Gender Perspective in Lung Neuroendocrine Tumors: A Critical Review

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 aimed to provide a critical analysis of the existing literature regarding sex roles in L-NETs.

We performed an extensive search of the available literature to provide a critical narrative review focused on key topics such as epidemiology, histopathological and molecular features, functioning syndromes, prognosis, and response/toxicity to treatments in L-NETs according to sex.

Female patients are more likely to have an L-NET than males. The reasons underlying these gender differences are still unclear; a biologic mechanism for the sex difference is possible, through a role of 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 the 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.

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. Graphical Abstract: for Graphical Abstract, see https://doi.org/10.1159/000546081.