Classification of Lung Cancer
William D. Travis, MD
T he pathologic diagnosis of lung cancer is undergoing a
remarkable transformation, largely driven by new thera-
pies that are dependent on histologic type and/or molecular
changes.1 Lung cancer is diagnosed pathologically by a his-
tologic or cytologic approach. Because 70% of lung cancer
patients present in advanced stages, the diagnosis is estab-
lished by small biopsies or cytologies. However, previous
classifications by the World Health Organization (WHO)
have not specifically addressed this problem. Because of the
rapid advances in lung adenocarcinoma occurring at every
level, there is a new lung adenocarcinoma classification spon-
sored by the International Association for the Study of Lung
Cancer, American Thoracic Society, and the European Respi-
ratory Society (IASLC/ATS/ERS) and developed by an inter-
national multidisciplinary panel, including pathologists, mo-
lecular biologists, oncologists, radiologists, and thoracic
surgeons.1 This new classification will result in significant
changes in the 2004 WHO Classification (Table 1). For the
first time in the history of lung cancer, new terminology are
proposed for classification of lung cancer in small biopsies
and cytology (Table 2).
This review will focus primarily on the histologic features
of lung cancer by addressing the new classification both in
resected specimens as well as small biopsies and cytology. In
the past, because of different therapeutic approaches, the
major differential diagnostic issue in lung cancer for pathol-
ogists has been the distinction of small cell lung carcinoma
(SCLC) versus nonsmall cell lung carcinoma (NSCLC). How-
ever, in the past 6 years, 3 new therapeutic advances have
defined the importance of classifying NSCLC further to dis-
tinguish squamous cell carcinoma from adenocarcinoma or
other histologic types. A major advance was the discovery
that EGFR mutations are almost always found in adenocarci-
nomas and that in advanced lung adenocarcinoma patients
they predict a better outcome and response to tyrosine kinase
inhibitors (TKIs) as first-line therapy, whereas those without
EGFR mutations have a better outcome with chemot-
herapy.2–5 In addition because of the risk of life-threatening
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New
York, NY.
Address reprint requests to William D. Travis, MD, Memorial Sloan-Ketter-
ing Cancer Center, 1275 York Ave, New York, NY 10021. E-mail: travisw@
mskcc.org
178 0037-198X/11/$-see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1053/j.ro.2011.02.003
hemorrhage, bevacizumab is contraindicated in patients with
advanced squamous cell carcinoma.6 Finally, patients with
adenocarcinoma or NSCLC not otherwise specified (NSCLC-
NOS; reported as large cell carcinoma in some of these stud-
ies) respond to pemetrexed whereas those with squamous
cell carcinoma do not.7–9 Another recent discovery is the
finding that computed tomography (CT) screening in a high-
risk population reduces lung cancer mortality by more than
20%.10 The modifications in the new IASLC/ATS/ERS lung
adenocarcinoma classification emphasize radiologic-patho-
logic correlations that may impact management of lung nod-
ules discovered by CT screening, particularly those that are
ground glass nodules (GGNs) or part solid nodules.1
This review will begin with the traditional histologic clas-
sification based primarily on resection specimens followed
by a few comments about the new criteria and terminology
for diagnosis in small biopsies or cytology. In most lung
cancers, the diagnosis can be established based on light mi-
croscopy alone. However, given the recent realization of the
clinical importance of distinguishing histologic types, more
effort is being made to incorporate special stains to classify
poorly differentiated tumors, particularly in small biopsies or
cytology. The international standard for histologic classifica-
tion of lung tumors is that proposed by the 2004 WHO with
an update by the IASLC/ATS/ERS Lung adenocarcinoma
classification (Table 1).1,11 There are 4 major histologic types
of lung cancer, including squamous cell carcinoma, adeno-
carcinoma, small cell carcinoma, and large cell carcinoma.
