In Reply.—We appreciate the submitted comments.
Reich and Regauer's hypothesis is not so different from ours.1 We also believe that low-grade squamous intraepithelial lesion (LSIL)/condyloma arises from original squamous epithelium of the exocervix or mature squamous metaplasia that arises from the columnar cells in the transformation zone and goes through the process of reserve cell proliferation, immature metaplasia, and then maturation (mature metaplasia). We also believe that papillary immature metaplasia (PIM) arises from immature squamous metaplasia infected with human papillomavirus (HPV). However, as shown in our figures (Figure 1, A and C through F), PIM can mature and disclose mature squamous epithelium and koilocytosis in many cases, as the presence of mucin-secreting cells in the middle layers of mature squamous epithelium and on top of the papillary lesions signifies.
Our additional thought was why and how PIMs have papillary configuration in most cases whereas the LSIL/condyloma are flat. The normal endocervical mucosa has a papillary configuration (see Figure 4, A). Additionally, PIM is more frequently identified in the endocervix and the transformation zone than elsewhere. Thus, we interpret this appearance of PIM as a variant of LSIL that had originated from HPV-infected immature squamous metaplastic cells at or proximal to the squamocolumnar junction.
“Top-down differentiation” in our paper denotes the process whereby the single-layered reserve cell formation is induced from the columnar epithelium lying above. “Bottom-up differentiation” refers to the reserve cell proliferation and immature and then mature squamous differentiation from the single-layered reserve cells. It explains not only the mechanism of PIM formation, but also for general process by which immature and mature squamous metaplasia forms.
However, we cannot fully agree that only the mature squamous epithelium allows low-risk HPV to complete the productive life cycle with assembly of the viral particles. Immature squamous epithelium infected with HPV likely also goes through the maturation process, then permitting the assembly process of the viral particles producing koilocytosis to complete, as our cases show.
The authors have no relevant financial interest in the products or companies described in this article.