The evolving science of lung neuroendocrine tumors: from diagnosis to treatment breakthroughs

The diagnosis and treatment of lung neuroendocrine tumors (Lung NETs – Lung neuroendocrine tumors) remain a rare but critically important healthcare challenge. Therefore, analysis of the latest research findings in this area of oncology is of particular interest.

Lung NETs represent a small but significant subgroup of lung cancers. These rare cancers account for up to 25% of all lung cancer cases and include:

• carcinoids;
• large-cell neuroendocrine carcinoma (LCNEC – large-cell neuroendocrine carcinoma);
• small-cell lung carcinoma (SCLC – small-cell lung carcinoma).

These tumor types have unique biological behavior and molecular markers, which makes their monitoring and prediction of disease course effective. Recent advances in molecular diagnostics and therapeutic strategies offer hope for more personalized approaches to treating this pathology.

TYPES AND CHARACTERISTICS OF LUNG NEUROENDOCRINE TUMORS

Based on differentiation, lung NETs are generally divided into two groups:

• Well-Differentiated Neuroendocrine Tumors (NETs);
• Poorly Differentiated Neuroendocrine Carcinomas (NECs).

Well-differentiated neuroendocrine tumors are further divided into:

• typical carcinoids (Typical Carcinoids, TC): low-grade tumors with fewer than 2 mitoses per 2 mm², characterized by slow progression and a favorable prognosis;
• atypical carcinoids (Atypical Carcinoids, AC): intermediate-grade tumors with 2–10 mitoses per 2 mm², sometimes with focal necrosis.

Poorly differentiated neuroendocrine carcinomas are divided into:

• large-cell neuroendocrine carcinomas (Large Cell Neuroendocrine Carcinomas, LCNECs): aggressive high-grade tumors with significant mitotic activity and necrosis;
• small-cell lung carcinomas (Small Cell Lung Carcinomas, SCLCs): extremely aggressive tumors associated with high mortality.

These tumor categories are defined by histological characteristics such as:

• cell morphology;
• mitotic count;
• presence of necrosis.

MOLECULAR SUBTYPES

Advances in molecular biology have identified unique genetic and epigenetic profiles in lung NETs. Studies emphasize the role of mutations in genes such as MEN1, TP53, and RB1. For example, well-differentiated NETs are often characterized by alterations in chromatin-remodeling genes, whereas poorly differentiated NETs demonstrate high rates of mutations in tumor-suppressor genes such as TP53 and RB1.

In addition, new molecular subtypes are emerging, such as “supra-carcinoids” and grade 3 NETs. These subtypes blur the traditional boundaries between well-differentiated and poorly differentiated categories, emphasizing the need for more nuanced diagnostic criteria. For example, grade 3 NETs show morphological features of carcinoids but demonstrate higher rates of proliferation and aggressiveness.

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CHALLENGES IN CLINICAL DIAGNOSIS

Diagnosis of lung NETs can be particularly difficult because of their morphological diversity and overlap with other types of lung cancer. Immunohistochemical markers such as synaptophysin, chromogranin A, and CD56 are commonly used to confirm neuroendocrine differentiation. However, newer markers such as INSM1 and Ki-67 are proving invaluable, particularly for distinguishing poorly and well-differentiated tumors in small biopsy samples.

Ki-67 is a protein detected only in dividing cells. Ki-67 expression is a marker of tumor proliferative activity. Importantly, assessment of this marker is becoming increasingly significant for determining lung NET subtypes, particularly in small biopsies in which mitotic counts are difficult to evaluate.

INSM1 – insulinoma-associated gene 1 – is a sensitive marker of neuroendocrine differentiation in lung tumors.

CURRENT APPROACH TO TREATMENT

Lung NETs, encompassing both well-differentiated and poorly differentiated tumors, require individualized treatment strategies because of their diverse biological behavior and prognosis. Recent innovations in molecular biology and systemic therapy are changing the approach to treating these complex cancers.

1. Surgical interventions

Surgical treatment remains the main treatment for localized well-differentiated NETs, such as typical and atypical carcinoids. Depending on tumor grade and location, different surgical approaches may be used:

• parenchyma-sparing surgery (Parenchyma-Sparing Surgery). Wedge resection and segmentectomy are increasingly used for poorly differentiated localized carcinoids, minimizing damage to healthy lung tissue while achieving complete tumor removal;
• lobectomy. For more advanced or atypical carcinoids, lobectomy with lymph node dissection is the standard for ensuring local control and accurate staging;
• video-assisted thoracic surgery (Video-assisted thoracic surgery, VATS) and robotic-assisted surgery are gaining popularity because of their minimally invasive technique, resulting in faster recovery and fewer complications.

2. Systemic therapy

For advanced or metastatic lung NETs, systemic treatment is highly important. These treatments differ according to tumor type and molecular characteristics.

