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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.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.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.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.

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.

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.

Less than 50% of men who undergo radical prostatectomy for prostate cancer are cured of disease. We evaluate tumor expression of inhibin alpha, a putative tumor suppressor, and the related protein, follistatin, to determine whether expression correlated with failure to be cured by surgery.Tissues were selected from an archival collection of 379 prostatectomy specimens from men with followup of at least 5 years after surgery. Since previous studies showed that such men with only Gleason grade 3 cancer had a greater than 95% chance of no biochemical recurrence (increase in serum prostate specific antigen), our investigation was confined to 174 men with 2% or greater grade 4/5 cancer. These men had an intermediate rate of failure, providing an opportunity to analyze the potential contribution of inhibin alpha or follistatin to progression. Intensity of immunohistochemical labeling for inhibin alpha and follistatin in each cancer was compared with that in normal glands within the same tissue section.The majority of cases showed more intense expression of inhibin alpha in cancer than in normal glands. Those individuals whose cancers had the most elevated expression of inhibin alpha had a higher risk of recurrence, although this association was not statistically significant. Follistatin was expressed equivalently in normal and cancer cells in the majority of cases and did not correlate with recurrence.Our finding that inhibin alpha is frequently overexpressed in high grade prostate cancer suggests that the role of inhibin alpha as a tumor suppressor needs to be reevaluated. Furthermore, assessment of inhibin alpha as a serum marker of prostate cancer, as used to diagnose ovarian cancer, may be warranted.

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.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.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.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.

We evaluated secondary cancers in the prostate in relation to predictions of pathological stage and prognosis.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.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).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.

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.

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.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.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.We conclude that the increased ratio of hepsin-to-maspin may have an important role in prostate cancer progression and invasion.

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.

BACKGROUND Cytosine-adenine-guanine repeat length of the androgen receptor gene and the A49T and V89L polymorphisms of the 5α-reductase (SRD5A2) gene have been associated with prostate cancer. METHODS We investigated the relationship of the three genetic polymorphisms to tumor grade among 211 men who had undergone radical prostatectomy. Subjects had prostate cancer

Purpose: We examine the potential impact of extended systematic biopsy schemes in patients with a prior negative prostate biopsy.Materials and Methods: Between January 1999 and March 2001, 185 patients with a prior negative prostate needle biopsy underwent repeat biopsy. Systematic 10 core biopsies (sextant, lateral mid gland and lateral base) were performed in all patients. A subset of 111 patients underwent 6 additional biopsies directed anteriorly. All biopsy results were reviewed by a single pathologist. The overall and unique cancer detection rates were calculated for each biopsy site. McNemar’s test was then used to compare the yield of various simulated biopsy schemes to define the optimal biopsy regimen.Results: Overall, 67 of 185 patients (36%) were found to have cancer on repeat biopsy. The highest detection rate was found for the apex, lateral base and lateral mid sites. The mid lobar base site consistently yielded the lowest detection rate. These results were mirrored in the unique cancer dete...

Purpose: Serum prostate specific antigen (PSA) is widely used as a guide to initiate prostatic biopsies and to follow men older than 50 years old with and without prostate cancer. However, benign prostatic hyperplasia (BPH) is a common cause of serum PSA values between 2 and 10 ng./ml. A better understanding of the relationships among serum PSA, prostate cancer and BPH is important.Materials and Methods: A total of 875 men underwent radical prostatectomy at our institution between December 1984 and January 1997. Of these men 784 had a serum PSA of 2 to 22 ng./ml., including 579 with the largest cancer located in the peripheral zone of the prostate. Of the 579 men 406 had serum PSA followups for greater than 3 years after radical prostatectomy. We examined Pearson correlations (R2) between preoperative serum PSA, and the volume of Gleason grades 4/5 and 3 to 1 cancer in 784 men, separating peripheral zone from transition zone cancers. We used broken line regression with break points of 7 and 9 ng./ml. preo...

Purpose: Because Gleason grade 4/5 cancer is the primary cause of failure to cure prostate cancer, we examined the molecular profiles of this high grade cancer in search of potentially new therapeutic interventions as well as better serum markers than prostate specific antigen.Materials and Methods: We compared the gene expressions in fresh frozen tissues from 9 men with Gleason grade 4/5 cancer to 8 men with benign prostatic hyperplasia (BPH) treated with radical retropubic prostatectomy. Labeled complementary RNA from each of the 17 tissues was applied to HuGeneFL probe arrays representing approximately 6,800 genes (Affymetrix, Inc., Santa Clara, California). After removing all genes undetectable in BPH and grade 4/5 cancers, and transforming the data into a parametric distribution, we chose only those up and down-regulated genes with a p difference in fluorescence between grade 4/5 cancer and BPH of p

Purpose: We examined the association of androgen receptor gene cytosine-adenine-guanine (CAG) repeat length and the 2 single nucleotide polymorphisms A49T and V89L in the type II 5α-reductase gene with prostate enlargement measured as the weight of the surgically removed prostate.Materials and Methods: A total of 68 men with a prostate weighing 80 gm. or greater were compared with 197 controls with a prostate weighing less than 80 gm. These men had undergone radical prostatectomy between 1992 and 1996. DNA was extracted from archival prostate tissue uninvolved with cancer and genotyped for 3 polymorphic markers. The effects of genetic variants and clinicopathological variables on prostate enlargement risk were estimated by logistic regression.Results: The age adjusted odds ratio estimate of prostate enlargement risk in men with 23 or greater versus 20 or fewer CAG repeats was 0.41 (95% confidence interval 0.19 to 0.89). This risk reduction was consistently found when an alternative prostate enlargement de...

