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Objective: Knowledge regarding cell biologic characteristics of small solid glandular buds in the prostate and their relationship with branching activity in the human prostate is still fragmentary. Our object was to demonstrate, on the basis of immunophenotype, loci that harbor the potential for branching activity within the adult human prostate., Materials and Methods: Semiserial sectioning was performed on 13 adult prostates in an effort to identify structures in the prostate that could be considered foci of growth. Selected slides were stained with biomarkers for basal/luminal cells (keratins), proliferation (MIB-1), apoptosis inhibitor (bcl-2), intercellular adhesion (E-cadherin), and stromal-epithelial interactions (tenascin-C). Results were compared with fetal and prepubertal human prostates and microdissected rat prostates., Results: Five histologic epithelial structures were identified in 19 paraffin blocks, which on serial sectioning showed morphologic transitions with a common pattern, consisting of reduction in number and caliber of acini until small solid buds of epithelial cells were reached. Immunophenotypically, the small solid glandular buds had a basal-cell keratin phenotype, expression of bcl-2 in virtually all cells, high proliferative activity, prominent intracellular localization of E-cadherin, and enhanced periglandular tenascin-C immunoreactivity. The budding tips in fetal and prepubertal prostates revealed an immunostaining pattern identical to the small solid glandular buds in the adult, but different to the rat prostate., Conclusions: Our data suggest that dispersed small solid glandular buds have a capacity for growth, and as such may be considered foci of resumed reawakening branching activity with in the adult human prostate.

A system for computerised analysis of ultrasonographic prostate images (AUDEX=Automated Urologic Diagnostic EXpert system) for the detection of prostate carcinoma was developed. The ultimate goal is to develop a system that is reliable and non-observer dependent. Results of an earlier study with a small group were encouraging and this study describes the results of the computerised analysis in a larger group. Sixty-two patients who were scheduled to undergo a radical prostatectomy were prospectively analysed. The radical prostatectomy specimens were step-sectioned in the transverse plane, corresponding to the ultrasound pictures. Malignant regions identified by each study were quantified and compared by computer calculation. No correlation was observed between ultrasound analysis and pathology result. For the AUDEX analysis an overall sensitivity of 85% and a specificity of 18% with only a diagnostic accuracy of 57% was noticed when presence or absence of malignancy was evaluated by octant (total 496). When applying a cut-off value of 0.5 ml the numbers were 71%, 33% and 55%, respectively. Correlation was significantly better for the ventral octants. In this study the earlier results of our AUDEX system could not be confirmed. Although sensitivity was good, specificity and especially diagnostic accuracy were lower than expected. We have to conclude that the current settings are inappropriate for routine clinical use. Prostate Cancer and Prostatic Diseases (2001) 4, 56-62

The progression of carcinomas is associated with the loss of epithelial morphology and a concomitant acquisition of a more mesenchymal phenotype, which in turn is thought to contribute to the invasive and/or metastatic behavior of the malignant process. Changes in the expression of cadherins, "cadherin switching," plays a critical role during embryogenesis, particularly in morphogenetic processes. Loss of E-cadherin is reported to be associated with a poor prognosis; however, thus far, evidence (R. Umbas, et al., Cancer Res. 54: 3929-3933, 1994) for up-regulation of other cadherins has only been reported in vitro, ie., we have found evidence (M. J. G. Bussemakers et al., Int. J. Cancer, 85: 446-450, 2000) for cadherin switching in prostate cancer cell lines (up-regulation of N-cadherin and cadherin-11, two mesenchymal cadherins, in cell lines that lack a functional E-cadherin-catenin adhesion complex). Here, we report on the immunohistochemical analysis of the expression of N-cadherin and cadherin-11 in human prostate cancer specimens. N-cadherin was not expressed in normal prostate tissue; however, in prostatic cancer, N-cadherin was found to be expressed in the poorly differentiated areas, which showed mainly aberrant or negative E-cadherin staining. Cadherin-11 is expressed in the stroma of all prostatic tumors, in the area where stromal and epithelial cells are found. In addition, cadherin-11 is also expressed in a dotted pattern or at the membrane of the epithelial cells of high-grade cancers. In a number of metastatic lesions, N-cadherin and cadherin-11 are expressed homogeneously. These data raise the possibility that cadherin switching plays an important role in prostate cancer metastasis.

