Understanding Lung Neuroendocrine Tumors: A Comprehensive Patient Guide

Table of Contents

• Introduction to Lung Neuroendocrine Tumors
• How This Research Was Conducted
• How Common Are These Tumors?
• Types and Grades of Lung Neuroendocrine Tumors
• Pre-Cancerous Conditions
• Symptoms and Clinical Features
• How These Tumors Are Staged
• Molecular and Biological Characteristics
• Diagnostic Approaches
• Treatment Options
• What This Means for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Introduction to Lung Neuroendocrine Tumors

Lung neuroendocrine tumors (LNETs) are a group of rare cancers that develop from specialized cells called neuroendocrine cells. These particular cells have characteristics of both nerve cells and hormone-producing cells, and in the lungs, they're known as Kulchitsky cells or argentaffin cells.

These tumors were first described in the early 1900s by Siegfried Oberndorfer, who noticed they tended to grow more slowly than typical cancers. The lung is actually the second most common location for neuroendocrine tumors in the body, after the gastrointestinal tract. LNETs account for approximately 25% of all neuroendocrine tumors and about 1-2% of all lung cancers, though some experts believe they might represent up to 20% of lung cancer cases.

What makes these tumors particularly challenging is their tremendous variability. They range from very slow-growing, less aggressive tumors to extremely aggressive cancers that spread quickly. This wide spectrum of behavior means that accurate diagnosis and classification are absolutely essential for determining the right treatment approach and predicting outcomes.

How This Research Was Conducted

This article is based on a systematic review of the available medical literature published between 1981 and 2020. The researchers began by searching medical databases using specific keywords related to neuroendocrine lung tumors.

Initially, they identified 103 potentially relevant studies. After applying strict criteria—including excluding papers not written in English and those where the full text wasn't available—they narrowed this down to 78 high-quality studies that were thoroughly analyzed for this comprehensive review.

The research team included specialists from various medical fields including thoracic surgery, internal medicine, cardiovascular surgery, anesthesiology, and gynecology, bringing together diverse expertise to provide a complete picture of these complex tumors.

How Common Are These Tumors?

Lung neuroendocrine tumors are considered rare cancers. The incidence rates vary depending on the specific type of tumor:

• Pulmonary carcinoids have an incidence of 0.2-2 cases per 100,000 people in both the United States and European Union
• Research has shown an alarming increase in incidence of up to 6% per year for LNETs
• One US study between 2004-2014 found a 7% annual increase in LNET cases
• Another US study showed incidence increased from 1.09 per 100,000 in 1990 to 5.25 per 100,000 in 2004

This increase appears to be primarily driven by more cases of carcinoid tumors rather than the more aggressive types. Lung tumors overall consist of 75-80% neuroendocrine tumors, with breakdowns as follows:

• 1-2% are carcinoid tumors
• 3% are large cell neuroendocrine carcinoma (LCNEC)
• 15-20% are small cell lung cancer (SCLC)

Pulmonary carcinoids typically appear between the 4th and 6th decade of life, with a median age of 45 years. Interestingly, they are the most common primary lung tumors in children and teenagers. Unlike other lung cancers, smoking is not a significant risk factor for carcinoid tumors, though it is strongly associated with SCLC and LCNEC.

Typical carcinoids are about 10 times more common than atypical ones, but atypical carcinoids metastasize in 50% of cases. Approximately 28% of patients with LNETs have synchronous metastases (cancer spread detected at the same time as the primary tumor) at diagnosis.

Types and Grades of Lung Neuroendocrine Tumors

The World Health Organization (WHO) has established a classification system that groups lung neuroendocrine tumors into four main categories based on specific microscopic features:

Typical Carcinoid (TC): These are tumors with carcinoid appearance under the microscope, with fewer than 2 cell divisions (mitoses) per 2 mm² area (equivalent to 10 high-power microscope fields), no necrosis (dead tissue), and size of 0.5 cm or larger.

Atypical Carcinoid (AC): These have carcinoid morphology but with 2-10 mitoses per 2 mm² or the presence of necrosis (typically spotty pattern).

Large Cell Neuroendocrine Carcinoma (LCNEC): These show neuroendocrine patterns (organoid clusters, palisades, trabecular cells) with a high mitotic rate of more than 11 per 2 mm² (median of 70), often with large areas of necrosis. The cells are large with low nuclear-to-cytoplasm ratio.

Small Cell Lung Cancer (SCLC): These consist of small cells with scant cytoplasm, fine granular chromatin, absent nucleoli, and a very high mitotic rate (median of 80 per 2 mm²) with frequent large zones of necrosis.

In 2018, experts from WHO and the International Agency for Research on Cancer established a grading system:

• G1: Well-differentiated neuroendocrine carcinoma (typical carcinoid)
• G2: Moderately differentiated neuroendocrine carcinoma (atypical carcinoid)
• G3: Poorly differentiated neuroendocrine carcinoma (includes LCNEC and SCLC)

Some researchers have proposed further categorizing high-grade neuroendocrine tumors into three types based on molecular characteristics: aggressive primary high-grade NETs (70-75% of SCLC), secondary high-grade NETs (20-25% of LNETs), and indolent NETs (5% of LNETs, including some carcinoids in women and young patients).

