Reliability of small amounts of cancer in prostate biopsies to reveal pathologic grade.

OBJECTIVES: To examine grade reliability when biopsies contain very small amounts of prostate cancer. Prostate biopsy findings are known to undergrade prostate cancer compared with the pathologic specimens yet remain the only grade guiding disease management. METHODS: The presence of a clinically significant grade change from biopsy cores to matched prostatectomy specimens was examined in 371 patients. The biopsies were characterized for primary and secondary Gleason grade, number of positive cores, and total linear length of cancer. The pathologic specimens were characterized for cancer volume and relative percentage by grade. The rates of upgrading or downgrading were tested against all clinical and biopsy information for any significant predictive value. RESULTS: The overall rate of upgrading was 40.7% and downgrading was 16.1%. Upgrading was constant and independent of any clinical or biopsy tumor volume indexes. Specifically, when cancer was present in only one biopsy core and measured 2 mm or less (n = 48), it was just as predictive of the pathologic grade as that from any greater number of positive cores and any greater extent of cancer length present. Downgrading was less frequent for biopsies with small amounts of cancer. CONCLUSIONS: Histologic grading from small amounts of cancer in prostate biopsies is reliable and not more prone to grading errors. A repeat biopsy for these patients may not be indicated.

Preoperative PSA velocity is an independent prognostic factor for relapse after radical prostatectomy.

PURPOSE: Preoperative prostate-specific antigen (PSA) velocity (PSAV), or the rate of PSA rise before diagnosis, predicts for risk of cancer death after radical prostatectomy (RP). We evaluated the relative merit of established preoperative factors, including biopsy indices and preoperative PSAV, for their impact on relapse after RP. PATIENTS AND METHODS: The outcomes of 202 men who underwent RP were reviewed. Biopsies were characterized for grade, percentage positive cores, and total linear tumor length. Surgical specimens were characterized for cancer volume, relative percentage by grade, extracapsular extension, and margin status. Univariate and multivariate analyses were performed with respect to relapse-free survival after RP. RESULTS: Thirty-one patients relapsed after RP (defined as PSA > or = 0.2 ng/mL), with a median time to failure of 16 months. Median follow-up was 48 months. Kaplan-Meier relapse-free survival at 5 years was 89%, compared with 73% for PSAV < or = 2 v > 2 ng/mL/year (P = .003). On multivariate analysis, only the biopsy Gleason sum (P < .008; relative risk, > 4.8) and the preoperative PSAV (P < .04; relative risk, 3.0 to 4.7) remained significant. Patients with a PSAV of > 2 ng/mL/year were more likely to be pT3 (P = .007), have positive margins (P = .01), have tumors > 1 mL (P = .05), and possess > 10% grade 4/5 tumors (P = .04). CONCLUSION: The preoperative PSAV is a significant independent clinical factor predicting for relapse after RP and also predicts for larger, more aggressive, and more locally advanced tumors. Its inclusion will be useful in risk stratification, evaluation for alternatives to surgery, and patient selection for neoadjuvant or adjuvant therapies as part of randomized clinical trials.

Comparative gene and protein expression in primary cultures of epithelial cells from benign prostatic hyperplasia and prostate cancer.

Primary cultures are widely used to investigate the disease-specific biology of prostate cancer and benign prostatic hyperplasia (BPH). To identify genes differentially expressed between epithelial cells cultured from adenocarcinomas versus BPH tissues, we used probe array technology. Gene expression profiles were evaluated on Affymetrix Human Cancer G110 Array Chips containing approximately 1900 cancer-related genes. After defined statistical analysis, genes that were over-expressed in cancer cultures were identified. Protein expression of four of the differentially expressed genes was measured in immunoblots, and the expression of two other genes was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). While no gene or protein was consistently over-expressed in all cancer versus BPH cell cultures, cytokeratin 16 protein was highly elevated in several of the cancer cultures, suggesting that a hyperproliferative phenotype may be characteristic of prostate cancer cells.

Propionibacterium acnes associated with inflammation in radical prostatectomy specimens: a possible link to cancer evolution?

