Thin variant of high-grade squamous intraepithelial lesion - relationship with high-risk and possibly carcinogenic human papilloma virus subtypes and somatic cancer gene mutations

Histopathology. 2019 Sep;75(3):405-412. doi: 10.1111/his.13869. Epub 2019 Jun 28.


Aim: To further characterise the thin variant of high-grade squamous intraepithelial lesions (HSILs) of the cervix defined by the World Health Organization as full-thickness HSILs with nine or fewer cell layers.

Methods and results: We examined 31 excisional cervical specimens featuring exclusively p16INK4a -overexpressing thin HSILs with respect to size, location at the squamocolumnar junction or endocervical mucosa, human papilloma virus (HPV) subtypes (pretherapeutic clinical HPV tests and HPV genotyping on lesional tissue after excision), and somatic mutations in 50 cancer genes. Thin HSILs were typically solitary lesions, located at the squamocolumnar junction (20/31; 65%), in the endocervical columnar epithelium (6/31; 19%), and in both locations (5/31; 16%). The horizontal extension of thin HSILs ranged from 100 µm to 8 mm, with 30% being <1 mm. HPV data were available for 27 specimens. Twenty of 27 (74%) thin HSILs showed high-risk HPV subtypes: HPV16 (n = 8), HPV16 with coinfection (n = 2), HPV18 (n = 1), HPV31 (n = 1), HPV33 (n = 2), HPV52/58 (n = 2), and 'other' high-risk HPV genotypes (n = 4). Five of 27 (19%) thin HSILs showed possibly carcinogenic subtypes: HPV53 (n = 3), HPV73 (n = 1), and HPV82 (n = 1). One thin HSIL was induced by low-risk HPV6 and one by the unclassified subtype HPV44. Somatic gene mutations were not identified.

Conclusion: Thin HSILs were typically small lesions without somatic gene mutations. Two-thirds of thin HSILs developed after a transforming infection with high-risk HPV subtypes, and one-third were induced by non-high-risk HPV subtypes. If cervical cancer screening relies solely on presently available clinical HPV DNA tests, a significant percentage of women with HSIL will be missed.

Keywords: HPV cervical cancer screening; cancer hotspot panel; cervical carcinogenesis; cervical intraepithelial neoplasia; p16INK4a overexpression; somatic gene mutations.

MeSH terms

  • Adult
  • Female
  • Humans
  • Middle Aged
  • Papillomaviridae / genetics
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / virology*
  • Squamous Intraepithelial Lesions of the Cervix / pathology*
  • Squamous Intraepithelial Lesions of the Cervix / virology*
  • Young Adult