These major types can be subclassified into more specific
subtypes (Table 1).11 More detailed reviews of the pathology,
cytology, and molecular biology of lung cancer can be found
elsewhere.11–13
Preinvasive Lesions
Preinvasive lesions have historically consisted of squamous
carcinoma dysplasia and carcinoma in situ, atypical adeno-
matous hyperplasia (AAH), and diffuse idiopathic neuroen-
docrine cell hyperplasia (DIPNECH). However, in the new
IASLC/ATS/ERS lung adenocarcinoma classification, adeno-
carcinoma in situ (AIS) has been added as a new preinvasive
lesion for adenocarcinoma because these patients should
have a 100% 5-year disease-free survival.1 The pathology of
preinvasive lesions for lung cancer has attracted increasing
Classification of lung cancer 179

Table 1 Histologic Classification of Lung Cancer in Resected interest in recent years a result of the growing importance of
Specimens* early detection of lung cancer with the screening of high-risk
Preinvasive lesions patients by fluorescence bronchoscopy14,15 and by spiral or
Squamous dysplasia/carcinoma in situ helical CT.10,16
Atypical adenomatous hyperplasia This discussion will be limited to AAH, AIS, and
Adenocarcinoma in situ (nonmucinous, mucinous or DIPNECH, which are lesions with characteristic radiologic
mixed nonmucinous/mucinous)
findings, so there will be no comments regarding squamous
Diffuse idiopathic pulmonary neuroendocrine cell
hyperplasia dysplasia and carcinoma in situ, except that they represent a
Squamous cell carcinoma continuous spectrum of bronchial preneoplasia that repre-
Variants sent a preinvasive lesion for squamous cell carcinoma.17
Papillary
Clear cell
Small cell Atypical Adenomatous Hyperplasia
Basaloid Atypical adenomatous hyperplasia is a small, millimeter-
Small cell carcinoma sized atypical pneumocyte proliferation that resembles, but
Combined small cell carcinoma falls short of criteria for nonmucinous AIS. AAH is most
Adenocarcinoma
commonly encountered as an incidental histologic finding in
Minimally invasive adenocarcinoma (<3 cm lepidic
predominant tumor with <5 mm invasion)
5%-20% of lung cancer resection specimens.1,11,18 –21 AAH
Nonmucinous, mucinous, mixed mucinous/non- are usually than 5 mm in diameter and they are often multi-
mucinous ple.18,19 AAH appear histologically as a focal proliferation of
Invasive Adenocarcinoma atypical pneumocytes usually separated by small gaps prolif-
Lepidic predominant (formerly nonmucinous BAC erating along alveolar walls. By CT, AAH are small GGNs
pattern, with >5 mm invasion) usually measuring 5 mm or less.1
Acinar predominant
Papillary predominant
Micropapillary predominant Adenocarcinoma in Situ
Solid predominant AIS is introduced as a preinvasive lesion in the new IASLC/
Variants of invasive adenocarcinoma
ATS/ERS adenocarcinoma classification for tumors measur-
Invasive mucinous adenocarcinoma (formerly
mucinous BAC) ing 3 cm or less that have pure lepidic growth without inva-
Colloid sion.1 Most of these cases are nonmucinous, with a
Fetal (low and high grade) proliferation of type II pneumocytes or Clara cells, but rarely
Enteric they may be mucinous with tall columnar goblet cells having
Large cell carcinoma abundant apical mucin. Patients with these lesions if com-
Variants pletely resected have been reported to have 100% 5-year
Large cell neuroendocrine carcinoma
disease free survival.22–29 By CT, these lesions typically con-
Combined large cell neuroendocrine carcinoma
Basaloid carcinoma sist of a GGN if nonmucinous and a solid nodule if mucinous
Lymphoepithelioma-like carcinoma AIS.1
Clear cell carcinoma
Large cell carcinoma with rhabdoid phenotype
Adenosquamous carcinoma
Diffuse Idiopathic Pulmonary
Sarcomatoid carcinomas Neuroendocrine Cell Hyperplasia
Pleomorphic carcinoma DIPNECH is a rare condition consisting of extensive neu-
Spindle cell carcinoma roendocrine (NE) cell proliferation and tumorlets primarily
Giant cell carcinoma
involving small airways.30,31 Approximately one-half of pa-
Carcinosarcoma
Pulmonary blastoma tients present with interstitial lung disease manifest by airway
Other obstruction as the result of bronchiolar fibrosis.30,31 The re-
Carcinoid tumor maining patients present with multiple pulmonary nodules,
Typical carcinoid often discovered in follow-up for an extrathoracic malig-
Atypical carcinoid nancy. Because carcinoid tumors occur in DIPNECH patients
Carcinomas of salivary gland type and they are often multiple, it is thought to represent a pre-
Mucoepidermoid carcinoma
invasive lesion for carcinoid tumors.11,31 CT shows centri-
Adenoid cystic carcinoma
Epimyoepithelial carcinoma lobular nodules and pulmonary nodules corresponding to
tumorlets and carcinoid tumors, respectively. In patients
BAC, bronchioloalveolar carcinoma.
