Lung Neuroendocrine Tumors Research Articles

ODP300 c-MET expression in MEN1-associated neuroendocrine tumors

Abstract Multiple studies have shown that approximately 50-70% of patients with MEN1 die of causes directly related to MEN1 particularly gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). While non-functional GEP-NETs are the most common in the general population, gastrinomas (40%) are the most common functional GEP-NETs in patients with MEN1. c-MET is a proto-oncogene that encodes for c-MET, a tyrosine kinase receptor which promotes tumor cell motility, proliferation, survival, invasion, and metastasis. Studies in patients with sporadic gastrinomas and pancreatic NETs (PNETs) have shown that c-MET expression correlates with decreased survival. While c-MET inhibitors are currently in various stages of investigation for treatment of carcinoids and sporadic PNETs, data regarding their efficacy in patients with MEN1-related GEP NETs is lacking. The majority of trials in patients with GEP-NETs exclude or do not report the number of patients with MEN1. Importantly, somatic MEN1 mutations are observed in 20-40% of sporadic NETs (gastrinomas, PNETs, lung NETs, etc.) but correlation of cMET expression with the presence of somatic or germline MEN1 mutations has not been reported. We sought to investigate the expression of c-MET in tumor tissue from germline MEN1 patients with metastatic GEP-NETs. Methods We identified subjects with a germline positive MEN1 mutation and pathologically confirmed distant metastasis who had a follow-up visit between 2018-2020. Of these, we selected subjects with available tissue specimens (including either multiple organ sources or different tumor types). Where available, we identified specimens from multiple source or tumor types. Immunohistochemistry (IHC) to detect c-MET was performed with anti-MET (Cell Signaling) using the DAKO IHC kit (Agilent). IHC slides were imaged and observed to score the level of c-MET staining (-, 1+ to 5+). A score of 3+ or higher was considered consistent with overexpression. We investigated if age at initial GEP-NET presentation, tumor type, tissue source, tumor grade, total number of surgeries for GEP-NET, number of sites of distant metastasis and disease status from overall GEP-NET burden over the preceding 12 months (stable/progressive) predicted c-MET expression. Results Eight subjects with available tissue specimens were identified, of which six had tissue from multiple organs while five had tissue from multiple tumor types. Six subjects (75%) showed increased expression of c-MET in one or more tumor specimen(s). The frequency of c-MET overexpression varied with tumor types – carcinoids (n=2/2; 100%), gastrinomas (n=3/5; 60%) and non-functional tumors (n=3/6; 50%). c-MET expression also varied among different tumors in the same patient. Tumor tissue from liver (n=2/2), duodenum (n=3/4), stomach (n=1/1), ovary (n=1/1), pancreas (n= 1/5), and lymph nodes (n=1/3), all showed over-expression of c-MET. No clear predictors of c-MET overexpression emerged. Conclusion Our finding suggests a role for c-MET expression in personalizing therapy for patients with MEN1-related NETs with distant metastases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m.

Tumores neuroendocrinos pulmonares, cáncer de pulmón de células pequeñas y tumores metastásicos en el pulmón

Lung neuroendocrine tumors encompass an extensive spectrum of lung tumors. They range from neoplasms with lower metastatic potential to others with a high degree of malignancy that represent approximately 19% of all primary malignant bronchopulmonary tumors. The most frequent is small-cell lung carcinoma (79%) followed by large cell neuroendocrine carcinoma (16%) while typical and atypical carcinoids represent the approximately 5% of remaining tumors. In limited stages, the treatment of choice is a combination of cisplatin and etoposide along with concurrent radiotherapy. In advanced disease, the treatment approach is systemic and based mainly on chemotherapy (CT). However, at present, immunotherapy plays an important role in the treatment of microcytic lung carcinoma and was included as first-line therapy together with CT. The lungs are the second most common location of metastatic disease, encompassing all histological types (almost 30% of cases) and are the only site of metastasis in 20% of cases.

