Thoracic Neuroendocrine Tumors

Etiology

The etiology of NETs is not fully understood, and although some studies suggest a potential link with smoking, the causal relationship remains uncertain. Evidence indicates that more patients with atypical carcinoids are smokers compared to those with typical carcinoids. Other research studies have identified certain air pollutants and chemicals as risk factors.[6] Pulmonary NETs are hypothesized to have associations with various comorbidities and malignancies, indicating potential shared risk factors. Furthermore, research suggests that individuals diagnosed with pulmonary NETs may exhibit an elevated risk of developing secondary primary cancers relative to the general population. This interplay between pulmonary NETs and other neoplastic conditions underscores the complexity of their etiological profile and necessitates further investigation into the underlying mechanisms involved.[7]

In rare cases, pulmonary NETs can be associated with multiple endocrine neoplasia type 1 (MEN-1) syndrome. Furthermore, there have been reports of sporadic instances in which the MEN-1 gene is found to be inactivated, suggesting a potential genetic component to the development of these tumors.[8] The etiology of thymic NETs remains unclear. MEN-1 syndrome is associated with 25% of cases of thymic NETs and develops predominantly in males.[9] No association with carcinogens or environmental factors has been established for sporadic cancer cases. However, there is evidence of a higher incidence of thymic NETs in MEN-1 patients who are heavy smokers.[10] Pulmonary NETs are relatively rare compared to thymic NETs and are predominantly observed in females with MEN-1 syndrome.[11]

Epidemiology

NETs are uncommon malignancies that can affect the lungs. While they can occur at any age between 5 and 90, the mean age of presentation of typical carcinoids is 58.8. Notably, atypical carcinoids (AC) present approximately 10 years earlier than typical carcinoids (TC). Approximately 8% of these tumors are diagnosed during the second decade of life, making them the most common primary pulmonary tumor in childhood. The WHO classification recognizes 4 major types of pulmonary neuroendocrine tumors: TC, AC, large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC). The most common pulmonary NET is SCLC (20%), followed by LCNEC (3%), TC (2%), and AC (0.2%).[12]

Some data suggest a higher incidence of NETs among individuals of white ethnicity and women than men.[13] In recent decades, the incidence of NETs, including pulmonary NETs, has demonstrated an upward trend. This increase can be attributed to several factors, such as advancements in medical investigations and improved detection rates.[14]

Pathophysiology

The precise mechanisms underlying the development and progression of NETs are not fully understood. However, in some cases, it is believed that these tumors may arise from proliferating pulmonary neuroendocrine cells through a condition known as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumorlets.[15] Carcinoid tumorlets are histologically identical to NETs but are smaller, measuring less than 0.5 cm in diameter. The exact significance of tumorlets is unknown, but they are often associated with inflammatory or fibrosing conditions. DIPNECH is a rare condition characterized by the widespread presence of pulmonary carcinoid tumorlets and, occasionally, tumors. This condition occurs almost exclusively in women and can cause symptoms when the lungs are extensively involved.[16]

The exact pathophysiology of these tumors' development is not fully understood. Although rare, thymic NETs have been associated with various paraneoplastic syndromes. Up to one-third present concomitantly with paraneoplastic conditions. The most common being Cushing syndrome, presenting in 30% to 35% cases, in which thymic NETs may secrete ectopic adrenocorticotropic hormone.[17][18] 

Humoral hypercalcemia of malignancy secondary to parathyroid hormone-related peptide secretion can be present in up to 30% of patients.[18] Unlike NETs involving other organs, thymic NETs rarely present with carcinoid syndrome.[19] Acromegaly secondary to ectopic production of growth hormone-releasing hormone and syndrome of inappropriate antidiuretic hormone, albeit uncommon, have been described in the literature.[20] As previously mentioned, MEN-1 syndrome is associated with 25% of cases of thymic NETs, and roughly 8% of patients with MEN-1 syndrome develop a thymic NET.[9] Recent studies have shown that frequent 11q deletions in TC and AC include the MEN-1 gene locus, suggesting this is a distinct genetic event in pulmonary NETs. Further losses, specifically at 10q and 13q, have been associated with AC, which indicates that genetic factors may be driving their more aggressive behavior.[21]