Purpose: Because of the recent increase in nonpalpable prostate cancer (clinical stage T1c) in men, preoperative needle biopsy findings have had an important role for treatment decisions. We examine the correlation among histopathological features of 6 systematic biopsies and radical prostatectomy specimens in which 1 investigator reviewed all histological sections.Materials and Methods: We studied a total of 450 men with clinical stage T1c prostate cancer from whom needle biopsies were matched with radical prostatectomy specimens, and selected 222 patient biopsies that were obtained from 6 or more separate regions of the prostate. The pretreatment parameters of serum prostate specific antigen (PSA), PSA density, number of positive needle biopsies, distribution of positive cores, linear cancer length, and percent Gleason grade 4/5 on the biopsy were determined and compared with histopathological features of prostate cancer in the radical prostatectomy specimens. All biopsies and radical prostatectomies we...

BACKGROUND Peripheral zone (PZ) and transition zone (TZ) cancers of the prostate remain confined to their zone of origin under 4 cc volume, with progressive molding to TZ boundary. In PZ cancer, growth in perineural spaces over 4 cc volume directs cancer toward the base, around subcapsular nerve trunks, and often transcapsular. This tendency to stereotyped patterns of cancer spread in the prostate is investigated systematically here for the first time. METHODS Cancers in 571 radical prostatectomy specimens were sorted by zone of origin and tumor volume. A traced map of each cancer at 3 mm transverse intervals was assessed for location, contour, selected linear measures and the “transverse (largest) reference plane”. RESULTS Spread along prostate capsule characterized all but the smallest PZ cancers and was most extensive transversely. By 4 cc volume, most PZ cancers' transverse reference plane filled one side of PZ. Above 4 cc, bilateral spread, TZ invasion, and nodularity progressively increased, but dominant growth was toward the base along nerves to the superior pedicle; here capsule penetration was most common. TZ cancers arose mainly in anterior-mid TZ, invading anterior fibromuscular stroma (AFM) while small. AFM was massively invaded in many large tumors. Larger TZ cancers (> 4 cc) invaded anterolateral PZ but seldom penetrated posterior PZ. CONCLUSIONS Patterns and extent of spread of carcinoma in the prostate are stereotyped following a few principles regarding stromal interactions. Using these, sequential maps were presented of evolving prostate cancer contours at consecutive increasing volumes. Prostate 49:48–57, 2001. © 2001 Wiley-Liss, Inc.

Background Recent identification of eosinophilic prostatic secretory granules (PSG) as the major secretory mechanism of the prostate gland and their loss in neoplasia has prompted scrutiny of their chemical constituents. Polyamines, in particular spermine and spermidine (sp/spd) are the major cations found within prostatic secretions, yet their secretory mechanism in normal and neoplastic tissues has not been investigated. Methods Normal prostatic tissues and adenocarcinoma from intact and chemically castrated men were preserved in a glutaraldehyde-based fixative (Solufix®). Immunostains for sp/spd were performed before and after harsh acid hydrolysis whereby all protein was removed from tissue sections. Results Sp/spd immunoreactivity correlated with PSG as recognized in routine stains in tissues from intact patients before and after acid digestion. Decrease in sp/spd in untreated carcinomas was directly related to loss of PSG. After chemical castration, normal glands were mostly devoid of sp/spd while surviving malignant cells stained positively, despite a significant reduction or absence of PSG. Similarly, cancers progressing after castration were intensely decorated with anti-spermine, despite an almost complete loss of PSG. Cytoplasmic sp/spd staining of these androgen resistant clones was in contrast to normal glands no longer acid resistant. Conclusions The intense eosinophilia of PSG is attributable to polyamines. Androgen blockade arrests sp/spd production in normal tissue. In contrast, sp/spd production continues in androgen resistant tumor clones, thereby uncoupling polyamines from their normal androgen dependent environment. Prostate 49:278–284, 2001. © 2001 Wiley-Liss, Inc.

Purpose: We compared pathological findings with prostate specific antigen (PSA) failure rates following radical prostatectomy for large volume cancers (6 cc or greater).Materials and Methods: A total of 191 men whose radical prostatectomy specimen had a cancer volume of 6 cc or greater were followed for a mean of 3.6 years (range 0.3 to 11.1) and 112 (58.6%) had PSA failure (PSA 0.07 ng./ml. or greater and increasing). Percent Gleason grade 4/5 (the Stanford modified Gleason scale), cancer volume, seminal vesicle invasion, regional lymph nodes, capsular penetration, positive surgical margin, location of the largest cancer in the peripheral or transition zone, prostate weight, patient age, preoperative PSA and clinical stage were analyzed using univariate and multivariate Cox proportional hazards analyses.Results: In univariate regression analysis percent Gleason grade 4/5, lymph node involvement, cancer volume, cancer location in the peripheral zone, capsular penetration and positive surgical margins were...

