In urothelial cell type non-muscle invasive urinary bladder carcinoma, TNM stage and WHO grade are widely used to classify patients into low and high-risk groups for prognostic and therapeutic decision-making. However, stage and grade reproducibility and prediction accuracy are wanting. This may lead to suboptimal treatment. We evaluated whether proliferation features, nuclear area of the epithelial cancer cells and the composition of stromal and tumor infiltrating lymphocytes have independent prognostic value. In 183 primary non-muscle invasive bladder cancer patients with long follow-up (median for stage progression cohort: 119 months, range 5-173; median for tumor recurrence cohort: 82, range 3-165) proliferation features Ki67, PPH3 and Mitotic Activity Index (MAI), Mean Nuclear Area (MNA), lymphocyte subsets (CD8+, CD4+, CD25+) and plasma cells (CD138+) were assessed on consecutive sections. Post-resection instillation treatments (none, mitomycin, BCG) were strictly standardized during the intake period. Risk of recurrence was associated with expression of Ki67 (� 39 vs. > 39) and Multifocality (p = 0.01). Patients with low Ki67 had a higher recurrence rate than those with high Ki67. Lymphocyte composition did not predict recurrence. Stage progression was strongly associated with high values for MAI (>15) and CD25+ (>0.2%). In a multivariate analysis the combination of MAI and CD25+ was the single most prognostic feature (p<0.001). Validation of these results in additional, independent studies is warranted.
BackgroundThe major cause of cervical intraepithelial neoplasia (CIN) is persistent infection with human papillomavirus (HPV). Most CIN grade 2 and 3 lesions are treated with cone excision, although a substantial proportion (6-50%) of CIN2-3 lesions will regresses spontaneously. Predictors for regression of CIN2-3 are desirable in order to reduce this overtreatment.MethodsIn this prospective cohort study, 145 consecutive women with first-time onset CIN2-3 in colposcopy-directed biopsies and standardized biopsy-cone excision interval were included. The genotype of the high-risk human papillomaviruses (=hrHPV) and clinical factors including sexual behaviour, parity, contraception and smoking were assessed. Patients were divided into two groups according to lesions containing HPV16 (hrHPV16+) and high-risk non-HPV16 (hrHPV16-) genotypes.ResultsWomen whose partners consistently used condoms showed a significantly higher regression rate than women using other types of contraception (53% versus 13%, p<0.0001). However, this effect was only seen in hrHPV16- patients (73% regression rate versus 13%, p<0.0001). HrHPV16+ patients had a significantly higher number of sexual partners and more current smokers compared to hrHPV16- patients. The regression rate was not significantly different in CIN2-3 lesions containing HPV16 (hrHPV16+) versus hrHPV16- genotypes.ConclusionsHeterogeneity among hrHPV genotypes excists. HPV-genotype analyses can identify women who significantly increase their chance of regression by consistent condom use.
Protein expression of Myristoylated alanine-rich C kinase substrate like-1 (MARCKSL1) has been identified as a prognostic factor in lymph-node negative (LN-) breast cancer patients. We aim to validate MARCKSL1 protein expression as a prognostic marker for distant metastasis-free survival (DMFS) in a new cohort of LN- breast cancer patients. MARCKSL1 expression was evaluated in 151 operable T1,2N0M0 LN- breast cancer patients by immunohistochemistry. Median follow-up time was 152 months, range 11–189 months. Results were compared with classical prognosticators (age, tumor diameter, grade, estrogen receptor, and proliferation) using single (Kaplan-Meier) and multivariate (Cox model) survival analysis. Thirteen patients (9%) developed distant metastases. With both single and multiple analysis of all features, MARCKSL1 did not show a significant prognostic value for DMFS (p = 0.498). Of the assessed classical prognosticators, only tumor diameter showed prognostic value (hazard ratio 9.3, 95% confidence interval 2.8–31.0, p <0.001). MARCKSL1 expression could not be confirmed as a prognostic factor in this cohort. Possible reasons include changes in diagnostic and treatment guidelines between the discovery and validation cohorts. Further studies are needed to reveal the potential biological role of this protein in breast cancer.
Urothelial carcinoma is the most common type of carcinoma of the urinary bladder in the Western world. Currently TNM stage and WHO grade are the most important histopathologic parameters to classify patients into low- and high-risk groups and to decide appropriate treatment. However, as differentiating between stage Ta and T1 on surgical specimens is difficult and grade has only poor to fair reproducibility, these parameters do not precisely predict tumor recurrence or stage progression. As a consequence, patients undergo an intensive follow-up regimen and as such the treatment cost per patient for bladder cancer is one of the highest among all cancer types. Therefore, better prognostic and predictive markers are warranted. The aim of the present study was to clarify whether CD8+, CD4+, CD25+, and/or CD138+ immune cell markers, as well as quantitative features Ki67, mitotic activity index (MAI), and mean nuclear area of the 10 largest nuclei (MNA), can identify non-muscle invasive bladder cancer (NMIBC) patients at high risk for tumor recurrence and stage progression. Tissue samples from 183 patients diagnosed with primary NMIBC were obtained by transurethral resection of the bladder (TURB) or from biopsies. Sections were stained by immunohistochemistry using monoclonal antibodies for T lymphocyte subsets (CD4+, CD8+, and CD25+), plasma cells (CD138+) and Ki67. MAI and MNA were assessed on HES (hematoxylin, erythrosine, and saffron) stained sections. A highly reproducible, interactive image analysis system was used for quantification of all immune cell markers and Ki67. MAI and MNA were counted manually. Out of all the investigated markers, only Ki67 showed significance with tumor recurrence (95% CI, 0.4-0.9; p=0.05) in a 10-year follow-up. The group with high Ki67 (>39%) had significantly longer recurrence-free survival than the group with lower values. Furthermore, out of all the examined immunologic markers, only CD25+ was significantly associated with stage progression in a survival analysis (95% CI, 1.8-106.2; p=0.001). The group of patients with high CD25+ (>0.24%) had significantly shorter progression-free survival than the group with lower values. The median values of MAI and CD25+ were significantly higher in pT1 tumors than pTa tumors (median 16.0, 2.5 for MAI and 0.1%, 0.95% for CD25+ respectively; p<0.001). In univariate analysis age, WHO73, WHO04, Stage, MAI10, and CD25 were all correlated with significant differences in progression-free survival. Furthermore, using survival analysis, the combination of MAI and CD25+ could define a group of patients with 100% (N=81/183) progression-free survival (95% CI, 1.6-4.1; p<0.001). In a multivariate analysis including (age, WHO73, WHO04, combination CD25/MAI10), the combination of CD25/MAI10 was the single most prognostic feature. In conclusion, our study suggests that MAI and CD25+ could be used to identify NMIBC at risk for progression of disease. In addition, Ki67 could be a candidate for assessing the risk of recurrence in NMIBC. This abstract is also being presented as Poster A06. Citation Format: Melinda Lillesand, Vebjørn Kvikstad, Ok Målfrid Mangrud, Einar G. Gudlaugsson, Bianca van Diermen-Hidle, Ivar Skaland, Jan P.A. Baak, Emiel A.M. Janssen. Can immunologic biomarkers (CD4/CD8/CD25/CD138) predict tumor recurrence and progression in NMIBC? [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR03.
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