Cervical Precancers Originate From Infected Proliferating Reserve Cells

Abstract

Human papillomavirus (HPV)-induced invasive cervical squamous cell cancer (SCC) develop via high-grade squamous intraepithelial lesion (HSIL). In contrast to classic thick HSIL, thin HSIL (≤9 cell layers) are poorly documented. This study compares histology, HPV genotypes, and aberrations in 50 cancer genes of 45 thin HSIL to 45 thick HSIL, 20 pT1a SCC, and 40 ≥pT1b SCC. Thin HSIL arose from proliferating reserve cells within endocervical epithelium or immature metaplasia throughout the transformation zone after infection with high-risk HPV genotypes (36/45; 80%), and 20% non–high-risk HPV genotypes compared with 2.5% thick HSIL, pT1a SCC, and ≥pT1b SCC. Thin HSIL were multifocal proliferations with varying epithelial thickness between 1 and 2 to 9 cell layers, with occasional transitions to thick HSIL or concomitant lesions of thick HSIL. Overall, 40% thin HSIL were located distant to and most thick HSIL occurred near or at the squamocolumnar junction. Only 20% thick HSIL showed koilocytosis. All HSIL lacked somatic gene mutations, compared with 30% pT1a and 55%≥pT1b SCC. Overrepresented rare germline variants in the MET, JAK3, and FGFR3 genes occurred in all patient groups. In summary, thin and thick HSIL arose independently of somatic gene mutations. The maturation level of the squamous epithelium at the time of transforming infection determines if a thick HSIL develops directly from HPV-infected proliferating reserve cells via thin HSIL or in stratified glycogenated squamous epithelium via low-grade squamous intraepithelial lesion. These observations raise doubts about the biological relevance of separation into thin and thick HSIL. The oncogenic potential of HPV genotypes but also germline variants may influence the natural history.

Factors associated with human papillomavirus persistence after loop electrosurgical excision procedure in patients with cervical squamous intraepithelial lesion

“…In previous studies, satellite lesions presented in 44.4% patients who with CIN and satellite lesions was related to the reappearance of CIN after loop excision with clear margins. 21,22 In a recent study, Regauer et al 23 found that patients could be observed with multiple foci of HPV-induced thin HSIL in the early stages of developing thin HSIL. IOP-HPV test could evaluate the remaining cervical tissue immediately after treatment for the detection of minimal residual disease.…”

Underdiagnosis of cervical intraepithelial neoplasia by colposcopy and its association with thin high‑grade squamous intraepithelial lesions

“…Classic HSILs typically arise from LSILs after HR-HPV infection of mature stratified metaplastic squamous epithelium (MSE). HSILs can also develop from early MSE (11), these lesions (defined as thin HSILs) occur in non-stratified or very thin immature squamous epithelia, which explains why certain HSILs develop without an anteceding LSIL (11)(12)(13). The frequency of thin HSILs has been reported in only a few studies.…”