Management of Neuroendocrine Tumors: NETs of Lung

Origin
Marianne Pavel, MD; Piero Ferolla, MD, PhD

Faculty and Disclosures

CME Released: 05/13/2011; Valid for credit through 05/13/2012

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An estimated 25% to 30% of all neuroendocrine tumors (NETs) have their origin in the bronchial
tract and lungs.[1,2]Although lung NETs account for fewer than 1% of all pulmonary neoplasms,
the incidence of these neoplasms has risen precipitously since the mid 1970s (Figure).[3]

Figure. Rising incidence of neuroendocrine tumors of the lung (United States, 1973-2005).
From Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.[3]
Differential Diagnosis
Lung NETs vary widely in their pathology, from low- and intermediate-grade NETs (typical and
atypical carcinoid, respectively) to aggressive and rapidly fatal small cell lung cancer
(SCLC).[1,4] Histologic differentiation of these tumors can be challenging and is critical to effective
treatment (Table).
Table. Neuroendocrine Tumors of the Lung

Tumor Type

Diagnostic Criteria

Typical carcinoid

< 0.5 cm
< 2 mitoses per 2 mm2 (10 HPF*)
No necrosis
Carcinoid morphology

Atypical carcinoid

2-10 mitoses per 2 mm2 (10 HPF) or necrosis (punctate)

Carcinoid morphology

Large cell neuroendocrine

carcinoma

11 mitoses per 2 mm2 (10 HPF), median 70 per 2 mm2 (10

HPF)
Necrosis (large zone)
Neuroendocrine morphology (organoid nesting, palisading,
rosettes, trabeculae)
Cytologic features of a non-small cell lung carcinoma

Small cell carcinoma

11 mitoses per 2 mm2 (10 HPF), median 80 per 2 mm2 (10

HPF)
Necrosis (large zones)
Scant cytoplasm, finely granular nuclear chromatin, absent or
faint nucleoli
*

10 high-power fields (HPF) in a microscope with field of view of 0.2 mm2

From Travis WD. Annals of Oncology. 2010;21(Supplement 7):vii65vii71[2]; Bertino EM, et

al. Cancer. 2009;115:4434-4441.[4]
Although NETs of the lung arise from cells capable of producing serotonin and
adrenocorticotropin hormone, hypersecretion of bioactive amines is comparatively rare in typical
and atypical carcinoids of the lung.[1,4] Symptoms characteristic of carcinoid lung NETs -including obstructive pneumonia, atelectasis, and wheezing -- are more commonly the result of
central airway obstruction due to tumor mass.[4]
Treatment
Surgery is the primary treatment for typical and atypical carcinoid lung NETs. 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 cases of typical carcinoid lung NETs, and 5-year survival exceeds 90%.[2]
Lung NETs are typically underrepresented in clinical trials of NET treatments. In recent years,
only a phase 2 retrospective study of the dacarbazine derivative temozolomide[5] and the phase
3 RAD001 in Advanced Neuroendocrine Tumors Trial 2 (RADIANT-2)[6] have reported results
specific to lung NETs. Ekeblad and colleagues performed a retrospective analysis of 36 patients
with histologically confirmed metastatic or inoperable malignant NETs treated with oral
temozolomide (100-200 mg/m2/d for 5 days every 28 days). The study group included 10
patients with typical carcinoid NETs and 3 with atypical carcinoid NETs. After a median followup of 7 months (range, 217 months), 31% of patients with lung carcinoids had stable disease
and 31% showed a partial radiologic response. The most frequently reported adverse event was
grade 1-2 stomachache (N = 6), and 4 patients required dose reductions due to hematologic
toxicity.[5]
In RADIANT-2, which evaluated the impact of combination therapy with the oral mammalian
target of rapamycin (mTOR) inhibitor everolimus and the somatostatin analogue octreotide LAR
in patients with advanced NET and carcinoid symptoms, only 6.9% of patients in the
experimental arm and 2.3% of patients in the control arm were diagnosed with lung NETs.
Patients were randomly assigned to receive octreotide LAR 30 mg intramuscularly every 28
days plus everolimus 10 mg per day (N = 216) or octreotide LAR plus placebo (N = 213).
Although treatment with everolimus plus octreotide was associated with longer progression-free
survival overall -- 16.4 months vs 11.3 months in control patients (P = 0.026) -- patients with
lung NETs had more favorable outcomes with octreotide plus placebo.[6]
Summary
The role of targeted therapy for typical and atypical carcinoid lung NETs remains incompletely
defined, with data from relatively few clinical trials to help guide clinical decision making. Recent
in vitro studies indicate that somatostatin receptors are overexpressed in metastatic typical
carcinoid tumors of the lung[7] and that the mTOR is found in most lung NETs -- with higher
expression in typical and atypical carcinoids.[8] In addition, a recent preclinical study of the
impact of the mTOR inhibitor everolimus found that it suppressed the viability of typical and
atypical carcinoid lung cells in culture.[9] Further research is needed to clarify the role of

somatostatin analogues, mTOR inhibitors, and other targeted therapies on these diverse and
clinically challenging tumors.
In the accompanying discussion, Drs. Marianne Pavel and Piero Ferolla review a case that
illustrates the challenges inherent in the management of patients with lung NETs.