*Modified from the 2004 World Health Organization Classification11 who present with clinical manifestations of interstitial lung
and the 2011 International Association for the Study of Lung disease the CT can be normal or it can show mosaic perfusion
Cancer/American Thoracic Society/European Respiratory Soci- from air trapping, bronchial wall thickening and bronchiec-
ety Classification of Lung Adenocarcinoma.1 tasis.31,32
180 W.D. Travis

Table 2 Proposed IASLC/ATS/ERS Classification for Small Biopsies/Cytology

2004 WHO Classification Small Biopsy/Cytology: IASLC/ATS/ERS
Adenocarcinoma Morphologic adenocarcinoma patterns clearly present:
Mixed subtype Adenocarcinoma, describe identifiable patterns present (including
Acinar micropapillary pattern not included in 2004 WHO classification)
Papillary Comment: If pure lepidic growth—mention an invasive component cannot
Solid be excluded in this small specimen
Bronchioloalveolar carcinoma Adenocarcinoma with lepidic pattern (if pure, add note: an invasive
(nonmucinous) component cannot be excluded)
Bronchioloalveolar carcinoma Mucinous adenocarcinoma (describe patterns present)
(mucinous)
Fetal Adenocarcinoma with fetal pattern
Mucinous (colloid) Adenocarcinoma with colloid pattern
Signet ring Adenocarcinoma with (describe patterns present) and signet ring features
Clear cell Adenocarcinoma with (describe patterns present) and clear cell features
No 2004 WHO counterpart - most will be Morphologic adenocarcinoma patterns not present (supported by special
solid adenocarcinomas stains):
Non-small cell carcinoma, favor adenocarcinoma
Squamous cell carcinoma Morphologic squamous cell patterns clearly present:
Papillary Squamous cell carcinoma
Clear cell
Small cell
Basaloid
No 2004 WHO counterpart Morphologic squamous cell patterns not present (supported by stains):
Non-small cell carcinoma, favor squamous cell carcinoma
Small cell carcinoma Small cell carcinoma
Large cell carcinoma Non-small cell carcinoma, not otherwise specified (NOS)
Large cell neuroendocrine carcinoma Non-small cell carcinoma with neuroendocrine (NE) morphology (positive
(LCNEC) NE markers), possible LCNEC
Large cell carcinoma with NE Non-small cell carcinoma with NE morphology (negative NE markers) —
morphology (LCNEM) see comment
Comment: This is a non-small cell carcinoma where LCNEC is
suspected, but stains failed to demonstrate NE differentiation.
Adenosquamous carcinoma Morphologic squamous cell and adenocarcinoma patterns present:
Non-small cell carcinoma, with squamous cell and adenocarcinoma
patterns
Comment: this could represent adenosquamous carcinoma.
No counterpart in 2004 WHO Morphologic squamous cell or adenocarcinoma patterns not present but
classification immunostains favor separate glandular and adenocarcinoma
components
Non-small cell carcinoma, NOS, (specify the results of the
immunohistochemical stains and the interpretation)
Comment: this could represent adenosquamous carcinoma.
Sarcomatoid carcinoma Poorly differentiated NSCLC with spindle and/or giant cell carcinoma
(mention if adenocarcinoma or squamous carcinoma are present)
IASLC/ATS/ERS, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society; LCNEC,
large cell neuroendocrine carcinoma; LCNECM, large cell carcinoma with NE morphology; NE, neuroendocrine; NOS, not otherwise
specific; NSCLC, nonsmall cell lung cancer; WHO, World Health Organization.

