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. 2025 May;97(5):e70397.
doi: 10.1002/jmv.70397.

Molecular Insights Into the Natural History of Anal HSIL

Aude Jary  1   2 , Ramon P van der Zee  1   2   3 , Vita Jongen  4   5   6 , Timo J Ter Braak  1   2 , Yongsoo Kim  1   2 , Chris J L M Meijer  1   2 , Carel J M van Noesel  2   7 , Henry J C de Vries  4   5   8 , Maarten F Schim van der Loeff  3   4   5 , Renske D M Steenbergen  1   2
Affiliations

Molecular Insights Into the Natural History of Anal HSIL

Aude Jary et al. J Med Virol. 2025 May.

Abstract

Anal squamous cell carcinoma is commonly associated with human papillomavirus (HPV) infection and preceded by low- and high-grade anal lesions (LSIL; HSIL). We performed a molecular comparison on paired LSIL- and HSIL-lesions collected in a longitudinal fashion to assess their relationship. Fifty biopsies from 22 men diagnosed with LSIL at baseline (T0) who developed HSIL during follow-up (T1) were subjected to a comprehensive molecular analysis: HPV-typing and HPV16 variant, cellular DNA methylation levels, and copy number aberrations (CNA). After histopathological revision, 23 biopsies were classified as LSIL and 27 as HSIL. Both methylation levels and CNA were significantly increased in HSIL compared to LSIL. In 15 out of 22 patients, LSIL at T0 was associated with HSIL at T1. Among them, six showed HPV-type persistence with similar or increased methylation levels and CNA in the HSIL at follow-up. Six patients harbored a different HPV-type in the follow-up biopsy, while in three patients, HPV was not detected or not-typable in one or both lesions. A subset of HSIL preceded by LSIL displayed both HPV-type persistence and an increase in molecular alterations, suggesting that some LSIL may progress to HSIL. In contrast, the HPV-type switch in another subset of HSIL preceded by LSIL, may suggest an alternative pathway of anal carcinogenesis, where HSIL develop directly.

Keywords: AIN1; AIN2; AIN3; HSIL; LSIL; anal lesion progression; copy number aberrations; methylation markers.

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Conflict of interest statement

R.D.M.S. and C.J.L.M.M. are minority shareholders of Self‐screen B.V., a spin‐off company of VUmc; Self‐screen B.V. develops, manufactures and licenses high‐risk HPV and methylation marker assays for cervical cancer screening and holds patents on these tests. R.D.M.S. declares consultancy fee from Astra Zeneca. C.J.L.M.M. is part‐time CEO of Self‐Screen and served occasionally on the scientific advisory board and/or the speakers bureau of Qiagen. M.S.V.D.L. served on the Advisory Board of NovoSanis and his institution receives funding from GSK for an investigator‐initiated study. The other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart of the study.
Figure 2
Figure 2
Methylation levels (A) and genome‐wide Z‐score (B) from anal LSIL and HSIL‐lesions collected in MSM living with HIV. No dysplasia (n = 3) is grouped with LSIL. HSIL, high‐grade squamous intraepithelial lesion; LSIL, low‐grade squamous intraepithelial lesion.
Figure 3
Figure 3
Chromosome arm‐specific Z‐score from anal LSIL (n = 11) and HSIL (n = 19) lesions collected in MSM living with HIV. Each line corresponds to one lesion, in blue those with a normal chromosome arm‐specific Z‐score and in red those with abnormal chromosome arm‐specific Z‐score corresponding to a gain (z‐score > 4) or a loss (z‐score < −4). No dysplasia (n = 3) is grouped with LSIL. HSIL, high‐grade squamous intraepithelial lesion; LSIL, low‐grade squamous intraepithelial lesion.
Figure 4
Figure 4
Histopathology, methylation markers, and chromosomal aberrations in patients who progressed from anal LSIL to HSIL with HPV‐persistence. Bis indicates a second biopsy form same time point. HSIL, high‐grade squamous intraepithelial lesion = AIN2 and AIN3; LSIL, low‐grade squamous intraepithelial lesion = AIN1.
Figure 5
Figure 5
Histopathology, methylation markers, and chromosomal aberrations in patients who had a persistence of anal LSIL or HSIL lesions. Bis indicates a second biopsy form same time point. HSIL, high‐grade squamous intraepithelial lesion = AIN2 and AIN3; LSIL, low‐grade squamous intraepithelial lesion = AIN1.
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