ProstAsure Index in the detection of prostate cancer.
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Humans↗
Biomedical subjects
D G Bostwick
Publications and source records attributed to D G Bostwick.
Microvessel density in prostate cancer: prognostic and therapeutic utility.
Microvessel density is a promising prognostic factor in management of patients with prostate cancer. Unlike cancer cell-based factors, microvessel density is a host stromal factor that has apparently limited heterogeneity within a cancer. Its predictive value for pathological stage has been demonstrated in most but not all reports. Further, recent studies reveal that microvessel density may be predictive of cancer recurrence and perhaps survival in some patients. Inhibition of angiogenesis may be an effective chemopreventive approach, particularly for men at high risk of prostate cancer. The patient described in the case study may benefit from microvessel density determination. Manual or computer-assisted counting of microvessels in the diagnostic needle biopsy specimen would provide a value that could be compared with published findings to predict pathological stage and outcome, particularly in combination with Gleason score and serum prostate-specific antigen concentration. The probability of extraprostatic extension may be sufficiently high that a urologist may choose not to operate on the patient. Similarly, the probability of recurrence after surgery or radiation may be sufficiently high to warrant adjuvant therapy.
Antineoplastic Agents↗
Practical clinical application of predictive factors in prostate cancer. A review with an emphasis on quantitative methods in tissue specimens.
Predictive factors stratify cancer patients into homogeneous groups for treatment. There is an acute need for accurate predictive factors in patients with prostate cancer given the marked variation in treatment recommendations. These factors should be obtained prior to therapy and should include patient factors, serum factors and tissue-specific factors derived from biopsies. This review evaluates the current state of knowledge regarding quantitative methods in prostate tissue specimens, classifying predictive factors in prostate cancer into four categories. The first category, predictive factors recommended for widespread clinical use, includes Gleason grade; nontissue markers include clinical stage and serum prostate-specific antigen. The second category, predictive factors that are often collected but of unproven significance, includes DNA ploidy and volume of cancerous material in the needle biopsy. The third category, predictive factors not used for routine patient management, includes cell proliferation markers (mitotic figures, proliferating cell nuclear antigen, Ki-67 and MIB-1), apoptotic markers, microvessel density and perineural invasion. The fourth category, predictive factors under investigation, includes morphometric features, such as nuclear roundness and size, chromatin texture, silver-staining nucleolar organizer regions and nucleolar size. Standards are required for virtually every aspect of morphometric study, and these features require validation before their acceptance as clinically relevant in prostate cancer. Predictive factors in radical prostatectomies include cancer volume and extent in radical prostatectomy specimens and quantitation of number and size of lymph node metastases. Neural network models provide greater accuracy for combinations of predictive factors than traditional statistical methods of analysis, such as logistic regression and Cox models, and are expected to be incorporated into routine use in the next few years.
Humans↗
Determination of gene and chromosome dosage in prostatic intraepithelial neoplasia and carcinoma.
OBJECTIVE: To review the utility of fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) and comparative genomic hybridization (CGH) in the determination of gene and chromosome dosage in cancer specimens and to discuss the genetic association between prostatic intraepithelial neoplasia (PIN) and adenocarcinoma as detected by these three techniques. STUDY DESIGN: FISH, PCR, and CGH were applied to the same specimens to clarify discrepancies observed by a single technique alone and to further understand prostate carcinogenesis. RESULTS: The most common genetic alterations in PIN and carcinoma were (1) gain of chromosome 7, particularly 7q31; (2) loss of 8p and gain of 8q; and (3) loss of 10q, 16q and 18q. CONCLUSION: Using different techniques on the same specimen was useful to determine genetic relationships between cancer and its precursors. PIN and prostatic carcinoma foci have a similar proportion of genetic changes, but foci of carcinoma usually have more alterations. This supports the hypothesis that PIN is the most likely precursor of prostatic carcinoma.
Adenocarcinoma↗
Ultrastructure of prostatic intraepithelial neoplasia.