Invasive Lung Cancers
Squamous Cell Carcinoma
Squamous cell carcinoma accounts for approximately 20% of lung
cancers in the United States.33 Two-thirds of squamous cell carci-
nomas present as central lung tumors while many among the re-
maining third are peripheral.12,34–36 Squamous cell carcinoma
shows morphologic features of intercellular bridging, squamous
pearl formation and individual cell keratinization (Fig. 1).11 Several
subtypes of squamous cell carcinoma are recognized, including
papillary, clear cell, small cell,37 and basaloid subtypes.11
Adenocarcinoma
Adenocarcinomas account for 38% of all lung cancers in
the United States.33,38 In the new lung adenocarcinoma
classification, there are a significant number of major
changes (Table 1).1 First, the term bronchioloalveolar car-
Classification of lung cancer
Figure 1 Squamous cell carcinoma: The tumor grows in nests with a
desmoplastic stroma. The tumor cells demonstrate keratinization
and squamous pearls. Hematoxylin and eosin, "100.
cinoma (BAC) is no longer used because tumors forme-
rly classified under this term fall into 5 different places in
this classification. Second, new concepts of AIS (as men-
tioned previously) and minimally invasive adenocarci-
noma (MIA) have been introduced. Third, comprehensive
histologic subtyping is recommended for evaluation of
invasive lung adenocarcinomas with classification accord-
ing to the predominant subtype. Fourth, micropapillary
adenocarcinoma is introduced as a new subtype with a
poor prognosis. Fifth, for tumors previously classified as
“mixed subtype” with a predominant component formerly
called nonmucinous BAC, the term lepidic predominant
adenocarcinoma is recommended and the term “mixed
subtype” is discontinued. Sixth, tumors formerly classified
as mucinous BAC are now classified as invasive mucinous
adenocarcinoma (formerly mucinous BAC). Finally, for
adenocarcinomas diagnosed in small biopsies, specific ter-
Figure 2 Adenocarcinoma, lepidic pattern. The alveolar walls are
slightly thickened and line the alveolar walls in a lepidic fashion.
The tumor cells have a cuboidal to low columnar morphology.
Hematoxylin and eosin, "400.
181
Figure 3 Adenocarcinoma, micropapillary pattern. These tumor
cells are growing in small papillary clusters lacking a fibrovascular
core. Hematoxylin and eosin, "400.
minology and diagnostic criteria are proposed along with
recommendations for strategic management of tissue and
EGFR mutation testing in patients with advanced adeno-
carcinoma.1
Adenocarcinoma Classification
in Resected Specimens
Minimally Invasive Adenocarcinoma
MIA was introduced to define patients with a near 100%
5-year disease-free survival.1,29 It is defined as a lepidic pre-
dominant tumor measuring 3 cm or less that has 5 mm or less
of an invasive component.1 Most of these are nonmucinous,
but very rarely mucinous cases may occur. CT of nonmuci-
nous MIA typically shows a GGN with a solid component
measuring 5 mm or less. Mucinous MIA present as a solid
nodule on CT.1
Invasive Adenocarcinoma
Overtly invasive adenocarcinomas are classified according to
the predominant subtype after the use of comprehensive his-
tologic subtyping to estimate the percentages of the various
components in a semiquantitative fashion in 5%-10% incre-
ments. The term lepidic predominant adenocarcinoma con-
sists of mixed subtype tumors containing a predominant le-
pidic growth pattern of type II pneumocytes and/or Clara
cells (formerly known as nonmucinous BAC) that have an
invasive component !5 mm (Fig. 2). A micropapillary pre-
dominant subtype is added because of recognition as a poor
prognostic category (Fig. 3).1,39 Signet ring and clear cell
carcinoma subtypes are now recorded as cytologic features
whenever present with a comment about the percentage
identified. Although these are seen mostly in the solid sub-
type, they can also be seen in acinar or papillary patterns as
well.
By CT there is a good correlation between amount of the
ground glass component and lepidic growth on biopsy versus
182
Figure 4 Invasive mucinous adenocarcinoma (formerly mucinous
BAC). The tumor consists of columnar cells with abundant apical
mucinous cytoplasm and small nuclei mostly in a basal orientation.
