Automated assessment of CD8+ T-lymphocytes and stroma fractions complement conventional staging of colorectal cancer.

BACKGROUND: Tumor development is critically dependent on the supporting stroma consisting of inflammatory cells and fibroblasts. This study intended to improve prognostic prediction for early colorectal cancer (CRC) by combined estimation of T-lymphocyte and stroma fractions with conventional markers. METHODS: In total 509 and 1041 stage II/ΙΙΙ CRC from the VICTOR and QUASAR 2 trials were included as a training set and a validation set, respectively. Intratumoral CD8+ T-lymphocytes and stroma were identified and quantified by machine-based learning on digital sections. The primary endpoint was to evaluate the prognostic value of the combined marker for time to recurrence (TTR). FINDINGS: For low-risk patients (n = 598; stage Ⅱ, and stage ΙΙΙ pT1-3 pN1 with neither lymphatic (L-) nor vascular (V-) invasion), low stroma fraction (n = 511) identified a good prognostic subgroup with 5-year TTR of 86% (95% CI 83-89), versus the high stroma subgroup TTR of 78% (HR = 1.75, 95% CI 1.05-2.92; P = 0.029). For high-risk patients (n = 394; stage ΙΙΙ pT3 pN1 L+/V+, pT4, or pN2), combined low CD8+ and high stroma fraction identified a poor prognostic subgroup (n = 34) with 5-year TTR of 29% (95% CI 17-50), versus the high CD8+ fraction and low stroma fraction subgroup (n = 138) of 64% (HR = 2.86, 95% CI 1.75-4.69; P < 0.001). INTERPRETATION: Quantification of intratumoral CD8+ T-lymphocyte and stroma fractions can be combined with conventional prognostic markers to improve patient stratification.

Prognostic value of DNA ploidy and automated assessment of stroma fraction in prostate cancer.

The combination of DNA ploidy and automatically estimated stroma fraction has been shown to correlate with recurrence and cancer death in colorectal cancer. We aimed to extend this observation and evaluate the prognostic importance of this combined marker in prostate cancer. DNA ploidy status was determined by image cytometry and the stroma fraction was estimated automatically on hematoxylin and eosin stained sections in three tumor samples from each patient to account for tumor heterogeneity. The optimal threshold for low (≤56%) and high (>56%) stroma fraction was identified in a discovery cohort (n = 253). The combined marker was validated in an independent patient cohort (n = 259) with biochemical recurrence as endpoint. The combined marker predicted biochemical recurrence independently in the validation cohort. Multivariable analysis showed that the highest risk of recurrence was observed for patients with samples that had both non-diploid ploidy status and a high stroma fraction (hazard ratio: 2.51, 95% confidence interval: 1.18-5.34). In conclusion, we suggest the combination of DNA ploidy and automatically estimated stroma fraction as a prognostic marker for the risk stratification of prostate cancer patients. It may also be a potential generic marker as concurrent results have been described in colorectal cancer.

Revisiting tumour aneuploidy - the place of ploidy assessment in the molecular era.

Chromosome instability (CIN) is gaining increasing interest as a central process in cancer. CIN, either past or present, is indicated whenever tumour cells harbour an abnormal quantity of DNA, termed 'aneuploidy'. At present, the most widely used approach to detecting aneuploidy is DNA cytometry - a well-known research assay that involves staining of DNA in the nuclei of cells from a tissue sample, followed by analysis using quantitative flow cytometry or microscopic imaging. Aneuploidy in cancer tissue has been implicated as a predictor of a poor prognosis. In this Review, we have explored this hypothesis by surveying the current landscape of peer-reviewed research in which DNA cytometry has been applied in studies with disease-appropriate clinical follow up. This area of research is broad, however, and we restricted our survey to results published since 2000 relating to seven common epithelial cancers (those of the breast; endometrium, ovary, and uterine cervix; oesophagus; colon and rectum; lung; prostate; and bladder). We placed particular emphasis on results from multivariate analyses to pinpoint situations in which the prognostic value of aneuploidy as a biomarker is strong compared with that of existing indicators, such as clinical stage, histological grade, and specific molecular markers. We summarize the implications of our findings for the prognostic use of ploidy analysis in the clinic and for the theoretical understanding of the role of CIN in carcinogenesis.