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Annals of Oncology 21 (Supplement 7): vii65–vii71, 2010
doi:10.1093/annonc/mdq380
Advances in neuroendocrine lung tumors
W. D. Travis*
Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, NY, USA
tumorlets and DIPNECH
Pulmonary neuroendocrine (NE) tumors include a spectrum
of tumors from the low-grade typical carcinoid (TC) and
intermediate-grade atypical carcinoid (AC) to the high-grade
large-cell NE carcinoma (LCNEC) and small-cell carcinoma
(SCLC) (Table 1) [1]. NE lung tumors comprise 20%–25% of
all invasive lung malignancies. The most common NE lung
tumor is SCLC, which accounts for 15%–20% of invasive lung
malignancies [2]. In surgical series, LCNEC represents 3% of
lung cancers. Carcinoid tumors represent 1%–2% of invasive
lung malignancies and only 10% of carcinoids represent AC,
so these account for only 0.1%–0.2% of invasive lung cancers
[3]. Diffuse idiopathic pulmonary NE cell hyperplasia
(DIPNECH) is a very rare condition that represents
a preinvasive lesion for carcinoid tumors. Treatment of SCLC
is usually chemotherapy. It is difficult to diagnose AC and
LCNEC in small biopsies or cytology and a definitive diagnosis
usually requires a surgical specimen. These tumors are also
clinically problematic because the optimal therapy for AC
and LCNEC is not established [3].
The purpose of this article is to summarize the spectrum
of pulmonary NE tumors with emphasis on the pathology
and diagnostic criteria. A summary of the spectrum of NE lung
neoplasms is presented in Table 1 and the diagnostic criteria
in Table 2.
Nodular proliferations of NE cells that measure <0.5 cm in
greatest diameter are tumorlets. These are usually incidental
histologic findings of no clinical significance encountered in
lung specimens showing various inflammatory and/or fibrotic
conditions such as bronchiectasis, interstitial fibrosis, chronic
abscesses or tuberculosis.
When patients are found to have widespread peripheral
airway NE cell hyperplasia and/or multiple tumorlets, the
diagnosis of ‘DIPNECH’ can be made. Since a subset of these
patients has one or more carcinoid tumors, DIPNECH is
thought to represent a preinvasive lesion for carcinoid tumors
[4, 5]. This must be distinguished from NE cell hyperplasia and
tumorlets found associated with inflammation/fibrosis and
local proliferation found in lung surrounding up to 75% of
carcinoid tumors.
DIPNECH may present as a form of interstitial lung disease
with airway obstruction due to the frequent association with
bronchiolar fibrosis or it can present as multiple pulmonary
nodules often mistaken for metastatic cancer. Davies et al. [5]
reported 19 cases with 15 females and 16 nonsmokers. There
were two major types of clinical presentation: one (n = 9)
presenting with mild interstitial lung disease such as
symptomatic cough and/or dyspnea averaging 8.6 years before
diagnosis and the second (n = 10) in patients found incidentally
to have pulmonary nodules on routine radiologic evaluation
for another disorder, mostly cancer. Tumorlets and TC were
found in nine patients. Three patients had AC and one had
multiple endocrine neoplasia type I (MEN1) syndrome. Most
*Correspondence to: Dr W. D. Travis, Department of Pathology, Memorial Sloan
Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
Tel: +1-212-639-3325; Fax: +1-212-717-3576; E-mail: [email protected]
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
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article
introduction
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Pulmonary neuroendocrine (NE) tumors include a spectrum of tumors from the low-grade typical carcinoid (TC)
and intermediate-grade atypical carcinoid (AC) to the high-grade large-cell neuroendocrine carcinoma (LCNEC)
and small-cell carcinoma (SCLC). Nodular NE proliferations ‡0.5 cm are classified as carcinoid tumors and smaller
ones are called tumorlets. When NE cell hyperplasia and tumorlets are extensive they represent the rare preinvasive
lesion for carcinoids known as diffuse idiopathic pulmonary NE cell hyperplasia. Carcinoid tumors have significant
clinical, epidemiologic and genetic differences from the high-grade SCLC and LCNEC. Multiple endocrine neoplasia
type I can be found in TC and AC patients but not those with LCNEC and SCLC. Also both LCNEC and SCLC
can demonstrate histologic heterogeneity with other major histologic types of lung carcinoma such as
adenocarcinoma or squamous cell carcinoma, but is not characteristic of TC or AC. Genetic changes are very high in
SCLC and LCNEC, but usually low for TC, intermediate for AC. The diagnosis of SCLC, TC and AC can be made
by light microscopy without the need for special tests in most cases, but for LCNEC it is required to demonstrate NE
differentiation by immunohistochemistry or electron microscopy.