BACKGROUND: Prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostatic adenocarcinoma. However, the ultrastructural features of PIN have not been defined in properly fixed tissues. METHODS: In this study, we examined a total of 84 acini from 11 cases of high-grade PIN and matched benign epithelium and adenocarcinoma from patients undergoing radical prostatectomy. Specimens from each case were immediately fixed in glutaraldehyde after surgical removal and processed routinely to ensure optimal preservation. RESULTS: High-grade PIN displayed ultrastructural features that were intermediate between those of benign epithelium and adenocarcinoma. These included the presence of cells with a variable number of cytoplasmic secretory vacuoles, luminal apocrine blebs, large nuclei with coarsely clumped chromatin, enlarged nucleoli, prominent apical microvilli, intact or discontinuous basal cell layer, and intact basement membrane. CONCLUSIONS: Our results indicate that PIN shares many ultrastructural characteristics with adenocarcinoma, supporting its role as a premalignant lesion.
Adenocarcinoma↗
Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC).
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Carcinoma, Renal Cell↗
Neurofilament heavy chain-like messenger RNA and protein are present in benign prostate and down-regulated in prostatic carcinoma.
Differences in gene expression between benign and malignant human prostate specimens were investigated using the differential display technique. RNA samples from paired benign and malignant areas microdissected from opposite sides of the same prostate gland were used for reverse transcription PCR. A 477-bp band was identified that was consistently present in benign prostate but absent or diminished in intensity in malignant tissue. This band was cloned, and the sequence demonstrated 99% identity with a region in the fourth exon of the human neurofilament heavy chain gene (NF-H). Northern blotting with a cDNA probe derived from this band confirmed the presence of a similarly sized message of approximately 3.9 kb in both prostate and brain, and reverse transcription PCR using primers specific to an upstream region of exon 4 confirmed NF-H-like mRNA expression in benign prostatic tissue. Immunostaining with a monoclonal antibody to NF-H showed a positive reaction in benign prostatic epithelial cells but complete absence of staining in prostatic cancer cells. These data demonstrate the presence of a NF-H-like gene product in normal prostatic epithelial cells that is down-regulated or absent in prostatic carcinomas.
Base Sequence↗
A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer.
We have isolated a prostate-specific gene (NKX3.1) in humans that is homologous to the Drosophila NK homeobox gene family. Northern blot analyses indicate that this gene is expressed at high levels in adult prostate and at a much lower level in testis, but is expressed little or not at all in several other tissues. In an androgen-dependent prostate carcinoma line, LNCaP, NKX3.1 mRNA is expressed at a basal level that was increased markedly upon androgen stimulation; the NKX3.1 mRNA was undetectable in several other human tumor cell lines including two androgen-independent prostate carcinoma lines. The NKX3.1 gene maps to chromosome band 8p21, a region frequently reported to undergo a loss of heterozygosity associated with tissue dedifferentiation and loss of androgen responsiveness during the progression of prostate cancer. Based on these data we propose that NKX3.1 is a candidate gene for playing a role in the opposing processes of androgen-driven differentiation of prostatic tissue and loss of that differentiation during the progression of prostate cancer.
Adult↗
An enhanced prognostic system for clinically localized carcinoma of the prostate.
BACKGROUND: This investigation was conducted to develop an enhanced prognostic system based on readily available and independently predictive tumor-related factors for patients with clinically localized prostate carcinoma. METHODS: The outcome of 500 patients treated solely with irradiation for clinical TNM classifications T1-4, NO or NX, MO prostate carcinoma was used to identify factors independently associated with disease relapse. Logistic regression constructed a risk score equation, and optimized cutoff points to characterize patient groups with low, intermediate, or high risks for relapse were established with receiver operating characteristic curve analysis. RESULTS: Clinical tumor stage (P < 0.00001), Gleason score (P = 0.0002), and pretherapy serum prostate specific antigen (P < 0.00001) were independently associated with clinical or biochemical relapse. These factors were included in a risk score equation that defined patient groups with a distinctly different outcome. For the low, intermediate, and high risk groups, the relapse-free probabilities at 5 years after irradiation were 92%, 67%, and 24%, respectively (P < 0.00001). CONCLUSIONS: Readily available, pretherapy disease-related characteristics formed the basis of an enhanced prognostic system for patients with clinically localized prostate carcinoma. A multivariate prognostic system of this nature estimated patient prognosis in a more exacting fashion than a system exclusively based on anatomic factors.
Carcinoma↗
Androgen deprivation as a strategy for prostate cancer chemoprevention.
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Androgen Antagonists↗
Artificial neural networks improve the accuracy of cancer survival prediction.