PURPOSE: Inflammation is commonly observed in the prostate gland and has been implicated in the development of prostate cancer. The etiology of prostatic inflammation is unknown. However, the involvement of a carcinogenic infectious agent has been suggested. MATERIALS AND METHODS: Prostatic tissue from 34 consecutive patients with prostate cancer was cultured to detect the presence of bacterial agents. Prostatic inflammation was assessed by histological examination of wholemount tissue sections. RESULTS: The predominant microorganism detected was Propionibacterium acnes, found in 35% of prostate samples. A significantly higher degree of prostatic inflammation was observed in cases culture positive for P. acnes (p =0.007). P. acnes was separated into 3 groups based on cell surface properties, phenotype and genetic grouping. All skin control isolates were classified as group 1 whereas most prostatic isolates were classified as groups 2 and 3. CONCLUSIONS: P. acnes has been isolated from prostatic tissues in men who underwent radical prostatectomy for localized cancer and has been shown to be positively associated with prostatic inflammation. This inflammation may then be linked to the evolution of carcinoma. Furthermore, organisms infecting these patients with prostate cancer differ genetically and phenotypically from the commonly identified cutaneous P. acnes isolates, suggesting that specific subtypes may be involved in development of prostatic inflammation.

Positive family history of prostate cancer not associated with worse outcomes after radical prostatectomy.

OBJECTIVES: To determine the clinical outcomes in men with (FH) and without (NFH) a family history of prostate cancer after radical prostatectomy. METHODS: We performed a retrospective analysis of 557 men with localized prostate cancer treated by radical prostatectomy between 1989 and 2000. We defined a positive FH as having one or more first-degree relatives such as a father or brother with prostate cancer. The clinical and pathologic features, as well as biochemical disease-free survival, defined as an undetectable prostate-specific antigen level (less than 0.2 ng/mL), were compared between the FH and NFH groups. RESULTS: Compared with the NFH group, the FH men were younger at surgery (median 62 years versus 64 years, P = 0.01), had a lower median preoperative prostate-specific antigen level (7.2 ng/mL versus 7.8 ng/mL, P = 0.05), and were more likely to have only low-grade disease at the final pathologic evaluation (26.2% versus 17.8%, P = 0.05). At a median follow-up of 7.5 years (mean 7.6 +/- 2.9 years), 17% of the FH group had biochemical disease recurrence compared with 30% in the NFH group. The actuarial disease-free survival rate at 5 and 10 years for the two groups was 86% and 80% compared with 73% and 66%, respectively (P = 0.01). When controlled for pathologic variables in a multivariate analysis, FH was not an independent predictor of disease-free survival. CONCLUSIONS: The association of improved disease-free survival in the FH patients may have been driven by an earlier age at diagnosis and more favorable pathologic features.

Vascular invasion predicts recurrence after radical prostatectomy: stratification of risk based on pathologic variables.

OBJECTIVES: To determine whether vascular invasion (VI) is an independent predictor of prostate cancer recurrence and/or survival and to stratify risk of recurrence in patients with VI. METHODS: Vascular invasion status was documented in 620 radical prostatectomy specimens with an average of 7.5 years of follow-up. The relationship between VI and other clinical and pathologic features was tested. Vascular invasion as an independent predictor of recurrence was investigated by logistic regression analysis. Survival analyses and stratification of VI patients was developed with Kaplan-Meier survival curves. RESULTS: Vascular invasion was identified in 110 patients (18%) and correlated significantly (P <0.0001) with high Gleason grade, extracapsular extension (EPE), seminal vesicle invasion, increasing cancer volumes, positive margins, and elevated preoperative prostate-specific antigen (PSA) levels. Logistic regression analysis demonstrated that VI was a strong and independent predictor for disease recurrence, when considered with grade, EPE, seminal vesicle invasion, lymph node involvement, cancer volume, preoperative PSA levels, and positive margins. At 12 years after radical prostatectomy, patients with VI demonstrated significantly lower disease-specific survival (P = 0.0005). Among patients with VI, stratification of grade, EPE, and the number of VI foci identified three significantly different prognostic groups. CONCLUSIONS: In long-term follow-up, VI was a significant predictor of prostate cancer recurrence and death after radical prostatectomy. In patients with VI, high Gleason grade, EPE, and more than five foci of VI are associated with poor prognosis.

The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years?

