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Large Cell Neuroendocrine Versus Small Cell Carcinoma: When, Whether and
How to Make the Distinction

Jeffrey L. Myers, M.D.


A. James French Professor and Director, Division of Anatomic Pathology
The University of Michigan, Ann Arbor, MI

Objectives
At the end of this presentation attendees will understand, 1) current criteria for separating
large cell neuroendocrine from small cell carcinoma, and 2) the clinical, biological,
histologic and phenotypic overlap between the two.

Key Points
• Small cell carcinoma (SCLC) is defined on basis of cytologic criteria.
• Large cell neuroendocrine carcinoma (LCNEC) is defined by a combination
of histologic (i.e. neuroendocrine morphology, necrosis) and cytologic (i.e.
large cell size, cytoplasm, nucleoli, coarse chromatin, high mitotic rate)
criteria as well as the presence of neuroendocrine differentiation demonstrated
using immunohistochemistry.
• LCNEC is separated from atypical carcinoid tumors based primarily on
consistent presence of necrosis and higher mitotic rate.
• SCLC and LCNEC overlap in their clinical, biological, histopathologic,
immunophenotypic, and genetic characteristics making separation difficult,
and perhaps unimportant, in some patients.

INTRODUCTION1-4
A revised WHO classification of lung tumors was published in 1999 and again in 2004,
building on the popular foundation provided in the 1981 version. Like its predecessors,
the updated WHO classification scheme relies heavily on routine light microscopy for
tumor classification. Immunohistochemical stains have been established as an important
diagnostic adjunct for certain tumor types, particularly tumors with neuroendocrine
differentiation. The current scheme does not specifically categorize neuroendocrine
neoplasms together, separating carcinoid tumors (typical and atypical) from more
conventional forms of carcinomas. Small cell carcinoma (SCLC) remains a distinct
carcinoma category, while large cell neuroendocrine carcinomas (LCNEC) are a subset of
the larger group of large cell carcinomas. This review focuses on the two high grade
variants of neuroendocrine neoplasms and those features that separate SCLC from
LCNEC.

SMALL CELL CARCINOMA 5-29


Small cell lung cancer (SCLC) accounts for around 15% of all bronchogenic carcinomas,
and is considered a high grade representative of the family of neuroendocrine lung
tumors. Small cell carcinoma is strongly associated with cigarette smoking. Men are
affected more commonly than women by a ratio of about 2:1, and most patients present in
the 6th or 7th decade of life. Nearly all patients have advanced stage disease at
presentation, and for that reason surgery is reserved for rare patients in whom tumor is
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confined to the lung. In a review limited to patients who underwent some sort of surgical
procedure, survival for stage I and II (“limited”) disease was 50% at two years, but only
14% at 5 years. The survival at 5 years was not significantly different from that seen in
patients with “extensive” (stage III and IV) disease. Combination chemotherapy with or
without radiation remains the mainstay of therapy in most patients.

Small cell carcinoma is a highly malignant epithelial neoplasm composed of relatively


small cells with distinctive round to oval nuclei characterized by a diffuse ("salt and
pepper") chromatin pattern and inconspicuous nucleoli. Cell size is variable, however,
and comprises a range that merges with that seen in non-small cell carcinomas. In
addition, a minor population of larger cells with prominent but small nucleoli is common
in surgical specimens and does not, by itself, exclude the diagnosis. The cells generally
have only scant cytoplasm and are arranged in broad sheets which frequently show
necrosis. Focal areas demonstrating various growth patterns associated with
neuroendocrine neoplasia (i.e. nested/organoid, peripheral palisading, trabecular, rosettes)
occur in a substantial number of sufficiently preserved tumors. Extensive crush artifact
and basophilic staining of blood vessel walls (Azzopardi phenomenon) are characteristic
but not pathognomonic of this tumor. Cytogenetic and molecular studies fail to
demonstrate a single specific abnormality, although abnormalities in p53, bcl2/bax,
cyclin D1, RB loss and LOH at 3p occur in a high percentage of both SCLC and large
cell neuroendocrine carcinomas (see below).

