Open Access

Clinicopathological characteristics and genetic analysis of pulmonary carcinoid tumors: A single‑center retrospective cohort study and literature review

  • Authors:
    • Xiongfei Li
    • Yuelong Hou
    • Tao Shi
    • Yue He
    • Dian Ren
    • Zuoqing Song
    • Sen Wei
    • Gang Chen
    • Jun Chen
    • Song Xu
  • View Affiliations

  • Published online on: January 24, 2020
  • Pages: 2446-2456
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Pulmonary carcinoid tumors, including typical and atypical carcinoids, are well‑differentiated neuroendocrine tumors (NETs) that represent 1‑2% of all lung cancer cases. In the present study, all cases of well‑differentiated NETs diagnosed at Tianjin Medical University General Hospital (Tianjin, China) between 2006 and 2016 were reviewed, and 20 pulmonary carcinoid cases were identified. The clinical features of these cases were summarized, and the results of pathological and imaging examinations were collated. As a low‑grade malignant pulmonary neoplasm, the molecular biological mechanism of pulmonary carcinoids is yet to be elucidated. To investigate the underlying molecular mechanisms behind pulmonary carcinoids and to determine an effective molecular targeted therapeutic strategy, next‑generation sequencing (NGS) was performed using tissue samples from six patients to determine additional molecular biological characteristics that may help guide targeted therapy. A total of 27 somatic mutations in 21 genes were detected. Of note, mutations in the KIT proto‑oncogene receptor tyrosine kinase, Erb‑B2 receptor tyrosine kinase 4, MET proto‑oncogene receptor tyrosine kinase and insulin‑like growth factor 1 genes occurred in two out of six cases. Since treatments for advanced carcinoids are relatively ineffective, molecular profiling may contribute to the identification of novel treatments. In addition, the literature on mutations in pulmonary carcinoids was reviewed and available clinical information and features of this tumor type were summarized.


Neuroendocrine tumors (NETs) are a subtype of neoplasms that can arise in the majority of organs and share a number of common biochemical and pathologic features (1). Pulmonary NETs comprise 20–30% of all NETs (2), and NETs in the lung can be divided into four subtypes according to their malignancy grade: Typical carcinoids (TCs), atypical carcinoids (ACs), large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung cancers (SCLCs). Of these subtypes, typical and atypical carcinoids are generally termed pulmonary carcinoids and constitute 1–2% of all pulmonary malignancies; however, their incidence has notably increased in recent decades; Petursdottir et al (3) reported that the incidence of PC increased from 1.9/1,000,000 (1955–1964) to 5.8/1,000,000 (2005–2015) per year in Iceland (4). Complete surgical resection is the primary choice of treatment for early-stage lung carcinoids (2). However, efficient management strategies for advanced-stage lung carcinoids are limited (2). As the development of precision medicine has progressed, molecular targeted therapy has achieved breakthroughs for the treatment of pulmonary carcinoids, including epidermal growth factor receptor (EGFR) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, bevacizumab and tyrosine kinase inhibitors (TKIs) (57). The present study aimed to analyze the clinicopathological characteristics of patients admitted to Tianjin Medical University General Hospital (Tianjin, China) center who underwent surgical resection for pulmonary carcinoids, and gene mutation profiling was performed to explore the underlying molecular mechanisms. In addition, gene mutation information of pulmonary carcinoids was summarized from relevant literature.

Materials and methods

Ethical approval

The present study was conducted in accordance with the standards of the Declaration of Helsinki for medical research involving human subjects. All subjects provided written informed consent, and the study protocol was approved by the clinical research ethical review board at Tianjin Medical University General Hospital (Tianjin, China).

