Endometrial carcinoma : prognostic factors and protein expression profiling

Endometrial carcinoma is the most common gynaecological cancer in the western world. It is usually diagnosed at an early stage since it presents with irregular vaginal bleeding when the tumour is still limited to the uterus and the prognosis is generally favourable. However, despite good prognosis in early stage, the majority of relapses occur in stage I since the majority of patients are diagnosed with stage I tumours. The acknowledged prognostic factors, stage, histopathologic subtype and grade are not able to accurately predict which patients are at risk of relapse. Over the years much effort has been made to find better and more objective prognostic factors. The aim of this thesis was to add knowledge to this subject.

DNA ploidy, MIB-1 and p53 have been studied in 376 patients, stages I-IV, from the Stockholm Gotland region, who were consecutively admitted to Radiumhemmet with endometrial carcinoma during 1994-95. DNA ploidy performed by image analysis was found to be an independent prognostic factor of relapse free survival (RFS) (p=0.003) as well as stage (p< 0.001) and histopathologic subtype (p=0.002). Both MIB-1 and p53 were analysed by immunohistochemistry and were found to be prognostic factors in univariate analysis, but not in multivariate analysis.

DNA ploidy, MIB-1 and p53 were also separately studied in the 284 surgical stage I patients. In multivariate analysis, aneuploidy (p=0.001) and non-endometrioid subgroup (p=0.004) were the only significant predictors of poor prognosis. In the surgical stage I endometrioid subgroup DNA ploidy was the only independent predictor of prognosis (p=0.001). As in the previous study both MIB-1 and p53 were significant prognostic factors in univariate analysis but not in multivariate analysis. The acknowledged prognostic factor of myometrial invasion had no prognostic impact on disease-free survival in these patients, who were treated with adjuvant radiotherapy.

Immunohistochemical expression of the invasion marker Laminin-5 gamma 2 chain was evaluated in 80 endometrial tumours. The Laminin-5 gamma 2 chain has to our knowledge not been studied in endometrial cancer previously. The results showed that the majority of endometrial tumours expressed the Laminin-5 gamma 2 chain (68/80). In univariate analysis this was a prognostic factor of cause-specific survival (p=0.0 17) but not in multivariate analysis. There was no correlation with stage, histopathology, grade or DNA ploidy.

By 2 dimensional gel electrophoresis the protein expression pattern of five samples of normal endometrium, eight diploid endometrioid carcinomas and seven aneuploid tumours (three endometrioid and four uterine papillary serous cancers) were studied. There were distinct separate protein expression patterns in these three groups - normal endometrium, endometrial carcinoma of low (diploid) and high (aneuploid) malignancy potential. Fifty-two proteins were able to provide three separate clusters representing normal endometrium, diploid and aneuploid tumours. These 52 proteins have the potential to be used as a prognostic marker-panel for endometrial cancer in the future.

List of scientific papers

I. Lundgren C, Auer G, Frankendal B, Moberger B, Nilsson B, Nordstrom B (2002). "Nuclear DNA content, proliferative activity, and p53 expression related to clinical and histopathologic features in endometrial carcinoma. " Int J Gynecol Cancer 12(1): 110-8
https://pubmed.ncbi.nlm.nih.gov/11860545

II. Lundgren C, Auer G, Frankendal B, Nilsson B, Nordstrom B (2004). "Prognostic factors in surgical stage I endometrial carcinoma. " Acta Oncol 43(1): 49-56
https://pubmed.ncbi.nlm.nih.gov/15068320

III. Lundgren C, Frankendal B, Silfversward C, Nilsson B, Tryggvason K, Auer G, Nordstrom B (2003). "Laminin-5 gamma2-chain expression and DNA ploidy as predictors of prognosis in endometrial carcinoma. " Med Oncol 20(2): 147-56
https://pubmed.ncbi.nlm.nih.gov/12835517

IV. Lundgren C, Lahmann J, Becker S, Roblick U, Schedvins K, Boman K, Frankendal B, Nordstrom B, Auer G (2004). "Protein expression in endometrial carcinoma." (Submitted)