Dissecting the prognostic role of metabolic markers in lung neuroendocrine Tumors: The MONET study.

Correlation between FDG uptake and glucose transporter type 1 expression in neuroendocrine tumors of the lung

Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and belongs to the family of pulmonary neuroendocrine tumors. This tumor subgroup additionally includes large-cell neuroendocrine carcinomas (LCNEC) and pulmonary carcinoids (PCA), which occur in 3% and 2% of all lung cancer patients, respectively. Carcinoids are usually clinically benign, whereas SCLC and LCNEC are characterized as high-grade malignant tumors. Clinical and histologic studies have suggested similarities between SCLC and LCNECs: Both lung tumor subtypes are associated with heavy smoking and reveal an aggressive tumor growth resulting in a poor overall survival. We have performed comprehensive and multilevel genomic profiling on SCLC and LCNECs, including genome, exome, and transcriptome sequencing. SCLC and LCNEC tumors reveal high mutation rates with an average of 9.5 and 8.6 mutations per megabase, respectively. Our sequencing studies have shown that SCLC tumors are characterized by bi-allelic inactivation of TP53 and RB1 in almost 100% of the cases. LCNECs, on the other hand, are composed of two mutually exclusive subgroups, which we categorized as “type I LCNECs” and “type II LCNECs.” Type I LCNECs harbor TP53 and STK11 or KEAP1 alterations. Despite sharing genomic alterations with lung adenocarcinomas and squamous cell carcinomas, type I LCNECs exhibit a high neuroendocrine profile with close similarity to SCLC tumors. Type II LCNECs harbor loss of TP53 and RB1, thus showing genetic resemblance to SCLC. However, these tumors were revealed to be different from the majority of SCLC with reduced levels of neuroendocrine markers, an upregulated immune signaling profile, and high activity of the NOTCH pathway. Conclusively, our studies show marked biologic differences between high-grade neuroendocrine lung tumors and we emphasize the precise distinction of LCNEC subgroups from SCLC. Citation Format: Julie George. The genomic landscape of SCLC and other neuroendocrine lung tumors [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA28.

Controversial issues and new discoveries in lung neuroendocrine tumors

Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors

Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations

Large Cell Neuroendocrine Carcinoma of the Lung Metastatic to the Shoulder Joint, Causing Suprascapular Nerve Palsy

Lung neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms comprising four histologic types, namely typical and atypical carcinoid (TC and AC), large-cell neuroendocrine and small cell carcinoma (SCC). Classification criteria include the number of mitoses per 2 mm2, the occurrence and extent of necrosis, cytological and histological features and immunohistochemistry for neuroendocrine markers. The classification system and the diagnostic workflow of lung NETs are apparently easy to apply and well established. However, several unresolved issues still exist in classification and pathological characterization of these tumors, probably because inter-observer diagnostic reproducibility remains disappointing, likely due to inconsistency in recognizing necrosis, mitoses and cytological details, especially in small biopsy or cytological materials. Furthermore, the lack of strong prognostic and grading criteria leads to the incomplete interpretation of some rare intermediate entities that stand in between AC and large cell neuroendocrine carcinoma (LCNEC) categories.

Ki-67 Antigen in Lung Neuroendocrine Tumors: Unraveling a Role in Clinical Practice

Tumor spread through air spaces (STAS) is an important prognostic factor for lung cancer, including lung neuroendocrine tumors (NETs). The comparative oncological efficacy of lobar resection (LR) and sub-lobar resection (SR) for clinical stage IA (cIA) STAS-positive NETs remains unclear. This retrospective study aimed to review outcomes in patients with consecutive peripheral cIA (tumors ≤ 2cm) STAS-positive NET patients (excluding small cell lung cancer) who underwent surgery between 2012 and 2020 at six high-volume tertiary Chinese institutions. SR was commonly performed for patients ineligible for LR for various reasons. The primary endpoint was recurrence-free survival (RFS), while the secondary endpoint was overall survival (OS). Propensity score matching (PSM) was utilized to minimize selection bias. Among the 599 eligible patients, PSM resulted in 328 LR and 164 SR cases with well-balanced baseline characteristics. During a median follow-up of 6.8 years, LR significantly improved 5-year RFS (68.3% versus 54.3%, hazard ratio (HR) [95% confidence interval (CI)] = 0.595 [0.449-0.787], P < 0.001) and OS (79.0% versus 72.6%, HR [95%CI] = 0.650 [0.484-0.872], P = 0.025), and reduced postoperative recurrence (34.5% versus 51.2%, P < 0.001) and mortality (32.3% versus 46.3%, P = 0.002) rates compared to SR. Subgroup analysis revealed that LR improved RFS (59.2% versus 42.5%, HR [95%CI] = 0.553 [0.408-0.749], P < 0.001) and OS (74.0% versus 63.7%, HR [95%CI] = 0.710 [0.509-0.989], P = 0.043) compared to SR in patients with large cell neuroendocrine carcinoma (LCNEC), while both approaches yielded comparable prognoses in patients with carcinoid. Furthermore, segmentectomy exhibited survival outcomes comparable to those of wedge resection. Collectively, LR demonstrated better survival outcomes than SR for cIA STAS-positive NETs, with the benefit being influenced by the tumor histology. LCNEC was associated with a 3.3-fold higher risk of recurrence and a 4.0-fold higher risk of mortality than carcinoid.