Three variants of SCLC were recognized by the 1981 WHO classification: 1) oat cell
("lymphocyte-like") carcinoma which corresponds to the classically described small cell
carcinoma, 2) intermediate cell type which differs in that the cells tend to have more
cytoplasm, are less regular in contour, and are often polygonal or fusiform, 3) combined
small cell carcinoma in which definite small cell carcinoma is admixed with a clearly
identifiable squamous cell, adenocarcinoma or large cell component. The Pathology
Committee of the International Association for the Study of Lung Cancer (IASLC)
proposed separating SCLC into, 1) SCLC (pure or classical type), 2) mixed small
cell/large cell carcinoma, and 3) combined small cell/non-small cell (i.e. squamous cell or
adeno-) carcinoma. Although SCLC can be distinguished from non-small cell
carcinomas with a great deal of consistency by light microscopy, subclassification using
previously proposed categories was subject to frequent interobserver disagreement.
Furthermore, a number of studies demonstrated no significant clinical, therapeutic, or
prognostic differences between subtypes. The revised WHO classification scheme
includes only combined SCLCs as a distinct variant.

Diagnosis of SCLC can be made with confidence and a high degree of interobserver
agreement in greater than 90% of cases. In difficult cases the differential diagnosis
includes other forms of intermediate and high grade neuroendocrine (i.e. atypical
carcinoid tumors and large cell neuroendocrine carcinomas – see below) and non-
neuroendocrine (i.e. squamous cell, adeno-, and large cell) carcinomas. Immunostains
for neuroendocrine-associated proteins (e.g. chromogranin, synaptophysin) are of limited
value since a substantial subset of SCLCs lack immunohistochemical evidence of
neuroendocrine differentiation, and a minor subset of non-small cell carcinomas are
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positive. Keratin profiles can be helpful in selected cases. In the end, however, there is
no single stain and no combination of stains that consistently and categorically allows
separation of these entities, a differential diagnosis that still hinges primarily on a
combination of cytologic and histologic findings.

LARGE CELL NEUROENDOCRINE CARCINOMA30-63


Small cell carcinoma and atypical carcinoid tumors can usually be diagnosed on the basis
of light microscopy alone. Immunohistochemical staining for neuropeptides (i.e. neuron
specific enolase, chromogranin, synaptophysin, serotonin, bombesin) can be helpful in
difficult cases but are not required for diagnosis. Application of these techniques to non-
small cell carcinomas will reveal neuroendocrine differentiation in two additional groups
of tumors -- so-called large cell neuroendocrine carcinomas (LCNEC) and non-small cell
carcinomas with neuroendocrine differentiation.

Large cell neuroendocrine carcinoma refers to a subset of high grade neuroendocrine


tumors characterized by, 1) a "neuroendocrine" histological growth pattern (i.e. organoid,
palisading, trabecular, rosette-like); 2) "large" polygonal cells with lower N:C ratio than
SCLC, coarse vesicular chromatin, and conspicuous nucleoli; 3) high (> 10/2 mm2)
mitotic rate; 4) necrosis; 5) immunophenotypic and/or ultrastructural evidence of
neuroendocrine differentiation. Historically tumors of this type were referred to by a
variety of terms (e.g. atypical carcinoid tumors, intermediate variant of SCLC, large cell
neuroendocrine tumor, and large cell carcinoma with neuroendocrine differentiation),
indicating the difficulty in identifying these poorly differentiated carcinomas as a distinct
nosological entity. Nonetheless, LCNECs appear to be highly aggressive bronchogenic
carcinomas with a prognosis similar to that for SCLC.

Rates of interobserver agreement for the diagnosis of LCNEC are low, a feature that sets
it apart from SCLC. This likely reflects the considerable histologic and cytologic overlap
between LCNEC and SCLC at one end of a spectrum, and overlap with other forms of
non-small cell lung carcinoma at the other. Perhaps the most difficult criteria to apply is
the presence of a “neuroendocrine” growth pattern, something that frequently resides
within the eye of the beholder. Cytologic features by themselves do not reliably separate
LCNEC from SCLC; several studies have shown substantial overlap in cell size.
Immunohistochemical studies are of limited value in that certain proteins (e.g. CD117,
bcl-2, PAX-5, CRMP5) are expressed more frequently in high grade rather than lower
grade neuroendocrine lung tumors but do not consistently separate LCNEC from SCLC.

While difficulty in separating LCNEC from SCLC may be the bad news, the good news
is that large retrospective case series suggest that there may be limited value in making
the distinction at all. A number of studies have shown survival rates for patients who
undergo surgery for early stage LCNEC that are superimposable on those reported for
rare patients with early stage SCLC treated surgically. The survival rates for both are
lower than that observed in patients with other forms of early stage but high grade non-
neuroendocrine lung carcinoma. Comparisons of patients with late stage disease also
show a similar survival experience that is different from lower grade forms of
neuroendocrine lung tumors but similar to that seen in other types of late stage non-
neuroendocrine lung carcinoma.
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Table: Summary of Neuroendocrine Lung Neoplasms

typical atypical
SCLC LCNEC
carcinoid carcinoid
Age (yrs) 45 55 62 63
M:F 1:1 1:1 2:1 4:1
Smokers (%) 30-50% 60-70% >95% >95%
Central 75% 60% >90% 40%
Stage
I 90% 60% <10% 45%
≥ II 10% 40% ≥90% 55%
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Arthur Purdy Stout Society
Large Cell Neuroendocrine
vs
Small Cell Carcinoma
When, Whether and How to Make the Distinction

March 8, 2009

Jeffrey L. Myers, M.D.


