Search Results (141)

Background: Lung carcinoids—typical and atypical—are rare neuroendocrine tumors (NETs) representing 1–2% of lung cancers. Despite clinicopathological differences, their clinical management often mirrors lung cancer protocols rather than NET-specific recommendations. Objectives: Portray a 12-year real-world experience with lung carcinoids at a Comprehensive Cancer Center, identifying gaps in diagnostic work-up, treatment decision-making, and follow-up. Methods: Retrospective observational cohort study of adult patients with histologically confirmed lung carcinoids diagnosed at IPO Porto between January 2013 and December 2024. Demographic, clinical, imaging, and treatment data were collected from electronic patient records. Analyses were descriptive. Results: Among 179 identified cases, 129 met eligibility criteria. Median age was 62 years (range 18–84); 53.6% were women and 53.5% were non-smokers; 84.5% had ECOG-PS 0–1. The most frequent presentation was respiratory symptoms (34.1%), followed by incidental findings (43.4%, of which ~20% were during staging or surveillance of other cancers). Typical carcinoids accounted for 49.6% and atypical for 43.4%. FDG-PET/CT was requested in 70.9% of cases, including many with typical carcinoid, and SSTR-PET/CT in 64.6% (dual PET in 38.8%). Most patients (65.1%) presented with stage I disease; 17.1% were stage IV. Mean time-to-first treatment was 83 days (range 1–259). Surgery was the first treatment option for 78.3% of patients. Conclusions: This real-world series highlights heterogeneity in diagnostic pathways, excessive FDG-PET use in typical carcinoids, and non-standardized follow-up. Dedicated multidisciplinary lung-NET boards and national reference centers are needed to homogenize and streamline patient management. Full article

Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive tumor for which the most effective systemic therapy remains uncertain. In metastatic LCNEC, chemotherapy approaches typically alternate between small-cell lung cancer (SCLC)-like and non-small-cell lung cancer (NSCLC)-like regimens. Emerging data indicate that treatment selection may be optimized through molecular subtype classification. This study aimed to evaluate the outcomes of SCLC-like and NSCLC-like chemotherapy (CT) regimens in relation to LCNEC molecular subtypes. Methods: This retrospective analysis included all patients diagnosed with LCNEC at Gaziantep University between January 2010 and October 2024. Individuals with available tumor tissue and complete clinical data were enrolled. LCNEC cases were categorized as SCLC-subtype or NSCLC-subtype according to the presence of TP53 and RB1 alterations. Platinum combined with etoposide, irinotecan, or topotecan was defined as SCLC-like CT, whereas platinum with taxanes or gemcitabine was considered NSCLC-like CT. Survival outcomes of both treatment types were compared across molecular subgroups using the Kaplan–Meier method. Results: Sixty-one patients met the inclusion criteria. The median overall survival (mOS) was 11.0 months (95% CI: 6.3–15.7). No significant difference in mOS was observed between SCLC-like and NSCLC-like regimens in the total cohort. When stratified by molecular subtype, patients with the SCLC subtype who received SCLC-like CT showed a longer mOS compared to those treated with NSCLC-like CT (15 [9.9–20.1] vs. 6 [3.9–8.1] months, respectively; p = 0.47), although this difference did not reach statistical significance. Conclusions: These findings suggest that molecular subclassification may help inform the choice of optimal systemic therapy in patients with LCNEC. Full article

