Cervical Intraepithelial Neoplasia Group Research Articles

VEGF, FGF2, TGFB1 and TGFBR1 mRNA expression levels correlate with the malignant transformation of the uterine cervix

Angiogenesis is a complex procedure induced by the secretion of numerous growth factors from endothelial cells. Vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (FGF2), transforming growth factor-β1, 2, 3 (TGFB1, 2, 3), and transforming growth factor-β receptors (TGFBR1, 2, 3) mRNA expression pattern was evaluated in tissue samples with cervical intraepithelial neoplasia (CIN) and cervical cancer, compared to that of normal cervical tissues, and correlated to the clinical stage of the disease. Transcript levels of the above genes were assessed by RT-PCR analysis in a total of 44 cervical specimens. VEGF, TGFB1, TGFBR1, and FGF2 transcript levels were significantly different in the normal, CIN and cancer specimen groups ( P=0.015, 0.001, 0.008, and 0.029, respectively). Higher TGFBR1 mRNA levels were observed in parallel with increased severity of the lesion, whereas FGF2 exhibited lower transcript levels. A highly significant increase of VEGF mRNA expression was found upon cervical neoplastic transformation ( P<0.0001). High-grade squamous intraepithelial lesions exhibited higher VEGF mRNA levels than low-grade lesions ( P=0.039). TGFBR1 and TGFBR3 receptors demonstrated significant co-expressions with TGFB2 ( P<0.0001), and TGFB1 ( P=0.005 and 0.002, respectively) in normal cervical specimens. However, a disruption of co-expression patterns was observed in the groups of CIN and cancer cases, compared to normal tissues. Our findings show that VEGF, FGF2, TGFB1 and TGFBR1 mRNA expression levels correlate with the malignant transformation of the uterine cervix. The involvement of the examined markers in cervical carcinogenesis is furthermore supported by the observed disruption of their mRNA co-expression patterns.

The evidence for an etiological relationship between oral contraceptive use and dysplastic change in cervical tissue

A case-control study of 112 patients with cervical intraepithelial neoplasia (CIN) and 131 control subjects was conducted. Estradiol receptor levels were determined in the total (cytosolic-nucleosolic) fraction of the neoplastic cervical specimens taken during the late proliferative phase of their cycle from 58 premenopausal patients who had been oral contraceptive (OC) users for at least 2 years and from 54 premenopausal women who had not been OC users. All specimens contained variable amount of estradiol receptor (from 7.6 to 53.0 fmol estradiol/mg protein and 7.2 to 29.3 fmol estradiol/mg protein in patients who were OC users and non-users, respectively). A significant correlation was found between estradiol receptor concentration and histological grading in both groups, likewise higher levels of estradiol receptor were observed in the low-grade CIN group tissue from patients who were OC users (p < 0.05). At the same time 17 beta-estradiol and progesterone levels were also determined in the serum of all women who had not used an OC for at least 12 months. The mean +/- SD estradiol serum levels in non-users of OC with CIN (0.189 +/- 0.08 ng/ml, follicular phase) were greater than the mean +/- SD (1.163 +/- 0.33 ng/ml, luteal phase) progesterone serum concentration. Serum estradiol levels were significantly higher (p < 0.05) in OC users, whereas progesterone levels were not (p > 0.05). OC users had an increased risk (odds ratio = 1.31, 95% CI 1.0-2.3) of cervical neoplasia.

The evidence for an etiological relationship between oral contraceptive use and dysplastic change in cervical tissue

A case-control study of 112 patients with cervical intraepithelial neoplasia (CIN) and 131 control subjects was conducted. Estradiol receptor levels were determined in the total (cytosolic-nucleosolic)fraction of the neoplastic cervical specimens taken during the late proliferative phase of their cycle from 58 premenopausal patients who had been oral contraceptive (OC) users for at least 2 years andfrom 54 premenopausal women who had not been OC users. All specimens contained variable amount of estradiol receptor (from 7.6 to 53.0 fmol estradiol/mg protein and 7.2 to 29.3 fmol estradiol/mg proteinin patients who were OC users and non-users ,respectively). A significant correlation was found between estradiol receptor concentration and histological grading in both groups ,likewise higher levels ofestradiol receptor were observed in the low-grade CIN group tissue from patients who were OC users (p < 0.05). At the same time 17 β-estradiol and progesterone levels were also determinedin the serum of all women who had not used an OC for at least 12 months. The mean ± SD estradiol serum levels in non-users of OC with CIN (0.189 ± 0.08 ng/ml ,follicular phase) were greaterthan the mean ± SD (1.163 ± 0.33 ng/ml ,luteal phase) progesterone serum concentration. Serum estradiol levels were significantly higher (p < 0.05) in OC users ,whereas progesteronelevels were not (p > 0.05). OC users had an increased risk (odds ratio = 1.31 ,95% CI 1.0-2.3) of cervical neoplasia.