Study design

Patient data were reviewed between January 2006 and December 2016 at Tianjin Medical University General Hospital, and information on 20 patients with lung carcinoid tumors with complete medical records was collected. The clinical features and imaging data from patient records were summarized. All pulmonary carcinoid cases were reviewed according to the World Health Organization criteria (2015) and were staged according to the American Joint Committee on Cancer staging manual (8th edition) criteria (8,9). Carcinoid tumors of the lung were classified as typical carcinoids (TCs) or atypical carcinoids (ACs) based on the following histological differences: The number of mitoses per 10 high-power fields (TC mitotic index, <2; AC mitotic index, 2–10; SCLC/LCNECs mitotic indices, >10) (10); the presence of necrosis; increased cellularity with disorganization; nuclear pleomorphism; hyperchromatism; and an abnormal nuclear: Cytoplasmic ratio (11,12). In general, macroscopic pulmonary carcinoid tissues appeared as smooth, highly vascular, gray-yellow and notably demarcated masses (1,9,13,14). The diagnosis of pulmonary carcinoid can be established by hematoxylin and eosin (HE) staining of a histopathologic section. However, immunohistochemical (IHC) staining is more precise for the diagnosis of pulmonary carcinoids compared with HE; specifically, staining for synaptophysin, chromogranin A and neural cell adhesion molecule (NCAM) can distinguish high-grade NETs (LCNECs and SCLCs) from pulmonary carcinoids (15).

Tissue sections (5 µm thick) were prepared from paraffin-embedded tissue blocks using formalin (10% methanol) solution as a fixative. The sections were stained using hematoxylin for 5 min and eosin (HE) for 1 min at room temperature.


Stainings for chromogranin A (CgA), synaptophysin (Syn), CD56, thyroid transcription factor 1 (TTF-1), P63, S-100, CK7 and Ki67 were performed by immunohistochemistry for six carcinoid tumors. The tumor tissue samples were fixed in formalin solution (10% methanol) for 48 h at room temperature. The tissues were dehydrated in xylene and graded ethanol series. After being immersed into paraffin wax twice at 60°C and embedded into paraffin blocks, the tumor tissues were cut into 5 µm thick sections. Tissues were deparaffinized in xylene and rehydrated in a graded ethanol series. Microwave pretreatment in 5 mM Tris-HCl (pH 10.0) for 15 min was performed to facilitate heat-induced antigen retrieval. After being rinsed in phosphate buffered saline (PBS), the sections were incubated with primary antibodies against CgA (1:100; Santa Cruz Biotechnology, Inc.; 1:100; cat. no. sc-393941), Syn (Santa Cruz Biotechnology, Inc.; 1:100; cat. no. sc-17750), CD56 (Santa Cruz Biotechnology, Inc.; 1:50; cat. no. sc-7326), TTF-1 (Santa Cruz Biotechnology, Inc.; 1:100; cat. no. sc-53136), P63 (Santa Cruz Biotechnology, Inc.; 1:50; cat. no. sc-25268), S-100 (Santa Cruz Biotechnology, Inc.; 1:100; cat. no. sc-53438), CK7 (Agilent Technologies, Inc.; 1:200; cat. no. M7018) and Ki67 (Santa Cruz Biotechnology, Inc.; 1:100; cat. no. sc-23900) at 4°C overnight. Subsequently, samples were incubated with a secondary antibody mouse IgGκ light chain binding protein (m-IgGκ BP) conjugated to horseradish peroxidase (HRP) (Santa Cruz Biotechnology, Inc.; 1:50; cat. no. sc-516102) for 30 min at room temperature. Diaminobenzidine was used for visualization and followed by hematoxylin for counterstaining at room temperature for 1 min. A light microscope was used to evaluate the staining results at ×100 magnification. All staining slides were evaluated by two researchers to evaluate samples individually.

Next-generation sequencing

The DNA of 20 lung carcinoid tumors was extracted using QIAamp DNA FFPE tissue kit (Qiagen) according to the manufacturer's instructions and evaluated, and via quality control (according to the extent of DNA degradation), six cases were selected for sequencing. Targeted capture sequencing of 56 cancer-associated genes was performed in 6 pulmonary carcinoid tumors (Lung core TM 56 genes; Burning Rock Biotech; Table SI).

