuroendocrine Carcinoma Comparison with Small Cell Carcinoma
LCNEC small cell ca
≤ 3 x lymphocytes, nucleoli, cytoplasm
Neuroendocrine Lung Tumors – Myers
Large Cell Neuroendocrine Carcinoma Practical Approach?
LCNEC?
any way to make this
SCLC? • finely dispersed chromatin? • inconspicuous nucleoli? • scant cytoplasm? • is cell size the only issue? • clinical context?
– central mass in smoker with mediastinal adenopathy?
any way to make this
SCLC? YES!
SCLC
Large Cell Neuroendocrine Carcinoma Practical Approach?
any way to make this
SCLC?
NO
compelling reason to
acknowledge neuroendocrine differentiation?
• LCNEC already diagnosed • IHC stains and it really, really looks
neuroendocrine but ≠ atypical carcinoid • been called SCLC but it isn’t
Large Cell Neuroendocrine Carcinoma Practical Approach?
Neuroendocrine Lung Tumors – Myers
LCNEC
any way to make this
SCLC?
NO
compelling reason to
acknowledge neuroendocrine differentiation?
YES!
Large Cell Neuroendocrine Carcinoma Practical Approach?
LCC, sq cell
ca, adca
any way to make this
SCLC?
NO
compelling reason to
acknowledge neuroendocrine differentiation?
NO
Large Cell Neuroendocrine Carcinoma Practical Approach?
As a result of this presentation, attendees who were fully engaged will be able to,
• apply criteria for separating low grade from high grade neuroendocrine tumors, and
• articulate the clinical, biological, histologic, immunohistochemical, and molecular overlap between them.
Neuroendocrine Lung Neoplasms