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Thoracic Neuroendocrine Tumors and the Role of Emerging Therapies

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (20 December 2025) | Viewed by 16654

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Special Issue Editors

Dr. Nagla Abdel Karim

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Guest Editor

Inova Schar Cancer Institute, Department of Medicine, University of Virginia, Fairfax, VA 22031, USA
Interests: lung cancer; thoracic oncology; phase I clinical trials/experimental therapeutics

Dr. Asad Ullah

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Guest Editor

Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
Interests: cancer epidemiology; cancer diagnosis; genomic profiling of cancer; emerging therapies in cancer, neuroendocrine neoplasm; melanoma
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Dr. Jaffar Khan

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Indiana School of Medicine, Indiana University, Indianapolis, IN, USA
Interests: neuroblastoma; ganglioneuroblastoma; pediatric neck mass; malignancy; neoplasm; pancreas; malignant neoplasm; biphasic; Carcinosarcoma; Pancreatic Ductal Carcinoma; seer; mesothelioma; peritoneal; hipec; radiation; Surgery; Parathyroid carcinoma; seer program; Cancer Staging; incidence; survival; mortality; gist; metastatic gists; MOLECULAR; sdh; dog1; spindle cell tumors; programmed death-ligand; immunosuppression; Autoimmunity; adenocarcinoma
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Prof. Dr. Fernando Mendes

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1. Coimbra Health School (ESTeSC), Polytechnique University of Coimbra, Rua 5 de Outubro, São Martinho do Bispo, 3045-043 Coimbra, Portugal
2. H&TRC—Health & Technology Research Center, Coimbra Health School, Polytechnic University of Coimbra, Rua 5 de Outubro, 3045-043 Coimbra, Portugal
3. Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, Universidade de Coimbra, Pólo III—Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
4. Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal
5. European Association for Professions in Biomedical Sciences, 1000 Brussels, Belgium
Interests: lung cancer; inflammation; radiation effects; immune oncology; biomarkers
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Special Issue Information

Dear Colleagues,

Thoracic Neuroendocrine Tumors (NETs) are classified into well-differentiated (low-grade typical carcinoids [TCs] and intermediate-grade atypical carcinoids [ACs]) and poorly differentiated (high-grade large cell neuroendocrine carcinoma LCNEC) or small cell lung carcinoma (SCLC) neuroendocrine carcinoma. Despite the increasing incidence of thoracic NETS, awareness [1] and the development of personalized approach therapies in these patients lag.

Well-differentiated carcinoids, as atypical carcinoid tumors in the lung, can recur and become challenging. Unfortunately, the guidelines regarding adjuvant therapies remain unclear, and current regimens' survival benefit is questionable [2]. There is a critical need to update the classification, diagnosis, and treatment of lung NETs. The development of molecular markers to provide evidence supporting the treatment of this underserved type of NET is an area of unmet need.

Effective systemic therapies for patients with advanced, progressive neuroendocrine lung tumors are very rare. However, recently, everolimus was associated with significant improvement in progression-free survival in patients with progressive lung neuroendocrine tumors [3]. Further drug development is needed.

To date, there is only one biomarker-based clinical trial, S1929, in the poorly differentiated NETs; SCLC that has recently completed enrollment for screening, that attempts to stratify patients with SCLC to receive PARP inhibitor based on SLFN11 that is expressed by more than half of patients with SCLC. Further knowledge of predictive factors and novel therapies is needed.

References:

Neuroendocrine Tumors of the Lung: Current Challenges and Advances in the Diagnosis and Management of Well-Differentiated Disease. Hendifar, Marchevsky, and Tuli. Journal of Thoracic Oncology Vol. 12 No. 3: 425–436.
Survival Benefit of Adjuvant Chemotherapy in Pulmonary Carcinoid: A systematic Review. Philip Sobash and Nagla Abdel Karim. NCCN Virtual Annual Conference 2021 General Poster Session.
Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Yao, Fazio, Singh et. al. The Lancet. Volume 387, Issue 10022, 5–11 March 2016, Pages 968–977.

