Assessment of morphometric measurements of prostate carcinoma volume.

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 (pi / 6 x width x height x 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 r(2) = 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, r(2) 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. r(2) 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 (r(2) 0.652).

An analysis of 148 consecutive transition zone cancers: clinical and histological characteristics.

PURPOSE: To improve our understanding of transition zone cancer in terms of the diagnosis and biological behavior we examined all morphological and clinical variables in 148 consecutive cases of untreated transition zone cancer after radical retropubic prostatectomy. We matched 79 cases by total cancer volume to 79 of pure peripheral zone cancer with no secondary tumors. MATERIALS AND METHODS: Using the Stanford technique of prospective 3 mm. step sections we identified 175 of 996 men (18%) with untreated transition zone cancer after radical retropubic prostatectomy who had the largest cancer volume in the transition zone. We excluded 27 patients from study due to previous transurethral prostatic resection or incomplete data. Preoperative serum prostate specific antigen (PSA) was determined by the Tosoh AIA-600 PSA assay. Postoperatively a PSA of 0.07 ng./ml. and increasing represented biochemical failure when the assay was done in the ultrasensitive mode. RESULTS: Of the 148 cases of transition zone cancer 80% had organ confined disease, 70% stage T1c impalpable disease, 63% a positive initial prostatic biopsy, 62% unilateral cancer in the transition zone, 52% a secondary tumor only in the peripheral zone, 61% serum PSA 10 ng./ml. or greater preoperatively, 36% cancer volume greater than 6 cc and 24% at least 50% Gleason grade 4/5 cancer. Only 20% of the tumors were located in the proximal third of the transition zone near the bladder. The number of secondary tumors in the transition zone ranged from 1 to 12 (median 3) and secondary tumor volume ranged from 0.01 to 4.8 cc (median 0.6). Mean distance plus or minus standard deviation from the posterior prostatic capsule to the posterior border of the transition zone cancer was 12. 0 +/- 7.6 mm. (median 12.3). While only 15% of patients had capsular penetration, 29% had anterior positive surgical margins, 2.7% seminal vesicle invasion and 3.4% lymph node metastasis. When 79 transition zone cancers were matched by volume with 79 peripheral zone cancers, there were no differences in percent Gleason grade 4/5, serum PSA or prostate weight, although differences in clinical stage T1c to T2c and organ confined cancer were highly significant (p <0.0001). Kaplan-Meier curves showed that at 5 years of followup 49.2% of the men with peripheral zone cancer had undetectable PSA compared with 71.5% of those with transition zone cancer (log rank test p = 0.0002). CONCLUSIONS: Our report should make it easier to diagnose transition zone cancer. The 72% biochemical PSA cure rate is significantly higher than the 49% cure rate for peripheral zone cancer. Since cancer volume and percent Gleason grade 4/5 disease were the same in these 2 groups matched by cancer volume, the differences in behavior of peripheral and transition zone cancers must be sought at the molecular level unless anatomical location alone explains the differences in progression. Pathologists should differentiate transition from peripheral zone cancer when analyzing radical prostatectomy specimens.

Examination of the 3 molecular forms of serum prostate specific antigen for distinguishing negative from positive biopsy: relationship to transition zone volume.

PURPOSE: We evaluated the relative usefulness of total, free and complexed serum prostate specific antigen (PSA), and their ratios for distinguishing positive from negative biopsy of prostates in a university referral practice. MATERIALS AND METHODS: We compared 90 consecutive men who had 2 sets of 6 negative systematic biopsies with 70 who had at least 5 mm. of prostate cancer in systematic biopsies during the same period at our institution. Total prostate and transition zone volumes were determined by transrectal ultrasound. The Bayer, DPC and Hybritech assays were performed to measure total, free and complexed serum PSA. Receiver operating characteristics curves were constructed for all forms of serum PSA and their ratios as well as prostate size to distinguish true positive (sensitivity) from false-positive (1 minus specificity) fractions. RESULTS: Complexed PSA was only marginally better than total serum PSA. Free-to-total, complexed-to-total and prostate size had highly significant areas under the curves of greater than 80%. Free PSA only was better than complexed or total PSA. When factored by prostate volume, total PSA performed as well as the PSA ratios, and transition zone volume was consistently better than total prostate volume. DPC free-to-total ratios were equivalent to Hybritech ratios in all respects. CONCLUSIONS: Complexed PSA is only marginally better than total PSA for distinguishing negative from positive biopsy of prostates. It is inferior to free PSA and far less useful than free-to-total or complexed-to-total ratios. Prostate size is a decisive variable in men in whom we avoided the expected 25% false-negative biopsy rate in terms of specificity and hopefully avoided insignificant cancer in terms of sensitivity. In the future the performance of PSA serum markers should be related to a transition zone volume of less than 20, 20 to 60 and greater than 60 gm. when comparing assays to each other.

