Fuad S. Freiha

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.

Prostate Specific Antigen in the Diagnosis and Treatment of Adenocarcinoma of the Prostate. II. Radical Prostatectomy Treated Patients

Serum prostate specific antigen was determined (Yang polyclonal radioimmunoassay) in 102 men before hospitalization for radical prostatectomy. Prostate specimens were subjected to detailed histological and morphometric analysis. Levels of prostate specific antigen were significantly different between patients with and without a Gleason score of 7 or greater (p less than 0.001), capsular penetration greater than 1 cm. in linear extent (p less than 0.001), seminal vesicle invasion (p less than 0.001) and pelvic lymph node metastasis (p less than 0.005). Prostate specific antigen was strongly correlated with volume of prostate cancer (r equals 0.70). Bivariate and multivariate analyses indicate that cancer volume is the primary determinant of serum prostate specific antigen levels. Prostate specific antigen was elevated 3.5 ng. per ml. for every cc of cancer, a level at least 10 times that observed for benign prostatic hyperplasia. Prostate specific antigen is useful as a preoperative marker because no patient with lymph node metastasis had serum levels of less than 10 ng. per ml. (4 times the upper limit of normal range). Of the patients with greater than 50 ng. per ml. two-thirds had microscopic lymph node metastasis and 90 per cent had seminal vesicle invasion. Serum prostatic acid phosphatase levels showed a significantly weaker correlation with cancer volume (r equals 0.51) and every other pathological parameter. Of the patients 73 per cent had serum prostatic acid phosphatase levels in the normal range (0 to 2.1 ng. per ml.), including 7 per cent who had pelvic lymph node metastasis. Postoperative prostate specific antigen values were available in 97 of 102 patients, with a mean and maximum followup of 12 and 38 months. No patient with pelvic lymph node metastasis achieved an undetectable prostate specific antigen level without adjunctive therapy (hormonal or radiation). No difference in preoperative or postoperative prostate specific antigen levels, cancer volume, seminal vesicle invasion or incidence of pelvic lymph node metastasis was seen between patients with no capsular penetration and those with minimal capsular penetration (1 cm. or less total linear extent of full thickness penetration), providing the first quantitative evidence that small amounts of capsular penetration may not be of biological or prognostic significance.

Morphometric and Clinical Studies on 68 Consecutive Radical Prostatectomies

Morphometric reconstructions of 68 consecutive radical prostatectomies were analyzed for cancer volume, extent of complete capsular penetration, microscopic seminal vesicle and lymph node invasion, and histological differentiation, all of which were strongly interrelated. At less than 3.0 cc cancer volume, only 6 of 34 prostates (18 per cent) showed capsular penetration compared to 27 of 34 (79 per cent) with tumors of greater than 3.0 cc. Seminal vesicle invasion occurred once in 34 tumors of less than 3.0 cc and 15 times in those greater than 3.0 cc. All 6 patients with metastases to lymph nodes, 2 with early postoperative development of bone metastases and 4 of 5 with reappearance of detectable prostate specific antigen postoperatively had cancer volumes of greater than 4.0 cc. Correlation of digital rectal examination with cancer volume showed that of 39 palpable nodules in prostates with a cancer volume of less than 4.0 cc 30 (77 per cent) occupied 50 per cent or less of the length of 1 lobe (clinical stage B1 in our classification). Of 22 palpable lesions in tumors of greater than 4.0 cc 21 (95 per cent) exceeded 50 per cent of 1 lobe in the longitudinal extension (stage B2) or they represented bilaterally palpable disease (stage B3). Capsular penetration into the periprostatic fat occurred most commonly in the dorsolateral area of the neurovascular bundle, including 10 of 12 tumors less than 4.0 cc in volume (stage B1) and 19 of 21 with greater than 4.0 cc in tumor volume (stages B2 and B3). All 10 of the stage B1 cancers were free of contralateral lobe capsular penetration while 1 of the 13 stage B2 nodules had minimal contralateral capsule penetration in the area of the neurovascular bundle. We believe that the modified nerve-sparing radical prostatectomy should be limited to the contralateral side in stage B disease.

Histologic differentiation, cancer volume, and pelvic lymph node metastasis in adenocarcinoma of the prostate

The Gleason grading system for prostate cancer was applied quantitatively to analysis of entire tumors in 209 radical prostatectomy specimens from patients with clinical Stage A and Stage B carcinoma. Percentage of poorly differentiated tumor (Gleason histologic pattern 4 and/or 5) was related to quantitated cancer volume, cancer location within the prostate, and presence or absence of pelvic lymph node metastasis. A strong correlation was found between cancer volume, percentage of poorly differentiated cancer, and nodal metastasis. Twenty‐two of 38 patients with more than 3.2 cc of Gleason histologic pattern 4‐5 cancer had nodes with positive results, compared with one of 171 patients with less than 3.2 cc of pattern 4‐5 cancer. Gleason histologic patterns 1 and 2 cancer was found mainly in a small subgroup of tumors whose site of origin was in the anatomic transition zone and whose volume was less than 1 cc. Gleason “cribriform” histologic pattern 3 cancer was thought to represent mainly intraductal carcinoma. Its increase in area with increasing cancer volume paralleled the increase in pattern 4 cancer and was counter to the decrease in other types of pattern 3 cancer.