A. James French Professor
and
Director, Anatomic Pathology
University of Michigan, Ann Arbor, MI
myerjeff@umich.edu
Large Cell Neuroendocrine vs
Small Cell Carcinoma
Objective
At the end of this talk attendees will
understand,
• current criteria for separating large cell
neuroendocrine from small cell carcinoma,
and
• the clinical, biological, histologic and
phenotypic overlap between the two
WHO Classification of Lung Tumors*
Neuroendocrine Lung Neoplasms

9small cell carcinoma


large cell carcinoma
9large cell neuroendocrine carcinoma
carcinoid tumor
9typical carcinoid tumor
9atypical carcinoid tumor
*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
Comparison*

typical atypical
carcinoid carcinoid SCLC LCNEC
Age (yrs) 45 55 62 63
M:F 1:1 1:1 2:1 4:1
Smokers (%) 30-50% 60-70% >95% >95%
Central 75% 60% >90% 40%
Stage
I 90% 60% <10% 45%
≥ II 10% 40% ≥90% 55%

*modified after Flieder. Curr Opin Pulm Med 2002; 8: 275-80.


SMALL CELL CARCINOMA
General

• cigarette smoking
• ~ 15% of incident cases
• men ≥ women (~1-2:1)
• central >> peripheral
SMALL CELL
CARCINOMA

small cell ca rates in US


• ↓ in men
• ↑ in white women
• ↓ in black women
(since 1990)

from Devesa Int J Cancer 2005; 117: 294


SMALL CELL CARCINOMA
Survival*

survival
cStage % of pts 1 year 5 years
I 7% 41% 28%
II 4% 73% 21%
III 32% 54% 11%
IV 57% 22% 1%

*from Shepherd et al. J Thorac Oncol 2007


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 CELL CARCINOMA
WHO Definition

• small cells with scant cytoplasm, ill-


defined cell borders
SMALL CELL CARCINOMA
WHO Definition

• small cells with scant cytoplasm, ill-


defined cell borders
• finely granular nuclear chromatin,
and absent or inconspicuous
nucleoli
••finely granular chromatin
finely granular chromatin
••absent/inconspicuous
absent/inconspicuous nucleoli
nucleoli
“In 29 cases, a varying percentage of cells
demonstrated nucleoli that were conspicuous but
small.” Nicholson et al. AJSP 2002
SMALL CELL CARCINOMA
WHO Definition

• 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; prominent nuclear molding
round,
round, oval
oval and
and spindle-shaped
spindle-shaped
prominent
prominent nuclear
nuclear molding
molding
high mitotic count (>10/2 mm22)
high mitotic count (>10/2 mm )
SMALL CELL CARCINOMA
WHO Definition

• 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; prominent nuclear molding
• mitotic count is high (>10/2 mm2)
SMALL CELL CARCINOMA
Histologic Variants

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
Immunohistochemical Profile
small cell squamous
ca cell ca adca
keratin + + +

dot-like,
perinuclear
staining pattern
SMALL CELL CARCINOMA
Immunohistochemical Profile
small cell squamous
ca cell ca adca
keratin + + +
CRG +/– –/ + –/ +
SYN +/– –/ + –/ +
“NE” Differentiation in Non-small Cell
Lung Carcinomas Using TMAs*

Sq cell ca Adenoca
CRG 1 (0.4%) 1 (0.4%)
SYN 10 (4.3%) 23 (11.2%)
CD56 29 (12.4%) 11 (5.1%)

*Ionescu et al. Am J Surg Pathol 2007; 31: 26


“NE” Differentiation in Non-small Cell
Lung Carcinomas

Sq cell ca Adenoca
CRG* 4% 6%
SYN* 28% 25%
CRG/SYN/
41% 35%
CD57 (leu 7)†

*Data collected from 10 peer reviewed publication, 1990 – 2005


†Schleusener et al. Cancer 1996; 77: 1284.
SMALL CELL CARCINOMA
Immunohistochemical Profile
small cell squamous
ca cell ca adca
keratin + + +
CRG +/– –/ + –/ +
SYN +/– –/ + –/ +
34βE12 – +
p63 – +
TTF-1 + –
combined small cell + squamous
cell ca TTF-1

p63 34βE12 (ker903)