The concentration of the DNA samples was measured using the Qubit dsDNA assay (Invitrogen; Thermo Fisher Scientific, Inc.) to ensure that the content of genomic DNA was ≥100 ng. The volume was adjusted to a total of 100 µl using 1X Tris-low EDTA buffer, and the solution was transferred to a Covaris microtube for fragmentation using Covaris M220 (Covaris, Inc.) according to the manufacturer's protocol. The DNA was fragmented (average DNA fragment size, 180–220 bp), which was followed by hybridization with the capture probe baits, hybrid selection with magnetic beads and PCR amplification. A high-sensitivity DNA assay was then used to assess the quality and size range. Available indexed samples were sequenced on a NextSeq 500 (Illumina, Inc.) bioanalyzer with pair-end reads.

Raw data from the NextSeq 500 runs were processed with Flexbar software (version 2.7.0) to generate clean FASTQ data, trim adapter sequences and filter and remove poor-quality reads (16). The depth for the sequencing in the present study was ~1,000 and Varscan (v. 2.3) was used to call single nucleotide variations and insertions/deletions with MAPQ >60, base quality >30 and allele frequency (AF) >1% (17). The variants that comprised >3 non-duplicated paired reads or >5 non-duplicated reads were considered as true mutations. Subsequently, clean FASTQ data were aligned to the hg19 (GRCH37) assembly using BWA-sample (Burrows Wheeler Aligner software; version 0.7.12-r1039;, and PCR duplicates were removed using the Mark Duplicates tool in Picard Tools (version 1.124, All variants were annotated using ANNOVAR (version 20160201) (18). Finally, variation frequency (>0.5%) was used to eliminate erroneous base calling and to generate final mutations, and manual verification was performed using Integrative Genomics Viewer version 2.3.72 (1921).

Statistical analysis

Clinicopathological characteristics of the patients with TC and AC were compared using the unpaired Student's t-test (for mean age and tumor diameter), Kruskal-Wallis test [pathological N and Tumor-Node-Metastasis (TNM) staging] and χ2 test (all other characteristics). A two-tailed P<0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed using SPSS 22.0 software (IBM Corp.).


Clinical features of the study cohort

The clinicopathological characteristics of 20 patients who underwent surgical resection for pulmonary carcinoid tumors at Tianjin Medical University General Hospital were reviewed and summarized (Table I). Generally, atypical carcinoids are less frequent and the ratio of TCs to ACs is 8–10:1 (4,22); however, of the 20 included cases, 9 were typical carcinoid tumors and 11 were atypical carcinoid tumors. The underlying reasons for this discrepancy are not clear. There was a male predominance in the included population (male:female, 15:5) and the age of patients ranged from 14–71 years with a median age of 48 years. None of the patients with TC tumors presented with lymphatic metastasis, whereas 5/11 (45.45%) patients with AC tumors had lymphatic metastasis, including three cases of N1 and two cases of N2 metastasis. The P-value of the Kruskal-Wallis test was 0.024, which indicated that ACs exhibited a higher malignancy stage. Other clinical characteristics, including the surgical approach, surgical procedure, prescribed adjuvant therapy, tumor sites and TNM stage were considered and compared between TC and AC, and no significant differences were observed (Table I).

Table I.

Clinicopathological characteristics of patients with pulmonary carcinoid who underwent surgical resection at Tianjin Medical University General Hospital (Tianjin, China).

Table I.

Clinicopathological characteristics of patients with pulmonary carcinoid who underwent surgical resection at Tianjin Medical University General Hospital (Tianjin, China).