PURPOSE: We assessed how well preoperative serum prostate specific antigen (PSA) reflects the largest cancer in consecutive untreated radical prostatectomies during the last 20 years at Stanford University. MATERIALS AND METHODS: A total of 1,317 consecutive radical prostatectomies were divided into 4, 5-year periods between August 1983 and July 2003, and examined sequentially in 3 mm step sections by 1 pathologist. The largest cancer and 5 other histological variables in each prostate were measured. Preoperative clinical stages were tabulated for each 5-year period. Means, Pearson correlation coefficients, % change and multiple regression were used to compare selected variables. RESULTS: Most parameters decreased linearly during the 20 years, including palpable nodules on digital rectal examination from 91% to 17%, mean age from 64 to 59 years, mean serum PSA from 25 to 8 ng/ml, and index (largest) cancer volume from 5.3 to 2.4 cc. Percent Gleason grade 4/5 of the largest cancer averaged 27% to 35% and prostate weight 44 to 53 gm. Contrasting August 1983 to December 1988 with January 1999 to July 2003, 6 histological cancer parameters had statistically significant relationships to serum PSA in the first period. In the last 5 years serum PSA was related only to prostate size. CONCLUSIONS: Serum PSA was related to prostate cancer 20 years ago. In the last 5 years serum PSA has only been related to benign prostatic hyperplasia. There is an urgent need for serum markers that reflect the size and grade of this ubiquitous cancer.

Time trends in pathologic features of radical prostatectomy--impact of family history.

We investigated whether the clinical or pathological features of patients with a family history of prostate cancer treated by radical prostatectomy differ from patients without a family history. A retrospective analysis of patients treated by radical prostatectomy between 1989 through 2000 was performed. The clinical and pathologic features of patients with a family history (defined as at least one first-degree relative with prostate cancer, N = 103) were compared with those with no family history (N = 456). In addition, the patients were stratified into two groups, those treated from 1989 through 1992 and those treated after 1992. In the entire cohort from 1989 through 2000, patients with a family history had a greater proportion of well-differentiated tumors than the NFH group (26.2% vs. 17.8%; P = 0.05). From 1989 to 1992 there was no statistical difference between patients with a family history (FH) and those without a family history (NFH) with respect to age, prostate specific antigen (PSA), PSA density, clinical or pathologic stage, Gleason grade, or total tumor volume. However, after 1992 the FH group tended to be younger than the NFH group (61.1 vs. 63.4; P = 0.02) and have a lower PSA (6.8 vs. 7.9; P = 0.01) at the time of diagnosis. We believe these differences are predominantly driven by more aggressive screening in patients with a family history of prostate cancer rather than any true genetic differences.

Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis.

Estrogen receptor (ER)-beta is thought to exert anti-proliferative effects in the normal prostate but supports prostate cancer (PCa) cell survival. We previously reported that the receptor's expression declined as PCa developed in the gland but reappeared in lymph node and bone metastases. To investigate whether hypermethylation was the underlying mechanism for these phenomena, we first identified two CpG islands (CGIs) encompassing 41 CpG dinucleotides, located separately in the untranslated exon 0N and the promoter region of ER-beta. Using immunostained, laser capture-microdissected samples from 56 clinical specimens, we demonstrated an inverse relationship exists between the extent of ER-beta CGI methylation and receptor expression in normal, hyperplastic, premalignant, and malignant foci of the prostate and in lymph node and bone metastases. Treatment of PCa cell lines (LNCaP and DU145), that express little ER-beta mRNA, with a demethylating agent increased levels of receptor expression thus corroborating our in vivo findings that methylation is involved in ER-beta silencing. Methylation centers in the promoter region and exon 0N were identified by hierarchical cluster analysis of bisulfite sequencing data obtained from 710 alleles. Methylation at these centers was insignificant in normal epithelium, reached 80 to 90% in grade 4/5 PCa, but declined to less than 20% in bone metastases. In addition, progressive methylation spreading from the exonic CGI to the promoter CGI, which correlated with loss of ER-beta expression, was detected in microdissected samples and in cell cultures. Using a new class of methylated oligonucleotides that mediate sequence-specific methylation in cellulo, we demonstrated that methylation of the promoter CGI, but not the exonic CGIs, led to transcriptional inactivation of ER-beta. Our results present the first evidence that epigenetic regulation of ER-beta is a reversible and tumor stage-specific process and that gene silencing via methylated oligonucleotides may have therapeutic potential in the treatment of advanced PCa.

