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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.

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Objective: Immunochemical detection of the protein p16^INK4a in cervical cytology is used in combination with Ki-67. Cells positive for both proteins are certain to have been transformed by high-risk HPV. p16/Ki-67 immunocytochemistry provides a significant improvement in specificity over cytology and HPV DNA testing. However, p16/Ki-67 immunocytochemistry also has its limitations. Study Design: The research is based on the follow-up of 1,131 patients for whom p16/Ki-67 immunocytochemistry was performed with cytology. Dependencies on the age of patients with LSIL, number of p16/Ki-67-positive cells, and different results during repeated examinations were analyzed. Results: In LSIL, positive p16/Ki-67 is less specific for ≥CIN2/HSIL for patients younger than 30 years compared to patients aged 30 years or older (61.1 vs. 75.7%, p < 0.013). Using a score of 10 p16/Ki-67-marked cells as a positive result instead of 1 led to significantly higher specificity (89.0 vs. 70.2%, p < 0.001). This modified threshold offers better risk assessment in LSIL. In repeated immunocytochemical investigations, 28.4% of the results deviated from the first examination. Conclusion: The abovementioned discrepancies can be interpreted as hints about the molecular biological causes of suboptimal performance of p16/Ki-67. An efficient and reliable application of p16/Ki-67 immunocytochemistry requires knowledge of its methodological limitations.

Regardless of the study designs and significant differences of the resulting statistics in the literature, there is consensus concerning the significantly higher specificity and positive prediction of the p16/Ki-67 immunocytochemistry compared to cytology or HPV DNA test results. Therefore, p16/Ki-67 immunocytochemistry is useful in cases of persistent group IIID1/LSIL and equivocal cytological findings (group III-p/ASC-H). Especially in the former group, the frequency of colposcopic examinations can be reduced. In this respect, adding p16/Ki-67 immunochemistry likely improves patient management. However, an indication for treatment solely based upon a positive immunocytochemical finding is unjustified.

Risikobewertung von Zytologiebefunden im Zervixkarzinom-Screening Mit der ab 2020 gültigen Krebsfrüherkennungsrichtlinie gelten im deutschen Zervixkarzinom-Screening erstmals Algorithmen zur Abklärung auffälliger Befunde. Bisher besteht lediglich Konsens hinsichtlich der Therapiebedürftigkeit einer CIN3 (zervikale intraepitheliale Neoplasie). Das Management bei Zellbildern der Gruppe IIID ebenso wie bei den Gruppen II und III ist durchaus unterschiedlich mit Kontrollzytologie, HPV(humane Papillomviren)-Test, Immunzytochemie und Kolposkopie. Für ein risikoadaptiertes Procedere mit Vermeidung von Überdiagnostik bei Gewährleistung der nötigen Sicherheit für die Patientinnen sollte das Risiko der einzelnen zytologischen Befunde bekannt sein.

The validity of cytological diagnostic procedures for the detection of pre- and early cervical cancer stages is limited due to biological conditions, the uncertainty of cell sampling, and the subjective nature of microscopic assessment. Particularly in class III?D cases (Munich II) this can lead to a stigmatization of patients and uncertainty with regard to further clinical follow-up and therapy. Prior to carrying out additional investigations such as high-risk HPV testing or the examination of biomarkers, the positive predictive values of patients with a class III?D cytological diagnosis need to be assessed in routine practice. To this end, all relevant data from patients from our practice classed as class III?D (pap smears) between 2002 and 2008 (n?=?1190; 38.2?% histological diagnosis = therapeutic endpoint) and their current HPV status were recorded. Cytology, histology, persistence, age and follow-up were recorded. The database was used for comparative statistical analysis. Overall, the positive predictive value of conventional pap smear for CIN 2+ was calculated to be 32.3?% (mean follow-up: 39.7 months). The following values were calculated for high-risk HPV testing: sensitivity 94.8?%, specificity 39?%, positive predictive value 42.8?%, negative predictive value 94?%. The additional information obtained from high-risk HPV testing resulted in a significantly better positive predictive value only in patients older than 40 years. However, there was no evidence for an individual risk stratification approach which would reduce uncertainty in the management of III?D patients.

Especially the cytological diagnoses of mild and moderate dysplasia are often followed by unnecessary stigmatization of patients and uncertainty in further clinical follow-up and therapy. Data from 222 patients including additional investigations by high-risk human papillomavirus (HPV) testing and combined immunocytochemistry for p16(INK4a) and Ki-67 were documented, including cytological and histological follow-up. Overall for cytology, high risk HPV testing and dual staining the following characteristics concerning the presence of cervical intraepithelial neoplasia (CIN) 2+ were calculated (in %): sensitivity 100, 95.8 and 92.4, specificity -, 23.3 and 72.8, positive predictive value 53.6, 59.1 and 79.7, negative predictive value -, 82.8 and 89.3, respectively.There was a statistically significant advantage for higher specificity and positive predictive value for dual staining, especially for cytological diagnosis of low grade dysplasia. An objective individual risk stratification of patients with cytology of mild or moderate dysplasia is not available but the uncertainty in the management of these patients will be clearly reduced.