BACKGROUND The authors have shown that the primary determinants of prostate carcinoma progression are tumor volume and the percent of the tumor comprised of Gleason Grade 4/5 cells. In the current study the authors evaluated six different techniques for the morphometric measurements of prostate carcinoma volume. METHODS A computer-assisted image analysis (NIH Image, developed and maintained by the National Institutes of Health, Bethesda, MD) was used to analyze all 108 step-sectioned prostate specimens obtained between January 1 and December 31, 1997. The authors used the Stanford technique of 0.3-cm step-sections, measuring the volume of the tumor at both 0.3-cm and 0.6-cm intervals. The other 4 methods included the authors' previous method based on an earlier image program, the ellipsoidal method (π ÷ 6 × width × height × length), an estimation of the square area of the largest tumor, and the maximum tumor dimension (MTD). RESULTS The authors first checked the accuracy of NIH Image analysis by measuring 24 circles of widely different sizes. The mean coefficient of variation was 1.7% and the correlation between the mean circle areas measured by the NIH Image software and true circle area essentially was perfect (correlation coefficient [r] = 1 and r2 = 0.999; P < 0.0001). In comparison with the authors' original computer image program using 0.3-cm step-sections measured by a different observer, r2 with the NIH Image analysis was 0.93. Using NIH Image only, the 0.6-cm step-section method missed measurable cancers in 16.7% of 108 radical prostatectomies in comparison with the 0.3-cm step-method. The mean tumor volume with the 0.6-cm section method (P < 0.0001) and the ellipsoidal method (P < 0.05) were significantly higher than with the 0.3-cm section method. r2 from linear regressions using the 0.3-cm step section method as the standard versus the ellipsoidal method was 0.594, and was 0.89 versus the 0.6-cm step-section method, 0.652 versus the square area estimation, and 0.527 versus the MTD method. CONCLUSIONS The results of the current study support NIH Image as a powerful software program for the morphometric measurement of prostate carcinoma volume. Pathologic processing with 0.3-cm section slices was found to be more accurate for tumor volume than the 0.6-cm section slices. The ellipsoidal method, the square area of the largest tumor, and the MTD all were found to be inferior to computer-assisted image analysis measurements. In certain clinical situations in which only estimates of tumor volume are required, the square area of the largest tumor appears to be the best choice (r2 0.652). Cancer 2000;89:1056–64. © 2000 American Cancer Society.

Objectives: Autopsy studies show that prostate cancer begins in the 4th and 5th decade of life. We sought to determine if increasing age at the time of diagnosis is related to morphologic and clinical predictors of cancer progression. Materials and Methods: We examined 7 morphologic variables known to impact progression of prostate cancer plus clinical stage and serum PSA in relation to increasing age. 981 untreated men undergoing radical prostatectomy were divided into 5 increasing age groups. Prostate size, which is known to increase with age, was used as a positive control. We compared the median and inter-quartile range for each grouping. Results: Increase in prostate weight was highly significant at all age differences. The % Gleason grade 4/5 cancer and cancer volume showed the most statistically significant changes with ageing, followed by non-organ confined cancer and capsular penetration both of which are highly correlated with cancer volume. Serum PSA was significant at 12, 17, and 22 years of age differences, but may be related more to prostate size than to increasing cancer volume. The presence of positive lymph nodes, seminal vesicle invasion, and palpable cancer were unrelated to increasing age. Conclusions: With the exception of increasing prostate size, % Gleason grade 4/5 cancer and cancer volume are the most significantly related variables to increasing age. Since % Gleason grade 4/5 cancer and cancer volume are also the primary determinants of failure to cure prostate cancer by radical prostatectomy, these age related changes suggest that detection of prostate cancer later in life will be accompanied by increased amounts of high grade cancer and larger tumor volumes. They also explain why, in so many younger men (age 45–60), the largest prostate cancer is often clinically insignificant (< 0.5 cc) at the time of radical prostatectomy.

BACKGROUND Cribriform prostatic intraepithelial neoplasia (C-PIN) identifies a unique histological pattern: dysplastic cells line ductal/acinar walls but also span across gland lumens. C-PIN is distinct from other forms of dysplasia; it is seldom seen except within invasive cancer, it is more frequent in larger/higher-grade cancers; and it appears to contribute independently to aggressive behavior. Hence, C-PIN may represent a separate, more aggressive entity: intraductal carcinoma of the prostate (IDC-P). Here, support for that distinction stems from a histologic/biologic subclassification of IDC-P, whose elements are linked to features of invasive cancer. METHODS Histologic criteria were tested against 26 radical prostatectomies, using immunostains for prostate-specific antigen, MUC-2, androgen receptor (differentiation), and Ki-67 (proliferation). Invasive cancer grade, stage, and follow-up were compared. RESULTS Architecture of the central (luminal) cell compartment defined three subclasses of IDC-P: A (trabecular), B (cribriform), and C (solid/comedo), which represented progressive dedifferentiation with a reciprocal increase in proliferation. The IDC-P subpattern correlated with cancer stage, grade, and clinical course. CONCLUSIONS IDC-P is a separate entity, distinct from PIN; cancers associated with IDC-P are more aggressive than those associated with only PIN. It comprises a spectrum of histological patterns which appear to be determined in concert with invasive cancer, whose prognosis it worsens. Prostate 43:11–19, 2000. © 2000 Wiley-Liss, Inc.

Objectives: In an effort to decrease the frequency of postoperative positive surgical margins (+SM), a modified extrafascial radical prostatectomy technique was developed and evalua

Recent changes in tissue fixation strategy, using glutaraldehyde, have clarified the secretory mechanisms of the normal prostate identifying cytoplasmic prostatic secretory granules, structures not preserved by formalin fixation. This normal secretory mechanism was absent in most adenocarcinomas, depicting an important metabolic change in transformed prostate cells. The current study further investigates differences between benign and malignant prostate secretion and relates them to the production of corpora amylacea by benign glands and crystalloids or mucin by cancer. In all normal prostate cells examined (6 cases), prostate secretory granules (PSG) were approximately 1-microm, brightly eosinophilic granules filling the cytoplasm of secretory cells and released in packets by a specialized apocrine cell structure. After apocrine decapitation and luminal dispersal, some of the cytoplasmic and PSG remnants condensed to form eosinophilic bodies (EB) with a glycoprotein rim and central protein core. EB were observed adsorbing and layering onto the surface of prostatic corpora amylacea representing their chief mode of enlargement. Biochemical analysis and x-ray diffraction studies confirmed sulfated glycosaminoglycans of similar structure as the main constituent of both PSG and corpora amylacea. Peripheral zone amphiphilic "dark cell" carcinoma (9 cases) contained almost no PSG, and showed neither apical decapitation nor EB formation, but mucin secretion was frequently detected. Crystalloids that share the same staining characteristics and sulfur content as PSG and corpora amylacea were identified in 3 selected "clear cell" carcinomas, all of which showed at least focal PSG secretion. The recognition of these differing secretory mechanisms and their deviation from normal further defines the histological criteria and spectrum of prostate malignancy.