NOL4 is a novel nuclear marker of small cell carcinoma and other neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) such as small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have characteristic histologies, but immunohistochemistry using neuroendocrine markers is still desirable to confirm diagnosis. CD56 is the most sensitive marker, but also stains various normal tissues and other tumors. Recently, we reported that nucleolar protein 4 (NOL4) is present in the blood of SCLC patients and found it was stained in the SCLC nuclei. In this study, we compared expressions of NOL4 and CD56, using 64 cases of SCLC, 18 cases of LCNEC, 6 cases of atypical carcinoid tumor, 7 cases of typical carcinoid tumor, 68 cases of lung adenocarcinoma, and 62 cases of lung squamous cell carcinoma. For primary lung NENs, sensitivity, specificity, positive predictive value (PPV) and negative predictive value of NOL4 were 77.5%, 95.8%, 93.2%, and 85.1%, respectively, while those of CD56 were 92.1%, 93.3%, 91.1%, and 94.1%. The specificity and PPV of NOL4 were higher than those of CD56, although the differences were not statistically significant. However, NOL4 retains its nuclear immunoreactivity in areas of crush artifact or necrosis. Furthermore, NOL4 was not expressed in adjacent normal tissues including bronchial cells and pneumocytes. Therefore, a combination of NOL4 staining with other cytoplasmic or membranous neuroendocrine markers might enhance diagnostic utility for SCLC and other NENs.

WIN Symposium 2022 - Abstract Poster Presentations.

WIN Symposium 2022 - Abstract Poster Presentations.

Lung carcinoid tumours: histology and Ki-67, the eternal rivalry.

WHO classification of Thoracic Tumours defines lung carcinoid tumours (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated. A retrospective series of 370 LCT from two oncology centers was centrally reviewed. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR-2A, Ascl1, and p53) were studied and correlated with Overall Survival (OS), Cancer-specific survival (CSS) and Disease-free survival (DFS). Carcinoid histology was confirmed in 355 patients: 297 (83.7%) TC and 58 (16.3%) AC. Ki-67 at 3% was the best value in predicting DFS. Ki-67 ≥ 3% tumours were significantly associated with AC histology, stage III-IV, smoking, vascular invasion, tumour spread through air spaces OTP negativity, and TTF-1, Ascl1 and p53 positivity. After adjustment for center and period of diagnosis, both Ki-67 (≥3 versus <3) and histology (AC versus TC) alone significantly added prognostic information to OS and CSS multivariable model with age, stage and OTP; addition of both variables did not provide further prognostic information. Conversely, an improved significance of the DFS prediction model at multivariate analysis was seen by adding Ki-67 (≥3 versus <3, P adj=0.01) to TC and AC histological distinction, age, lymph node involvement, residual tumour and OTP. Ki-67 ≥ 3% plays a potentially pivotal role in LCT prognosis, irrespective of histological grade.

Angioside: The role of Angiogenesis and Hypoxia in Lung Neuroendocrine Tumours According to Primary Tumour Location in Left or Right Parenchyma.

Well-differentiated lung neuroendocrine tumours (Lu-NETs), classified as typical (TC) and atypical (AC) carcinoids, represent 30% of NETs. Angiogenesis plays an essential role in NET development and progression. A higher vascular network is a marker of differentiation, with positive prognostic implications. Materials and Methods: We retrospectively evaluated microvessel density (MVD) by CD34 immunohistochemical (IHC) staining and hypoxia by IHC staining for Hypoxia-inducible factor 1α (HIF-1α), comparing right- and left-lung parenchyma in 53 lung NETs. Results: The median age was 66 years (39–81), 56.6% males, 24.5% AC, 40.5% left-sided tumours and 69.8% TNM stage I. The mitotic count was <2/10 per 10 HPF in 79.2%, and the absence of necrosis in 81.1%, 39.6% with Ki67, was ≤2%. The MVD, the number of vessels and the average vessel area median values were significantly higher in the right than the left parenchyma (p: 0.025, p: 0.019, p: 0.016, respectively). Hypoxia resulted present in 14/19 (73.6%) left tumours and in 10/20 (50%) right tumours in the parenchyma (p: 0.129). Conclusions: This study suggests a biological rationale for a different angiogenesis and hypoxia according to the Lu-NETs’ location. In our study, left primary tumours were less vascularized and most likely to present hypoxia than right primary tumours. This finding could have potentially useful prognostic and predictive implications for Lu-NETs.

