The Cervical Squamocolumnar Junction Is Not the Same as the "Transformation Zone": Evidence for Two Related but Divergent Populations with Different Cancer Risks
Michael Herfs, Sara O Vargas, Brooke Howitt, Yusuke Yamamoto, Marisa R Nucci, Jason Hornick, Frank D McKeon, Wa Xian, Christopher P Crum. Brigham and Women's Hospital, Boston, MA; University of Liege, Liege, Belgium; Children's Hospital, Boston, MA; A-STAR, Singapore, Singapore
Background: A fundamental precept in cervical carcinogenesis is the existence of a target cell of origin that is uniquely vulnerable to carcinogenic HPV infection and capable of multiple tumor phenotypes. A recent study has proposed a cuboidal non-squamous cell of origin that resides in the squamocolumnar (SC) junction.
Design: Using expression arrays derived from SC junction cells, antibodies to SC junction-specific gene products were applied to mouse and human embryo and adult cervical specimens in order to identify, characterize and determine the dynamics of SC junction cell development. Remodeled cervical epithelia (epithelial metaplasia, microglandular hyperplasia), low and high grade SILs were also analyzed to ascertain their relationship to SC junctional cell population.
Results: In embryonic and adult cervices, cuboidal embryonic/SC junction cells were tightly linked to subjacent metaplastic basal/reserve cells, the latter expanding from beneath embryonic or SC junction cells to form transformation zone/metaplastic epithelium. This basal pattern of transdifferentiation was termed reverse or top-down differentiation and was associated with a progressive loss of the SC junction immunophenotype and acquisition of squamous markers. In contrast to most LSILs, HSILs displayed an expression of SC junction markers on the apical surface, suggesting an initial infection of the SC junction cells by HPV followed by loss of the SC junction immunophenotype during transdifferentiation to the expanded basal- oriented metaplastic progeny. HPV DNA in situ hybridization and p16ink4 staining verified HPV infection in the superficial SC junction cells.
Conclusions: This study indicates that most HSILs are strongly linked to direct infection of SC junction cells followed by transdifferentiation, whereas LSILs are a consequence of the infection of less vulnerable metaplastic cells in the transformation zone that have already completed their exit from the SC junction cell compartment. This geographically-dictated, population-specific (SC junction) vulnerability raises the distinct possibility that cervical cancer risk in a given individual is a function of not only carcinogenic HPV infection but also of infected cell biology.
Category: Gynecologic & Obstetrics
Tuesday, March 5, 2013 8:00 AM
Proffered Papers: Section E, Tuesday Morning