Abstract
Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975–1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Independent transcriptomic studies have shown that prostate tumors can be categorized into three roughly common molecular subtypes with different clinical behavior [1, 2]
Cell proliferation was considerably higher in PCS1/luminal B than in PCS2/luminal A, whereas the opposite was seen for tumor cell differentiation [1, 2]
In this paper PSA and Ki67 immunoreactivity was analyzed as surrogate markers for tumor cell differentiation and proliferation, respectively, and combined to differentiate prostate cancer patients managed by watchful waiting into subgroups with different prognosis and, with different biological characteristics with therapeutic implications
Summary
The luminal A like subtype showed signs of luminal cell differentiation and secretory activity (monitored for example by tumor cell PSA synthesis) and low cell proliferation, a phenotype similar to that of the normal prostate epithelium, while the luminal B-like showed signs of luminal cell dedifferentiation, low PSA expression, and high cell cycle activity [6, 7]. These observations in primary tumors and metastases suggest that clinically relevant subgroup of prostate cancer can be defined by exploring markers of cell differentiation and cell proliferation. By using the combinatory PSA and Ki67 staining data, patients were categorized into 4 different groups: (1) PSA high/Ki67 low, (2) PSA high/Ki67 high, (3) PSA low/Ki67 low, and (4) PSA low/Ki67 high, in ways described below
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