While some are growing along alveolar walls in a lepidic fashion,
some acinar areas of invasion are present (center). Hematoxylin and
eosin, "100.
the solid component on CT and the invasive components by
biopsy.39 However, few studies have addressed this issue ac-
cording to the new classification.
Adenocarcinoma Variants
The variants of lung adenocarcinoma consist of invasive mu-
cinous adenocarcinoma (formerly mucinous BAC), colloid
adenocarcinoma, fetal adenocarcinoma, and enteric adeno-
carcinoma.1 Invasive mucinous adenocarcinomas (formerly
mucinous BAC) are separated from the nonmucinous inva-
sive adenocarcinomas because of the frequent association
with KRAS mutation, lack of thyroid transcription factor-1
(TTF-1), and frequent multicentric lung lesions. Histologi-
cally, these tumors show varying amounts of lepidic, acinar,
papillary, or micropapillary growth consisting of columnar
cells with abundant apical mucin and small basally oriented
nuclei (Fig. 4).1 CT findings frequently show localized or
multifocal consolidation with air bronchograms forming
nodules and lobar consolidation.
Prognosis of Adenocarcinoma
Subtypes in Resected Specimens
Few studies have evaluated prognosis of the adenocarcinoma
subtypes according to the new classification. Multiple studies
have demonstrated 100% 5-year disease free survival for
AIS.22–29 Although the specific criteria for MIA proposed in
the new classification were not used in previous studies, there
is data from multiple studies suggesting that these tumors
will also have a 100% or near 100% 5-year disease free sur-
vival.28,29,40,41
Yoshizawa et al39 recently reported a study of 514 stage I
adenocarcinomas and demonstrated 3 groups of tumors ac-
cording to grades of clinical behavior: low grade AIS and MIA
with 100% 5-year disease-free survival, intermediate-grade
W.D. Travis
nonmucinous lepidic predominant, papillary predominant,
and acinar predominant with 90%, 83%, and 84% 5-year
disease-free survival, respectively, and high grade: invasive
mucinous adenocarcinoma, colloid predominant, solid pre-
dominant and micropapillary predominant with 75%, 71%,
70%, and 67% 5-year disease-free survival, respectively.
Potential Impact of
Classification on TNM Staging
A potential major impact of the proposed classification stems
from the recognition that the lepidic or “in situ” component
of lung adenocarcinomas represent noninvasive pattern. This
raises the consideration that the size T factor may be best
determined by the size of the invasive component of lung
adenocarcinomas in early stage lung adenocarcinomas rather
than the total tumor size similar to the approach in breast
cancer. Invasive size has been shown to be an independent
prognostic marker for early stage lung adenocarcinoma in 2
studies.39,42 This needs to be studied by CT to determine
whether prognosis is best predicted according to the size of
the solid component rather than total tumor size, including
the ground glass component.1
Adenocarcinoma Classification
in Small Biopsies and Cytology
For the first time in lung cancer classification, formal criteria
for diagnosis of lung cancer in small biopsies and cytology
were proposed by the new IASLC/ATS/ERS lung adenocarci-
noma classification (Table 2).1 Because 70% of lung cancers
present in advanced stages and are unresectable, they are
diagnosed in these small specimens. These new criteria were
driven by the need to separate adenocarcinoma from squa-
mous cell carcinoma because clinical trials have demon-
strated that patients with adenocarcinoma or NSCLC not
otherwise specified (NOS) rather than squamous cell carci-
noma have a been shown to respond better to TKIs if they
have an EGFR mutation or to pemetrexed. In addition pa-
tients with squamous cell carcinoma have been shown to
have greater risk of life-threatening hemorrhage compared
with those with adenocarcinoma.