Aims: Investigation of the histopathological changes in prostatectomy specimens of patients with prostate cancer after high intensity focused ultrasound (HIFU) and identification of immunohistochemical markers for tissue damage after HIFU treatment., Methods: Nine patients diagnosed with adenocarcinoma of the prostate underwent unilateral HIFU treatment seven to 12 days before radical prostatectomy. The prostatectomy specimens were analysed histologically. Immunohistochemical staining and electron microscopy were performed to characterise more subtle phenotypic changes., Results: All prostatectomy specimens revealed well circumscribed HIFU lesions at the dorsal side of the prostate lobe treated. Most epithelial glands in the centre of the HIFU lesions revealed signs of necrosis. Glands without apparently necrotic features were also situated in the HIFU lesions, raising the question of whether lethal destruction had occurred. This epithelium reacted with antibodies to pancytokeratin, prostate specific antigen (PSA), and Ki67, but did not express cytokeratin 8, which is indicative of severe cellular damage. Ultrastructural examination revealed disintegration of cellular membranes and cytoplasmic organelles consistent with cell necrosis. HIFU treatment was incomplete at the ventral, lateral, and dorsal sides of the prostate lobe treated., Conclusions: HIFU treatment induces a spectrum of morphological changes ranging from apparent light microscopic necrosis to more subtle ultrastructural cell damage. All HIFU lesions are marked by loss of cytokeratin 8. HIFU does not affect the whole area treated, leaving vital tissue at the ventral, lateral, and dorsal sides of the prostate.

To analyse the origin of multifocal prostate cancer lesions, radical prostatectomy specimens from 17 patients were examined. As a marker of genetic lineage, the allelotype based on 33 microsatellite loci was compared between the different tumours present in a given case. Some results provide evidence suggestive of a clonal origin of multiple tumours in a subset of the prostates. In five cases, for example, comparison of multifocal tumour lesions within a given case revealed at least two concordant changes in allelic imbalance (AI) sequence dosages at different loci. In addition, considerable heterogeneity of allelotype was found within and among tumour foci of a given case. In five of the six tumours analysed for intratumour heterogeneity, for example, more than five discordant AI changes were found in one tumour region but not in the other. Conclusions regarding the clonality of such heterogeneous lesions are difficult to draw. A high frequency of AI changes in four lesions exhibiting prostatic intraepithelial neoplasia (mean 6.5 changes per lesion, range 3-6) was found, compared with eight primary tumours present in the same cases (mean 5.8 changes per lesion, range 3-6). The interpretation of AI associated with clinically detected prostate cancer remains a highly complex issue. The fact that no clear evidence was obtained for either a clonal or a non-clonal origin of multiple lesions in a given prostate indicates that several different mechanisms are likely to operate in establishing the allelotype and that additional evidence from unique mutations or selective gene inactivation may be necessary to obtain definitive results., (Copyright 1999 John Wiley & Sons, Ltd.)

Background: High-intensity focused ultrasound (HIFU) consists of focused ultrasound waves emitted from a transducer that are capable of inducing tissue damage. Experimental studies have shown clear damage of malignant tissue exposed to HIFU, but knowledge of in vivo effects is limited. We studied the safety and efficacy of HIFU in patients with a T1-2 N0) M0 prostate carcinoma., Methods: HIFU treatment was performed under general anesthesia with the Ablatherm device (Technomed Medical Systems, Lyon, France), 7-12 days prior to radical prostatectomy. Only the lobe in which carcinoma was confirmed was treated. The radical prostatectomy specimen was examined histopathologically, and the changes were compared with treatment goals., Results: So far, 9 patients have been treated. On histology, a sharp delineation was noted between areas treated with HIFU and untreated areas. On the dorsal border, however, incomplete destruction of tissue was noted, and in 2 cases a small residual tumor was seen in this region. In all cases complete necrosis was seen in the treated region., Conclusions: Histology reports of radical prostatectomy specimens of patients operated 7-12 days after HIFU treatment showed marked and complete necrosis in the treated area. Due to incomplete tissue destruction at the dorsal side, however, a small focus of residual vital tumor was found in 2 of 9 patients.

