Implications of continued upregulation of p16INK4a evolution from high-grade squamous intraepithelial lesion to invasive squamous carcinoma of the cervix
- Author:
Phaik-Leng CHEAH
;
Lai-Meng LOOI
;
Kein-Seong MUN
;
NAZARINA
;
Kean-Hooi TEOH
- Publication Type:Journal Article
- Keywords:
p16INK4a, pathogenesis, low-grade intraepithelial lesions (LSIL), high-grade intraepithelial lesions (HSIL), invasive cervical squamous carcinoma (SCC)
- From:The Malaysian Journal of Pathology
2011;33(2):83-87
- CountryMalaysia
- Language:English
-
Abstract:
On integration into the host cervical keratinocyte genome, human papillomavirus (HPV) E7 protein
binds pRB, releasing E2F from normally incompetent pRB-E2F complexes and allowing propagation
of G1-S transition by the E2F. p16 INK4a, a tumour suppressor protein, increases in refl ex response to
counter this. 29 histologically re-confi rmed low-grade squamous intraepithelial lesions (LSIL), 27
high-grade squamous intraepithelial lesions (HSIL) and 30 invasive cervical squamous carcinoma
(SCC) were immunohistochemically stained for p16INK4a expression using the CINtec Histology Kit
(REF 9511, mtm laboratories AG, Heidelberg, Germany) to re-affi rm the notion that integration
of HPV occurs predominantly in SCC and possibly HSIL and less in LSIL and normal squamous
epithelium (NSqE). Implicit was also the attempt to understand the role of E2F, as indicated by
p16INK4a, in evolution of SCC from HSIL. No ethnic predilection was noted for LSIL, HSIL or SCC.
Patients with SCC were signifi cantly older by about 14-years compared with HSIL (p<0.05) while
there was no signifi cant age difference between HSIL and LSIL. p16INK4a expression was signifi cantly
increased (p<0.05) in both HSIL (88.9%) and SCC (83.3%) compared with LSIL (3.4%) and NSqE
(0%); the NSqE being normal squamous epithelium noted in 17 of the LSIL, 19 HSIL and 5 SCC.
From these fi ndings there is suggestion that fundamental upstream events viz HPV integration, E7
upregulation followed by E2F activation occurs at point of transformation to HSIL and continues
unrelentingly for another one to two decades before hitherto unclear factors convert a non-invasive
lesion into an overtly invasive malignant counterpart. Interestingly, the occurrence of HSIL and
LSIL in almost the same age group could mean that alteration from episomal to integrated form of
HPV may not incur a prolonged incubation period, unlike from HSIL to SCC
