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In recent years, the pathological evaluation of prostate biopsy specimens has made great improvements in diagnostic accuracy and comprehensiveness. In this article, we review major pathological findings on prostate biopsy, their interpretation and reporting, as well as their clinical significance and utility. We discuss especially the clinically relevant histological features in either a positive or negative biopsy. We emphasize that both Gleason score and extent of cancer involvement in a needle core biopsy are important predictors of clinical outcome after either radical prostatectomy or radiation. Special issues regarding diagnosis and grading of minimal cancer on needle core biopsies are discussed. We also highlight the current standards on high-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation on needle core biopsies. In summary, the pathology reports on needle biopsies are far beyond the simple presence or absence of cancer; they contain invaluable information to clinicians on patient management and counseling.

Background: Maspin, a novel serine protease inhibitor, has been shown to inhibit prostate tumor cell motility and invasion in vitro and to inhibit prostate tumor growth and metastasis in vivo. Maspin expression in high-grade prostate carcinoma (PC) is reduced compared with that in low-grade PC. Interestingly, however, compared with low-grade PC, benign secretory prostate epithelial cells express significantly less maspin. This observation appears paradoxical to a putative tumor suppressive role of maspin in prostate carcinogenesis, and this finding issue needs to be clarified., Methods: We examined maspin expression simultaneously in benign basal cells, benign secretory cells, high-grade prostate intraepithelial neoplasia (HGPIN), low-grade PC, and high-grade PC in 46 radical prostatectomy specimens plus 51 autopsy prostate glands by a combination of immunohistochemistry and in situ hybridization., Results: Benign basal cells consistently expressed maspin at a high level. In PC, the loss of basolateral maspin expression coincides with loss of the basal cell layer. Maspin expression in secretory cells, on the other hand, appears to undergo a biphasic differential regulation, i.e., essentially absent in benign secretory cells, dramatically up-regulated in HGPIN, then progressively down-regulated through low-grade PC to high-grade PC. Maspin expression in PC is inversely correlated with tumor grade. Furthermore, maspin expression in HGPIN is inversely correlated with the Gleason's grade of the adjacent PC., Conclusions: An up-regulation of maspin expression precedes, rather than occurs at, the critical transition from premalignant prostate lesion of HGPIN to PC. Our data suggest maspin may mark an important transitional phase and play an important role in the premalignancy of the prostate gland., (Copyright 2002 Wiley-Liss, Inc.)

The marked discrepancy between the prevalence of preclinical prostate cancer and the incidence of clinically manifest disease indicates a long latency phase and significant heterogeneity in the progression potential of early neoplastic lesions. There are a variety of histologic changes within prostatic epithelium that have been termed atypical or dysplastic. The 2 most widely studied of these lesions are prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH). Although associations between AAH and adenocarcinoma are spurious, those linking high-grade PIN (HGPIN) to cancer are far more established. There is a significantly increased risk for patients with isolated HGPIN to have prostate cancer confirmed on subsequent biopsy, suggesting that HGPIN is a marker for prostate carcinoma in addition to its potential role as a premalignant lesion. Autopsy studies reveal that HGPIN is found in association with cancer in 63% to 94% of malignant and 25% to 43% of benign prostates. Data on age and race reveal that African American men develop more extensive HGPIN at a younger age than white men. A wide spectrum of molecular/genetic abnormalities appears to be common to both HGPIN and prostate cancer. Data loss of 8p, 10q, 16q, 18q, and gain of 7q31, 8q, multiple copies of the c-myc genes, along with changes in chromatin texture, telomerase activity, cell cycle status, and proliferative indices collectively suggest that HGPIN is intermediate between benign epithelium and prostatic carcinoma with respect to these markers. These data indicate that HGPIN is important in neoplastic progression, and may present an appropriate target/marker for chemoprevention.