SMALL CELL CARCINOMA
Immunohistochemical Profile
small cell squamous
ca cell ca adca
keratin + + +
CRG +/– –/ + –/ +
SYN +/– –/ + –/ +
34βE12 – + –
p63 – + –
TTF-1 + – +
Large Cell Carcinoma
WHO 2004

• 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 Neuroendocrine Carcinoma
Definition

• neuroendocrine morphology
• necrosis (extensive)
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
large cell neuroendocrine
carcinoma
vs.
atypical carcinoid tumor
ATYPICAL CARCINOID TUMOR
Definition*

• “neuroendocrine” growth pattern


• uniform cytology ± “atypia”
• 2-10 mits/2 mm2
• ± 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.
Large Cell Neuroendocrine Carcinoma
Comparison with Atypical Carcinoid

atypical
Asamura et al. J Clin Oncol 2006; 24: 70-6
carcinoid LCNEC
NE morphology 9 9
necrosis 9 9
atypia 9 9
mitotic rate 2-10/2 mm2 >10/2 mm2
ATYPICAL CARCINOID TUMOR
Definition*

9 (8.5%) of 106 cases


• “neuroendocrine”
had < 2 mits/2 mm2 growth pattern
Beasley et al Hum Pathol 2000; 31: 1255
• uniform cytology ± “atypia”
• 2-10 mits/2 mm2

*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of


Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.
ATYPICAL CARCINOID TUMOR
Definition*

71 (67%) of 106 cases


• had
“neuroendocrine”
necrosis growth pattern
Beasley et al Hum Pathol 2000; 31: 1255
• uniform cytology ± “atypia”
• 2-10 mits/2 mm2
• ± 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.
Large Cell Neuroendocrine Carcinoma
Comparison with Atypical Carcinoid

atypical carcinoid LCNEC

10 mits/2 mm2
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
Chromogranin
Large Cell Neuroendocrine Carcinoma
Definition

• neuroendocrine morphology
• necrosis (extensive) LCNEC vs
• 2
>10 mitosis/2 mm (10 hpf) other NSCLC

• cytologic features of NSCLC:


– large size, low N:C, nucleoli, coarse
chromatin
LCNEC vs
• immunohistochemical confirmation
SCLC
Large Cell Neuroendocrine Carcinoma
Definition

Is cell size a reliable criterion


for separating large cell
neuroendocrine carcinoma
from
small cell carcinoma?
SCLC vs LCNEC
Nuclear Size Overlap*
• n = 12 LCNEC and 16 SCLC
• measured tumor cell (TC) and
lymphocyte (L) nuclear areas
• histograms for each peak TC/L:
A=2 100
100

B=3 e.g. type A


(peak TC/L = 2)
C=4
D=5 50
50

E=6
F no peak
Marchevsky et al. Am J Clin 00
11 22 33 44 55 66 77
Pathol 2001; 116: 466.
SCLC vs LCNEC
Nuclear Size Overlap*
8
“small” 5 (31%) of 16 “SCLC” had
7
predominant population
SCLC of
6
cells 4-6 times larger
LCNECthan
5 lymphocytes
4

3 “large”
2 * *
1 *
0
TC/L = 2 TC/L = 3 TC/L = 4 TC/L = 5 TC/L = 6 no peak
(Type A) (Type B) (Type C) (Type D) (Type E) (Type F)

Marchevsky et al. Am J Clin Pathol 2001; 116: 466.


LCNEC SCLC vs LCNEC
Nuclear Size Overlap*

The frequency distribution


of tumor nuclear diameter/
SCLC lymphocyte size ratios in
SCLC (2.75 ± 0.86)
overlaps with
LCNEC (3.22 ± 0.86)

*Hiroshima et al. Mod Pathol 2006; 19: 1358


Large Cell Neuroendocrine Carcinoma
Definition

Is cell size a reliable criterion


for separating large cell
neuroendocrine carcinoma
from
small cell carcinoma?
NO!
Large Cell Neuroendocrine Carcinoma
Definition

Is immunohistochemistry
useful for separating large
cell neuroendocrine
carcinoma from
small cell carcinoma?
SCLC vs LCNEC
Role of Immunohistochemistry*
100% p .0018
SCLC p .0150
p .0422
LCNEC
80%

p .0022 p .0369
60%

40%

20%

0%
CRG SYN CD56 mASH1 NeuroD TTF p63 p16 PTEN

*Hiroshima et al. Mod Pathol 2006; 19: 1358


SCLC vs LCNEC
Role of Immunohistochemistry*
100%
100%

c-kit pos
bcl-2 pos
c-kit/bcl-2 pos
c-kit/bcl-2
50%
50%
expression in
SCLC &
LCNEC