IgG antibodies against human papillomavirus type 16 E7 proteins in cervicovaginal washing fluid from patients with cervical neoplasia.

Little information is available about the cervicovaginal mucosal antibodies against human papillomavirus (HPV) proteins. In this study specific IgG antibodies against HPV 16 E7 protein were determined in paired samples of cervicovaginal washing fluid and serum from patients with cervical cancer (n = 22), cervical intraepithelial neoplasia (CIN) (n = 38), healthy individuals (n = 22), and serum from children (n = 41) by a radioactive immunoprecipitation assay (RIPA). HPV 16 E7 specific IgG antibodies were found in cervicovaginal washings (n = 8) and in sera (n = 8) of the patients with cervical cancer. About 60% of the patients with HPV 16 positive cervical cancer had HPV 16 E7 specific IgG antibodies. Titration studies showed that the IgG antibody reactivity in cervicovaginal washings was higher than in the paired serum samples of six patients with cervical cancer (P < 0.001). In the CIN group we found no IgG reactivity in the serum, but in five patients we found a low IgG reactivity in the cervicovaginal washings. No IgG reactivity was found in cervicovaginal washings and sera from healthy individuals and sera from children. HPV 16 E7 specific IgG antibodies seem to be locally produced in a number of patients with HPV 16 positive (pre)malignant cervical lesions. For more definitive evidence for the local production of these antibodies immunostaining should be performed to demonstrate the presence of specific anti-HPV 16 E7 IgG producing plasma cells in the cervical epithelium.

Analysis of MHC class I and II expression in relation to presence of HPV genotypes in premalignant and malignant cervical lesions.

Cervical intraepithelial neoplasia (CIN) grades I to III lesions (n = 94) and squamous cell carcinomas of the uterine cervix (n = 27) were analysed for MHC class I and II expression and presence of HPV genotypes. MHC class I and II expression was studied by immunohistochemistry and HPV typing was performed by general primer- and type-specific primer mediated PCR (GP/TS PCR). Both techniques were performed on paraffin embedded tissue sections. Results show disturbed MHC class I heavy chain expression in CIN I to CIN III, as well as in cervical carcinomas. Upregulated MHC class II expression on dysplastic epithelial cells was also found in the different CIN groups and carcinomas. Prevalence of HPV genotypes increased with the severity of the lesion, mainly due to the contribution of the HPV types 16 and 18. No correlation could be established between the presence of specific HPV genotypes and any MHC expression pattern in the different CIN groups or cervical carcinomas. In some cases these data were confirmed by RNA in situ hybridisation showing HPV 16 E7 transcripts in the same dysplastic/neoplastic cells from which MHC status was determined. The results indicate that local differences may exist in the type of cellular immune response to HPV induced lesions.

Differences in biologic maturation, sexual behavior, and sexually transmitted disease between adolescents with and without cervical intraepithelial neoplasia

Because several cofactors may influence the development of cervical intraepithelial neoplasia (CIN) in young women, we compared differences in behaviors (sexual activity, contraception, and cigarette use), sexually transmitted disease (STD) infection rates (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and herpes simplex virus), and cervical maturation (age of menarche and percentage of cervical ectopy) in groups of sexually active female adolescents with and without CIN. Those with CIN were compared with three non-CIN groups: (1) teenagers who were referred to a teen colposcopy clinic but had no evidence of CIN (high-risk group), (2) teenagers seen at a gynecology clinic without STD symptoms (asymptomatic group), and (3) teenagers seen at the gynecology clinic with STD symptoms (symptomatic group). The percentage of cervical ectopy was measured by colpophotography. Subjects with CIN had more lifetime sexual partners than the asymptomatic group (p less than 0.001) and were more likely to smoke cigarettes than either gynecology clinic group (p less than 0.01). No differences in behaviors existed between the CIN and high-risk groups. The mean age of menarche in those with CIN was 1 year older than all three non-CIN groups (p less than 0.05), and those with CIN had a greater area of ectopy than those without CIN (p less than 0.02). Those with CIN were more likely to have a past or present history of C. trachomatis infection than the two gynecology clinic groups; no difference was found between the CIN and high-risk groups. We conclude that cofactors such as smoking, sexual promiscuity, and C. trachomatis infection may influence cervical vulnerability. However, cervical biologic immaturity is an important risk factor for development of CIN in adolescent girls.

