Cervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions

Abstract

Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ, but LSILs include SCJ and SCJ subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ and SCJ using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ LSIL in all cases (100%). However, for SCJ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ and SCJ LSILs, 60.2% and 94.9% were p16 positive, 23% and 74.4% showed strong (full-thickness) p16 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions.

Figure 1

Examples of SCJ- LSIL, SCJ+ LSIL and HSIL analyzed in this study (H&E). Note the relative immaturity and the higher cellularity of the SCJ+ LSILs relative to the SCJ- LSILs.

Figure 2

LSILs (CIN1s) stained for p16^ink4, Ki67 and the SCJ-specific markers. A schematic showing proposed origin is at the top. Note the absence of staining of the ectocervical/TZ LSILs and uniform staining of junctional LSILs.

Figure 3

HSILs (CIN2/3) stained for p16^ink4, Ki67 and the SCJ-specific markers. The ratio of SCJ+ to SCJ- HSILs is over 10:1 in this study in keeping with the epidemiological ratio of cervix to vaginal squamous neoplasia.