Neoadjuvant hormonal therapy (NHT) induces morphologic changes in prostate adenocarcinoma that result in the assignment of higher Gleason scores on average than in pretreatment biopsy specimens. This outcome has led to the recommendation that the Gleason scoring system not be applied to prostate adenocarcinoma specimens after NHT. We reviewed the radical prostatectomy specimens of 116 patients who had received NHT. Gleason scores were assigned on the post-treatment specimens by applying the usual criteria; in addition, an estimated pretreatment Gleason score was assigned on the basis of knowledge of the morphologic alterations associated with NHT. Finally, an estimate of the degree of therapy effect was assigned: little or no evidence of hormonal effect (grade 1) to marked therapy-related changes (grade 3). Both the post-treatment and the estimated pretreatment Gleason score correlated significantly with biochemical progression (P = 0.03 and P = 0.03, respectively; log-rank test). The degree of therapy effect did not correlate with progression (P = 0.46; log-rank test). This limited analysis suggests that despite the morphologic alterations induced by NHT, post-treatment Gleason score remains a significant prognostic measure. Further studies in more uniformly treated populations are required to confirm this observation.

Purpose: Investigators who have examined age specific reference ranges recommend a higher prostate specific antigen (PSA) cutoff for biopsy for black than for white men older than 50 years. We controlled for PSA to determine whether age specific reference range cutoffs for diagnosis defined by the Walter Reed Army Medical Center group (Walter Reed group) would improve the disproportionate prostate cancer prognosis between black and white men., Materials and Methods: We studied 651 consecutive patients who underwent radical prostatectomy at Wayne State University between 1991 and 1995 with a mean followup of 34 months (range 1.5 to 75). Log rank tests were used to determine the homogeneity of survival functions between black and white men with similar PSA ranges, and between groups defined by age specific PSA reference ranges for each race., Results: Disease stage and grade were similar or worse in black men for any PSA range, and biochemical disease-free survival was similar or worse within each range. Black men had a higher percentage of high grade prostate cancer than white men 60 to 69 years old who would not have undergone biopsy using the Walter Reed group proposed PSA cutoff., Conclusions: Black men have similar or worse prostate cancer severity and outcome than white men with similar PSA ranges. Using age specific reference ranges for the PSA test defined by the Walter Reed group, black men have worse outcome than white men after radical prostatectomy. Therefore, we recommend that the PSA cutoff for biopsy should not be higher for black men at any age range.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a known activator of latent MMP-2 (pro-MMP-2), and increased MMP-2 expression has been associated with tumor aggressiveness in prostate cancer. However, expression of MT1-MMP in human prostate tissue has not been described. We investigated the expression and immunolocalization of MT1-MMP and MMP-2 in the epithelial components of benign prostate epithelium, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate cancer. Tissue sections from the peripheral zone of 50 prostates (radical prostatectomy specimens) were chosen based on their containing benign glands, HGPIN, and prostate cancer glands. All 50 sections were immunostained for MT1-MMP and MMP-2 and were evaluated for staining pattern, uniformity, and intensity. Western blotting and gelatin zymography were done to confirm expression of MT1-MMP and activity of MMP-2, respectively. Comparisons were made between benign epithelium, HGPIN, and cancer. In benign glands, basal cells (BCs) uniformly stained intensely for MT1-MMP, whereas secretory cells (SCs) were rarely positive (P < 0.0001). Conversely in HGPIN, SCs showed consistent cytoplasmic staining (P < 0.0001). In cancer cells, staining was heterogeneous and varied from no staining to very intense staining in select glands. MMP-2 in normal tissue stained both BCs and the apical region of SCs, whereas in HGPIN, staining was observed in the SC in a predominantly cytoplasmic pattern. Similar to MT1-MMP, staining in cancer tissue for MMP-2 was heterogeneous; however, there was a significant association between the pattern of MMP-2 and MT1-MMP staining within the epithelial components of the cancer glands in individual specimens (P < 0.001). Finally, MMP-2 and MT1-MMP were confirmed to be expressed in the prostate tissues by gelatin zymography and Western blotting. In conclusion, we found that consistent changes in localization and intracellular distribution of MMP-2 and MT1-MMP were associated with the transition from benign prostate epithelium to HGPIN, suggesting that regulation of these enzymes is altered during the earliest stages of prostate cancer.