Purpose: Sampling error is an inherent problem of prostate biopsy. Consequently the determination of whether a given carcinoma is clinically significant based on biopsy results is problematic. We assess the dimensions of sampling error and, thereby, provide insight into the potential value of prognostic markers applied to needle biopsies., Materials and Methods: We constructed 3-dimensional computer models of 21 prostatectomy specimens, including outlines of carcinomas, regions of abnormal E-cadherin expression and individual Gleason patterns. The 6 random systematic core biopsy technique and modifications were simulated using a computer algorithm., Results: In 6 of 21 cases the area of abnormal E-cadherin expression and/or high grade carcinoma was not sampled on 6 random systematic core biopsy. The areas missed were either small or inconsistently under sampled regions of the prostate. Modifying the placement of biopsy needles improved the detection of these features. In addition, percent tumor in the needle appeared to be well correlated to percent tumor in the prostate (r = 0.891, r2 = 0.642)., Conclusions: To avoid underestimating the aggressiveness of prostatic carcinoma at least 6 biopsies should be taken from each patient. A more extensive sampling is probably not warranted in all patients but it may prove useful in those in whom extent of disease is unclear or whose general health makes treatment decisions difficult. A reliable estimate of tumor volume in the prostatectomy specimen can be made based on relative amount of tumor in the biopsy specimen on an individual basis.

Background: Tenascin (tenascin-C) has been suggested to be associated with active epithelial-stromal interactions. We evaluated tenascin expression in tissue remodelling processes presumably associated with PIN and prostate carcinoma (PCa)., Materials and Methods: Tenascin immunoreactivity was evaluated in 38 PIN lesions (low-grade = 5, high-grade = 33) from 27 paraffin-embedded PCa specimens, and compared with expression in pre-existent (normal) prostate, benign prostatic hyperplasia (BPH), and PCa., Results: Periepithelial stromal tenascin expression was low in low-grade PIN, and similar to normal glands and BPH, whereas expression in high-grade PIN was high and partly overlapped that of well-/moderately differentiated PCa. High-grade PCa usually expressed little, if any tenascin., Conclusions: The variable periglandular tenascin expression in high-grade PIN may reflect the biologic behaviour of this lesion, and may be indicative of variable levels of tissue remodelling. In well/moderately differentiated PCa tenascin expression levels may be an indicator of tumour progression.

Conventional fixation of large solid surgical specimens is a slow process. Consequently, autolytic damage to tissues may occur if the fixative does not reach the central part of the specimen in time. However, as there is also a time relationship between formalin fixation and antigen masking, fixation for too long can also be detrimental. In seeking the optimum balance for fixation, microwave irradiation might be of assistance. This study set out to evaluate methods for fixing entire prostate glands within a brief period of time, using microwave-stimulated formalin fixation. The results show that entire prostates can be optimally fixed if formalin is present throughout the tissue as the temperature is increased by microwave irradiation. This is achieved by injecting the fixative into the prostate at multiple sites immediately following prostatectomy. The technique described ensures standardization of a critical step during tissue processing, leading to uniform microscopic results with both routine and immunohistochemical stains. It is a simple, rapid method, suitable for routine diagnostic use. Using this modified approach, DNA of much larger sizes can be extracted from paraffin-embedded material, which could expand the possibilities for molecular analysis.

Purpose: To assess whether a TurboFLASH (fast low-angle shot) magnetic resonance (MR) sequence can improve the accuracy of fast spin-echo (SE) endorectal coil MR imaging in the staging and localization of prostate cancer., Materials and Methods: In 57 patients with prostate cancer, MR imaging was performed with the following sequences: T1-weighted SE, T2-weighted fast SE, single-section gadolinium-enhanced dynamic subtracted TurboFLASH (one image every 1.25 or 2.5 seconds), and late-phase gadolinium-enhanced T1-weighted SE. Retrospectively, two blinded independent readers graded onset and steepest slope of enhancement and assessed tumor involvement and capsular penetration. MR findings were correlated with histopathologic results., Results: On TurboFLASH images, prostate cancer was characterized by early and rapidly accelerating enhancement compared with that of surrounding tissues. Average sensitivity, specificity, and accuracy for detection of tumor involvement for the two readers with TurboFLASH images were 73.5%, 81.0%, and 77.5%. These values with fast SE images were 57.5%, 80.5%, and 72.0%. Depiction of capsular penetration and delineation and staging of tumor were better when TurboFLASH images were included with fast SE images. Differences between the two sequences, however, were not statistically significant., Conclusion: Because the TurboFLASH sequence did not statistically significantly improve tumor localization and staging results, routine use is not recommended. The technique may be useful for selected patients with equivocal evidence of capsular penetration.