Background/Objectives: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid proliferation, early metastasis, and near-universal relapse after initial therapy. While chemo-immunotherapy modestly improves first-line outcomes, survival after progression remains poor and highlights the urgent need for biomarker-directed strategies. Methods: A comprehensive literature search was conducted using major medical databases looking at key relevant studies on SCLC antibody studies. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Recent advances in antibody–drug conjugates (ADCs) and T-cell engagers (TCEs) have transformed therapeutic development by targeting antigens selectively expressed on SCLC cells, enabling more precise and potentially durable tumor control. DLL3 has emerged as the most clinically relevant target to date, with the bispecific TCE tarlatamab demonstrating meaningful and durable response, manageable cytokine-release toxicity, and ultimately achieving accelerated FDA approval for previously treated extensive-stage SCLC. Concurrently, DLL3-directed ADCs have shown variable efficacy, underscoring the importance of payload selection, linker chemistry, and antigen density. Beyond DLL3, next-generation ADCs targeting TROP2, B7-H3, and SEZ6 have reported encouraging early-phase activity, including response rates exceeding those of existing second-line cytotoxic options, though myelosuppression, interstitial lung disease, and hepatic toxicity remain key considerations. Conclusions: Collectively, these emerging immunotherapies illustrate a shift toward antigen-specific targeting in a disease historically defined by limited therapeutic innovation. Continued optimization of antigen selection, payload and linker engineering, and biomarker-driven trial design will be critical for translating early promise into durable clinical benefit and reshaping the treatment landscape for SCLC. Full article

Lineage plasticity, the ability of cancer cells to alter their differentiated state through transcriptional and epigenetic reprogramming, has emerged as a key mechanism of therapeutic resistance across cancers. This adaptive process can manifest in multiple ways, including epithelial–mesenchymal transition, acquisition of stem-like features, and histological transformation, the most striking and clinically apparent example. In EGFR-mutant lung adenocarcinoma (LUAD), lineage plasticity is increasingly recognized as a prevalent mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs). Among its visible manifestations, histologic transformation into small-cell lung cancer (SCLC) is the most frequent, while squamous transformation and other phenotypic shifts also occur. Transformed tumors typically retain the initiating EGFR mutation but lose EGFR dependence, acquire neuroendocrine features, and display aggressive clinical behavior with poor clinical outcomes compared with both de novo SCLC and non-transformed LUAD. Recent studies show that plasticity arises through combined genomic, transcriptomic, and epigenetic reprogramming, often foreshadowed by molecular alterations before overt histological change. Spatial and single-cell profiling reveal heterogeneous trajectories and intermediate states, while functional models and multi-omics approaches have begun to identify therapeutic vulnerabilities distinct from both de novo EGFR-mutated SCLC and classical EGFR-mutated LUAD. Thus, lineage plasticity, whether manifested as histologic transformation or through more subtle epigenetic reprogramming, represents a formidable resistance mechanism in NSCLC. Defining its molecular basis and temporal dynamics will be essential for early detection, prognostication, and the development of tailored therapies. Full article

Objectives: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by rapid proliferation, early metastasis, and limited therapeutic response. Metabolic reprogramming is increasingly recognized as a key feature of small cell lung cancer progression, yet the contribution of specific metabolic enzymes remains incompletely understood. This study aimed to investigate the role of asparagine synthetase in small cell lung cancer tumorigenicity and disease progression. Methods: Integrative analyses were performed using public transcriptomic datasets, proteomic profiling, and functional assays in vitro and in vivo. Asparagine synthetase expression levels were evaluated in normal lung, non-small cell lung cancer, and small cell lung cancer tissues using public microarray datasets. Loss of function studies were conducted using shRNA mediated knockdown in murine and human small cell lung cancer cell models. Tumor growth and survival were assessed using xenograft mouse models. Results: Asparagine synthetase expression was significantly elevated in small cell lung cancer compared with normal lung and non-small cell lung cancer tissues. Genetic depletion of asparagine synthetase impaired cellular proliferation and colony forming capacity in vitro. In vivo, asparagine synthetase knockdown suppressed tumor growth and was associated with prolonged survival in xenograft mouse models. Conclusions: These findings demonstrate that asparagine synthetase contributes to tumor growth and metabolic adaptability in small cell lung cancer. The results support a functional role for asparagine synthetase in malignant progression and suggest that targeting asparagine metabolism may represent a potential therapeutic approach in aggressive small cell lung cancer. Full article