This article addresses the handling, processing, and reporting of radical prostatectomy specimens with the goal of providing general guidelines and practical suggestions for the surgical pathologist. During the last decade, pathologists in academic and community institutions have witnessed a surge in the number of radical prostatectomy specimens evaluated in their departments. Unlike the relative familiarity most pathologists have with other major oncologic resections, radical prostatectomy specimens present an interesting and occasionally frustrating challenge with respect to gross evaluation, sampling, and reporting.

Background: We previously reported that African-American men (AAM) have tumors located in the anterior compartment more often than American Caucasian men (ACM) in radical prostatectomy specimens [Tiguert et al.: Prostate 37:230-235, 1998]. In this study, we evaluated the distribution of glandular tissue in the anterior compartment of normal prostate specimens, with specific attention to the anterior fibromuscular area, in order to determine the frequency and origin of glands in this region., Methods: We analyzed 94 prostatectomy specimens obtained from autopsied men between ages 20-30 years. Men in this age group were chosen because few pathological changes are present in the prostate in this age range. The anterior compartment of the prostate was defined by drawing a horizontal line, anterior to the urethra, through the midpoint of the anterior-posterior diameter parallel to the rectal surface. In each slide, anterior compartment prostatic tissue was identified and characterized as peripheral zone, transitional zone, and fibromuscular stroma. Any glandular elements identified in the anterior prostatic compartment were recorded in terms of zonal origin and number of glands., Results: Prostates from 76 AAM and 18 ACM were examined. Overall, prostatic glands were absent in the anterior compartment in only 2% of cases. Glands were derived from the peripheral zone only in 6 (6.5%) cases, peripheral zone and transitional zone in 53 (56.5%), transitional zone only in 13 (14%), and anterior fibromuscular stroma in 20 (21%). There was no difference between the two races in terms of the number of glands present. The morphology of the peripheral zone was not different between the two races, with glands from the peripheral zone joining in the anterior compartment in 33% of AAM compared to 56% of ACM (P = 0.123)., Conclusions: Anterior prostatic glands can arise from the peripheral zone, transitional zone, or fibromuscular stroma. There are no racial differences in terms of the number of anterior glandular elements, and also in the architecture of the peripheral zone.

Objective: To summarize studies that have investigated the morphologic, spatial and volumetric relationship between prostate cancer and its putative precursors, high grade prostatic intraepithelial neoplasia (HGPIN) and atypical adenomatous hyperplasia (AAH)., Methods: Studies addressing the relationship between morphologic parameters of prostate cancer (i.e., stage, grade, volume and anatomic distribution) and both HGPIN and AAH are reviewed. Similar data based on our institutional experience with surgical and autopsy series of step-sectioned, totally embedded prostate glands are also presented., Results: Most investigators have demonstrated significant associations between HGPIN and carcinoma in terms of coexistence, "zonal" origin and physical proximity. The two lesions have a high tendency to be present simultaneously; both originate predominantly in the peripheral zone and are often found within the same microscopic field. Reports on the relationship between HGPIN and the stage of prostate cancer are less consistent, and the associations of this lesion with cancer grade and volume are exceedingly complex. HGPIN appears to be associated with moderately to poorly differentiated, smaller, often-multifocal tumors and is less frequent in large, high grade cancers. There are data suggesting a trend-of a reciprocal relationship between more extensive and diffuse HGPIN and large-volume prostate cancers. Conversely, there is a wide spectrum of volume distribution of the two lesions in glands harboring smaller tumors. Similar data concerning AAH are limited., Conclusion: There are strong and consistent data supporting various aspects of the morphologic associations between HGPIN and prostate cancer. The indications that glands harboring larger tumors tend to contain less extensive HGPIN could raise the hypothesis that as carcinoma becomes larger, it may replace areas of the gland previously occupied by HGPIN. Alternatively, prostate cancer can evolve from ducts with HGPIN and gradually overgrow their precursor. There is a relative dearth of similar information concerning AAH.

