Diagnostic and therapeutic approach to neuroendocrine lung tumours: a narrative review

Introduction

Lung neuroendocrine tumours (NETs) represent a broad and heterogeneous spectrum of malignancies that differ substantially in their biological behaviour, clinical course, metastatic propensity, molecular characteristics, and treatment responses. These neoplasms are classified into well-differentiated low-grade typical carcinoids (TC), well-differentiated atypical carcinoids (AC), and the poorly differentiated high-grade neuroendocrine carcinomas—namely large-cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). Although well-differentiated carcinoids are biologically distinct from high-grade neuroendocrine carcinomas, a subset of aggressive well-differentiated NETs may demonstrate features that overlap with high-grade disease (1-3). Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is acknowledged by the World Health Organization (WHO) as a pre-invasive condition and a potential early step in the development of lung NETs. Carcinoid tumours of the lung account for less than 2% of all primary pulmonary malignancies (4), with TCs representing up to 90% of the well-differentiated NET subgroup (5). TCs most often arise during the fifth or sixth decade of life, while ACs tend to appear approximately one decade later; neither form shows a strong association with sex or smoking history (6). LCNEC comprises around 3% of lung cancers and shares several clinicopathological features with SCLC. It occurs predominantly in older male smokers, typically over the age of 60 years (7). SCLC, representing 10–15% of all lung cancers, is also primarily diagnosed in older adults—particularly men—and has a strong epidemiological link to heavy tobacco exposure (8). DIPNECH is defined by a widespread proliferation of pulmonary neuroendocrine cells and is frequently associated with tumourlets and neuroendocrine cell hyperplasia in resected tissue from peripheral well-differentiated NETs, further supporting its identification as a precursor lesion in the pathogenesis of lung NET (9).

To date, current treatments for neuroendocrine lung tumours depend on histologic subtype and disease stage. For well-differentiated tumours (TCs and ACs), surgical resection is the only curative option for localized disease. For progressive disease, everolimus (an mTOR inhibitor) is the only Food and Drug Administration (FDA)-approved systemic agent for unresectable, locally advanced lung NETs while peptide receptor radionuclide therapy (PRRT) is considered for SSTR2-positive tumors after progression on somatostatin analogues (SSAs) and other systemic therapies. Radiotherapy may be used for local control in select cases, particularly for unresectable or symptomatic lesions. Treatment selection is individualized, considering tumor grade, SSTR expression, disease burden, and progression status, but many questions about neuroendocrine lung tumors management remain unanswered.

Key knowledge gaps in the diagnosis and therapeutic management of lung NETs include: lack of robust, prospective data to guide optimal treatment sequencing and selection for advanced and metastatic lung NETs, particularly regarding the use and timing of SSAs, everolimus, temozolomide, platinum-based chemotherapy, and PRRT; insufficient predictive and prognostic biomarkers to inform personalized therapy and risk stratification; uncertainty regarding the role and benefit of adjuvant therapy in resected TCs and ACs, with no established protocols and a lack of prospective trials in high-risk patients; challenges in the pathological classification and diagnosis of high-grade neuroendocrine carcinomas (LCNEC and SCLC), especially in small biopsies; limited data on optimal surveillance and follow-up protocols after initial treatment; need for improved understanding of the molecular and genomic landscape to identify actionable targets and develop new therapies.

This review summarises current diagnostic strategies and therapeutic approaches to pulmonary NETs, offering an updated synthesis of the most recent literature. We present this article in accordance with the Narrative Review reporting checklist (available at https://shc.amegroups.com/article/view/10.21037/shc-2025-4/rc).

Methods

This review outlines key aspects of the diagnostic and therapeutic management of pulmonary NETs. A comprehensive literature search was conducted using PubMed, Medline, and Google Scholar to identify relevant publications. The search strategy employed the following MeSH terms: “neuroendocrine lung tumours”, “typical carcinoid”, “atypical carcinoid”, “large-cell neuroendocrine lung cancer”, and “small cell lung cancer”. Eligible studies included those reporting patient demographics, clinical presentation, and management strategies for lung NETs. We considered clinical trials, cohort studies, and case-control studies published in English prior to August 2025. Reference lists of selected articles were also manually reviewed to identify additional relevant studies. Exclusion criteria were opinion pieces, letters to the editor, abstracts, and preprints that had not undergone peer review (Table 1).

