The role of TRUS-guided biopsies for determination of internal and external spread of prostate cancer.

This study hopes to define local extent of newly diagnosed prostate cancer by comparing sextant biopsies with transrectal ultrasound-guided diagnostic and staging biopsies. The study group consists of 110 men with sextant biopsy proven prostate cancer who presented for an opinion for prognosis and treatment options. All patients were rediagnosed and staged by transrectal ultrasound-guided and staging biopsies. Tumor diagnosis was substantiated in 94.5% (104 of 110). For the 5.4% (6 of 110) not detected by transrectal ultrasonography, review of their outside slides revealed 83.3% (5 of 6) with cancer < or =2 mm with a Gleason score of < or =6. These have the criteria of latent cancers. For the remaining 104 patients with transrectal ultrasound proven cancer, 30% (31 of 104) had extracapsular extension. Sextant and directed biopsy confirmed stage T3 in 3.8% (4 of 104). For clinical stages T1c and T2, 19% and 30%, respectively, had extracapsular extension. Perineural invasion was 1.9 times greater for directed biopsies than sextant biopsies (P < .001. The mean Gleason score was greater for directed biopsies than sextant biopsies, although no statistical difference was found (P > .05). For these 104 patients, 50% (52 of 104) had perineural invasion, of which 38.5% (20 of 52) had proven extracapsular extension. In our hands, transrectal ultrasound-directed and staging biopsies afford more substantive results than sextant biopsies for detecting extracapsular extension. For our cohort of sextant T1-T2 diagnosed cancer (n = 100), 27% were upstaged to T3-T4 by transrectal ultrasound-directed staging biopsy. Thus, transrectal ultrasound-directed staging biopsy has the ability to diagnose unsuspected extracapsular extension and objectifies prognosis and choice of definitive treatment.

p53 and bcl-2 immunohistochemical alterations in prostate cancer treated with radiation therapy.

OBJECTIVES: Radiation therapy is definitive treatment for localized prostate cancer. It causes cellular deoxyribonucleic acid (DNA) damage, which, if irreparable, results in apoptosis or programmed cell death. Overexpression of mutant p53 and/or bcl-2 proteins prolongs cell survival despite exposure to damaging agents. We examined whether abnormal expression of either gene could help to explain radiation therapy failures in prostate cancer. METHODS: Archival tissue from patients who had failed radiation therapy as treatment for prostate cancer was obtained before and after treatment. These cancer samples were examined immunohistochemically for accumulation of p53 and bcl-2 proteins. Comparison was made with specimens from patients who had no evidence of recurrent or persistent disease at least 3 years following radiation therapy. RESULTS: High rates of p53 immunopositivity were found in the prostate tissue from all groups studied. More patients who had failed radiation therapy were found to have bcl-2 immunopositive specimens than were those without evidence for recurrent disease (41% preradiation and 61% postradiation versus 8%, P <0.05). More patients who failed radiation therapy had both p53 and bcl-2 immunopositive prostate tissue than did those who were treated successfully (32% preradiation and 48% postradiation versus 8%). CONCLUSIONS: bcl-2 immunopositivity, with or without concomitant detection of p53, was found in significantly more cancers of patients who failed radiation therapy. Positive staining for bcl-2 may serve as a marker for determining the radiation sensitivity of a tumor and thus may help to guide treatment options. It is also notable that a high proportion of the prostate cancers examined were immunopositive for p53.

Long-term follow-up of stages T2-T3 prostate cancer pretreated with androgen ablation therapy prior to radical prostatectomy.