Pre-Cancerous Conditions

Research suggests that some LNETs may develop from pre-existing conditions called precursor lesions. The most recognized of these is lung neuroendocrine cell hyperplasia, which is often found in patients with chronic lung diseases such as bronchiectasis, obliterative bronchiolitis, and interstitial lung disease.

In about 25% of carcinoid tumor cases, doctors find neuroendocrine hyperplasia in the lung tissue surrounding the tumor. When this cell proliferation forms nodules smaller than 0.5 cm, it's called a "tumorlet." These show no mitosis or necrosis under microscope and have a low Ki67 index (a marker of cell proliferation).

Another condition called diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) involves fibrosis and small nodular aggregates of neuroendocrine cells. This condition appears more often in women and patients with obliterative bronchiolitis. About 5% of typical and atypical carcinoid cases are associated with multiple endocrine neoplasia type 1 (MEN-1), a genetic syndrome.

Some tumors show "multidirectional differentiation," meaning they contain different types of cells such as mucus-producing cells or squamous cells alongside the neuroendocrine components, which explains the mixed forms of LNETs that sometimes occur.

Symptoms and Clinical Features

The symptoms patients experience with LNETs depend on the tumor's location, type, size, and how aggressive it is. The most common clinical manifestations of carcinoid tumors include:

• Coughing
• Shortness of breath (dyspnea)
• Recurrent respiratory infections
• Coughing up blood (hemoptysis)

Peripheral LNETs (those farther out in the lungs) are generally asymptomatic and are often discovered accidentally during imaging for other reasons. Based on their hormone activity, these tumors fall into two categories:

Functioning (secreting) tumors: These produce hormones or hormone precursors. More than 90% of LNETs are non-functioning, but when they do secrete hormones, they can cause specific syndromes:

• Adrenocorticotropic hormone (ACTH) secretion leading to Cushing's syndrome
• Antidiuretic hormone (ADH) secretion causing syndrome of inappropriate antidiuretic hormone (SIADH)
• Serotonin secretion leading to carcinoid syndrome

Non-functioning tumors: These don't produce significant hormones.

Some paraneoplastic syndromes (conditions caused by cancer but not by direct tumor invasion) are associated with LNETs, including Lambert-Eaton myasthenic syndrome and cerebellar syndrome with limbic encephalitis.

How These Tumors Are Staged

Staging of lung neuroendocrine tumors follows the same TNM system used for other lung cancers, as recommended by the 7th edition of the Union International Cancer Control/American Joint Committee on Cancer (UICC/AJCC). This system applies to all types of LNETs including typical carcinoid, atypical carcinoid, LCNEC, and SCLC.

The TNM system evaluates three aspects:

• T (Tumor): Size and extent of the main tumor
• N (Nodes): Whether cancer has spread to nearby lymph nodes
• M (Metastasis): Whether cancer has spread to distant organs

This staging is crucial because it helps determine treatment options and predict prognosis. All types of LNETs can metastasize to lymph nodes and other organs, though the likelihood varies significantly by tumor type.

Molecular and Biological Characteristics

Understanding the molecular features of LNETs has become increasingly important for diagnosis and treatment. Immunological markers help doctors differentiate between tumor types:

The most commonly used markers include chromogranin A, synaptophysin, CD56, and neuron-specific enolase (NSE). The Ki-67 antigen is particularly useful for distinguishing between well-differentiated and poorly differentiated NETs. Researchers have found that considering Ki-67 levels along with mitotic index and presence of necrosis leads to more accurate diagnosis.

Some studies have identified a "highly proliferative carcinoid" category with Ki-67 over 20% but mitotic index under 10 per mm². Location-specific markers include TTF1 for lung tumors, CDX2 for intestinal tumors, and ISL and PAX8 for pancreatic and rectal tumors.

Genetic studies have revealed important patterns:

• SCLC tests positive for TTF1 in over 90% of cases
• TP53 and RB1 gene mutations help differentiate LCNEC subtypes
• RB1 loss occurs in 80-100% of high-grade NETs
• Two molecular subtypes of LCNEC have been identified: Type I with TP53 and STK11/KEAP1 mutations (37% of cases), and Type II with TP53 and RB1 inactivation (42% of cases)

PD-L1, a protein that helps cancer cells evade the immune system, is present in 10.4% of LCNEC cases and 5.8% of SCLC cases, but not in bronchial carcinoids. This has important implications for immunotherapy treatments.

Other promising markers being studied include CXCL-12 cytokines for atypical carcinoids, stathmin-1 for high-grade tumors, Nestin for differentiating LCNEC from carcinoids, and DLL3 gene expression in LCNEC and SCLC.

Blood tests showing low levels of 5-HIAA (a serotonin breakdown product) with high chromogranin A may indicate poorer outcomes. Inflammation markers like neutrophil-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) may also provide prognostic information.

Diagnostic Approaches

Diagnosing LNETs requires a multifaceted approach. More than 40% of cases are discovered accidentally during routine chest X-rays. The gold standard imaging technique is thoracic computed tomography (CT) with contrast enhancement.