Background: In ectopic adrenocorticotropic hormone (ACTH) syndrome, locating the responsible lesion is often challenging. Case Presentation: A 68-year-old woman was transferred to Nara Medical University hospital for a detailed investigation of her ACTH-dependent Cushing’s syndrome. Because of hypercortisolism-induced immunosuppression, she subsequently developed severe Nocardia pneumonia and was forced to temporarily depend on noninvasive positive pressure ventilation (NIPPV). Intravenous antifungal agents and antibiotics were administered, resulting in significant symptomatic improvement. Metyrapone was administered to suppress excessive cortisol. Contrast-enhanced magnetic resonance imaging of the pituitary revealed a 4 mm sized poorly enhanced area, and microadenoma was suspected. Although cavernous venous sampling was indispensable prior to trans-spheroidal surgery (TSS), this examination could not be performed because of the presence of deep vein thrombosis. TSS was performed for both diagnostic and therapeutic purposes, but hypercortisolism did not improve. Moreover, immunohistochemical findings of the specimen revealed nonfunctional pituitary tumor. Methods: We re-evaluated the responsible lesion causing ACTH-dependent Cushing’s syndrome. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed weak and abnormal FDG uptake in the right pericardium, but the possibility of nonspecific uptake could not be ruled out. However, gallium-68 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic-acid-D-Phe¹-Tyr³-octreotide (⁶⁸Ga-DOTATOC)-PET demonstrated the same degree of abnormal uptake; therefore, a functional pulmonary tumor was strongly suspected. Results: Video-Assisted Thoracic Surgery (VATS) was performed, and histopathological findings of the specimen revealed a neuroendocrine tumor with positive ACTH staining. After VATS, ACTH and cortisol levels were normalized. Conclusions: Here, we report a case of ACTH-dependent Cushing’s syndrome caused by a lung neuroendocrine tumor, in which ⁶⁸Ga-DOTATOC PET was helpful in detecting the functional tumors. Full article

Background/Objectives: Neuroendocrine tumors (NETs) of the lung account for about 30% of NETs. In localized and locally advanced forms, radical surgical resection is the standard of care. Although considered indolent tumors, they appear to be susceptible to post-surgical recurrence, with rates differing between typical and atypical carcinoid. Although still debated, several clinicopathologic factors are potentially associated with recurrence. The aim of this retrospective/prospective observational study is to evaluate the predictive role of clinicopathological factors and radiomics features in patients with NET of the lung. Methods: From January 2021 to April 2024, 45 consecutive patients who underwent radical (R0) surgery for lung NET at the ENETS Center of Excellence of the Sant’Andrea Hospital were enrolled, all with at least 12 months of postoperative follow-up and availability of preoperative unenhanced chest CT. Clinicopathologic and radiomic factors were considered (107 radiomic features). Of the individual characteristics, the impact on recurrence was assessed by univariate logistic regression. Results: Among the 45 patients included, 4 patients (8.9%) experienced disease recurrence. Among the clinicopathological features, major age at diagnosis (p = 0.020), atypical carcinoid (p = 0.010), presence of functional syndrome (p = 0.002), advanced stage at diagnosis (p = 0.013), necrosis (p = 0.017) higher Ki-67 (p = 0.001), higher mitotic count (p = 0.006), and pathologic lymph node (p = 0.006) were associated with disease recurrence. Three radiomic features were found to predict recurrence: DependenceEntropy (p = 0.049), DependenceNonUniformityNormalized (p = 0.024), and Elongation (p = 0.039). In this preliminary analysis, multivariate analysis was not performed due to the small sample size. Conclusions: This study has shown that radiomics can be a valuable tool in predicting recurrence. Currently, to our knowledge, no other studies on the possible application of radiomics as prognostic factors in patients with lung NET have been published. These encouraging findings warrant further investigations with larger, multicenter cohorts to validate these results and implement them by constructing a predictive model of recurrence. Full article

