Journal of Cancer Therapy, 2013, 4, 1466-1471
Published Online December 2013 (http://www.scirp.org/journal/jct)
http://dx.doi.org/10.4236/jct.2013.410176
Open Access JCT
Update on Therapeutic Strategy in Lung Carcinoids*
Sara Pusceddu1#, Milena Vitali1, Eva Haspinger1, Luca Tavecchio2, Riccardo Giovannetti2,
Andrea Bille2 , Laura Concas1, Marina Garassino1, Massimo Milione3,
Filippo de Braud1, Roberto Buzzoni1
1Medical Oncology Unit, Fondazione IRCCS—Istituto Nazionale dei Tumori, Milan, Italy; 2Thoracic Surgery Unit, Fondazione
IRCCS—Istituto Nazionale dei Tumori, Milan, Italy; 3Pathology Unit, Fondazione IRCCS—Istituto Nazionale dei Tumori, Milan,
Italy.
Received November 4th, 2013; revised November 27th, 2013; accepted December 3rd, 2013
Copyright © 2013 Sara Pusceddu et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-
dance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the intellectual
property Sara Pusceddu et al. All Copyright © 2013 are guarded by law and by SCIRP as a guardian.
ABSTRACT
An estimated 25% to 30% of all neuroendocrine tumors (NETs) have their origin in the bronchia l t r ee and into the l u n gs.
Although lung NETs account for less than 1% of all pulmonary malignancies, the incidence of these neoplasms has
risen precipitously since the mid 1970s. Currently, according to the 2004 World Health Organization categorization,
these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade typical car-
cinoid (TC), intermediate-grade atypical carcinoid (AC), high-grade large-cell neuroendocrine carcinoma (LCNEC) and
small-cell carcinoma (SCLC). Surgery is the treatment of choice for typical and atypical carcinoid lung NETs with
loco-regional disease. At diagnosis up to 64% of patients with atypical carcinoid lung NETs present with lymph node
metastases, and 5-year survival ranges from 61% to 88%. In contrast, lymph node metastases are present in fewer than
15% of typical carcinoid lung NETs, and 5-year survival exceeds 90%. To date, there is no recognized standard of
treatment for advanced carcinoid lung NETs. In recent years only two trials reported intriguing results regarding lung
NETs: a phase 2 retrospective study of dacarbazine derivative temozolomide and the phase 3, RADIANT-2 trial in ad-
vanced NETs. Successful management requires a multidisciplinary team management. This review is restricted to typi-
cal/atypical NETs.
Keywords: Bronchial; Pulmonary; Carcinoids; Neuroendocrine Tumours
1. Introduction
Around 25% - 30% of all neuroendocrine tumors (NETs)
have their origin in the bronchial tree and into the lungs.
Bronchopulmonary (BP) typical carcinoids (TCs) and
atypical carcinoids (ACs) are uncommon, representing
1% - 5% of all pulmonary malignancies with an inci-
dence rate of 5 - 10 cases per million population per year
[1-3].
The incidence of these neoplasms has risen over the
past 30 years, and these variants are associated with rela-
tively slow growth, and generally show a favorable out-
come [3].
Compared with other non-small cell lung cancers
(NSCLCs), and high grade lung NETs (SCLC and
LCNET), advanced typical or atypical carcinoid lung
tumors, are less aggressive, and are characterized by an
indolent course. The survival is generally good, with an
estimate 5-year overall survival rate of 61% to 88% for
ACs and of 90% for TCs; this explains the relative high
prevalence of these tumours [4].
Atypical carcinoids are more likely to have peripheral
location, to show lymph node metastases, and are more
likely to be tobacco-related [5].
The vast majority of symptomatic patients have symp-
toms directly involving the bronchopulmonary tree. Ty-
pical symptoms of carcinoid lung NETs include obstruc-
tive pneumonia, atelectasis, and wheezing which are the
results of central airway obstruction due to tumor mass,
(see Figure 1).
*The authors declare that there is no conflict of interests regarding the
p
ublication of this article.
#Corresponding author. Peripheral pulmonary carcinoid tumors most often are

Update on Therapeutic Strategy in Lung Carcinoids 1467
asymptomatic and usually are discovered incidentally
[5].
Although NETs of the lung ar ise from cells capable to
produce serotonin and adrenocorticotropin hormones, the
hypersecretion of bioactive amines is comparatively rare
in typical and atypical lung NETs. The most common
hormonal syndrome associated with the bronchial carci-
noids is the ectopic adrenocorticotropic hormone (ACTH)
syndrome. About 10% - 15% of all ACTH-dependent
Cushing syndrome is ectopic. There is an equal male to
female incidence. It may occur at any age from 5 to 90
years [6]. Bronchial NETs may be part of multiple endo-
crine neoplasia type 1 syndrome (MEN-1), in 5% - 15%
of cases [7].
