Molecular Biomarkers & Histopathological Parameters
in Prostate Cancer Diagnostics & Prognostics
Acta Universitatis Tamperensi
s No. 1620

By Teemu Tolonen
September 2011
Tampere University Press
Distributed by Coronet Books
ISBN: 9789514484667
172 pages
$85.00 Paper original

A prostate needle biopsy is one of most common types of samples that pathologists use to diagnose a malignancy. The main aims of this study were to investigate the mechanisms leading to multifocal prostate cancer and to identify new diagnostic methods and prognostic markers for prostate needle biopsies.

Prostatic adenocarcinoma is an architecturally diverse tumor that typically shows multifocal growth and several grades. Multiple tumor nodules may arise either from microscopic infiltrations of the primary cancer focus or are more likely de novo. Apoptosis is also involved in the development of prostate cancer. We studied apoptosis regulation in general, with a special emphasis on its role as a possible mechanism underlying multifocality. All essential histological features of the prostate specimen were sampled using tissue microarrays. The expression of two important regulators of apoptosis, BAX and BCL-2, was immunohistochemically studied in 1182 foci representing morphologically normal epithelium of cancerous prostates, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, adenocarcinomas (grades 1 to 5), and capsular perineural invasions. BAX expression steadily increased in more malignant phenotypes, while BCL-2 expression was biphasic, with overexpression observed in prostatic intraepithelial neoplasia (PIN) and in poorly differentiated cancers.

Interestingly, both proteins were overexpressed in a subset of morphologically normal foci of cancerous prostates, but not in controls or in cases of hyperplasia. This observation is consistent with the field-effect theory, which may explain the multifocality observed in prostate cancer. Currently, 4000-5000 patients are diagnosed with prostate cancer in Finland annually, most of whom are identified by frequent prostate specific antigen (PSA)-testing of asymptomatic men. Prostate cancer is diagnosed from needle biopsies, and an increasing number of biopsies with small foci and atypical features are a diagnostic challenge for pathologists. The vast majority of prostate cancers are adenocarcinomas, making routine application of immunohistochemistry possible. The impact of routine, dual-color immunostaining (2IHC) on diagnostic sensitivity and pathologists’ workloads was examined using interval sections from 200 prostate needle biopsies. In our 2IHC staining protocol, the neoplastic epithelium was visualized with a blue chromogen, and the basal cells were stained brown. Our results suggest that routine 2IHC leads to increased sensitivity and efficiency in cancer detection. Most of the small cancers detected with the aid of 2IHC were low-grade (75 %), but a number of very small foci with poorly differentiated cancer (25 %) were also observed. No minimal criteria for a definitive cancer diagnosis, however, have been established.

In addition to the biological changes observed in more recently diagnosed prostate cancers, the Gleason classification system of needle biopsies underwent major refinements in 2005. We studied the prognostic value of the modified Gleason score (GS) and other histopathological features of needle biopsies from 247 patients who were primarily endocrine-treated. Hematoxylin and eosin (H&E)-stained slides were scanned, and the evaluation of the digitalized slides was performed using a web-based virtual microscope. Our results show that the modified GS is one of the strongest independent prognostic factors for primarily hormone-treated patients. Moreover, we show that both the worst GS in a single biopsy and the overall GS performed equally well as prognostic factors. In addition, the new recommendations lead to an increase in GSs in general, and the use of modified the GS may have shifted the cut-off between low- and high-grade cancer from GS 6 vs. 7 to GS 3+4 vs. 4+3. Local spreading of prostate cancer usually occurs through the prostatic capsule in the perineural space. More than three foci of perineural cancer invasion in the biopsies independently predicted recurrence of the disease in hormone-treated patients. In addition, the expression of three promising biomarkers predictive of survival (EZH2, Ki-67, and MCM7) was analyzed with the aid of digital image analysis. In patients with GS 7, a Ki-67 labeling index greater than 10 % distinguished patients with an early PSA recurrence. In conclusion, new diagnostic applications and prognostic tools for prostatic needle biopsies were identified. These methods will hopefully be useful to pathologists in the PSA era.


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