BACKGROUND: The TNM staging system originated as a response to the need for an accurate, consistent, universal cancer outcome prediction system. Since the TNM staging system was introduced in the 1950s, new prognostic factors have been identified and new methods for integrating prognostic factors have been developed. This study compares the prediction accuracy of the TNM staging system with that of artificial neural network statistical models. METHODS: For 5-year survival of patients with breast or colorectal carcinoma, the authors compared the TNM staging system's predictive accuracy with that of artificial neural networks (ANN). The area under the receiver operating characteristic curve, as applied to an independent validation data set, was the measure of accuracy. RESULTS: For the American College of Surgeons' Patient Care Evaluation (PCE) data set, using only the TNM variables (tumor size, number of positive regional lymph nodes, and distant metastasis), the artificial neural network's predictions of the 5-year survival of patients with breast carcinoma were significantly more accurate than those of the TNM staging system (TNM, 0.720; ANN, 0.770; P < 0.001). For the National Cancer Institute's Surveillance, Epidemiology, and End Results breast carcinoma data set, using only the TNM variables, the artificial neural network's predictions of 10-year survival were significantly more accurate than those of the TNM staging system (TNM, 0.692; ANN, 0.730; P < 0.01). For the PCE colorectal data set, using only the TNM variables, the artificial neural network's predictions of the 5-year survival of patients with colorectal carcinoma were significantly more accurate than those of the TNM staging system (TNM, 0.737; ANN, 0.815; P < 0.001). Adding commonly collected demographic and anatomic variables to the TNM variables further increased the accuracy of the artificial neural network's predictions of breast carcinoma survival (0.784) and colorectal carcinoma survival (0.869). CONCLUSIONS: Artificial neural networks are significantly more accurate than the TNM staging system when both use the TNM prognostic factors alone. New prognostic factors can be added to artificial neural networks to increase prognostic accuracy further. These results are robust across different data sets and cancer sites.
Breast Neoplasms↗
Prostatic intraepithelial neoplasia in dogs with spontaneous prostate cancer.
Prostatic intraepithelial neoplasia (PIN) is the most likely precursor of human prostate cancer. The prevalence and immunophenotype of PIN in dogs with spontaneous prostate cancer has not been previously described. To investigate the association between PIN and prostate cancer, we evaluated the prostates of dogs with spontaneous prostate carcinoma. The prevalence of PIN was determined in formalin-fixed prostates from 29 dogs with spontaneous prostate cancer. Using immunoperoxidase techniques, we compared basal cell layer integrity (high molecular weight keratin 34 beta-E12), proliferative index (MIB-1), and microvessel density (Factor VIII-related antigen) in 14 prostates which contained benign epithelium, PIN, and carcinoma. PIN was present in 19 of 29 (66%) prostates from dogs with spontaneous prostate cancer. The basal cell layer was intact in benign epithelium, disrupted in 72% of acini with PIN, and absent in carcinoma. The mean proliferative index was 17%, 25%, and 40% for benign epithelium, PIN, and carcinoma, respectively, and these differences were significant. The mean microvessel density in foci of PIN and carcinoma (32 and 39 vessels per mm2, respectively) was greater than in benign epithelium (23 vessels per mm2). High-grade PIN is common in the prostates of dogs with spontaneous carcinoma. The basal cell layer is partially disrupted in PIN, whereas it is absent in prostate cancer. The proliferative index and microvessel density of PIN are intermediate between benign epithelium and cancer. These results are similar to those reported for human PIN and prostate cancer, and indicate that PIN is part of a morphologic continuum in the progression of prostate cancer. To our knowledge, this is the first description of high-grade PIN spontaneously occurring in animals. The canine prostate may serve as a useful model for examining factors that modulate PIN and prostate cancer progression.
Animals↗
Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization.