Total pulmonary carcinoid tumors (n=20)

CharacteristicsTypical carcinoids (n=9)Atypical carcinoids (n=11)P-value
Median age (range), years48 (28–66)49 (14–71)0.396
Sex, n (%) 0.069
  Male5 (55.6)10 (90.9)
  Female4 (44.4)1 (9.1)
Smoking history, n (%) 0.653
  Never5 (55.6)5 (45.5)
  Current/former4 (44.4)6 (54.5)
History of malignancy, n (%)3 (33.3)4 (36.4)0.888
Median tumor diameter (range), cm4 (1.5–9.1)5.5 (2.1–12.5)0.252
Incidence of PET evaluation, n (%)4 (44.4)3 (27.3)0.423
Pathological N stage, n (%) 0.024
  N09 (100)6 (54.5)
  N10 (0)3 (27.3)
  N20 (0)2 (18.2)
TNM stage, n (%) 0.872
  I4 (44.4)5 (45.5)
  II2 (22.2)3 (27.3)
  III2 (22.2)2 (18.2)
  IV1 (11.1)1 (9.1)
Tumor site 0.946
  Left upper lobe1 (11.1)1 (9.1)
  Left lower lobe2 (22.2)3 (27.3)
  Left hilum1 (11.1)2 (18.2)
  Right upper lobe1 (11.1)0 (0)
  Right middle lobe1 (11.1)1 (9.1)
  Right lower lobe2 (22.2)2 (18.2)
  Right hilum1 (11.1)2 (18.2)
Surgical approach, n (%) 0.492
  VATS7 (77.8)7 (63.6)
  Thoracotomy2 (22.2)4 (36.4)
Procedure, n (%) 0.493
  Wedge1 (11.1)0 (0)
  Segmentectomy2 (22.2)2 (18.2)
  Lobectomy6 (66.7)9 (81.8)
Adjuvant therapy, n (%) 0.659
  Chemotherapy2 (22.2)2 (18.2)
  Radiotherapy1 (11.1)2 (18.2)

[i] PET, positron emission tomography; VATs, video-assisted thoracoscopic surgery; TNM, tumor-node-metastasis; patients were staged according to the American Joint Committee on Cancer staging manual (8th edition) criteria.

Computed tomography images of six patients whose samples were submitted for NGS analysis are presented in Fig. 1A. The imaging features of pulmonary carcinoids are often similar to those of other lung cancers and have few defining characteristics. The majority of carcinoids appear as round or ovoid peripheral lung nodules with smooth or lobular margins (23) and generally exhibit marked enhancement in enhanced CT due to their high vascularity (24). Representative images of HE and IHC staining are presented in Fig. 1B. The specific markers of the six carcinoid tumors were also summarized in Fig. 1C. The present analysis revealed that ACs exhibited a higher percentage of antigen Ki-67-positive cells and more mitoses per 10 high-power fields; and considering the diagnostic criteria of AC vs. TC, this result was logical and expected.

Gene mutation analysis of lung carcinoid tumors

The results of NGS are presented in Table II and Fig. 2. Following the gene mutation profiling of six pulmonary carcinoid tumors, a total of 27 mutations in 21 genes were identified, including JAK2, KIT proto-oncogene receptor tyrosine kinase (KIT), RB transcriptional coexpressor 1 (Rb), neurofibromin 1, TSC complex subunit 1 (TSC1), TSC2, Erb-B2 receptor tyrosine kinase 4 (ERBB4), NOTCH1, mitogen-activated protein kinase kinase 1, platelet-derived growth factor receptor α, ERBB2, MET proto-oncogene receptor tyrosine kinase (MET), EGFR, patched 1, insulin-like growth factor 1 receptor (IGF1R), kinase insert domain receptor, smoothened frizzled class receptor, CDK6, fibroblast growth factor receptor 1 (FGFR1), FGFR2 and CDK4. Of these, 11 were proto-oncogenes and 6 were tumor suppressor genes, which indicated that they may participate in tumorigenesis, tumor growth, invasion and metastasis.

Table II.

Gene mutations of patients with pulmonary carcinoids from our cohort.

Table II.

