Computer modeling of prostate biopsy: tumor size and location--not clinical significance--determine cancer detection.

PURPOSE: Sampling error is an inherent problem of prostate biopsy, and the determination of clinical significance based on biopsy results is problematic. We quantify the dimensions of these problems by computer simulation. MATERIALS AND METHODS: We constructed 3-dimensional solid computer models of 59 autopsy prostates containing clinically undetected prostate cancer, and performed simulations of the standard prostate biopsy method. RESULTS: Biopsy simulation detected 19 tumors from the 59 prostates, the majority of which were in the most accessible portion of the prostate, the posterior peripheral zone. Using 0.5 cc or greater tumor volume or less than 0.5 cc and Gleason sum 7 or greater as criteria of significance, the model detected 58% (11 of 19) significant tumors and 20% (8 of 40) insignificant tumors. With 0.25 cc or greater tumor volume or less than 0.25 cc and Gleason sum 7 or greater as criteria 15 of 29 significant (52%) and 4 of 30 insignificant (13%) tumors were detected. Among significant tumors defined by either volume criterion there was a statistical difference between detected and undetected tumors in terms of mean tumor volume and mean ratio of tumor volume-to-prostate volume. Among insignificant tumors defined by either criterion there was no such difference. CONCLUSIONS: As much as 20 to 40% of currently detected prostate cancer may be histologically insignificant, as 4 of 19 cancers were detected when 0.25 cc was used as volume determinant of clinical significance and 8 of 19 were detected when 0.5 cc volume was used. These tumors are detected randomly. On the other hand, perhaps only one-half to three-fourths of clinically significant prostate cancers are being detected, and then only because the volume and anatomic location make them hard to miss.

Prostatic acid phosphatase levels (enzymatic method) from completely sectioned, clinically benign, whole prostates.

Clinically benign, whole untrimmed prostates were obtained from 104 patients at autopsy, completely sectioned, and examined microscopically. The histological and gross findings of the prostate were correlated with premortem prostatic acid phosphatase levels (PAP, enzymatic method, ACA, Dupont Co.) to determine how often carcinoma of the prostate (CAP) affected PAP levels and to identify other findings within the prostate associated with elevated PAP levels. Sixty (58%) prostates did not have CAP, 34 (33%) had CAP smaller than 1 ml in volume, and 10 (10%) had CAP larger than 1 ml in volume. PAP levels were elevated (greater than 1 U/L) in 8 of 60 (13%) prostates without CAP, in 2 of the 34 (6%) prostates with CAP smaller than 1 ml, and in 1 of the 10 (10%) prostates with CAP larger than 1 ml. These differences were not statistically significant. Likewise, a statistically significant correlation between PAP levels and patient age, patient race, severe inflammation, of high grade prostatic intraepithelial neoplasia (PIN) was not found. However, there was a statistically significant correlation between PAP levels and prostate weight (p < 0.0001). This study suggest that PAP cannot distinguish between patients with clinically undetected CAP and patients without CAP. Furthermore, elevated PAP levels are often not due to metastatic CAP and additional evidence should be present, even in patients with known CAP, before an elevated PAP level is considered to be conclusive evidence of metastatic CAP.

Serum prostate specific antigen levels in non-specific granulomatous prostatitis.

OBJECTIVE: To evaluate serum prostate-specific antigen (PSA) levels in patients with granulomatous prostatitis, an inflammatory condition that can clinically mimic malignancy. PATIENTS AND METHODS: The study comprised 10 consecutive patients (age range 53-80 years) with histologically-documented granulomatous prostatitis and who had serum PSA levels recorded before and after diagnosis. RESULTS: PSA levels in six of the patients were normal (< 4.0 ng/mL) at diagnosis. The other four had slightly elevated PSA levels, with three being between 4.0 and 6.0 ng/mL and the other 10.1 ng/mL. In six of the patients, there was a dramatic decrease (> 40%) in PSA level within 6-12 months after the histological documentation of granulomatous prostatitis. At the final follow-up, all 10 patients had normal PSA levels. CONCLUSION: Granulomatous prostatitis may cause a relatively mild and transient increase in serum PSA level which resolves when the inflammation subsides.

The incidence of unsuspected metastases from clinically benign prostate glands with latent prostate carcinoma.