Small cell lung cancer (SCLC) is accounting for 15% of all lung cancer cases and belongs to the family of pulmonary neuroendocrine tumors. This tumor entity additionally includes large-cell neuroendocrine carcinomas (LCNEC) and pulmonary carcinoids (PCA), which occur in 3% and 2% of all lung cancer patients, respectively. Whereas lung carcinoids are clinically benign, SCLC and LCNEC are characterized as high-grade malignant tumors, which are associated with heavy smoking and a poor 5-year survival rate of less than 5%. We aimed to characterize the genomic alterations in neuroendocrine lung tumors and performed whole genome, whole exome and transcriptome sequencing on up to 110 SCLC cases, over 40 pulmonary carcinoids and over 50 LCNEC tumors. SCLC and LCNEC tumors reveal high mutation rates with an average of 9.5 and 8.6 mutations per megabase, respectively. Our sequencing studies have shown that SCLC tumors are characterized by bi-allelic inactivation of TP53 and RB1 in almost 100% of the cases. Recurrent significant genomic alterations affected among others TP73 (13%) and NOTCH family genes (25%). Further studies in a pre-clinical mouse model confirmed NOTCH as tumor suppressor and as a regulator of neuroendocrine differentiation in SCLC (George et al., 2015). LCNEC tumors showed TP53 and RB1 alterations in up to 20% of the cases. Additionally, LCNECs were found with STK11 and KEAP1 mutations, which occurred mutually exclusive to RB1 alterations (P&amp;lt;0.05). In light of these distinct mutational characteristics, we analyzed the transcriptome sequencing data of neuroendocrine lung tumors in comparison to lung adenocarcinomas (LUAD) and lung squamous cell carcinomas (LUSQ). An unsupervised clustering approach led to the identification of five expression clusters: LUAD, LUSQ and PCA formed distinct transcriptional classes; the majority of SCLC and LCNEC tumors clustered into two subgroups. While a few LCNEC tumors clustered with LUAD, LUSQ and PCA, RB1-mutated LCNEC tumors predominantly clustered with SCLC samples (P &amp;lt;0.05). KEAP1 and STK11 mutated LCNECs did not segregate with a particular histological tumor type. Neuroendocrine lung tumors confirmed high expression levels of neuroendocrine markers. A detailed comparison of LCNEC and SCLC tumors revealed that the majority of the SCLC and a few LCNEC tumors were found in a transcriptional group that showed high expression of the neuroendocrine lineage transcription factor ASCL1, gastrin releasing peptide (GRP) and DLL3, which was less pronounced in transcriptional subsets formed by the majority of LCNEC tumors. Patient tumors that clustered to the transcriptional class marked by higher ASCL1 expression were identified to have a worse overall survival (P&amp;lt;0.05). In summary, these findings point to transcriptional differences in SCLC and LCNEC tumors and emphasize the precise analysis of these histological tumor types with respect to their molecular biology and therapeutic treatment option. Citation Format: Julie George, Lynnette Fernandez-Cuesta, Vonn Walter, Neil Hayes, Roman Thomas. Comparative analysis of small cell lung cancer and other pulmonary neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 122.