Histopathology

Pulmonary NETs are cataloged based on the WHO classification: low-grade (typical) NETs (TCs), intermediate-grade (atypical) NETs (ACs), LCNEC, and SCLC.[22] Histological classification is based upon the presence or absence of necrosis, mitotic activity, and large cell or small cell cytology. The nuclear chromatin, in general, is finely granular, while LCNEC may show prominent nucleoli. Tumor cells may form trabeculae, rosettes, festoons, glands, and solid sheets.[22] TCs and ACs are both classified as well-differentiated. However, AC exhibits more aggressive clinical behavior compared to TC. LCNEC and SCLC represent 2 distinct types of poorly differentiated neuroendocrine carcinomas, classified separately. Despite differences in grade and clinical behavior, all pulmonary neuroendocrine neoplasms share key features, including the ability to synthesize neuropeptides and the presence of submicroscopic cytoplasmic dense-core granules.[23]

TCs generally have a more benign course, whereas SCLC has a more aggressive course. ACs and LCNECs fall in the middle of the spectrum. These pathological classifications indicate a correlation with prognosis.[18][24] Factors significantly affecting prognosis include primary tumor size greater than 3 cm, histological atypia, and nodal metastases.[25]

Macroscopic Findings

Central pulmonary NETs exhibit well-defined boundaries and have a round to oval shape. They can be either sessile or pedunculated. Histologically, these tumors display a finely granular chromatin pattern and moderate to abundant eosinophilic cytoplasm. They often occupy and fill the bronchial lumen.[26]

As central pulmonary NETs grow, they may extend between the cartilaginous plates into adjacent tissues. Pulmonary NETs can range widely in size, from small nodules measuring approximately 0.5 cm to larger masses up to 9 to 10 cm in diameter at the time of diagnosis. On average, ACs are larger than TCs.[26] In 1 retrospective series of 121 patients who underwent surgical resection of pulmonary NETs, patients with ACs demonstrated a significantly larger tumor size than patients with TCs. Patients with ACs also had an increased number of lymph node metastases when compared with patients with TCs.[27]

Histopathology

The growth patterns of NETs suggest neuroendocrine differentiation. The most common patterns observed are organoid and trabecular arrangements. However, other growth patterns may also be present, such as rosette formation, papillary growth, pseudoglandular growth, and follicular growth. The tumor cells typically appear uniform, with finely granular nuclear chromatin, inconspicuous nucleoli, and moderate to abundant eosinophilic cytoplasm.[12]

The stroma surrounding NETs is highly vascularized but can also display extensive hyalinization, cartilage, or bone formation. There have been reports of stromal amyloid deposition and prominent mucinous stroma within these tumors. TCs are characterized by having fewer than 2 mitoses per 2 mm², lacking necrosis, and measuring at least 0.5 cm in diameter. In contrast, ACs exhibit similar histological features to TCs but are defined by the presence of 2 to 10 mitoses per 2 mm² or necrosis.[28] Necrosis in ACs is usually punctate. Mitotic activity should be counted in the area with the highest number of mitoses, encompassing as many viable tumor cells as possible. The counting should be reported per 2 mm² rather than based on a specific number of high-power fields.[12]

Immunohistochemistry

Immunohistochemistry is crucial in diagnosing NETs, especially in small biopsy samples. A recommended antibody panel for immunostaining includes chromogranin A, synaptophysin, and CD56. However, none of these markers can differentiate between typical and atypical carcinoids. Additionally, most NETs react to pan-cytokeratin antibodies, commonly used to identify epithelial cells. Some peripheral tumors may also exhibit staining with thyroid transcription factor 1, although this marker is less specific for NETs. In evaluating biopsy or cytology samples, the Ki-67 labeling index is valuable, especially in cases where crush artifacts make assessing the mitotic index challenging. By measuring the Ki-67 labeling index, which indicates the percentage of cells undergoing active cell division, misdiagnosis of NETs as high-grade neuroendocrine carcinomas can be avoided.[12]

History and Physical

Approximately 25% of individuals with pulmonary NETs may not experience any noticeable disease symptoms. These tumors are often incidentally discovered during diagnostic tests or screenings for unrelated conditions.