Key words: Atypical carcinoid, carcinoid, large-cell neuroendocrine carcinoma, lung, neuroendocrine,
neuroendocrine body, neuroendocrine cell hyperplasia, small-cell carcinoma, tumorlet, typical carcinoid
symposium article
of these patients had a stable clinical course, but a few
progressed to severe airflow obstruction [5].
Histologically DIPNECH is characterized by prominent NE
cell hyperplasia and tumorlets. Some patients also have
Table 1. The spectrum of neuroendocrine lung tumorsa
I.
NE, neuroendocrine.
a
Modified from [4].
b
The histological type of the other component of non-small-cell carcinoma
should be specified.
Table 2. Criteria for diagnosis of neuroendocrine tumors [4]
Typical carcinoid
A tumor with carcinoid morphology and <2 mitoses per 2 mm2 (10 HPFa),
lacking necrosis and ‡0.5 cm
Atypical carcinoid
A tumor with carcinoid morphology with 2–10 mitoses per 2 mm2
(10 HPFa) OR necrosis (often punctate)
Large-cell neuroendocrine carcinoma
A tumor with a neuroendocrine morphology (organoid nesting,
palisading, rosettes, trabeculae)
High mitotic rate: ‡11 per 2 mm2 (10 HPFa), median of 70 per 2 mm2
(10 HPFa)
Necrosis (often large zones)
Cytologic features of a non-small-cell lung carcinoma (NSCLC): large-cell
size, low nuclear to cytoplasmic ratio, vesicular or fine chromatin, and/
or frequent nucleoli. Some tumors have fine nuclear chromatin and lack
nucleoli, but qualify as NSCLC because of large cell size and abundant
cytoplasm.
Positive immunohistochemical staining for one or more NE markers
(other than neuron-specific enolase) and/or neuroendocrine granules by
electron microscopy.
Small-cell carcinoma
Small size (generally less than the diameter of three small resting
lymphocytes)
Scant cytoplasm
Nuclei: finely granular nuclear chromatin, absent or faint nucleoli
High mitotic rate (‡11 per 2 mm2, median of 80 per 2 mm2)a
Frequent necrosis often in large zones
a
10 high-power fields (HPF) in a microscope with field of view of 0.2 mm2;
however the number of HPF to reach 2 mm2 vary depending on the field of
view, see [13].
vii66 | Travis
carcinoid tumors. Tumorlets may cause airway narrowing
and/or obliteration. The surrounding lung parenchyma is
generally normal.
carcinoid tumors
clinical features
There is no marked sex predilection for pulmonary carcinoids
[1, 6, 7]. TC and AC occur at any age with an average of
45–55 years and they occur equally in both sexes.
Approximately half of patients with TC and AC are
asymptomatic at diagnosis [1]. Patients typically present with
dyspnea, hemoptysis, cough and post-obstructive pneumonia
[7]. Carcinoids situated in the lung periphery are more likely an
incidental radiologic finding. The most common
paraneoplastic syndromes include the carcinoid syndrome [7],
and Cushing’s syndrome [8, 9]. MEN1 patients can have lung
carcinoids, which occur in 5% of cases [10]. The recently
published seventh edition UICC/AJCC TNM system,
recommended TNM for staging of pulmonary carcinoids
[11, 12].
pathologic features
Carcinoid tumors present in the lung periphery in 40% of
cases. Endobronchial growth is common in central carcinoids.
