Medical Oncologist
Pulmonary Neuroendocrine Neoplasms
Typical & atypical carcinoids • LCNEC • Small-cell lung cancer (SCLC)
Pulmonary neuroendocrine neoplasms are not a single disease. They include tumours with very different biological behaviour — from typically slow-growing typical carcinoids to high-grade neuroendocrine carcinomas such as LCNEC and SCLC.
Accurate classification is important because it influences prognosis, the diagnostic work-up required and treatment selection. Assessment is based on histopathological features, mitotic count and necrosis, Ki-67 where informative, disease stage and, as appropriate, specific imaging and molecular tests.
The aim is to define the biology of the disease as accurately as possible so that the treatment strategy can be tailored to the individual patient.
When can a specialist assessment be helpful?
In rare pulmonary neuroendocrine neoplasms, particularly when there is uncertainty about the precise classification of the disease or an important treatment decision must be made, a comprehensive review of the histological material, imaging and treatment course to date can be helpful.
What are the main types?
Pulmonary neuroendocrine neoplasms comprise several tumour categories, with important differences in biological behaviour, prognosis and treatment.
Typical carcinoid
A well-differentiated neuroendocrine tumour that usually has a more indolent biological course. Diagnosis is based primarily on histological features, a low mitotic count and the absence of necrosis. The treatment approach depends on the stage, the location of the tumour and whether the disease can be managed surgically.
Atypical carcinoid
Also a well-differentiated neuroendocrine tumour, but with a higher risk of recurrence or metastatic disease than a typical carcinoid. The distinction is based mainly on mitotic count and the presence of necrosis. Accurate staging and systematic follow-up are particularly important when planning treatment.
LCNEC
A rare, high-grade neuroendocrine carcinoma, usually with aggressive clinical behaviour and marked biological heterogeneity. Contemporary molecular studies have identified different patterns and subgroups of the disease. These findings improve our understanding of LCNEC and are being investigated as a basis for more individualised treatment strategies.
Small-cell lung cancer (SCLC)
A high-grade neuroendocrine carcinoma characterised by rapid growth and frequent early dissemination. Management depends on the extent of disease and may include a combination of systemic therapy and radiotherapy. In metastatic disease, immunotherapy has been incorporated into first-line treatment alongside chemotherapy.
Combined forms
In some cases, LCNEC or SCLC may coexist within the same tumour with another non-neuroendocrine histological component, such as adenocarcinoma or squamous cell carcinoma. Recognition of this combined histology is important for a comprehensive pathological assessment and may be taken into account when planning treatment.
How are diagnosis and staging carried out?
Diagnosis of a pulmonary neuroendocrine neoplasm requires adequate tissue and careful pathological assessment. The biopsy approach depends on the location of the tumour and any suspected lymph-node sites.
Bronchoscopy and EBUS
For centrally located lesions, bronchoscopy may be used to obtain biopsies. When mediastinal or hilar lymph nodes require assessment, endobronchial ultrasound (EBUS) allows targeted lymph-node sampling and can contribute to both diagnosis and staging. Peripheral lesions may require image-guided percutaneous biopsy.
Small bronchoscopic biopsies often require caution when assigning a definitive classification, because limited tissue may not adequately represent the tumour’s mitotic activity, necrosis or heterogeneity. This is particularly important when distinguishing typical from atypical carcinoid and, in some cases, different neuroendocrine carcinomas. Where precise classification affects a treatment decision, additional tissue or review by a pathologist experienced in pulmonary neuroendocrine neoplasms may be required.
Histopathological Assessment Is Crucial
The distinction between typical and atypical carcinoid, LCNEC and SCLC is based on tumour morphology, mitotic activity, the presence of necrosis and expression of neuroendocrine markers. Ki-67 may provide additional information, but in pulmonary carcinoids it does not replace morphological classification based on mitoses and necrosis. Specialist pathological review may be particularly valuable in small or diagnostically difficult biopsies.
Imaging for Staging
The extent of disease is assessed with CT and, depending on the tumour type and clinical question, FDG PET/CT, somatostatin receptor imaging with DOTATATE/DOTATOC PET/CT or brain MRI may be used. Somatostatin receptor imaging is particularly important in well-differentiated NETs, whereas in high-grade neuroendocrine carcinomas FDG PET/CT may provide different information about the extent and biology of the disease.
How is the appropriate treatment selected?
There is no single treatment suitable for every pulmonary neuroendocrine tumour. Selection depends on the precise histological type, the stage and extent of disease, its rate of progression, symptoms, somatostatin receptor expression and previous treatments. In many cases, the decision requires input from several specialties.
Surgery
For localised typical and atypical carcinoids, surgery is the preferred approach for potentially curative treatment and long-term disease control. The extent of surgery is tailored to the site and size of the tumour, lymph-node involvement and the patient’s functional status. Although aggressive neuroendocrine carcinomas are usually diagnosed at a more advanced stage, surgical resection has a clear role in carefully selected cases when disease is confined to the lung.
Management of hormonal and paraneoplastic symptoms
Managing symptoms caused by the disease itself is an important part of the treatment strategy. In functioning neuroendocrine tumours — that is, tumours that secrete hormones or other biologically active substances and cause specific symptoms — prompt control of hormonal hypersecretion may be required alongside anticancer treatment.
Paraneoplastic syndromes with important clinical consequences may also occur in neuroendocrine carcinomas. Effective tumour control often helps improve these manifestations, but specific treatment of the syndrome itself is also required in many cases. For this reason, both accurate differential diagnosis and selection of the appropriate treatment approach require systematic, individualised assessment.