The most common presenting symptoms of bronchopulmonary NETs are:

• Coughing or wheezing
• Hemoptysis
• Dyspnea
• Recurrent pneumonia
• Symptoms related to the consequences of collapse or pneumonia distal to airway obstruction [2]
  • Sometimes patients may present with stridor.

Since pulmonary NETs are primarily neuroendocrine in origin, some patients may present with symptoms of carcinoid syndrome:

• Facial flushing
• Shortness of breath
• Hyper- or hypotension
• Weight gain
• Hirsutism
• Asthma-like symptoms
• Bronchospasm
• Electrolyte disturbances (eg, hyponatremia, hypokalemia)

Small NETs may be asymptomatic and are usually discovered incidentally during medical examinations or imaging tests conducted for unrelated reasons. In most cases, pulmonary NETs do not exhibit endocrine symptoms at the clinical level. These tumors are often considered "endocrinologically silent" because they do not commonly produce significant amounts of hormones or bioactive substances that result in noticeable clinical effects. Clinical syndromes secondary to peptide production are uncommon; they include carcinoid syndrome, Cushing syndrome, and acromegaly.[2]

Thymic NETs present as a mass located in the anterior mediastinum. Thymic NETs are rare, accounting for less than 5% of all anterior mediastinal neoplasms, and occur more frequently in males, typically in their fourth and fifth decades of life. In most cases, thymic NETs go unrecognized until they reach advanced stages, as patients often remain asymptomatic or symptoms at presentation are ambiguous.[29] These tumors exhibit aggressive behavior, with a tendency to invade locally. Hence, 50% of patients present with invasion to local organs at the time of diagnosis, and 20% to 30% have distant metastatic disease, which occurs via lymphatic or hematogenous spread.[30][9] 

Most patients present with symptoms of mass compression to local structures, while only a third of cases are asymptomatic. Symptoms can vary depending on the extent of invasion. Common complaints include cough, dyspnea, chest pain, and hoarseness from recurrent laryngeal nerve invasion.[9] Superior vena cava syndrome has been observed in up to 20% of patients at presentation.[9]

Evaluation

Biochemical Evaluation

Plasma chromogranin A (CGA) levels, synaptophysin, neuron-specific enolase (NSE), blood count, electrolytes, and liver and kidney function are tests indicated in the diagnostic process and follow-up of NETs [31].

Specific tests are performed when symptoms suggesting hormonal secretion are present. They include:

• Urinary 5-hydroxyindoleacetic acid, a metabolite of serotonin, is often elevated in patients with carcinoid syndrome.
• Serum cortisol levels and 24-hour urine free cortisol levels will be elevated.
• Adrenocorticotropic hormone levels are indicated in patients with suspected Cushing disease. These will be increased.
• Plasma growth hormone-releasing hormone and insulin growth factor-I levels are indicated in patients with signs of acromegaly. These will be elevated.[32]

Laboratory Studies

As previously discussed, most NET cases do not produce hormones. Therefore, the utility of laboratory evaluation is limited to specific circumstances. CGA levels, if initially elevated at diagnosis, may help monitor disease activity, especially in patients with metastatic disease.[33] However, CGA is not a diagnostic tool due to its insufficient sensitivity and specificity.[34] Molecular profiling of tumor tissue may be considered, particularly for ACs. Genetic counseling and testing should be regarded as essential for individuals with inherited genetic syndromes.

