CIN Patients Research Articles

Factors associated with cone margin involvement in CIN patients undergoing conization-equivalent electrosurgical procedure

Most studies of cervical conization have considered the frequency of complications and the outcome of follow-up. The determinants of cone margin positivity have been inadequately described. In a series of CIN patients undergoing conization-equivalent electrosurgical procedure, we evaluated the factors associated with (i) any cone margin involvement, and (ii) endocervical margin involvement (with or without other locations) as contrasted with all other conditions. Study population included 718 patients. Potential determinants of margin involvement were or were treated as categorical. Univariate analysis was based on the chi-square test. Multivariate associations were estimated by multiple logistic regression models. Cone margin involvement was observed in a total of 195 patients (27%). In univariate analysis, the frequency was positively related to histologic grade, time period, lesion size, and cone width and depth. In multivariate analysis, histology diagnosis and time period retained a strong association. The effect of lesion size was of borderline significance. The endocervical location emerged as a multivariate determinant of margin positivity. The effect of cone width and depth was not confirmed. Endocervical margin involvement was observed in 98 cases (14%). In univariate analysis, the frequency was positively associated with histologic grade, time period, and age, and inversely related to the visibility of the squamous-columnar junction. Multivariate analysis confirmed the strong effect of histology diagnosis and time period. The association with age and visibility of the squamous-columnar junction was weaker. Histology diagnosis and time period were the strongest determinants of cone margin involvement. Endocervical margin positivity was also related to patient age and visibility of the squamous-columnar junction. Cone width and depth had no protective effect.

HIV+ Patients Have Increased Lymphocyte Infiltrates in CIN Lesions

Objective. The objective of our study was to analyze immunocyte infiltrates in CIN lesions from HIV+ patients to assess whether local immunosuppression, defined as a decrease in T cell infiltrates, could explain the aggressive nature of CIN in HIV-infected patients.Materials and methods. Cervical tissue was obtained from 6 HIV+ CIN patients, 6 HIV− CIN patients, who underwent LLETZ (large loop excision of the transformation zone) for CIN, and 17 normal patients who underwent hysterectomy for benign indications. The following cell surface markers were analyzed: CD20 (B cells), CD4 (T helper cells), and CD8 (T suppressor/cytotoxic cells). Each tissue section was visualized with a Leica microscope at 400× and the image was captured for analysis by Harmony Group image analysis software.Results. A significantly higher number of lymphocytes (both B and T cells) was detected in the stroma of HIV+/CIN tissue compared to either HIV−/CIN or normal tissue. There was also a significant increase in CD8+ cells in the HIV+/CIN group compared to HIV−/CIN or normal tissue. There was a trend toward a decreased CD4+/CD8+ ratio in the HIV+/CIN compared to the other two groups; however, this did not reach statistical significance.Conclusions. This study indicates that HIV+/CIN cervical tissue has a greater number of tissue lymphocytes recruited to the neoplastic site compared to HIV− individuals. In addition, HIV+ patients may have a decreased CD4/CD8 ratio in locally infiltrating immunocytes in CIN lesions. The local immunomodulatory effects of HIV may be detectable early in infection and therefore may explain the aggressive nature of CIN in the HIV+ patient.

Factors associated with cone margin involvement in CIN patients undergoing conization-equivalent electrosurgical procedure

Factors associated with cone margin involvement in CIN patients undergoing conization-equivalent electrosurgical procedure

Mutational and Functional Analysis of HPV-16 URR Derived from Korean Cervical Neoplasia

Objective. The YY1 mutation has been suggested as one of the indicators that explains development of cervical neoplasia by episomal-type HPV. To extend this hypothesis, we examined whether a mutation(s) in the YY1 site is functionally related to the invasiveness of cervical neoplasia and the physical status of HPV DNA.Methods. The URR sequences were obtained by PCR amplification of HPV-16 genome from CIN and invasive cancer patients and cloned into pUC18 for sequencing and into pBLCAT8+ for functional CAT assay.Results. Our previous data classified HPV-infected patients into three groups: 3 cancer cases carrying episomal HPV DNA; 12 cancer cases carrying integrated HPV DNA; 12 CIN cases carrying episomal HPV DNA. The specific variants in HPV-16 URR were found in Korean women: G→A transition at nt 7520 (100%, 27/27), A→C transition at nt 7729 (70%; 19/27), and G→A transition at nt 7841 (78%; 21/27). Selective mutations were observed at the YY1 binding sites of HPV-16 URR in the 3 patients with invasive cervical cancer who have the episomal forms of HPV-16 DNA: A→C transition at nt 7484 and G→A transition at nt 7488 (YY1-binding site 2; from 7481 to 7489). Additionally, C→T transition at nt 7785 (YY1-binding site 3; from 7781 to 7790) was found in 2 of 3 patients. No YY1 site mutations were detected in the 12 CIN patients and in the HPV-integrated invasive cancer patients. To determine whether these mutations have effects on the expression of HPV E6/E7 genes driven by URR, the transient transfection assay was employed using URR-CAT reporter plasmid. The relative activities of three URR mutants from episomal HPV-16 DNA of cervical cancers were two- to fourfold higher than that of the HPV-16 URR prototype. In contrast, the URRs from integrated HPV-16 DNA in cervical cancer and from episomal HPV-16 DNA in CIN, where no mutation of the YY1 binding site was detected, showed similar levels of promoter activity to that of the URR prototype.Conclusions. Our results support the hypothesis that the mutation at the YY1 binding site is functionally related to the development of cervical neoplasia caused by episomal HPV-16 DNA in Korean cervical cancer patients. Thus, mutation in the YY1 site of episomal HPV-16 URR may play a corresponding role of HPV integration in the progression of cervical cancer.