Chemotherapy

• SCLC and LCNEC. High-grade NETs such as SCLC and LCNEC are usually treated with platinum-based regimens, for example cisplatin or carboplatin combined with etoposide. Despite initial effectiveness, these cancers frequently recur, emphasizing the need for alternative approaches.
• Carcinoids. Chemotherapy is used less frequently for poorly differentiated carcinoids but may be considered in progressive disease. Regimens such as temozolomide or capecitabine combined with bevacizumab have shown promise in selected cases.

Targeted therapy

• Everolimus. Approved for advanced, nonfunctional lung and gastrointestinal NETs; this mTOR protein inhibitorslows tumor growth by targeting cellular proliferation pathways.
• Sotorasib. Effective against LCNEC with KRAS G12C mutations. This targeted therapy represents a new era of personalized medicine for molecularly defined subgroups.
• DLL3-Directed Therapies. Experimental drugs targeting the DLL3 protein, which is overexpressed in SCLC and LCNEC, offer a different therapeutic approach. For example, rovalpituzumab tesirine, an antibody-drug conjugate (ADC), initially demonstrated successful results but encountered setbacks in trials, prompting further investigation and refinement.

Antibody-drug conjugates represent an innovative class of medicines combining chemotherapeutic agents with monoclonal antibodies. This method allows the antitumor drug to be delivered directly to target cells, substantially increasing treatment effectiveness and reducing systemic adverse effects.

The monoclonal antibodies within ADCs recognize specific molecular markers on the surface of tumor cells and bind only to them. After binding, the conjugate enters the cell, where the chemotherapeutic agent is released and destroys the tumor cell from within. This targeted method provides high selectivity and minimizes damage to healthy tissues.

Immunotherapy

• PD-L1 Inhibitors. Immune checkpoint inhibitors such as atezolizumab have become part of the standard treatment regimen for SCLC at the progression stage, significantly improving survival outcomes.
• Experimental strategies. New approaches are being investigated, including bispecific T-cell engagers and chimeric antigen receptor (CAR) T cells targeting DLL3. Chimeric antigen receptors are recombinant antigen receptors that redirect T-lymphocyte function within the molecule. The aim of these therapies is to enhance immune recognition of neuroendocrine tumors by overcoming their immunosuppressive microenvironment.

3. New and experimental treatments

Understanding the molecular and biological subtypes of lung NETs is stimulating the development of innovative therapeutic approaches.

Radioligand Therapy, RLT

Radiolabeled somatostatin analogues, such as lutetium-177 DOTATATE, have shown strong results in the treatment of metastatic gastrointestinal NETs and are currently being studied for the treatment of lung carcinoids. This therapy provides localized irradiation of somatostatin receptor-expressing tumors while sparing healthy tissues.

Epigenetic therapy

Epigenetic alterations, such as chromatin-remodeling defects, are common in carcinoids and LCNEC. Drugs targeting histone deacetylases (HDAC) and DNA methyltransferases are being tested in preclinical models and early-stage trials.

Targeted therapy of MYC-driven states

MYC is one of the most extensively studied cancer genes. Recent studies have identified therapeutic targets for MYC-driven states. Recent findings from observations of arginine deprivation and Aurora kinase inhibition are encouraging regarding the potential use of these unique dependencies in NET therapy.

Modulation of the tumor microenvironment

Studies of the tumor microenvironment identify a unique immune environment for each molecular subtype of lung NET. For example:

1. grade 3 NETs and “supra-carcinoids” demonstrate different immune profiles based on immune checkpoint markers such as PD-1 and PD-L1;
2. immunotherapy that modulates this environment, such as dendritic cell vaccines and combined checkpoint inhibitors, is under investigation.

4. Precision (personalized) medicine and molecular profiling

Molecular profiling is increasingly influencing decisions in favor of particular treatment approaches. The following research directions are noteworthy:

• next-generation sequencing (Next-Generation Sequencing, NGS). This method allows identification of actionable mutations such as KRAS, TP53, and RB1 and also helps stratify patients for targeted therapy or inclusion in clinical trials;
• liquid biopsy. This is an important advance for detecting circulating tumor DNA (circulating tumor DNA, ctDNA), providing non-invasive monitoring of disease progression and treatment response.

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CONCLUSION

Methods for diagnosing and treating lung neuroendocrine tumors are progressively evolving. This is driven by an understanding of the molecular basis of the disease process, although substantial limitations remain in the application of treatments for high-grade tumors such as SCLC and LCNEC. However, advances in immunotherapy and targeted therapy open enormous opportunities. Collaborative efforts in research and clinical practice are paving the way toward more effective, personalized treatment strategies, offering hope to patients facing these rare and complex cancers.