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Grading immunohistochemical markers p16 INK4a and HPV E4 identifies productive and transforming lesions caused by low‐ and high‐risk HPV within high‐grade anal squamous intraepithelial lesions
Author(s) -
Leeman A.,
Jenkins D.,
Marra E.,
Zummeren M.,
Pirog E.C.,
Sandt M.M.,
Eeden A.,
Schim van der Loeff M.F.,
Doorbar J.,
Vries H.J.C.,
Kemenade F.J.,
Meijer C.J.L.M.,
Quint W.G.V.
Publication year - 2020
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.18342
Subject(s) - grading (engineering) , immunohistochemistry , medicine , biopsy , lesion , pathology , malignant transformation , squamous intraepithelial lesion , pathological , oncology , biology , cancer , cervical cancer , cervical intraepithelial neoplasia , ecology
Summary Objectives Because current guidelines recognise high‐grade anal squamous intraepithelial lesions ( HSIL s) and low‐grade SIL s ( LSIL s), and recommend treatment of all HSIL s although not all progress to cancer, this study aims to distinguish transforming and productive HSIL s by grading immunohistochemical ( IHC ) biomarkers p16 INK 4a (p16) and E4 in low‐risk human papillomavirus (lr HPV ) and high‐risk (hr) HPV ‐associated SIL s as a potential basis for more selective treatment. Methods Immunostaining for p16 and HPV E4 was performed and graded in 183 biopsies from 108 HIV ‐positive men who have sex with men. The causative HPV genotype of the worst lesion was identified using the HPV SPF 10‐ PCR ‐ DEIA ‐Li PA 25 version 1 system, with laser capture microdissection for multiple infections. The worst lesions were scored for p16 (0–4) to identify activity of the hr HPV E7 gene, and pan HPV E4 (0–2) to mark HPV production and life cycle completion. Results There were 37 normal biopsies, 60 LSIL s and 86 HSIL s, with 85% of LSIL s caused by lr HPV and 93% of HSIL s by hr HPV . No normal biopsy showed E4, but 43% of LSIL s and 37% of HSIL s were E4 positive. No differences in E4 positivity rates were found between lr HPV and hr HPV lesions. Most of the lesions caused by lr HPV (90%) showed very extensive patchy p16 staining; p16 grade in HSIL s was variable, with frequency of productive HPV infection dropping with increasing p16 grade. Conclusions Combined p16/E4 IHC identifies productive and nonproductive HSIL s associated with hr HPV within the group of HSIL s defined by the Lower Anogenital Squamous Terminology recommendations. This opens the possibility of investigating selective treatment of advanced transforming HSIL s caused by hr HPV , and a ‘wait and see’ policy for productive HSIL s.What's already known about this topic?For preventing anal cancer in high‐risk populations, all patients with high‐grade squamous intraepithelial lesions (HSILs) are treated, even though this group of lesions is heterogeneous, the histology is variable and regression is frequent.What does this study add?By adding human papillomavirus (HPV) E4 immunohistochemistry to p16 INK4a (p16), and grading expression of both markers, different biomarker expression patterns that reflect the heterogeneity of HSILs can be identified. Moreover, p16/E4 staining can separate high‐risk HPV‐associated HSILs into productive and more advanced transforming lesions, providing a potential basis for selective treatment.