BACKGROUND. Prostate secretory granules (PSG) represent the basic secretory unit of the prostate gland, containing many of its exocrine proteases. Recent analysis of intraluminal corpora amylacea, a proposed by-product of PSG secretion, detected sulfated glycosaminoglycans (GAG) possibly keratan sulfate (KS),indicating a secretory mechanism for GAG in the human prostate surface epithelial cell. METHODS. Immunostains using anti-KS and anti-prostate-specific antigen (PSA) were evaluated on 10 sequential radical prostatectomy specimens, three of which had received neoadjuvant antiandrogen therapy. Extracts of normal secretory tissue as well as a sample composed almost entirely of prostatic stroma were subjected to Western blot analysis, using the same antibody panel. RESULTS. Keratan sulfate secretion from the normal prostate epithelial cell has been confirmed and correlates, as does PSA, with the presence of cytoplasmic PSG. No such correlation exists in most adenocarcinomas or in benign epithelium after androgen ablation. Western blot analyses confirmed tissue immunostains and demonstrated a secretory proteoglycan of 70-95 kDa. CONCLUSIONS. Recognition of PSG heralds a novel secretory mechanism within the human prostate gland that is linked to the secretion of KS. The role of KS in normal prostate secretion remains unknown, although it appears downregulated in neoplastic and androgen-ablated cells. (C) 2000 Wiley-Liss, Inc.

BACKGROUND Prostate ducts and acini whose lumens are filled with malignant cells represent a well-recognized histological pattern recently termed intraductal carcinoma of the prostate (IDC-P). These tumors are often associated with rapid disease progression, and most recur after radical surgery. Controversy exists as to whether IDC-P should be recognized as a separate entity, an extension of high-grade dysplasia (PIN) or invasive carcinoma as described by the Gleason grading system. This study investigates the use of molecular markers in defining the position of IDC-P in the evolutionary hierarchy of prostate cancer progression. METHODS IDC-P, high-grade dysplasia, and invasive cancers from a cohort of 20 selected radical prostatectomy specimens were screened for loss of heterozygosity (LOH), using 12 polymorphic microsatellite markers frequently lost in prostate cancer. RESULTS LOH was absent in Gleason grade 3 cancer, infrequent in high-grade dysplasia (9%) and Gleason grade 4 cancer (29%), but common in IDC-P (60%). In IDC-P, and to a lesser extent Gleason grade 4 cancers, multiple sites of allelic loss in individual cases were usual. CONCLUSIONS Allelic instability provides further evidence that IDC-P is not a simple extension of dysplasia, nor does it represent invasion of Gleason grade 3 cancers into the ductal/acinar system. IDC-P and Gleason grade 4 cancer represent late but possibly separate events in prostate cancer evolution. Prostate 44:265–270, 2000. © 2000 Wiley-Liss, Inc.

Cytoplasmic clarity is a histological feature of normal prostatic secretory cells, but in this study, tissue fixation in strong (>2.5%) glutaraldehyde dramatically altered cytological staining. Secretory cytoplasm appeared red and granular on routine stains because of myriad intensely staining eosinophilic granules (PSG). Immunostaining for prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) showed their exclusive localization to the PSG. Electron microscopy confirmed these findings and also showed that after fixation in many agents, including formaldehyde, PSG appeared empty, accounting for the artefactual "clear cell" appearance on light microscopy. PSG were most densely concentrated apically in a bud-shaped luminal compartment in which cytokeratin was selectively absent. Normal exocrine secretion was visualized as detachment of apocrine buds or their in situ disintegration. Distinctively in dysplasia and almost all carcinomas, PSG were rare to absent, and proteases were free in the cytoplasm, often concentrated beneath the apical membrane. The apocrine compartment was absent, with no observed secretory mechanism. Tumor cells had dark amphiphilic cytoplasm after all fixatives. This provided a reliable method of distinguishing malignant from benign glands in tissues fixed in strong glutaraldehyde. Clear cell carcinomas, whose cytoplasm mimicked routinely fixed normal secretory cells, surprisingly had almost no PSG. Instead, their "granules" were lipid-filled vacuoles reflecting a secretory pathway not seen in normal cells, dysplasia, or the common "dark cell" carcinomas. These observations may define two distinctive biological pathways of prostate cancer evolution and may facilitate diagnostic decisions on needle biopsy samples.

Purpose: We examined cancer volume, percent Gleason grade 4/5 cancer, cancer location (peripheral versus transition zone), capsular penetration and biochemical cure rates in men undergoing radical prostatectomy to determine differences among clinical stages T1c, T2a, T2b and T2c.Materials and Methods: Detailed chart reviews confirmed the precise clinical stages assigned to 791 consecutive men treated only with radical prostatectomy. All prostates were examined prospectively by the Stanford technique of 3 mm. step sections. For biochemical cure rates a subset of 366 men were followed for a minimum of 5 years. Failure was defined as prostate specific antigen Tosoh [dagger] 0.07 ng./ml. or greater and rising. T1c was defined as impalpable cancer.[dagger] TOSOH Medics, Foster City, California.Results: T1c and T2a stages had half as much cancer volume as T2b and T2c cancers, 10 versus 25% Gleason grade 4/5 and half as much capsular penetration (30 versus 61%). Biochemical cure rates were 70 and 72% for...