Incidence of psychiatric illness in patients with neuroendocrine tumors: a comparative population-based analysis.

Diversion of tryptophan to tumoral hormonal production has been suggested to result in psychiatric illnesses in neuroendocrine tumors (NET). We measured the occurrence of psychiatric illness after NET diagnosis and compare it to colon cancer (CC). We conducted a population-based retrospective cohort study. Adults with NET were matched 1:1 to CC (2000-2019). Psychiatric illness was defined by mental health diagnoses and mental health care use after a cancer diagnosis, categorized as severe, other, and none. Cumulative incidence functions accounted for death as a competing risk. A total of 11,223 NETs were matched to CC controls. Five-year cumulative incidences of severe psychiatric illness for NETs vs. CC was 7.7% (95%CI 7.2-8.2%) vs 7.6% (95%CI 7.2-8.2%) (p = 0.50), and that of other psychiatric illness was 32.9% (95%CI 32.0-33.9%) vs 31.6% (95%CI 30.8-32.6%) (p = 0.005). In small bowel and lung NETs, 5-year cumulative incidences of severe (8.1% [95%CI 7.3-8.9%] vs. 7.0% [95%CI 6.3-7.8%]; p = 0.01) and other psychiatric illness (34.7% [95%CI 33.3-36.1%] vs. 31.1% [95%CI 29.7-32.5%]; p < 0.01) were higher than for matched CC. The same was observed for serotonin-producing NETs for both severe (7.9% [95%CI 6.5-9.4%] vs. 6.8% [95%CI 5.5-8.2%]; p = 0.02) and other psychiatric illness (35.4% [95%CI 32.8-38.1%] vs. 31.9% [95%CI 29.3-34.4%]; p = 0.02). In all NETs, there was no difference observed in the incidence of psychiatric illness compared to CC. For sub-groups of small bowel and lung NETs and of serotonin-producing NETs, the incidence of psychiatric illness was higher than for CC. These data suggest a signal towards a relationship between those sub-groups of NETs and psychiatric illness.

BRONCHOPULMONARY CARCINOID AND TYPE 1 MULTIPLE ENDOCRINE NEOPLASIA (MEN)

BRONCHOPULMONARY CARCINOID AND TYPE 1 MULTIPLE ENDOCRINE NEOPLASIA (MEN)

Construction and validation of nomograms based on the log odds of positive lymph nodes to predict the prognosis of lung neuroendocrine tumors.

