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New imaging techniques are more sensitive in prostate cancer and reveal sites of disease that may never have been seen with conventional imaging, resulting in stage migration and potentially a change in the clinical management. Until long-term data provide a better understanding of the natural history of the disease defined by more sensitive imaging, patients and clinicians should recognise the considerable uncertainty about whether these improve outcomes. It is hoped that the next iteration of the TNM classification will recognise the problem in some way.

Background: In prostate cancer (PCa) screening men and their physicians aim to rule out the presence of potentially life threatening PCa. To date, prostate specific antigen (PSA) testing and systematic prostate biopsy (Bx)-in case of an elevated PSA-are still the main modes of PCa detection. Often uncertainty remains when a PSA-test is < 3.0 ng/mL or a Bx shows a benign result, leading to the continuous repeating of procedures. Here we assess the potential consequences of false negatives by studying follow-up data of a purely PSA-based approach with applying sextant Bx, an approach considered to have a high risk of missing PCa diagnosis. Methods: Our study population consisted of 19,970 men from the ERSPC project section Rotterdam, initially screened in 1993-1999. We assessed clinically significant Gleason ≥3+4 PCa (csPCa) diagnosis within the 4-year screening interval and subsequent screening round 4 years later in men having a PSA < 3.0 ng/mL at initial screening (no Bx) and men with Bx (PSA > 3.0 ng/mL), but no PCa detected at that time. In addition, we addressed PCa mortality and PCa diagnosis for men with a negative PSA test and negative Bx, who were retested every 4 years covering a 15-year follow-up. Results: A total of 14,935 men had PSA < 3.0 ng/mL in the initial screening round, of whom 75 (0.5%) were diagnosed with csPCa at a subsequent screening examination and 2 ( < 0.1%) in the 4-year screening interval. For 2,260 men with a previously negative Bx at first screening, the figures were 17 (0.8%) and 2 (0.1%) respectively. Indolent PCa (Gleason ≥3+3) was diagnosed in 312 (2%) men with PSA < 3.0 ng/mL initially and 115 (5%) men with initial negative Bx. After a 15-year follow-up, 45 (0.3%) PCa deaths occurred in men with initially low PSA, and 29 men (0.2%) had metastasis. For men with negative Bx, 11 (0.5%) PCa deaths occurred and 4 (0.2%) experienced metastasis. Conclusions: The false negative rates for men with PSA < 3.0 ng/mL and negative sextant Bx are extremely low but not negligible. Proper risk stratification before deciding to biopsy is expected to hardly miss any clinical significant PCa diagnosis. This is especially relevant with the increased use of the relatively expensive multi-parametric magnetic resonance imaging (mpMRI) guided targeted Bx procedures.

The localization and intensity of androgen receptor immunostaining was studied in the testes of 37 subfertile men with oligozoospermia and normal serum gonadotropin levels using a polyclonal antibody raised against a synthetic peptide corresponding to the first 20 N-terminal amino acid residues of the androgen receptor (AR). Furthermore, we investigated whether or not the immunoexpression of the AR in human Sertoli cells, in histologically normal testis tissue, is dependent on the stage of the spermatogenic cycle, as has been found in the rat. In the human testis, AR immunoexpression was observed in Sertoli cells, peritubular myoid cells, Leydig cells, and periarteriolar cells, but not in germinal cells. We found no evidence for a stage-dependent immunoexpression of AR in Sertoli cells. The intensity of AR immunoexpression varied substantially between biopsy specimens of different patients. There was, however, no correlation of the intensity of AR immunoexpression in either Sertoli cells or peritubular myoid cells with spermatogenic adequacy as measured by the method of Johnsen. When, in this study, the intensity of peritubular myoid cell staining was used as a standard to evaluate the intensity of Sertoli cell staining, no correlation was detected as well. Furthermore, serum gonadotropin levels were not correlated with AR immunoexpression levels in Sertoli cells and peritubular myoid cells. These results indicate that immunodetectability of the AR is not related to the condition of the spermatogenic epithelium in patients with oligozoospermia. Inappropriate expression of the AR is neither a cause nor a consequence of idiopathic infertility in the present group of patients

Heterogeneity in human androgen receptor (hAR) expression in prostate cancer is considered to be implicated in tumor progression. hAR expression was therefore studied immunohistochemically in localized and locally progressive, hormone refractory (HR) prostate cancer. Because altered functional activity of the hAR may be due to changes in the structural integrity of the hAR gene, exons 2 to 8 of the hAR gene were assessed for mutations by single-strand conformation polymorphism (SSCP) analysis and exon 1 was analyzed for the size of the CAG repeat. The hormone binding capacity, a prerequisite for ligand-regulated receptor function, was determined by a ligand binding assay. Coexpression of the hAR and prostate-specific antigen (PSA) was studied by a sequential double immunoenzymatic staining to verify whether PSA expression is a parameter of hAR function. Almost all human prostatic carcinomas revealed heterogeneous hAR expression, regardless of tumor differentiation and progression. Putative predominance of hAR-negative tumor areas in HR prostate cancer was not observed. No hAR gene mutations or major changes in the CAG repeat were found in the 18 HR carcinomas or in the 9 control samples. Moreover, all selected hAR-expressing cancers were able to bind the synthetic androgen methyltrienolone (R1881). Immunoenzymatic double staining revealed even PSA expression in hAR-negative tumor areas. PSA immunohistochemistry in human prostatic carcinomas therefore is of no use in determining hAR functional activity. Thus, most prostatic carcinomas, even when progressed to a state of hormone insensitivity, contain a structurally intact hAR gene, heterogeneously expressed with retained androgen binding capacity.

The reactivity of 33 choroidal and ciliary body melanomas with monoclonal antibody Ki-67, which recognizes a proliferation associated nuclear antigen, has been assessed and compared with clinicopathologic parameters. In 23 cases, 8 Gy irradiation was given 2 days before enucleation. Nonirradiated melanomas had a significantly higher proliferation rate as defined by staining with monoclonal antibody Ki-67 as compared with irradiated tumors (P = 0.007). Similarly, a strong relationship was found between pre-enucleation irradiation and low mitotic activity (P = 0.001). There was no significant correlation between the presence of Ki-67-positive nuclei and histologic classification, largest tumor diameter, localization of the tumor, age, sex, scleral invasion, pigmentation, and lymphocytic infiltration. The relevance of Ki-67 immunohistochemistry for the assessment of the life prognosis of patients with uveal melanoma has to be studied prospectively