Treatment of cervical intraepithelial neoplasia in a prospective study comparing large-loop excision of the transformation zone, laser vaporization, and knife cone biopsy.

Our aim was to compare cervical intraepithelial neoplasia (CIN) treatment results in the use of large-loop excision of the transformation zone (LLETZ), laser vaporization, and cold-knife cone biopsy. We included in the study patients with CIN lesions diagnosed at the Hospital Universitario Materno-Infantil Vall d'Hebron and Hospital Clinic i Provincial de Barcelona, Barcelona, Spain, between March 1991 and March 1994. Patients with unsatisfactory colposcopy were excluded from the study. One hundred twenty-three patients were included in this study: 98 patients were compared for LLETZ treatment versus laser vaporization, and 69 CIN3 patients were compared for three treatments: LLETZ, laser vaporization, and knife cone biopsy. Patients were followed at 3-month intervals for at least 1 year. Follow-up included physical examination, cervical Papanicolaou (Pap) smear, cervical colposcopy, and a colposcopically guided biopsy when required. Treatment failure (persistence or recurrence) was defined by the presence of CIN confirmed histologically by a colposcopically guided biopsy. The mean age of patients was 34.1 years. The agreement between histology from the colposcopically guided biopsy and the surgical specimen was 60%, and the kappa coefficient was 40.7% (moderate agreement). Three cases of microinvasive carcinoma were diagnosed in patients whose initial diagnosis was CIN3 on colpobiopsy (4% of invasion in the initial CIN3 group of patients). In a comparison of LLETZ with laser treatment for all CIN grades, the unique independent prognostic factor for persistence-recurrence of the disease was the colposcopic size of the primary lesion (relative risk, 4.9; Cl, 1.33-18.45). We conclude that the LLETZ procedure for CIN treatment demonstrates an advantage over destructive methods for detection of occult microinvasive and invasive cancer. This process is a simple outpatient technique with the same failure as that of laser vaporization in all CIN grades. In the treatment of CIN3, cold-knife cone biopsy had better cure rates. Close follow-up is required in these patients, because of their risk of developing recurrent CIN or invasive carcinoma.

Analysis of IgG reactivity against Human Papillomavirus type-16 E7 in patients with cervical intraepithelial neoplasia indicates an association with clearance of viral infection: results of a prospective study.

IgG reactivity against the immunodominant region aa6-35 of Human Papillomavirus (HPV) type-16 E7 was determined in a peptide-based ELISA in a cohort study of women with initial mild to moderate cervical dyskaryosis. On the basis of HPV DNA patterns, as determined by PCR in cervical smears prior to IgG testing, HPV-16-positive patients were grouped as having either a cleared, a fluctuating, or a persistent HPV-16 infection. In a cross-sectional study at the start of serological follow-up, positive IgG reactivities were found more often in the total group of HPV-16-positive patients (20.0%) than in patients consistently typed as HPV-negative over a period of at least 12 months prior to testing (3.1%, p < 0.04). The highest proportion of positive responders was found in patients with a cleared HPV-16 infection (29.4%). Also, IgG reactivities found in HPV-16 clearance patients were significantly higher than in patients with a persistent infection (p < 0.008). In a subsequent longitudinal study over a period of up to 27 months, consistently positive reactivities were observed in patients with cleared viral infections who showed seroreactivity in the cross-sectional study, while mostly negative reactivities were found in patients with viral persistence. HPV-16 E7-specific IgG subclass responses were determined in a selection of 19 CIN and 11 HPV-16-positive cervical carcinoma (CeCa) patients with positive E7-specific IgG responses. IgG2 was predominant in the CIN patients, suggesting the presence of IFNgamma (Th1) at the site of HPV infection. In the CeCa patients IgG1 and IgG2 were produced equally, possibly indicating a rise in Th2 cytokines. Our data suggest that HPV-16 E7 IgG reactivity in a subset of CIN patients with viral clearance may result from successful Th1 responses.

Spezifische serologische Untersuchungen mit einem neuartigen authentischen HPV-Antigen (Virus-like Particles) auf HPV-6 Antikörper bei gynäkologischen Patientenkollektiven

A serological assay for genital HPV infection would provide important additional information to HPV DNA diagnostic methods, since it would evaluate prior exposure to the viruses, detect significant systemic immunologic response to virus infection, and could be performed in most clinical laboratories. Serum samples from three groups of patients attending a gynecology clinic were analysed by direct ELISA for specific IgG antibodies to baculovirus-expressed HPV-6 and BPV-1-L1-VLPs. Positive IgG reactivity to HPV-6-L1-VLPs were 4/72 (6%) in a control group, 28/73 (38%) in a condyloma group and 17/62 (17%) in cervical intraepithelial neoplasia patients. Individual IgG ELISA values of condyloma and CIN patients for HPV-6-L1-VLPs demonstrated no correlation to results with BPV-1-L1-VLPs. These data show that HPV-6-L1-VLPs are effective antigens for serological studies and can detect species specific antibodies with important implications for diagnosis, epidemiology, insights to natural course of disease, prognosis and evaluation of vaccination.

Colposcopic Index of HPV and CIN Patients

There were 115 patients who had atypical transformation zone on colposcopic examination which attended this study. This prospective study was held in the author's private colposcopy clinic from July 1, 1989 until December 31, 1991. The colposcopic index was used to describe the colposcopic sign of those lesions and histopathology results were adopted as the gold standard of diagnosis. This colposcopic index had an accuration rate of 95.7% compared to histopathology diagnosis.