BackgroundThis research aimed to investigate the predictive performance of log odds of positive lymph nodes (LODDS) for the long-term prognosis of patients with node-positive lung neuroendocrine tumors (LNETs).MethodsWe collected 506 eligible patients with resected N1/N2 classification LNETs from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The study cohort was split into derivation cohort (n=300) and external validation cohort (n=206) based on different geographic regions. Nomograms were constructed based on the derivation cohort and validated using the external validation cohort to predict the 1-, 3-, and 5-year cancer-specific survival (CSS) and overall survival (OS) of patients with LNETs. The accuracy and clinical practicability of nomograms were tested by Harrell’s concordance index (C-index), integrated discrimination improvement (IDI), net reclassification improvement (NRI), calibration plots, and decision curve analyses.ResultsThe Cox proportional-hazards model showed the high LODDS group (-0.79≤LODDS) had significantly higher mortality compared to those in the low LODDS group (LODDS<-0.79) for both CSS and OS. In addition, age at diagnosis, sex, histotype, type of surgery, radiotherapy, and chemotherapy were also chosen as predictors in Cox regression analyses using stepwise Akaike information criterion method and included in the nomograms. The values of C-index, NRI, and IDI proved that the established nomograms were better than the conventional eighth edition of the TNM staging system. The calibration plots for predictions of the 1-, 3-, and 5-year CSS/OS were in excellent agreement. Decision curve analyses showed that the nomograms had value in terms of clinical application.ConclusionsWe created visualized nomograms for CSS and OS of LNET patients, facilitating clinicians to bring individually tailored risk assessment and therapy.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): Prevalence, clinicopathological characteristics and survival outcome in a cohort of 311 patients with well-differentiated lung neuroendocrine tumours.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is considered to be a rare condition associated with lung neuroendocrine tumours (NET), and its natural history is poorly described. We aimed to assess the prevalence and clinicopathologic characteristics of DIPNECH in the lung NET population, and to investigate predictors of time-to-progression (TTP) and overall survival (OS). We retrospectively identified patients diagnosed with DIPNECH between April 2005 and December 2020. Clinical data were collected from medical records. The relationship between baseline characteristics and TTP and OS was analysed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazards model. Of 311 patients with well-differentiated lung NETs, 61 (20%) had DIPNECH and were included in the study. Baseline demographics described 95% female, 59% never smokers and mean body mass index 34.4 kg m-2 ; 77% were typical carcinoids (TC), 13% atypical carcinoids (AC), and 10% both TC and AC (multicentric). At presentation, 54% of patients were asymptomatic. Multicentric NETs were demonstrated in 16 (26%) on histopathology, and a further 32 (52%) had synchronous NETs suggested on imaging (multiple nodules ≥ 5 mm). Seven (11%) patients developed metastases and the median OS from time of first metastasis was 37 months. AC histopathology and NET TNM stage ≥ IIA were associated with poorer TTP and OS. Of the DIPNECH cohort, the 15-year survival rate was 86%. DIPNECH may be more prevalent in the lung NET population than previously appreciated, especially in women. Although our results confirm that DIPNECH is predominantly an indolent disease associated with TC, 23% developed AC and these patients may warrant closer observation.

No Impact of PolySia-NCAM Expression on Treatment Response in Neuroendocrine Neoplasms of the Lung.

Simple SummaryPolysialic acids (polySia) are localized on the neuronal cell adhesion molecule (NCAM). They are expressed on numerous tumors of neural crest origin. These include lung neuroendocrine tumors such as atypical carcinoid, large cell neuroendocrine and small cell carcinomas. Interfering with polySia is considered a potential approach in the development of tumor therapies. In this study, we investigated whether polySia expression has an impact on disease progression, treatment response, and prognosis. To this end, tissue samples from 28 patients were analyzed by immunohistochemistry for polySia-NCAM presence. In conclusion, NCAM-polySia is not very useful as a prognostic factor for poor disease outcome. However, it is still interesting as a therarpeutic target for individual tumor therapy, as a majority of patients (78.6%) showed a strong staining signal for NCAM-polySia.Background: Polysialic acids (abbr. polySia) are found on numerous tumors, including neuroendocrine lung tumors. They have previously been shown to impact metastatic potential, as they can influence the signaling and adhesion properties of neuronal cell adhesion molecules (abbr. NCAM) and other cell adhesion molecules. Therefore, the aim of this small pilot study was to analyze whether there was a correlation between polySia-NCAM expression and specific clinical or histopathologic characteristics, and if polySia-NCAM expression had an impact on treatment response, disease progression and prognosis of lung neuroendocrine neoplasms. Methods: This work was based on an analysis of 28 digitized patient records and corresponding patient samples. The response to therapy was radiologically determined at the time of diagnosis and at certain intervals during therapy following the current RECIST1.1 and volumetric sphere calculation. To analyze whether polySia-NCAM expression had prognostic relevance, polySia-NCAM-positive and -negative cases were compared in a Kaplan-Meier survival analysis. Findings: A majority of 78.6% lung neuroendocrine neoplasms showed a strong staining signal for polySia-NCAM. There was a significant correlation between expression and histopathological grade (p = 0.0140), since carcinoids were less likely polySia-NCAM-positive compared to small cell lung carcinoma (abbr. SCLC) and large cell neuroendocrine carcinomas of the lung (abbr. LCNEC). There was no significant association between polySia-NCAM expression and clinical characteristics (age: p = 0.3405; gender: p = 0.6730; smoking history: p = 0.1145; ECOG: p = 0.1756, UICC8 stage: p = 0.1182) or radiologically determined disease progression, regardless of the criteria used to categorize response (RECIST 1.1: p = 0.0759; sphere: p = 0.0580). Furthermore, polySia-NCAM expression did not affect progression-free survival (p = 0.4198) or overall survival (p = 0.6918). Interpretation: PolySia-NCAM expression was more common in high-grade compared to low-grade neuroendocrine neoplasms of the lung; however, this small pilot study failed to show an association between polySia-NCAM expression and response to therapy.