Somatostatin analogues
In well-differentiated, SSTR-positive pulmonary typical carcinoids, somatostatin analogues may be used to control hormonal symptoms and, in appropriately selected patients, tumour growth.
SPINET is the largest prospective study to date conducted specifically in pulmonary carcinoids and supports clinical activity for lanreotide, particularly in typical carcinoids, although the study was stopped early because of low enrolment.
PRRT and functional imaging
Somatostatin receptor imaging with DOTATATE/DOTATOC PET/CT helps assess the expression and distribution of receptors across the disease. In selected patients with advanced, SSTR-positive pulmonary carcinoid, PRRT may be a treatment option outside the approved indication in the European Union, as the current authorisation for ^177Lu-DOTATATE concerns progressive, well-differentiated, SSTR-positive gastroenteropancreatic NETs. In selected cases, FDG PET/CT may provide additional information about the biological heterogeneity of the disease and contribute to the overall treatment assessment.
Systemic treatment
Systemic anticancer treatment may be required in advanced disease. In metastatic SCLC, first-line treatment includes a combination of chemotherapy and immunotherapy.
In LCNEC, platinum combined with etoposide often remains the basis of systemic treatment. Evidence for adding immune checkpoint inhibitor therapy has increased in recent years, with some prospective and retrospective studies showing clinical benefit. However, because LCNEC is rare and biologically heterogeneous, the available evidence remains limited and the role of immunotherapy is not supported to the same degree as in SCLC or NSCLC.
Targeted systemic therapies
In advanced, well-differentiated pulmonary NETs, medicines that inhibit specific molecular pathways involved in tumour growth may be used. These include everolimus, an inhibitor of the mTOR pathway, and now cabozantinib, a multikinase inhibitor, in appropriately selected patients.
Use of these treatments does not require a specific tumour mutation to be identified. In some cases, however, broader molecular testing may reveal additional treatment options or support enrolment in a clinical trial.
Radiotherapy and local treatments
Radiotherapy may be used for local control, symptom management or as part of treatment for specific stages of SCLC or LCNEC. In selected patients who cannot undergo surgery, stereotactic radiotherapy techniques may also provide high local control for typical carcinoids, according to a recent study presented at ASCO. Similarly, local interventional techniques such as thermal ablation or cryoablation may be used for appropriately selected metastatic lesions, in collaboration with an interventional radiologist.
The appropriate sequence of treatments is as important as the choice of each individual treatment and is often reassessed as the biology and extent of disease change.
Research in LCNEC
LANCE is a prospective, non-randomised real-world study investigating the addition of atezolizumab to platinum and etoposide chemotherapy in patients with metastatic pulmonary LCNEC. Its findings add prospective data in a field where the available clinical evidence remains limited and requires confirmation in larger randomised studies.
Molecular Heterogeneity and Emerging Research Directions
Current research seeks to understand more fully the marked molecular heterogeneity of high-grade pulmonary neuroendocrine carcinomas. Different molecular and transcriptional patterns have been described in SCLC and LCNEC, which may in future contribute to more individualised treatment strategies. Small-cell lung cancer (SCLC) Different molecular and transcriptional patterns have been described in SCLC, based principally on the expression of specific transcription factors: SCLC-A: predominant ASCL1 expression SCLC-N: predominant NEUROD1 expression SCLC-P: predominant POU2F3 expression SCLC-I: lower expression of the above factors and a more pronounced inflammatory and immune profile. These subtypes have different biological characteristics and potential treatment sensitivities. However, this classification currently remains primarily a research framework and is not an established routine system for selecting treatment for an individual patient. Large-cell neuroendocrine carcinoma (LCNEC) Genomic and transcriptional studies in LCNEC have also demonstrated marked molecular heterogeneity. Different molecular patterns have been described, including alterations in TP53, RB1, STK11 and KEAP1, which contribute to a better understanding of the biological differences between tumours. The potential clinical relevance of these features remains an active area of research. At present, they are not used as established routine biomarkers for treatment selection, although they may be relevant in the context of clinical trials and the future individualisation of treatment.
Frequently Asked Questions
Scientific References & Clinical Guidelines
WHO Classification of Tumours Editorial Board. Thoracic Tumours. WHO Classification of Tumours, 5th Edition, Volume 5. IARC, 2021. Evangelou G, Trontzas IP, Gkiozos I, et al. The Effectiveness of Atezolizumab in Metastatic Large Cell Neuroendocrine Carcinoma of the Lungs: Insights from the LANCE Pilot Study. Biomedicines. 2024;12(6):1161. doi:10.3390/biomedicines12061161. Baudin E, et al. European Society of Neuroendocrine Tumors (ENETS) 2025 guidance paper for lung and thymic carcinoids. J Neuroendocrinol. 2026;38(4):e70174. Baudin E, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(4):439–451. Baudin E, et al. Treatment of advanced BP-NETs with lanreotide autogel/depot vs placebo: the phase III SPINET study. Endocr Relat Cancer. 2024;31(9):e230337. Fazio N, et al. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis. Cancer Sci. 2018;109:174–181. Zidan L, et al. Efficacy and Safety of 177Lu-DOTATATE in Lung Neuroendocrine Tumors: A Bicenter Study. J Nucl Med. 2022;63:218–225. — on PRRT in SSTR-positive lung NETs. Chan JA, et al. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. N Engl J Med. 2025;392:653–665. — CABINET, in previously treated progressive extrapancreatic and pancreatic NETs. Nassar AH, et al. Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma. Nat Commun. 2025;16:7717. Rudin CM, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019.