Tumors average 2–3 cm in size and are usually round. The
cut surface is tan to yellow.
An organoid growth pattern is the most common histologic
pattern in both TC and AC. Tumor cells have uniform
cytologic features with a moderate amount of eosinophilic
cytoplasm with an eosinophilic hue (Figure. 1). Nuclear features
usually consist of finely granular chromatin. In TC nucleoli are
inconspicuous or absent, but they can be seen in AC.
The criteria for diagnosis of AC includes a carcinoid tumor
with mitoses between 2 and 10 per 2 mm2 area or the presence
of necrosis (Figure. 2) [13]. The necrosis usually consists of
small punctate foci. Other features such as pleomorphism,
Figure. 1. Typical carcinoid. This tumor shows an organoid nesting pattern
with a prominent vascular stroma. The tumor cells are uniform with
a moderate amount of eosinophilic cytoplasm and finely granular nuclear
chromatin. No necrosis or mitoses are seen.
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Tumors with NE morphology
A. Typical carcinoid (‡0.5 cm)
B. Atypical carcinoid
C. Large-cell neuroendocrine carcinoma
Combined large-cell neuroendocrine carcinomab
D. Small-cell carcinoma
Combined small-cell carcinomab
II. Non-small-cell carcinomas with NE differentiation
III. Other tumors with NE properties
A. Pulmonary blastoma
B. Primitive neuroectodermal tumor
C. Desmoplastic round cell tumor
D. Carcinomas with rhabdoid phenotype
E. Paraganglioma
Annals of Oncology
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Annals of Oncology
AC patients have a significantly reduced 5-year survival of
61%–88% compared with TC (92%–100%) [6, 19–21]. In TC,
lymph node metastases are present in 4%–14% of cases
compared with 35%–64% in AC. These tumors are relatively
resistant to chemotherapy and radiation therapy; therefore,
when possible, metastatic disease is sometimes best managed
surgically. There is no proven optimal therapy for metastatic
unresectable TC or AC.
LCNEC
Figure. 2. (A) Atypical carcinoid. This tumor shows a punctate focus
necrosis within sheets and nests of carcinoid tumor cells. (B) There is
a single mitosis (center) in one tumor cell. The cells have finely granular
nuclear chromatin.
vascular invasion and increased cellularity are not as helpful
in separating TC from AC [13, 14].
immunohistochemistry
Chromogranin, CD56 and synaptophysin are the most helpful
NE immunohistochemical markers. A low proliferation rate
(£5%) is seen in TC by Ki-67 staining compared with AC where
it is usually between 5% and 20% [15, 16]. In small crushed
biopsies Ki-67 staining can be helpful to separate TC or AC
from high-grade LCNEC or SCLC, which have very high
proliferation rates [15, 16].
treatment and prognosis
Carcinoids are treated primarily by surgical resection [7, 17].
Patients with TC have an excellent prognosis and rarely die of
tumor [7]. Lobectomy is the treatment of choice in most cases,
particularly central tumors. For peripheral tumors limited
resection may be possible. Even patients with TC who have
lymph node metastases have an excellent survival [18].
Volume 21 | Supplement 7 | October 2010
clinical features
In surgical resected series, LCNEC accounts for 3% of cases
[23, 24]. There is a very high frequency of cigarette smoking
with heavy smoking histories [14]. Most LCNEC patients are
males and the median age is 60 years [24]. Paraneoplastic
syndromes such as ectopic hormone production are rare [24,
25]. Chest pain is the most common symptom, followed by
hemoptysis, dyspnea, cough, fever and weight loss with up to
24% of patients being asymptomatic [26]. By computed
tomography, tumors occur mostly in the lung periphery (84%)
and the upper lobes (63%) [27].
pathology
LCNECs are usually peripheral tumors with a mean size of
3–4.0 cm (range 0.9–12 cm) [13, 28, 29]. Grossly the tumor
is circumscribed with a necrotic, tan–red cut surface [27].