Dr. Nagla Abdel Karim
Dr. Asad Ullah
Dr. Jaffar Khan
Prof. Dr. Fernando Mendes
Guest Editors

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Keywords

thoracic neuroendocrine tumors
lung NETs
low-grade typical carcinoids
TCs
intermediate-grade atypical carcinoids
ACs
high-grade large cell neuroendocrine carcinoma LCNEC
small cell lung carcinoma (SCLC) neuroendocrine carcinoma

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Research

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20 pages, 8974 KB

Open AccessArticle

Novel Blood-Based Extracellular Vesicle-Derived Biomarkers in Small Cell Lung Cancer Identified via Proximity Extension Assay

by Hubert Krzyslak, Weronika Maria Szejniuk, Marwan Malluhi, Henrik Steglich-Arnholm, Ursula Falkmer, Jonas Ellegaard Mortensen, Søren Risom Kristensen and Shona Pedersen

Cancers 2026, 18(4), 580; https://doi.org/10.3390/cancers18040580 - 10 Feb 2026

Viewed by 824

Abstract

Background: Small cell lung cancer (SCLC) is an aggressive malignancy with rapid progression and early metastasis, yet it lacks validated biomarkers for early diagnosis and treatment monitoring. Extracellular vesicles (EVs) are nano-sized particles released by cells that carry cargo reflective of their origin, making them promising candidates for liquid biopsy-based biomarker discovery. Methods: Plasma-derived EVs were isolated from 29 SCLC patients and 28 healthy controls (HCs) using ultracentrifugation and characterized via nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Proteomic profiling was performed using the Olink^® Immuno-Oncology panel. Group differences were analyzed using multivariate models (Boruta, Elastic Net, and partial least squares discriminant analysis). Diagnostic potential was assessed using ROC analysis, and predictive response associations were evaluated by correlating EV protein changes with tumor size reduction (FDR-adjusted Spearman). Results: Of the 58 detected proteins, 36 were significantly upregulated in SCLC. PDGF-B, CXCL5, CCL17, EGF, and LAP-TGF-β1 showed good discriminatory performance (AUC 0.95–0.98). Additionally, a two-protein panel (LAP-TGF-β1 and PDGF-B) achieved an out-of-fold AUC of 0.96 (CI 0.89–1.00). NOS3, VEGFR-2, and ANGPT2 levels correlated inversely with tumor reduction after chemotherapy. Conclusions: These exploratory findings highlight EV proteomics as a minimally invasive platform for potential SCLC diagnosis and monitoring. Full article

(This article belongs to the Special Issue Thoracic Neuroendocrine Tumors and the Role of Emerging Therapies)

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15 pages, 2574 KB

Open AccessArticle

Treatment, Prognostic Markers, and Survival in Thymic Neuroendocrine Tumors, with Special Reference to Temozolomide-Based Chemotherapy

by Zixuan Cheng, Fuhuan Yu, Ruao Chen, Lingjun Cui, Yingying Chen, Chao Deng, Yanfen Shi and Huangying Tan

Cancers 2024, 16(14), 2502; https://doi.org/10.3390/cancers16142502 - 10 Jul 2024

Cited by 3 | Viewed by 2306

Abstract

Background: Thymic neuroendocrine tumors (Th-NETs) are rare and aggressive, with a scarcity of research on predicting patient prognosis. Our study aimed to assess the impact of prognostic markers and temozolomide (TMZ)-based chemotherapy on survival in Th-NETs. Methods: We retrospectively reviewed the medical records of patients diagnosed with Th-NETs between 2013 and 2023 at our institution. We collected clinicopathological data, including tumor pathological grading, staging, serum concentrations of neuron-specific enolase (NSE) and pro-gastrin-releasing peptide, levels of inflammatory factors, and expression of oxygen 6-methylguanine-DNA methyltransferase (MGMT). Treatment details (such as surgery and chemotherapy) and survival outcomes were also documented. Results: A total of 32 patients were included in our study after excluding those without complete available information. The median progression-free survival (PFS) was 12.5 months (95%CI, 8–16 months) for 19 patients who received TMZ-based chemotherapy. Twenty-one patients underwent surgery as the primary treatment, demonstrating a median disease-free survival (DFS) of 51.0 months. The inflammatory factor neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic indicator of DFS in postoperative patients and PFS in TMZ-treated patients. The overall 3-, 5-, and 10-year survival rates were 86.6%, 69.5%, and 33.8%, respectively. Ki67 level exceeding 10% (p = 0.048) and absence of surgical resection (p = 0.003) were significantly associated with worse overall survival (OS). Conclusion: Surgical treatment was currently the primary method for treating Th-NETs, and postoperative adjuvant therapy was an essential consideration for specific patient cohorts. Despite widespread positive MGMT expression, TMZ-based chemotherapy showed promise. Some potential prognostic biomarkers such as NLR and NSE need more attention. Full article