Extended prostate biopsy scheme improves reliability of Gleason grading: implications for radiotherapy patients.

BACKGROUND: With sextant prostate biopsies, there is up to a 1-in-3 chance that the underlying pathologic Gleason grade is higher. Knowledge of the underlying grade might have significantly altered the therapeutic recommendations and management for patients electing radiotherapy for localized prostate cancer (e.g., eligibility for brachytherapy, androgen suppression with external beam radiotherapy, elective pelvic radiotherapy). This study examines the concordance patterns between biopsy and matched radical prostatectomy Gleason grade among patients undergoing an extended 10-core biopsy scheme to assess its reliability compared to sextant biopsies. METHODS AND MATERIALS: Seventy-eight consecutive patients underwent an extended 10-core peripheral zone biopsy scheme (sextant plus two lateral mid and two lateral base biopsies) and subsequent radical prostatectomy at this institution between mid-2000 and mid-2003. No patient received androgen suppression. All histologic grading were made by a single pathologist (J.E.M.). Needle biopsies were characterized for location, linear involvement of cancer within positive cores, and total number of positive cores. Radical prostatectomy specimens were step-sectioned at 3-mm intervals and were characterized for total cancer volume and percentage of each Gleason grade present. Clinical parameters available included digital rectal exam, preoperative PSA, and ultrasound prostate volume. A "clinically significant" upgrading of the biopsy was defined as any of the following: (1) a biopsy Gleason score (bGS) of 6 to a pathologic GS (pGS) of 7 or higher, (2) a bGS 3 + 4 to a pGS of 4 + 3 or higher, and (3) a bGS of 7 to a pGS of 8 or higher. Statistical analyses were performed on the patterns Gleason score concordance between biopsies and matched radical prostatectomies. RESULTS: An exact Gleason score match between biopsy and prostatectomy was observed in 62% of patients using the sextant biopsy scheme (SB), an upgrading of 1 or more grade points was seen in 25% and a downgrading of 1 or more points in 13% for SB. These rates of grade discordance are comparable to those of published sextant series. An exact match using the extended biopsy scheme (EB) was 63% (p = 0.61 compared with SB), whereas upgrading was 13% (p = 0.045 compared with SB) and downgrading was 24% (p = 0.06 compared with SB). A "clinically significant" upgrading as defined here was present in 38.1% of the SB group compared with 23.1% of the EB group (p = 0.039). For patients with bGS of 6, a clinically significant upgrading occurred in 66.7% with SB and in 36.8% with EB (p = 0.068). Upgrading of the primary Gleason grade from 3 to 4/5 was seen in 41.8% for the SB and in 25.5% for the EB group (p = 0.078). No clinical factors (T-stage, PSA, prostate volume, % positive cores, linear extent of cancer) were found to predict for a clinically significant upgrading of biopsies on logistic regression analysis. CONCLUSIONS: The extended 10-core biopsy scheme significantly improves on sextant biopsies in predicting the underlying pathologic Gleason score for prostate cancer. In particular, it is superior to sextant biopsies in revealing the presence of an underlying high-grade component. The potential clinical impact this improvement has for patients ultimately selecting radiotherapy suggests that an extended biopsy scheme should become the standard of care. Nevertheless, even with this improvement, there still remains up to a 1-in-5 chance that the underlying grade will be higher.

Impact of prior biopsy scheme on pathologic features of cancers detected on repeat biopsies.

The object of our study was to characterize the biopsy features of cancers detected in a repeat biopsy population stratified on the basis of the type of prior negative biopsy. We studied 218 patients with a prior negative biopsy who underwent a 10-core extended systematic biopsy scheme, and a subset (n = 139) underwent additional 6 anteriorly directed biopsies. Clinicopathologic features of patients with cancer on the biopsy were compared as a function of type of prior negative biopsy. Overall and unique cancer detection rates were calculated for each of the biopsy sites. Cancer detection rates tended to be higher in patients who had undergone a prior sextant biopsy compared to a prior extended biopsy scheme (39% vs. 28%). Trends towards more positive cores and greater total core length of cancer involvement were seen in patients who had undergone a prior negative sextant biopsy. Apical and laterally directed biopsies had higher overall and unique cancer detection rates in patients who had undergone a prior negative sextant biopsy. Anteriorly directed biopsies had a low unique cancer detection rate in all patients. We conclude that in patients undergoing repeat biopsy, the detection rate is affected by the extent of the prior biopsy. Clinicopathologic features of cancers detected on repeat biopsy tend to be worse in patients who have undergone a prior negative sextant biopsy compared to a negative prior extended biopsy.

