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.

人乳头瘤病毒 (HPV) 诱导的浸润性宫颈鳞状细胞癌 (SCC) 通过高级鳞状上皮内病变 (HSIL) 发展。与经典的厚 HSIL 相比，薄 HSIL（≤9 细胞层）的记录很少。本研究比较了 45 个薄 HSIL 与 45 个厚 HSIL、20 个 pT1a SCC 和 40 个≥pT1b SCC 的 50 个癌症基因的组织学、HPV 基因型和畸变。薄 HSIL 是由感染高危 HPV 基因型（36/45；80%）和 20% 非高危 HPV 基因型后宫颈内膜上皮内增殖的储备细胞或整个转化区的未成熟化生细胞引起的，而厚 HSIL 为 2.5% 、pT1a SCC 和≥pT1b SCC。薄 HSIL 是多灶性增殖，上皮厚度在 1 至 2 至 9 细胞层之间变化，偶尔转变为厚 HSIL 或厚 HSIL 的伴随病变。总体而言，40% 的薄 HSIL 位于鳞柱交界处较远的位置，而大多数厚 HSIL 发生在鳞柱交界附近或处。仅 20% 厚的 HSIL 显示出空细胞增多。与 30% pT1a 和 55%≥pT1b SCC 相比，所有 HSIL 均缺乏体细胞基因突变。所有患者组中均出现MET、JAK3 和FGFR3基因的罕见种系变异。总之，薄HSIL和厚HSIL的产生与体细胞基因突变无关。转化感染时鳞状上皮的成熟水平决定了厚HSIL是否直接由HPV感染的增殖储备细胞通过薄HSIL发展而来，或者通过低度鳞状上皮内病变形成复层糖原鳞状上皮。这些观察结果对分离成薄 HSIL 和厚 HSIL 的生物学相关性提出了质疑。HPV 基因型以及种系变异的致癌潜力可能会影响自然史。