For better detection of well-differentiated NETs, single photon emission CT using 99mTc-Tektrotyd tracer that targets somatostatin receptors has proven highly effective. For low-grade NETs, 68Ga-DOTANOC positron emission tomography (PET-CT) shows superior sensitivity.

18-fluorodeoxyglucose PET-CT is most useful for detecting low and intermediate grade NETs, with sensitivity equal to other PET techniques. Somatostatin receptor PET is particularly valuable for identifying metastatic disease.

Bronchoscopy is extremely useful for diagnosing all forms of NETs, especially those with bronchial involvement. It's a safe procedure and remains the most commonly used method for obtaining tissue samples for definitive diagnosis.

The diagnostic process typically involves:

1. Imaging studies to locate the tumor
2. Biopsy to obtain tissue samples
3. Microscopic examination by a pathologist
4. Immunohistochemical staining to identify specific markers
5. Sometimes genetic testing to guide treatment decisions

Treatment Options

The primary goal of treatment for localized LNETs is complete surgical removal whenever possible. The specific surgical approach depends on factors like tumor size, location, and type.

For advanced LNETs that cannot be completely removed surgically, treatment options include:

• Somatostatin analogs for controlling hormone-related symptoms
• Everolimus for progressive tumors
• Peptide receptor radionuclide therapy (PRRT) for tumors expressing somatostatin receptors
• Chemotherapy regimens similar to those used for small cell lung cancer
• Immunotherapy for tumors expressing PD-L1

Treatment planning requires a multidisciplinary team including thoracic surgeons, medical oncologists, radiation oncologists, pulmonologists, and pathologists to create individualized treatment strategies based on tumor characteristics and the patient's overall health.

What This Means for Patients

This comprehensive review highlights several important points for patients diagnosed with lung neuroendocrine tumors:

First, it's crucial to understand that LNETs represent a diverse group of tumors with vastly different behaviors and outcomes. Getting an accurate diagnosis of the specific type and grade of tumor is essential for determining the most appropriate treatment approach.

Second, the increasing incidence of these tumors means more research attention is being directed toward understanding them and developing better treatments. The molecular characterization of these tumors is leading to more targeted therapies that may improve outcomes while reducing side effects.

Third, the complex nature of these tumors requires care at centers with experience in managing neuroendocrine tumors. The multidisciplinary approach involving multiple specialists ensures that all aspects of the disease are addressed comprehensively.

Finally, patients should know that treatment strategies are continually evolving as research reveals new insights about these tumors. Participating in clinical trials when appropriate can provide access to cutting-edge treatments while contributing to medical knowledge.

Study Limitations

While this review provides valuable insights, it's important to recognize its limitations. As a literature review rather than original research, it's subject to publication bias—the tendency for studies with positive results to be published more often than those with negative findings.

The included studies span four decades, during which diagnostic criteria, classification systems, and treatment approaches have evolved significantly. This heterogeneity makes direct comparisons between older and newer studies challenging.

Additionally, the rarity of these tumors means that most studies included relatively small numbers of patients, which can limit the statistical power of the findings. Many studies were retrospective (looking back at existing data) rather than prospective (following patients forward in time), which introduces potential biases.

Finally, the rapid advances in molecular testing and targeted therapies mean that some of the information, particularly regarding treatment approaches, may become outdated relatively quickly as new research emerges.

Patient Recommendations

Based on this comprehensive review, here are important recommendations for patients:

1. Seek specialized care: Given the complexity and rarity of LNETs, treatment at centers with expertise in neuroendocrine tumors is strongly recommended.
2. Ensure comprehensive testing: Make sure your diagnostic workup includes appropriate immunohistochemical staining and potentially molecular testing to accurately classify your tumor.
3. Discuss all treatment options: Based on your specific tumor type and stage, discuss surgical options, medical therapies, and emerging treatments like targeted therapies and immunotherapy.
4. Consider genetic counseling: Since about 5% of carcinoid cases are associated with MEN-1 syndrome, genetic counseling may be appropriate, especially if you have a family history of endocrine disorders.
5. Ask about clinical trials: Inquire about available clinical trials that might offer access to promising new treatments.
6. Seek support: Connect with patient support organizations focused on neuroendocrine tumors for additional resources and community support.
7. Maintain follow-up care: These tumors require long-term monitoring even after successful initial treatment, as some can recur years later.

Source Information

Original Article Title: Lung neuroendocrine tumors: A systematic literature review (Review)

Authors: Cornel Savu, Alexandru Melinte, Camelia Diaconu, Ovidiu Stiru, Florentina Gherghiceanu, Ștefan Dragoș Octavian Tudorica, Oana Clementina Dumitrașcu, Angelica Bratu, Irena Balescu, Nicolae Bacalbasa

Publication: Experimental and Therapeutic Medicine 23: 176, 2022

Received: June 25, 2021; Accepted: July 27, 2021

DOI: 10.3892/etm.2021.11099

This patient-friendly article is based on peer-reviewed research and was developed to help patients understand complex medical information about lung neuroendocrine tumors. Always consult with your healthcare team for advice tailored to your specific situation.