Transition zone carcinoma of the prostate gland: a common indolent tumour type that occasionally manifests aggressive behaviour.

AIMS: Tumours arising in the transition zone (TZ) of the prostate gland are often well differentiated and considered clinically unimportant. We have observed examples of high-grade TZ cancers that prompted this study. METHODS: Review of 654 radical prostatectomy specimens previously assessed by systematic whole organ histology identified 187 (29%) TZ cancers of which 76 (11.6%) represented the index (main) tumour. These were compared with a volume-matched group of 76 peripheral zone (PZ) carcinomas. RESULTS: Fifty-nine of 76 TZ index carcinomas had additional minor tumours mainly located in the PZ. Compared to PZ tumours of similar size, TZ tumours had significantly lower Gleason scores, less Gleason grade 4/5 and lower rates of capsular penetration and positive surgical margins. However, within this TZ tumour group, seven carcinomas had a major Gleason grade 4 or 5 component with high rates of capsular penetration (57%) and positive surgical margins (43%). Positive anterior and bladder neck margins were more common in TZ carcinoma than peripheral tumours and transperineal biopsy was the method of choice for TZ cancer diagnosis. CONCLUSIONS: A subset of TZ carcinoma characterised by high tumour grade has a significant risk of extraprostatic spread, margin positivity and possible biochemical failure. We recommend transperineal prostate biopsy for TZ tumour diagnosis and histological sampling of the anterior TZ at radical prostatectomy, even if macroscopically normal, to detect patients at risk from aggressive TZ carcinoma.

Adenoid cystic/basal cell carcinoma of the prostate: clinicopathologic findings in 19 cases.

Adenoid cystic/basal cell carcinoma (ACBCC) of the prostate has been considered to have indolent biologic potential. However, outcome data are scant, with only one documented metastasis and death. We describe clinicopathologic features of ACBCC in 19 patients and document outcome in 15. Patients ranged in age from 43 to 83 years. All but one presented with urinary obstruction. ACBCC was diagnosed by transurethral resection in 15 cases, by needle biopsy in 3 cases, and unexpected in 1 case. Four patients had concurrent acinar adenocarcinoma. Histologically, cribriform or adenoid cystic patterns predominated in 12 cases and basal cell carcinoma pattern in 7. Five cases had prominent perineural invasion. ACBCC was immunoreactive for p63 and cytokeratins 7 and 34 beta E12 but not cytokeratin 20. After diagnosis, 5 patients underwent radical prostatectomy, 2 underwent pelvic exenteration, and the rest had no treatment. ACBCC showed extraprostatic extension in 5 cases and involved the bladder margin in 3. Metastases developed in 4 (21%) patients: liver (2), lung (2), bowel (1), and corpus cavernosum (1). In 15 cases with follow-up (0.3-11.8 years), two patients died of cancer (at 1.5 and 3 years after diagnosis), 3 remain alive with cancer, and 10 have no evidence of cancer. Thus, ACBCC of the prostate is a potentially aggressive neoplasm requiring ablative therapy.

Genetic profiling of Gleason grade 4/5 prostate cancer: which is the best prostatic control tissue?

PURPOSE: We examined the variation in gene expression profiles of prostate cancer caused by zone specific genes. MATERIALS AND METHODS: Ten normal central zone, 10 transition zone (benign prostatic hyperplasia) and 6 normal peripheral zone tissues from radical retropubic prostatectomies were compared to each other and to 12 peripheral zone Gleason grade 4/5 cancers. Test chips and HuGeneFL6800 (Affymetrix, Inc., Santa Clara, California) chips were used to assay the transcribed genes. Data were obtained with the Microarray Suite Version 4.0.1 (Affymetrix, Inc.) and analyzed statistically. RESULTS: Substantially different gene expression profiles were found depending upon which of the 3 zonal tissues were used as a control. All 3 profiles were compared for efficiency (ability to locate genes) and for robustness (the magnitude of difference between the control and the Gleason grade 4/5 tissue). Microscopically normal appearing peripheral zone tissue at the gene level shows many characteristics of Gleason grade 4/5 cancer. CONCLUSIONS: Gene expression profiles of prostate cancer are affected by the zonal location of the control tissue and the cancer.

