Carcinogenic HPV infection in the cervical squamo-columnar junction

Recent studies have suggested the involvement of a unique population of cells at the cervical
squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion
or SIL) and advanced (squamous cell and adeno-carcinomas) cervical neoplasia. However,
there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are
instrumental in the initial phases of neoplasia. This study was designed to 1) determine if
normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and 2) trace
their transition to early SIL. Sections of cervix from high-risk reproductive age women were
selected and SCJ cells were analyzed by using several techniques which increasingly
implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR),
immunostaining for HPV16 E2 (an early marker of HPV infection), p16ink4, Ki67 and HPV
L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the
excision specimen, HPV DNA was isolated from 8 of 10 with visible SCJ cells, 6 of which
were HPV16/18 DNA positive. In 5 of these latter cases, the SCJ cells were positive for
p16ink4 and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also
detected in micro-dissected SCJ cells. Early squamous atypia associated with the SCJ cells
demonstrated in addition diffuse p16ink4 immunoreactivity, elevated proliferative index and
rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing
SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their
progression to SIL is heralded by an expanding metaplastic progeny with increased
proliferation and p16ink4 expression. Whether certain SCJs are more vulnerable than others to
carcinogenic HPV genotypes and what variables determine transition to high grade SIL
remain unresolved, but the common event appears to be a vulnerable cell at the SCJ.