Gender perspective in Lung Neuroendocrine Tumors: a critical review

Background: The role of gender has gained attention in oncology. In the setting of lung neuroendocrine tumors (L-NETs) the existence of differences between male and females has been suggested, but no clear-cut data are available. We aim to provide a critical analysis of the existing literature regarding sex role in L-NETs. Methods: We performed an extensive search of the available literature to provide a critical narrative review focused on key topics as epidemiology, histopathological and molecular features, functioning syndromes, prognosis and response/toxicity to treatments in L-NETs according to sex. Results: Female patients are more likely to have a L-NET than males. The reasons underlying this gender differences are still unclear; a biologic mechanism for the sex difference is possible, through a role for hormones in regulating gene expression and promoting neuroendocrine cell proliferation. A difference in immunohistochemical biomarkers has been found; thyroid transcription factor-1 (TTF-1) expression appears to be associated with female gender; at molecular level in the majority of studies L-NET mutational profile is not stratified for sex. In terms of prognosis, a correlation between male gender and a more aggressive disease has been found. Patient's gender has been recognized as a key modulator in the response/resistance to anticancer treatments, however for L-NETs the available data regarding the activity of different treatments and their toxicities are scarce as in clinical trials designed for L-NETs a stratified evaluation of drugs' activity according to patients' sex is largely missing. Conclusions: There is emerging evidence suggesting a gender role in L-NETs, however further studies are needed to better understand the pathogenesis of these tumors and to plan tailored treatments.