Background: Recently the potential of magnetic resonance (MR) methods for non-invasive diagnosis and therapy evaluation of prostate cancer has improved substantially. In this study proton MR spectroscopy (1H MRS) was explored for the detection of cancer in the prostate., Patients and Methods: Employing an endorectal probe localized 1H MRS and contrast enhanced MR imaging was performed on the prostate of healthy volunteers and of patients with benign prostatic hyperplasia (BPH) and/or prostate cancer (PCa)., Results: 1H MR spectra of the human prostate showed major signals for citrate, creatine and choline compounds. For cancer tissue the average citrate/choline signal ratio was significantly lower than for BPH and non-cancerous peripheral and central zone tissue, but individual ratios overlapped with ratios for normal central zone and BPH tissue. Low citrate/choline ratios in tumour tissue correspond with early MR contrast enhancement., Conclusions: 1H MRS has potential for non-invasive detection and follow-up of tumours in the prostate.

Amyloid deposits within the seminal vesicles are a common finding at autopsy. The incidence increases with age. Amyloid deposits can mimic tumor extension into the seminal vesicles due to prostate or bladder cancer on T2-weighted MR images. We describe a case of seminal vesicle amyloidosis demonstrating the MR appearance and the characteristic pathologic findings. Recognizing seminal vesicle amyloidosis may prevent overstaging prostate cancer on MR images.

In order to understand the clinical and biological implications of prostate cancer multifocality and heterogeneity, we investigated their occurrence in relation to variables such as tumour volume, local invasion, and biopsy findings. In a series of 61 completely sectioned whole-mount radical prostatectomy specimens with clinical stage T2 prostate cancer, we mapped histological grade heterogeneity and tumour multifocality. We also evaluated 55 prostate biopsy cases to assess the accuracy of pre-operative grading. Among all of the prostates, only 28 per cent had a single tumour and in 16 per cent one histological grade of cancer was evident. Extracapsular invasion was not restricted to the largest tumour in each case, but also occurred in tumours of relatively small volume and low histological grade. Variability of histological grade was directly proportional to tumour volume. Both grade heterogeneity and tumour multifocality of the prostatectomy specimen showed no significant relationship to the grade accuracy of biopsies. Biopsy grading error proved greatest among small, well-differentiated, tumours. Whole-mount sectioning of prostatectomy specimens in patients with clinically localized adenocarcinoma demonstrates that grade heterogeneity is most closely related to tumour volume; that the largest (index) tumour lesion may not be representative of the pathological stage; and that grading error in prostate needle biopsies can be only partly explained by grade heterogeneity or tumour multifocality.

Objective: To evaluate the accuracy of MR imaging of the prostate with an endorectal surface coil in determining presence, localization, volume, and local stage of prostate carcinoma., Subjects and Methods: MR images of 34 patients with biopsy-proven cancer were correlated retrospectively with the histologic mappings of radical prostatectomy specimens. The volume and number of tumor lesions of MR images were calculated and compared with the surgical specimens used as the gold standard. Tumor stage based on MR imaging was compared with the pathologic stage according to the TNM classification. Predictive values were calculated separately for all lesions and for the lesions correctly localized with MR imaging., Results: MR imaging correctly depicted the location of 67% of the tumors. Twenty percent of the lesions depicted by MR imaging appeared to be false-positive errors. The tumors that were missed were located centrally and ventrally in the prostate. Tumor volume as shown by MR imaging was within a 25% range of the actual tumor volume in 10 cases, overestimated in 16 cases, and underestimated in eight cases. Histopathology showed capsular penetration in 12 of 34 patients (35%) and in 14 of 52 lesions (27%). Sensitivity, specificity, and positive predictive values were 43%, 84%, and 55%, respectively. Histologically, capsular penetration extended less than 1 mm into the periprostatic adipose tissue in seven patients. Sensitivity for capsular penetration less than 1 mm was 14%. Sensitivity for capsular penetration more than 1 mm was 71%. Accuracy for differentiating a pT2 from a pT3 tumor was 68%., Conclusion: Results from this study indicate that the accuracy of the technique was not satisfactory for predicting actual tumor volume. Tumor detection and localization was more accurate in the peripheral zone than in the central zone. Accuracy was poor for detecting capsular penetration of less than 1 mm, but accuracy was much better for penetration of more than 1 mm. Because recent reports suggest that capsular penetration of less than 1 mm does not adversely affect surgical cure, MR imaging still may be practical in the selection of patients for radical prostatectomy.

Staging prostate cancer is a systematic classification of the extent of disease based on clinical and pathological criteria. Despite general acceptance of the TNM staging system, a lot of controversy and uncertainty with respect to staging still exists. This paper gives an overview of different staging modalities and emphasizes the need for incorporation of prognostic factors, such as tumour grade and volume, in the staging system.