MA02.03 The Evolution of Lung Neuroendocrine Tumors

In the context of the lungNENomics project, we have generated comprehensive molecular profiles of the rare and understudied lung neuroendocrine tumors (LNETs). We revealed three molecular groups of LNETs that challenge the current WHO classification: low-aggressive groups A1 and A2, and the more aggressive group B. Additionally, we revealed the existence of a subgroup of very aggressive LNETs, that we named supra-carcinoids, with the histopathological features of LNETs but the molecular and clinical characteristics of the higher-grade large-cell neuroendocrine carcinoma.

MA01.07 From Molecular to Histological Characterization of Lung Carcinoids via Computer Vision and Spatial Genomics

Lung neuroendocrine tumors (LNETs) are rare cancers subdivided into low-grade (typical) and intermediate-grade (atypical) carcinoids. Atypical carcinoids are more aggressive, with a 4- to 6-fold increased risk of developing metastatic disease and to relapse within the first 10 years after surgical treatment. We performed the first comprehensive molecular characterization of lung carcinoids and identified 3 robust molecular clusters; A1, A2 and B (Alcala, Nature Com., 2019; Gabriel, Gigascience, 2020).

MA01.09 Characterising Aggressive Pulmonary Carcinoids Through Integrative Omics Analysis Within the lungNENomics Project

Typical and atypical carcinoids are well differentiated lung neuroendocrine tumours (LNETs) that belong to the group of lung neuroendocrine neoplasms, which also include highly aggressive lung neuroendocrine carcinomas (LNECs). Although carcinoids show relatively good prognosis in comparison to carcinomas, metastatic disease and relapse do occur. In a previous study we introduced the concept of molecular groups of carcinoids: A (further separated into A1 and A2) and B, which did not clearly correspond to individual histological types.

EP14.02-001 Could the Oxidative Stress Be Used as a Marker for Neuroendocrine Lung Tumors?

In many neuroendocrine tumors, the vascular density (neuroendocrine main feature) is higher in the low-grade tumors than high-grade ones. This observation, so-called “neuroendocrine paradox”, gives to the angiogenesis a role as differentiation marker instead of prognostic marker. But the neoplastic angiogenesis is associated also with the oxidative stress. Thus, our goal is to verify if the oxidative stress could have a preeminent role in the lung NET compared with other neoplasms. Furthermore, we try to identify specific markers of oxidative stress in these tumors.

EP14.01-009 A Comparative Study of Histological Predictors of Outcome in Patients with Lung Typical and Atypical Carcinoids

Lung carcinoids fall in the most indolent extreme of the spectrum of lung neuroendocrine tumors, being considered malignancies with a favorable prognosis. They can be subdivided histologically in typical and atypical carcinoids and this classification difference reflects on the rates of recurrence and metastasis, with atypical carcinoids being slightly more aggressive that typical ones.The main goal of this study is to assess the differences in prognosis between typical and atypical carcinoids and potential criteria that should raise our awareness and prolong the follow-up time of our patients.