Summary Penile metastases from prostate cancer are rare and are usually a manifestation of wide-spread cancer dissemination. Isolated urethral metastases form a small fraction of these cases, have a longer survival rate and may represent spread by implantation following instrumentation. We report a case of prostatic carcinoma presenting with an isolated metastasis to the penile urethra after catheterisation and transurethral prostatectomy. The primary tumor had a prominent intraductal component whose architectural features were mimicked in the metastasis. The possible mechanisms of spread and the diverse appearances of cancer associated with an intraductal component are discussed.

To evaluate the role of androgens in the pathogenesis of prostatic dysplasia, we compared the localization of androgen receptor (AR) in proliferative and nonproliferative cells in normal and dysplastic acini. Basal cells, the only proliferating cells identified in normal acini, contained AR mRNA but lacked an immunodetectable receptor. Both AR mRNA and immunodetectable receptor were present, however, in secretory and stromal cells. Androgen receptor localization in dysplastic lesions was identical to normal but here the proliferative marker Ki-67 was found in both basal and secretory cells. Our findings suggest that androgens do not directly initiate the division of basal cells, the putative precursors of secretory cells. Instead, the hormone may act through its fully translated receptor to mainly mediate the differentiation of secretory cells. The presence of both AR and Ki-67 in dysplastic secretory cells may indicate an abnormal direct androgen-mediated proliferation in this compartment. This is consistent with previous evidence that secretory cell differentiation is impaired in dysplasia.

Malignant epithelial masses within prostatic duct lumens have been equated with several conflicting entities, including Gleason cribriform grade 3 carcinoma and cribriforming dysplasia. We identified 51 radical prostatectomy cancers containing intraductal lesions among 130 cases, with total cancer volumes between 4 and 10 cc. Such lesions with duct lumen-spanning septa or masses were rare in areas away from invasive cancer (22 foci), while dysplasia (prostatic intraepithelial neoplasia) was common (1,490 foci). Consequently, these lesions were interpreted as being part of the evolution of invasive carcinoma rather than precursors; they were designated "intraductal carcinoma" as distinct from dysplasia. Intraductal cancer areas within invasive carcinoma usually represented cancer extension within the branches of a single segment of the duct-acinar system from near the urethra to the gland capsule. In 51% of cases with intraductal spread, the invasive component produced large ( > 0.5 mm) tumor masses in perineural spaces, which in turn correlated strongly with extensive capsule penetration and frequent positive surgical margins selectively at the superior nerve pedicle. The amount of grade 4/5 cancer, the amount of intraductal carcinoma, and the large perineural tumor mass appeared to be related to postprostatectomy progression of cancer, as measured by elevation of ultrasensitive serum prostate-specific antigen. It was concluded that intraductal prostatic adenocarcinoma is a common morphologic entity with precisely defined histologic criteria and a unique biologic significance, as reflected by an enhanced capacity for extensive spread within ducts and perineural spaces. It was proposed that the diversity of diagnoses attached to most cribriform malignant lesions can be unified by the concept of this single entity.

Patterns of cell proliferation in the prostate were compared between benign epithelium and dysplasia. Proliferating cell nuclear antigen (PCNA) immunostaining was used to quantitate proliferation, and basal cells were tallied separately from secretory cells with the aid of keratin immunostaining. Using a novel technique, absolute cell densities (cells/mm) were determined and used to calculate growth fractions. In benign epithelium, 83% of PCNA+ cells were basal cells, while only 7% of PCNA+ cells in dysplasia were basal cells and there was a clear separation between groups. This dramatic shift of the proliferative compartment to the secretory cells in dysplasia was accompanied only by a moderate increase in overall secretory cell density and moderate reduction in basal cell density, but these ranges overlapped those of benign epithelium. The median PCNA+ secretory cell “growth fraction” was 0.12% in benign epithelium and 1.06% in dysplasia. The findings presented give further support to the concept that dysplasia represents an evolutionary stage in the malignant transformation of prostatic epithelium. The patterns of change in PCNA immunostaining may reflect certain aspects of the biologic nature of malignant transformation. © 1995 Wiley-Liss, Inc.

Purpose: When 6 systematic prostate needle core biopsies are positive for cancer bilaterally, prediction of clinical cancer volume is limited by the unpredictable presence of contralateral incidental tumors. Criteria were sought to improve prediction.Materials and Methods: Core cancer lengths were summed unilaterally (3 biopsies) and bilaterally (6) in 65 patients with bilateral positive cores. Of the patients 31 had true bilateral cancer spread and 34 had unilateral disease with contralateral incidental tumors.Results: For both groups correlation with prostatectomy cancer volume (r = 0.65, p less than 0.001) was the same for the sum of 3 ipsilateral cores as for all 6 cores.Conclusions: Core cancer length sum of 3 ipsilateral biopsies predicts the largest prostatectomy cancer volume as well as the bilateral sum. Contralateral biopsies do not contribute to prediction nor distinguish bilateral spread from contralateral incidental cancers.

Transrectal prostate ultrasound and systematic sextant biopsies have improved peripheral zone cancer diagnosis but they may miss many cancers arising in the transition zone. Biopsies directed into the transition zone have been used to detect residual prostate cancer in patients diagnosed by transurethral resection and they have been suggested as potentially useful additions to systematic sextant biopsies. To define the indications for transition zone biopsies 187 men underwent evaluation including systematic sextant biopsies and transition zone biopsies. These patients were classified into 4 categories based on clinical presentation. Category 1 included 26 men with palpable nodularity and an elevated prostate specific antigen (PSA), of whom 16 (61.5%) had positive biopsies but none was positive only in the transition zone biopsies. Category 2 consisted of 49 men with sonographic abnormalities in the transition zone, of whom 15 (30.6%) had positive biopsies, including 2 (13.3%) with only positive t...