(This article belongs to the Special Issue Thoracic Neuroendocrine Tumors and the Role of Emerging Therapies)

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10 pages, 491 KB

Open AccessArticle

Pro-Gastrin-Releasing Peptide as a Biomarker in Lung Neuroendocrine Neoplasm

by Violetta Rosiek, Angelika Kogut and Beata Kos-Kudła

Cancers 2023, 15(13), 3282; https://doi.org/10.3390/cancers15133282 - 22 Jun 2023

Cited by 12 | Viewed by 4231

Abstract

There is a lack of effective biomarkers for diagnosing lung neuroendocrine neoplasms (LNENs). A known small cell lung cancer (SCLC) biomarker is a pro-gastrin-releasing peptide (ProGRP), but not for all LNENs, especially for bronchopulmonary carcinoids. This study aimed to evaluate the diagnostic value of ProGRP and chromogranin A (CgA) in diagnosing LNENs. The ProGRP and CgA levels in 290 cases of LNENs and 54 healthy controls (HCs) were measured. The median ProGRP concentration in the group of LNEN patients was 136.4 pg/mL, higher than that of HCs at 6.5 pg/mL. Most of the LNEN cohort was well-differentiated tumors (typical and atypical carcinoids, n = 262, 91.7% of all LNENs). The sensitivity, specificity, and area under the curve (AUC) of ProGRP when distinguishing LNENs vs. HCs were 94.8%, 100%, and 0.995. CgA (AUC = 0.375) could not determine LNENs vs. HCs. Therefore, based on these results, ProGRP may be considered as an effective marker for diagnosing LNENs. Full article

(This article belongs to the Special Issue Thoracic Neuroendocrine Tumors and the Role of Emerging Therapies)

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13 pages, 1360 KB

Open AccessArticle

Demographics and Clinicopathologic Profile of Pulmonary Sarcomatoid Carcinoma with Survival Analysis and Genomic Landscape

by Asad Ullah, Asim Ahmed, Abdul Qahar Khan Yasinzai, Kue Tylor Lee, Israr Khan, Bina Asif, Imran Khan, Bisma Tareen, Kaleemullah Kakar, Gul Andam, Saleh Heneidi, Jaffar Khan, Hina Khan, Nabin R. Karki, Jaydira Del Rivero and Nagla Abdel Karim

Cancers 2023, 15(9), 2469; https://doi.org/10.3390/cancers15092469 - 26 Apr 2023

Cited by 3 | Viewed by 3576

Abstract

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) with an aggressive clinical nature and poor prognosis. With novel targeted therapeutics being developed, new ways to effectively treat PSC are emerging. In this study, we analyze demographics, tumor characteristics, treatment modalities, and outcomes of PSC and genetic mutations in PSC. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database were reviewed to analyze cases of pulmonary sarcomatoid carcinoma from 2000 to 2018. The molecular data with the most common mutations in PSC were extracted from the Catalogue Of Somatic Mutations in Cancer (COSMIC) database. Results: A total of 5259 patients with PSC were identified. Most patients were between 70 and 79 years of age (32.2%), male (59.1%), and Caucasian (83.7%). The male-to-female ratio was 1.45:1. Most tumors were between 1 and 7 cm in size (69.4%) and poorly differentiated (grade III) (72.9%). The overall 5-year survival was 15.6% (95% confidence interval (95% CI) = 14.4–16.9)), and the cause-specific 5-year survival was 19.7% (95% CI = 18.3–21.1). The five-year survival for those treated with each modality were as follows: chemotherapy, 19.9% (95% CI = 17.7–22.2); surgery, 41.7% (95% CI = 38.9–44.6); radiation, 19.1% (95% CI = 15.1–23.5); and multimodality therapy (surgery and chemoradiation), 24.8% (95% CI = 17.6–32.7). On multivariable analysis, age, male gender, distant stage, tumor size, bone metastasis, brain metastasis, and liver metastasis were associated with increased mortality, and chemotherapy and surgery were associated with reduced mortality (p < 0.001). The best survival outcomes were achieved with surgery. The most common mutations identified in COSMIC data were TP53 31%, ARID1A 23%, NF1 17%, SMARCA4 16%, and KMT2D 9%. Conclusions: PSC is a rare and aggressive subtype of NSCLC, usually affecting Caucasian males between 70 and 79. Male gender, older age, and distant spread were associated with poor clinical outcomes. Treatment with surgery was associated with better survival outcomes. Full article