The role of c-myc in prostatic carcinogenesis is poorly understood. The pathogenetic relationship between high-grade prostatic intraepithelial neoplasia (PIN), prostatic carcinoma, and metastases is not well-defined. We used fluorescence in situ hybridization (FISH) with a region-specific probe for c-myc (band 8q24) and chromosome enumeration probes for chromosomes 7, 8, 10, 12, and Y to evaluate genetic changes in matched PIN (48 foci), localized prostatic carcinoma (71 foci), and lymph node metastases (23 foci) in 25 totally embedded whole-mount stage D1 (T2-3 N1-3 M0) radical prostatectomy and pelvic lymphadenectomy specimens. The c-myc protein expression in these lesions was evaluated by immunohistochemistry. Foci with extra copies of c-myc could be divided into three groups: (a) those with simple gain of a whole chromosome 8 (no increase in c-myc copy number relative to the chromosome 8 centromere), which was identified in 42, 25, and 46% of foci of PIN, carcinoma, and metastases, respectively; (b) those with an intermediate increase in c-myc copy number relative to the chromosome 8 centromere, which was found in 8, 11, and 25% of foci of PIN, carcinoma, and metastases, respectively; and (c) those with substantial amplification of c-myc (large increases in c-myc copy number relative to the chromosome 8 centromere), which was detected in 0, 8, and 21% of foci of PIN, carcinoma, and metastases, respectively. Substantial amplification of c-myc was strongly correlated with increasing cancer nuclear grade and immunohistochemical evidence of c-myc protein overexpression. Numeric chromosomal anomalies were found in 67, 68, and 96% of foci of PIN, carcinoma, and metastases, respectively. The most frequent anomaly in PIN and carcinoma was a gain of chromosome 8, and the presence of this anomaly strongly correlated with Gleason score. Carcinoma foci usually contained more FISH anomalies than paired PIN foci, but three prostates contained one or more PIN foci with more anomalies than carcinoma. Thirteen primary tumor foci exhibited intratumor genetic heterogeneity by FISH. One or more foci of the primary tumor usually shared FISH anomalies with the matched metastases. Our FISH results indicate that: (a) gain of chromosome 8 and amplification of c-myc are potential markers of prostate carcinoma progression; (b) PIN is likely a precursor of carcinoma; (c) intraglandular and intratumoral genetic heterogeneity is relatively common; and (d) usually a single focus of cancer gives rise to metastases.
Aged↗
A multiple prognostic index predictive of disease outcome after irradiation for clinically localized prostate carcinoma.
BACKGROUND: This investigation was conducted to identify independent pretherapy disease-related factors associated with disease outcome in patients with clinically localized carcinoma of the prostate (CaP) and to develop models that incorporated relevant covariates for estimating the risk of disease relapse after irradiation (RT). METHODS: The outcome of 500 patients treated only with RT between March 1987 and June 1993 for clinical Stages T1-4N0,XM0 CaP was evaluated. The risk of disease relapse as a function of individual prognostic variables, and combinations thereof, was determined using logistic regression. RESULTS: With a median follow-up of 43 months (range, 4-103 months), 69 patients (14%) had clinical evidence of local recurrence (27 patients), regional lymph node relapse (4 patients), or metastatic relapse (38 patients) within 5 years of RT. Forty additional patients (8%) had biochemical relapse based solely on the post-RT serum prostate specific antigen (PSA) profile. Clinical tumor stage (P = 0.0006), Gleason score (P = 0.001) of the diagnostic biopsy specimen, and pretherapy PSA (P < 0.0001) were associated with disease relapse. The risk of any relapse within 5 years of RT was determined and graphically displayed as risk estimate plots for combinations of these pretherapy prognostic variables. CONCLUSIONS: The combination of pretherapy clinical tumor (T) stage, Gleason score, and PSA level can be used to obtain improved estimates of the risk for disease relapse in patients treated solely with RT for clinically localized CaP. Risk estimate plots of this type may facilitate exchange of therapeutic outcome information, be instrumental in pretherapy decision-making for the new patient with this condition, and aid in the selection of patients for future studies.
Humans↗
Evaluating radical prostatectomy specimens: therapeutic and prognostic importance.
The pathologic staging of prostate cancer involves determination of the anatomic extent and burden of tumor based on the best available data. Proper examination of radical prostatectomy specimens is critical in determining cancer stage, stratifying patient need for adjuvant treatment, and prediction of patient outcome. Differences exist in methods of handling and sampling specimens, although publication of practice protocols in recent years has led to convergence of opinion. In this report, we evaluate the current aspects of pathologic staging of prostate cancer and assessment of prostatectomy specimens. Recent international agreement on pathologic staging of prostate cancer should allow valid comparisons of surgical treatment from different institutions. The vanishing cancer phenomenon is also briefly discussed.
Carcinoma↗
Prostate pathology case study seminar.
Great strides have been made in the past decade in our understanding of the pathology of the prostate. Diagnostic criteria have been proposed, debated, and refined for a number of entities, including prostatic intraepithelial neoplasia, atypical adenomatous hyperplasia, basal cell proliferations, postatrophic hyperplasia, verumontanum mucosal gland hyperplasia, and numerous new variants of prostatic adenocarcinoma such as ductal adenocarcinoma, mucinous carcinoma, signet ring cell carcinoma, and lymphoepithelioma-like carcinoma. This report presents a series of case studies in prostate pathology which illustrate some of the contemporary issues which confront the pathologist and urologist.