Gene mutations of patients with pulmonary carcinoids from our cohort.

CaseHistologyGeneAA changeMutation typeFrequency (%)
1TCJAK2K1030RMissense variant50.60
KITA755TMissense variant50.40
RB1F198LMissense variant9.23
NF1S1100TMissense variant2.24
2TCTSC2R57HMissense variant4.33
TSC1S1038RMissense variant3.12
TSC1S1039GMissense variant3.08
ERBB4R1155aNonsense variant2.51
NOTCH1E242KMissense variant2.26
KITP37S?Frameshift variant2.09
3TCERBB4I944VMissense variant35.80
MAP2K1D67NMissense variant2.89
PDGFRAR293HMissense variant2.56
ERBB2R47HMissense variant2.29
METR988CMissense variant1.68
EGFRNASplice donor variant1.15
4TCPTCH1K251TMissense variant49.00
IGF1RG8RMissense variant2.65
5TCMETV1088MMissense variant41.30
KDRA532VMissense variant2.35
6ACSMOP743TMissense variant47.50
CDK6I159KMissense variant7.72
IGF1RP1290LMissense variant4.38
FGFR1DDDD163DDeletion variant4.15
FGFR2L192Deletion variant3.56
IGF1RS1180FMissense variant2.63
CDK4V281EMissense variant2.06

{ label (or @symbol) needed for fn[@id='tfn2-ol-0-0-11347'] } TC, typical carcinoid; AC, atypical carcinoid; AA, amino acid

a termination codon which signals the end of translation.

The majority of the identified mutations were missense mutations (81.48%), followed by deletion mutations (7.4%) and one case each of nonsense, frameshift and splice donor mutations (Fig. 2A). All carcinoids had multiple mutated genes, and two patients (33.3%) had multiple mutations in a single gene, including the TSC1 and IGF1R genes (Fig. 2B). The KIT, ERBB4, MET and IGF1R genes were mutated in two patients (33.3%). These four genes were considered to be mutated at a high frequency (Fig. 2A) and were followed (in order of frequency) by 17 other genes that were each mutated in only one case (16.73% of cases) (Fig. 2A).

Two KIT mutations were identified on chromosome 4, but on different exons: Case 1 presented with a missense mutation (G>A mutation in exon 16; AF 50.4%), whereas case 2 presented with a frameshift mutation (A>AT mutation in exon 2; AF 2.09%) (Table II). Two ERBB4 mutations were revealed on chromosome 2. Case 2 harbored a nonsense G>A mutation in exon 27, whereas case 3 had a missense T>C mutation in exon 23, resulting in a 35.8% mutation frequency (Table II). The two MET mutations were both missense mutations on chromosome 7. Case 3 presented with a C>T base change in exon 14, whereas case 5 had a G>A base change in exon 15, yielding a 41.3% mutation frequency (Table II). A total of three IGF1R mutations were identified on chromosome 15 in two patients on different exons: Case 4 presented with a G>A mutation in exon 16, whereas case 6 presented with two C>T changes in exons 19 and 21.


As pulmonary carcinoid is a tumor with a low malignancy rate, resection is often an effective treatment option for early disease; however, for patients with advanced unresectable pulmonary carcinoids, no standardized or authoritative postoperative adjuvant therapy scheme has been established (25,26). In recent years, as the development of precision medicine has progressed, targeted therapy has achieved significant breakthroughs for pulmonary carcinoids, an example of which is mTOR inhibitors (57). However, the progression of therapy in pulmonary carcinoids is still limited due to its low prevalence (26), and an in-depth understating of the underlying molecular mechanisms is necessary. Thus, large-scale clinical drug research targeted at pulmonary carcinoids should be proposed as soon as possible. Surgical resection is appropriate for localized diseases; these include locoregional pulmonary carcinoids, cases with limited sites of metastatic disease and local recurrent diseases, such as liver metastases (26).