2. Treatment
2.1. Histopathological Features
NETs of the lung origin comprise of a heterogeneous
population of tumors ranging from well-differentiated
bronchial NETs to highly malignant and poorly different-
tiated small-cell lung cancer (SCLC) and large-cell neu-
roendocrine carcinoma (LCNEC).
TCs and SCLCs are more frequently found to be cen-
trally located in the lung, while ACs and LCNECs more
often show a peripheral localization [4].
Based on the present World Health Organization
(WHO) 2004 classification of lung NETs that combined
architectural growth patterns of tumor cells (organoid
growth versus small-cell diffuse growth), mitotic index
and the presence of necrosis (see Table 1); ACs are dis-
tinguished from TCs by the demonstration of necrosis
and/or presence of 2 - 10 mitoses per 2 mm2 (10 ×
high-power field) [4]. In TC, there are <2 mitoses per 2
mm2 (10 × high-power field), no necrosis is present and
the tumor is >0.5 cm in diameter. Histological subtype
and nodal status are the most important prognostic fac-
tors (see Figure 2-3) [4] .
Up to 35% - 64% of patients with atypical carcinoid
lung NETs present with lymph node metastases, and
5-year survival ranges from 61% to 88%. In contrast,
lymph node metastases are present in fewer than 15% of
cases of typical carcinoid lung NETs, and 5-year survival
exceeds 90% [4].
2.2. Biochemical Evaluation and Radiological
Assessment
Biochemical evaluation of well differentiated lung NETs
include plasma chromograninA, plasma-neuron-specific
Figure 1. Computerized tomographic study of atypical carcinoid lung tumor of the left mainstem bronchus and resultant
lung atelectasis.
Table 1. Neuroendocrine tumors of the lung from travis WD classification.
Histological type Morphology Necrosis Mitotic count
TC Carcinoid morphology < 0.5 cm absent <2/10 HPF
AC Carcinoid morphology present focal 2 - 9/10 HPF
LCNEC Neuroendocrine morphology (organoid nestin g,
palisanding, rosettes, trabeculae present (extensive) >9/10 HPF
SCLC Scant cytoplasm, finely granular nuclear chromatin,
absent or faint nucleoli present (extensive) >50/10 HPF
T
C: typical carcinoid, AC: atypic al carcinoid, LCNEC: large cell neuroendocrine carcinoma, SCLC: small c ell lung cancer, HPF: high power fields.
Open Access JCT

Update on Therapeutic Strategy in Lung Carcinoids 1468
Figure 2. Pulmonary atypical carcinoid primary tumor: (A)
well-differentiated neuroendocrine tumor lung in contact
with a bronchial structure (black arrow). Mitotic index:
three mitosis in 10 HPF (example of mitosis in Figure A
yellow box). The tumor is characterized by “pseudosetti-
form” structures (C) and showing diffuse cytoplasmic posi-
tivity for synaptophysin and dot like for chromogranin-A
(B). The proliferation index assessed by MIB-1/Ki-67 is
3.5% (D).
enolase (NSE), and in selected cases with carcinoid syn-
drome, dU-5-hydroxy indol-acetic acid. In patients with
Cushing’s disease and acromegaly, plasma ACTH and
urine cortisol, and plasma GHRH and insulin growth
factor (IGF-I) can be evaluated respectively [4].
Computed tomography (CT) scanning of the chest may
suggest a diagnosis of lung NETs. Around 10% of pa-
tients will have multiple lesions and calcifications are
evident in up to 30% of the tumours [7].
Bronchoscopy, if necessary with additional en doscop ic
ultrasonography with biopsies, is the best procedure to
detect and to diagnose central bronchial NETs [7].
Since 80% of typical bronchial well differentiated car-
cinoids (TCs and ACs) express somatostatin receptors [8].
The octreotide scan or octreoscan®, called also soma-
tostatin receptor scintigraphy (SRS), is used to detect car-
cinoids; good results were reported with octreotide-de-
rivatives labelled with 111In-pentetreotide for single
photon emission computed tomography (SPECT) due to
its high affinity to somatostatin type receptor 2 and 5
(SSTR-2 and SSTR-5), mainly expressed in both TCs
and ACs [9]. The overall sensitivity and specificity in
detection is as high as 93% and 87%, respectively [10].