In cases of paraneoplastic syndromes, such as Cushing syndrome, a high cortisol concentration can be detected in the serum, and 24-hour urine cortisol levels are also elevated. Hypercalcemia and hypophosphatemia can be observed in humoral hypercalcemia of malignancy, along with elevated levels of parathyroid hormone–related peptide concentration, and may also be used to monitor disease recurrence.[33] 

Radiological Assessment

NETs can be visible on a standard chest x-ray in 40% of cases. However, the gold standard for the radiological detection and evaluation of pulmonary NETs is computed tomography (CT) with intravenous contrast. Both chest x-rays and CT scans typically show well-defined, round, and sometimes slightly lobulated masses in cases of pulmonary NETs. Central pulmonary NETs can exhibit calcification. When the tumor involves the bronchial airway, secondary effects can be observed, including atelectasis, bronchiectasis, and areas of hyperlucency on CT scans.[35]

Fluorodeoxyglucose positron emission tomography may reveal higher uptake in ACs than TCs, reflecting differences in metabolic activity. This technique is most helpful in discerning well-differentiated NETs from high-grade neuroendocrine carcinomas, such as small-cell or large-cell neuroendocrine tumors, which typically demonstrate intense FDG uptake.[36] Octreotide single-photon emission CT and other novel imaging techniques, such as gallium-labeled somatostatin analogs, have shown promise in improving the detection sensitivity of pulmonary NETs.[37] Imaging for somatostatin receptors using indium-111-labeled octreotide may increase sensitivity for the diagnosis, staging, and follow-up of recurrence.[38] Thymic NETs pose a diagnostic challenge as symptoms at presentation are typically equivocal. Therefore, clinicians must attain a high level of suspicion. Occasionally, thymic NETs may be found incidentally during workup for other conditions.

Imaging Studies

Initial evaluation with CT of the chest, using intravenous (IV) contrast, is the test of choice for assessing anterior mediastinal masses. Cross-sectional imaging, combined with IV contrast, helps characterize the mass and improve localization, while providing information regarding local invasion or regional metastases. Findings of a large, heterogeneous, lobulated, and most often invasive, anterior mediastinal mass with areas of hemorrhage or necrosis suggest thymic NETs. Magnetic resonance imaging (MRI), specifically cardiac MRI, can provide more detailed information about invasion into nearby structures such as the proximal great vessels, heart structures, or pericardium. 

Over the past decade, somatostatin receptor-based imaging has become more popular for diagnosing and staging NETs. Thymic NETs, like other NETs, demonstrate an overexpression of somatostatin receptors; thus, the use of radiolabeled somatostatin analogs, such as the gallium Ga-68 DOTATOC (OctreoScan), allows thymic NETs to be identified and distinguished from other malignancies that arise in the anterior mediastinum.[39] Other advantages of these techniques include distinguishing between primary malignancies in the thymus and metastatic disease, as they can scan the entire body. In addition, the sole recognition of somatostatin receptors on the tumor allows the early utilization of peptide receptor radioligand therapy in advanced cases.[40][41] Ruling out lymphomas or germ cell tumors is critical, as these malignancies are typically treated medically rather than surgically, which is the case for thymic NETs.

Bronchoscopy

Bronchoscopy is crucial in diagnosing pulmonary NETs, as these tumors are usually centrally located and visible during bronchoscopic evaluation.[42] Bronchoscopic evaluation with tissue biopsy is the gold standard for diagnosing pulmonary NETs. However, due to the highly vascular nature of these tumors, bronchoscopic biopsy carries a risk of bleeding. 

Biopsy

Based on CT chest findings and characteristics of the mass and level of invasion, medical teams can determine if surgical resection or tissue biopsy is indicated. For small, encapsulated masses, surgical resection of the tumor should be attempted. For larger masses with unclear margins, a tissue biopsy is recommended before attempting surgical resection to ascertain the need for a possible role of chemotherapy.[34][43]

Most biopsies are performed through a CT-guided core needle biopsy, which can diagnose a thymic NET in most cases.[43] In alternative situations, where there may not be enough tumor cells to secure a definitive diagnosis through immunohistochemistry or flow cytometry, or the tumor location does not allow for a CT-guided approach, endoscopic or transbronchial ultrasound-guided fine needle biopsy or endobronchial ultrasound-guided transbronchial needle aspiration may be preferred.[9] These techniques are also preferred when mediastinal lymph node metastatic disease is present.

