John E. McNeal

Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate.

To compare the clinical usefulness of the serum markers prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), we measured them by radioimmunoassay in 2200 serum samples from 699 patients, 378 of whom had prostatic cancer. PSA was elevated in 122 of 127 patients with newly diagnosed, untreated prostatic cancer, including 7 of 12 patients with unsuspected early disease and all of 115 with more advanced disease. The PSA level increased with advancing clinical stage and was proportional to the estimated volume of the tumor. The PAP concentration was elevated in only 57 of the patients with cancer and correlated less closely with tumor volume. PSA was increased in 86 percent and PAP in 14 percent of the patients with benign prostatic hyperplasia. After radical prostatectomy for cancer, PSA routinely fell to undetectable levels, with a half-life of 2.2 days. If initially elevated, PAP fell to normal levels within 24 hours but always remained detectable. In six patients followed postoperatively by means of repeated measurements, PSA--but not PAP--appeared to be useful in detecting residual and early recurrence of tumor and in monitoring responses to radiation therapy. Prostate massage increased the levels of both PSA and PAP approximately 1.5 to 2 times. Needle biopsy and transurethral resection increased both considerably. We conclude that PSA is more sensitive than PAP in the detection of prostatic cancer and will probably be more useful in monitoring responses and recurrence after therapy. However, since both PSA and PAP may be elevated in benign prostatic hyperplasia, neither marker is specific.

Zonal distribution of prostatic adenocarcinoma: correlation with histologic pattern and direction of spread

For 104 prostate glands obtained at radical prostatectomy for adenocarcinoma, we mapped the tumor outline and determined the tumor volume, grade, and location relative to the transition zone boundary and location of the central zone. Among the 88 cancers whose probable zone of origin could be identified, 68% arose in the peripheral zone, 24% arose in the transition zone, and 8% arose in the central zone. Transition zone carcinomas had usually been diagnosed by transurethral resection (TUR) and often appeared to arise within BPH nodules; only two of 67 non-transition zone carcinomas had been diagnosed at TUR. Two-thirds of 21 transition zone cancers showed a distinctive histologic appearance; they were made up of columnar clear cells lining glands of widely variable size and contour. The transition zone boundary appeared to act as a barrier to the spread of non-transition zone carcinomas. We conclude that carcinoma typically arises in the region of the prostate that is susceptible to benign prostatic hyperplasia and that the great majority of Stage A (TUR) cancers are transition zone cancers. Non-transition zone cancers detectable at TUR are predominantly large tumors that are poorly differentiated and lack the clear cell histologic pattern.

Normal histology of the prostate

The prostate gland contains three major glandular regions--the peripheral zone, the central zone, and the transition zone--which differ histologically and biologically. The central zone is relatively resistant to carcinoma and other disease; the transition zone is the main site of origin of prostate hyperplasia. There are also several important nonglandular regions concentrated in the anteromedial portion of the gland. Each glandular zone has specific architectural and stromal features. In all zones, both ducts and acini are lined by secretory epithelium. In each zone, there is a layer of basal cells beneath the secretory lining, as well as interspersed endocrine-paracrine cells. Frequent deviations from normal histology include post-inflammatory atrophy, basal cell hyperplasia, benign nodular hyperplasia, atypical adenomatous hyperplasia, and duct-acinar dysplasia. These lesions may at times be confused with carcinoma, especially in biopsy material.

Origin and development of carcinoma in the prostate

Detailed histologic study of 45 cancerous prostate glands in 134 autopsies provided new information on the natural history of prostatic carcinoma. Origin of carcinoma was limited to one of two histologically distinct regions, but with no apparent predilection for the “posterior lobe” or sub capsular area. Carcinoma selectively originated from active gland epithelium rather than a trophic glands, and distinctive premalignant changes accompanied its origin. Evidence from volume distribution data suggests that there are not two types of prostatic carcinoma with different biologic potential, but a single species having slow growth rate with a logarithmic growth curve. The development of carcinoma in the gland follows predictable patterns, including early involvement of the capsule and perineural spaces. The later course of tumor growth is characterized by loss of differentiation and the ability to penetrate the capsule and periurethral stroma. This suggests a gradual increase in biologic malignant potential which is closely linked to tumor size. Probably the capacity for distant metastasis is almost limited to large carcinomas, and penetration of the gland capsule may be the most important predisposing factor.

Capsular penetration in prostate cancer : significance for natural history and treatment

We established the location and extent of complete capsule penetration by prostate cancer in 176 radical prostatectomy specimens and related these findings to cancer volume, location of positive surgical margins, and presence of nodal metastases or seminal vesicle (SV) invasion. Extent of capsule penetration, cancer volume, and positive nodes/SV were strongly intercorrelated. It could not be shown that capsule penetration was related to prognosis independently of its correlation with cancer volume. Twelve cubic centimeters was a critical cancer volume; above that, combinations of extensive capsule penetration, positive surgical margins, and positive nodes/SV were almost universal. In cancers under 12 cc, positive surgical margins were only moderately correlated with cancer volume; they often represented surgical resection into the capsule rather than a complication of capsule penetration by tumor and were most common at the apex, where dissection is most difficult. In non-transition zone cancers (148 cases), capsule penetration was most common posterolaterally, where nerves penetrate the capsule. In transition zone cancers (28 cases), capsule penetration was much less common and was located more anteriorly. Apical positive margins were also relatively common in transition zone cancers, but seminal vesicle invasion was never seen.

An Abbreviated Standard Procedure for Accurate Tumor Volume Estimation in Prostate Cancer

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.

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&bgr;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.

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.

Modified Extrafascial Radical Retropubic Prostatectomy Technique Decreases Frequency of Positive Surgical Margins in T2 Cancers 3

Objectives: In an effort to decrease the frequency of postoperative positive surgical margins (+SM), a modified extrafascial radical prostatectomy technique was developed and evaluated.Methods: 402 consecutive radical prostatectomy specimens removed for clinical stage T2 cancers from 1987 to 1994 were histologically examined prospectively for tumor volume, extraprostatic extension and +SM. Surgical technique modification was introduced in 1990. We compared the histologic status and biological outcome of the prostatectomy cases in 1987–1989 (n = 166) to those treated from 1990 to 1994 (n = 236).Results: The two series were comparable in (1) clinical stage and preoperative (PSA, (2) tumor volume, grade and location, and (3) capsular penetration, seminal vesicle and lymph node status. +SM fell from 32 to 25% overall, but for 146 (36%) prostates with a tumor volume <2 cm3, +SM fell from 21 to 6% which was statistically significant. Outcome measured by biological progression showed a decrease from 33% for +SM to 13% for –SM for cases with a tumor volume <2 cm3. For cancer volumes >2 cm3, the incidence of +SM did not vary significantly. We describe the anatomic details necessary for exposure of periprostatic fascias and extrafascial dissection at (1) the prostatourethral junction which ensures wide excision of the anterior and apical aspect of the prostate, (2) the posterior and apical area (development of the prerectal space), lateral and posterior areas at the base of the prostate which ensures wide excision of the rectoprostatic fascia (Denonvilliers’s fascia) and lateral prostatic fascia.Conclusions: Differences in surgical technique probably accounted for the significant decrease in +SM for those T2 cancers with volumes ≤2 cm3 which represents 36% of the T2 cancers in our series. Recent screening with PSA (T1c cancers) increases the incidence of these cancers ≤2cm3. This modified uni– or bilateral anatomic extrafascial prostatectomy with improved +SM and biological progression rates for T2 cases should be evaluated for T1c cases.

Clinical observations on the doubling time of prostate cancer

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.