Pulmonary carcinoids are low-grade malignant tumors, and their underlying molecular biological mechanism is yet to be fully elucidated. To understand previous results of pulmonary carcinoid gene sequencing, published literature (PubMed; January 2018) on mutations in pulmonary carcinoids was examined, and available clinical information was summarized in Table III, comprising 13 studies that referenced 61 cases, including 29 ACs, 31 TCs and 1 indeterminate carcinoid (22,2738). The majority of the articles retrieved utilized first-generation sequencing technology to reveal mutations in single genes or chromosomes, including PI3K, p53TP53, Rb, menin 1, K-ras, c-Met, ELAV-like RNA-binding protein 4, 3p14 and 9p, and no significant associations were observed between specific gene mutations and cancer type, age or sex (22,2738). A total of three studies (including 21 patients) reported NGS data for carcinoids. The mutations of KIT, ERBB4 and MET were also reported in these studies, which supported the findings of the present study (2729). Notably, one study that used NGS to investigate carcinoids did not provide the original sequencing data and, consequently, the sequencing results were not summarized in Table III; however, it was reported in the study that FGFR1 was highly expressed in carcinoids (39). In addition, Rossi et al (40) also reported that ERBB4 alteration was detected in carcinoids. Recently, Asiedu et al (41) used mRNA expression, single nucleotide polymorphism genotyping and a combination of exome and whole-genome sequencing to detect genomic alterations in 31 TC and 11 AC tumors. Compared with the results of Asiedu et al (41), only a limited number of mutated genes were common to the genes identified using NGS in the present study. The differences between the current study and the previous studies may be attributable to the examination of different targeted gene panels and the different demographic of patients included. In the present study, four genes were revealed to be mutated at a high frequency, including KIT, ERBB4, MET and IGF1R, which were mutated in 33.3% patients. These genes encode typical tyrosine-protein kinases or receptor tyrosine kinases that are cell surface receptors for multiple signaling pathways and serve an essential role in the regulation of cell survival, proliferation and apoptosis (4245). Mutations in these genes are important therapeutic targets of molecular targeted therapeutic drugs, such as the TKIs imatinib and sunitinib (4245).

Table III.

Gene mutation analysis of pulmonary carcinoids from previously published literature.

Table III.

Gene mutation analysis of pulmonary carcinoids from previously published literature.