If biopsy results remain inconclusive, a surgical approach is recommended. The location of the tumor will determine the type of surgical approach. Anterior mediastinotomy is indicated in cases where the mass invades the anterior chest wall. On the other hand, if the mass has invaded either side of the chest, a video-assisted thoracoscopic (VATS) approach is warranted.[9] A VATS approach is also helpful if there are concerns for possible lung metastases.

Treatment / Management

Despite having a good prognosis, NETs can be challenging to diagnose due to their nonspecific symptoms. Patients with NETs may present with cough, fever, and shortness of breath. The differential diagnosis is broad, including chronic obstructive airway disease, pneumonia, tuberculosis, sarcoidosis, adenocarcinoma of the lung, squamous carcinoma of the lung, and heart failure. In some cases, the tumor may be discovered incidentally during imaging studies for unrelated reasons. 

Collaboration across disciplines is essential in providing patient-centered care for individuals with thoracic NETs, which present unique challenges due to their rarity, biologic heterogeneity, and variable clinical behavior. A multi-disciplinary, team-based approach enhances healthcare delivery and patient outcomes by facilitating comprehensive evaluation, personalized treatment planning, and longitudinal surveillance. Given the broad range of differential diagnoses and the need for a definitive diagnosis, a biopsy is typically necessary. The workup may involve collaboration between pulmonologists, radiologists, and pathologists to appropriately evaluate and interpret clinical findings, imaging studies, and tissue samples. Meticulous staging and planning are required before surgery. Smoking cessation and rigorous chest physiotherapy should be advised for smokers. Calculation of post-operative pulmonary reserve requires careful evaluation by a respiratory clinician.

The interventional radiologist can assist with the biopsy of peripherally located lesions. The biopsy of centrally located lung masses usually requires invasive techniques, such as bronchoscopy; therefore, it is often omitted to preserve surgical fields and avoid procedures that require anesthesia. This poses a particular problem for NETs, as the scope of surgery and adjuvant treatment is not fully understood, leading to overtreatment. The involvement of a pathologist could alleviate this problem. After administering anesthesia to the patient, a bronchoscopy and needle biopsy of the lung lesion and suspected lymph nodes should be performed. The pathologist could then create frozen sections and readily analyze them to help define the extent of resection, thereby avoiding overtreatment.

Pharmacists are crucial in the healthcare team and can help manage post-operative pain. They collaborate with the medical team to prescribe appropriate pain medication, considering individual patient factors and potential drug interactions. Physiotherapists and pulmonary rehabilitation specialists play a crucial role in the post-operative care of patients undergoing lung surgery. They can help with early mobilization, breathing exercises, and respiratory rehabilitation.

Guidelines issued by professional societies, such as the Society of Thoracic Surgeons and the Society of Surgical Oncology, provide evidence-based recommendations for treating pulmonary NETs. These guidelines are valuable resources for healthcare professionals in treatment planning and surveillance. They help ensure patients receive optimal, standardized care based on the best available evidence.

The outcome of pulmonary NETs is favorable and depends on timely intervention. Prompt consultation with interprofessional teams improves patient recovery and survival. Interprofessional collaboration for the care of thoracic NET aligns diagnostic precision, surgical expertise, oncologic therapy, and long-term follow-up. This ultimately enhances outcomes by providing safer interventions, tailored treatment plans, and durable surveillance.