OBJECTIVE: Our previously reported non-randomized clinical trial proved the ability of preoperative androgen ablation therapy (AAT) to decrease positive surgical margins and to down stage a subset of biopsy proven stage T3 cancer. This study focuses on progression of disease in this group over a 4-5 year period. MATERIALS AND METHODS: This study group consisted of 258 consecutive radical prostatectomies that evolved into three groups: 1) 124 patients with clinical stage T2b-c cancer given AAT; 2) 118 patients with clinical stage T2a not given AAT; 3) 16 patients with proven stage T3 by TRUS guided biopsy and given AAT. RESULTS: Comparison of AAT (n = 140) to no AAT (n = 118) resulted in positive surgical margin rates of 15.3% vs. 49.2%. Specimen confined disease had tumor progression as measured by serum prostate specific antigen of 16.9% (15/89) for AAT (pC.001) vs 10% (5/49) for no AAT (p = 0.288). For known stage T3/C, 43.8% (7/16) downstaged, and 85.7% (6/7) were free of disease at 46.7 mos (mean). The 56.3% with nonconfined (persistent) cancer after AAT had progression usually by one year. CONCLUSION: Neoadjuvant androgen ablation therapy before radical prostatectomy decreased by 3-fold the rate of positive surgical margins (+SM). The vast majority of these patients with +SMs were treated with either external beam radiation or AAT. A near two fold increase of specimen confined disease was found in those given AAT (p < .001). However, the rates of progression (16.9% and 10.2% respectively) were greater in the AAT though not statistically significant (p = 0.288).

Pathology review in an early prostate cancer detection program: results from the American Cancer Society-National Prostate Cancer Detection Project.

Biopsy materials obtained in the American Cancer Society National Prostate Cancer Detection Project were reviewed at the Central Pathology Laboratory at the Armed Forces Institute of Pathology. Of 265 cases submitted, 177 were diagnosed as prostatic carcinoma, 7 as prostatic intraepithelial neoplasia (PIN), 13 as atypical glands or atypical hyperplasia, and the remaining 68 were benign hyperplasias. Irrespective of the means of detectin or the grading system used (Gleason or WHO-Mostofi), a large majority of the cancers were detected as low-grade tumors. Of 27 cases of PIN reported, 20 were associated with cancer, leaving 7 cases with the sole diagnosis of PIN. These data may indicate the increased use of prostate-specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasound (TRUS) in the United States is shifting the spectrum of prostate cancer pathology toward early low-grade tumors.

p53 in prostate cancer: frequent expressed transition mutations.

BACKGROUND: Carcinoma of the prostate is the second most common cause of cancer deaths in men. Little is known about the pathogenesis of this disease and the molecular genetic events that contribute to its development. Molecular studies have begun to reveal biologic characteristics of this disease, notably, the loss of genetic material as determined by studies of restriction fragment length polymorphism, oncogene activation, and production and response to growth factors. PURPOSE: Our goal was to characterize p53 gene mutations in human carcinoma of the prostate and to analyze base-pair changes within the coding regions of p53 mRNA (exons 4 through 11). METHODS: Forty-four prostate tissue specimens and four metastatic lesions were obtained from 48 prostate carcinoma patients who had surgical resection. RNA was either immediately extracted or the specimens were snap-frozen in liquid N2 and stored at -70 degrees C until used. Total RNA was extracted from tumor specimens. Expression of p53 was analyzed by polymerase chain reaction (PCR) analysis of mRNA (RNA/PCR). Following confirmation of the RNA/PCR products by Southern blotting, quantitation of message levels was performed by laser densitometry. Absolute area integrations of the curves representing each tissue were then compared after adjustment for the housekeeping gene c-N-ras. Two overlapping regions (exons 4-6 and 6-11) were examined by a nonisotopic PCR single-strand conformation polymorphism (SSCP) analysis system. All specimens displaying SSCP abnormalities were sequenced in both directions to confirm the findings. RESULTS: Of the 48 prostate specimens, three (6%) (two primary and one metastatic) displayed nearly undetectable expression of p53 mRNA (samples PS-70, L113, and PS-95) and 17 (35%) of 48 expressed mutant p53 mRNA encoding amino acid substitutions within exons 4-11 (14 of 17) and/or deletions within the p53 transcripts (three of 17). Overall, the frequency of p53 gene abnormalities that would result in altered protein expression was 20 (42%) of 48 in the tissue samples from prostate carcinoma patients. Nucleotide base-pair transitions of A-->G or T-->C were the most frequent. CONCLUSIONS: p53 mutations are common in prostate cancer. The patterns of p53 gene mutations are dramatically different from data obtained on other cancers and indicate the possible involvement of a carcinogenic agent(s). IMPLICATIONS: Further studies are required to determine the biologic role of p53 gene alterations in the development and progression of this disease and to determine whether p53 mutations can be useful as prognostic markers or for the selection of better treatments for prostate cancer patients.