OBJECTIVE: To determine how many latent prostate gland carcinomas (unsuspected carcinomas in clinically benign prostate glands) metastasize. DESIGN: The prostate glands and the pelvic and paraaortic lymph nodes were removed at autopsy from 209 consecutive patients with clinically benign prostate glands. The prostate glands were completely sectioned and examined microscopically using full cross sections. Pelvic and para-aortic lymph nodes were identified and examined microscopically for metastases. RESULTS: Seventy-nine (38%) of the prostate glands had latent prostate carcinomas. None of the pelvic or paraaortic lymph nodes contained metastases. CONCLUSION: This study suggests that few latent prostate-gland carcinomas metastasize.

Evaluation of age-specific normal ranges for prostate-specific antigen.

OBJECTIVES: To compare the traditional normal range (TNR) of 0.0 to 4.0 ng/mL for serum prostate-specific antigen (PSA) to age-specific normal ranges (ASNRs). METHODS: An autopsy series of completely sectioned, clinically benign prostates from 171 consecutive Caucasian men over the age of 40 years was selected. These patients were divided into those having no prostate cancer at autopsy, prostate cancer less than 1 cc in volume, and prostate cancer at least 1 cc in volume. The PSA values of each group were compared using both the TNR and the ASNR. RESULTS: Twenty-three of 105 (21.9%) patients with no cancer had elevated PSA values by the TNR, whereas only 18 (17.1%) were elevated using the ASNR. Nine of 54 (16.7%) with cancer less than 1 cc were elevated using the TNR, and 7 of 54 (13.0%) using the ASNR. Of 12 patients with cancer at least 1 cc, all had elevated PSA levels using the TNR and 11 (91.7%) were elevated using the ASNR. All discrepancies between the TNR and ASNR occurred in the 60- to 79-year age range. CONCLUSIONS: Use of ASNRs appears helpful in increasing the specificity of PSA by eliminating some elevated values in patients in their 60s and 70s.

Incidence, racial differences, and prognostic significance of prostate carcinomas diagnosed with obstructive symptoms.

BACKGROUND: It is unknown how often prostate carcinomas are diagnosed as a result of urinary obstructive symptoms or whether prostate carcinomas diagnosed because of obstructive symptoms have a favorable or unfavorable prognosis. It is also unknown whether racial differences in obstructive symptoms could help explain why black men with prostate carcinoma are diagnosed with more advanced stages and grades of prostate carcinoma than are white men with prostate carcinoma. METHOD: At a single Veterans Administration Medical Center, 478 consecutive cases of prostate carcinoma diagnosed between 1973 and 1985 were identified. The incidence of obstructive symptoms at diagnosis, racial differences in obstructive symptoms, and the survival of patients with and without obstructive symptoms, stratified by stage and grade, were determined. In addition, racial differences in the frequency of surgical intervention required to relieve the obstructive symptoms were determined. RESULTS: All patients diagnosed with Stage A prostate carcinoma and most (82%) patients diagnosed with Stage C prostate carcinoma had obstructive symptoms. Those diagnosed with Stage B and Stage D prostate carcinomas had with similar frequencies (53% and 55%, respectively) of obstructive symptoms. Survival, stratified by stage and grade, was similar for men with and without obstructive symptoms. The incidences of obstructive symptoms and the frequency of surgical intervention to relieve the obstructive symptoms, stage for stage, were similar for white and black men. CONCLUSION: Survival, stratified by stage and grade, is not affected adversely by obstructive symptoms. Neither racial differences in the incidence of obstructive symptoms nor the frequency with which obstructive symptoms require surgical correction explain why black men with CAP consistently are diagnosed more frequently with Stage D prostate carcinoma and less frequently with Stage A CAP than white men with CAP.

Characteristics of prostatic infarcts and their effect on serum prostate-specific antigen and prostatic acid phosphatase.

OBJECTIVES: To determine how prostatic infarcts affect serum prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) levels. METHODS: Two hundred eighteen clinically benign, whole prostates were obtained at autopsy, completely sectioned, and examined histologically. PSA and PAP levels were determined from premortem serum. RESULTS: Six of the 218 (2.8%) prostates had infarcts. The infarcts were usually multiple and usually located in the central and/or middle concentric zones of the middle third of the prostate without a preference for a particular lobe. Serum PSA by immunoradiometric assay were elevated in all 6 cases. Serum PAP by both enzymatic assay (ACA), and immunoradiometric assay were available for 5 cases and were elevated by both methods in 2 cases, approached elevated levels by both methods in 1 case, and were normal by both methods in 2 cases. The PSA and PAP levels appeared to be affected more by the age than by the size of the infarct. CONCLUSIONS: Prostatic infarcts elevate PSA levels more frequently than PAP levels, and prostatic infarcts may be responsible for some unexplained elevations of serum PSA and PAP levels.