New radiopharmaceuticals, labeled with Gallium-68
with an improved biodistribution and increased tumour
uptake, have been synthesized for PET/CT combining
imaging techniques which leads to 68Ga-DOTATOC
PET and 68Ga-DOTATATE PET/CT [11,12].
These last techniques seem to be superior to standard
fluoro-deoxy-glucose positron emission tomography
(FDG-PET/TC), in the detection of well-differentiated
Figure 3. Lymph node metastasis from pulmonary atypical
carcinoid: the lymph node is completely replaced by the
tumor (A). The lesion presents nodal diffuse cytoplasmic
positivity for Synaptophysin and dot-like for Chromogranin
A (B). The proliferation index assessed by MIB-1/Ki-67 is
3.7% (C). Positivity for m-Tor (D) and 4EBP1 (E) is intense
and widespread with positive internal controls.
neuroendocrine tumou rs because of the higher sensitivity
in low-grade tumour.
68 Ga-DOTATATE has superior affinity and uptake at
the SSTR-2, and combined PET and CT imaging with
this tracer has superior spatial resolution compared with
conventional 111In-pentetreotide imaging, and actually it
is the most sensitive and most accurate imaging techni-
ques to detect small receptor-positive BP carcinoid le-
sions [13].
Staging with FDG-PET is recommended only for more
aggressive bronchial NETs such as LCNEC and SCLC.
The role of FDG-PET imaging is not well defined for BP
carcinoids, for the high rate of FDG-PET false negative
due to low grade, low mitotic count and often small di-
mension [12,14].
2.3. Management of Locally Advanced Disease
Surgical resection remains the treatment of choice for
patients with pulmonary carcinoids [7 ].
Bronchoscopic laser excision of intraluminal typical
bronchial NETs should be considered as a suboptimal
treatment and reserved for inoperable patients or per-
formed as a preoperative disobliterating procedure [15].
The surgical techniques of choice are lobectomy or
sleeve resection. Pneumonectomy should be avoided
except in selected cases. Limited resection should be
performed for known carcinoid tumors. Unknown lung
lesions should undergo wedge excisional biopsy. If in-
traoperative frozen section is consistent with carcinoid
and the margins are negative, mediastinal lymph node
dissection should be performed. If the patient is node
negative then completion lobectomy is not required. In
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Update on Therapeutic Strategy in Lung Carcinoids 1469
node-positive patients with adequate pulmonary reserve,
lobectomy should be performed regardless of histology.
If atypical features are found during permanent patho-
logic evaluation then interval completion lobectomy may
be considered in good-risk patients [15].
Systemic nodal dissection should be performed since
lymphonodal metastases may be present in up to 15% of
cases in TC and >50% in AC. TCs exhibit a good prog-
nosis with a 5-year survival rate in 92% - 100% of cases.
ACs are regarded as intermediate in grade and are asso-
ciated with a poor prognosis and a 5-year survival rates
of 61% - 88% [4].
2.4. Management of Advanced/Metastatic
Disease
There is no recognized first-line therapy for advanced
carcinoid lung tumours [7].
Cytotoxic treatment combined with surgical resection
when indicated, has been the standard for metastatic lung
NETs, although the available chemotherapy regimens
demonstrate a rather poor effect. A combination of cis-
platinum and etoposide is mainly used in high proliferat-
ing tumors.
Available chemotherapy regimens for TCs and ACs
include a combination of streptozotocin plus 5-fluoro-
uracil/doxorubicin, or capecitabine/oxaliplatin. Temozo-
lomide alone or in combination with bevacizumab, has
demonstrated clinical benefit [7].
Ekeblad and colleagues performed a retrospective
analysis of 36 patients with histo logically confirmed me-
tastatic or inoperable malignant NETs treated with oral
temozolomide (100 - 200 mg/m2/d for 5 days every 28
days). The study group included 10 pts with TCs and 3
with ATs. After a median follow-up of 7 months (range,
2 - 17 months), 31% of patients with lung carcinoids had
stable disease (SD) and 31% showed a partial radiologic
response ( P R ) [16].
No chemotherapies randomized trials have been per-
formed that could guide the treatment, and at present,
there is no established standard regimen and the role of
chemotherapy in BP carcinoids continues to be debated.
