Investigation of hormone-receptor interactions by means of fluorescence labeling.

Fluorescent-labeled hormones can be used to study hormone-receptor interactions by means of fluorescence polarization, visualization by fluorescence microscopy, or separation methods, e.g., dextran-coated charcoal. Subcellular fragments, single cells, and tissue preparations are amenable to study; in this work rat uterine cytosol was used unless otherwise noted. Estrone labeled with fluorescein at position 17 gives 50% inhibition in the radiometric dextran-coated charcoal assay at 8.3 X 10(-7) M as compared to 3.4 and 3.5 X 10(-8) M for diethylstilbestrol and estradiol, respectively. Scatchard plots from fluorescence polarization are hyperbolic and consistent with two classes of binding sites having association constants 5.6 X 10(10) and 6.4 X 10(7) M-1. Binding by high-affinity sites, which were present at about 3 times the concentraion of "specific" sites (radiometric dextran-coated charcoal assay), was abrogated by estradiol or diethylstilbestrol. Kinetic measurements showed that binding sites that can be blocked by excess estradiol or diethylstilbestrol are those that are both slowly associating and slowly dissociating. Staining of tissues by estrone labeled with fluorescein at position 17 as seen in the fluorescence microscope showed specificity. In normal rat uterus only epithelial cells were stained. In one human infiltrating ductal carcinoma only the malignant ductoid elements stained, while in another there was essentially no staining.

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.

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.

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.

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.

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.

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 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.

Adenosis of the prostate: a dysplastic lesion that can be confused with prostate adenocarcinoma.

A ten-year period, 1966 through 1975, provided 2842 prostate specimens at The Wesley Medical Center, These specimens were classified as (1) adenocarcinoma, (2) adenosis, or (3) hyperplasia. During a follow-up period of 5--15 years (average 7.7 years), prostate carcinoma developed in seven of 108 patients (6.5%) with adenosis. During the same follow-up period prostate carcinoma developed in at least 84 of 2263 patients (3.7%) with hyperplasia. Adenosis is considered to be a dysplastic lesion because patients with histologic lesions limited to adenosis have approximately the same likelihood of prostate carcinoma developing as patients with hyperplasia.

The origin of invasive carcinoma of the bladder.

One-hundred and four consecutive cases of invasive bladder carcinoma were studied. Twenty of the 104 cases had a history of papillary neoplasms of the bladder while the remaining 84 cases did not. Further, 22 of the 104 cases had cystoscopies, months to years prior to the diagnosis of invasive bladder carcinoma, which documented the absence of previous papillary neoplasms of the bladder. Therefore, this study suggests that papillary neoplasms of the bladder may not be the most common precursor of invasive bladder carcinoma. Consequently, vigorously attacking the highly visible papillary neoplasms of the bladder may not be as fruitful in preventing invasive bladder carcinoma as attempting to identify the presence of other less visible nonpapillary lesions which may be the most frequent precursors of invasive bladder carcinoma.

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.

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 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.

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.

Intracristal crystalline inclusions in mitochondria of a neuroblastoma.

Mitochondrial inclusions were found in a neuroblastoma of the paranasal tissues in a 23-year-old male. They were present in almost every cell, were intracristal in location, and had a helical substructure. They are similar to previously reported intramitochondrial crystalline inclusion bodies.

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.

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.

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.

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.

Histologic grading study of prostate adenocarcinoma: the development of a new system and comparison with other methods--a preliminary study.

A new grading system for adenocarcinoma of the prostate (MDAH System) and its simplified version, both based on the percentage of tumor that is differentiated (gland-forming) or undifferentiated (non-gland-forming), were compared with the grading systems of Mostofi and Gleason. In a study group of 182 patients with Stage C adenocarcinoma of the prostate, the MDAH system identified 84 patients (46%) as Grade 1, 75 (41%) as Grade 2--3, and 23 (13%) as Grade 4. Kaplan-Meier survival curves predicted a 91% five-year survival for Grade 1 patients, a 60% 5-year survival for Grade 2--3 patients, and a 15% five-year survival for Grade 4 patients. Wilcoxon (Gehan modification) tests showed that the survival was significantly different among Grades 1, 2--3, and 4. The MDAH System is an improvement over other grading systems in that it is a simple, low-power microscopic method that depends only on the percentage of gland formation in the tumor and further reflects the biologic behavior of the tumor as measured by the patient's survival.