Long-term survival of stage A prostate carcinoma, atypical hyperplasia/adenosis and BPH.

Between 1972 and 1986, 134 patients with stage A carcinoma of the prostate (CAP) were diagnosed at a single Veterans Administration medical centre and followed annually by the hospital tumour registry. Seventy-four were classified as stage A1, defined as non-palpable, well-differentiated CAP, regardless of amount, found unexpectedly on transurethral resection of the prostate (TURP). Twenty-eight were classified as stage A2, defined as non-palpable, moderately or poorly differentiated CAP, regardless of amount, found unexpectedly on TURP. The remaining 32 were reclassified as atypical hyperplasia/adenosis (AH/A) rather than CAP. The survival of each group was compared with the survival of a control group from the same medical centre who had TURPs showing histologically proven benign prostatic hyperplasia (BPH). Survival and tumour progression were similar for patients with stage A1 CAP, AH/A and BPH. Furthermore, patients with stage A1 CAP, with or without therapy, had similar survivals as patients with BPH in each age group (under 65, 65-74 and over 74 years). Stage A2 CAP was associated with a significantly worse survival and more tumour progression. Within stage A1 CAP and stage A2 CAP the percentage of chips with CAP or the amount of CAP removed did not affect survival.

Serum prostate-specific antigen levels in stage A1 prostatic cancer.

Quantitation of serum prostate-specific antigen (PSA) has recently come into widespread use. Controversy exists regarding its usage in screening for carcinoma of the prostate (CAP), based partly on concern that it may detect small foci of CAP that will not cause any significant morbidity or mortality. This study was conducted to evaluate serum PSA levels in stage A1 CAP. The authors identified 143 consecutive men who had PSA levels drawn within 8 weeks of transurethral resection performed for presumed benign prostatic hyperplasia. One hundred twenty-four of these (86.7%) had no cancer, 11 (7.7%) were found to have stage A1 CAP, and eight (5.6%) were found to have CAP beyond stage A1. The mean PSA level in patients with stage A1 CAP was 2.3 ng/mL, and the benign (no cancer) group had a mean PSA level of 3.8 ng/mL. Ten of the 11 patients in the stage A1 group had PSA values less than 4.0 ng/mL. Therefore, it was found that most patients with stage A1 CAP did not have elevated PSA levels. In the authors' experience, elevation of PSA levels caused by CAP is indicative of a tumor burden greater than that found in stage A1 CAP.

Stage at presentation and survival of white and black patients with prostate carcinoma.

BACKGROUND: Black men are known to have a higher incidence and mortality from prostate carcinoma than white men and are more likely to have a more advanced stage or grade of disease diagnosed. METHODS: In a Veterans Administration Medical Center where black and white men have the same eligibility for medical care, the authors reviewed the stage at presentation of 861 consecutive cases of prostate carcinoma diagnosed from 1969-1990. In addition, survival, stratified by race, stage, and grade, was determined on all men in whom prostate cancer was diagnosed from 1969-1985 (525 patients). RESULTS: It was found that 26% of white and 52% of black men with prostate carcinoma presented with Stage D disease. Similar proportions of white and black men with prostate carcinoma presented with Stage D disease between 1969-73 as between 1986-90. The overall survival was poorer for black men because of their higher proportion of Stage D disease, but stratified for grade and stage, survival was similar in both races. CONCLUSIONS: This study suggests that factors other than eligibility for medical care may be responsible for the higher proportion of black men with prostate carcinoma presenting with Stage D prostate carcinoma.

Ultrasound detection of prostate cancer in postmortem specimens with histological correlation.

Transrectal ultrasound detection of prostatic adenocarcinoma was correlated to 63 histological whole mount step sectioned prostatic specimens harvested from 148 consecutive autopsies at our institutions. No patient had known or palpably suspected prostatic adenocarcinoma on premortem digital rectal examination. Prostate specific antigen (PSA) was assayed in each case from premortem serum samples. Of 19 cancers 6 (32%) were detected by transrectal ultrasound and all were hypoechoic. Of the 13 nondetected cancers 7 were isoechoic, 3 were mixed hypoisoechoic, 2 were hypoechoic and 1 was mixed hyperisoechoic. PSA greater than 4 ng./ml. would have aided in cancer detection by suggesting the need for biopsy or further biopsy in 5 cancers with significant volume, which were missed by transrectal ultrasound. The sensitivity (32%) and specificity (64%) of transrectal ultrasound appear too low for use in clinical screening for prostatic adenocarcinoma. PSA and transrectal ultrasound together appear more effective than sonography alone in prostatic adenocarcinoma detection in this series.