LCNECs are diagnosed according to the following criteria:
(i) NE morphology with organoid nesting, palisading or
rosette-like structures (Figure. 3A), (ii) high mitotic rate >10
mitoses per 2 mm2 (average 60–80 mitoses per 2 mm2), (iii) nonsmall-cell cytologic features including large-cell size, low nuclear/
cytoplasmic ratio, nucleoli or vesicular chromatin (Figure. 5B)
and (iv) NE differentiation by immunohistochemistry with
antibodies such as chromogranin (Figure. 3B), CD56 or
synaptophysin, or by electron microscopy [4, 13].
The diagnosis of LCNEC is difficult to establish based on
small biopsies or cytology. [24, 30]. This is because the NE
pattern is difficult to see morphologically in small tissue
samples or cytology. Also NE differentiation can be difficult to
demonstrate by immunohistochemistry in small pieces of
tissue. For these reasons the diagnosis of LCNEC requires
a surgical lung biopsy.
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LCNEC is a high-grade non-small-cell NE carcinoma classified
as a variant of large-cell carcinoma in the 1999 and 2004 WHO
classifications [4, 22]. There are four major categories of NE
phenotypes in large-cell carcinomas: (i) LCNEC with NE
features by light microscopy as well as immunohistochemistry
and/or electron microscopy, (ii) large-cell carcinoma with NE
morphology (LCNEM) with NE morphology but no NE
differentiation by electron microscopy or
immunohistochemistry, (iii) large-cell carcinomas with NE
differentiation (LCC-NED) with no NE morphology but NE
differentiation by immunohistochemistry or electron
microscopy and (iv) classic large-cell carcinoma (LCC), which
lacks both NE morphology and NE differentiation by special
studies [14, 22].
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When a LCNEC has components of adenocarcinoma,
squamous cell carcinoma, giant cell carcinoma and/or spindle
cell carcinoma it is called combined LCNEC [4, 13]. The most
common component is adenocarcinoma, but squamous cell,
giant cell or spindle cell carcinoma can also occur. If the second
component is SCLC the tumor becomes a combined SCLC
and LCNEC.
microscopy (LCC-NEM) [22]. Only a few papers have reported
clinical data on these patients but they are generally similar
to those for LCNEC [26, 28].
non-small-cell carcinomas with NE differentiation. NSCLC with
NE differentiation (NSCLC-NED) (Table 1) represent the
10%–20% of NSCLCs that show NE differentiation by
immunohistochemistry or electron microscopy, but not by
light microscopy [33]. This phenomenon occurs most often in
adenocarcinomas. However, this finding does not appear to
have significant implications for prognosis or responsiveness to
chemotherapy [33].
treatment and prognosis
The clinical outcome for LCNEC patients is poor with overall
5-year survival ranging from 15% to 57%. This broad range
in reported outcome may be related to differences in stage
distribution and the extent of surgical staging in the various
studies.
Several studies have demonstrated significantly worse
survival for LCNEC patients compared with those with other
non-small-cell carcinomas, but not compared with SCLC
[28, 34].