Surgery

Surgical resection is the primary treatment of choice for patients with thoracic NETs. The goal is to remove the tumor while preserving as much healthy lung tissue as possible.[32] The extent of the resection depends on several factors, including the type of NET (eg, typical or atypical) and the involvement of surrounding lung tissue.(A1)

Extensive resections may be necessary in cases of ACs or when the distal lung parenchyma is destroyed. The surgical technique of choice is often lobectomy. In some instances, sleeve or wedge resection may also be performed. Since pulmonary NETs frequently arise from the main or lobar bronchi, bronchoplastic procedures are usually required during surgical resection to preserve lung function and maintain proper airway continuity. A wedge resection is favored in peripheral pulmonary NETs and is often sufficient.[2]

Systemic Therapy

Systemic therapy is used for advanced or metastatic pulmonary NETs. The choice of systemic treatment depends on several factors, including the tumor grade, the extent of metastasis, and individual patient characteristics. The goal of medical management is to control hormone-related symptoms and prevent disease progression.

Adjuvant Therapy

The use of adjuvant therapy in pulmonary NETs is an ongoing debate, and there is no consensus on its role in managing these tumors.[2] The National Comprehensive Cancer Network (NCCN) guidelines recommend considering adjuvant chemotherapy with cisplatin and etoposide, with or without radiation, in stage III ACs.[2] The European Neuroendocrine Tumor Society also recommends adjuvant treatment for ACs with positive lymph nodes, but not for TCs.[2]

Localized Disease

Official guidelines for treating thymic NETs are unavailable, as data from prospective trials are lacking and are mainly based on case reports and case series. Complete surgical resection with negative margins, which remains the therapy of choice, entails the resection of the entire anterior mediastinal compartment, including hilar and mediastinal lymph nodes, given the high rate of nodal metastasis.[30][9] Unfortunately, due to their size, most thymic NETs are deemed not amenable to resection at diagnosis. The role of neoadjuvant chemotherapy or radiation therapy (RT) remains unclear, as data are based solely on case reports.[9][30]

In cases of local invasion, despite total complete surgical resection, microscopic resection may not be achieved, and the rate of recurrence is high.[9] Adjuvant chemotherapy and RT are reasonable options following total resection for control of the residual disease. According to the NCCN, in patients who have had an incomplete resection, RT, preferably with chemotherapy based on cisplatin or carboplatin plus etoposide, is recommended for patients with moderately or poorly differentiated disease.[9] However, the evidence supporting the use of adjuvant RT or chemotherapy is limited.

Metastatic or Recurrent Disease

Even in the instance of recurrent disease, if the tumor is deemed to be resectable, surgical resection should be attempted.[30] In cases of unresectable or metastatic disease, systemic therapy is favored.[44] For tumors with evidence of somatostatin receptor expression, somatostatin analogs are chosen, although data regarding the benefits of this therapy for thymic NETs are scant. In such circumstances, octreotide and lanreotide are considered reasonable options, especially in the rare instance of patients presenting with carcinoid syndrome.[45](A1)

A platinum-based chemotherapy regimen, such as carboplatin and etoposide, is used for intermediate to poorly differentiated tumors, based again on treatment guidelines for poorly differentiated NETs of the gastrointestinal tract and lung.[46] Other systemic therapies, such as everolimus, which have shown survival benefits in patients with advanced, nonfunctional lung and GI NETs, have been adopted as a treatment option for thymic NETs, due to their similarities.[47] The role of RT remains palliative for symptomatic patients with recurrent or metastatic disease.(B2)

Differential Diagnosis

The differential diagnoses of pulmonary NET include:

• Metastatic NETs from other locations, especially those originating from the GI tract
• SCLC
• Salivary gland-type tumors
• Metastases of lobular breast carcinoma, paraganglioma, and glomangioma
• Tumorlets
• Thymic carcinoma
• Thymoma
• Paraganglioma
• Lymphoma
• Germ cell tumors [12]

Surgical Oncology

Stage I to III NETs are treated with surgical resection, the only curative treatment modality for pulmonary NETs. The extent of surgical resection depends on the tumor characteristics, location, and stage of the disease. For stage I pulmonary NETs, which are localized and confined to the lung without the involvement of lymph nodes, surgical resection with lobectomy is often the treatment of choice. However, pneumonectomy or bilobectomy may be needed for centrally located lesions.[48] In cases where the tumor is smaller and located in the peripheral regions of the lung, segmentectomy or wedge resection may be considered an alternative.