A Randomized Trial of Radical Cystectomy Versus Radical Cystectomy Plus Cisplatin, Vinblastine and Methotrexate Chemotherapy for Muscle Invasive Bladder Cancer

PURPOSE Standard treatment for muscle invasive transitional cell cancer of the bladder is radical cystectomy. Despite careful staging, the majority of cancers with regional lymph node involvement and/or invasion to adjacent organs eventually recur. We investigated the benefit of chemotherapy with cisplatin, methotrexate and vinblastine (CMV) after radical cystectomy. MATERIALS AND METHODS A prospective trial was done in which patients were randomized after cystectomy to receive either 4 cycles of CMV chemotherapy or observation. At relapse, patients were treated with standard CMV chemotherapy for metastatic disease at our institution. RESULTS Of 55 patients who entered this trial 1 was ineligible and in 4 it is too soon to be evaluated. Of the 50 evaluable patients 25 were randomized to receive adjuvant CMV chemotherapy and 25 were observed. In the CMV arm 12 (48%) and in the observation arm 5 (25%) never had recurrence. With a median followup of 62 months and no patient with less than 2 years of followup, the freedom from progression in the adjuvant chemotherapy group was superior to that in the observation group (median 37 versus 12 months, respectively, p = 0.01). Median survival in the adjuvant group was 63 months compared to 36 months for the observation group. Surprisingly, some cases with relapse could be salvaged with CMV chemotherapy, perhaps contributing to this lack of difference in overall survival (p = 0.32). CONCLUSIONS Treatment with CMV chemotherapy after radical cystectomy is an acceptable approach in patients with stages p3b and p4N0 or N1 transitional cell carcinoma of the bladder. Further studies must be performed to determine whether these results can be extrapolated to patients with more limited disease (stages p2 and p3a) who are currently treated with radical cystectomy or definitive irradiation.

Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study.

Fifty-eight patients with metastatic transitional cell carcinoma of the urinary tract received cisplatin, methotrexate, and vinblastine (CMV) combination chemotherapy. Complete responses (CRs) were noted in 14 of the 50 (28%) evaluable patients and partial responses (PRs) in 14 patients for an overall response rate of 56% (95% confidence limits of 42% to 70%). The median duration of the 14 CRs was 9 months. Six of the 14 CRs (43%) remain in unmaintained remission from 6 + to 35 + months from onset of treatment. The median survival of evaluable patients receiving CMV was 8 months. Median survival for CRs was 11 months v 7 months for PRs (P less than .05) and 6 months for nonresponders. Renal and hematologic toxicities with this regimen were moderate. CMV is an effective regimen for patients with metastatic transitional cell carcinoma of the bladder. Prolonged disease-free survival may result from a CR to this regimen.

The Role of Perineural Space Invasion in the Local Spread of Prostatic Adenocarcinoma

In 176 radical prostatectomy specimens areas of capsule penetration by cancer and positive surgical margins were quantified and located over the prostate surface. The presence of cancer within the perineural space was sought in these areas and compared to the normal distribution of prostatic nerve branches. Capsule penetration was found in 78 of 156 stage B carcinomas, and in 39 of these 78 (50 per cent) it occurred entirely by cancer extension through the capsule within perineural spaces. In the remaining 39 prostates capsule penetration by perineural space invasion predominated but direct spread also was found. Most often, perineural space invasion followed the oblique vertical course of nerve branches that extended superiorly to the superior pedicle near the prostate base. In such cases capsule penetration areas were localized near the superior margin of the cancer, and in 11 per cent positive superior pedicle margins resulted from continued perineural space invasion outside the capsule. In cancers near the prostate apex capsule penetration by perineural space invasion produced positive margins in 89 per cent of 18 cases because of the short inferior pedicle. The role of perineural space invasion by cancer was less prominent in 4 of 20 stage A cancers that showed capsule penetration.

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.

Identification of Residual Cancer in the Prostate Following Radiation Therapy: Role of Transrectal Ultrasound Guided Biopsy and Prostate Specific Antigen

Transrectal, ultrasound guided needle biopsies were performed in 27 men greater than 18 months (mean 5.2 years) after radiation therapy for prostate cancer. Of the patients 18 (67 per cent) originally had localized (stage A or B), 6 had stage C and 3 had stage D1 prostate cancer. In addition to biopsies directed at any hypoechoic regions of the prostate, multiple systematic biopsies were performed from the apex to the base bilaterally and the seminal vesicles also were biopsied regardless of appearance. Of 27 patients 25 (93 per cent) had post-irradiation biopsies positive for cancer, including 5 of 5 with prostate induration and 20 of 22 (91 per cent) with normal post-irradiation digital rectal examinations. Ultrasound findings per se were poorly correlated with pathological findings in the irradiated prostate. Directed biopsies of hypoechoic areas were positive for cancer in 67 per cent of the cases and isoechoic areas were positive for cancer in 65 per cent. Seminal vesicle biopsies were positive in 7 patients (26 per cent), including 4 with normal post-irradiation rectal examinations and 4 with normal ultrasound appearance. Of 12 patients 10 (83 per cent) with serum prostate specific antigen levels less than 10 ng. per ml. had positive biopsies, as did all 15 with levels greater than 10 ng. per ml.