Preinvasive disease of the airway

Abstract

Squamous cell carcinoma of the lung arises from preinvasive progenitors in the central airways. The archetypal model appears to be a stepwise morphological progression until there is invasion of the basement membrane. However, not every lesion appears to follow this course and many individuals can have stable disease, or indeed regress to normal epithelium. From our increased understanding of the molecular pathology it is becoming apparent that the respiratory epithelium accumulates progressive genetic and epigenetic insults in response to carcinogens. Still, little is known about how to predict those 'at risk' of progression, and it is likely that in the future molecular signatures will underpin prediction models of developing invasive lung cancer. Currently, autofluorescence bronchoscopy gives us the ability to follow the natural history of these lesions, with the prospect that detecting and treating lesions early may improve survival. However, treatment remains controversial, and radical therapies are offered to individuals with carcinoma in situ who may never develop invasive cancer. This has paved the way for the use of minimally invasive bronchoscopic treatments, which, while apparently effective, have not been tested in randomised controlled trials. In this paper we describe the known biology and natural history of preinvasive lesions and review the current treatment strategies.

Exploiting the potential of lung stem cells to develop pro-regenerative therapies

“…Promisingly, removal of senescent cells from the lungs using either genetic ablation or treatment with senolytic drugs, such as dasatinib and quercetin, can restore stem cell markers and improve lung function in experimental models of both pulmonary fibrosis ( Lehmann et al, 2017 ; Schafer et al, 2017 ) and COPD ( Ganesan et al, 2010 ), and clinical trials are ongoing ( Justice et al, 2019 ). Since senescence is also a hallmark of pre-invasive squamous cell lung cancer lesions ( Venkatesan et al, 2021 ) and senolytic CAR-T cells have shown promise in pre-clinical models ( Amor et al, 2020 ), senolytic therapy may also provide an opportunity to intercept lung cancers at an early stage of development, avoiding invasive bronchoscopic or even surgical procedures ( Thakrar et al, 2017 ). A logical extension of these studies in established disease will be the investigation of senolytic drugs as prophylactic therapies.…”

Single CT Appointment for Double Lung and Colorectal Cancer Screening: Is the Time Ripe?

“…The CT correlates of these histologic entities vary from lung nodules with pure ground glass (non-solid) density to mixed (part solid) and solid density (see below). Dysplastic lesions of the central airways which are precursors of squamous cell carcinoma are well detected by fluorescence bronchoscopy [ 28 ] and can escape chest LDCT.…”

Interrogating the Precancerous Evolution of Pathway Dysfunction in Lung Squamous Cell Carcinoma Using XTABLE

“…LUSC progresses through a series of premalignant stages characterized by alterations of the normal bronchial epithelium (Figure 1) (20)(21)(22)(23). These endobronchial premalignant lesions (PMLs) are classified as low-grade (squamous metaplasia, mild and moderate dysplasia) and high-grade (severe dysplasia, and carcinomas in-situ) (Figure 1).…”

“…However, not all PMLs progress to LUSC. Although obvious differences exist between the multiple studies published on the topic, high-grade PMLs have a higher risk of progression than low grade, and high levels of chromosomal instability (CIN) are also predictive of progressive PMLs (22,(24)(25)(26). This potential role of CIN as biomarker of PMLs progression has been observed in low and high grade PMLs (24,25).…”