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clinicopathological criteria also define the mitotic index of progressive, well-differentiated, non-functional endocrine
these tumors (number of mitoses per 2 mm in the area tumors of the lung or gastrointestinal tract to receive
2
of highest mitotic activity with the most viable tumor everolimus or placebo with the primary endpoint of PFS.
[41]
cells). [68,69] The mitotic index of typical carcinoid is < 2, Patients receiving everolimus had significantly improved
atypical carcinoid is 2-10, whereas SCLC and LCNECs median PFS of 7.1 months compared to placebo.
[41]
have mitotic indices > 10. [67,68] Lung tumors can also Sunitinib was studied in a phase II trial in patients with
be distinguished by grade, with TC classified as low relapsed or refractory SCLC and the treatment was poorly
grade, AC as intermediate grade and SCLC/LCNECs tolerated and resulted in limited gain in PFS. Tyrosine
[74]
as high grade. [68,69] Identity of these tumors is typically kinase inhibitors such as imatinib have also been studied in
confirmed by immunohistochemistry using the cellular pulmonary NETs with disappointing results. [75]
proliferation Ki-67, as well as neuroendocrine markers
such as synaptophysin, chromogranin A and neural cell The genetic basis of pulmonary NET formation has been
adhesion molecule (NCAM) to distinguish SCLC from explored in recent years. There are many cases of targeted
non-small cell lung cancer (NSCLC). TC have no necrosis analysis identifying inactivating mutations in TP53, RB1
and Ki-67 ≤ 5%, AC can have focal necrosis and Ki-67 and PIK3CA genes. [76-79] Genome-wide studies have
≤ 20% and SCLC have Ki-67 > 50%. Pulmonary NETs been performed [80-83] to identify copy number alterations,
may also exist, albeit at much lower incidence than other somatic single nucleotide variants and alterations in gene
pulmonary NETs, as heterogeneous, combination tumors expression associated with SCLC. From these studies,
consisting of mixtures of SCLC and LCNEC, or SCLC potential driver mutations were identified in cancer-
and NSCLC with neuroendocrine differentiation. These associated genes such as TP53, RB1, CREBBP, EP300,
[67]
mixed phenotypes may indicate clonal selection and/or MLL and the SOX family. A separate study conducted
phenotypic plasticity of a pluripotent cancer stem cell. whole genome sequencing of 110 SCLC and identified
biallelic inactivation of TP53, RB1, CREBBP, EP300,
Pulmonary NETs have a low incidence in the US, with a rate TP73, RBL1/2, as well as inactivating mutations in Notch
of 1.6/100,000 individuals. TCs comprise 1-2% and ACs family genes in 25% of cases. [83,84]
make up only 0.1-0.2% of all pulmonary tumors, whereas
SCLC and LCNET make up 20% and 1.6-3%, respectively. As with pancreatic NETs, cancer stem cells provide a
Overall survival is good for the well-differentiated TC plausible mechanism for drug resistance, recurrence and
tumors (92-100% OS) and moderate for AC (61-88% OS), metastasis of SCLC. However, due to limited availability
whereas the higher grade, poorly differentiated SCLC and of human clinical samples, the majority of the work to
LCNET have a grim prognosis with OS as low as 5%. identify markers of SCLC has been performed in cell
[70]
There are limited treatment options for pulmonary NETs lines by isolating side populations of cells with stem-
and the only curative therapies for TC and AC is surgery. like features. Using the SCLC cell lines NCI-H82, H146
[85]
These tumors are historically refractive to chemotherapy and H526, Salcido et al. isolated a population of cells
and exhibit response rates as low as 22%. In the case with high rates of proliferation, efficient self-renewal and
[71]
of advanced disease, such as that seen with patients decreased cell surface expression of CD56 and CD90.
initially presenting with SCLC and LCNEC, surgery is These isolated cells also overexpress many genes associated
rarely performed and systemic chemotherapy is the first with cancer stem cells and drug resistance, including genes
line treatment. Combination etoposide plus carboplatin involved in the Notch signaling pathway. In a separate
[85]
chemotherapy has high response rates (about 90%) study, a side population of cells was isolated from lung
but within 1 year the majority of tumors recur and are cancer cell lines established from primary tumors. This
[86]
refractory to further treatment. mTORC1 inhibitors side population was strongly positive for CD44 and co-
[71]
(everolimus, temsirolimus) have been used in combination expressed CD90, while having mesenchymal morphology,
with standard of care chemotherapy, but these compounds resistance to irradiation, and increased expression of stem
exhibited only moderate efficacy with the liability of dose- cell related genes Nanog and Oct4. CD133 is a common
[86]
limiting toxicities. mTOR inhibitors have also been cell surface antigen in SCLC stem cell populations and
[72]
combined clinically with SSAs in the RADIANT-2 trial was upregulated in cell populations as one of several stem
(NCT00412061) that included enteropancreatic NETs as cell markers in six separate studies from various SCLC
well as pulmonary TC and ACs. Subgroup analyses from cell lines. [87-92] In one of these studies, it was found that
this study found a median PFS of 5.6 months for the few CD133+ cells express increased neuropeptide receptors
TC and AC patients who received only the octreotide which revealed an avenue for therapeutic intervention.
[90]
LAR and no advantage for the patients receiving the Subsequent testing of neuropeptide receptor antagonists
combination therapy. A follow-up trial called the LUNA revealed that one of the analogs, Peptide 1, decreased
[73]
trial (NCT01563354) is a prospective, randomized, open- cell growth and increased apoptosis in SCLC cell lines.
label, three-arm design to study advanced lung (TC and Further, Peptide 1 produced a significant reduction in
AC) and thymic NET response to pasireotide LAR, tumor volume in mouse xenograft models, exhibiting very
everolimus or both in combination. The RADIANT-4 trial few CD133 positive cells after treatment, compared with
(NCT01524783) enrolled adult patients with advanced, tumors treated with etoposide. In other studies, inhibitors
[90]
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦ 283