Adenocarcinoma↗
The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma.
High-grade prostatic intraepithelial neoplasia (PIN) is considered the most likely precursor of invasive prostatic adenocarcinoma, and is characterized by cellular proliferations within preexisting ducts and glands with cytological changes mimicking cancer. The extent and multicentricity of this clinically important histopathologic lesion have not been fully defined. We sought to determine whether the extent and zonal distribution of PIN are related to prostate cancer. A total of 195 whole-mounted radical prostatectomy specimens were evaluated. All patients had clinically localized cancer, and none had received preoperative therapy. The zonal location and multicentricity of PIN were recorded, and the volume of PIN was measured using a grid-counting method according to pattern (tufting, micropapillary, cribriform, and flat) and spatial proximity to cancer (less than or equal to 2 mm from cancer, and greater than 2 mm from cancer). The results were correlated with patient age, prostate volume, cancer volume, pathological stage, and Gleason grade. High-grade PIN was identified in 86% of cases, usually with multiple architectural patterns of PIN in each positive case: tufting (97% of cases), micropapillary (66% of cases), cribriform (19% of cases), and flat (21% of cases). The mean volume of PIN was 1.32 cm3 (standard error [SE], 0.10; range, 0 to 8.12 cm3), and was greater for PIN within 2 mm of cancer (mean, 1.0 cm3) than for PIN more than 2 mm from cancer (mean, 0.3 cm3). PIN was usually multicentric (64.5% of cases) and located in the nontransition zone (63%) or all zones (36%) of the prostate. There was a positive correlation of total volume of PIN and volume of cancer, but this correlation was significant only for PIN within 2 mm of cancer. The volume of PIN was positively correlated with age, pathological stage, and Gleason score; most of these positive correlations were caused by PIN within 2 mm of cancer rather than that greater than 2 mm from cancer. Our results indicate that the extent and zonal distribution of high-grade PIN and carcinoma are strongly associated, and that PIN is frequently multicentric. This supports the hypothesis that PIN is a premalignant lesion.
Adenocarcinoma↗
Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker.
OBJECTIVES: We describe the expression of a potentially new tumor marker, human glandular kallikrein 2 (hK2), that may be useful as an adjunct to prostate-specific antigen (PSA) in the diagnosis and monitoring of prostate cancer. METHODS: We evaluated 257 radical prostatectomy specimens removed at the Mayo Clinic with pathologic Stage 12 adenocarcinoma to compare the cytoplasmic expression of hK2, PSA, and prostatic acid phosphatase (PAP) in benign tissue, high-grade prostatic intraepithelial neoplasia (PIN), and adenocarcinoma. Two monoclonal antibodies, hK2-A523 and hK2-G586, specific for hK2 were used, as well as antibodies against PSA (PSM-773) and PAP (polyclonal). RESULTS: Intense epithelial cytoplasmic immunoreactivity was observed in every case for hK2-A523, hK2-G586, PSA, and PAP (100% of cases, respectively). The intensity and extent of hK2 expression for both antibodies were greater in cancer than high-grade PIN; furthermore, high-grade PIN was greater than benign epithelium. Cases of Gleason primary grade 4 and 5 cancer showed hK2 staining in almost every cell, whereas there was greater heterogeneity of staining in lower grades of cancer. In marked contrast to hK2, PSA and PAP immunoreactivity was most intense in benign epithelium and stained to a lesser extent in PIN and carcinoma. The number of immunoreactive cells for hK2 and PSA was not predictive of cancer recurrence. CONCLUSIONS: hK2 was expressed in every cancer, and the expression incrementally increased from benign epithelium to high-grade PIN and adenocarcinoma. PSA and PAP displayed inverse immunoreactivity compared with hK2. The expression of hK2 and PSA was not predictive of cancer recurrence in patients with Stage T2 carcinoma. Expression of hK2 indicates that this kallikrein antigen is both prostate localized and tumor associated. Tissue expression of hK2 appears to be regulated independently of PSA and PAP. Further studies are needed to determine whether tissue immunoreactivity of hK2 will prove clinically useful in the diagnosis and monitoring of prostate cancer.
Acid Phosphatase↗