Pulmonary carcinoids (PCs)

Epidemiology

PCs represent a small fraction—about 1–2%—of all primary malignant lung tumors and account for approximately one-quarter to one-third of well-differentiated neuroendocrine tumors (NET). They are considered uncommon neoplasms, with an age-adjusted incidence estimated at 0.2–2 cases per 100,000 individuals per year (10). A modest predominance in females has been reported, and PCs appear more frequently in white populations compared with Black individuals or other ethnic groups. Diagnosis typically occurs between the fourth and sixth decades of life, with TCs presenting around a mean age of 45 years and ACs around 55 years. Notably, PCs constitute the most common primary pulmonary malignancy in children and adolescents, where TC is the usual histologic subtype. Most individuals diagnosed with PCs are either never-smokers or have only a minimal smoking history. Nonetheless, ACs demonstrate a stronger correlation with current or past tobacco exposure compared with TCs. PCs generally manifest as single nodules; however, in patients with multiple endocrine neoplasia type 1 (MEN1), up to 5% may develop multiple lesions, necessitating differentiation from pulmonary hamartomas. ACs occur far less frequently than TCs, with reported ratios ranging between 8:1 and 10:1 (10).

Diagnosis and pathology

PCs arise from mature neuroendocrine cells within the diffuse pulmonary neuroendocrine system and exhibit neuroendocrine morphology and differentiation. They are classified as low-grade malignancies (TC) or intermediate-grade malignancies (AC). Unlike high-grade neuroendocrine carcinomas—such as SCLC and LCNEC—PCs do not share the same molecular profile or direct causative pathways (11).

Histologically, TCs demonstrate fewer than two mitoses per 2 mm² without necrosis, whereas ACs show 2–10 mitoses per 2 mm² and/or focal necrosis (10). Differentiating between these subtypes on small biopsies or cytology samples is challenging, requiring careful morphological and immunohistochemical assessment. The detection of mitotic figures or necrosis suggests AC, but in many small specimens, reliable distinction is not possible. The Ki-67 proliferation index may assist in excluding high-grade tumors (e.g., SCLC, LCNEC) when low, but it does not reliably separate TC from AC (12). Clinically, PCs may cause respiratory symptoms such as persistent cough, hemoptysis, wheezing, dyspnea, chest discomfort, or recurrent pulmonary infections—particularly in centrally located tumors. Peripheral lesions are more often asymptomatic. In rare cases, diagnosis is prompted by hormone-related symptoms. In patients with functional hormonal syndromes, biochemical evaluation should include plasma serotonin and 5-hydroxyindoleacetic acid (5-HIAA) measurement. Some well-differentiated PCs produce adrenocorticotropic hormone (ACTH), leading to Cushing’s syndrome, and serum ACTH testing should be performed when clinically indicated (13). Contrast-enhanced computed tomography (CT) is the imaging standard for diagnosing PCs, generally using a standard lung CT protocol. Radiological findings can be nonspecific and may mimic adenocarcinoma or squamous cell carcinoma. PCs typically appear as well-defined, round or ovoid nodules with smooth or lobulated margins, more frequently central than peripheral (14-16). They are usually hypervascular, showing marked homogeneous enhancement after contrast administration. Calcifications are uncommon, and when present, may complicate differentiation from hamartomas. Compared to other lung cancers, PCs tend to grow slowly. Centrally located tumors may produce indirect CT signs of bronchial obstruction, including atelectasis, obstructive pneumonitis, air trapping, and less often, bronchiectasis or pulmonary abscess (17). Functional nuclear imaging, such as somatostatin receptor scintigraphy (SRS) with single-photon emission computed tomography (SPECT)/CT or Gallium-68 positron emission tomography (PET)/CT, offers higher specificity than conventional imaging for detecting PCs, facilitates whole-body staging, and may help predict response to PRRT (18). Bronchoscopy is recommended for centrally located tumors to obtain histological confirmation. Flexible bronchoscopy is preferred in most cases, but rigid bronchoscopy may be advantageous for tissue acquisition and therapeutic procedures, including tumor debulking (19,20). Key adverse prognostic factors include larger tumor size, nodal metastases, and higher Ki-67 index for TCs; on the other hand, independent predictors of poor outcome for ACs include advanced age, higher stage, nodal metastases, and elevated mitotic count or Ki-67 index (19,20).