For low proliferating tumors, treatment with soma-
tostatin analogs might b e an option for functional tumors
with clinical symptoms. Treatment with these agents has
resulted in PR in 5% - 10%, SD in 30% - 50% and
symptomatic improvement in 40% - 60% of cases. In
nonfunctioning tumors, the use of somatostat in an alogs is
still controversial, but after the PROMID and CLARI-
NET trials indicating antitumor efficacy of octreotide
long acting release (LAR) and Lanreotide Autogel drugs
in gastroenteropancreatic NETs, it is now also widely
accepted for nonfunctioning tumors of other origins.
Peptide receptor radiotherapy is an option in patients
with tumors that present with a high content of soma-
tostatin receptors [17,18].
The molecular biology of the lung carcinoids, gener-
ally show an overexpression of EGF (epidermal growth
factor) of IGF (insulin-like growth factor) and their re-
ceptors. The RAS-RAF-MAP kinase pathway is overact-
tive, and there is usually overactivity of PI3 kinase and
the mTOR pathway. Recent in vitro studies indicate that
somatostatin receptors are overexpressed in metastatic
typical carcinoid tumors of the lung [8] and that the
mTOR is found in most lung NETs with higher expres-
sion in typical and atypical carcinoids (see Figure 3).
[19].
In addition, a recent preclinical study of the impact of
the mTOR inhibitor, everolimus, found that it suppressed
the viability of typical and atypical carcin oid lung cells in
culture [20]. Thus, there is a theoretical rationale for the
use of both Tyrosine-kinase inhibitor (TKIs) and mTOR
inhibitors.
Despite Lung NETs are typically underrepresented in
clinical trials of NET treatments, recently, a phase 3
RAD001 in Advanced Neuroendocrine Tumors Trial
(RADIANT-2) has reported results specific for BP car-
cinoids NE Ts [21].
In RADIANT-2, which evaluated the impact of com-
bination therapy with the oral mammalian target of ra-
pamycin (mTOR) inhibitor everolimus and the soma-
tostatin analogue octreotide LAR in patients with ad-
vanced NET and carcinoid symptoms; only 6.9% of pa-
tients in the experimental group and 2.3% of pts in the
control group were diagnosed with lung NETs. Patients
were randomly assigned to receive octreotide LAR 30
mg intramuscularly every 28 days combined with ever-
olimus 10 mg per day (N = 216) or octreotide LAR plus
a placebo (N = 213). Treatment with everolimus com-
bined with octreotide was associated with longer pro-
gression-free survival overall: 16.4 months in patients
treated with everolimus and octreotide vs 11.3 months in
control patients (P = 0.026); patients with lung NETs
show trend to improve progression free survival with
Everolimus plus Octreotide (P = 0.228) [21,22].
Based on that, the ongoing RADIANT-4 trial (NCT
01524783) is looking at progressive nonfunctioning
NETs, including lung carcinoids where patients are
treated with everolimus or placebo. Finally a trial spe-
cifically looking at lung NETs, the LUNA trial (NCT
01563354), where patients are randomly assigned to
everolimus, the somatostatin analog pasireotide, or the
combination of both, is ongoing and is still enrolling pa-
tients.
An other trial with biological target therapies, which
some preliminary data had been reported from, is the
PAZONET trial. The PAZONET trial looked at progres-
sive new endocrine tumors and showed a clinical benefit
in 85% of patients treated with pazopanib, including pa-
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Update on Therapeutic Strategy in Lung Carcinoids 1470
tients with lung carcinoids [23].
However the role of targeted therapies for typical and
atypical carcinoid lung NETs remains incompletely de-
fined, with data from relatively few clinical trials to help
guide clinical decision making.
3. Summary and Conclusions
Diagnosis remains challenging. Proper distinction sh ould
be made between well or moderate differentiate subtypes
(AT and CT carcinoids) and poorly differentiated forms
(LCNC and SCLC).
The role of histology and systematic nodal dissection
performed during surgery is the key.
Imaging techniques, like radiolabeled peptide scinti-
graphy with 111In-pentetreotide or 68Ga-DOTATOC/
DOTATATE PET/CT are useful in well differentiated
bronchial NETs rather than LCNEC and SCLC histo-
types, where FDG-PET/TC scans are more informative
than somatostatin receptor scintigraphy. Surgery is the
treatment of choice for typical and atypical carcinoid
lung NETs with loco-regional disease. For advanced
disease, no standard treatment or therapeutic algoritm is
available. Somatostatin analogues may be recommended
as first line treatment, while the role of targeted therapy
for typical and atypical lung carcinoid remains unclear,
with data from relatively few clinical trials to help guide
clinical decision making.
Further research is needed to clarify the role of soma-
tostatin analogues, mTOR inhibitors, and other targeted
therapies on these rare and clinically challenging tumors.
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