The role of transrectal ultrasound-guided staging biopsy and androgen ablation therapy prior to radical prostatectomy.

Radical prostatectomy is the most common therapy for localized prostate cancer. Unfortunately, resection is associated with positive surgical margins in 35-50% of cases. We report the use of ultrasound-guided staging biopsies to stage tumors preoperatively with greater accuracy. We also report the use of androgen ablation therapy (AAT) as an adjunct to radical prostatectomy in an attempt to downstage tumors preoperatively and decrease the incidence of positive margins. Between 1 June 1991 and 31 July 1992, 131 patients underwent radical prostatectomies, 119 of whom underwent AAT before surgery and 12 of whom did not. Specimens were examined for the presence of positive surgical margins, extracapsular extension, and perineural invasion. Cases pretreated with AAT had a 9.2% positive surgical margin rate compared with 33% in untreated subjects. Extracapsular extension was seen in 22 of 119 (18.5%) of AAT, and 5 of 12 (41.7%) of non-AAT, cases. Perineural invasion was nearly 3 times less likely in AAT patients. Moreover, perineural invasion was significantly less marked in AAT patients. We present a subset of 11 patients who were definitively proven as pathologic stage C cancer by transrectal ultrasound (TRUS)-guided needle biopsy. These cases had prostate cancer intermixed with fatty tissue and pigmented seminal vesicle epithelium, elements not found in the prostate. In this selected stage C subset, gland shrinkage, evidence of downstaging, and tumor obliteration were seen after AAT. We conclude that TRUS-guided staging biopsy can definitively stage prostate cancer as stage C when tumor is intermixed with extraprostatic elements, and AAT appears to decrease the incidence of positive surgical margins by tumoral necrosis and selective perineural kill. We believe that these findings demonstrate the antitumor effects of AAT and deserve further scrutiny in a large randomized clinical trial.

Hormone ablation therapy as neoadjuvant treatment to radical prostatectomy.

Two hundred consecutive patients with presumed localized prostate cancer had radical prostatectomy alone (n = 119) or were treated for an average period of 3 months with combination therapy using the antiandrogen flutamide and one luteinizing hormone-releasing hormone (LHRH) agonist (Lupron or Zoladex). The positive margins decreased from 35.3% in the group undergoing prostatectomy alone to 11.5% in the group of men who received combination therapy before radical prostatectomy. In 41 apical tumors, the incidence of positive margins decreased from 50% in the control group to 18.6% in the combination therapy group. In stage C disease, the incidence of positive tumor showed a tendency to decrease with the extended duration of endocrine treatment with a rate of 37.5% after 3 months and 16.7% after 6 months. Whether the decreased incidence of positive surgical margins will all translate into prolonged survival remains to be verified by long-term follow-up of these patients. However, the initial results obtained in the present study are very encouraging.

The use of the epiglottis as an autologous composite graft in eyelid reconstruction.

The use of the epiglottis as a composite graft in eyelid reconstruction is presented. Anatomy, histology, and physiology of the epiglottis are discussed. Two cases in which the epiglottis was used in reconstruction of lower eyelid deformities are reported.

Predicted prostate specific antigen results using transrectal ultrasound gland volume. Differentiation of benign prostatic hyperplasia and prostate cancer.

