Update on Therapeutic Strategy in Lung Carcinoids

doi:10.4236/jct.2013.410176

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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.

Email: #[email protected]

Received November 4th, 2013; revised November 27th, 2013; accepted December 3rd, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-

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

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

C: typical carcinoid, AC: atypic al carcinoid, LCNEC: large cell neuroendocrine carcinoma, SCLC: small c ell lung cancer, HPF: high power fields.

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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

Open Access JCT

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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