Objectives: Lung neuroendocrine tumors (LNETs) are rare, comprising 1–2% of lung cancers. This study aimed to compare overall survival (OS) and recurrence-free survival (RFS) after lobar resection versus sublobar resection for LNETs and to identify factors associated with prognosis and resection extent. Methods: We retrospectively analyzed patients with clinical stage I (T ≤ 4 cm, N0M0) typical or atypical carcinoid who underwent curative resection at Hadassah Medical Center and Kaplan medical Center between 2010 and 2024. Results: Seventy patients (mean age 56.8 ± 16 years; 63% female) were included. Lobar resection was performed in 40 (57%) and sublobar resection in 30 (43%; 15 segmentectomies, 15 wedge resections). Pathology revealed 50 typical carcinoid (71.43%) and 20 atypical carcinoid (28.57%). Final pathological stage was I in 57 patients (81.42%), II in 9 (12.86%), and III in 4 (5.71%), reflecting surgical upstaging in 13 patients (18.57%), all due to nodal involvement. Atypical carcinoid was associated with worse RFS, nodal upstaging, and adjuvant therapy (all p < 0.01). Patients undergoing sublobar resection were older, had higher comorbidity scores, more frequently presented with peripheral tumors, and underwent less frequent lymph node assessment (all p < 0.01). At a median follow-up of 3.8 years for OS and 2.0 years for RFS, survival rates were 95.7% for both. Neither OS, RFS, nor postoperative normalization of plasma pro-gastrin-releasing peptide (ProGRPp) levels differed significantly between lobar resection and sublobar resection (p = 0.94, p = 0.42, and p = 0.205, respectively). Conclusions: Sublobar resection may represent an acceptable surgical option for selected patients with clinical stage I LNETs, particularly for peripheral tumors ≤ 2 cm in older or comorbid patients. The high rate of nodal upstaging underscores the need for lymph node assessment, irrespective of resection extent. Full article

Background and Clinical Significance: Ectopic ACTH secretion is a rare, potentially life-threatening cause of Cushing’s syndrome that can be overlooked when small neuroendocrine tumors evade standard imaging. Case Presentation: A 34-year-old woman presented with rapidly progressing clinical signs/symptoms of Cushing’s syndrome and demonstrated marked hypercortisolism (cortisol 2428 nmol/L; ACTH 163 ng/mL; urinary free cortisol 815 μg/24 h; K+ 2.4 mmol/L). Small hypermetabolic nodules were noted in her right lung on ¹⁸F-FDG PET/CT but were initially deemed to be infectious; DOTANOC PET-CT and inferior petrosal sinus sampling were non-diagnostic. After medically induced inhibition of cortisol, repeat PET/CT showed a persistent 13 mm lung nodule. Biopsy confirmed a well-differentiated pulmonary carcinoid (Ki-67 3%), and lobectomy achieved biochemical remission. Conclusions: Diagnostic delay stemmed from human factors despite early suggestive imaging. Ectopic ACTH secretion should remain high on the differential diagnosis in rapidly evolving, severe ACTH-dependent Cushing’s disease; early, decisive diagnosis and coordinated care overseen by endocrinologists—preferably in expert centers—can shorten exposure to deleteriously high cortisol levels and improve outcomes. Full article

Background: Large-cell carcinoma (LCC) and large-cell neuroendocrine carcinoma (LCNEC) are kinds of rare lung tumors classified as distinct forms of non-small-cell lung cancer (NSCLC). They both differ in cellular morphology, neuroendocrine marker expression, and clinical outcomes. Thus, LCC and LCNEC exhibit different clinicopathological characteristics and survival outcomes. This study seeks to assess how clinicopathological and immunohistochemical features influence the need for adjuvant chemotherapy in individuals with early-stage, surgically resected LCC or LCNEC. Methods: This multicenter retrospective analysis included 79 patients who underwent surgical resection for large-cell carcinoma (LCC) or large-cell neuroendocrine carcinoma (LCNEC) between January 2008 and March 2025. We evaluated prognostic factors that influence survival in patients with LCC and LCNEC and assessed the effect of adjuvant chemotherapy on survival outcomes. Results: This study included 79 patients—39 diagnosed with LCC and 40 diagnosed with LCNEC. All patients were in stages I–III and received curative surgery. The median age was 61 years for LCC patients and 58.5 years for LCNEC patients. The median overall survival (mOS) was 80.1 months for patients with LCC and 34.2 months for those with LCNEC. Multivariate Cox regression analysis revealed that age (HR: 0.279), stage (HR: 0.198), and chromogranin A expression (HR: 0.088) were independent prognostic factors for overall survival in LCC patients. In LCNEC patients, stage (HR: 0.20), synaptophysin expression (HR: 0.30), type of surgery (HR: 0.31), and adjuvant chemotherapy (HR: 0.264) were identified as factors influencing overall survival. Adjuvant chemotherapy improved overall survival in LCNEC patients (67.0 vs. 17.8 months). Conclusions: Patients with LCNEC generally have poorer prognoses than those with LCC, exhibiting reduced overall survival periods. Disease stage is the most significant factor influencing overall survival for both groups. Notably, in LCNEC patients, adjuvant chemotherapy was found to independently improve survival outcomes regardless of stage. Full article