Background: The pathophysiology of increased color Doppler (CD) flow has not previously been addressed in histologic evaluations of microvascular parameters. In this study, the authors attempted to define the differences between benign and malignant biopsy cores found in regions of the prostate with normal and high CD flow., Methods: Forty patients were retrospectively chosen for CD histologic comparison, each of whom had a core from a sextant biopsy with the following characteristics: malignant tissue with distinct increased CD flow (n=11), malignant tissue with normal CD flow (n=10), benign tissue with distinctly increased CD flow (n=9), or benign tissue with normal CD flow (n=10). All biopsy cores were stained with factor VIII-related antigen to identify microvasculature and to determine the number of microvessels per square millimeter (mm2) in an average cross-sectional area of microvessels, the percentage of tissue occupied by microvasculature, and the Gleason score., Results: In biopsies of benign tissue, high CD flow was associated with greater numbers (P < 0.025) of vessels of similar size than in normal flow benign biopsies. Biopsies of malignant tissue contained significantly greater numbers (P < 0.01) of much smaller vessels (P < 0.0005) than biopsies of benign tissue. In biopsies of malignant tissue, no significant differences in microvasculature parameters were noted between high and normal CD flow, yet biopsies with high CD flow had average Gleason score of 6.7 compared with only 5.9 for biopsies with normal CD flow (P < 0.025)., Conclusions: Increased CD flow in biopsies of benign tissue was correlated with a greater number of vessels/mm2, yet all biopsies of malignant tissue had more vessels/mm2 than those of benign tissue. Increased CD flow in biopsies of malignant tissue cannot be explained by standard microvasculature analysis but significantly guides biopsies to regions with a greater Gleason score.

Research into molecular and cellular defects underlying prostate cancer would be advanced by in vitro models of prostate tumor cells representing patient tumors. We have propagated, in serum-free medium, epithelial cell cultures derived from nondiploid prostate tumors and normal human prostate. The serial passage tumor cells exhibited nondiploid karyotype and transformed phenotypes of focus formation and anchorage-independent growth. In contrast, the normal prostate cells showed diploid karyotype and lacked transformed phenotypes. Both the tumor and normal cells were positive for prostate-specific antigen and cytokeratins 18 and 19 and negative for keratin 15. These results demonstrate that the nondiploid prostate tumors and normal prostate epithelial cell cultures retained their respective in vivo properties and should allow studies to elucidate molecular alterations involved in human prostate cancer.

Because of a lack of information of the optimum nutritional requirements, epithelial cells derived from normal human prostate and prostate tumors have been difficult to propagate in vitro, which hinders research in prostate carcinogenesis. In an effort to establish optimum nutritional conditions and differences in growth characteristics of normal human prostate (NP), benign prostatic hyperplasia (BPH), and prostatic carcinoma (PCA), we have compared the effects of several growth factors on cell proliferation and elucidated growth properties of low passage epithelial cells derived from NP, BPH, and PCA of an African-American patient. Primary and low passage cultures were propagated in serum-free keratinocyte basal medium (KBM) supplemented with insulin (5 micrograms/ml), hydrocortisone (0.5 microgram/ml), epidermal growth factor (EGF, 10 ng/ml), bovine pituitary extract (BPE; 50 micrograms/ml), cholera toxin (10 ng/ml), and antibiotics. Almost all NP, BPH, and PCA cells were positive for cytokeratins and prostate-specific antigen (PSA). The NP, BPH, and PCA cells were essentially diploid and lacked mutations in c-K-ras and c-Ha-ras oncogenes, and p53 tumor suppressor gene. However, they exhibited progressively accelerating growth parameters. The population doubling times of NP, BPH and PCA were 51 hr, 37 hr, and 29 hr, respectively; their saturation densities were 2.9 x 10(4)/cm2, 3.3 x 10(4)/cm2, and 7.2 x 10(4)/cm2, respectively. The NP and BPH cells required all of the growth factors in the medium, as deletion of any one of the above factors strongly inhibited their growth. The PCA cells, however, were independent of EGF and hydrocortisone. PC-3, an established human prostate cancer cell line, was independent of the growth factors tested. Fetal bovine serum (FBS) inhibited the growth of NP, BPH and PCA cells. In contrast, FBS stimulated the growth of the PC-3 cells in a concentration-dependent manner. These results indicate that in the absence of any apparent karyotype alterations and mutations in c-K-ras, c-Ha-ras and p53 genes, epithelial cells derived from NP, BPH, and PCA exhibit significant differences in their growth properties and responses to growth factors. These variations may represent early changes involved in prostate cancer, while gene mutations and cytogenetic alterations occur in advanced and/or metastatic tumors.