Several recent studies have shown that LCNEC responds to
cisplatin-based chemotherapeutic regimens similar to those
used for SCLC [35–37]. However, these are retrospective
studies of small numbers of patients who received adjuvant
therapy following surgery and more validation is needed. Data
regarding radiation are insufficient to know whether it is
effective in LCNEC [38].
small-cell carcinoma
Figure. 3. Large-cell neuroendocrine carcinoma. (A) The tumor grows in
sheets with prominent peripheral palisading and vague rosette-like
structures. Several mitoses are seen. The tumor cells have abundant
cytoplasm, prominent nucleoli. (B) Chromogranin strongly stains the
tumor cells.
vii68 | Travis
clinical features
The most common pulmonary NE tumor is SCLC and it
accounts for an estimated 28 000 of the 219 440 lung cancer
cases diagnosed in the United States in 2009 [39]. The
frequency of SCLC cases among all lung cancers cases over the
past 30 years in the USA decreased from 17% to 13% according
to the US National Cancer Institute’s Surveillance,
Epidemiologic, and End Results (SEER) database [40]. There
is a strong association with cigarette smoking [41]. SCLC
presents with four major types of manifestation: constitutional,
pulmonary, the result of extrathoracic spread or due to
paraneoplastic disorders [41]. The most common symptoms
are fatigue, cough, dyspnea, decreased appetite, weight loss,
pain and hemoptysis. Chest images demonstrate a large mass
invading or compressing the mediastinum with mediastinal or
hilar adenopathy. Superior vena cava syndrome can be found
in 10% of patients [41]. SCLC can present as a solitary
pulmonary nodule in <5% of cases. Metastases to extrathoracic
locations such as the bone, brain, liver and adrenals are present
in most patients at presentation [41]. Several paraneoplastic
syndromes are known to occur in SCLC patients: syndrome of
inappropriate antidiuretic hormone, Cushing’s syndrome or
neurologic paraneoplastic syndromes such as autoimmune
neuropathies and encephalomyelitis [41].
A distinct limited versus extensive staging system exists for
SCLC as recommended by the Veterans’ Administration Lung
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immunohistochemistry/electron microscopy
NE differentiation must be demonstrated by
immunohistochemistry or electron microscopy to diagnose
LCNEC [4, 13]. NE immunohistochemical markers are usually
best performed as a panel of chromogranin (Fig. 3B), CD56/
NCAM and synaptophysin [14]. In 41%–75% of cases, thyroid
transcription factor-1 (TTF-1) will be positive [31, 32]. The
proliferation index by Ki-67 staining is very high with staining
of 50%–100% of tumor cells.
large-cell carcinoma with NE morphology. Some large-cell
carcinomas have NE morphology, but no NE differentiation
can be demonstrated by immunohistochemistry or electron
Annals of Oncology
Annals of Oncology
Study Group (VALSG) for SCLC [42]. According to this
system, two-thirds of patients have extensive disease at
diagnosis, and one-third have limited-stage disease [40]. The
recent seventh edition AJCC/UICC TNM staging system
proposes the use of TNM for SCLC based on an analysis of
a large database of >8000 patients demonstrated that TNM
staging is effective for SCLC [12, 43].
resected specimens. Crush artifact is common in small
transbronchial or mediastinal biopsy specimens. Lesions other
than SCLC that can cause confusion include NSCLC,
lymphoma, carcinoid and chronic inflammation.
Immunohistochemistry can be very helpful in this setting. In
resected specimens the tumor cells of SCLC appear larger than
in small biopsies because of better fixation [45].
While a panel of immunohistochemical stains is often helpful
in the diagnosis of SCLC the most important special stain is
a good quality hematoxylin and eosin stain. The most common
cause of problems in diagnosis results from sections that are
too thick or poorly stained. If the histologic features are classic,
it may not be needed. The optimal panel of stains for diagnosis
of SCLC includes a pancytokeratin antibody such as AE1/AE3,
CD56, chromogranin and synaptophysin, TTF-1 and Ki-67.
If keratin is negative, other tumors need to be excluded
including lymphoma (CD45 and CD20), primitive
neuroectodermal tumors (PNETs, CD99) and melanoma
(S100). In 70%–80% of SCLCs TTF-1 is positive [31, 32]. Ki-67
is most helpful in separating SCLC from carcinoids because the
proliferation is very high (80%–100%).