0%
0%

typical atypical small cell ca LCNEC (14)


carcinoid (16) carcinoid (6) (7)

*LaPoint et al. Appl IHC Mol Morphol 2007; 15: 401-6


SCLC vs LCNEC
Role of Immunohistochemistry*
90%

Diffuse (> 10%)


2-3+ intensity
60%
PAX-5
expression in
30% SCLC &
LCNEC
0%

typical carcinoid atypical small cell ca LCNEC (3)


(44) carcinoid (7) (26)

*Sica et al. Am J Clin Pathol 2008; 129: 556-62


Large Cell Neuroendocrine Carcinoma
Conclusion

Neither cell size nor


immunohistochemistry are
useful for separating large cell
neuroendocrine carcinoma
from
small cell carcinoma?
NEUROENDOCRINE LUNG TUMORS
Diagnostic Reproducibility*

Unanimous Majority
(5 of 5) (4 of 5)
typical carcinoid 58% 92%
atypical carcinoid 50% 75%
SCLC 70% 90%
LCNEC 40% 50%

*Travis et al. Hum Pathol 1998; 29: 272


Does separating
LCNEC from SCLC
have value?
If so, when?
LCNEC versus SCLC?
Survival

P = .9147

Asamura, 2006

J Clin Oncol 24: 70-6


Impact of LCNEC
Histology on Survival
in Early Stage
Disease?

“Large cell neuroendocrine histology has a


significant adverse prognostic impact on pathologic
stage Ia non-small cell carcinoma.”
Iyoda 2006
Takei 2002

LCNEC versus
SCLC?
Survival in Stage
I Disease

P =.1851

Asamura 2006
Fig 5. Kaplan-Meier curves for overall survival stratified according to chemotherapeutic protocols in the
adjuvant setting and tumor stage

Rossi, G. et al. J Clin Oncol; 23:8774-8785 2005 “SCLC-based” = platinum-etoposide

LCNEC is more likely to respond to


chemotherapeutic strategies targeting
SCLC
Copyright © American Society of Clinical Oncology
SCLC vs LCNEC
Summary
of cytological “criteria” for LCNEC, only
the presence of cytoplasm is useful
no consistent difference at level of
protein expression
low rates of interobserver agreement
among experts
no difference in therapeutic response
or natural history
SCLC vs LCNEC
Summary
of cytological “criteria” for LCNEC, only
the presence of cytoplasm is useful
no consistent difference at level of
protein expression
low rates of interobserver agreement
among experts
no difference in therapeutic response
or natural history
SCLC vs LCNEC
Summary
of cytological “criteria” for LCNEC, only
the presence of cytoplasm is useful
no consistent difference at level of
protein expression
low rates of interobserver agreement
among experts
no difference in therapeutic response
or natural history
SCLC vs LCNEC
Summary
of cytological “criteria” for LCNEC, only
the presence of cytoplasm is useful
no consistent difference at level of
protein expression
low rates of interobserver agreement
among experts
no difference in therapeutic response
or natural history
Large Cell Neuroendocrine Carcinoma
Practical Approach?

any way to
make this
SCLC?
• finely dispersed chromatin?
• inconspicuous nucleoli?
• scant cytoplasm?
• is cell size the only issue?
LCNEC? • clinical context?
– central mass in smoker with
mediastinal adenopathy?
Large Cell Neuroendocrine Carcinoma
Practical Approach?

any way to
make this YES!
SCLC?

SCLC
Large Cell Neuroendocrine Carcinoma
Practical Approach?

any way to
make this
SCLC?
compelling
reason to
NO 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?

any way to
make this
SCLC?
compelling
reason to
NO acknowledge
neuroendocrine
differentiation?
LCNEC
YES!
Large Cell Neuroendocrine Carcinoma
Practical Approach?

any way to
make this
SCLC?
compelling
reason to
LCC, NO acknowledge
sq cell neuroendocrine
differentiation?
ca, adca
NO
SCLC vs LCNEC
Key Points
• SCLC is defined on the basis of cytologic criteria
• LCNEC is defined by a combination of histologic
and cytologic criteria + “proof” of NE
differentiation (immunohistochemistry)
• LCNEC is separated from atypical carcinoid
based on consistent presence of necrosis and
higher mitotic rate
• SCLC and LCNEC overlap in clinical, biological,
histopathologic, immunophenotypic and genetic
characteristics