Aims: To study the prevalence, extent and evolution of high-grade prostatic intraepithelial neoplasia (HGPIN) in African-American and Caucasian men of a wide age range in order to help clarify the role this lesion may play in the racial differences of prostate cancer., Methods: The lesion was documented in step-sectioned, entirely submitted prostates of two study populations: 525 autopsied men who died of trauma and 1,000 patients who had retropubic radical prostatectomy for clinically localized carcinoma of the prostate., Results: We found that HGPIN starts in young individuals and increases progressively with advancing age in both races but is more prevalent in African-Americans. Additionally, the more extensive form of HGPIN with multifocal or diffuse involvement of the gland appears at a younger age in African-Americans., Conclusions: Microscopic foci of HGPIN can be documented in males in the 3rd and 4th decades with the lesion becoming more extensive in older men. The finding that HGPIN is both more prevalent and its more diffuse form appears earlier in African-Americans, indicates a potentially important role for this lesion in the race-related discrepancies associated with this disease.

In order to more clearly define the status of epidermal growth factor receptor (EGFR) in prostate cancer, expression of EGFR transcript and protein was analyzed in paired samples of benign and malignant tissues from 30 radical prostatectomy specimens. Prostate tumors and high grade prostatic intraepithelial neoplasias (PINs) expressed significantly less EGFR protein than benign tissues or low grade PINs (P < 0.001). Expression of EGFR mRNA was analyzed in a subset of the same samples, and was higher in more prostate tumors than benign specimens (P < 0.05). However, differences in mean mRNA expression between malignant and benign tissues were not significant. EGFR mRNA was expressed at moderate or low levels in equivalent numbers of PIN lesions. These results suggest that, although EGFR mRNA expression is somewhat elevated in prostate tumors, EGFR protein expression may be down-regulated in the same malignant tissues. Furthermore, our data demonstrate phenotypic similarity between prostate tumors and high grade PIN at the level of EGFR protein expression.

Background: DNA ploidy analysis has been investigated as a prognostic indicator in prostate cancer. Most of the data is derived from retrospective studies using paraffin-embedded tissue. This method has drawbacks related to the quality of DNA histograms and uncontrolled data collection., Methods: DNA ploidy analysis of freshly resected prostatic tissue was prospectively compared with conventional prognostic variables in 97 men treated with radical prostatectomy for localized prostate cancer., Results: Regarding the patients, 31.9% were African American and 66% had pathologic Stages C or D1 disease. Only 9.6% of patients with Stages A2 and B had a prostate-specific antigen (PSA) value greater than 10 ng/ml, whereas 97% of patients with PSA values greater than 20 ng/ml had pathologic Stages C and D1. PSA levels correlated with Gleason score (P = < 0.05); 51% and 100% of patients with Gleason score 5-7 and 8-10, respectively, had PSA values greater than 10 ng/ml. Twenty-two patients (23%) had DNA aneuploid tumors. Comparisons of mechanical to enzymatic cell suspensions indicated that DNA aneuploidy was better preserved in mechanical cell preparations. DNA ploidy correlated with pathologic stage (P = < 0.05) and Gleason score (P = < 0.05). Fifteen of 79 patients (18.9%) with Gleason score 5-7 had DNA aneuploid tumors versus 71.4% of patients with Gleason score 8-10. PSA groups correlated with ploidy status (P = 0.01). Although the majority of patients (19 of 22) with DNA aneuploid tumors had elevated preoperative PSA levels, none had a PSA value greater than 50 ng/ml., Conclusions: DNA ploidy analysis correlated with established prognostic indicators in prostate cancer; however, its independent correlation with natural history and treatment outcome must be established for it to have an effect on therapeutic decisions.