Background and Clinical Significance: Neuroendocrine neoplasms (NENs) are a group of malignancies that may remain clinically silent for many years. The presence of hepatic metastases can be the first clue leading to diagnosis. Case Presentation: We report the case of a 67-year-old man with intermittent tiredness and suspicious hepatic nodules detected on routine abdominal ultrasound. Contrast-enhanced ultrasonography showed arterial hyperenhancement with early washout, suggestive of metastases. Synchronous high-grade neuroendocrine carcinomas (NECs) of the lung and cecum were identified. Although the liver lesions were initially presumed to arise from the cecal tumor, liver biopsy immunohistochemistry was TTF-1 positive/CDX2 negative, whereas the cecal lesion was TTF-1 negative/CDX2 positive. This mutually exclusive immunophenotype confirmed two separate primary carcinomas. Given the high-grade histology, the patient received platinum-based chemotherapy and achieved a partial response. Conclusions: This case illustrates the diagnostic complexity of synchronous lesions and highlights the “mirage of the first lesion” phenomenon, in which the initially detected tumor may not represent the true primary site. A comprehensive, multidisciplinary strategy is crucial for establishing the correct diagnosis and guiding optimal management. Full article

Pulmonary neuroendocrine tumors (PULMONARY NETs) are heterogeneous tumors ranging from well-differentiated to highly aggressive neoplasms. The aim of this study is to prospectively test pre-operative circulating free DNA (cfDNA) in PULMONARY NET patients undergoing surgery and evaluate its relationship to clinicopathological features. From February to December 2024, 136 patients with suspected primary lung cancer underwent pre-operative blood sampling, of whom 21 were diagnosed with PULMONARY NETs. Total cell-free nucleic acid extraction was performed using the Genexus Purification System (Thermofisher). cfDNA was quantified using a fluorometric assay with the Qubit dsDNA HS Assay kit (Thermofisher) and a capillary electrophoresis-based assay (cell-free DNA ScreenTape kit) on the Tape Station 4200 systems (Agilent). A cfDNA quality assessment was also obtained (cfDNA sizing and % cfDNA). Most patients had Stage I (18/21.85.7%) typical carcinoids (16/21.76.2%). Nodal involvement was detected in one patient (0.5%). Six months after surgery, all patients were alive without recurrence. Larger tumors presented higher levels of cfDNA. The mean tumor size in patients with cfDNA > 40 ng was 266 mm (±16.7 mm), compared to 13.2 mm (±7.3 mm) for cfDNA < 40 ng (p-value = 0.018). Higher levels of cfDNA were observed in patients with pStages greater than IA (p-value = 0.007). Although limited by a small sample group and biases of a surgical series, we observed that larger/advanced PULMONARY NETs presented higher cfDNA levels pre-operatively. Full article