Transrectal prostate ultrasound and systematic sextant biopsies have improved peripheral zone cancer diagnosis but they may miss many cancers arising in the transition zone. Biopsies directed into the transition zone have been used to detect residual prostate cancer in patients diagnosed by transurethral resection and they have been suggested as potentially useful additions to systematic sextant biopsies. To define the indications for transition zone biopsies 187 men underwent evaluation including systematic sextant biopsies and transition zone biopsies. These patients were classified into 4 categories based on clinical presentation. Category 1 included 26 men with palpable nodularity and an elevated prostate specific antigen (PSA), of whom 16 (61.5%) had positive biopsies but none was positive only in the transition zone biopsies. Category 2 consisted of 49 men with sonographic abnormalities in the transition zone, of whom 15 (30.6%) had positive biopsies, including 2 (13.3%) with only positive transition zone biopsies. Category 3 consisted of 65 men with normal rectal examination and elevated PSA level, of whom 24 (36.9%) had biopsies positive for cancer, including 8 (33.3%) with only positive transition zone biopsies. Category 4 consisted of 47 men with a clinical presentation highly suspicious of prostatic malignancy but no cancer on prior systematic sextant biopsies, of whom 17 (37.7%) had positive biopsies, including 9 (53.0%) with only positive transition zone biopsies. We conclude that transition zone biopsies are useful in patients with a high suspicion of prostate cancer and negative prior systematic sextant biopsies. Cancer can also be demonstrated in many men with a normal digital rectal examination and an elevated PSA level. Patients with transition zone abnormalities on ultrasound images or palpable nodularity do not have substantially increased cancer detection with the addition of transition zone biopsies. Approximately 30% of prostate cancers originate in the transition zone.' Although most transition zone cancers were previously considered latent: transition zone tumors have become appreciated as substantial contributors to the morbidity and mortality of prostate can~er.~'~ Historically, diagnosis of all transition zone cancels was made incidentally by transurethral resection of the prostate or open enucleation. The recently recognized malignant potential of all of these tumors necessitates a means of early detection. Application of traditional methods of prostate cancer diagnosis has proved difficult. Digital rectal examination is a particularly poor detector because the anterior location of the transition zone and intervening peripheral zone result in transition zone tumors being perceived as generalized enlargement and mistaken for the more common benign prostatic hyperplasia (BPH), especially when combined with only moderate prostate specific antigen (PSA) elevation^.^ Imaging studies have also not proved reliable in the identification of transition zone cancers. With transrectal prostate ultrasound the echo patterns demonstrated by the transition zone, especially when involved with BPH, are much more hypoechoic and heterogeneous than the peripheral zone, which can mask the presence of tumors or more commonly give false-positive Computerized tomography and magnetic resonance imaging are also incapable of

Detection of microscopic seminal vesicle invasion with prostate cancer by transrectal ultrasound-guided seminal vesicle biopsies provides a method of evaluation that is much less subjective than digital rectal examination or imaging techniques. The accuracy of seminal vesicle biopsy is analyzed in 73 patients undergoing transrectal ultrasound-guided biopsy of 145 seminal vesicles followed by radical prostatectomy. Of 133 benign seminal vesicle biopsies 11 (8.3%) were found in the surgical specimen to have cancer involving an average of 6% of the seminal vesicle area. Of 8 seminal vesicle biopsies showing cancer adjacent to seminal vesicle epithelium 100% demonstrated seminal vesicle invasion in the surgical specimen extending for an average of 19% of the seminal vesicle area. Three biopsies exhibited cancer but no seminal vesicle epithelium; only 1 (33%) of these had seminal vesicle invasion for 5% of the seminal vesicle area. One biopsy revealed normal prostate tissue. Careful placement of bilateral biopsy sites cephalad to the prostate base (not traversing any portion of the prostate gland) is recommended. Caution should be exercised when basing treatment decisions on seminal vesicle biopsies that do not reveal seminal vesicle epithelium histologically.

Denonvilliers' fascia consists of a single fibromuscular structure covering the posterior aspect of the prostate and surrounding the seminal vesicles. This structure has multiple layers that are fused together, and to the stroma of the prostate and seminal vesicles. A separate posterior layer of Denonvilliers' fascia was not seen during radical prostatectomy. The cleavable interprostatorectal plane extends posteriorly throughout the thickness of Denonvilliers' fascia and anteriorly to the muscular wall of the rectum. Medially this fascia is fused with the prostatic capsule into a single sheath and contains thick smooth muscle bundles in continuity with the prostatic stroma. In a series of 243 radical prostatectomy specimens for prostate cancer, we studied the morphological relationship of Denonvilliers' fascia with the prostatic capsule and stroma, and traced the progression of prostatic cancer in relation to the anatomical landmarks. In 19% of the cases tumor was found progressing within Denonvilliers' fascia, in the medial posterior area of the prostate, unrelated to perineural space invasion. For specimens with an intracapsular cancer volume of less than 12 cc, which may be cured by radical prostatectomy alone, the frequency of invasion of Denonvilliers' fascia was 13%. In these cases cephalad progression of cancer was seen almost exclusively in Denonvilliers' fascia overlying the central zone at the prostate base and surrounding the seminal vesicles. Invasion of Denonvilliers' fascia can lead to positive surgical margins if complete excision of this fascia is not performed during radical prostatectomy. Even among large tumors in our series there were no cases of tumor invasion completely through the full thickness of Denonvilliers' fascia at the posterior medial area and, therefore, rectal wall invasion was never suspected at this level.