Detection of iga antibodies against human papillomavirus in cervical secretions from patients with cervical intraepithelial neoplasia

Although human papillomavirus (HPV) is involved in the etiology of cervical carcinoma, there are no cervical carcinoma-specific HPV serologic tests available. We investigated the presence of broadly cross-reactive IgA antibodies to papillomavirus (PV) in cervico-vaginal secretions from patients with condylomata and cervical intraepithelial neoplasia (CIN). Purified bovine PV (BPV) virions were used as antigen in an enzyme-linked immunosorbent assay (ELISA). Forty-two women whose ages ranged from 20 to 50 participated in the study. Eight of 9 patients with CIN had IgA antibodies against PV in their cervical secretions. Three of 9 patients with koilocytosis and condylomas but no CIN had IgA antibodies to PV. Six of 24 women with normal Pap-smear and colposcopy also had IgA antibodies against PV in their cervical secretions. The proportion of IgA-positive cervical secretions was significantly higher in the CIN group than in the normal group (p less than 0.005). Our data suggest that IgA antibodies to PV may be a useful marker for CIN.

Cytomegalovirus in women with cervical intra-epithelial neoplasia

SummaryThe role of cytomegalovirus (CMV) was investigated in patients presenting with cervical intra-epithelial neoplasia (CIN). Endocervical swabs, cervical microbiopsy specimens and serum were tested in combination for evidence of CMV infection in the study and control groups. None of the swabs or the biopsy specimens grew CMV, indicating difficulty in its culture as well as absence of active infection. We could find no difference in the incidence of immune serum litres against CMV in the controls compared with the CIN group. Three patients with invasive cervical carcinoma were found to have titres suggestive of a recent CMV infection.

Evidence for Possible Interaction between Human Papillomavirus and Environmental Cofactors in Women with Cervical Intraepithelial Neoplasia

ABSTRACT Although human papillomavirus (HPV) is now thought to have a major causative role in the genesis of cervical cancer, the majority of women with genital HPV infection do not develop cervical malignancy. It has, therefore, been proposed that other cofactors must be closely involved. A group of 200 women with cervical intraepithelial neoplasia (CIN) were studied for the occurrence of the proposed cofactors: herpes simplex virus (HSV), human cytomegalovirus (CMV), Chlamydia trachomatis, oral contraceptive steroids, and cigarette smoking. These women were compared with a similar group of women who had histologic evidence of HPV cervical infection only. No statistically significant differences were found between the two groups in current or previous HSV infection, current or previous C. trachomatis infection, previous CMV infection, or contraceptive usage. Women in the CIN groups who smoked were statistically significantly (p < 0.02) heavier smokers than women with HPV only who smoked. A possible dose-...

Premalignant lesions and microinvasive carcinoma of the cervix in Jewish women: an epidemiological study.

During the years 1979-1982 cervical smears were taken from 3974 women at the cervical pathology unit at the Serlin Maternity Hospital, Tel Aviv Medical Center, Tel Aviv. There were 69 patients with positive cytology who had colposcopic directed biopsies which revealed cervical intraepithelial neoplasia (CIN) or a microinvasive lesion; a prevalence rate of 17 per 1000. Epidemiological characteristics of the 69 patients with CIN and microinvasion revealed that these women were younger than those with negative cytology, had more sexual partners and pregnancies, started their sexual activities earlier, and only half of them were married. In the whole series 57% of the women were of Ashkenazi origin and 43% were of Eastern and Sephardic origin, whereas in the group with positive cytology the proportion of women of Eastern and Sephardic origin was twice that of Ashkenazi origin, 64 and 36%, respectively. Only 4.5% of women in the CIN group declared themselves as religiously observant compared with 9.8% in the control group.

SEROLOGICAL EVIDENCE FOR THE ASSOCIATION OF PAPILLOMAVIRUS AND CERVICAL NEOPLASIA

Serum was collected from patients with anogenital warts, cervical intraepithelial neoplasia (CIN), and invasive squamous carcinoma of the uterine cervix. All sera were screened with a solid-phase enzyme-linked immunosorbent assay for an IgG antibody to a group-specific papillomavirus antigen. All three study groups had higher antibody levels than did control groups of children and adults. The invasive-cancer group had a higher geometric mean titre than the CIN or anogenital wart groups. It is proposed that patients with invasive squamous cancer of the cervix are exposed to human papillomavirus (HPV) antigens and that HPV has a role in the aetiology of cervical squamous-cell carcinoma.