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Radiopharmaceutical with tumor-targeting molecule and diagnostic radioisotope.

Lung-NETs

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).

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For a more detailed review of the current knowledge on diagnosing and treating lung NETs, you can download an ebook chapter from the library.

References:

  • Li, Zhen, et al. 2020. “Emerging Non‑invasive Detection Methodologies for Lung Cancer (Review).” Oncology Letters 19(5): 3389–99. DOI: 10.3892/ol.2020.11460.

  • Asiedu, Michael K., et al. 2018. “Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors.” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 24(7): 1691–1704. DOI: 10.1158/1078-0432.CCR-17-0252.

  • Metovic, Jasna, et al. 2021. “Morphologic and Molecular Classification of Lung Neuroendocrine Neoplasms.” Virchows Archiv: An International Journal of Pathology 478(1): 5–19. DOI: 10.1007/s00428-020-03015-z.

  • Travis, William D., et al. 2015. “The 2015 World Health Organization Classification of Lung Tumors.” Journal of Thoracic Oncology 10(9): 1243–60. DOI: 10.1097/JTO.0000000000000630.

  • Klöppel, Günter. 2017. “Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications.” Visceral Medicine 33(5): 324–30. DOI: 10.1159/000481390.

  • Dasari, Arvind, et al. 2017. “Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States.” JAMA Oncology 3(10): 1335–42. DOI: 10.1001/jamaoncol.2017.0589.

  • Halperin, Daniel M., et al. 2017. “Frequency of Carcinoid Syndrome at Neuroendocrine Tumour Diagnosis: A Population-Based Study.” The Lancet. Oncology 18(4): 525–34. DOI: 10.1016/S1470-2045(17)30110-9.

  • van den Broek, Medard FM, et al. 2021. “The Management of Neuroendocrine Tumors of the Lung in MEN1: Results From the Dutch MEN1 Study Group.” The Journal of Clinical Endocrinology & Metabolism 106(2): e1014–27. DOI: 10.1210/clinem/dgaa800.

  • Abenavoli, Elisabetta, et al. 2020. “Typical Lung Carcinoids: Review of Classification, Radiological Signs and Nuclear Imaging Findings.” Clinical and Translational Imaging 8(2): 79–94. DOI: 10.1007/s40336-020-00364-2.

  • Kanakis, George, et al. 2015. “Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role.” Neuroendocrinology 101(3): 211–22. DOI: 10.1159/000381061.

  • Brabander, Tessa, et al. 2017. “Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]Octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors.” Clinical Cancer Research 23(16): 4617–24. DOI: 10.1158/1078-0432.CCR-16-2743.

  • Castillón, Jaume Capdevila, et al. 2023. “SEOM-GETNE Clinical Guidelines for the Diagnosis and Treatment of Gastroenteropancreatic and Bronchial Neuroendocrine Neoplasms (NENs) (2022).” Clinical & Translational Oncology 25(9): 2692–2706. DOI: 10.1007/s12094-023-03205-6.

  • Baudin, Eric, et al. 2021. “Lung and Thymic Carcinoids: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up.” Annals of Oncology 32(4): 439–51. DOI: 10.1016/j.annonc.2021.01.003.