No abstract

Observer prognostic variability in staging and grading is considerable with potentially strong implications for patients. Interobserver variation did not decrease using the new 1999 WHO grading classification.

Few sentinel node (SN) studies in ovarian cancer have been reported, mainly because of the risk of tumor dissemination associated with the injection of tracers into the ovarian cortex. To our knowledge, the injection of tracers into the ovarian ligaments has not been explored. The aim of this study was to determine the feasibility of the SN procedure in ovarian cancer with tracer injection into the ovarian ligaments and to establish whether the procedure is safe for the healthcare workers. Methods: The study included patients who were at high risk of ovarian malignancy. Blue dye and radioactive colloid were injected into the proper ovarian ligament and suspensory ligament of the ovary. To measure professional radiation exposure, ring dose meters were worn by the surgeon, theater nurse, and pathologist during 3 procedures. Results: An SN procedure was performed in 21 patients, and at least 1 SN location was identified in all patients using the γ probe before retroperitoneal exploration. SNs were located in the paraaortic and paracaval regions only in 67% of the patients, in the pelvic region only in 9%, and in both the paraaortic/paracaval and the pelvic regions in 24%. All but 2 SNs were found on the ipsilateral side. In 6 patients who underwent retroperitoneal exploration, 1-4 SNs were identified using the γ probe and resected. Blue-stained SNs were detected in 2 patients. Positive SNs were detected in 1 patient with lymph node metastases. The amount of radiation exposure to the surgeon, theater nurse, and pathologist did not exceed the safe limit. Conclusion: The identification of SNs in all cases suggests that the SN procedure performed by injection of tracers in the ovarian ligaments is feasible and promising. The procedure is safe for the involved personnel. Further investigation is necessary to determine the clinical application of this new technique.

Background and Aims:

Fifteen to thirty percent of cases with histologically confirmed CIN2-3 in cervical biopsies regress spontaneously (ie, show CIN1 or less in the follow-up cervical cone). The balance between immune-reactive cells from the host and high-risk human papillomavirus (hrHPV) genotypes may provide a biological explanation for this phenomenon. We retrospectively studied 55 cases of CIN2-3 in a cervical biopsy with subsequent cervical cone to assess whether hrHPV genotypes (by AMPLICOR and Linear Array tests) CD4, CD8, CD25, CD138 and Foxp3 cells (by quantitative immunohistochemistry) in the cervical biopsies can predict regression (defined as CIN1 or less in the follow-up cone biopsy). Eighteen percent of the CIN2-3 cases regressed (median biopsy-cervical cone time interval: 12.0 weeks, range: 5.0-34.1 weeks). HPV-16 correlated with low CD8 þ and high CD25 þ . None of the regressing CIN2-3 lesions contained HPV-16. The regressing CIN2-3 lesions had lower numbers of stromal CD138 þ and higher numbers of stromal CD8 þ cells; higher stromal and intra-epithelial ratios of CD4 þ /CD25 þ cells; higher ratios of CD8 þ /CD25 þ cells and lower ratios ofþ cells in the stroma. With multivariate survival analysis, stromal CD8 þ cell numbers, CD4 þ /CD25 þ cell ratios and CD138 þ cell numbers are found to be independent regression predictors. In conclusion, in non-HPV-16 CIN2-3 lesions, assessing stromal immune cells can be a useful prognostic indicator of regression or persistence.

The most promising cytological biomarkers for cervical cancer screening are p16(INK4a)/Ki-67 dual immunostaining, methylation of CADM1 and MAL and viral integration. Although some of the biomarkers are very promising for this purpose, no studies have evaluated how accurately these biomarkers classify or predict the outcome. Additional clinical trials are needed to determine the true clinical value of these promising cytological biomarkers.

Topical imiquimod could be an alternative, noninvasive, treatment modality for high-grade cervical intraepithelial neoplasia (CIN). However, evidence is limited, and there are no studies that compared treatment effectiveness and side effects of topical imiquimod cream to standard large loop excision of the transformation zone (LLETZ) treatment. A multi-center, nonrandomized controlled trial was performed among women with a histologic diagnosis of CIN 2/3. Women were treated with either vaginal imiquimod (6.25 mg 3 times weekly for 8 to 16 wk) or LLETZ according to their own preference. Successful treatment was defined as the absence of high-grade dysplasia at the first follow-up interval after treatment (at 20 wk for the imiquimod group and at 26 wk for the LLETZ group). Secondary outcome measures were high-risk human papillomavirus (hrHPV) clearance, side effects, and predictive factors for successful imiquimod treatment. Imiquimod treatment was successful in 60% of women who completed imiquimod treatment and 95% of women treated with LLETZ. hrHPV clearance occurred in 69% and 67% in the imiquimod group and LLETZ group, respectively. This study provides further evidence on topical imiquimod cream as a feasible and safe treatment modality for high-grade CIN. Although the effectiveness is considerably lower than LLETZ treatment, imiquimod treatment could prevent initial surgical treatment in over 40% of women and should be offered to a selected population of women who wish to avoid (repeated) surgical treatment of high-grade CIN.

The natural history of high-grade cervical intraepithelial neoplasia (CIN) is largely unpredictable and current histopathological examination is unable to differentiate between lesions that will regress and those that will not. Therefore, most high-grade lesions are currently treated by surgical excision, leading to overtreatment and unnecessary complications. Prognostic biomarkers may differentiate between lesions that will regress and those that will not, making individualized treatment of high-grade CIN possible. This review identifies several promising prognostic biomarkers. These biomarkers include viral genotype and viral DNA methylation (viral factors), human leukocyte antigen-subtypes, markers of lymphoproliferative response, telomerase amplification and human papillomavirus-induced epigenetic effects (host factors) and Ki-67, p53 and pRb (cellular factors). All identified biomarkers were evaluated according to their role in the natural history of high-grade CIN and according to established criteria for evaluation of biomarkers (prospective-specimen-collection, retrospective-blinded-evaluation [PROBE] criteria). None of the biomarkers meets the PROBE criteria for clinical applicability and more research on prognostic biomarkers in high-grade CIN is necessary.