Prognostic factors for multifocal prostate cancer in radical prostatectomy specimens: lack of significance of secondary cancers.

PURPOSE: We evaluated secondary cancers in the prostate in relation to predictions of pathological stage and prognosis. MATERIALS AND METHODS: A total of 222 men with T1c (impalpable) prostate cancer and 6 or more systematic needle biopsies were matched with radical prostatectomy and classified into 3 groups according to tumor multifocality and secondary cancer volumes, including a single tumor in 54 (24%), an index (largest) tumor with secondary cancers less than 0.5 cc in 86 (39%) and an index tumor with secondary cancers greater than 0.5 cc in 82 (37%). Logistic analysis was used to predict adverse histological features. Cox proportional hazards analysis was used to predict prostate specific antigen (PSA) failure after radical prostatectomy. RESULTS: There were no differences among the 3 groups with respect to preoperative serum PSA, number of positive cores, percent Gleason grade 4/5 cancer in the needle biopsy or histological features in radical prostatectomy specimens. On logistic analysis neither serum PSA nor pre-radical biopsy predicted adverse histological features in radical prostatectomy specimens. The Cox regression model showed that primary predictors of PSA failure were percent Gleason grade 4/5 cancer in the biopsy (HR = 2.6, p = 0.015) and prostatectomy (HR = 2.4, p = 0.04) specimens, and the number of positive cores (HR = 2.5, p = 0.04). When comparing PSA failure rates among the 3 groups, the multifocal group with smaller secondary cancers showed a better prognosis than the single tumor group (p = 0.019). CONCLUSIONS: Secondary cancers in multifocal prostate tumors did not adversely influence the results of preoperative clinical parameters, including PSA and needle biopsy findings. Percent Gleason grade 4/5 cancer in needle biopsies and prostatectomy specimens is the most powerful predictor of biochemical failure in men with stage T1c prostate cancer after radical prostatectomy.

Intraoperative lymph node staging of prostate cancer: the case against.

BACKGROUND: Intraoperative frozen section analysis of obturator nodes is an accepted screening procedure, excluding from prostatectomy that group of node-positive patients who are presumed to almost always have disseminated cancer. The overall efficacy of this procedure depends not only on the near inevitability of cancer progression in these patients, but also the procedure morbidity (previously estimated at 8.4%), the additional costs (currently estimated at A$1200) and the infrequency of positive nodes. We evaluate the efficacy of lymph node staging for prostate cancer. METHODS: We have evaluated the efficacy of intraoperative screening by node dissection in 123 prostatectomy cases. These cases were prescreened from a series of 261 radical prostatectomies by evaluating preoperative serum PSA and Gleason grade. RESULTS: Three patients were identified with nodal disease, representing a detection rate of 2.4%. The present study confirms that current trends in prostate cancer identification and selection of individuals for radical surgery very rarely identify node-positive disease even after preselection with accepted 'high-risk' markers. CONCLUSION: Considering the attendant cost and morbidity, there appears to be no justification for lymph node dissection as a routine preliminary to prostatectomy.

Alpha-methylacyl-CoA racemase (P504S) expression in evolving carcinomas within benign prostatic hyperplasia and in cancers of the transition zone.