Therapy

Surgical resection is the mainstay of curative treatment, aiming for complete tumor removal with maximal preservation of lung parenchyma. The surgical technique is determined by tumor size, location, and histological subtype. Standard management includes anatomical resection with systematic lymph node dissection. For peripheral tumors, lobectomy or segmentectomy is preferred, with a minimum of six lymph nodes (including three mediastinal, one subcarinal) assessed (10). Segmentectomy is favored over wedge resection in patients with limited pulmonary reserve, while central lesions may require bronchoplastic procedures to preserve lung tissue. Sublobar resections for peripheral ACs may carry an increased risk of recurrence (21).

Advanced ACs are more aggressive than TCs and require multidisciplinary care. Management goals include symptom control—particularly for hormone-mediated syndromes—and delaying tumor progression. Approximately 30% of patients with advanced PCs present with hormone-related symptoms, most often carcinoid syndrome. Long-acting SSAs, such as octreotide and lanreotide, are considered first-line agents for symptom control (22,23). No standardized adjuvant therapy exists after complete resection, although adjuvant treatment may be considered in ACs with nodal involvement and high proliferative index (10). For selected patients with low tumor burden and slow progression, active surveillance with imaging every 3–6 months may be appropriate. SSAs can stabilize disease in 30–70% of well-differentiated NETs, with monthly long-acting formulations preferred for their tolerability (24). Well-differentiated PCs often express somatostatin receptor subtype 2, detectable on SRS or Gallium-68 PET/CT, which also aids in selecting candidates for PRRT. Radio-labelled SSAs, including yttrium-90 DOTA-Tyr³-octreotide (⁹⁰Y-DOTATOC) and lutetium-177 DOTA-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE), have shown efficacy in metastatic TCs and ACs with strong tracer uptake (25). Systemic chemotherapy is generally reserved for progressive, unresectable disease, but response rates are modest and evidence is limited by small, heterogeneous studies (26). Everolimus, an mTOR inhibitor, is an option in TC or AC after other treatments fail, as activation of the PI3K/AKT/mTOR pathway has been demonstrated in lung NETs (27). Antiangiogenic agents such as sunitinib are under investigation, while preclinical studies suggest EGFR inhibitors like erlotinib may suppress tumor growth in EGFR-expressing PCs (28,29). Novel targeted strategies include agents acting on fibroblast growth factor, MET, VEGF, and PDGF pathways (30). Recent clinical trials for lung neuroendocrine tumor subtypes other than SCLC have focused on expanding systemic therapy options and personalizing treatment. For well-differentiated TCs and ACs, everolimus is established as a standard agent following the RADIANT-4 trial, which demonstrated improved progression-free survival in advanced, nonfunctional lung NETs (1). PRRT with ¹⁷⁷Lu-DOTATATE, while FDA-approved for gastroenteropancreatic NETs, is increasingly used off-label for somatostatin receptor-positive lung NETs, and ongoing trials are evaluating next-generation PRRT agents, including alpha-emitters such as ²²⁵Ac (RYZ101) for SSTR2-positive disease (1).