METHODS: The diagnostic performance of transrectal ultrasound (TRUS) gland volume and prostate specific antigen (PSA) results were evaluated in 204 men consecutively scheduled to undergo transurethral prostatic resection (TUR). RESULTS: Nonpalpable prostate cancer was detected by TRUS alone in 18% (29 of 161) and by TUR alone in 9% (14/161), for an overall cancer incidence of 27%. A predicted PSA value (TRUS gland volume x 0.20 ng/ml/g = polyclonal PSA) was used for comparison with serum PSA for each patient. TRUS positive predictive value improved from 52% to 86% when serum PSA exceeded the predicted value. The specificity and positive predictive value of PSA at 2.5 ng/ml were 23% and 37%, respectively, which increased to 88% and 72%, respectively, when serum PSA exceeded the predicted value. CONCLUSIONS: Predicted PSA values produce decision levels near the 95th percentile for each patient and assist individual biopsy decisions better than grouped gland volume ranges. Wider application of TRUS and PSA in any clinical setting or early detection program is now possible.

Histologic changes of irradiated prostatic carcinoma diagnosed by transrectal ultrasound.

Digital rectal examination and transrectal ultrasound was used to evaluate the clinical status of 125 men previously treated for prostate carcinoma by definitive radiation. Transrectal ultrasound-guided biopsy of a hypoechoic lesion was performed on all 125 men, with 71.2% of them found to have persistent carcinoma. These irradiated carcinomas exhibited increased tumor aggressiveness by both histologic (Gleason score) and biologic (DNA ploidy) parameters. Following radiation therapy 30.6% of pretreatment diploid tumors were found to be aneuploid after treatment. Similarly, there was a 24% increase in the number of poorly differentiated (Gleason score 8 to 10) tumors following radiation therapy. A number of patients with persistent carcinoma postradiation therapy, but with clinically localized disease, may be "cured" by subsequent surgery. Salvage radical prostatectomy found localized cancer in 16 of 20 patients (80%). The use of transrectal ultrasound for early detection and staging was crucial for patient selection for definitive salvage therapy.

Preoperative radiation therapy for locally advanced carcinoma of the rectum. Clinicopathologic correlative review.

During a three-year period, 27 patients with the diagnosis of adenocarcinoma of the rectum were referred to the Department of Radiation Oncology and accepted for preoperative radiation therapy. The referral was based solely on endoluminal ultrasound staging (ELUS) of an unfavorable lesion (n = 12) or ultrasound staging with the clinical impression of a fixed (n = 9) or tethered (n = 6) lesion. High-dose (4,500-5,600 cGy) preoperative radiation was followed by definitive surgery in four to seven weeks. The gross and microscopic pathology observed in 23 specimens of this group of patients formed the basis of this report. The microscopic findings that persist after radiation allow an accurate determination of the tumor stage existing prior to radiation. Correlations are made between the original evaluation of the tumor, including ELUS, and the microscopic findings. ELUS accurately predicted the depth of tumor penetration in 20 to 23 of 23 specimens and the lymph node status in 16 of 23 specimens. In the context of the pathologic findings as described, downstaging was not demonstrated. Following this radiation protocol, a marked reduction in tumor mass was demonstrated, as well as evidence of tumor destruction in the remaining mass, varying from minimal to total elimination of viable tumor. The concept that radiation fibrosis exists only as it approximates or replaces neoplasm is offered. In the context of this pathologic finding, improved resectability occurred for certain tumors. It is recommended that ELUS be added to the clinical evaluation of rectal adenocarcinoma. It is also recommended that the pathologic findings described be used when reporting the stage of rectal tumors that have received high-dose preoperative radiation therapy.

Prostate cancer: transrectal ultrasound and pathology comparison. A preliminary study of outer gland (peripheral and central zones) and inner gland (transition zone) cancer.

