Biological behavior of CIN lesions is predictable by multiple parameter logistic regression models.

OBJECTIVES: Progression and regression of premalignant cervical lesions cannot be predicted using conventional cytomorphological or histomorphological parameters. However, markers such as human papillomavirus (HPV) or makers indicating proliferation, genetic instability and chromosomal aberration may be of predictive value assessing short-term biological behavior of cervical intraepithelial neoplasia. In this paper, we have studied the usage of logistic regression models with Ki-67 labeling index (LI), chromosome index for chromosome 1 (CI#1) and aneusomy for chromosome 1 in cervical smears to predict progressive and regressive behavior of premalignant cervical lesions. METHODS: Retrospectively, the intake smears of 42 women showing regression in follow-up and of 31 women showing progression in follow-up were assessed. RESULTS: A multiparameter logistic regression model containing the parameters Ki-67 LI, CI#1 and the fraction of cells with four copies of chromosome 1 per nucleus appeared to be the best predicting model, overall correct classification of 93.2% (area under the receiver operating characteristic curve 0.96 +/- 0.02). After cross-validation, the model correctly classified 66 of 73 samples (90.4%). Moreover, the model predicted biological behavior perfectly assessing the smear taken subsequently to the intake smear of 46 women. CONCLUSION: Although measuring parameters indicating proliferation and chromosome 1 aberration is laborious, this study demonstrates that short-term progressive and regressive behavior is highly predictable using a model combing these parameters. We also showed that in the triage management of high-risk human papillomavirus-positive women with minimally abnormal smears applying a model as such can be useful.

Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways.

Two separate pathways leading to vulvar carcinoma have been suggested. First, a human papillomavirus (HPV)-dependent pathway, in which premalignant stages of vulvar cancer are the classic vulvar intraepithelial neoplasia (VIN) lesions. Second, an HPV-independent pathway, associated with differentiated VIN III lesions and/or lichen sclerosus. To obtain insight into the mechanisms underlying these pathways, we determined the relationship between HPV DNA and the expression of p14(ARF) and p16(INK4A) in non- and (pre)malignant vulvar lesions. Seventy-three archival samples of non- and (pre)neoplastic vulvar lesions were selected and tested for hr-HPV DNA using a broad-spectrum HPV detection/genotyping assay (SPF(10)-LiPA) and the expression of p14(ARF) and p16(INK4A). The prevalence of HPV increased with the severity of the classic VIN lesions; in VIN I no hr-HPV was detected, in VIN II 43%, and in VIN III 71% of the samples were hr-HPV-positive. Roughly the same was true for the expression of p14(ARF) and p16(INK4A). The simultaneous expression of p14(ARF) and p16(INK4A) was highly associated with the presence of hr-HPV DNA. Hr-HPV was detected in only a single case of the differentiated VIN III lesions, whereas no expression of p14(ARF) was found and 16(INK4A) was present in only two cases. All 16 samples of vulvar cancer were hr-HPV DNA- negative, although in respectively 63% and 25%, p14(ARF) and p16(INK4A) was expressed. No relation was found between hr-HPV and the expression of p14(ARF) and p16(INK4A) in the 20 nonneoplastic vulvar lesions. Our results provide further evidence that vulvar squamous cell carcinoma is a multifactorial disease that develops from two different pathways. First, an HPV-dependent pathway with a remarkable resemblance to CIN lesions and cervical carcinoma and second, an HPV-independent pathway in which differentiated VIN III lesions that are hr-HPV-negative may be precursors.