Hierarchical identification of a transcriptional panel for the histological diagnosis of lung neuroendocrine tumors.

Background: Lung cancer is a complex disease composed of neuroendocrine (NE) and non-NE tumors. Accurate diagnosis of lung cancer is essential in guiding therapeutic management. Several transcriptional signatures have been reported to distinguish between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) belonging to non-NE tumors. This study aims to identify a transcriptional panel that could distinguish the histological subtypes of NE tumors to complement the morphology-based classification of an individual. Methods: A public dataset with NE subtypes, including 21 small-cell lung cancer (SCLC), 56 large-cell NE carcinomas (LCNECs), and 24 carcinoids (CARCIs), and non-NE subtypes, including 85 ADC and 61 SCC, was used as a training set. In the training set, consensus clustering was first used to filter out the samples whose expression patterns disagreed with their histological subtypes. Then, a rank-based method was proposed to develop a panel of transcriptional signatures for determining the NE subtype for an individual, based on the within-sample relative gene expression orderings of gene pairs. Twenty-three public datasets with a total of 3,454 samples, which were derived from fresh-frozen, formalin-fixed paraffin-embedded, biopsies, and single cells, were used for validation. Clinical feasibility was tested in 10 SCLC biopsy specimens collected from cancer hospitals via bronchoscopy. Results: The NEsubtype-panel was composed of three signatures that could distinguish NE from non-NE, CARCI from non-CARCI, and SCLC from LCNEC step by step and ultimately determine the histological subtype for each NE sample. The three signatures achieved high average concordance rates with 97.31%, 98.11%, and 90.63%, respectively, in the 23 public validation datasets. It is worth noting that the 10 clinic-derived SCLC samples diagnosed via immunohistochemical staining were also accurately predicted by the NEsubtype-panel. Furthermore, the subtype-specific gene expression patterns and survival analyses provided evidence for the rationality of the reclassification by the NEsubtype-panel. Conclusion: The rank-based NEsubtype-panel could accurately distinguish lung NE from non-NE tumors and determine NE subtypes even in clinically challenging samples (such as biopsy). The panel together with our previously reported signature (KRT5-AGR2) for SCC and ADC would be an auxiliary test for the histological diagnosis of lung cancer.

Landscape of pathogenic germline variants in patients with lung cancer.

388570 Background: Few studies have aimed to investigate the prevalence and spectrum of pathogenic germline variants (PGVs) in patients diagnosed with lung cancer. Given the growing opportunities for precision therapies based on PGVs in DNA damage-repair (DDR)/homologous recombination-repair (HRR) genes and the importance of identifying PGVs to inform future cancer screening and cascade testing, we investigated the prevalence and potential clinical implications of PGVs in individuals with lung cancer. Methods: Deidentified data were retrospectively reviewed for 7,788 individuals diagnosed with lung cancer for whom germline DNA sequencing and exon-level copy number analysis were performed between 2014-2022 at a commercial diagnostic laboratory. The diagnosis of lung cancer was based on ICD-10 codes or language on the test requisition suggesting a primary lung cancer diagnosis. Individuals with requisitions suggesting lung metastases, neuroendocrine tumors or sarcomas as the basis for testing were excluded. Number of genes tested varied per ordering clinician preference. Clinically actionable PGVs were defined as those associated with clinical management recommendations or trial eligibility per current, standard of care guidelines. Descriptive statistics were utilized. Results: The cohort was predominantly female (71.1%), White (64.5%), and most had a history of &gt; 1 cancer (71.1%). A median of 79 genes (range 1-159) were tested. Testing identified 1,503 PGVs in 81 known cancer-risk genes in 1,161/7,788 (14.9%) patients; an additional 229 (2.9%) patients carried a single PGV in a gene associated with autosomal recessive inheritance. PGV rates stratified by self-reported ancestry: Black/African American, 11.8%; Asian or Pacific Islander, 11.8%; Hispanic, 14.5%; White, 15.4%. Among genes with &gt;1,000 individuals tested, PGVs were most common in BRCA2 (2.8%), CHEK2 (2.1%), ATM (1.9%), TP53 (1.3%), BRCA1 (1.2%), and EGFR (1.0%). Of 1,161 individuals, 712 (61.3%) had a PGV in a DDR/HRR gene, making them potentially eligible for a clinical treatment trial, and 1,104/1,161 (95.1%) had a PGV that was potentially clinically actionable. Conclusions: From this large cohort of individuals with lung cancer, 14.9% had PGVs, nearly all of which were clinically actionable. Notably, HRR PGVs were common (64%). Currently, the U.S. Food and Drug Administration has approved and the National Comprehensive Cancer Network Guidelines endorse targeted therapies for patients with breast, pancreatic, prostate, and ovarian cancers who carry HRR PGVs. Recently, the NCCN Guidelines panel recommended germline testing be considered for all patients diagnosed with colorectal cancer. Given the profound implications for both patients and their families that result from identifying PGVs, our results suggest that all patients with lung cancer also be considered for germline genetic testing.