Background. The serum marker prostate-specific antigen (PSA) has been shown to be proportional to the volume of prostate cancer (Yang polyclonal assay). One gram of cancer on average produces 3.5 ng/ml of PSA elevation. Thus, changes in PSA in untreated patients should reflect tumor growth rate and the shape of the growth curve. Methods. Forty-three patients with previously untreated prostate cancer had serial PSA determinations during a period of at least 12 months (mean, 30 months; range, 12–63 months). There was no treatment between the initial and final PSA. PSA was measured five or more times in half of these patients. Log-PSA values were plotted versus time, tested for linearity, and compared between different clinical stages and histologic grades. Results. PSA values increased with time in 86% of patients but remained stable in 14%. The increase of PSA was exponential (log-linear) throughout the measured interval. Doubling times were faster in patients with higher disease stages and grades. Seventy-nine percent of all patients had a doubling time of more than 24 months. Twenty of 28 cancers thought to be clinically organ confined doubled at rates exceeding 48 months. Tumor doubling times were overestimated in patients with large-volume benign prostatic hyperplasia because hyperplasia increases serum PSA at an average rate of 0.3 ng/ml. Conclusions. The authors conclude that prostate cancer has a constant (log-linear) growth rate that is very slow. This extraordinarily slow doubling time has substantial consequences for therapeutic decisions and for screening programs.

Background. Using the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and American total mortality rates, the authors calculated the probability at birth of having a diagnosis of prostate cancer within a man's life to be 8.8% and then subtracted the incidence of microscopic Stage A cancers too small to ever be clinically significant. This gave a final probability of 8%. Methods. Prostates were examined after 139 consecutive unselected cystoprostatectomies from patients with bladder cancers in whom it was unknown whether they had prostate cancer

Background. In the prostate there is a uniquely high prevalence of microcarcinomas relative to larger cancers. The probability of metastasis has been found to correlate closely with increasing cancer volume. It is important to explore the relationship of microcarcinomas to these larger clinically significant cancers by comparing their histologic features and to trace their relationship to dysplasia, a proposed precursor lesion. Methods. The histologic features of 107 microcarcinomas were related to associated dysplasia lesions

Beim Adenokarzinom der Prostata wurde gezeigt, das das quantifizierte Tumorvolumen der alleinig wichtigste Parameter fur Lymphknotenmetastasen und generalisierte Ausbreitung beim individuellen Patienten ist. Es besteht ein praktischer Bedarf fur ein System zur Tumorvolumenschatzung, welches das von Standardtechniken verlangte serielle Schneiden der Prostatektomiepraparate vermeidet. Zu diesem Zweck wurden bei 145 Prostatektomiepraparaten die durch Computerplanimetrie des ganzen Satzes histologischer Schnitte erhaltenen Tumorvolume mit Tumorvolumen verglichen, die visuell geschatzt wurden und deren Anzahl ausgewahlter Schnitte gemas dreier abgekurzter Protokolle weniger als die Halfte betrug. Zwei von diesen abgekurzten Protokollen ergaben Tumorvolumenschatzungen, die in 96 % und 89 % der Falle innerhalb von ± 20 % des Computerwertes des vollen Satzes histologischer Schnitte waren. Diese Erkenntnisse definieren ein einfaches und relativ kostengunstiges Verfahren, um in einer systematischen Art und Weise wichtige prognostische Informationen aus den morphologischen Daten von Prostatektomiepraparaten beim Adenokarzinom der Prostata zu gewinnen. Quantitated tumor volume is reported to be the single most important morphologic predictor for lymph node metastasis and distant spread in the individual patient with adenocarcinoma of the prostate. There is a practical need for a system of tumor volume estimation that avoids the serial blocking of prostatectomy specimens required by standard techniques. Accordingly, in 145 prostatectomy specimens, cancer volumes obtained from computer planimetry of the full set of slides were compared with cancer volumes estimated visually in samples with fewer than half the standard number of slided selected according to three abbreviated protocols. Two of these abbreviated protocols gave cancer volume estimates that were within ± 20 % of the computer value on the full slide set in 96 % and 89 % of cases. These findings define a simple and relatively inexpensive procedure for deriving important prognostic information in a systematic fashion from the morphologic date obtained in prostatectomy specimens for adenocarcinoma of the prostate.

The serum marker prostate-specific antigen (PSA) has been shown to be proportional to the volume of prostate cancer (Yang polyclonal assay). Therefore, changes in PSA with time in untreated patients should reflect tumor growth rate and the shape of the growth curve. Forty-three patients with untreated prostate cancer had serial PSA measurements over an average time span of 30 months. The increase of PSA was exponential (log-linear) throughout the measured interval. Doubling times were faster in patients with higher stages and grades. Twenty of 28 cancers thought to be clinically organ confined doubled at rates exceeding 4 years. Tumor doubling times were overestimated in patients with large volume benign prostatic hyperplasia since hyperplasia increases serum PSA, albeit 12 times less than cancer. We conclude that prostate cancer has a constant (log-linear) growth rate which is very slow. This slow doubling time has substantial consequences for therapeutic decisions and for screening programs.

A prospective study of the use of a low osmolar gadolinium-based intravenous contrast material for MRI of the abnormal prostate was performed. Eight patients scheduled for prostatectomy, six with prostate cancer and two with benign prostatic hyperplasia (BPH), were imaged preoperatively on a 1.5 T system using a pelvic coil array and employing Gadodiamide (0.3 mmol/kg). T2-weighted fast-spin echo (FSE) imaging was also performed in the same axial planes employed for gadolinium-enhanced studies. Detailed pathologic correlation was performed for the six patients with carcinoma. While regions of BPH and cancer enhanced to a similar degree following intravenous contrast agent, BPH enhancement was more heterogeneous than cancer. No advantages in detecting prostate cancer, in differentiating cancer from BPH or normal prostatic tissue, or in assessing extra-prostatic spread of cancer were observed for the contrast-enhanced studies compared to T2-weighted FSE imaging.

