Prediction of Non-Progression in Prostate Cancer Patients under Active Surveillance by DNA-Karyometry

Abstract

The option of Active Surveillance for patients with localized prostate cancer depends on a low Gleason-Score (GS) of 6. Nevertheless about 30%have to face clinical progression within five years.Our hypothesis is that automated measurements of DNA-content of prostate cancer cells yield a DNA-grade of malignancy [1][2][3][4] that is able to predict non-progression of prostate cancers at much higher accuracy than the subjective GS.Nuclear DNA-measurements were performed from cancer tissue in residual biopsy-material of 80 patients from the HAROW-study. Local-and a reference pathologists GSs were available. Follow-up of mean 4,1 years included repeated PSA-values, number and GSs of positive biopsies, clinical stage, and in19cases results from prostatectomies.Reproducibility of GSs was 55% without and 45% with differentiation between 6 and 7a. Progression occurred in 37.5% if upgrade of any inclusion criterion was used as evidence and in 18,8% if only PSA-DT <36 months or upstaging to pT3. Prevalence of DNA-grade 1 was 40%.Sensitivity, specificity and negative predictive value of local pathologists GS, reference pathologists GS and DNA-karyometry were: 0%, 95.0% and 74.0%, 20.0%, 86.7% and 76.5%, 85.0%, 51.0% and 90.6%, if upgrade of any criterion of inclusion was used as evidence of progression and 5.9%, 96.8% and 79.2%, 23.5%, 87.3% and 80.9%, 100%, 50.8% and 100% if only PSA-DT < 36 months and/or upstaging to pT3 were used.Thus, objective automated DNA-karyometry can much more reliably exclude progression of prostate cancers under Active Surveillance within four years as compared with subjective Gleason-scoring.

DNA Karyometry for Automated Detection of Cancer Cells

“…In a previous study on 80 patients, we could prove the superior prognostic validity of an automatically obtained DNA grade of malignancy ( Figure 2 ) in early-stage prostate cancer patients [ 5 ]. During the follow-up period of 4.1 years, the probability to exclude a progression of an untreated, localized prostate cancer under active surveillance was 100% for objective DNA karyometry, but only 80.9% for the subjective microscopic Gleason score [ 6 ]. This means that patients with Gleason score 6 and 7 prostate cancers, who reveal an objectively assessed DNA grade 1 of malignancy, can safely rely on this conservative strategy.…”

“…The software used was that of MotiCyte screener (Version no. 2.3, creator David Friedrich, Aachen, Germany) with digital nuclear classifiers [ 21 , 22 , 23 , 24 , 25 ], specified for effusions [ 4 ], prostate cancers [ 6 ], and oral smears. The classifiers were trained on Feulgen/pararosaniline-stained slides to automatically discriminate normal and abnormal nuclei, lymphocytes, granulocytes, and artefacts (e.g., lytic and defocused nuclei) in oral smears.…”

“…Enzymatic cell separation specimens from needle-biopsies of 80 patients with clinical stage T1a/b and T2a/b prostate cancers, Gleason scores 6 and 7, as described by Böcking et al (2017) [ 6 ], were used. Pararosaniline/Feulgen-stained sedimentation slides were automatically scanned using a MotiCyte-auto (Motic, Xiamen, China).…”

“…In addition to the fact that most cancer cell-positive cytological diagnoses are subsequently validated by histological ones on tissues of the resected respective lesions, the diagnostic accuracy reaches high levels [ 2 , 3 , 4 , 5 ]. Furthermore, objective and prognostically valid grading of the malignancy of special types of cancer, such as the prostate, measuring the DNA content of thousands of cancer cells in enzymatic cell separation specimens, is another task that needs automation of diagnostic cytometry [ 6 ].…”

“…Conventional subjective histologic grading according to Gleason does not provide sufficient safety [ 17 ]. Objective and valid grading of the malignancy of prostate cancers has repeatedly been shown to add relevant prognostic information [ 6 ]. Instead, objective measurement of nuclear DNA in a representative number of cancer cells yields a prognostically valid DNA grade of malignancy [ 18 , 19 ] ( Figure 2 ).…”