LCNEC

Epidemiology

LCNEC is an uncommon yet highly aggressive variant of non-small cell lung cancer (NSCLC) characterized by neuroendocrine differentiation, comprising approximately 3–5% of all lung cancers (31). It is less prevalent than SCLC but typically demonstrates more aggressive clinical behavior than conventional NSCLC. LCNEC primarily affects older adults, with a median age at diagnosis between 60 and 70 years, and shows a slight male predominance. Tobacco smoking is the major risk factor, with most patients having a history of cigarette use (32). Although some geographic and ethnic differences in incidence have been suggested, data remain limited due to the rarity of the disease. Pre-existing lung conditions, such as chronic obstructive pulmonary disease (COPD), may further increase the risk.

Diagnosis and pathology

Histopathologically, LCNEC is defined by a combination of neuroendocrine architectural patterns—such as organoid nesting, palisading, trabecular arrangements, and rosette formation—with cytologic features typical of non-small cell carcinoma, including large cell size, prominent nucleoli, abundant cytoplasm, and a high mitotic rate (>10 mitoses per 2 mm², with median counts often near 70) (33). Immunohistochemical confirmation requires the expression of at least one classic neuroendocrine marker: synaptophysin, chromogranin A, or CD56 (34). Additional markers such as INSM1 and ASCL1 have shown promise, but their role in LCNEC diagnosis remains to be fully clarified. While not part of the WHO diagnostic criteria, Ki-67 is useful for distinguishing LCNEC from carcinoids, particularly in small biopsies with crush artifacts; Ki-67 indices in LCNEC typically range from 70–100%, though overlap with highly proliferative carcinoids (20–60%) can occur (35). LCNEC encompasses a broad morphologic spectrum, generally divided into two subtypes: NSCLC-like LCNEC and SCLC-like LCNEC (36-38). The NSCLC-like subtype has large cells, abundant cytoplasm, and prominent nucleoli, along with neuroendocrine features such as nesting and rosettes. These tumors may resemble adenocarcinoma (solid or cribriform patterns), large-cell carcinoma, or basaloid squamous cell carcinoma, and are characterized by mutations typically found in smoking-related adenocarcinomas, including STK11, KEAP1, and KRAS, with a general absence of RB1 alterations (39). They are often chemoresistant and aggressive (39). In contrast, the SCLC-like subtype displays nuclear features similar to SCLC (small or intermediate-sized cells, coarse chromatin) but with more prominent nucleoli or greater cytoplasmic volume. The presence of visible intercellular membranes can help support an LCNEC diagnosis, as these are usually absent in SCLC due to its scant cytoplasm (40). This subtype is characterized by RB1 and TP53 alterations, similar to SCLC, and often shows aggressive, treatment-resistant behavior. Diagnosis can be challenging in small or poorly preserved biopsy specimens, but the growing use of larger tissue samples for molecular testing has improved diagnostic feasibility. A semiquantitative scoring system has been proposed for biopsies, integrating neuroendocrine morphology, necrosis, Ki-67 index, and neuroendocrine marker expression (41). Recent advances in diagnosis, particularly molecular subtyping using next-generation sequencing, have identified two major LCNEC subgroups: SCLC-like (RB1/TP53 mutations) and NSCLC-like (KRAS/KEAP1/STK11 mutations). This stratification has prognostic and therapeutic implications: SCLC-like LCNEC tends to have a shorter overall survival but may respond better to platinum-etoposide regimens, while NSCLC-like LCNEC may benefit from NSCLC-type chemotherapy (42-44).