TCs, which have favorable histology and are localized without lymph node involvement, can often be managed with more limited resections and still achieve a cure. However, for ACs, which have a higher risk of recurrence and metastasis, the surgical guidelines for NSCLC are followed. Lobectomy is often considered for lesions smaller than 2 cm, and mediastinal lymph node dissection is performed in all patients. The role of mediastinal lymph node dissection in pulmonary NETs is still debatable, with limited evidence supporting its benefits in reducing local recurrence and improving survival. However, performing mediastinal lymph node dissection in all patients with pulmonary NETs is generally recommended, as it allows for accurate staging and helps guide further treatment decisions.[49]

Historically, open thoracotomy was the standard approach for pulmonary resection. In recent years,video-assisted thoracoscopic surgery (VATS) has gained popularity and become the preferred technique for resection of pulmonary NETs. The advantages of VATS include reduced morbidity, shorter hospital stays, and faster recovery. Numerous studies have demonstrated VATS's short-term and long-term benefits, making it the standard approach for surgical procedures.[50][51] Even in cases where an open thoracotomy is performed, the technique has evolved and improved. The incisions are smaller and muscle-sparing, resulting in reduced trauma to the chest and enhanced postoperative recovery. As most pulmonary NETs are intrabronchial in location and tend to grow slowly, there has been an emphasis on developing parenchymal-sparing procedures for pulmonary resection. These include sleeve lobectomy and sleeve pneumonectomy, which have been performed with excellent long-term results.

Radiation Oncology

NETs are less responsive to RT than SCLC; therefore, it has a limited role in managing pulmonary NETs. However, in some instances, RT may be used as part of the treatment approach for pulmonary NETs.The NCCN guidelines recommend using adjuvant cisplatin and etoposide with or without radiation in stage III ACs.[2] The European Neuroendocrine Tumor Society also advocates adjuvant treatment in ACs with positive lymph nodes, but not for TCs.[2] Chemoradiotherapy is often recommended for the treatment of locally advanced, unresectable diseases. A commonly used dose for radiotherapy in this setting is 60 Gy.

Medical Oncology

Adjuvant chemotherapy is not recommended for stage I to III NETs as the risk of recurrence is low. This treatment is, however, recommended for stage III ACs.[2] If surgery is not an option for locally advanced ACs, chemoradiotherapy is recommended. Chemotherapy forms the backbone of metastatic stage IV NET treatment, although efficacy data are lacking due to the rarity of these cases. Independent trials of pulmonary NETs are rare. NCCN guidelines recommend close radiological surveillance with chest CT with IV contrast and multiphasic abdominal and pelvic CT or MRI every 3 to 6 months for cases with low tumor burden and low-grade NETs. Systemic therapy is initiated at the time of progression. Various options for systemic treatment include somatostatin analogs, chemotherapy, mammalian target of rapamycin (mTOR)  inhibitors, and anti-vascular endothelial growth factor agents.

Somatostatin Analogs

The use of somatostatin analogs in pulmonary NETs is extrapolated from the experience with GI tract NETs. Small studies show that despite low response rates, somatostatin receptor-targeted therapies improve the symptoms of carcinoid syndrome and disease progression. The PROMID study demonstrated the activity of long-acting somatostatin in midgut NETs. The effect was most pronounced in patients with low hepatic tumor burden and those who underwent primary tumor resection. Compared to the placebo, the time to disease progression was prolonged; however, the overall survival benefit remains unclear.[52]

Chemotherapy

NETs are less responsive to chemotherapy compared to more aggressive counterparts, such as SCLCs. However, without more effective alternatives, chemotherapy regimens used in SCLC are sometimes used to treat advanced or metastatic pulmonary NETs. Cisplatin and etoposide showed an overall response rate of 44% in small case series with a disease control rate of 75%.[53] The combination of temozolomide and capecitabine has also demonstrated activity in advanced pulmonary NETs.[54]