CaseAuthorYearAgeSexTypeMutation Gene/ChromosomeCountry(Refs.)
1Hiyama et al199377MACpoint mutation Cys>Phep53Japan(38)
Deletion mutationRb
2Lohmann et al199365FTCNeutral mutation Cys>Tyrp53Germany(22)
3 68MTCMissense mutation Glu>Lysp53
4 72FTCMissense mutation Val>Metp53
5Debelenko et al199746NATCFrameshift mutation 1650insCMEN1USA(37)
6 56NATCAlteration of splicing, frameshift mutation 764+3A>GMEN1
7 63NATCFrameshift mutation 134del13 (GACGCTGTTCCCG)MEN1
8 49NATCFrameshift mutation 1699delA and 1702G>CMEN1
9Sagawa et al1998NANAACpoint mutationK-rasUSA(36)
10Couce et al 52FACK-ras c12 Gly>Ser missense mutationK-rasUSA(35)
11 39FACK-ras c12 Gly>Asp missense mutationK-ras
12 61FACExon 8 c298 Glu>Stop missense mutationp53
13Sugio et al2003NANAACLoss of heterozygosity in 3p143p14Japan(34)
14 NANAACLoss of heterozygosity in 9p9p
15Snabboon et al200568FTCDeletion mutation at exon 10 (1793delG)MEN1Thailand(33)
16D'Alessandro et al201029FTCExon 5 c.733-16C>TELAVL4Italy(32)
17 50MTCExon 5 c.666A>TELAVL4
Exon 5 c.712C>TELAVL4
18 70FTCSomatic mutation Exon 4 c.424delAELAVL4
Exon 5 c.559G>AELAVL4
19 47MACExon 4 c.387C>TELAVL4
Single nucleotide polymorphismELAVL4
Exon 5 c.687T>C
c.1367+56C>T 3′UTRELAVL5
20 54MACSomatic mutation Exon 5ELAVL4
Exon 5 c.704G>AELAVL4
21Capodanno et al2012NANATCMissense mutation c.1576 A>GPI3KItaly(31)
22 NANATCMissense mutation c.1639 G>API3K
23 NANATCMissense mutation c.1639 G>API3K
24 NANATCMissense mutation c.1639 G>API3K
25 NANAACMissense mutation c.1639 G>API3K
26 NANATCMissense mutation c.2993 T>CPI3K
27 NANAACMissense mutation c.3007 T>CPI3K
28 NANAACMissense mutation c.3017 T>CPI3K
29 NANAACMissense mutation c.3022 T>CPI3K
30 NANATCMissense mutation c.3034 G>API3K
31 NANAACMissense mutation c.3041 A>GPI3K
32 NANAACMissense mutation c.3050 A>TPI3K
33 NANAACMissense mutation c.3062 A>GPI3K
34 NANATCMissense mutation c.3061 T>API3K
35 NANAACMissense mutation c.3068 G>API3K
36 NANATCMissense mutation c.3133 G>API3K
37 NANATCMissense mutation c.3145 G>API3K
38 NANATCMissense mutation c.3145 G>API3K
39 NANAACMissense mutation c.3155 C>TPI3K
40Voortman et al2013NANATCMissense mutation Exon 14 T1010I mutationc-MetUSA(30)
41Armengol et al201569MaleTCMissense mutation c.1796C>TBRAFFinland(29)
Missense mutation c.1496G>ASMAD4
Missense mutation c.3074C>TSMAD4
Missense mutation c.38G>AKRAS
42Vollbrecht et al2015NANAACMissense mutation c.311T>AEGFRGermany(28)
Missense mutation c.311T>AEGFR
Insertion mutation c.2516_2517insCGNAS
Deletion mutation c.1912delAKIT
Missense mutation c.1015C>TPTEN
43 NANAACDeletion and insertion mutationKDR
44 NANAACMissense mutation c.2744C>AERBB4
45 NANAACMissense mutation c.3788G>AAPC
Insertion mutation c.855_856insGFGFR1
Insertion mutation c.3730_3731insCMET
46 NANAACDeletion and insertion mutationRET
47 NANAACDeletion and insertion mutationERBB2
48 NANAACMissense mutation c.3367C>TAPC
Missense mutation c.112G>AKRAS
49 NANAACDeletion mutation c.862delGHNF1A
50 NANAACMissense mutation c.2602C>TERBB2
Missense mutation c.1100T>GSMO
51 NANAACDeletion and insertion mutationKIT
Missense mutation c.274C>TPI3K
Missense mutation c.167C>TSMARCB1
52 NANAACInsertion mutation c.3730_3731insCMET
53 NANATCDeletion and insertion mutationRET
54 NANATCMissense mutation c.3386T>CAPC
55 NANATCMissense mutation c.2624C>TERBB2
56 NANATCDeletion and insertion mutationERBB2
57 NANATCMissense mutation c.2531G>AGNAS
58 NANATCMissense mutation c.2318A>CEGFR
Missense mutation c.274T>AIDH1
Missense mutation c.267A>CIDH1
59 NANATCDeletion and insertion mutationPDGFRA
60 NANATCMissense mutation c.920C>TABL1
Missense mutation c.505C>TSMAD4
61Lou et al201723MaleNANAPI3KChina(27)

[i] NA, not available; Rb, RB transcriptional corepressor 1; MEN1, menin 1; ELAV4, ELAV-like RNA-binding protein 4; PI3K, phosphatidylinositol 3-kinase, putative; NA, not applicable.