Effect of zinc sulfate and acetylcysteine on experimental gastric ulcer: in vitro study.

A small ulcer produced in vitro by monopolar electrocoagulation on endoscopically obtained human antral biopsies and incubated in Trowel T-8 medium at 37 degrees C for 8 h has many histologic features of chronic gastric ulcer in man. Zinc sulfate and acetylcysteine in low concentrations had a significant healing effect in this ulcer model. Since the beneficial effect of zinc sulfate and acetylcysteine was counteracted by N-ethylmaleimide, a known blocker of sulfhydryl compounds, the beneficial effect of these two compounds probably was mediated through sulfhydryl compounds. Using special stain, N-(4-aminophenyl)maleimide, the sulfhydryl groups were localized in the epithelial cells of the surface layer and gastric glands.

Prostate-specific antigen levels from completely sectioned, clinically benign, whole prostates.

Clinically benign whole, untrimmed prostates and pelvic lymph nodes were obtained from 105 patients at autopsy. All 105 patients had premortem serum from which prostate-specific antigen (PSA) levels were obtained. Sixty-eight did not have carcinoma of the prostate (CAP), 28 had CAP less than 1 ml and 9 had CAP larger than 1 ml. Eleven untrimmed prostates weighed 80 g or more and eight had elevated PSA levels (more than 4.0 ng/ml): five of eight without CAP, two of two with CAP less than 1 ml, and one of one with CAP larger than 1 ml. Ninety-four whole untrimmed prostates weighed less than 80 g and 20 had elevated PSA levels: ten of 60 without CAP, two of 26 with CAP less than 1 ml, and eight of eight with CAP larger than 1 ml. This study suggests that PSA levels from patients with untrimmed prostates weighing 80 g or more (equivalent to a 60-g trimmed prostate) are usually elevated regardless whether CAP is present. However, CAP less than 1 ml, in untrimmed prostates less than 80 g, usually does not elevate PSA levels whereas CAP larger than 1 ml usually does (P less than 0.0001). The likelihood that elevated PSA levels, from patients with untrimmed prostates less than 80 g, are due to CAP larger than 1 ml increases as the PSA level increases.

Atypical hyperplasia in prostates of 20 to 40 year old men.

One hundred prostates from 20 to 40 year old men obtained at necropsy were completely sectioned and studied microscopically. Atypical hyperplasia was found in 10 (20%) of 20-29 year old men and in 12 (24%) of 30-40 year old men. The prostates with atypical hyperplasia had similar weights as those without, and the atypical hyperplasia was most common in the lateral lobes of the prostate and near the apex. The atypical hyperplasias were (i) usually mild in degree rather than moderate or severe; (ii) almost equally divided between circumscribed and "infiltrating" lesions; (iii) usually occurred as multiple foci within the same prostate rather than as a single focus of atypical hyperplasia; and (iv) were not associated with inflammation. The finding that atypical hyperplasia is common in men between the ages of 20 and 40 years may be helpful in increasing the understanding of the histopathology of the prostate.

The dedifferentiation of metastatic prostate carcinoma.

Two hundred consecutive staging lymphadenectomies with metastatic prostate adenocarcinoma and 100 consecutive autopsies with widely disseminated metastatic prostate adenocarcinoma were identified. The metastases from 41% of the staging lymphadenectomies were entirely differentiated (gland forming) and an additional 43% were predominantly (50% or more) differentiated. In contrast, the metastases from 70% of the autopsies were entirely undifferentiated (non-gland forming) and an additional 18% were predominantly undifferentiated. Further, five patients with completely or predominantly differentiated metastases in staging lymphadenectomies were found to have widespread completely or predominantly undifferentiated metastases at autopsy 4-7 years later. These findings suggest that dedifferentiation occurs within metastases and that dedifferentiation within metastases may be important in understanding the widespread dissemination of metastatic prostate carcinoma.

The characteristics of embryonal carcinoma cells in teratocarcinomas.