Human papillomavirus (HPV) infections are strongly linked to the pathogenesis of uterine cervical neoplasms, and have been implicated in other cancers of the female genital tract. In contrast, the association of HPV with the cancers of the male urogenital tract is less evident, except in anal and penile cancers. However, recent studies reporting the prevalence of HPV infections in human prostate cancers (60-100% HPV 16 positive vs. no infection of HPV) have raised controversies regarding the prevalence of HPV in benign and neoplastic human prostate. We investigated the prevalence of HPV infections in prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinomas in 23 surgically resected prostates. Polymerase chain reaction (PCR) was used to amplify HPV 6b/11, 16, and 18 specific DNA sequences, using type specific HPV primers selected from the transforming gene E6-E7. The areas of PIN and cancer in 6 microns H&E stained tissue sections were identified, and respective areas of PIN and cancer were isolated from the adjacent serial sections and used for DNA amplification and HPV detection (Fig. 1). Our results demonstrated the presence of HPV 16 in three carcinomas (13%), using type specific primers in PCR amplified samples. We were not able to demonstrate the presence of other HPV types (HPV 6b/11 or HPV 18) in any of the samples using specific primers. Two of these prostates showed relatively strong positive signals by dot blot analysis, when hybridized with a 32P-labeled HPV 16 type specific oligonucleotide probe. One more sample showed weak positivity, when hybridized with a 32P-labeled HPV 16 type specific oligonucleotide probe. Subsequently, we have confirmed these results by Southern hybridization of the samples transferred to nylon membrane after agarose gel electrophoresis and detected by HPV 16 type specific oligonucleotide probe, using chemiluminescent assay. We, therefore, conclude that HPV infections of the prostate in general are not as common as has been previously claimed by other investigators.

Tumor differentiation and proliferative activity are important predictors of biological behavior. While routine histological evaluation is fairly adequate to assess differentiation, tumor proliferative activity is difficult to measure. Silver staining for nucleolar organizer regions (AgNORs) is reported to be helpful for assessing tumor proliferation. We investigated the AgNOR counts in 20 formalin fixed, paraffin embedded human prostate tissues in three microscopic fields of 330X, using an image analysis system. A total of 200-700 nuclei were evaluated on histologically controlled areas of nonneoplastic prostate tissue, prostatic intraepithelial neoplasia (PIN), and invasive carcinoma. The values were compared to flow cytometrically obtained synthesis phase fractions (SPF) and immunohistochemically semi-quantitated, proliferative cell nuclear antigen (PCNA) patterns. AgNOR counts were also compared to tumor stage and Gleason's score. The pattern of PCNA staining in formalin fixed specimens was widely variable, probably due to differences in preservation of antigen. The positive counts varied from 0 to 55%, with a mean value of 8.55 +/- 15.9. The SPF values ranged from 5 to 13% with a mean value of 8.50 +/- 2.37. Two of 20 tumors were aneuploid and 18 were of diploid range. The mean AgNOR values in nonneoplastic nuclei (1.836 +/- 0.299), PIN (3.129 +/- 0.295), and invasive tumor cell nuclei (4.737 +/- 0.369) were highly significant (P < 0.0001) when paired differences were compared. AgNOR counts correlated significantly with tumor Gleason's score (P < 0.0145). However, the correlation coefficient for SPF and AgNOR values was not significant (P > 0.24), possibly because of the small number of samples examined. The highest AgNOR counts were found in the two aneuploid tumors. We conclude that AgNOR count may be a potential indicator of cellular proliferation, and possibly a marker of tumor differentiation.