It is well known that the diagnosis of SCLC can be difficult
in 5% of cases even for expert lung cancer pathologists in
the separation from non-small-cell carcinoma [46, 47]. In
problematic cases it is best to use a consensus approach among
other pathology colleagues. If this does not lead to a consensus
diagnosis, such a problem case may need to be referred for
extramural consultation.
treatment and prognosis
SCLC patients have a very poor survival of 12%, 7% and 5%, at
2, 3 and 5 years, respectively [48]. Factors that are associated
with adverse outcome include performance status, Cushing’s
syndrome, continued smoking and metastases to sites such as
the liver, brain, bone marrow and bone [41].
The primary approach to therapy for SCLC is combination
chemotherapy, typically with etoposide plus either cisplatin
or carboplatin [41]. Patients with limited stage disease are
usually given chemotherapy concurrently with radiation. Some
early stage patients undergo surgical resection.
molecular changes in pulmonary NE
tumors
Figure. 4. Small-cell carcinoma. This tumor consists of dense sheets of
small cells with scant cytoplasm, finely granular nuclear chromatin, frequent
mitoses; nucleoli are inconspicuous or absent.
Volume 21 | Supplement 7 | October 2010
NE lung tumors show a spectrum of molecular changes that
largely reflect the differences in histologic grade. Many
molecular abnormalities are found in LCNEC and SCLC
compared with fewer in the carcinoids. These are reviewed
in more detail elsewhere [15, 49, 50].
In a study of loss of heterozygosity (LOH) for 3p, RB, 5q21,
9p and p53 in pulmonary NE tumors, Onuki et al. [51] found
at a higher frequency of LOH in the high-grade LCNEC and
SCLC compared with the carcinoids. SCLC also showed
significantly more frequent 5q21 LOH compared with LCNEC.
p53 showed an increasing frequency of changes by
immunohistochemistry, LOH and mutation analysis from TC
to AC and high-grade SCLC and LCNEC [51]. No p53
mutations were found in TC, with 25% in AC, 59% in LCNEC
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pathology
The diagnosis of SCLC is established based on small specimens
such as bronchoscopic biopsies, fine needle aspirates, core
biopsies and cytology in almost all cases, because of the
presentation in advanced stages. Fortunately these specimens
are diagnostic in most all cases. In resected cases, the tumor
is usually a circumscribed peripheral lung nodule measuring
2–4 cm in size with a tan, necrotic cut surface.
SCLC is diagnosed histologically primarily based on light
microscopy (Figure. 4). Tumor cells are round to fusiform and
they grow in sheets and nests with frequent necrosis that is
often extensive. Necrosis is common, frequently with large
areas. Tumor cells typically have scant cytoplasm and measure
less than the diameter of three small resting lymphocytes
with finely granular nuclear chromatin. Nucleoli are
inconspicuous or absent [4, 44]. The mitotic rate is high,
averaging 60–80 per 2 mm2; however, mitoses can be difficult
to identify in small biopsy specimens.
When there is also a component of NSCLC such as
adenocarcinoma, squamous cell carcinoma, large-cell
carcinoma, spindle cell carcinoma or giant cell carcinoma the
tumor is classified as combined SCLC. This diagnosis should be
accompanied by a description of the non-small-cell
component(s) [4, 44]. Combined SCLC may occur in up to
28% of surgically resected cases [4, 44]. For combined SCLC/
large-cell carcinoma there should be at least 10% large or giant
cells, but for the components of adenocarcinoma, squamous
cell or spindle cell carcinoma the amount does not matter
[4, 44].
There are two settings in which diagnostic difficulties are
encountered by pathologists: crush artifact and surgically
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and 71% in SCLC. These results are similar to data reported
by others in high-grade NE carcinomas with p53 expression
ranging between 40% and 86% and p53 mutations from 27%
to 59% [15, 49, 50].
international registry of pulmonary NE
tumors
disclosures
The author has declared no conflict of interest.
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An International Registry of Pulmonary NE Tumors is being
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