Multiple independent tumors were identified in specimens from 117 of 234 prostatectomies for clinical adenocarcinoma; there were 266 incidental cancers in these 117 prostates. The clinically detected carcinoma was the largest (or only) tumor in all 202 Stage B cases. However, among 32 Stage A cases (detection by transurethral resection), there were 8 prostates in which an incidental tumor was larger than the clinically manifest cancer. These were all small tumors except for two incidental cancers with a volume greater than 2cm3; roughly 80% of incidental carcinomas were smaller than 0.5 cm3, whereas fewer than 20% of manifest tumors were smaller than 0.5 cm3. Comparison with a series of cancers found incidentally at cystoprostatectomy for bladder cancer showed the same volume distribution as incidental (smaller) carcinomas in patients with prostate cancer. This distribution was thought to reflect the volume distribution of prostate cancer in the general population older than 50 years of age. It was concluded that additional incidental tumors are common in patients with prostate cancer, but their sum of volumes is seldom as large as the clinical cancer volume.

Quantitated tumor volume is reported to be the single most important morphologic predictor for lymph node metastasis and distant spread in the individual patient with adenocarcinoma of the prostate. There is a practical need for a system of tumor volume estimation that avoids the serial blocking of prostatectomy specimens required by standard techniques. Accordingly, in 145 prostatectomy specimens, cancer volumes obtained from computer planimetry of the full set of slides were compared with cancer volumes estimated visually in samples with fewer than half the standard number of slides selected according to three abbreviated protocols. Two of these abbreviated protocols gave cancer volume estimates that were within +/- 20% of the computer value on the full slide set in 96% and 89% of cases. These findings define a simple and relatively inexpensive procedure for deriving important prognostic information in a systematic fashion from the morphologic data obtained in prostatectomy specimens for adenocarcinoma of the prostate.

Apical invasion and positive apical margins were assessed in 165 consecutive radical prostatectomies. Apical invasion, denned as cancer in the distal 8 mm of the prostate, was evident in more than 80% of the cases, and apical margins occurred in 16% of specimens with apical cancer. Clinical judgment was not effective in predicting t apical cancer. Frequency of apical margins increased in proportion to greater cancer volume, from 9.8% in cancers smaller than 4 cc to 30.7% in cancers larger than 12 cc. However, most positive margins in the group with cancers smaller than 4 cc were caused by inadvertent incision into the prostate during the operation, whereas the vast majority of apical margins in cancers larger than 4 cc were caused by capsule penetration of the tumor. Although margins associated with capsule penetration occurred characteristically in the posterior (rectal) portion of the apex, margins caused by incision into the prostate were distributed over the entire apical surface of the gland. Positive margins at the urethral stump were quite uncommon (occurring in four cases). These findings suggest that modifications of surgical technique might reduce the frequency of this complication.

Sarcomatoid renal cell carcinoma (SRCC) is an aggressive tumor variant thought to arise predominantly from dedifferentiation of clear cell carcinoma. A few reports of SRCC associated with non–clear cell tumors led to the presumption that SRCC may arise from any renal cell carcinoma, although direct evidence of this is lacking. Cytogenetic studies on 3 previously documented SRCCs associated with papillary renal cancers showed either 3p deletions or absence of trisomy 7, 17 in the sarcomatoid tumors, suggesting origin from a coexistent clear cell tumor. The present case represents the first conclusive evidence of direct progression of non–clear cell carcinoma to SRCC with both tumor components containing multiple copies of chromosomes 7 and 17. Many genetic anomalies, including p53 mutations, frequently recognized in SRCC were not recognized in this case, highlighting the importance of cytogenetic evaluation of all SRCC. The patient is well and without evidence of tumor progression 1 year after surgery, and the sinister outlook of SRCC in association with clear cell carcinoma may not apply in SRCC of non–clear cell origin.

Separation of renal cell tumors into different prognostic groups is an imperative function of the diagnostic pathologist. Recently, chromophobe renal carcinoma has been described as a tumor that is morphologically distinct from conventional “clear cell” carcinoma and that has a low metastatic potential. Identification is based on routine light microscopic features and is confirmed by special stains, immunohistochemistry, and electron microscopy. We present a variant of chromophobe renal carcinoma that did not show the typical cytomorphologic features on light microscopy after formaldehyde fixation. After fixation in Solufix (a commercial fixative), these features were recognized and the diagnosis was confirmed. The tumor also showed an unusual form of calcification and psammoma body formation not previously recognized in chromophobe tumors. Molecular biological assessment was inconclusive, but excluded a chromosome 3p deletion usually found in conventional renal carcinoma. The use of a different primary fixative may provide a cost-effective screening tool to detect variant renal tumors and may have important prognostic implications.

In a series of 100 prostatectomy specimens obtained for adenocarcinoma, 107 additional incidental microscopic (less than 0.05 cm3) carcinomas were identified. Their morphologic features including location, histologic grade, and associated premalignant changes were documented. In 51 cases there was strong evidence of transition between microcarcinoma and the premalignant lesion, duct-acinar dysplasia. Invasive cancer was usually related to dysplasia through a characteristic intermediate morphologic stage of transitive glands. These glands were smaller than prostatic ducts; they appeared to arise by budding from dysplastic duct walls and showed the same distinctive lining epithelium. They were distinguished from invasive glands by their pseudo-stratified epithelial lining and by consistent association with a sparse, discontinuous basal cell layer. Cytoplasmic differentiation at the point of junction of invasive cancer with transitive or dysplastic glands was studied by immunohistochemical staining for the differentiation markers prostate-specific antigen and pepsinogen II, and staining for mucin. Markedly reduced cytoplasmic differentiation was common in dysplastic and transitive glands. Invasion often coincided with an abrupt increase in cytoplasmic differentiation with expression of ectopic differentiation products. This sequence of biologic changes should be tested in other carcinomas where the exact point of invasion can be identified.