Neuroendocrine tumors of the lung represent a broad spectrum of morphologic types that share specific morphologic, immunohistochemical, ultrastructural, and molecular characteristics. The classification of neuroendocrine lung tumors has changed over the last decades and currently four categories are distinguished: typical carcinoid tumor, atypical carcinoid tumor, large cell neuroendocrine carcinoma and small cell carcinoma. Neuroendocrine tumors of the lung comprise approximately 20% of all primary lung cancers. Among them, the most frequent is small cell carcinoma (13-17%). Because of differences in clinical behavior, therapy, and prognosis, a reliable histological diagnosis, as well as clinical and pathological staging system are essential for an appropriate medical proceedings. The most effective treatment of bronchial carcinoids and large cell neuroendocrine carcinoma in an early stage is complete surgical resection, whereas chemotherapy remains the primary treatment for small cell carcinoma. All carcinoids are malignant tumors with the potential to metastasize. The majority of patients with pulmonary carcinoid have an excellent survival, even if they present with lymph node metastases. Large cell neuroendocrine and small cell carcinoma progress rapidly and are generally widespread at the moment of diagnosis. Their overall prognosis is poor. Increased knowledge about pulmonary neuroendocrine tumors biology and the genetic characteristics, imply that carcinoid tumors appear to have a different etiology and pathogenesis than large cell neuroendocrine and small cell carcinoma. In practice, it could be easiest to conceptualize this group of pulmonary tumors as a spectrum of malignancy ranging from the low grade typical carcinoid to the highly malignant large cell neuroendocrine and small cell carcinoma. Typical carcinoid tumors associated with a fairly benign behavior should be classified as low-grade neuroendocrine tumor/carcinoma (G1) and atypical carcinoid tumors as intermediate-grade tumor/carcinoma (G2). Whereas, large cell neuroendocrine and small cell carcinoma should be grouped together under the designation of high-grade neuroendocrine tumor/carcinoma (G3).

EP1.12-40 Neuroendocrine Tumors of the Lung: Clinico-Pathological Characterization and Follow-Up of Patients Treated at an Argentinean University Hospital in the Last 10 Years

Reproducibility of neuroendocrine lung tumor classification

ES04.02 Pathology Overview for Carcinoid and NE Spectrum

Simple SummaryNeuroendocrine tumors are a rare group of neoplasms characterized by strikingly heterogeneous pathological features and clinical behavior. The incidence and prevalence of these tumors are rising. Studies have reported the incidence and prevalence of neuroendocrine tumors; however, specific data targeting lung neuroendocrine tumors are lacking. We conducted a retrospective analysis using a national database to report the incidence and survival trends of lung neuroendocrine neoplasms. We found that the overall survival and disease-specific survival trends varied significantly not only by stage and histological type but also by age, race, marital status, and insurance type. A small difference was also noted between the rural and urban populations. The rarity of these tumors poses several diagnostic and therapeutic challenges. Our findings generate the following hypothesis that increased awareness of these tumors, as well as better diagnostic modalities, may contribute to a higher incidence. Furthermore, newer therapeutic advances may have caused an improvement in the survival trends in recent years. Such population-based analysis is important to allot resources and guide future research in the field.Background: The incidence and prevalence of neuroendocrine neoplasms (NENs) are rapidly rising. Epidemiologic trends have been reported for common NENs, but specific data for lung NENs are lacking. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Associated population data were utilized to report the annual age-adjusted incidence and overall survival (OS) trends. Trends for large-cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) were reported from 2000–2015, while those for typical carcinoid (TC) and small cell lung cancer (SCLC) were reported from 1988–2015. Results: We examined a total of 124,969 lung NENs [103,890—SCLC; 3303—LCNEC; 8146—TC; 656—AC; 8974—Other]. The age-adjusted incidence rate revealed a decline in SCLC from 8.6 in 1988 to 5.3 in 2015 per 100,000; while other NENs showed an increase: TC increased from 0.57 in 1988 to 0.77 in 2015, AC increased from 0.17 in 2001 to 0.22 in 2015, and LCNEC increased from 0.16 in 2000 to 0.41 in 2015. The 5-year OS rate among SCLC, LCNEC, AC, and TC patients was 5%, 17%, 64%, and 84%, respectively. On multivariable analyses, OS and disease-specific survival (DSS) varied significantly by stage, sex, histological type, insurance type, marital status, and race, with a better survival noted in earlier stages, females, married, insured, Hispanic and other races, and urban population. Similarly, TC and AC had better survival compared to SCLC and LCNEC. Conclusion: The incidence of lung NENs is rising, possibly in part because of advanced radiological techniques. However, the incidence of SCLCs is waning, likely because of declining smoking habits. Such population-based studies are essential for resource allocation and to prioritize future research directions.