Although certain high-frequency gene mutations were identified, it is difficult to confirm whether the alteration of these genes may initiate and promote pulmonary carcinoid tumors and be effective against targeted therapy. In the future, systematic gene mutation profiling should be performed with a large number of samples to detect potential tumor-promoting genes and to identify potential novel treatment targets for pulmonary carcinoids. This profiling may have important therapeutic implications for the treatment of patients with pulmonary carcinoids.

There are certain limitations the present study; only 6 PCs were collected and this is too few to predict more precise and comprehensive molecular principles of PCs and to conduct survival analysis.

In conclusion, IGF1R, ERBB4, KIT and MET were identified as frequently mutated genes that may influence the tumorigenesis of pulmonary carcinoid tumors; therefore, targeted therapy against these genes may represent a promising therapeutic strategy for the treatment of this rare disease.

Supplementary Material

Supporting Data


The authors would like to thank Dr Shannon Chuai, Dr Zhou Zhang and Dr Junyi Ye (Burning Rock Dx, Guangzhou, China) for their technical support and Dr Dongbo Xu (Department of Pathology, Tianjin Medical University General Hospital, Tianjin, China) for her assistance in the pathological evaluation.


The present study was supported by the National Natural Science Foundation of China (grant no. 81772464), the Tianjin Key Project of Natural Science Foundation (grant no. 17JCZDJC36200), the Tianjin Science and Technology Plan Project (grant no. 19ZXDBSY00060), the Science & Technology Foundation for Selected overseas Chinese scholar Ministry of personnel of China, the Science & Technology Foundation for Selected overseas Chinese scholar Bureau of personnel of China Tianjin and the Tianjin Medical University General Hospital Young Incubation Foundation (grant no. ZYYFY2017040).

Availability of data and materials

The datasets used during the present study are available from the corresponding author upon reasonable request.

Authors' contributions

SX and JC conceived and designed the study. ZS, SW, GC and JC performed surgery. XL, YLH, TS and DR reviewed the patient electronic medical record for patients with pulmonary carcinoid. XL, YLH, TS and YH performed the genetic analysis. XL and YH performed the literature review and wrote the manuscript. SX and JC reviewed and edited the manuscript. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

The present study was conducted in accordance with the Helsinki Declaration and was approved by the Ethics Committee of Tianjin Medical University (Tianjin, China). Written informed consent was obtained from all patients with pulmonary carcinoid for blood sampling and tissue sequencing.

Patient consent for publication

Not applicable.

Competing interests

YH is affiliated with Burning Rock Biotech, who performed targeted capture sequencing of cancer-associated genes. The other authors declare that they have no competing interests.



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Li X, Hou Y, Shi T, He Y, Ren D, Song Z, Wei S, Chen G, Chen J, Xu S, Xu S, et al: Clinicopathological characteristics and genetic analysis of pulmonary carcinoid tumors: A single‑center retrospective cohort study and literature review. Oncol Lett 19: 2446-2456, 2020
Li, X., Hou, Y., Shi, T., He, Y., Ren, D., Song, Z. ... Xu, S. (2020). Clinicopathological characteristics and genetic analysis of pulmonary carcinoid tumors: A single‑center retrospective cohort study and literature review. Oncology Letters, 19, 2446-2456.
Li, X., Hou, Y., Shi, T., He, Y., Ren, D., Song, Z., Wei, S., Chen, G., Chen, J., Xu, S."Clinicopathological characteristics and genetic analysis of pulmonary carcinoid tumors: A single‑center retrospective cohort study and literature review". Oncology Letters 19.3 (2020): 2446-2456.
Li, X., Hou, Y., Shi, T., He, Y., Ren, D., Song, Z., Wei, S., Chen, G., Chen, J., Xu, S."Clinicopathological characteristics and genetic analysis of pulmonary carcinoid tumors: A single‑center retrospective cohort study and literature review". Oncology Letters 19, no. 3 (2020): 2446-2456.