A study was conducted to compare results of transrectal ultrasound with pathologic findings on 116 patients who underwent radical prostatectomy for treatment of prostate cancer. In 96% (111 of 116), transrectal ultrasound guided biopsies of a hypoechoic lesion proved cancer; seven patients had known Stage A cancer; one patient had cancer detected by palpation and not detected by ultrasound. Cancers in the outer gland (peripheral and central zones) were compared with cancers in the inner gland (transition zone) by both ultrasound and pathology. Forty-eight percent (52 of 108) of cancers originating in the outer gland showed extraprostatic extension (Stage C disease). The primary sites of tumor escape from the outer gland were the prostatic capsule (38%), anterior fibromuscular stroma (5%), seminal vesicle (18%), the base of the gland at the neurovascular bundle (21%), and the apex (31%). Twenty-two percent (17 of 54) of cancers originating in the inner gland (transition zone) showed extraprostatic extension (Stage C disease). The primary sites of tumor escape from the inner gland were the anterior fibromuscular stroma (6%) and apex (11%). Both histologic and biologic differences between outer and inner gland cancers were found when tumor size was controlled. Gleason scores were significantly different for inner and outer gland cancers, with mean scores of 6.2 +/- 1.6 and 7.4 +/- 0.9, respectively. An odds ratio of 8.6 confirmed the increased risk of extraprostatic extension for outer gland cancer. Outer gland cancers showed increased aggressive behavior of both histologic and biologic nature. The difference in biologic aggressiveness of outer and inner gland cancers has definite implications for treatment options. Use of other diagnostic parameters, such as DNA ploidy, may help to determine which cancers to treat and when to treat them; this may have more relevance for cancers originating in the inner gland. Strategic transrectal ultrasound guided biopsy affords accurate tumor mapping and staging when modes of internal spread and escape of cancer from both outer and inner gland are known. Thus, transrectal ultrasound may be our "window of observation" through which additional research may explain the histologic and biologic discrepancies between outer and inner gland cancers.

Nonpalpable cancer of the prostate: assessment with transrectal US.

Palpable cancer of the prostate is widely believed to be clinically significant. The authors compared the clinical significance of palpable prostate cancer with nonpalpable prostate cancer discovered with transrectal ultrasound (US). A strong association between lesion volume measured with preoperative transrectal US and volumetric measurements in 60 radical prostatectomy specimens permitted the use of tumor size measured with transrectal US as a reasonable estimation of gross tumor volume. In a subsequent clinical series, 147 biopsy-proved cancers were grouped according to size measured at US, the findings at digital rectal examination (DRE), and the Gleason score. For the 147 patients with known prostate cancer, a statistically significant difference between Gleason scores of palpable and nonpalpable cancers could not be demonstrated when the size of the tumor and its location within the prostate were held constant. Assuming that the Gleason score is a reliable indication of malignant potential and clinical significance, the authors conclude that nonpalpable prostatic cancer detected with transrectal US alone may be just as clinically significant as prostatic cancer discovered with DRE.

Transrectal ultrasound, digital rectal examination, and prostate-specific antigen: preliminary results of an early detection program for prostate cancer.

Three hundred and ninety eight self-referred men with no histories of prostate problems were followed once each year for up to four years to determine the feasibility of early prostate cancer detection by digital rectal examination, transrectal ultrasound, and prostate-specific antigen. Evaluation of prostate-specific antigen was based on a polyclonal level of normal of 2.6 nanograms per milliliter by the Yang assay. Biopsies were performed when indicated by either transrectal ultrasound or digital rectal examination. The overall cancer detection rate for the four year period was 6.3 percent. A 3:1 cancer detection advantage of transrectal ultrasound over digital rectal examination was shown. Transrectal ultrasound and prostate-specific antigen each detected 92 percent of the proven cancers, and were complementary when either test was normal, together detecting 100 percent of the cancers. Thirty two percent (8/25) of all cancers were detected by digital examination, with digital exam having no predictive power after two study years. Prostate-specific antigen as an initial screening test for early prostate cancer may identify a suspicious group, whom may further be evaluated by transrectal ultrasound and digital exam. Results of this study lend credibility to the large scale randomized screening study proposed by the U.S. National Institutes of Health in which prostate-specific antigen and digital rectal examination are to be used as initial tests for prostate cancer detection.

Use of transrectal ultrasound and prostate-specific antigen in diagnosis of prostatic intraepithelial neoplasia.

1. PIN can present as a hypoechoic lesion on ultrasound. 2. Biopsy results prove a close relationship between PIN and cancer. 3. Measurements of age, lesion size, and PSA for diagnoses of PIN were intermediate values between non-cancer and cancer. 4. Sequential, precise transrectal ultrasound-guided biopsies of hypoechoic lesions are now possible, and close follow-up of patients with diagnoses of PIN is therefore possible.