The lung is increasingly recognized as an organ with dual endocrine and respiratory roles, participating in a complex bidirectional crosstalk with systemic hormones and local/paracrine activity. Endocrine and paracrine pathways regulate lung development, ventilation, immunity, and repair, while pulmonary cells express hormone receptors and secrete mediators with both local and systemic effects, defining the concept of the “endocrine lung”. This narrative review summarizes current evidence on the endocrine–pulmonary axis. Thyroid hormones, glucocorticoids, sex steroids, and metabolic hormones (e.g., insulin, leptin, adiponectin) critically influence alveologenesis, surfactant production, ventilatory drive, airway mechanics, and immune responses. Conversely, the lung produces mediators such as serotonin, calcitonin gene-related peptide, endothelin-1, leptin, and keratinocyte growth factor, which regulate vascular tone, alveolar homeostasis, and immune modulation. We also describe the respiratory manifestations of major endocrine diseases, including obstructive sleep apnea and lung volume alterations in acromegaly, immunosuppression and myopathy in Cushing’s syndrome, hypoventilation in hypothyroidism, restrictive “diabetic lung”, and obesity-related phenotypes. In parallel, chronic pulmonary diseases such as chronic obstructive pulmonary disease, interstitial lung disease, and sleep apnea profoundly affect endocrine axes, promoting insulin resistance, hypogonadism, GH/IGF-1 suppression, and bone metabolism alterations. Pulmonary neuroendocrine tumors further highlight the interface, frequently presenting with paraneoplastic endocrine syndromes. Finally, therapeutic interactions are discussed, including the risks of hypothalamic–pituitary–adrenal axis suppression with inhaled corticosteroids, immunotherapy-induced endocrinopathies, and inhaled insulin. Future perspectives emphasize mapping pulmonary hormone networks, endocrine phenotyping of chronic respiratory diseases, and developing hormone-based interventions. Full article

Small Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy representing approximately 15% of all lung cancers. Characterized by rapid progression, early metastasis, and high circulating tumor cell burden, SCLC has a poor prognosis. Although initial responses to chemotherapy, radiotherapy, and immunotherapy are common, relapse due to acquired resistance is nearly inevitable. Molecular studies have identified four transcription factor–driven subtypes—ASCL1, NEUROD1, POU2F3, and YAP1—each with distinct biological traits and therapeutic vulnerabilities. However, clinical classification remains largely homogeneous, limiting precision treatment strategies. Immunotherapy has modestly improved survival, as demonstrated in trials like IMpower133, CASPIAN, and ADRIATIC. Yet only a small subset of patients—approximately 12%—achieve long-term survival beyond five years. Understanding the biological and immunological profiles of these exceptional responders is critical. Future research should prioritize comprehensive biomarker integration, including PD-L1, TMB, DLL3, CD3, and emerging targets. Novel agents such as tarlatamab (DLL3-targeting) and ifinatamab deruxtecan (B7-H3–targeting) have shown encouraging efficacy in early-phase trials, though predictive markers remain elusive. A multi-dimensional approach combining tissue, blood, and immune profiling is essential to advance precision oncology in SCLC and improve patient selection for emerging therapies. Full article

Pulmonary carcinoids (PCs) are rare tumors, with an incidence ranging from 0.2 to 2 cases per 100,000 population per year. They account for 1–2% of all invasive pulmonary malignancies and represent approximately one-fourth to one-third of all well-differentiated neuroendocrine tumors (NETs) in the body. PCs are generally classified as low- to intermediate-grade malignant tumors, further subdivided into typical carcinoid (TC) and atypical carcinoid (AC), respectively. These tumors exhibit neuroendocrine morphology and differentiation, originating from mature cells of the pulmonary diffuse neuroendocrine system. Traditionally, they are categorized as central or peripheral based on their location relative to the bronchial tree; however, they can arise anywhere within the lung parenchyma. Over 40% of cases may be detected incidentally on a standard chest X-ray, although contrast-enhanced computed tomography (CT) remains the diagnostic gold standard. Surgical resection is the treatment of choice for PCs, with the goal of complete tumor removal while preserving as much healthy lung tissue as possible. In contrast, advanced cases are typically not amenable to surgery, and medical management is focused on controlling hormone-related symptoms and limiting tumor progression. This review aims to provide an overview of the current diagnostic and therapeutic approaches to pulmonary carcinoids. Full article