Carcinomas of the transition zone (TZ) constitute approximately 20% of all prostate cancers. The TZ is the site of origin of grade 1 and grade 2 cancers, the most well-differentiated of the Gleason grade tumors, as well as for benign prostatic hyperplasia (BPH). In this regard, grade 1 carcinoma has architectural features that closely mimic gland-rich BPH nodules. Although a relationship between cancers arising in this zone and BPH has been suspected, such an association remains undefined. To gain insight into the origin, development, and progression of cancers arising in the TZ, we used a highly specific rabbit monoclonal antibody (P504S) directed against alpha-methylacyl-CoA racemase (AMACR) to study the expression of the enzyme in 25 cases of evolving and fully developed carcinomas of this zone. AMACR has been proposed as a new molecular marker for prostate cancer, because the enzyme is reportedly overexpressed in high-grade dysplasias, also termed prostatic intraepithelial neoplasia, a purported precursor of prostatic carcinoma, and in all grades of prostatic carcinoma of the peripheral zone. Using P504S, P63, or antikeratin 34beta E12 antibodies, we found it possible to define areas of transition from hyperplasia to carcinoma in 6 BPH nodules. In 3 other cancer-containing BPH nodules, staining for AMCAR was observed in benign hyperplastic glands that were juxtaposed to carcinoma. Enzyme expression was also evident in 5 additional cases in which BPH was found adjacent to cancer. In contrast; AMACR was not visualized in any other BPH nodules that we studied. Thus, using the enzyme as a marker, we document for the first time that some carcinomas of the TZ arise from an AMCAR-positive transition lesion within a subset of BPH nodules. Moreover, the finding of enhanced AMACR expression in benign glands within cancer-containing nodules as well as in BPH lesions adjacent to carcinoma suggests that in some cases, up-regulation of the enzyme may precede morphological evidence of neoplastic transformation. AMACR was lightly expressed in transition lesions and grade 1 carcinomas but more strongly expressed in higher-grade TZ cancers, suggesting that enzyme expression is enhanced with progression in this zone. Because AMACR is involved in the beta oxidation of branched fatty acids and their derivatives, enhanced expression of the enzyme in evolving carcinomas in BPH nodules, as well as its up-regulation in juxtaposed morphologically benign glands and grade 1 carcinomas, suggests that increased utilization of fatty acids may play an important role in carcinoma development and progression in the TZ.

Hepsin and maspin are inversely expressed in laser capture microdissectioned prostate cancer.

PURPOSE: Recent studies have shown that hepsin, a serine protease, is over expressed in prostate cancers, implicating hepsin activity in tumor invasion. Using microarray technology we have previously identified 22 genes that were up-regulated in high grade prostate cancers compared with benign prostatic hyperplasia. Of them hepsin was the most differentially over expressed. In the current report we compare hepsin to maspin (BD Transduction Laboratories, San Diego, California), a serine protease inhibitor (serpin), to measure the balance between levels of serine proteases and serpins, which are considered to be a critical determinant of net proteolytic activity. MATERIALS AND METHODS: We combined the technique of laser capture microdissection with gene expression monitoring by micro-array analysis to investigate the gene expression profiles of prostate cells of different histological types. We also studied maspin immunohistochemically. RESULTS: We observed that hepsin as well as 7 of 22 previously reported up-regulated genes demonstrated a pattern of increasing expression with increasing malignant phenotype. In contrast, the expression of maspin (a serpin) decreased with increasing malignancy of prostate cancers. Using immunohistochemistry we observed that maspin protein is expressed strongly in benign prostatic tissues and slightly in grade 3 prostate cancers, and is absent in grade 4/5 cancers. CONCLUSIONS: We conclude that the increased ratio of hepsin-to-maspin may have an important role in prostate cancer progression and invasion.

Biochemical recurrence without PSA progression characterizes a subset of patients after radical prostatectomy. Prostate-specific antigen.

OBJECTIVES: To characterize a subset of patients with biochemical recurrence after radical prostatectomy but with little, if any, subsequent rise in serum prostate-specific antigen (PSA) and no clinical progression during long-term follow-up. METHODS: Of a series of 600 patients, 158 with biochemical recurrence after radical prostatectomy were examined. We identified a subset with measurable serum PSA levels during long-term follow-up, but with very low PSA velocity and no clinical recurrence. Serum PSA was measured with the ultrasensitive TOSOH assay with a PSA recurrence defined as a serum PSA of 0.07 ng/mL or greater. RESULTS: We identified 14 patients (8.8% of biochemical recurrences) with a detectable serum PSA level after radical prostatectomy yet without clinical or PSA progression at a mean follow-up after radical prostatectomy of 10.3 years. The mean time to PSA recurrence was 5.8 years, and the mean PSA velocity after recurrence was 0.028 ng/mL/yr. No clinical or pathologic features were found that could be used to identify this subset of patients. CONCLUSIONS: A subset of patients with biochemical recurrence after radical prostatectomy will not exhibit a progressive rise in serum PSA or clinical progression at 10 years follow-up. This suggests that serum PSA kinetics should be observed after biochemical recurrence before adjuvant hormonal therapy or radiotherapy.