Three-Tiered versus Two-Tiered Classification of Squamous Dysplasia in Cervical Cytology: Results of a Follow-Up Study.

OBJECTIVE: Regarding cytological findings of squamous dysplasia, a comparison was made between a three-tiered classification - low-grade squamous intraepithelial lesion (LSIL), high-grade SIL/cervical intraepithelial neoplasia 2 (HSIL/CIN2), and HSIL/CIN3 - and a two-tiered classification - LSIL and HSIL. The respective risk for CIN2+ and CIN3+ was calculated to make decisions regarding management. METHODS: A total of 2,949 women with first-time cytologic findings of squamous dysplasia (LSIL, HSIL/CIN2, or HSIL/CIN3) between January 2013 and June 2016 were enrolled. Subsequent cytological findings and histological diagnoses were evaluated until August 2018. For each category of findings, the risk for CIN2+ and CIN3+ was determined by Kaplan-Meier estimates. The differences in risk between the cytological categories were checked for significance using the log-rank test. RESULTS: For the categories LSIL, HSIL/CIN2, and HSIL/CIN3, the risk for CIN2+ after 12, 24, and 60 months was 3.4, 9.4, and 23.3%; 35.2, 44.8, and 59.8%; and 95.5, 97.8, and 98.9%, respectively. For CIN3+ the risk was 2.0, 5.5, and 13.5%; 28.6, 35.6, and 48.3%; 91.3, 95.6, and 97.9%, respectively. The differences in risk between the categories are highly significant, respectively (p < 0.001). CONCLUSION: A three-tiered classification of squamous dysplasia such as the Munich Nomenclature III for cytology is suitable for risk-adapted clinical management, especially to avoid overdiagnosis and overtreatment.

Predictive value of the combined p16 and Ki-67 immunocytochemistry in low-grade squamous intraepithelial lesions.

OBJECTIVE: The reliability of cytological diagnoses, especially for low-grade squamous intraepithelial lesions (LSIL), is limited. This leads to uncertainty in patient management. The application of adjunctive biomarkers is meant to improve this situation. Therefore, we examined the prognostic value of p16/Ki-67 immunostaining of LSIL cytology specimens. STUDY DESIGN: We analyzed the p16(INK4a) and Ki-67 immunocytochemistry (CINtec® PLUS, dual stain) of 260 patients with LSIL. Cytology and dual-stain results were correlated with histology at the time of treatment or with cytological follow-up. RESULTS: After an average duration of 24.9 months (1-58) and a histology rate of 36.2% [cervical intraepithelial neoplasia, grade 2 or higher (CIN2+) as positive], the statistical evaluation for cytology and dual stain resulted in a sensitivity of 98.3 and 90.0%, respectively, a specificity of 74.5% for dual stain, a positive predictive value (PPV) of 22.8 and 51.4%, and a negative predictive value (NPV) of 96.1% for dual stain. CONCLUSION: The combined immunocytochemical investigation of p16(INK4a) and Ki-67 leads to a significantly better PPV and a very good NPV for CIN2+ in LSIL, especially in women 30 years of age and older. An objective individualized prognosis may not be achieved with p16(INK4a)/Ki-67. Statistical data from our study, however, indicate that patient management can be significantly improved by the application of combined p16/Ki-67 immunocytochemistry as an adjunct to cytology.

Persistent carcinoma in cervical cancer screening: non-participation is the most significant cause.

OBJECTIVE: It was the aim of this study to determine the screening history of all invasive cervical carcinomas between 2004 and 2009 in one of the Federal States of Germany. STUDY DESIGN: The pooled data sets of all in-state laboratories, corrected and supplemented by data of the State Cancer Registry, were used. The screening histories of all patients, their age and tumor types were collated and analyzed. RESULTS: Of 617 patients with invasive carcinoma of the cervix, 373 (60%) had not had a cervical smear within the past 5 years. In 188 patients (31%), an incomplete screening history was found, whereas only 9% of women had participated regularly. In non-participants, late tumor stages (stage T1B and higher) were predominant and found in 86%. In contrast, in the group with regular screening histories more than half of all cases (54%) were microinvasive carcinomas (stage T1A) with excellent prognosis. Lack of follow-up or refusal of treatment by patients played a minor yet significant role. CONCLUSIONS: Non-participation is still by far the most common reason for persistent cases of cervical carcinoma in the German screening program.

Nuclear localization and interaction with COP1 are required for STO/BBX24 function during photomorphogenesis.

Arabidopsis (Arabidopsis thaliana) SALT TOLERANCE/B-BOX ZINC FINGER PROTEIN24 (STO/BBX24) is a negative regulator of the light signal transduction that localizes to the nucleus of plant cells and interacts with CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) in the yeast (Saccharomyces cerevisiae) two-hybrid system. The protein contains two B-box zinc-finger motives at the N terminus and a conserved motif at the C-terminal part required for the interaction with COP1. BBX24 accumulates during deetiolation of young seedlings in the first hours of exposure to light. However, this accumulation is transient and decreases after prolonged light irradiation. Here, we identified the amino acidic residues necessary for the nuclear import of the protein. In addition, we created mutated forms of the protein, and analyzed them by overexpression in the bbx24-1 mutant background. Our results indicate that the degradation of BBX24 occurs, or at least is initiated in the nucleus, and this nuclear localization is a prerequisite to fulfill its function in light signaling. Moreover, mutations in the region responsible for the interaction with COP1 revealed that a physical interaction of the proteins is also required for degradation of BBX24 in the light and for normal photomorphogenesis.

Does light taste salty?

As research advances acquisition of new data reveals novel aspects on already investigated issues. This is the case for SALT TOLERANCE (STO), an Arabidopsis protein that confers tolerance to high salt concentrations when ectopically expressed in yeast cells. For the last years, STO was considered to participate mainly in the response and tolerance of Arabidopsis to high salinity, as it does in yeast. However, recent investigations using gain- and loss-of-function mutants revealed a major role for STO as negative regulator of photomorphogenesis. Interestingly, and contrary to other negative regulators of light dependent inhibition of hypocotyl elongation, STO protein instability is controlled by COP1 activity in etiolated seedlings. Thus, light stabilizes STO protein levels during de-etiolation. Whether STO participates in other signaling cascades different from light signaling, as it has been shown in yeast and proposed in plants or not, is still an open question.