Mammalian Target of Rapamycin-Directed Therapy (mTOR)

The mTOR pathway has been implicated in the pathogenesis of NETs. The RADIANT-4 trial studied the role of everolimus in nonfunctional pulmonary and GI NETs. Out of 90 patients with pulmonary NETs, the median progression-free survival PFS was 9.2 months for everolimus compared to 3.6 months for placebo. The toxicities of everolimus included hyperglycemia, infections, and stomatitis.[47]

Staging

In pulmonary NETs, the classification system designates TC as a low-grade tumor.[55] The staging of TCs and ACs follows the TNM staging of lung cancer.[56] Most TCs are stage 1a.[55] AC is classified as intermediate grade. ACs are typically at a more advanced stage at presentation than TC.[55] See Image. Bronchial Carcinoid Tumors and Lung Carcinomas Tumor–Node–Metastasis (TNM) Staging, Table.

Prognosis

The prognosis of pulmonary NETs is influenced by tumor size, grade, disease stage, and older age. The 5-year survival rate varies depending on the stage of the disease. Generally, the prognosis improves with earlier-stage diagnosis. The approximate 5-year survival rates for stages I to IV are 93%, 85%, 75%, and 57%, respectively. TC has a better prognosis than atypical cases. The 5-year survival rate for patients with TC is 90%, while for AC, it is approximately 60%.[57] Nodal involvement is considered a poor prognostic factor. However, the impact of nodal involvement on prognosis remains uncertain.

Prognosis is determined by tumor TNM stage, resectability, histologic grade, proliferation index, and size.[58][59][60] Other factors associated with a poorer prognosis in TC include incomplete resection, age, gender, tumor site (central versus peripheral), and performance status. A 2015 European Association of Thoracic Surgeons NETs Working Group article revealed higher mortality for patients with increased age, male gender, central tumor location, higher TNM stage, and lower functional status.[61]

Thymic NETs' prognosis is worse than that of their counterparts in the GI tract or the lungs.[30] These tumors exhibit aggressive behavior, with a tendency to metastasize or recur locally. Their poor prognosis can also be attributed to delayed tumor detection. In an analysis of the Surveillance, Epidemiology, and End Results database, the overall survival for localized disease was estimated to be 110 months, compared to significantly lower survival rates for patients with regional spread and metastatic disease, at 59 and 35 months, respectively.[58]

Complications

Pulmonary NETs often involve major bronchi. This could lead to massive, potentially life-threatening hemoptysis. While carcinoid syndrome, Cushing syndrome, and acromegaly are potential complications of NETs, they are relatively infrequent. These syndromes occur when the tumor produces ectopic peptides or hormones, leading to specific clinical manifestations such as flushing, diarrhea, wheezing, and hormonal imbalances.[62][63] Vasoactive substances, such as serotonin, secreted by pulmonary NETs generally undergo first-pass metabolism in the lungs, inactivating them before they reach the systemic circulation. Carcinoid syndrome usually occurs in the setting of extensive hepatic tumor burden, extrahepatic metastasis, or the presence of a bronchial-to-systemic venous shunt that allows bypass of the pulmonary circulation.[4] These symptoms are more commonly associated with GI NETs than pulmonary NETs. 

Smokers have an increased risk of developing a second primary lung or other smoking-related cancer. Though rarely administered, chest irradiation increases the risk of secondary cancers and coronary artery disease. Other tobacco-related diseases like cardiovascular disease, stroke, and chronic obstructive pulmonary disease also impact survival. Disease-related complications include carcinoid or paraneoplastic syndromes such as Cushing or humoral hypercalcemia of malignancy.[30] Treatment and intervention-related complications may arise following thymectomy, including phrenic and recurrent laryngeal nerve injury, surgical site infection, mediastinitis, and wound dehiscence.[64][65]