Genomic and Gene Expression Studies Helped to Define the Heterogeneity of Small-Cell Lung Cancer and Other Lung Neuroendocrine Tumors and to Identify New Therapeutic Targets

Small-cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma, corresponding to about 15% of lung cancers, occurring predominantly in smokers and associated with a very poor prognosis. Key genetic alterations very frequently observed in SCLC are represented by the loss of TP53 and RB1, due to mutational events or deletions; frequent amplification or overexpression of MYC family genes (MYC, MYCL and MYCN); frequent genetic alterations by mutation/deletion of KMT2D, RB family members p107 (RBL1) and p130 (RBL2), PTEN, NOTCH receptors and CREBBP. The profile of expression of specific transcription factors allowed to differentiate four subtypes of SCLC defined according to levels of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POUF23 (SCLC-P) or YAP1 (SCLC-Y). A recent study identified the subgroup SCLC-I, characterized by the expression of inflammatory/immune-related genes. Recent studies have characterized at molecular level other lung neuroendocrine tumors, including large cell neuroendocrine cancers (LCNECs) and lung carcinoids. These molecular studies have identified some therapeutic vulnerabilities that can be targeted using specific drugs and some promising biomarkers that can predict the response to this treatment. Furthermore, the introduction of immunotherapy (immune checkpoint blockade) into standard first-line treatment has led to a significant clinical benefit in a limited subset of patients.

Clinical Features of de Novo Lung Neuroendocrine Tumor after Liver Transplantation for Hepatocellular Carcinoma

Objective: To analyze the clinical features of de novo lung neuroendocrine tumor (NET) after liver transplantation (LT) for hepatocellular carcinoma (HCC).&#x0D; Method: Retrospectively reviewed the clinical data of the 1253 patients who underwent LT from 2013 to 2022 in our institute.&#x0D; Result: Out of 1253 recipients of LT 7 patients suffered de novo lung carcinoma, of these 2 patients suffered lung NET accounting for 28.6% (2/7) of de novo lung carcinoma both at extensive stage. New on-set lung lesions and hilar and mediastinal lymphadenopathy were found by imaging tests; and were diagnosed as lung NETs in both patients through pathological examination. The interval between LT and diagnosis of lung NET ranged from 5.9 to 44.7 months. Both patients received cisplatin and etoposide as first-line chemotherapy and achieved partial remission. The progression-free survival period ranged from 1.9 to 2.2 months. Survival after diagnosis of lung NET ranged from 7.0 to 10.9 months. One of the patients tried to cease immunosuppressants during chemotherapy and incurred graft rejection.&#x0D; Conclusion: Lung NET may have a higher proportional incidence of de novo lung carcinoma in LT recipients. Early diagnosis is vital for the treatment of lung NET, while predictive and timely biopsy based on imaging findings is crucial for making an early diagnosis.