For tumors that show clear morphologic features of ade-
nocarcinoma or squamous cell carcinoma, these standard
terms are used. However, if the tumor only shows a carci-
noma with no clear squamous or glandular features (NSCLC-
NOS), a minimal immunohistochemical workup is recom-
mended using a single adenocarcinoma marker and
squamous marker. At the moment the best markers for ade-
nocarcinoma and squamous cell carcinoma are TTF-1 and
p63, respectively.1
One of the key aspects that potentially impacts radiologists
on this topic is the need to obtain sufficient tissue not only for
diagnosis, but also for molecular studies. This requires a stra-
tegic and multidisciplinary approach so the method of biopsy
results in either a core biopsy or a cell block from tissue
samples obtained for cytology.1 Because radiologists in some
Classification of lung cancer
Figure 5 Small cell carcinoma. The tumor is growing in sheets of
small cells with scant cytoplasm and the nuclei have finely granular
chromatin. Nucleoli are inconspicuous or absent. Multiple mitoses
are seen. Hematoxylin and eosin, "400.
institutions perform these biopsies,43 they need to be aware
of these issues.
Small Cell Carcinoma
SCLC accounts for 14% of all lung cancers (Table 2), and
more than 30,000 new cases occur in the United States each
year.33,38 SCLC presents as a central mass in approximately
two-thirds of cases, and frequently there are extensive lymph
node metastases. SCLC may present as a solitary coin lesion
in up to 5% of cases.44,45
If SCLC has a pure histology it is classified simply as small
cell carcinoma.11 If there is a combination with another nons-
mall cell carcinoma component, it is classified as combined
small cell carcinoma with mention of the specific compo-
nent(s) present, ie, combined small cell carcinoma and ade-
nocarcinoma.11 The amount of the nonsmall cell component
is not important for adenocarcinoma or squamous cell carci-
noma so long as the histology is clear. However, for com-
bined small cell and large cell carcinoma at least 10% of large
cells is required to make the diagnosis.11,46,47 The histologic
appearance of SCLC consists of tumor cells with small size, a
round to fusiform shape, scant cytoplasm, finely granular
nuclear chromatin and absent or inconspicuous nucleoli
(Fig. 5).11 Tumor cells frequently show nuclear molding and
smearing of nuclear chromatin attributable to crush artifact.
Necrosis is often extensive and mitotic rates are high, with an
average of 80 mitoses per 2-mm2 area. Tumor cells most often
grow in diffuse sheets, but NE morphologic patterns, such as
rosettes, peripheral palisading, and organoid nesting are
common.11,47 For combined SCLC, the clinical outcome and
approach to therapy is similar to that of pure SCLC.
Although immunohistochemistry is useful in the diagnosis
of SCLC, the most important stain is a good quality hema-
toxylin and eosin stain that is not too thick or over stained.
The diagnosis can be established without immunostains in
most cases and it is needed only in problematic cases. A
183
pancytokeratin antibody, such as AE1/AE3 is useful to con-
firm that the tumor is a carcinoma rather and the most useful
NE markers include CD56, chromogranin, and synaptophy-
sin, which are best used as a panel. TTF-1 expression is found
in 70%-80% of SCLC.48 –50
Large Cell Carcinoma
Large cell carcinoma accounts for 3% of all lung carcino-
mas.33 These tumors are most often situated in the peripheral
lung parenchyma, and they are typically large necrotic tu-
mors. This is a diagnosis of exclusion in a nonsmall cell
carcinoma that lacks specific differentiation, such as adeno-
carcinoma, squamous cell carcinoma or sarcomatoid carci-
noma.11 Therefore, the diagnosis of large cell carcinoma can-
not be made based on small biopsy or cytology.11 The tumor
is composed of sheets and nests of large polygonal cells with
vesicular nuclei and prominent nucleoli.11 The use of immu-
nohistochemical stains in large cell carcinoma has led to
some suggestions that they should be reclassified as adeno-
carcinoma if positive for markers such as TTF-1 or as squa-
mous cell carcinoma if positive for markers like p63.51,52
However, this is simply a rediscovery of ultrastructural ob-
servations that have been known for decades that most large