The orchiectomy specimens and the respective lymphadenectomies of 33 teratocarcinomas (teratoma and embryonal carcinoma) and 30 embryonal carcinomas were identified in a series of 457 consecutive germ cell tumors of the testis. Although teratocarcinomas were larger tumors the retroperitoneal lymphadenectomies revealed metastases in only 10 of 33 (30%) teratocarcinomas as compared to 19 of 30 (63%) embryonal carcinomas. Even after subtracting the teratoma component and stratifying for size of the embryonal carcinoma component, the teratocarcinomas were still less likely to metastasize than comparably sized pure embryonal carcinomas. Statistical significance was found between the differences in size and the differences in the rates of metastases, before and after stratifying for size of the embryonal carcinoma component of the teratocarcinomas. Further, all embryonal carcinomas metastasized as embryonal carcinoma while only 5 teratocarcinomas metastasized as embryonal carcinoma. This study supports experimental evidence that the embryonal carcinoma cells in teratocarcinomas are not necessarily identical to embryonal carcinoma cells in embryonal carcinomas.

The metastatic potential of prostate carcinomas composed entirely of single malignant glands.

Consecutive staging lymphadenectomies on 1046 patients with prostate carcinoma identified 275 patients with metastases in a total of 1115 regional lymph nodes. No prostate carcinomas composed entirely of single malignant glands metastasized and no patient had metastases composed entirely of single malignant glands. All prostate carcinomas that metastasized had cribriform and/or undifferentiated histological patterns in the prostate and in the metastases. These findings suggest that identification of cribriform and/or undifferentiated histological patterns, through rebiopsy or further examination of the surgical specimen, should be considered prior to subjecting patients with prostate carcinomas composed entirely of single malignant glands to therapy or procedures directed against the possibility of metastatic disease.

The relationship between non-invasive papillary lesions and invasive bladder carcinoma.

Ten patients with noninvasive papillary lesions who subsequently developed invasive bladder carcinoma were identified. Five of the 10 patients developed an invasive carcinoma in a location distinctly separate from any preceding papillary lesion. The remaining five patients developed an invasive carcinoma in the same general location as a preceding papillary lesion. These findings suggest that invasive bladder carcinomas, which develop in a patient with previous noninvasive papillary lesions, often arise from nonpapillary urothelium adjacent the noninvasive papillary lesion rather than directly from the preceding papillary lesion.

The dedifferentiation of prostate carcinoma.

Fifty-four patients with prostate carcinoma, each having 2 TURP (transurethral resection of the prostate) procedures separated by 3 to 11 years, were studied to determine whether the histologic appearance of prostate carcinoma remains the same for the life of the host or whether the histological appearance changes with time. Using the M. D. Anderson (MDAH) method of grading prostate carcinoma, 19 of 26 (73%) Grade 1 lesions, 9 of 12 (75%) Grade 2 lesions, and 7 of 8 (88%) Grade 3 lesions dedifferentiated into another grade at the time of the 2nd TURP. Eight cases that were Grade 4 at the time of the 1st TURP, remained Grade 4 lesions at the time of the 2nd TURP. Although 10 Grade 1, Grade 2, and Grade 3 lesions did not change grades, 8 of these 10 cases were less differentiated at the time of the second TURP than they were at the time of the first TURP. Furthermore, no Grade 1 lesions demonstrated evidence of metastases, but 19% of Grade 2 lesions, 55% of Grade 3 lesions, and 80% of Grade 4 lesions demonstrated evidence of metastases. This study suggests that the usual course of prostate carcinoma is dedifferentiation and that with dedifferentiation, the likelihood of metastases increases.

The origin of germ cell tumors of the testis.

Two hundred and eight cases of germ cell tumors of the testis were thoroughly studied. Fifty-one (24.5%) were embryonal carcinoma, 115 (55.3%) were seminoma, and 42 (20.2%) contained both embryonal carcinoma and seminoma. The average age of the patients with embryonal carcinoma, seminoma, and combined tumors was 27.6, 38.3, and 30.3 years. Furthermore, in the patients with combined tumors, those having a predominance of embryonal carcinoma had an average age of 28.3 years, while those having a predominance of seminoma had an average age of 33.4 years. This study supports the concept that the malignant potential of germ cells in younger patients is embryonal carcinoma, the malignant potential of germ cells in older patients is seminoma, and that in intermediate-aged patients the germ cells are capable of developing varying amounts of embryonal carcinoma and seminoma in the same tumor.