Therapy

treatment remains controversial (42). The most controversial aspects regarding the treatment of LCNEC center on the lack of standardized therapeutic guidelines, the optimal choice between SCLC-like and NSCLC-like chemotherapy regimens, and the emerging but unproven role of immunotherapy. First, LCNEC is a rare and biologically heterogeneous entity, with molecular subtypes resembling either SCLC or NSCLC. This has led to debate over whether SCLC-like regimens (platinum–etoposide or irinotecan) or NSCLC-like regimens (platinum–gemcitabine, taxanes, or pemetrexed) should be used as first-line therapy. Second, the role of immunotherapy is controversial. While immune checkpoint inhibitors (e.g., atezolizumab, durvalumab, pembrolizumab) have demonstrated efficacy in SCLC and NSCLC, LCNEC patients were excluded from pivotal trials, and data supporting their use in LCNEC are limited to small retrospective series and case reports. Finally, there is uncertainty regarding the use of adjuvant and neoadjuvant therapies, the benefit of surgery in early-stage disease, and the management of relapsed or refractory LCNEC, as most recommendations are extrapolated from SCLC and NSCLC guidelines rather than LCNEC-specific evidence (42). Surgical resection is recommended for early-stage, resectable disease, with reported 5-year survival rates between 27% and 67%. Lobar resection is generally preferred over sublobar approaches for stage I LCNEC. However, recurrence—particularly within the first two years—is common, supporting the use of multimodal strategies including adjuvant chemotherapy (43). For advanced or metastatic LCNEC, platinum-based regimens traditionally used for SCLC (e.g., cisplatin/etoposide) are frequently employed, although LCNEC tends to have lower chemosensitivity than SCLC (44). Recent evidence suggests that RB1 status may serve as a treatment selection biomarker—RB1 loss favouring SCLC-type regimens, and intact RB1 suggesting NSCLC-type therapies (44). The role of immunotherapy and targeted agents in LCNEC remains under investigation (45).

SCLC

Epidemiology

SCLC accounts for approximately 10–15% of all lung cancers, with an incidence of 1–5 cases per 100,000 individuals. Although its overall incidence has decreased from 8.8 per 100,000 in 2000 to 4.8 per 100,000 in 2019, a rising trend has been noted among women and individuals aged 75 years or older (46). SCLC is strongly linked to tobacco smoking, with around 95% of patients having a history of tobacco use. While smoking cessation reduces the risk, the incidence of SCLC remains higher than the general population even 30 years after quitting. Between 2.5% and 13% of cases occur in never-smokers, who generally experience better outcomes (47,48).

Diagnosis and pathology

Genetically, SCLC is characterized by the near-universal inactivation of the tumor suppressor genes RB1 and TP53, and its heterogeneity is largely driven by epigenetically regulated transcription factors (49). In rare cases, NSCLC harboring oncogenic mutations—such as EGFR or ALK—may undergo histological transformation into SCLC, particularly when accompanied by TP53 or RB1 alterations, resulting in poorer prognosis and survival (50). Clinically, patients with SCLC may present with cough, dyspnea, and hemoptysis, although up to 60% are asymptomatic at diagnosis. Systemic symptoms such as weight loss, anorexia, and fatigue are common in extensive-stage disease. Approximately 15% of patients have brain metastases at presentation, often manifesting as headache or focal neurological deficits, which contribute to reduced survival (51). Superior vena cava syndrome occurs in around 10% of cases, leading to headache, swelling of the face or neck, upper extremity edema, or voice changes due to vascular compression (52,53). Paraneoplastic syndromes are also observed, most notably the syndrome of inappropriate antidiuretic hormone secretion and ectopic Cushing’s syndrome caused by tumor-derived ACTH (54). Around 2–3% of patients develop Lambert-Eaton myasthenic syndrome, characterized by weakness, ataxia, and hyporeflexia due to autoimmune targeting of voltage-gated calcium channels and impaired acetylcholine release (55). Diagnosis requires tissue biopsy of the primary tumor, lymph nodes (often via endobronchial ultrasound), or metastatic sites. Histopathology reveals small, round blue cells with high nuclear-to-cytoplasmic ratio and high mitotic activity. The proliferative index (Ki-67) typically ranges from 50% to 100%. Immunohistochemical staining frequently shows positivity for cytokeratin, thyroid transcription factor-1 (TTF-1), and neuroendocrine markers including synaptophysin, chromogranin A, CD56, and insulinoma-associated protein-1. Differentiation from carcinoids and LCNEC is based on morphology and mitotic activity, as outlined by the WHO (2). Staging investigations generally include abdominal CT, brain magnetic resonance imaging (MRI), and PET/CT. SCLC is classified into limited-stage (LS-SCLC) and extensive-stage (ES-SCLC) disease. Limited-stage disease is defined as tumors confined to one hemithorax (with or without hilar nodal involvement) and amenable to coverage within a single radiation field. In 1986, the International Association for the Study of Lung Cancer expanded this definition to include contralateral mediastinal/supraclavicular nodes and ipsilateral pleural effusion (56,57). The tumor-ode-metastasis (TNM) classification aligns closely, categorizing stages I–III as limited stage and stage IV as extensive stage.