cell carcinomas show glandular and/or squamous differenti-
ation by electron microscopy.53–55 Therefore, until there is
some validated proof in clinical trials that such tumors be-
have differently or respond differently to various therapies,
there is no sound basis for changing the existing diagnostic
criteria of large cell carcinoma as listed previously. Large cell
carcinoma can occur as several variants, including large cell
neuroendocrine carcinoma (LCNEC),47,56,57 basaloid carci-
noma,58 lymphoepithelial-like carcinoma,59,60 clear cell car-
cinoma,61 and large cell carcinoma with rhabdoid pheno-
type.62
Large Cell Neuroendocrine Carcinoma
LCNEC comprises approximately 3% of resected lung can-
cers.63 The clinical features of LCNEC and differential diag-
nosis are reviewed elsewhere.57,63 It is a high-grade nonsmall
cell NE carcinoma (Table 3) that shows: (1) NE morphology:
organoid, palisading, trabecular or rosette-like growth pat-
terns; (2) nonsmall cell cytologic features: large size, polygo-
nal shape, low N/C ratio, coarse or vesicular nuclear chroma-
Table 3 Terminology for Pulmonary Neuroendocrine Lesions*
Common neoplasms with neuroendocrine morphology
A. Typical carcinoid
B. Atypical carcinoid
C. Large cell neuroendocrine carcinoma (LCNEC)
Combined LCNEC
D. Small cell carcinoma
Combined small cell carcinoma
Nonsmall cell lung carcinoma with neuroendocrine differentiation
(NSCLC-NED): adenocarcinoma, squamous cell carcinoma, or
large cell carcinoma with neuroendocrine features not seen by
light microscopy but detected by immunohistochemistry or ultra-
structure.
*From Travis et al.11,63
184 W.D. Travis

tin and frequent nucleoli; (3) high mitotic rate (11 or more
per 2 mm2) with a mean of 60 mitoses per 2 mm2; (4) fre-
quent necrosis; and (5) at least 1 positive NE immunohisto-
chemical marker or NE granules by electron microscopy.11
The diagnosis of LCNEC is very difficult to make on the basis
of small biopsy specimens, such as needle or bronchoscopic
biopsy specimens because it is hard to be certain of the NE
morphology and/or NE marker expression. The diagnosis of
combined LCNEC is made if an LCNEC also contain other
histologic types of NSCLC, such as adenocarcinoma or squa-
mous cell carcinoma (Table 3).11 The term “large cell carci-
noma, with NE morphology” is appropriate for tumors that
appear to be LCNEC by light microscopy but lack NE differ-
entiation by electron microscopy or immunohistochemis-
try.11,63
Adenosquamous Carcinoma Figure 6 Typical carcinoid tumor. This tumor consists of organoid
Adenosquamous carcinoma occurs in 0.3%-5% of all lung nests of uniform cells with moderate amount of eosinophilic cyto-
cancers64 and it is composed of at least 10% squamous cell plasm with a rich vascular stroma. Nuclei show finely granular
and adenocarcinoma components.11 Because of this sampling nuclear chromatin. No necrosis or mitoses are seen. Hematoxylin
requirement, this diagnosis cannot be made on small biopsy and eosin, "200.
or cytology in the absence of a resected specimen.
Sarcomatoid Carcinomas
granular cytoplasm with nuclei showing a finely granular
This group of lung carcinomas is poorly differentiated and
chromatin pattern (Fig. 6). Both typical and atypical carci-
expresses a spectrum of pleomorphic, giant cell, and spindle
noids can show a variety of histologic patterns, such as spin-
cell carcinoma as well as carcinosarcoma and pulmonary
dle cell, trabecular, palisading, rosette-like, papillary, scle-
blastoma.11,65 These tend to be large peripheral tumors with a
rosing papillary, glandular, and follicular patterns.
poor prognosis. Pleomorphic carcinomas in particular tend
Atypical carcinoids are defined as a carcinoid tumor with
to invade the chest wall and are associated with a poor prog-
mitoses between 2 and 10 per 2-mm2 area of viable tumor or
nosis.65 The diagnosis of pleomorphic carcinomas requires
the presence of necrosis.11,56,63 The necrosis in atypical car-
that the tumor consist of at least 10% spindle cell and/or giant
cinoids most often appears as small punctate foci within or-
cells and these tumors frequently contain a mixture of other
ganoid nests of tumor cells.
histologic types, such as adenocarcinoma and/or squamous
cell carcinoma.65 This diagnosis cannot be made based on a
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