Lung neuroendocrine tumors (Pulmonary-NETs) or carcinoids are well-differentiated tumors of neuroendocrine origin in the lung and can arise from a variety of mutations. Alterations in genes involved in signaling pathways for cell growth, e.g., IGF1R, ERBB4, KIT and MET, are frequently found (Li et al., Oncol Lett 2020). Around 40% of tumors harbor mutations in histone-modifying genes, such as MEN1 (Asiedu et al. Clin Cancer Res 2018).
Classification
Lung neuroendocrine neoplasms account for around 20% of tumors in the lung. 75% thereof are highly aggressive small cell neuroendocrine carcinomas (SCNC, also known as small cell lung cancer = SCLC), and another 15% are large cell neuroendocrine cancers (LCNC). Only 10% of Lung NENs are carcinoids, similar to GEP-NETs found in the digestive system (Metovic et al., Virchows Arch 2021). Lung-NETs are classified into typical carcinoids and atypical carcinoids. According to WHO criteria, this classification is performed based on mitotic count, unlike in GEP-NETs, where the Ki-67 index is typically used (Nicholson et al. J Thorac Oncol 2022).
TNE classification Lung |
Morphology |
Cytology |
Mitosis |
---|---|---|---|
Typical carcinoid |
Carcinoid |
- |
<2 |
Atypical carcinoid |
Carcinoid |
- |
2-10 |
Large cell NSC |
Neuroendocrine |
Large cell (> 20 μm) |
>10 (±70) |
Small cell carcinoma |
Neuroendocrine |
Small cell (> 20 μm) |
>10 (±80) |
Table 1: WHO Classification for NETs of the lung (Travis WD et al. 2015)
Epidemiology
Lung NETs are the second most common NET after GEP-NETs, accounting for roughly 25% of cases (Klöppel, Visceral Medicine 2017). The incidence has been reported at 1.5 per 100,000 people between 2000 and 2012 (Dasari et al., JAMA Oncol 2017), but the incidence is rising, as is the case with other NETs. Due to earlier detection and improved treatment options, the total number of patients living with Lung-NET is growing even quicker.
Clinical presentation
The extent to which patients develop typical symptoms like cough, wheezing, dyspnoea, stridor or post-obstructive pneumonia depends on the tumor's location. Centrally located tumors are often diagnosed after the patient has developed symptoms, while peripheral tumors are mostly found incidentally. The majority of lung NETs are non-functioning. Only a small fraction of tumors produce hormones in significant quantities, leading to Carcinoid Syndrome or Cushing Syndrome, depending on the produced hormonal substance (Halperin et al., The Lancet Oncology 2017). The prognosis depends on the genes that underlie the tumor. MEN1-associated lung NETs, for example, are often indolent and have a good prognosis (van den Broek et al., JCEM 2021).
SSTR imaging
Like other NETs, most lung NETs overexpress SSTR type 2, a receptor that regulates numerous metabolic processes, including cell growth and hormone secretion. Consequently, the receptor can be targeted for diagnostic and therapeutic purposes, analogous to GEP-NET.
SSTR-directed PET/CT imaging has a sensitivity of nearly 100% for typical and 83% for atypical carcinoids. It can detect primary tumor sites and metastases, though small primaries may be missed. Positive SSTR imaging is a prerequisite for SSTR-targeting radiopharmaceutical therapy (RPT). SPECT has been demonstrated to be inferior to PET/CT in lung pathology (Abenavoli et al., Clin Trans Imaging 2020). High-grade SCNCs and LCNCs, on the other hand, should be diagnosed using FDG-PET/CT due to their typically poor differentiation and high mitotic activity.
SSTR-directed therapy
As of early 2024, everolimus is the only FDA-approved therapy for patients with typical and atypical carcinoids of the lung. However, the high rates of SSTR2 expression of 74%, 66% and 82% in typical, atypical and metastatic carcinoids of lung origin (Kanakis et al., Neuroendocrinology 2015) suggest that the SSTR2-directed therapies employed in the treatment of GEP-NET could be effective against lung NET as well. Indeed, RPT with different radiolabelled SSAs has been tested in patients with lung NET, e.g., by ERASMUS, reaching a PFS of 20 months and an OS of 52 months in patients with metastatic disease (Brabander et al., Clin Cancer Res 2017).
The guidelines by the Spanish Society for Medical Oncology (SEOM) and the European Society for Medical Oncology (ESMO) recommend the use of RPT for patients with metastatic, non-resectable lung NET (Castillón et al., Clin Transl Oncol 2023; Baudin et al., Ann Oncol 2021).