Identification of cervical HSILs that regress
Identification of cervical HSILs that regress
Many women get HSIL=Cervical Intraepithelial Neoplasia=CIN caused by Human Papilloma Virus (HPV). Operation can have side effects and overtreats the CINs disappearing spontaneously. To prevent overtreatment, we study if biomarker proteins identify regressive CINs.
The first study investigated whether a correlation exists between spontaneous regression if the CIN23, resection margin status and length of the biopsy-cone excision interval. This was done as some doctors believe that “regression” does not exist, and disappearance of the CIN lesion in the follow-up is due to the fact that the punch biopsy has completely removed the CIN. If this is true, the presence of abnormal CIN cells in the resection margins of the biopsies would be associated with more frequent “persistent” of CIN. If, however, regression is an active process caused by the immune system of the patient, regression would increase with increasing biopsy-cone interval. Our results favour the hypothesis that CIN3 can regress spontaneously, possibly due to an immune response, and the results do not support the “curative punch biopsy” theory.
The second study analysed whether biomarkers expression in CIN3 can predict whether the disease is much more advanced than it looks like, and has already settled high up in the endocervical canal. If this is the case, and it is not removed, the effects for the patients can be disastrous as the (hidden) pre-cancer cells then can grow secretly and be even much more advanced when they are finally detected. This is of course very bad for the patient. Indeed, the biomarker proteins identified patients with endocervical neoplasia. This study has been accepted for publication in an international high-ranking journal (Kruse AJ, Skaland I, Munk AC, Janssen EAM, Gudlaugsson E and Baak JPA. LOW P53 AND RETINOBLASTOMA PROTEIN EXPRESSION IN CERVICAL INTRAEPITHELIAL NEOPLASIA GRADE 3 LESIONS IS ASSOCIATED WITH COEXISTENT ADENOCARCINOMA IN SITU. Hum Pathol, Accepted for Publication, September 3 2007) (expected to be published in May 2008).
In the third subproject of the study we study whether immune-reactive cells in CIN lesions collaborate with the epithelial protein biomarkers to induce regression.
This study is the most difficult, as very many patients must be analyzed to get good material, for the following reasons. In most operation materials, the tissue is good enough for a diagnosis, but not for a detailed analysis of many other cell characteristics. Moreover, the orientation of the tissues is not usually standardized in pathology laboratories in Norway, which is a serious disadvantage. Finally, many tissue blocks have been totally used to make microscopic sections. We solved this as follows. First, we searched the database from the Pathology department of the Stavanger University Hospital between 1987 and 2001 for the histological diagnosis CIN3. From the 2773 records, the following patients were excluded: double patients, patients with unknown follow-up, original histology diagnosis differed from CIN3 (coding errors), patients with a sampling method different from small biopsy, no follow-up. This left 399 patients. Of these, 308 had samples which were of adequate size in the original H&E section. Many patients had a punch-cone biopsy interval of less than 100 days (for follow-up studies, this is too short). These patients were excluded as well, leaving 184 patients. From the paraffin blocks, for immunohistochemistry 4µm sections were cut in series, and for HPV detection we used 5x 5µm sections. For the statistical analyses we included patients with adequate quality of the immunohistochemical stainings (n=150), and at the moment have analyzed 50 patients. From these cases the punch and cone slides were carefully revised and patients were classified as regression (CIN-1 or less in the cone biopsy) or no-regression (all others). Twelve patients (23%) regressed.
The preliminary results point to a synergistic effect between epithelial protein biomarkers and certain subpopulations of immune-reactive cells in predicting patients which regress. These findings must be confirmed in the other 100 patients, which should be ready by the summer 2008. However, in agreement with a previous study, HPV-genotype had no prognostic significance in this small retrospective study.
Cervical intraepithelial neoplasia grade 3 lesions can regress.
APMIS 2007 Dec;115(12):1409-14.