Therapy

Patients with LS-SCLC may be treated with curative intent using chemotherapy, radiation, surgery in selected cases, and consolidation immunotherapy (47,58,59). For LS-SCLC, standard therapy involves concurrent high-dose thoracic radiotherapy targeting the primary tumor and nodal sites with platinum-etoposide chemotherapy for 4–6 cycles, initiated in cycle 1 or 2 (60). Patients with stage I–IIA (T1-2N0M0) disease and negative mediastinal/hilar nodes may undergo lobectomy. Stereotactic body radiotherapy is an alternative for patients unsuitable for surgery (61). Postoperatively or after stereotactic radiotherapy, adjuvant platinum-etoposide chemotherapy for 4 cycles is recommended (62). Historically, 5-year overall survival for LS-SCLC with chemoradiation was 16.1–27.7%. The addition of 2 years of durvalumab consolidation has significantly improved outcomes, raising median survival from 33.4 to 55.9 months and achieving 3-year overall survival of 56.5% (63). In ES-SCLC, first-line therapy consists of platinum–etoposide plus an anti-PD-L1 antibody (atezolizumab or durvalumab). Following induction, patients typically continue with maintenance immunotherapy until disease progression or intolerance (47,64). The role of prophylactic cranial irradiation in ES-SCLC remains debated; either brain MRI surveillance every 3–6 months or prophylactic irradiation is acceptable, though MRI surveillance is more commonly adopted in current practice (65). While initial response rates to chemo-immunotherapy range between 60% and 80%, long-term outcomes remain poor, with 3-year overall survival of 17.6% and 5-year survival around 12% (66). Despite the addition of immunotherapy (atezolizumab or durvalumab) to platinum–etoposide chemotherapy, which is now standard first-line therapy for extensive-stage SCLC, the improvement in overall survival is modest—typically extending median survival by only 2–3 months, with most patients relapsing within 6 months and 5-year survival rates remaining below 7%. There are currently no validated predictive biomarkers that reliably identify patients who will benefit from immunotherapy or other systemic treatments in SCLC. Investigations into PD-L1 expression, tumor mutational burden, and molecular subtypes have shown only preliminary and inconsistent predictive value, and no biomarker is routinely used in clinical practice to guide therapy selection. Therapeutic options for relapsed or refractory SCLC are limited. For platinum-sensitive relapse (disease recurrence ≥6 months after first-line therapy), rechallenge with platinum-etoposide is recommended. For platinum-resistant relapse (<6 months), single-agent lurbinectedin or topotecan are preferred, but response rates are low and median progression-free survival is typically less than 4 months. Other agents such as irinotecan, paclitaxel, docetaxel, temozolomide, and gemcitabine have modest activity and are considered based on patient performance status and clinical trial eligibility. Overall, SCLC remains a disease with poor prognosis, rapid development of resistance, and a critical need for more effective therapies and reliable biomarkers to guide treatment (60-66).

DIPNECH

Epidemiology

DIPNECH is an uncommon pulmonary disorder characterized by abnormal proliferation of neuroendocrine cells within the bronchial and bronchiolar epithelium. The WHO formally recognized it as a distinct entity in 2021 (67). It predominantly affects older adults, with a higher prevalence among women. The precise pathogenesis remains unclear, although both genetic predisposition and environmental influences are thought to contribute.