Histological and clinical findings in 896 consecutive prostates treated only with radical retropubic prostatectomy: epidemiologic significance of annual changes.

PURPOSE: Recognizing that the unprecedented increase in new cases of prostate cancer between 1988 and 1996 actually peaked in 1992 and has now returned to baseline, we examined our clinical and histological database for annual trends in 896 consecutive men treated only with radical prostatectomy for clinical stages T1c to T2c from 1988 to 1996. MATERIALS AND METHODS: All radical prostatectomy specimens were examined prospectively in 3 mm. step sections by 1 pathologist. Using multiple logistic regression for dichotomous variables and multiple linear regression for continuous variables, both corrected for age, we assessed the annual trends for significant changes in T1c versus T2 clinical stages, preoperative serum prostate specific antigen (PSA), cancer volume, percent Gleason grade 4/5 in the cancer, location of the cancer in the transition or peripheral zone, organ confined status, seminal vesicle invasion, positive surgical margins, prostate weight and presence of clinically insignificant cancers (less than 0.5 cc in volume). RESULTS: There were no significant annual changes in the proportion of percent Gleason grade 4/5 cancer, serum PSA, prostate weight or clinically insignificant cancers less than 0.5 cc, and the annual changes for cancer volume were only of moderate significance. T1c cancers increased from 10% in 1988 to 73% in 1996 (p=0.0001), organ confined cancers from 40 to 75% (p=0.0001) and transition zone cancers from 10 to 21% (p=0.003). Seminal vesicle invasion decreased from 18 to 5% (p=0.001) and positive surgical margins from 30 to 14 (p=0.006). Mean patient age changed from 65 to 62 years (p=0.0001). CONCLUSIONS: We believe that the extraordinary rise and fall in prostate cancer detection rates from 1990 to 1994 primarily removed previously undetected T2 cancers from the pool at large, leaving impalpable T1c cancers as the primary reservoir of prostate cancers in the United States. Importantly, cancer volume, percent Gleason grade 4/5 cancer, serum PSA and cancers less than 0.5 cc have not had a highly significant change during these critical 9 years. These data argue strongly that current PSA testing has not resulted in the detection of clinically insignificant cancers, and that PSA screening should be expanded and not restricted.

Significance of demonstrable vascular space invasion for the progression of prostatic adenocarcinoma.

Histologically demonstrable vascular invasion by tumor has been reported as an index of poor prognosis correlating with increased probability of metastasis in many types of cancer other than prostatic. We quantitated vascular invasion foci in 357 radical prostatectomy specimens and developed improved criteria for their diagnosis and their distinction from fixation artifact. Vascular invasion foci were found in 7% of cancers less than 4 cc in volume and 24% of larger cancers. Most foci were selectively located either near the basal end of the cancer or near the transition zone border. Correlations among multiple morphologic variables showed significant correlation of vascular invasion only with the presence of intraductal carcinoma. The only statistically significant independent predictors of disease progression (serum prostate-specific antigen elevation) were vascular invasion, carcinoma grade, and cancer volume. Our findings suggest that further study of vascular invasion foci may disclose additional information about the biologic features of local and distant spread of prostatic carcinoma.

Spread of adenocarcinoma within prostatic ducts and acini. Morphologic and clinical correlations.

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.