The role of transrectal ultrasound in the early detection of prostate cancer.

Transrectal ultrasound allows tissue characterization of normal and abnormal internal anatomy of the prostate and therefore provides valuable information for the study of prostate cancer. In an early-detection program setting, the hypoechoic lesion proved to be twice as sensitive as a palpable abnormality in predicting the presence of cancer; for every two cancers detected by transrectal ultrasound, one was detected by digital rectal examination. When the presence of a hypoechoic lesion was the criterion for biopsy in a clinical setting, 41 percent proved to be cancer. Sixty-eight percent of these cancers were palpable; thus, for every four cancers detected by transrectal ultrasound, three were detected by digital rectal examination. Hence, in our diagnostic settings, transrectal ultrasound is more sensitive than digital rectal examination. Because transrectal ultrasound can measure tumor size and offer information regarding tumor spread, we recommend that transrectal ultrasound-guided biopsy be performed first on all palpable lesions. Up to 50 percent of negative biopsies guided by palpation have subsequently proved to be cancer with transrectal ultrasound-guided biopsy. If transrectal ultrasound-guided biopsy of a palpable lesion does not reveal cancer, however, a biopsy guided by palpation should be performed. Strategic transrectal ultrasound-guided biopsy for staging should be performed to obtain tissue from areas where microscopic extracapsular tumor extension is likely to be present. Based on presently available evidence, broader implementation and evaluation of transrectal ultrasound, a tool to be complemented by digital rectal examination and prostate-specific antigen, is advocated for the early detection of prostate cancer. It is hoped that the use of transrectal ultrasound will lead to increased survival, with good quality of life, in a cost-effective manner, for men at increasing risk from prostate cancer in the aging national population.

Transrectal ultrasonography in the evaluation of rectal and extrarectal disease.

Transrectal ultrasonography is a technique that is gaining popularity in the assessment of rectal and extrarectal disease. From April 1987 to May 1989, 53 transrectal sonograms were done to evaluate rectal disease. Twenty-seven of 30 adenocarcinomas have been correctly staged. The operative procedure and the decision to use preoperative radiotherapy have been influenced by the results of these studies. Recurrent tumors and less common anorectal disease have also been evaluated with this technique. When feasible to perform, ultrasonographically guided biopsies yield specimens that can provide added information on which to base a therapeutic approach.

Use of transrectal ultrasound in diagnosis, guided biopsy, staging, and screening of prostate cancer.

TRUS allows visualization of the internal anatomy of the prostate gland. Knowledge of zonal prostate anatomy allows more accurate staging of prostate cancer by use of strategic TRUS-guided biopsy of sites of possible tumor extension. These biopsies may be facilitated via the transrectal route using an automatic Biopsy system. TRUS is twice as sensitive as DRE and is capable of detecting nonpalpable prostate cancer. TRUS can detect nonpalpable tumors with average dimensions as small as 1.0 cm. This size is considered to be clinically significant.

Transrectal ultrasound. A case report related to the natural history of prostate cancer.

This is a case report of a man with prostate cancer diagnosed 10 years ago by digital rectal examination and prostatic biopsy. He was followed with serial transrectal ultrasound examinations for the last 22 months. Transrectal ultrasound enabled us to observe the natural history of his cancer. Because of accelerated tumor growth, a radical prostatectomy was performed. The tumor was confined within the prostate capsule and thus considered a "cure." Transrectal ultrasound is an invaluable tool for continuous monitoring of patients with prostate cancer.

Transrectal ultrasound in the diagnosis and staging of prostatic carcinoma.

Indications for TRUS are: (a) for diagnosis of nonpalpable cancer, or detection of cancer with greater accuracy than is possible at present; (b) for guidance of transrectal biopsies of hypoechoic lesions for histologic confirmation of cancer; (c) for guidance of staging biopsies to ensure diagnoses of extraprostatic extension; and (d) for staging previously diagnosed prostate cancer.