Diagnosis and pathology

Diagnosis relies on a combination of clinical assessment, imaging studies, and histopathological evaluation. Common presenting symptoms include chronic cough, exertional dyspnea, wheezing, and reduced exercise tolerance, largely attributable to airway narrowing caused by neuroendocrine cell proliferation and secondary constrictive bronchiolitis. High-resolution computed tomography (HRCT) of the chest often demonstrates characteristic—but non-specific—features such as bronchial wall thickening, small nodules, and air trapping, which may also be seen in other pulmonary disorders. Definitive diagnosis requires histological confirmation via surgical lung biopsy or resection, showing diffuse neuroendocrine cell hyperplasia within bronchial walls and bronchioles. Immunohistochemical staining for markers such as chromogranin A and synaptophysin facilitates identification. DIPNECH is regarded as a pre-invasive lesion and a potential precursor to carcinoid tumors; therefore, regular surveillance is essential to detect progression or complications.

Therapy

Management primarily targets symptom control and prevention of disease advancement. Inhaled bronchodilators and corticosteroids can improve airflow and reduce inflammation, while systemic corticosteroids may be used for more severe cases. SSAs (e.g., octreotide, lanreotide) have been employed to relieve symptoms and potentially suppress neuroendocrine cell activity. In selected patients, mTOR inhibitors such as everolimus—already used in the treatment of neuroendocrine tumors—may offer benefit. Optimal care requires a multidisciplinary approach involving pulmonologists and oncologists to ensure comprehensive disease management, symptom control, and surveillance. Follow-up typically includes periodic imaging, pulmonary function testing, and clinical evaluation. Current evidence for DIPNECH management is limited to case reports, small case series, and retrospective analyses (68-70), underscoring the need for larger prospective studies to establish evidence-based treatment strategies. DIPNECH remains underdiagnosed and is often misattributed to COPD or asthma, resulting in suboptimal management. Awareness among healthcare providers is crucial, particularly for patients who do not respond adequately to conventional asthma or COPD therapy (71). Emerging evidence suggests that SSAs and mTOR inhibitors may lead to symptomatic improvement in selected patients (72).

Limitations of the study

Limitations of the review are primarily related to the heterogeneity and rarity of pulmonary neuroendocrine tumors, which result in a paucity of high-quality prospective data, especially for rare subtypes like LCNEC and DIPNECH. Much of the evidence cited is derived from retrospective studies, small cohorts, and expert consensus rather than large randomized controlled trials, limiting the strength of recommendations. The review’s inclusion of studies dating back to 1986 may introduce variability in diagnostic criteria and treatment paradigms over time, and the reliance on English-language publications may omit relevant international data. The strongest data available are about SCLC and TCs/ACs, where randomized trials exist. For LCNEC, DIPNECH, and the use of targeted and immunotherapies, the evidence is largely based on retrospective analyses, molecular profiling studies, and early-phase clinical trials, which are hypothesis-generating but not definitive for clinical practice

Conclusions

Neuroendocrine lung tumours represent a heterogeneous spectrum of diseases, ranging from indolent carcinoids to highly aggressive carcinomas. Advances in imaging, pathology, and molecular profiling have improved diagnostic accuracy, while therapeutic strategies continue to evolve, integrating surgery, locoregional therapies, systemic chemotherapy, targeted agents, and immunotherapy (72-80). Despite progress, significant gaps remain in understanding tumor biology and optimizing treatment, underscoring the need for further research and well-designed clinical trials to improve outcomes for these patients. Clinical awareness of lung neuroendocrine tumors can be enhanced by multidisciplinary collaboration, standardized diagnostic algorithms, and education on the heterogeneity and non-specific presentations of these tumors, harmonizing guidelines and promoting routine use of advanced imaging and molecular profiling to improve early detection and individualized management. Future directions include integrating novel molecular biomarkers into classification systems, conducting prospective trials to address therapeutic uncertainties, and developing personalized treatment strategies based on tumor biology and predictive markers.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://shc.amegroups.com/article/view/10.21037/shc-2025-4/rc

Peer Review File: Available at https://shc.amegroups.com/article/view/10.21037/shc-2025-4/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2025-4/coif). F.P. serves as an unpaid editorial board member of Shanghai Chest from February 2025 to July 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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