(This article belongs to the Special Issue Thoracic Neuroendocrine Tumors and the Role of Emerging Therapies)

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16 pages, 3776 KB

Open AccessArticle

The Role of Surgery in Primary Chest Wall Tumors: Over 20 Years’ Experience in Resection and Reconstruction

by Giorgio Lo Iacono, Antonio Mazzella, Shehab Mohamed, Francesco Petrella, Giulia Sedda, Monica Casiraghi, Lara Girelli, Luca Bertolaccini and Lorenzo Spaggiari

Cancers 2023, 15(7), 2153; https://doi.org/10.3390/cancers15072153 - 5 Apr 2023

Cited by 11 | Viewed by 3249

Abstract

Background: Primary chest wall tumors comprise a heterogeneous group of neoplasms arising from soft tissues and bones. While surgical excision is the standard of care for benign tumors, the management of malignant tumors requires multimodal treatment. We conducted a predictive analysis of outcome, recurrence-free and overall survival. Methods: We retrospectively reviewed the clinical and pathological records of all patients treated in our center between 1998 and 2020. Results: 53 patients (15–85 years) were treated in our department. The average tumor diameter was 65 ± 35 mm (10–160 mm). Negative margins were obtained in 48 patients (90.6%), whereas in the remaining 5, R1 resection was accomplished. Median overall survival was 63,03 months (1–282 months). Overall survival was 90% at 1 year, 78% at 2 years, and 61% at 5 years. Our analysis identified tumor diameter, postoperative complications, and high grade of malignancy as factors that can influence prognosis. Conclusions: The treatment of primary chest wall tumors remains a very challenging process. Different histological types preclude definition of an unequivocal approach. Complete resection with healthy margins remains a definitive cornerstone in the treatment of these cancers as part of a more comprehensive approach. Full article

(This article belongs to the Special Issue Thoracic Neuroendocrine Tumors and the Role of Emerging Therapies)

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Review

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16 pages, 289 KB

Open AccessReview

Artificial Intelligence in Oncologic Thoracic Surgery: Clinical Decision Support and Emerging Applications

by Francesco Petrella and Stefania Rizzo

Cancers 2026, 18(2), 246; https://doi.org/10.3390/cancers18020246 - 13 Jan 2026

Cited by 2 | Viewed by 1025

Abstract

Artificial intelligence (AI) is rapidly reshaping thoracic surgery, advancing from decision support to the threshold of autonomous intervention. AI-driven technologies—including machine learning (ML), deep learning (DL), and computer vision—have demonstrated significant improvements in diagnostic accuracy, surgical planning, intraoperative navigation, and postoperative outcome prediction. In lung cancer and thoracic oncology, AI enhances imaging analysis, histopathological classification, and risk stratification, supporting multidisciplinary decision-making and personalized therapy. Robotic-assisted and AI-guided systems are optimizing surgical precision and workflow efficiency, while real-time decision-support tools and augmented reality are improving intraoperative safety. Despite these advances, widespread adoption is limited by challenges in algorithmic bias, data integration, regulatory approval, and ethical transparency. The literature emphasizes the need for multicenter validation, explainable AI, and robust governance frameworks to ensure safe and effective clinical integration. Future research should focus on digital twin technology, federated learning, and transparent AI outputs to further enhance reliability and accessibility. AI is poised to transform thoracic surgery, but responsible implementation and ongoing evaluation are essential for realizing its full potential. The aim of this review is to evaluate and synthesize the current landscape of artificial intelligence (AI) applications across the thoracic surgical pathway, from preoperative decision-support to intraoperative guidance and emerging autonomous interventions. Full article

(This article belongs to the Special Issue Thoracic Neuroendocrine Tumors and the Role of Emerging Therapies)

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